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Synthesis of acetate from carbon dioxide and molecular hydrogen is considered to be the first carbon assimilation pathway on earth. It combines carbon dioxide fixation into acetyl-CoA with the production of ATP via an energized cell membrane. How the pathway is coupled with the net synthesis of ATP has been an enigma. The anaerobic, acetogenic bacterium Acetobacterium woodii uses an ancient version of this pathway without cytochromes and quinones. It generates a sodium ion potential across the cell membrane by the sodium-motive ferredoxin:NAD oxidoreductase (Rnf). The genome sequence of A. woodii solves the enigma: it uncovers Rnf as the only ion-motive enzyme coupled to the pathway and unravels a metabolism designed to produce reduced ferredoxin and overcome energetic barriers by virtue of electron-bifurcating, soluble enzymes.
Activation of Notch1 signaling in neural progenitor cells (NPCs) induces self-renewal and inhibits neurogenesis. Upon neuronal differentiation, NPCs overcome this inhibition, express proneural genes to induce Notch ligands, and activate Notch1 in neighboring NPCs. The molecular mechanism that coordinates Notch1 inactivation with initiation of neurogenesis remains elusive. Here, we provide evidence that Prox1, a transcription repressor and downstream target of proneural genes, counteracts Notch1 signaling via direct suppression of Notch1 gene expression. By expression studies in the developing spinal cord of chick and mouse embryo, we showed that Prox1 is limited to neuronal precursors residing between the Notch1+ NPCs and post-mitotic neurons. Physiological levels of Prox1 in this tissue are sufficient to allow binding at Notch1 promoter and they are critical for proper Notch1 transcriptional regulation in vivo. Gain-of-function studies in the chick neural tube and mouse NPCs suggest that Prox1-mediated suppression of Notch1 relieves its inhibition on neurogenesis and allows NPCs to exit the cell cycle and differentiate. Moreover, loss-of-function in the chick neural tube shows that Prox1 is necessary for suppression of Notch1 outside the ventricular zone, inhibition of active Notch signaling, down-regulation of NPC markers, and completion of neuronal differentiation program. Together these data suggest that Prox1 inhibits Notch1 gene expression to control the balance between NPC self-renewal and neuronal differentiation.
TRPC channels are a family of nonselective cation channels that regulate ion homeostasis and intracellular Ca2+ signaling in numerous cell types. Important physiological functions such as vasoregulation, neuronal growth, and pheromone recognition have been assigned to this class of ion channels. Despite their physiological relevance, few selective pharmacological tools are available to study TRPC channel function. We, therefore, screened a selection of pharmacologically active compounds for TRPC modulating activity. We found that the synthetic gestagen norgestimate inhibited diacylglycerol-sensitive TRPC3 and TRPC6 with IC50s of 3–5 µM, while half-maximal inhibition of TRPC5 required significantly higher compound concentrations (>10 µM). Norgestimate blocked TRPC-mediated vasopressin-induced cation currents in A7r5 smooth muscle cells and caused vasorelaxation of isolated rat aorta, indicating that norgestimate could be an interesting tool for the investigation of TRP channel function in native cells and tissues. The steroid hormone progesterone, which is structurally related to norgestimate, also inhibited TRPC channel activity with IC50s ranging from 6 to 18 µM but showed little subtype selectivity. Thus, TRPC channel inhibition by high gestational levels of progesterone may contribute to the physiological decrease of uterine contractility and immunosuppression during pregnancy.
Our large brain, long life span and high fertility are key elements of human evolutionary success and are often thought to have evolved in interplay with tool use, carnivory and hunting. However, the specific impact of carnivory on human evolution, life history and development remains controversial. Here we show in quantitative terms that dietary profile is a key factor influencing time to weaning across a wide taxonomic range of mammals, including humans. In a model encompassing a total of 67 species and genera from 12 mammalian orders, adult brain mass and two dichotomous variables reflecting species differences regarding limb biomechanics and dietary profile, accounted for 75.5%, 10.3% and 3.4% of variance in time to weaning, respectively, together capturing 89.2% of total variance. Crucially, carnivory predicted the time point of early weaning in humans with remarkable precision, yielding a prediction error of less than 5% with a sample of forty-six human natural fertility societies as reference. Hence, carnivory appears to provide both a necessary and sufficient explanation as to why humans wean so much earlier than the great apes. While early weaning is regarded as essentially differentiating the genus Homo from the great apes, its timing seems to be determined by the same limited set of factors in humans as in mammals in general, despite some 90 million years of evolution. Our analysis emphasizes the high degree of similarity of relative time scales in mammalian development and life history across 67 genera from 12 mammalian orders and shows that the impact of carnivory on time to weaning in humans is quantifiable, and critical. Since early weaning yields shorter interbirth intervals and higher rates of reproduction, with profound effects on population dynamics, our findings highlight the emergence of carnivory as a process fundamentally determining human evolution.
Feedforward inhibition and synaptic scaling are important adaptive processes that control the total input a neuron can receive from its afferents. While often studied in isolation, the two have been reported to co-occur in various brain regions. The functional implications of their interactions remain unclear, however. Based on a probabilistic modeling approach, we show here that fast feedforward inhibition and synaptic scaling interact synergistically during unsupervised learning. In technical terms, we model the input to a neural circuit using a normalized mixture model with Poisson noise. We demonstrate analytically and numerically that, in the presence of lateral inhibition introducing competition between different neurons, Hebbian plasticity and synaptic scaling approximate the optimal maximum likelihood solutions for this model. Our results suggest that, beyond its conventional use as a mechanism to remove undesired pattern variations, input normalization can make typical neural interaction and learning rules optimal on the stimulus subspace defined through feedforward inhibition. Furthermore, learning within this subspace is more efficient in practice, as it helps avoid locally optimal solutions. Our results suggest a close connection between feedforward inhibition and synaptic scaling which may have important functional implications for general cortical processing.
The Symposium on Theoretical Aspects of Computer Science (STACS) is held alternately in France and in Germany. The conference of February 26-28, 2009, held in Freiburg, is the 26th in this series. Previous meetings took place in Paris (1984), Saarbr¨ucken (1985), Orsay (1986), Passau (1987), Bordeaux (1988), Paderborn (1989), Rouen (1990), Hamburg (1991), Cachan (1992), W¨urzburg (1993), Caen (1994), M¨unchen (1995), Grenoble (1996), L¨ubeck (1997), Paris (1998), Trier (1999), Lille (2000), Dresden (2001), Antibes (2002), Berlin (2003), Montpellier (2004), Stuttgart (2005), Marseille (2006), Aachen (2007), and Bordeaux (2008). ...
Background: Liver fibrosis in human immunodeficiency virus (HIV)-infected individuals is mostly attributable to co-infection with hepatitis B or C. The impact of other risk factors, including prolonged exposure to combined antiretroviral therapy (cART) is poorly understood. Our aim was to determine the prevalence of liver fibrosis and associated risk factors in HIV-infected individuals based on non-invasive fibrosis assessment using transient elastography (TE) and serum biomarkers (Fibrotest [FT]).
Methods: In 202 consecutive HIV-infected individuals (159 men; mean age 47 ± 9 years; 35 with hepatitis-C-virus [HCV] co-infection), TE and FT were performed. Repeat TE examinations were conducted 1 and 2 years after study inclusion.
Results: Significant liver fibrosis was present in 16% and 29% of patients, respectively, when assessed by TE (≥ 7.1 kPa) and FT (> 0.48). A combination of TE and FT predicted significant fibrosis in 8% of all patients (31% in HIV/HCV co-infected and 3% in HIV mono-infected individuals). Chronic ALT, AST and γ-GT elevation was present in 29%, 20% and 51% of all cART-exposed patients and in 19%, 8% and 45.5% of HIV mono-infected individuals. Overall, factors independently associated with significant fibrosis as assessed by TE (OR, 95% CI) were co-infection with HCV (7.29, 1.95-27.34), chronic AST (6.58, 1.30-33.25) and γ-GT (5.17, 1.56-17.08) elevation and time on dideoxynucleoside therapy (1.01, 1.00-1.02). In 68 HIV mono-infected individuals who had repeat TE examinations, TE values did not differ significantly during a median follow-up time of 24 months (median intra-patient changes at last TE examination relative to baseline: -0.2 kPa, p = 0.20).
Conclusions: Chronic elevation of liver enzymes was observed in up to 45.5% of HIV mono-infected patients on cART. However, only a small subset had significant fibrosis as predicted by TE and FT. There was no evidence for fibrosis progression during follow-up TE examinations.
This report describes the clinical courses of two acute myeloid leukemia patients. Both had MLL translocations, the first a t(10;11)(p11.2;q23) with MLL-AF10 and the second a t(11;19)(q23;p13.1) with MLL-ELL fusion. They achieved a clinical remission under conventional chemotherapy but relapsed shortly after end of therapy. Both had a history of invasive mycoses (one had possible pulmonary mycosis, one systemic candidiasis). Because no HLA-identical donor was available, a haploidentical transplantation was performed in both cases. Using a specially designed PCR method for the assessment of minimal residual disease (MRD), based on the quantitative detection of the individual chromosomal breakpoint in the MLL gene, all patients achieved complete and persistent molecular remission after transplantation. The immune reconstitution after transplantation is described in terms of total CD3+/CD4+, CD3+/CD8+, CD19+, and CD16+/CD56+ cell numbers over time. The KIR and HLA genotypes of donors and recipients are reported and the possibility of a KIR-mediated alloreactivity is discussed. This report illustrates that haploidentical transplantation may offer a chance of cure without chronic graft-versus-host disease in situations where no suitable HLA-identical donor is available even in a high-risk setting and shows the value of MRD monitoring in the pre- and posttransplant setting.
The decision in September 2011 in the UK to accept blood donations from non-practicing men who have sex with men (MSM) has received significant public attention. Will this rule change substantially boost the number of blood donations or will it make our blood less safe? Clearly, most European countries have a blood procurement problem. Fewer young people are donating, while the population is aging and more invasive therapies are requiring more blood. Yet if that was the reason for allowing non-practicing MSM to donate, clearly re-admission of some other, much larger populations that are currently deferred from donation should likewise be considered. As far as risks for blood safety are concerned, evidence has been provided that the current quality of infectious disease marker testing significantly mitigates against, although does not completely eradicate, risks associated with admission of donors with a high risk of carrying certain blood-transmissible agents. However, it could be argued that more effective recruitment of the non-donor pool, which is substantially larger than the group of currently ineligible donors, would be a better strategy. Recruitment of this group will benefit the availability of blood without jeopardizing the current excellent safety profile of blood.
Background: To improve and assess the effectiveness of disease management programs (DMPs), it is critical to understand how many people drop out of disease management programs and why.
Methods: We used routine data provided by a statutory health insurance fund from the regions North Rhine, North Wurttemberg and Hesse. As part of the German DMP for type 2 diabetes, the insurance fund received regular documentation of all members participating in the program. We followed 10,989 patients who enrolled in the DMP between July 2004 and December 2005 until the end of 2007 to study how many patients dropped out of the program. Dropout was defined based on the discontinuation of program documentation on a particular patient, excluding situations in which the patient died or left the insurance fund. Predictors of dropout, assessed at the time of program enrolment, were explored using logistic regression analysis.
Results: 5.5% of the patients dropped out of the disease management program within the observation period. Predictors of dropout at the time of enrolment were: region; retirement status; the number of secondary diseases; presence of a disabling secondary disease; doctors recommendations to stop smoking or to seek nutritional counselling; and the completion and outcome of the routine foot and eye exams. Different trends of dropout were observed among retired and employed patients: retired patients of old age, who possibly drop out of the program due to other health care priorities and employed people of younger age who have not yet developed many secondary diseases, but were recommended to change their lifestyle.
Conclusions: Overall, dropout rates for the German disease management programs for type 2 diabetes were low compared to other studies. Factors assessed at the time of program enrolment were predictive of later dropout and should be further studied to provide information for future program improvements.
The Late Miocene (11.6–5.3 Ma) is a crucial period in the history of the Asian monsoon. Significant changes in the Asian climate regime have been documented for this period, which saw the formation of the modern Asian monsoon system. However, the spatiotemporal structure of these changes is still ambiguous, and the associated mechanisms are debated. Here, we present a simulation of the average state of the Asian monsoon climate for the Tortonian (11–7 Ma) using the regional climate model CCLM3.2. We employ relatively high spatial resolution (1° × 1°) and adapt the physical boundary conditions such as topography, land-sea distribution and vegetation in the regional model to represent the Late Miocene. As climatological forcing, the output of a Tortonian run with a fully-coupled atmosphere-ocean general circulation model is used. Our regional Tortonian run shows a stronger-than-present East Asian winter monsoon wind as a result of the enhanced mid-latitude westerly wind of our global forcing and the lowered present-day northern Tibetan Plateau in the regional model. The summer monsoon circulation is generally weakened in our regional Tortonian run compared to today. However, the changes of summer monsoon precipitation exhibit major regional differences. Precipitation decreases in northern China and northern India, but increases in southern China, the western coast and the southern tip of India. This can be attributed to the changes in both the regional topography (e.g. the lower northern Tibetan Plateau) and the global climate conditions (e.g. the higher sea surface temperature). The spread of dry summer conditions over northern China and northern Pakistan in our Tortonian run further implies that the monsoonal climate may not have been fully established in these regions in the Tortonian. Compared with the global model, the high resolution regional model highlights the spatial differences of the Asian monsoon climate in the Tortonian, and better characterizes the convective activity and its response to regional topographical changes. It therefore provides a useful and compared to global models, a complementary tool to improve our understanding of the Asian monsoon evolution in the Late Miocene.
Water-filtered infrared-A (wIRA), as a special form of heat radiation with a high tissue penetration and a low thermal load to the skin surface, can improve the healing of acute and chronic wounds both by thermal and thermic as well as by non-thermal and non-thermic effects. wIRA increases tissue temperature (+2.7°C at a tissue depth of 2 cm), tissue oxygen partial pressure (+32% at a tissue depth of 2 cm) and tissue perfusion. These three factors are decisive for a sufficient supply of tissue with energy and oxygen and consequently also for wound healing and infection defense.
wIRA can considerably alleviate pain (without any exception during 230 irradiations) with substantially less need for analgesics (52–69% less in the groups with wIRA compared to the control groups). It also diminishes exudation and inflammation and can show positive immunomodulatory effects. The overall evaluation of the effect of irradiation as well as the wound healing and the cosmetic result (assessed on visual analogue scales) were markedly better in the group with wIRA compared to the control group. wIRA can advance wound healing (median reduction of wound size of 90% in severely burned children already after 9 days in the group with wIRA compared to 13 days in the control group; on average 18 versus 42 days until complete wound closure in chronic venous stasis ulcers) or improve an impaired wound healing (reaching wound closure and normalization of the thermographic image in otherwise recalcitrant chronic venous stasis ulcers) both in acute and in chronic wounds including infected wounds. After major abdominal surgery there was a trend in favor of the wIRA group to a lower rate of total wound infections (7% versus 15%) including late infections following discharge from hospital (0% versus 8%) and a trend towards a shorter postoperative hospital stay (9 versus 11 days).
Even the normal wound healing process can be improved.
The mentioned effects have been proven in six prospective studies, with most of the effects having an evidence level of Ia/Ib.
wIRA represents a valuable therapy option and can generally be recommended for use in the treatment of acute as well as of chronic wounds.
Aim of the study: Investigation, whether water-filtered infrared-A (wIRA) irradiation during moderate bicycle ergometer endurance exercise has effects especially on local fat reduction and on weight reduction beyond the effects of ergometer exercise alone.
Methods: Randomised controlled study with 40 obese females (BMI 30-40 (median: 34.5), body weight 76-125 (median: 94.9) kg, age 20-40 (median: 35.5) years, isocaloric nutrition), 20 in the wIRA group and 20 in the control group. In both groups each participant performed 3 times per week over 4 weeks for 45 minutes bicycle ergometer endurance exercise with a constant load according to a lactate level of 2 mmol/l (aerobic endurance load, as determined before the intervention period). In the wIRA group in addition large parts of the body (including waist, hip, and thighs) were irradiated during all ergometries of the intervention period with visible light and a predominant part of water-filtered infrared-A (wIRA), using the irradiation unit “Hydrosun® 6000” with 10 wIRA radiators (Hydrosun® Medizintechnik, Müllheim, Germany, radiator type 500, 4 mm water cuvette, yellow filter, water-filtered spectrum 500-1400 nm) around a speed independent bicycle ergometer.
Main variable of interest: change of “the sum of circumferences of waist, hip, and both thighs of each patient” over the intervention period (4 weeks). Additional variables of interest: body weight, body mass index BMI, body fat percentage, fat mass, fat-free mass, water mass (analysis of body composition by tetrapolar bioimpedance analysis), assessment of an arteriosclerotic risk profile by blood investigation of variables of lipid metabolism (cholesterol, triglycerides, high density lipoproteins HDL, low density lipoproteins LDL, apolipoprotein A1, apolipoprotein B), clinical chemistry (fasting glucose, alanin-aminotransferase ALT (= glutamyl pyruvic transaminase GPT), gamma-glutamyl-transferase GGT, creatinine, albumin), endocrinology (leptin, adiponectin (= adipo Q), homocysteine, insulin). All variables were at least measured before and after the intervention period. Ergometry (ECG, blood pressure behaviour, lactate curve with power at 2, 3 and 4 mmol/l) before the intervention period. In addition: nutrition training ahead of and during the intervention period with a nutrition protocol over one week for assessment of the daily energy intake; calculation of basic metabolic rate and total energy requirement. Assessment of undesired effects.
Only methods of non-parametric statistics were used, both descriptive (median, percentiles of 25 and 75 (= interquartile range), minimum, maximum) and confirmatory (two-sided Mann-Whitney U test for unpaired samples for the only one main variable of interest). Total error probability: .05 (5%). An intention to treat analysis ITT with last observed carry forward method was used preferably (presented results) and in addition an on treatment analysis OT. Only 2 (treatment group) and 4 (control group) drop-outs occurred (mostly due to lack of time).
Results: The “sum of circumferences of waist, hip, and both thighs of each patient” decreased during the 4 weeks significantly more (p<.001) in the wIRA group than in the control group: medians and interquartile ranges: -8.0 cm (-10.5 cm/-4.1 cm) vs. -1.8 cm (-4.4 cm/0.0 cm).
As well “body weight of each patient” decreased during the 4 weeks markedly more in the wIRA group than in the control group: medians and interquartile ranges: -1.9 kg (-4.0 kg/0.0 kg) vs. 0.0 kg (-1.5 kg/+0.4 kg); median of body weight changed from 99.3 kg to 95.6 kg (wIRA) vs. 89.9 kg to 89.6 kg (control). A similar effect showed the body mass index BMI.
Blood variables of interest remained unchanged or showed some slight improvements during the treatment period, concerning most variables with no obvious differences between the two groups; insulin showed a slight trend to decrease in the wIRA group and to increase in the control group.
Undesired effects of the treatment were not seen.
Discussion: The results of the study suggest, that wIRA – during moderate bicycle ergometer endurance exercise as lipolytic stimulus – increases local lipolysis with a local fat reduction (thighs) in the otherwise bradytrophic fatty tissue. The presumably underlying mechanisms of wIRA have already been proven: wIRA acts both by thermal effects and by non-thermal effects. Thermal effects of wIRA are the generation of a therapeutic field of warmth with the increase of tissue temperature, tissue oxygen partial pressure, and tissue blood flow, and by this regional metabolism. As fatty tissue normally has a slow metabolism (bradytrophic and hypothermic tissue) with a low rate of lipolysis, wIRA can increase lipolysis in fatty tissue and the mobilized fats are burned in musculature during the ergometer exercise.
Conclusion: The results of the study indicate, that wIRA irradiation during moderate ergometer endurance exercise can be used – in combination with an appropriate nutrition – to improve body composition, especially local fat distribution, and the reduction of fat and body weight in obese persons.
Keywords: water-filtered infrared-A (wIRA), weight reduction, local fat reduction, bicycle ergometer endurance exercise, lipolysis, randomised controlled study, intervention trial, body weight, body mass index BMI, analysis of body composition, tetrapolar bioimpedance analysis, lactate, lipid metabolism, cholesterol, triglycerides, high density lipoproteins HDL, low density lipoproteins LDL
Water-filtered infrared-A radiation (wIRA) is not implicated in cellular degeneration of human skin
(2007)
Background: Excessive exposure to solar ultraviolet radiation is involved in the complex biologic process of cutaneous aging. Wavelengths in the ultraviolet-A and -B range (UV-A and UV-B) have been shown to be responsible for the induction of proteases, e. g. the collagenase matrix metalloproteinase 1 (MMP-1), which are related to cell aging. As devices emitting longer wavelengths are widely used in therapeutic and cosmetic interventions and as the induction of MMP-1 by water-filtered infrared-A (wIRA) had been discussed, it was of interest to assess effects of wIRA on the cellular and molecular level known to be possibly involved in cutaneous degeneration.
Objectives: Investigation of the biological implications of widely used water-filtered infrared-A (wIRA) radiators for clinical use on human skin fibroblasts assessed by MMP-1 gene expression (MMP-1 messenger ribonucleic acid (mRNA) expression).
Methods: Human skin fibroblasts were irradiated with approximately 88% wIRA (780-1400 nm) and 12% red light (RL, 665-780 nm) with 380 mW/cm² wIRA(+RL) (333 mW/cm² wIRA) on the one hand and for comparison with UV-A (330-400 nm, mainly UV-A1) and a small amount of blue light (BL, 400-450 nm) with 28 mW/cm² UV-A(+BL) on the other hand. Survival curves were established by colony forming ability after single exposures between 15 minutes and 8 hours to wIRA(+RL) (340-10880 J/cm² wIRA(+RL), 300-9600 J/cm² wIRA) or 15-45 minutes to UV-A(+BL) (25-75 J/cm² UV-A(+BL)). Both conventional Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) and quantitative real-time RT-PCR techniques were used to determine the induction of MMP-1 mRNA at two physiologic temperatures for skin fibroblasts (30°C and 37°C) in single exposure regimens (15-60 minutes wIRA(+RL), 340-1360 J/cm² wIRA(+RL), 300-1200 J/cm² wIRA; 30 minutes UV-A(+BL), 50 J/cm² UV-A(+BL)) and in addition at 30°C in a repeated exposure protocol (up to 10 times 15 minutes wIRA(+RL) with 340 J/cm² wIRA(+RL), 300 J/cm² wIRA at each time).
Results: Single exposure of cultured human dermal fibroblasts to UV-A(+BL) radiation yielded a very high increase in MMP-1 mRNA expression (11 ±1 fold expression for RT-PCR and 76 ±2 fold expression for real-time RT-PCR both at 30°C, 75 ±1 fold expression for real-time RT-PCR at 37°C) and a dose-dependent decrease in cell survival. In contrast, wIRA(+RL) did not produce cell death and did not induce a systematic increase in MMP-1 mRNA expression (less than twofold expression, within the laboratory range of fluctuation) detectable with the sensitive methods applied. Additionally, repeated exposure of human skin fibroblasts to wIRA(+RL) did not induce MMP-1 mRNA expression systematically (less than twofold expression by up to 10 consecutive wIRA(+RL) exposures and analysis with real-time RT-PCR).
Conclusions: wIRA(+RL) even at the investigated disproportionally high irradiances does not induce cell death or a systematic increase of MMP-1 mRNA expression, both of which can be easily induced by UV-A radiation. Furthermore, these results support previous findings of in vivo investigations on collagenase induction by UV-A but not wIRA and show that infrared-A with appropriate irradiances does not seem to be involved in MMP-1 mediated photoaging of the skin. As suggested by previously published studies wIRA could even be implicated in a protective manner.
Water-filtered infrared-A (wIRA) can act as a penetration enhancer for topically applied substances
(2008)
Background: Water-filtered infrared-A (wIRA) irradiation has been shown to enhance penetration of clinically used topically applied substances in humans through investigation of functional effects of penetrated substances like vasoconstriction by cortisone.
Aim of the study: Investigation of the influence of wIRA irradiation on the dermatopharmacokinetics of topically applied substances by use of optical methods, especially to localize penetrating substances, in a prospective randomised controlled study in humans.
Methods: The penetration profiles of the hydrophilic dye fluorescein and the lipophilic dye curcumin in separate standard water-in-oil emulsions were determined on the inner forearm of test persons by tape stripping in combination with spectroscopic measurements. Additionally, the penetration was investigated in vivo by laser scanning microscopy. Transepidermal water loss, hydration of the epidermis, and surface temperature were determined. Three different procedures (modes A, B, C) were used in a randomised order on three separate days of investigation in each of 12 test persons. In mode A, the two dyes were applied on different skin areas without water-filtered infrared-A (wIRA) irradiation. In mode B, the skin surface was irradiated with wIRA over 30 min before application of the two dyes (Hydrosun® radiator type 501, 10 mm water cuvette, orange filter OG590, water-filtered spectrum: 590–1400 nm with dominant amount of wIRA). In mode C, the two dyes were applied and immediately afterwards the skin was irradiated with wIRA over 30 min. In all modes, tape stripping started 30 min after application of the formulations. Main variable of interest was the ratio of the amount of the dye in the deeper (second) 10% of the stratum corneum to the amount of the dye in the upper 10% of the stratum corneum.
Results: The penetration profiles of the hydrophilic fluorescein showed in case of pretreatment or treatment with wIRA (modes B and C) an increased penetration depth compared to the non-irradiated skin (mode A): The ratio of the amount of the dye in the deeper (second) 10% of the stratum corneum to the amount of the dye in the upper 10% of the stratum corneum showed medians and interquartile ranges for mode A of 0.017 (0.007/0.050), for mode B of 0.084 (0.021/0.106), for mode C of 0.104 (0.069/0.192) (difference between modes: p=0.0112, significant; comparison mode A with mode C: p<0.01, significant). In contrast to fluorescein, the lipophilic curcumin showed no differences in the penetration kinetics, in reference to whether the skin was irradiated with wIRA or not. These effects were confirmed by laser scanning microscopy. Water-filtered infrared-A irradiation increased the hydration of the stratum corneum: transepidermal water loss rose from approximately 8.8 g m-2 h-1 before wIRA irradiation to 14.2 g m-2 h-1 after wIRA irradiation and skin hydration rose from 67 to 87 relative units. Skin surface temperature increased from 32.8°C before wIRA to 36.4°C after wIRA irradiation.
Discussion: The better penetration of the hydrophilic dye fluorescein after or during skin irradiation (modes B and C) can be explained by increased hydration of the stratum corneum by irradiation with wIRA.
Conclusions: As most topically applied substances for the treatment of patients are mainly hydrophilic, wIRA can be used to improve the penetration of substances before or after application of substances – in the first case even of thermolabile substances – with a broad clinical relevance as a contact free alternative to an occlusive dressing.
Background: Water-filtered infrared-A (wIRA) is a special form of heat radiation with a high tissue-penetration and with a low thermal burden to the surface of the skin. wIRA is able to improve essential and energetically meaningful factors of wound healing by thermal and non-thermal effects.
Aim of the study: prospective study (primarily planned randomised, controlled, blinded, de facto with one exception only one cohort possible) using wIRA in the treatment of patients with recalcitrant chronic venous stasis ulcers of the lower legs with thermographic follow-up.
Methods: 10 patients (5 males, 5 females, median age 62 years) with 11 recalcitrant chronic venous stasis ulcers of the lower legs were treated with water-filtered infrared-A and visible light irradiation (wIRA(+VIS), Hydrosun® radiator type 501, 10 mm water cuvette, water-filtered spectrum 550–1400 nm) or visible light irradiation (VIS; only possible in one patient). The uncovered wounds of the patients were irradiated two to five times per week for 30 minutes at a standard distance of 25 cm (approximately 140 mW/cm2 wIRA and approximately 45 mW/cm2 VIS). Treatment continued for a period of up to 2 months (typically until closure or nearly closure of the ulcer). The main variable of interest was “percent change of ulcer size over time” including complete wound closure. Additional variables of interest were thermographic image analysis, patient’s feeling of pain in the wound, amount of pain medication, assessment of the effect of the irradiation (by patient and by clinical investigator), assessment of feeling of the wound area (by patient), assessment of wound healing (by clinical investigator) and assessment of the cosmetic state (by patient and by clinical investigator). For these assessments visual analogue scales (VAS) were used.
Results: The study showed a complete or nearly complete healing of lower leg ulcers in 7 patients and a clear reduction of ulcer size in another 2 of 10 patients, a clear reduction of pain and pain medication consumption (e.g. from 15 to 0 pain tablets per day), and a normalization of the thermographic image (before the beginning of the therapy typically hyperthermic rim of the ulcer with relative hypothermic ulcer base, up to 4.5°C temperature difference). In one patient the therapy of an ulcer of one leg was performed with the fully active radiator (wIRA(+VIS)), while the therapy of an ulcer of the other leg was made with a control group radiator (only VIS without wIRA), showing a clear difference in favour of the wIRA treatment. All mentioned VAS ratings improved remarkably during the period of irradiation treatment, representing an increased quality of life. Failures of complete or nearly complete wound healing were seen only in patients with arterial insufficiency, in smokers or in patients who did not have venous compression garment therapy.
Discussion and conclusions: wIRA can alleviate pain considerably (with an impressive decrease of the consumption of analgesics) and accelerate wound healing or improve a stagnating wound healing process and diminish an elevated wound exudation and inflammation both in acute and in chronic wounds (in this study shown in chronic venous stasis ulcers of the lower legs) and in problem wounds including infected wounds. In chronic recalcitrant wounds complete healing is achieved, which was not reached before. Other studies have shown that even without a disturbance of wound healing an acute wound healing process can be improved (e.g. reduced pain) by wIRA.
wIRA is a contact-free, easily used and pleasantly felt procedure without consumption of material with a good penetration effect, which is similar to solar heat radiation on the surface of the earth in moderate climatic zones. Wound healing and infection defence (e.g. granulocyte function including antibacterial oxygen radical formation of the granulocytes) are critically dependent on a sufficient energy supply (and on sufficient oxygen). The good clinical effect of wIRA on wounds and also on problem wounds and wound infections can be explained by the improvement of both the energy supply and the oxygen supply (e.g. for the granulocyte function). wIRA causes as a thermal effect in the tissue an improvement in three decisive factors: tissue oxygen partial pressure, tissue temperature and tissue blood flow. Besides this non-thermal effects of infrared-A by direct stimulation of cells and cellular structures with reactions of the cells have also been described. It is concluded that wIRA can be used to improve wound healing, to reduce pain, exudation, and inflammation and to increase quality of life.
Water-filtered infrared-A (wIRA) as a special form of heat radiation with a high tissue penetration and with a low thermal load to the skin surface acts both by thermal and thermic as well as by non-thermal and non-thermic effects. wIRA produces a therapeutically usable field of heat in the tissue and increases tissue temperature, tissue oxygen partial pressure, and tissue perfusion. These three factors are decisive for a sufficient tissue supply with energy and oxygen and consequently as well for wound healing and infection defense.
wIRA can considerably alleviate the pain (with remarkably less need for analgesics) and diminish an elevated wound exudation and inflammation and can show positive immunomodulatory effects. wIRA can advance wound healing or improve an impaired wound healing both in acute and in chronic wounds including infected wounds. Even the normal wound healing process can be improved.
A prospective, randomized, controlled, double-blind study with 111 patients after major abdominal surgery at the University Hospital Heidelberg, Germany, showed with 20 minutes irradiation twice a day (starting on the second postoperative day) in the group with wIRA and visible light VIS (wIRA(+VIS), approximately 75% wIRA, 25% VIS) compared to a control group with only VIS a significant and relevant pain reduction combined with a markedly decreased required dose of analgesics: during 230 single irradiations with wIRA(+VIS) the pain decreased without any exception (median of decrease of pain on postoperative days 2-6 was 13.4 on a 100 mm visual analog scale VAS 0-100), while pain remained unchanged in the control group (p<0.001). The required dose of analgesics was 57-70% lower in the subgroups with wIRA(+VIS) compared to the control subgroups with only VIS (median 598 versus 1398 ml ropivacaine, p<0.001, for peridural catheter analgesia; 31 versus 102 mg piritramide, p=0.001, for patient-controlled analgesia; 3.4 versus 10.2 g metamizole, p=0.005, for intravenous and oral analgesia). During irradiation with wIRA(+VIS) the subcutaneous oxygen partial pressure rose markedly by approximately 30% and the subcutaneous temperature by approximately 2.7°C (both in a tissue depth of 2 cm), whereas both remained unchanged in the control group: after irradiation the median of the subcutaneous oxygen partial pressure was 41.6 (with wIRA) versus 30.2 mm Hg in the control group (p<0.001), the median of the subcutaneous temperature was 38.9 versus 36.4°C (p<0.001). The overall evaluation of the effect of irradiation, including wound healing, pain and cosmesis, assessed on a VAS (0-100 with 50 as indifferent point of no effect) by the surgeon (median 79.0 versus 46.8, p<0.001) or the patient (79.0 versus 50.2, p<0.001) was markedly better in the group with wIRA compared to the control group. This was also true for single aspects: Wound healing assessed on a VAS by the surgeon (median 88.6 versus 78.5, p<0.001) or the patient (median 85.8 versus 81.0, p=0.040, trend) and cosmetic result assessed on a VAS by the surgeon (median 84.5 versus 76.5, p<0.001) or the patient (median 86.7 versus 73.6, p=0.001). In addition there was a trend in favor of the wIRA group to a lower rate of total wound infections (3 of 46, approximately 7%, versus 7 of 48, approximately 15%, p=0.208) including late infections after discharge, caused by the different rate of late infections after discharge: 0 of 46 in the wIRA group and 4 of 48 in the control group. And there was a trend towards a shorter postoperative hospital stay: 9 days in the wIRA group versus 11 days in the control group (p=0.037). The principal finding of this study was that postoperative irradiation with wIRA can improve even a normal wound healing process.
A prospective, randomized, controlled, double-blind study with 45 severely burned children at the Children’s Hospital Park Schönfeld, Kassel, Germany, showed with 30 minutes irradiation once a day (starting on the first day, day of burn as day 1) in the group with wIRA and visible light VIS (wIRA(+VIS), approximately 75% wIRA, 25% VIS) compared to a control group with only VIS a markedly faster reduction of wound size. On the fifth day (after 4 days with irradiation) decision was taken, whether surgical debridement of necrotic tissue was necessary because of deeper (second degree, type b) burns (11 of 21 in the group with wIRA, 14 of 24 in the control group) or non-surgical treatment was possible (second degree, type a, burns). The patients treated conservatively were kept within the study and irradiated till complete reepithelialization. The patients in the group with wIRA showed a markedly faster reduction of wound area: a median reduction of wound size of 50% was reached already after 7 days compared to 9 days in the control group, a median reduction of wound size of 90% was already achieved after 9 days compared to 13 days in the control group. In addition the group with wIRA showed superior results till 3 months after the burn in terms of the overall surgical assessment of the wound, cosmesis, and assessment of effects of irradiation compared to the control group.
In a prospective, randomized, controlled study with 12 volunteers at the University Medical Center Charité, Berlin, Germany, within each volunteer 4 experimental superficial wounds (5 mm diameter) as an acute wound model were generated by suction cup technique, removing the roof of the blister with a scalpel and a sterile forceps (day 1). 4 different treatments were used and investigated during 10 days: no therapy, only wIRA(+VIS) (approximately 75% wIRA, 25% VIS; 30 minutes irradiation once a day), only dexpanthenol (= D-panthenol) cream once a day, wIRA(+VIS) and dexpanthenol cream once a day. Healing of the small experimental wounds was from a clinical point of view excellent with all 4 treatments. Therefore there were only small differences between the treatments with slight advantages of the combination wIRA(+VIS) and dexpanthenol cream and of dexpanthenol cream alone concerning relative change of wound size and assessment of feeling of the wound area. However laser scanning microscopy with a scoring system revealed differences between the 4 treatments concerning the formation of the stratum corneum (from first layer of corneocytes to full formation) especially on the days 5-7: fastest formation of the stratum corneum was seen in wounds treated with wIRA(+VIS) and dexpanthenol cream, second was wIRA(+VIS) alone, third dexpanthenol cream alone and last were untreated wounds. Bacterial counts of the wounds (taken every 2 days) showed, that wIRA(+VIS) and the combination of wIRA(+VIS) with dexpanthenol cream were able to inhibit the colonisation with physiological skin flora up to day 5 when compared with the two other groups (untreated group and group with dexpanthenol cream alone). At any investigated time, the amount of colonisation under therapy with wIRA(+VIS) alone was lower (interpreted as more suppressed) compared with the group with wIRA(+VIS) and dexpanthenol cream.
During rehabilitation after hip and knee endoprosthetic operations the resorption of wound seromas and wound hematomas was both clinically and sonographically faster and pain was reduced by irradiation with wIRA(+VIS).
wIRA can be used successfully for persistent postoperative pain e.g. after thoracotomy.
As perspectives for wIRA it seems clinically prudent to use wIRA both pre- and postoperatively, e.g. in abdominal and thoracic operations. wIRA can be used preoperatively (e.g. during 1-2 weeks) to precondition donor and recipient sites of skin flaps, transplants or partial-thickness skin grafts, and postoperatively to improve wound healing and to decrease pain, inflammation and infections at all mentioned sites. wIRA can be used to support routine pre- or intraoperative antibiotic administration or it might even be discussed to replace this under certain conditions by wIRA.
Principles and working mechanisms of water-filtered infrared-A (wIRA) in relation to wound healing
(2007)
The experience of the pleasant heat of the sun in moderate climatic zones arises from the filtering of the heat radiation of the sun by water vapor in the atmosphere of the earth. The filter effect of water decreases those parts of infrared radiation (most parts of infrared-B and -C and the absorption bands of water within infrared-A), which would cause – by reacting with water molecules in the skin – only an undesired thermal load to the surface of the skin. Technically water-filtered infrared-A (wIRA) is produced in special radiators, whose full spectrum of radiation of a halogen bulb is passed through a cuvette, containing water, which absorbs or decreases the described undesired wavelengths of the infrared radiation. Within infrared the remaining wIRA (within 780-1400 nm) mainly consists of radiation with good penetration properties into tissue and therefore allows – compared to unfiltered heat radiation – a multiple energy transfer into tissue without irritating the skin, similar to the sun’s heat radiation in moderate climatic zones. Typical wIRA radiators emit no ultraviolet (UV) radiation and nearly no infrared-B and -C radiation and the amount of infrared-A radiation in relation to the amount of visible light (380-780 nm) is emphasized.
Water-filtered infrared-A as a special form of heat radiation with a high tissue penetration and with a low thermal load to the skin surface acts both by thermal (related to heat energy transfer) and thermic (temperature depending, with a relevant change of temperature) as well as by non-thermal (without a relevant transfer of heat energy) and non-thermic (not depending on temperature, without a relevant change of temperature) effects. wIRA produces a therapeutically usable field of heat in the tissue and increases tissue temperature, tissue oxygen partial pressure, and tissue perfusion. These three factors are vital for a sufficient tissue supply with energy and oxygen. As wound healing and infection defense (e.g. granulocyte function including their antibacterial oxygen radical formation) depend decisively on a sufficient supply with energy and oxygen, one explanation for the good clinical effect of wIRA on wounds and wound infections can be the improvement of both the energy supply per time (increase of metabolic rate) and the oxygen supply. In addition wIRA has non-thermal and non-thermic effects, which are based on putting direct stimuli on cells and cellular structures.
wIRA can considerably alleviate the pain (with remarkably less need for analgesics) and diminish an elevated wound exudation and inflammation and can show positive immunomodulatory effects. wIRA can advance wound healing or improve an impaired wound healing both in acute and in chronic wounds including infected wounds. Even the normal wound healing process can be improved.
Keywords: water-filtered infrared-A (wIRA), infrared-A radiation, wound healing, thermal and non-thermal effects, thermic and non-thermic effects, energy supply, oxygen supply, tissue oxygen partial pressure, tissue temperature, tissue blood flow, reduction of pain, wound exudation, inflammation, immunomodulatory effects, acute wounds, chronic venous stasis ulcers of the lower legs, problem wounds, wound infections, infection defense, contact-free method, absent expenditure of material, quality of life, prospective, randomized, controlled, double-blind studies
Sucrose- and H+-dependent charge movements associated with the gating of sucrose transporter ZmSUT1
(2010)
Background: In contrast to man the majority of higher plants use sucrose as mobile carbohydrate. Accordingly proton-driven sucrose transporters are crucial for cell-to-cell and long-distance distribution within the plant body. Generally very negative plant membrane potentials and the ability to accumulate sucrose quantities of more than 1 M document that plants must have evolved transporters with unique structural and functional features.
Methodology/Principal Findings: To unravel the functional properties of one specific high capacity plasma membrane sucrose transporter in detail, we expressed the sucrose/H+ co-transporter from maize ZmSUT1 in Xenopus oocytes. Application of sucrose in an acidic pH environment elicited inward proton currents. Interestingly the sucrose-dependent H+ transport was associated with a decrease in membrane capacitance (Cm). In addition to sucrose Cm was modulated by the membrane potential and external protons. In order to explore the molecular mechanism underlying these Cm changes, presteady-state currents (Ipre) of ZmSUT1 transport were analyzed. Decay of Ipre could be best fitted by double exponentials. When plotted against the voltage the charge Q, associated to Ipre, was dependent on sucrose and protons. The mathematical derivative of the charge Q versus voltage was well in line with the observed Cm changes. Based on these parameters a turnover rate of 500 molecules sucrose/s was calculated. In contrast to gating currents of voltage dependent-potassium channels the analysis of ZmSUT1-derived presteady-state currents in the absence of sucrose (I = Q/τ) was sufficient to predict ZmSUT1 transport-associated currents.
Conclusions: Taken together our results indicate that in the absence of sucrose, ‘trapped’ protons move back and forth between an outer and an inner site within the transmembrane domains of ZmSUT1. This movement of protons in the electric field of the membrane gives rise to the presteady-state currents and in turn to Cm changes. Upon application of external sucrose, protons can pass the membrane turning presteady-state into transport currents.
Background: Athletic competition has been a source of interest to the scientific community for many years, as a surrogate of the limits of human ambulatory ability. One of the remarkable things about athletic competition is the observation that some athletes suddenly reduce their pace in the mid-portion of the race and drop back from their competitors. Alternatively, other athletes will perform great accelerations in mid-race (surges) or during the closing stages of the race (the endspurt). This observation fits well with recent evidence that muscular power output is regulated in an anticipatory way, designed to prevent unreasonably large homeostatic disturbances.
Principal Findings: Here we demonstrate that a simple index, the product of the momentary Rating of Perceived Exertion (RPE) and the fraction of race distance remaining, the Hazard Score, defines the likelihood that athletes will change their velocity during simulated competitions; and may effectively represent the language used to allow anticipatory regulation of muscle power output.
Conclusions: These data support the concept that the muscular power output during high intensity exercise performance is actively regulated in an anticipatory manner that accounts for both the momentary sensations the athlete is experiencing as well as the relative amount of a competition to be completed.
Background and Aims: Chronic infection with the hepatitis B virus (HBV) is a major health issue worldwide. Recently, single nucleotide polymorphisms (SNPs) within the human leukocyte antigen (HLA)-DP locus were identified to be associated with HBV infection in Asian populations. Most significant associations were observed for the A alleles of HLA-DPA1 rs3077 and HLA-DPB1 rs9277535, which conferred a decreased risk for HBV infection. We assessed the implications of these variants for HBV infection in Caucasians.
Methods: Two HLA-DP gene variants (rs3077 and rs9277535) were analyzed for associations with persistent HBV infection and with different clinical outcomes, i.e., inactive HBsAg carrier status versus progressive chronic HBV (CHB) infection in Caucasian patients (n = 201) and HBsAg negative controls (n = 235).
Results: The HLA-DPA1 rs3077 C allele was significantly associated with HBV infection (odds ratio, OR = 5.1, 95% confidence interval, CI: 1.9–13.7; p = 0.00093). However, no significant association was seen for rs3077 with progressive CHB infection versus inactive HBsAg carrier status (OR = 2.7, 95% CI: 0.6–11.1; p = 0.31). In contrast, HLA-DPB1 rs9277535 was not associated with HBV infection in Caucasians (OR = 0.8, 95% CI: 0.4–1.9; p = 1).
Conclusions: A highly significant association of HLA-DPA1 rs3077 with HBV infection was observed in Caucasians. However, as a differentiation between different clinical courses of HBV infection was not possible, knowledge of the HLA-DPA1 genotype cannot be translated into personalized anti-HBV therapy approaches.
Purpose: Milk fat globule-epidermal growth factor-factor VIII (MFGE8) is necessary for diurnal outer segment phagocytosis and promotes VEGF-dependent neovascularization. The prevalence of two single nucleotide polymorphisms (SNP) in MFGE8 was studied in two exsudative or “wet” Age-related Macular Degeneration (AMD) groups and two corresponding control groups. We studied the effect of MFGE8 deficiency on retinal homeostasis with age and on choroidal neovascularization (CNV) in mice.
Methods: The distribution of the SNP (rs4945 and rs1878326) of MFGE8 was analyzed in two groups of patients with “wet” AMD and their age-matched controls from Germany and France. MFGE8-expressing cells were identified in Mfge8+/− mice expressing ß-galactosidase. Aged Mfge8+/− and Mfge8−/− mice were studied by funduscopy, histology, electron microscopy, scanning electron microscopy of vascular corrosion casts of the choroid, and after laser-induced CNV.
Results: rs1878326 was associated with AMD in the French and German group. The Mfge8 promoter is highly active in photoreceptors but not in retinal pigment epithelium cells. Mfge8−/− mice did not differ from controls in terms of fundus appearance, photoreceptor cell layers, choroidal architecture or laser-induced CNV. In contrast, the Bruch's membrane (BM) was slightly but significantly thicker in Mfge8−/− mice as compared to controls.
Conclusions: Despite a reproducible minor increase of rs1878326 in AMD patients and a very modest increase in BM in Mfge8−/− mice, our data suggests that MFGE8 dysfunction does not play a critical role in the pathogenesis of AMD.
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive loss of cognitive functions. Today the diagnosis of AD relies on clinical evaluations and is only late in the disease. Biomarkers for early detection of the underlying neuropathological changes are still lacking and the biochemical pathways leading to the disease are still not completely understood. The aim of this study was to identify the metabolic changes resulting from the disease phenotype by a thorough and systematic metabolite profiling approach. For this purpose CSF samples from 79 AD patients and 51 healthy controls were analyzed by gas and liquid chromatography-tandem mass spectrometry (GC-MS and LC-MS/MS) in conjunction with univariate and multivariate statistical analyses. In total 343 different analytes have been identified. Significant changes in the metabolite profile of AD patients compared to healthy controls have been identified. Increased cortisol levels seemed to be related to the progression of AD and have been detected in more severe forms of AD. Increased cysteine associated with decreased uridine was the best paired combination to identify light AD (MMSE>22) with specificity and sensitivity above 75%. In this group of patients, sensitivity and specificity above 80% were obtained for several combinations of three to five metabolites, including cortisol and various amino acids, in addition to cysteine and uridine.
5-Lipoxygenase (5-LO) catalyzes the two initial steps in the biosynthesis of leukotrienes (LT), a group of inflammatory lipid mediators derived from arachidonic acid. Here, we investigated the regulation of 5-LO mRNA expression by alternative splicing and nonsense-mediated mRNA decay (NMD). In the present study, we report the identification of 2 truncated transcripts and 4 novel 5-LO splice variants containing premature termination codons (PTC). The characterization of one of the splice variants, 5-LOΔ3, revealed that it is a target for NMD since knockdown of the NMD factors UPF1, UPF2 and UPF3b in the human monocytic cell line Mono Mac 6 (MM6) altered the expression of 5-LOΔ3 mRNA up to 2-fold in a cell differentiation-dependent manner suggesting that cell differentiation alters the composition or function of the NMD complex. In contrast, the mature 5-LO mRNA transcript was not affected by UPF knockdown. Thus, the data suggest that the coupling of alternative splicing and NMD is involved in the regulation of 5-LO gene expression.
Debt-induced crises, including the subprime, are usually attributed exclusively to supply-side factors. We examine the role of social influences on debt culture, emanating from perceived average income of peers. Utilizing unique information from a household survey representative of the Dutch population, that circumvents the issue of defining the social circle, we consider collateralized, consumer, and informal loans. We find robust social effects on borrowing, especially among those who consider themselves poorer than their peers; and on indebtedness, suggesting a link to financial distress. We employ a number of approaches to rule out spurious associations and to handle correlated effects.
Trading under limited pre-trade transparency becomes increasingly popular on financial markets. We provide first evidence on traders’ use of (completely) hidden orders which might be placed even inside of the (displayed) bid-ask spread. Employing TotalView-ITCH data on order messages at NASDAQ, we propose a simple method to conduct statistical inference on the location of hidden depth and to test economic hypotheses. Analyzing a wide cross-section of stocks, we show that market conditions reflected by the (visible) bid-ask spread, (visible) depth, recent price movements and trading signals significantly affect the aggressiveness of ’dark’ liquidity supply and thus the ’hidden spread’. Our evidence suggests that traders balance hidden order placements to (i) compete for the provision of (hidden) liquidity and (ii) protect themselves against adverse selection, front-running as well as ’hidden order detection strategies’ used by high-frequency traders. Accordingly, our results show that hidden liquidity locations are predictable given the observable state of the market.
In the aftermath of the global financial crisis, the state of macroeconomic modeling and the use of macroeconomic models in policy analysis has come under heavy criticism. Macroeconomists in academia and policy institutions have been blamed for relying too much on a particular class of macroeconomic models. This paper proposes a comparative approach to macroeconomic policy analysis that is open to competing modeling paradigms. Macroeconomic model comparison projects have helped produce some very influential insights such as the Taylor rule. However, they have been infrequent and costly, because they require the input of many teams of researchers and multiple meetings to obtain a limited set of comparative findings. This paper provides a new approach that enables individual researchers to conduct model comparisons easily, frequently, at low cost and on a large scale. Using this approach a model archive is built that includes many well-known empirically estimated models that may be used for quantitative analysis of monetary and fiscal stabilization policies. A computational platform is created that allows straightforward comparisons of models’ implications. Its application is illustrated by comparing different monetary and fiscal policies across selected models. Researchers can easily include new models in the data base and compare the effects of novel extensions to established benchmarks thereby fostering a comparative instead of insular approach to model development.
How do changes in market structure affect the US business cycle? We estimate a monetary DSGE model with endogenous
rm/product entry and a translog expenditure function by Bayesian methods. The dynamics of net business formation allow us to identify the 'competition effect', by which desired price markups and inflation decrease when entry rises. We
find that a 1 percent increase in the number of competitors lowers desired markups by 0.18 percent. Most of the cyclical variability in inflation is driven by markup fluctuations due to sticky prices or exogenous shocks rather than endogenous changes in desired markups.
This paper characterises optimal monetary policy in an economy with endogenous
firm entry, a cash-in-advance constraint and preset wages. Firms must make pro
fits to cover entry costs; thus the markup on goods prices is efficient. However, because leisure is not priced at a markup, the consumption-leisure tradeoff is distorted. Consequently, the real wage, hours and production are suboptimally low. Due to the labour requirement in entry, insufficient labour supply also implies that entry is too low. The paper shows that in the absence of
fiscal instruments such as labour income subsidies, the optimal monetary policy under sticky wages achieves higher welfare than under flexible wages. The policy maker uses the money supply instrument to raise the real wage - the cost of leisure - above its flexible-wage level, in response to expansionary shocks to productivity and entry costs. This raises labour supply, expanding production and
rm entry.
In the aftermath of the global financial crisis, the state of macroeconomicmodeling and the use of macroeconomic models in policy analysis has come under heavy criticism. Macroeconomists in academia and policy institutions have been blamed for relying too much on a particular class of macroeconomic models. This paper proposes a comparative approach to macroeconomic policy analysis that is open to competing modeling paradigms. Macroeconomic model comparison projects have helped produce some very influential insights such as the Taylor rule. However, they have been infrequent and costly, because they require the input of many teams of researchers and multiple meetings to obtain a limited set of comparative findings. This paper provides a new approach that enables individual researchers to conduct model comparisons easily, frequently, at low cost and on a large scale. Using this approach a model archive is built that includes many well-known empirically estimated models that may be used for quantitative analysis of monetary and fiscal stabilization policies. A computational platform is created that allows straightforward comparisons of models’ implications. Its application is illustrated by comparing different monetary and fiscal policies across selected models. Researchers can easily include new models in the data base and compare the effects of novel extensions to established benchmarks thereby fostering a comparative instead of insular approach to model development
Background: After focal neuronal injury the endocannabinioid system becomes activated and protects or harms neurons depending on cannabinoid derivates and receptor subtypes. Endocannabinoids (eCBs) play a central role in controlling local responses and influencing neural plasticity and survival. However, little is known about the functional relevance of eCBs in long-range projection damage as observed in stroke or spinal cord injury (SCI).
Methods: In rat organotypic entorhino-hippocampal slice cultures (OHSC) as a relevant and suitable model for investigating projection fibers in the CNS we performed perforant pathway transection (PPT) and subsequently analyzed the spatial and temporal dynamics of eCB levels. This approach allows proper distinction of responses in originating neurons (entorhinal cortex), areas of deafferentiation/anterograde axonal degeneration (dentate gyrus) and putative changes in more distant but synaptically connected subfields (cornu ammonis (CA) 1 region).
Results: Using LC-MS/MS, we measured a strong increase in arachidonoylethanolamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) levels in the denervation zone (dentate gyrus) 24 hours post lesion (hpl), whereas entorhinal cortex and CA1 region exhibited little if any changes. NAPE-PLD, responsible for biosynthesis of eCBs, was increased early, whereas FAAH, a catabolizing enzyme, was up-regulated 48hpl.
Conclusion: Neuronal damage as assessed by transection of long-range projections apparently provides a strong time-dependent and area-confined signal for de novo synthesis of eCB, presumably to restrict neuronal damage. The present data underlines the importance of activation of the eCB system in CNS pathologies and identifies a novel site-specific intrinsic regulation of eCBs after long-range projection damage.
Sucrose is known to repress the translation of Arabidopsis thaliana AtbZIP11 transcript which encodes a protein belonging to the group of S (S - stands for small) basic region-leucine zipper (bZIP)-type transcription factor. This repression is called sucrose-induced repression of translation (SIRT). It is mediated through the sucrose-controlled upstream open reading frame (SC-uORF) found in the AtbZIP11 transcript. The SIRT is reported for 4 other genes belonging to the group of S bZIP in Arabidopsis. Tobacco tbz17 is phylogenetically closely related to AtbZIP11 and carries a putative SC-uORF in its 5′-leader region. Here we demonstrate that tbz17 exhibits SIRT mediated by its SC-uORF in a manner similar to genes belonging to the S bZIP group of the Arabidopsis genus. Furthermore, constitutive transgenic expression of tbz17 lacking its 5′-leader region containing the SC-uORF leads to production of tobacco plants with thicker leaves composed of enlarged cells with 3–4 times higher sucrose content compared to wild type plants. Our finding provides a novel strategy to generate plants with high sucrose content.
Freshwater biodiversity has declined dramatically in Europe in recent decades. Because of massive habitat pollution and morphological degradation of water bodies, many once widespread species persist in small fractions of their original range. These range contractions are generally believed to be accompanied by loss of intraspecific genetic diversity, due to the reduction of effective population sizes and the extinction of regional genetic lineages. We aimed to assess the loss of genetic diversity and its significance for future potential reintroduction of the long-tailed mayfly Palingenia longicauda (Olivier), which experienced approximately 98% range loss during the past century. Analysis of 936 bp of mitochondrial DNA of 245 extant specimens across the current range revealed a surprisingly large number of haplotypes (87), and a high level of haplotype diversity (Hd = 0.875). In contrast, historic specimens (6) from the lost range (Rhine catchment) were not differentiated from the extant Rába population (F ST = 0.02, p = 0.61), despite considerable geographic distance separating the two rivers. These observations can be explained by an overlap of the current with the historic (Pleistocene) refugia of the species. Most likely, the massive recent range loss mainly affected the range which was occupied by rapid post-glacial dispersal. We conclude that massive range losses do not necessarily coincide with genetic impoverishment and that a species' history must be considered when estimating loss of genetic diversity. The assessment of spatial genetic structures and prior phylogeographic information seems essential to conserve once widespread species.
Background: Human Parvovirus B19 (PVB19) has been associated with myocarditis putative due to endothelial infection. Whether PVB19 infects endothelial cells and causes a modification of endothelial function and inflammation and, thus, disturbance of microcirculation has not been elucidated and could not be visualized so far.
Methods and Findings: To examine the PVB19-induced endothelial modification, we used green fluorescent protein (GFP) color reporter gene in the non-structural segment 1 (NS1) of PVB19. NS1-GFP-PVB19 or GFP plasmid as control were transfected in an endothelial-like cell line (ECV304). The endothelial surface expression of intercellular-adhesion molecule-1 (CD54/ICAM-1) and extracellular matrix metalloproteinase inducer (EMMPRIN/CD147) were evaluated by flow cytometry after NS-1-GFP or control-GFP transfection. To evaluate platelet adhesion on NS-1 transfected ECs, we performed a dynamic adhesion assay (flow chamber). NS-1 transfection causes endothelial activation and enhanced expression of ICAM-1 (CD54: mean±standard deviation: NS1-GFP vs. control-GFP: 85.3±11.2 vs. 61.6±8.1; P<0.05) and induces endothelial expression of EMMPRIN/CD147 (CD147: mean±SEM: NS1-GFP vs. control-GFP: 114±15.3 vs. 80±0.91; P<0.05) compared to control-GFP transfected cells. Dynamic adhesion assays showed that adhesion of platelets is significantly enhanced on NS1 transfected ECs when compared to control-GFP (P<0.05). The transfection of ECs was verified simultaneously through flow cytometry, immunofluorescence microscopy and polymerase chain reaction (PCR) analysis.
Conclusions: GFP color reporter gene shows transfection of ECs and may help to visualize NS1-PVB19 induced endothelial activation and platelet adhesion as well as an enhanced monocyte adhesion directly, providing in vitro evidence of possible microcirculatory dysfunction in PVB19-induced myocarditis and, thus, myocardial tissue damage.
The human DNA mismatch repair (MMR) process is crucial to maintain the integrity of the genome and requires many different proteins which interact perfectly and coordinated. Germline mutations in MMR genes are responsible for the development of the hereditary form of colorectal cancer called Lynch syndrome. Various mutations mainly in two MMR proteins, MLH1 and MSH2, have been identified so far, whereas 55% are detected within MLH1, the essential component of the heterodimer MutLα (MLH1 and PMS2). Most of those MLH1 variants are pathogenic but the relevance of missense mutations often remains unclear. Many different recombinant systems are applied to filter out disease-associated proteins whereby fluorescent tagged proteins are frequently used. However, dye labeling might have deleterious effects on MutLα's functionality. Therefore, we analyzed the consequences of N- and C-terminal fluorescent labeling on expression level, cellular localization and MMR activity of MutLα. Besides significant influence of GFP- or Red-fusion on protein expression we detected incorrect shuttling of single expressed C-terminal GFP-tagged PMS2 into the nucleus and found that C-terminal dye labeling impaired MMR function of MutLα. In contrast, N-terminal tagged MutLαs retained correct functionality and can be recommended both for the analysis of cellular localization and MMR efficiency.
Infants' poor motor abilities limit their interaction with their environment and render studying infant cognition notoriously difficult. Exceptions are eye movements, which reach high accuracy early, but generally do not allow manipulation of the physical environment. In this study, real-time eye tracking is used to put 6- and 8-month-old infants in direct control of their visual surroundings to study the fundamental problem of discovery of agency, i.e. the ability to infer that certain sensory events are caused by one's own actions. We demonstrate that infants quickly learn to perform eye movements to trigger the appearance of new stimuli and that they anticipate the consequences of their actions in as few as 3 trials. Our findings show that infants can rapidly discover new ways of controlling their environment. We suggest that gaze-contingent paradigms offer effective new ways for studying many aspects of infant learning and cognition in an interactive fashion and provide new opportunities for behavioral training and treatment in infants.
We present a computational method for the reaction-based de novo design of drug-like molecules. The software DOGS (Design of Genuine Structures) features a ligand-based strategy for automated ‘in silico’ assembly of potentially novel bioactive compounds. The quality of the designed compounds is assessed by a graph kernel method measuring their similarity to known bioactive reference ligands in terms of structural and pharmacophoric features. We implemented a deterministic compound construction procedure that explicitly considers compound synthesizability, based on a compilation of 25'144 readily available synthetic building blocks and 58 established reaction principles. This enables the software to suggest a synthesis route for each designed compound. Two prospective case studies are presented together with details on the algorithm and its implementation. De novo designed ligand candidates for the human histamine H4 receptor and γ-secretase were synthesized as suggested by the software. The computational approach proved to be suitable for scaffold-hopping from known ligands to novel chemotypes, and for generating bioactive molecules with drug-like properties.
Background: During early stages of brain development, secreted molecules, components of intracellular signaling pathways and transcriptional regulators act in positive and negative feed-back or feed-forward loops at the mid-hindbrain boundary. These genetic interactions are of central importance for the specification and subsequent development of the adjacent mid- and hindbrain. Much less, however, is known about the regulatory relationship and functional interaction of molecules that are expressed in the tectal anlage after tectal fate specification has taken place and tectal development has commenced.
Results: Here, we provide experimental evidence for reciprocal regulation and subsequent cooperation of the paired-type transcription factors Pax3, Pax7 and the TALE-homeodomain protein Meis2 in the tectal anlage. Using in ovo electroporation of the mesencephalic vesicle of chick embryos we show that (i) Pax3 and Pax7 mutually regulate each other's expression in the mesencephalic vesicle, (ii) Meis2 acts downstream of Pax3/7 and requires balanced expression levels of both proteins, and (iii) Meis2 physically interacts with Pax3 and Pax7. These results extend our previous observation that Meis2 cooperates with Otx2 in tectal development to include Pax3 and Pax7 as Meis2 interacting proteins in the tectal anlage.
Conclusion: The results described here suggest a model in which interdependent regulatory loops involving Pax3 and Pax7 in the dorsal mesencephalic vesicle modulate Meis2 expression. Physical interaction with Meis2 may then confer tectal specificity to a wide range of otherwise broadly expressed transcriptional regulators, including Otx2, Pax3 and Pax7.
Background: The European Centres of Reference Network for Cystic Fibrosis (ECORN-CF) established an Internet forum which provides the opportunity for CF patients and other interested people to ask experts questions about CF in their mother language. The objectives of this study were to: 1. develop a detailed quality assessment tool to analyze quality of expert answers, 2. evaluate the intra- and inter-rater agreement of this tool, and 3. explore changes in the quality of expert answers over the time frame of the project.
Methods: The quality assessment tool was developed by an expert panel. Five experts within the ECORN-CF project used the quality assessment tool to analyze the quality of 108 expert answers published on ECORN-CF from six language zones. 25 expert answers were scored at two time points, one year apart. Quality of answers was also assessed at an early and later period of the project. Individual rater scores and group mean scores were analyzed for each expert answer.
Results: A scoring system and training manual were developed analyzing two quality categories of answers: content and formal quality. For content quality, the grades based on group mean scores for all raters showed substantial agreement between two time points, however this was not the case for the grades based on individual rater scores. For formal quality the grades based on group mean scores showed only slight agreement between two time points and there was also poor agreement between time points for the individual grades. The inter-rater agreement for content quality was fair (mean kappa value 0.232+/-0.036, p<0.001) while only slight agreement was observed for the grades of the formal quality (mean kappa value 0.105+/-0.024, p<0.001). The quality of expert answers was rated high (four language zones) or satisfactory (two language zones) and did not change over time.
Conclusions: The quality assessment tool described in this study was feasible and reliable when content quality was assessed by a group of raters. Within ECORN-CF, the tool will help ensure that CF patients all over Europe have equal possibility of access to high quality expert advice on their illness.
The present study addresses the problem whether negative priming (NP) is due to information processing in perception, recognition or selection. We argue that most NP studies confound priming and perceptual similarity of prime-probe episodes and implement a color-switch paradigm in order to resolve the issue. In a series of three identity negative priming experiments with verbal naming response, we determined when NP and positive priming (PP) occur during a trial. The first experiment assessed the impact of target color on priming effects. It consisted of two blocks, each with a different fixed target color. With respect to target color no differential priming effects were found. In Experiment 2 the target color was indicated by a cue for each trial. Here we resolved the confounding of perceptual similarity and priming condition. In trials with coinciding colors for prime and probe, we found priming effects similar to Experiment 1. However, trials with a target color switch showed such effects only in trials with role-reversal (distractor-to-target or target-to-distractor), whereas the positive priming (PP) effect in the target-repetition trials disappeared. Finally, Experiment 3 split trial processing into two phases by presenting the trial-wise color cue only after the stimulus objects had been recognized. We found recognition in every priming condition to be faster than in control trials. We were hence led to the conclusion that PP is strongly affected by perception, in contrast to NP which emerges during selection, i.e., the two effects cannot be explained by a single mechanism.
Few studies have looked at the potential of using diffusion tensor imaging (DTI) in conjunction with machine learning algorithms in order to automate the classification of healthy older subjects and subjects with mild cognitive impairment (MCI). Here we apply DTI to 40 healthy older subjects and 33 MCI subjects in order to derive values for multiple indices of diffusion within the white matter voxels of each subject. DTI measures were then used together with support vector machines (SVMs) to classify control and MCI subjects. Greater than 90% sensitivity and specificity was achieved using this method, demonstrating the potential of a joint DTI and SVM pipeline for fast, objective classification of healthy older and MCI subjects. Such tools may be useful for large scale drug trials in Alzheimer’s disease where the early identification of subjects with MCI is critical.
Place based frequency discrimination (tonotopy) is a fundamental property of the coiled mammalian cochlea. Sound vibrations mechanically conducted to the hearing organ manifest themselves into slow moving waves that travel along the length of the organ, also referred to as traveling waves. These traveling waves form the basis of the tonotopic frequency representation in the inner ear of mammals. However, so far, due to the secure housing of the inner ear, these waves only could be measured partially over small accessible regions of the inner ear in a living animal. Here, we demonstrate the existence of tonotopically ordered traveling waves covering most of the length of a miniature hearing organ in the leg of bushcrickets in vivo using laser Doppler vibrometery. The organ is only 1 mm long and its geometry allowed us to investigate almost the entire length with a wide range of stimuli (6 to 60 kHz). The tonotopic location of the traveling wave peak was exponentially related to stimulus frequency. The traveling wave propagated along the hearing organ from the distal (high frequency) to the proximal (low frequency) part of the leg, which is opposite to the propagation direction of incoming sound waves. In addition, we observed a non-linear compression of the velocity response to varying sound pressure levels. The waves are based on the delicate micromechanics of cellular structures different to those of mammals. Hence place based frequency discrimination by traveling waves is a physical phenomenon that presumably evolved in mammals and bushcrickets independently.
Introduction: Despite the excellent anti-inflammatory and immunosuppressive action of glucocorticoids (GCs), their use for the treatment of inflammatory bowel disease (IBD) still carries significant risks in terms of frequently occurring severe side effects, such as the impairment of intestinal tissue repair. The recently-introduced selective glucocorticoid receptor (GR) agonists (SEGRAs) offer anti-inflammatory action comparable to that of common GCs, but with a reduced side effect profile.
Methods: The in vitro effects of the non-steroidal SEGRAs Compound A (CpdA) and ZK216348, were investigated in intestinal epithelial cells and compared to those of Dexamethasone (Dex). GR translocation was shown by immunfluorescence and Western blot analysis. Trans-repressive effects were studied by means of NF-κB/p65 activity and IL-8 levels, trans-activation potency by reporter gene assay. Flow cytometry was used to assess apoptosis of cells exposed to SEGRAs. The effects on IEC-6 and HaCaT cell restitution were determined using an in vitro wound healing model, cell proliferation by BrdU assay. In addition, influences on the TGF-β- or EGF/ERK1/2/MAPK-pathway were evaluated by reporter gene assay, Western blot and qPCR analysis.
Results: Dex, CpdA and ZK216348 were found to be functional GR agonists. In terms of trans-repression, CpdA and ZK216348 effectively inhibited NF-κB activity and IL-8 secretion, but showed less trans-activation potency. Furthermore, unlike SEGRAs, Dex caused a dose-dependent inhibition of cell restitution with no effect on cell proliferation. These differences in epithelial restitution were TGF-β-independent but Dex inhibited the EGF/ERK1/2/MAPK-pathway important for intestinal epithelial wound healing by induction of MKP-1 and Annexin-1 which was not affected by CpdA or ZK216348.
Conclusion: Collectively, our results indicate that, while their anti-inflammatory activity is comparable to Dex, SEGRAs show fewer side effects with respect to wound healing. The fact that SEGRAs did not have a similar effect on cell restitution might be due to a different modulation of EGF/ERK1/2 MAPK signalling.
Ubiquitination now ranks with phosphorylation as one of the best-studied post-translational modifications of proteins with broad regulatory roles across all of biology. Ubiquitination usually involves the addition of ubiquitin chains to target protein molecules, and these may be of eight different types, seven of which involve the linkage of one of the seven internal lysine (K) residues in one ubiquitin molecule to the carboxy-terminal diglycine of the next. In the eighth, the so-called linear ubiquitin chains, the linkage is between the amino-terminal amino group of methionine on a ubiquitin that is conjugated with a target protein and the carboxy-terminal carboxy group of the incoming ubiquitin. Physiological roles are well established for K48-linked chains, which are essential for signaling proteasomal degradation of proteins, and for K63-linked chains, which play a part in recruitment of DNA repair enzymes, cell signaling and endocytosis. We focus here on linear ubiquitin chains, how they are assembled, and how three different avenues of research have indicated physiological roles for linear ubiquitination in innate and adaptive immunity and suppression of inflammation.
Ubiquitin ligases and beyond
(2012)
First paragraph (this article has no abstract): In a review published in 2004 [1] and that still repays reading today, Cecile Pickart traced the evolution of research on ubiquitination from its origins in the proteasomal degradation of proteins through the revelation that it has a central role in cell cycle regulation and the recognition of regulatory roles for ubiquitin in intracellular membrane transport, cell signalling, transcription, translation, and DNA repair.
Synaptic long-term potentiation (LTP) at spinal neurons directly communicating pain-specific inputs from the periphery to the brain has been proposed to serve as a trigger for pain hypersensitivity in pathological states. Previous studies have functionally implicated the NMDA receptor-NO pathway and the downstream second messenger, cGMP, in these processes. Because cGMP can broadly influence diverse ion-channels, kinases, and phosphodiesterases, pre- as well as post-synaptically, the precise identity of cGMP targets mediating spinal LTP, their mechanisms of action, and their locus in the spinal circuitry are still unclear. Here, we found that Protein Kinase G1 (PKG-I) localized presynaptically in nociceptor terminals plays an essential role in the expression of spinal LTP. Using the Cre-lox P system, we generated nociceptor-specific knockout mice lacking PKG-I specifically in presynaptic terminals of nociceptors in the spinal cord, but not in post-synaptic neurons or elsewhere (SNS-PKG-I−/− mice). Patch clamp recordings showed that activity-induced LTP at identified synapses between nociceptors and spinal neurons projecting to the periaqueductal grey (PAG) was completely abolished in SNS-PKG-I−/− mice, although basal synaptic transmission was not affected. Analyses of synaptic failure rates and paired-pulse ratios indicated a role for presynaptic PKG-I in regulating the probability of neurotransmitter release. Inositol 1,4,5-triphosphate receptor 1 and myosin light chain kinase were recruited as key phosphorylation targets of presynaptic PKG-I in nociceptive neurons. Finally, behavioural analyses in vivo showed marked defects in SNS-PKG-I−/− mice in several models of activity-induced nociceptive hypersensitivity, and pharmacological studies identified a clear contribution of PKG-I expressed in spinal terminals of nociceptors. Our results thus indicate that presynaptic mechanisms involving an increase in release probability from nociceptors are operational in the expression of synaptic LTP on spinal-PAG projection neurons and that PKG-I localized in presynaptic nociceptor terminals plays an essential role in this process to regulate pain sensitivity.
We investigate the decisions of listed firms to go private once again. We start by revealing that while a significant number of firms which go public is VC-backed, an overproportional share of these VC-backed firms go private later on (they stay on the exchange for an average of 8.5 years). We interpret this very robust pattern such that IPOs of VC-backed firms are to a large extent a temporary rather than a permanent feature of the corporate governance of these firms. We investigate various potential hypotheses why VCs actually seem to be able to bring marginal firms to the exchange by relating the going-private decisions to various characteristics of the IPO market as well as to VC characteristics. We find strong support for the certification ability of VCs: more experienced and reputable VCs are more able to bring marginal firms to public exchanges via an IPOs. These marginal firms backed-by more reputable and experienced VCs are more likely to go private later on. Hence, our analysis suggests that IPOs backed by experienced VCs are most likely to be a temporary rather than the final stage in the life of the portfolio firm. We find no support that reputable VCs underprice their IPO-exits more implying that they have no need to leave more money on the table to take the marginal firms public.
Diatoms contribute largely to the total primary production of the ecosphere and are key players in global biogeochemical cycles. Their chloroplasts are surrounded by four membranes owing to their secondary endosymbiotic origin. Their thylakoids are arranged into three parallel bands and differentiation of thylakoid membranes into grana or stroma is not observed. The fucoxanthin chlorophyll a/c binding proteins act as the light harvesting proteins and play a role in photoprotection during excess light as well. The diatom genome encodes three different families of antenna proteins. Family I are the classical light harvesting proteins called "Lhcf". Family II are the red algae related Lhca-R1/2 proteins called "Lhcr" and family III are the photoprotective LI818 related proteins called "Lhcx".
All known Fcps have a molecular weight in the range of 17-23 kDa. They are membrane proteins and have shorter loops and termini compared to LHCs of higher plants and are therefore extremely hydrophobic. This makes the isolation of single specific Fcps using routine protein purification techniques difficult.
The purification of a specific Fcp containing complex has not been achieved so far and until this is done several questions concerning light harvesting antenna systems of diatoms cannot be answered. For e.g. Which proteins interact specifically? Are various Fcps differently pigmented? Which pigments interact with each other and how? Which proteins contribute to photosystem specific antenna systems? Can pure Fcps be reconstituted into crystals like LHCII proteins? In order to answer these questions specific Fcp containing complexes have to be purified. ...
The miniaturization of electronics is reaching its limits. Structures necessary to build integrated circuits from semiconductors are shrinking and could reach the size of only a few atoms within the next few years. It will be at the latest at this point in time that the physics of nanostructures gains importance in our every day life. This thesis deals with the physics of quantum impurity models. All models of this class exhibit an identical structure: the simple and small impurity only has few degrees of freedom. It can be built out of a small number of atoms or a single molecule, for example. In the simplest case it can be described by a single spin degree of freedom, in many quantum impurity models, it can be treated exactly. The complexity of the description arises from its coupling to a large number of fermionic or bosonic degrees of freedom (large meaning that we have to deal with particle numbers of the order of 10^{23}). An exact treatment thus remains impossible. At the same time, physical effects which arise in quantum impurity systems often cannot be described within a perturbative theory, since multiple energy scales may play an important role. One example for such an effect is the Kondo effect, where the free magnetic moment of the impurity is screened by a "cloud" of fermionic particles of the quantum bath.
The Kondo effect is only one example for the rich physics stemming from correlation effects in many body systems. Quantum impurity models, and the oftentimes related Kondo effect, have regained the attention of experimental and theoretical physicists since the advent of quantum dots, which are sometimes also referred to as as artificial atoms. Quantum dots offer a unprecedented control and tunability of many system parameters. Hence, they constitute a nice "playground" for fundamental research, while being promising candidates for building blocks of future technological devices as well.
Recently Loss' and DiVincenzo's p roposal of a quantum computing scheme based on spins in quantum dots, increased the efforts of experimentalists to coherently manipulate and read out the spins of quantum dots one by one. In this context two topics are of paramount importance for future quantum information processing: since decoherence times have to be large enough to allow for good error correction schemes, understanding the loss of phase coherence in quantum impurity systems is a prerequisite for quantum computation in these systems. Nonequilibrium phenomena in quantum impurity systems also have to be understood, before one may gain control of manipulating quantum bits.
As a first step towards more complicated nonequilibrium situations, the reaction of a system to a quantum quench, i.e. a sudden change of external fields or other parameters of the system can be investigated. We give an introduction to a powerful numerical method used in this field of research, the numerical renormalization group method, and apply this method and its recent enhancements to various quantum impurity systems.
The main part of this thesis may be structured in the following way:
- Ferromagnetic Kondo Model,
- Spin-Dynamics in the Anisotropic Kondo and the Spin-Boson Model,
- Two Ising-coupled Spins in a Bosonic Bath,
- Decoherence in an Aharanov-Bohm Interferometer.
Introduction: Erectile dysfunction (ED) is common in men with systemic sclerosis (SSc) but the demographics, risk factors and treatment coverage for ED are not well known.
Method: This study was carried out prospectively in the multinational EULAR Scleroderma Trial and Research database by amending the electronic data-entry system with the International Index of Erectile Function-5 and items related to ED risk factors and treatment. Centres participating in this EULAR Scleroderma Trial and Research substudy were asked to recruit patients consecutively.
Results: Of the 130 men studied, only 23 (17.7%) had a normal International Index of Erectile Function-5 score. Thirty-eight per cent of all participants had severe ED (International Index of Erectile Function-5 score ≤ 7). Men with ED were significantly older than subjects without ED (54.8 years vs. 43.3 years, P < 0.001) and more frequently had simultaneous non-SSc-related risk factors such as alcohol consumption. In 82% of SSc patients, the onset of ED was after the manifestation of the first non-Raynaud's symptom (median delay 4.1 years). ED was associated with severe cutaneous, muscular or renal involvement of SSc, elevated pulmonary pressures and restrictive lung disease. ED was treated in only 27.8% of men. The most common treatment was sildenafil, whose efficacy is not established in ED of SSc patients.
Conclusions: Severe ED is a common and early problem in men with SSc. Physicians should address modifiable risk factors actively. More research into the pathophysiology, longitudinal development, treatment and psychosocial impact of ED is needed.
Background: In Emergency and Medical Admission Departments (EDs and MADs), prompt recognition and appropriate infection control management of patients with Highly Infectious Diseases (HIDs, e.g. Viral Hemorrhagic Fevers and SARS) are fundamental for avoiding nosocomial outbreaks.
Methods: The EuroNHID (European Network for Highly Infectious Diseases) project collected data from 41 EDs and MADs in 14 European countries, located in the same facility as a national/regional referral centre for HIDs, using specifically developed checklists, during on-site visits from February to November 2009.
Results: Isolation rooms were available in 34 facilities (82,9%): these rooms had anteroom in 19, dedicated entrance in 15, negative pressure in 17, and HEPA filtration of exhausting air in 12. Only 6 centres (14,6%) had isolation rooms with all characteristics. Personnel trained for the recognition of HIDs was available in 24 facilities; management protocols for HIDs were available in 35.
Conclusions: Preparedness level for the safe and appropriate management of HIDs is partially adequate in the surveyed EDs and MADs.
From 12.12.2010 to 17.12.2010, the Dagstuhl Seminar 10501 "Advances and Applications of Automata on Words and Trees" was held in Schloss Dagstuhl - Leibniz Center for Informatics. During the seminar, several participants presented their current research, and ongoing work and open problems were discussed. Abstracts of the presentations given during the seminar as well as abstracts of seminar results and ideas are put together in this paper. The first section describes the seminar topics and goals in general. Links to extended abstracts or full papers are provided, if available.
Seminar: 10501 - Advances and Applications of Automata on Words and Trees. The aim of the seminar was to discuss and systematize the recent fast progress in automata theory and to identify important directions for future research. For this, the seminar brought together more than 40 researchers from automata theory and related fields of applications. We had 19 talks of 30 minutes and 5 one-hour lectures leaving ample room for discussions. In the following we describe the topics in more detail.
This article shows that there exist two particular linear orders such that first-order logic with these two linear orders has the same expressive power as first-order logic with the Bit-predicate FO(Bit). As a corollary we obtain that there also exists a built-in permutation such that first-order logic with a linear order and this permutation is as expressive as FO(Bit).
Background: Hepatitis C decreases health related quality of life (HRQL) which is further diminished by antiviral therapy. HRQL improves after successful treatment. This trial explores the course of and factors associated with HRQL in patients given individualized or standard treatment based on early treatment response (Ditto-study).
Methods: The Short Form (SF)-36 Health Survey was administered at baseline (n = 192) and 24 weeks after the end of therapy (n = 128).
Results: At baseline HRQL was influenced by age, participating center, severity of liver disease and income. Exploring the course of HRQL (scores at follow up minus baseline), only the dimension general health increased. In this dimension patients with a relapse or sustained response differed from non-responders. Men and women differed in the dimension bodily pain. Treatment schedule did not influence the course of HRQL.
Conclusions: Main determinants of HRQL were severity of liver disease, age, gender, participating center and response to treatment. Our results do not exclude a more profound negative impact of individualized treatment compared to standard, possibly caused by higher doses and extended treatment duration in the individualized group. Antiviral therapy might have a more intense and more prolonged negative impact on females.
Background: Europe was certified to be polio-free in 2002 by the WHO. However, wild polioviruses remain endemic in India, Pakistan, Afghanistan, and Nigeria, occasionally causing polio outbreaks, as in Tajikistan in 2010. Therefore, effective surveillance measures and vaccination campaigns remain important. To determine the poliovirus immune status of a German study population, we retrospectively evaluated the seroprevalence of neutralizing antibodies (NA) to the poliovirus types 1, 2 and 3 (PV1, 2, 3) in serum samples collected from 1,632 patients admitted the University Hospital of Frankfurt am Main, Germany, in 2001, 2005 and 2010.
Methods: Testing was done by using a standardized microneutralization assay.
Results: Level of immunity to PV1 ranged between 84.2% (95%CI: 80.3-87.5), 90.4% (88.3-92.3) and 87.5% (85.4-88.8) in 2001, 2005 and 2010. For PV2, we found 90.8% (87.5-90.6), 91.3% (89.3-93.1) and 89.8% (88.7-90.9), in the same period. Seroprevalence to PV3 was 76.6% (72.2-80.6), 69.8% (66.6-72.8) and 72.9% (67.8-77.5) in 2001 and 2005 and 2010, respectively. In 2005 and 2010 significant lower levels of immunity to PV3 in comparison to PV1 and 2 were observed. Since 2001, immunity to PV3 is gradually, but not significantly decreasing.
Conclusion: Immunity to PV3 is insufficient in our cohort. Due to increasing globalization and worldwide tourism, the danger of polio-outbreaks is not averted - even not in developed countries, such as Germany. Therefore, vaccination remains necessary.
Background: Ewing sarcoma patients have a poor prognosis despite multimodal therapy. Integration of combination immunotherapeutic strategies into first-/second-line regimens represents promising treatment options, particularly for patients with intrinsic or acquired resistance to conventional therapies. We evaluated the susceptibility of Ewing sarcoma to natural killer cell-based combination immunotherapy, by assessing the capacity of histone deacetylase inhibitors to improve immune recognition and sensitize for natural killer cell cytotoxicity.
Methods: Using flow cytometry, ELISA and immunohistochemistry, expression of natural killer cell receptor ligands was assessed in chemotherapy-sensitive/-resistant Ewing sarcoma cell lines, plasma and tumours. Natural killer cell cytotoxicity was evaluated in Chromium release assays. Using ATM/ATR inhibitor caffeine, the contribution of the DNA damage response pathway to histone deacetylase inhibitor-induced ligand expression was assessed.
Results: Despite comparable expression of natural killer cell receptor ligands, chemotherapy-resistant Ewing sarcoma exhibited reduced susceptibility to resting natural killer cells. Interleukin-15-activation of natural killer cells overcame this reduced sensitivity. Histone deacetylase inhibitor-pretreatment induced NKG2D-ligand expression in an ATM/ATR-dependent manner and sensitized for NKG2D-dependent cytotoxicity (2/4 cell lines). NKG2D-ligands were expressed in vivo, regardless of chemotherapy-response and disease stage. Soluble NKG2D-ligand plasma concentrations did not differ between patients and controls.
Conclusion: Our data provide a rationale for combination immunotherapy involving immune effector and target cell manipulation in first-/second-line treatment regimens for Ewing sarcoma.
Much is known about the computation in individual neurons in the cortical column. Also, the selective connectivity between many cortical neuron types has been studied in great detail. However, due to the complexity of this microcircuitry its functional role within the cortical column remains a mystery. Some of the wiring behavior between neurons can be interpreted directly from their particular dendritic and axonal shapes. Here, I describe the dendritic density field (DDF) as one key element that remains to be better understood. I sketch an approach to relate DDFs in general to their underlying potential connectivity schemes. As an example, I show how the characteristic shape of a cortical pyramidal cell appears as a direct consequence of connecting inputs arranged in two separate parallel layers.
The small bowel is essential to sustain alimentation and small bowel Crohn's disease (CD) may severely limit its function. Small bowel imaging is a crucial element in diagnosing small
bowel CD, and treatment control with imaging is increasingly used to optimize the patients outcome. Thereby, capsule endoscopy, Balloon-assisted enteroscopy, and Magnetic resonance imaging have become key players to manage CD patients. In this review, role of small bowel imaging is detailed discussed for use in diagnosing and managing Crohn's disease patients.
Editorial : Andreas Dombret "Regulating Systemically Important Financial Institutions is Vitally Important" ; Research Money/Macro : Dimitris Christelis, Dimitris Georgarakos, Michael Haliassos "International Portfolio Differences: Environment versus Characteristics" ; Research Finance : Raimond Maurer, Ralph Rogalla, Yuanyuan Shen "Optimal Asset Allocation in Retirement with Open-end Real Estate Funds" ; Research Law : Theodor Baums "Shareholder Suits in German Company Law – An Empirical Study" ; Policy Platform : Helmut Siekmann, Patrick Tuschl "Constitutional Ruling on Court of Auditors' Review of Banks" ; Interview : Michael S. Barr "Information Does not Necessarily Lead to Understanding"
The study of meson production in proton-proton collisions in the energy range
up to one GeV above the production threshold provides valuable information about
the nature of the nucleon-nucleon interaction. Theoretical models describe the interaction
between nucleons via the exchange of mesons. In such models, different
mechanisms contribute to the production of the mesons in nucleon-nucleon collisions.
The measurement of total and differential production cross sections provide information
which can help in determining the magnitude of the various mechanisms.
Moreover, such cross section information serves as an input to the transport calculations
which describe e.g. the production of e+e− pairs in proton- and pion-induced
reactions as well as in heavy ion collisions.
In this thesis, the production of ω and η mesons in proton-proton collisions at 3.5
GeV beam energy was studied using the High Acceptance DiElectron Spectrometer
(HADES) installed at the Schwerionensynchrotron (SIS 18) at the Helmholtzzenturm
f¨ur Schwerionenforschung in Darmstadt.
About 80 000 ω mesons and 35 000 η mesons were reconstructed. Total production
cross sections of both mesons were determined. Furthermore, the collected statistics
allowed for extracting angular distributions of both mesons as well as performing
Dalitz plot studies.
The ω and η mesons were reconstructed via their decay into three pions (π+π−π0)
in the exclusive reaction pp −→ ppπ+π−π0. The charged particles were identified
via their characteristic energy loss, via the measurement of their time of flight and
momentum, or using kinematics.
The neutral pion was reconstructed using the missing mass method. A kinematic
fit was applied to improve the resolution and to select events in which a π0 was
produced.
The correction of measured yields for the effects of spectrometer acceptance was done
as a function of four variables (two invariant masses and two angles). Systematic
studies of the acceptance for different input distributions were performed.
The measured yields were normalized to the number of measured events of elastic
scattering. Systematic errors due to the methods of the data analysis and the
background subtraction were investigated.
Production angular distributions of ω and η mesons were measured. Both mesons
exhibit a slightly anisotropic angular distribution.
The Dalitz plot of ω meson production shows indications of resonant production.
However, the deviation of the distribution from the one expected by phase space
simulations is not large.
The Dalitz plot of η meson production shows a signal of the production via the
N(1535) resonance, The contribution of N(1535) to the production was quantified
to be about 47%. The angular distribution of η mesons does not show significant
differences between resonant and non resonant production.
The total production cross section of ω mesons in the reaction pp −→ ppω was
determined to be 106.5 ± 0.9 (stat) ± 7.9 (sys) [μb] where stat indicates statistical
error and sys indicates systematic error, while that of η mesons was determined to
be 136.9 ± 0.9 (stat) ± 10.1 (sys) [μb] in the reaction pp −→ ppη
Occurrence and sources of 2,4,7,9-tetramethyl-5-decyne-4,7-diol (TMDD) in the aquatic environment
(2011)
The aim of the present study was to identify the sources of 2,4,7,9-tetramethyl-5-decyne-4,7-diol (TMDD) into the aquatic environment and to investigate its occurrence in rivers and wastewater treatment plants (WWTPs). Therefore, TMDD was analyzed in 441 wastewater samples from influents and effluents of 27 municipal WWTPs, in 6 sludge samples, in 52 wastewater samples from 3 sewage systems of municipal WWTPs, in 489 surface samples from 24 rivers, in 9 wastewater samples of 3 paper-recycling industries and in 65 groundwater samples. TMDD was also analyzed in household paper products, in 23 samples of toilet
papers, in 5 types of paper towels and in 12 types of paper tissues. The samples were collected between 2007 and 2011. The water samples were extracted with solid phase extraction (SPE) and the household paper samples with Soxhlet extraction. Gas chromatography-mass spectrometry (GC-MS) was used for quantification purposes. Between November 2007 and January 2008, TMDD was detected in the river Rhine at Worms with permanent high concentrations (up to 1330 ng/L). The results showed that TMDD is uniformly distributed across the river at Worms. An increase of the mean TMDD concentration from approximately 500 ng/L to 1000 ng/L was registered in January 2008. Due to the minor fluctuations of the TMDD concentration during the sampling period it is expected that the input of TMDD into the river is continuous. Therefore, TMDD might rather originate from effluents of municipal WWTPs than from temporal sources. The mean TMDD load based on the analysis of 147 water samples collected in the River Rhine was 62.8 kg/d which is equivalent to 23 t/a suggesting that TMDD must be used and/or produced in high quantities in order to be found in those high concentrations. To determine if TMDD is discharged by effluents of municipal WWTPs into the rivers, 24 hours influent and effluent samples of four municipal WWTPs in the Frankfurt/Rhine-Main metropolitan region were collected during November 2008 and February 2010 and analyzed for TMDD. The TMDD influent concentrations varied between 134 ng/L and 5846 ng/L and the effluent concentrations between <LOQ (limit of quantitation) and 3539 ng/L. The TMDD elimination rates in the four WWTPs varied between 33% and 68%. The results showed that effluents of municipal WWTPs are an important source of TMDD in the aquatic environment because TMDD is not completely removed from the sewage during the wastewater treatment. Weekly and daily variations of the TMDD concentration in the influents of two municipal WWTPs indicated that both private households and indirect industrial dischargers contribute to the introduction of TMDD into the municipal sewage systems. A more detailed study of the TMDD elimination rate in the different wastewater treatment stages was carried out in the WWTP Niederrad/Griesheim in Frankfurt am Main. The results showed that the removal of TMDD is mainly carried out during the aerobic biological treatments, where the elimination rate was 46%. In contrast, during the anoxic treatment the removal efficiency was only 1.4% and during the mechanical treatment the elimination rate was 19%. To determine the sources of TMDD in the sewage, household paper products (paper tissues, toilet papers and paper towels) were analyzed for TMDD using Soxhlet extraction. TMDD was detected in 83% of the samples (n=40). The highest mean TMDD concentrations were found in recycled toilet paper (0.20 μg/g) and in paper towels (0.11 μg/g). In paper tissues and non-recycled toilet paper the mean TMDD concentrations were lower 0.080 μg/g and 0.025 μg/g respectively. According to these results the high TMDD influent concentrations found previously in municipal WWTPs (mean 1.20 μg/L) cannot be explained due to migration of TMDD from the household paper products into the sewage. Thus indirect industrial dischargers are the cause of the high influent TMDD concentrations. Effluents of municipal WWTPs with different indirect industrial dischargers (textile-, metal processing-, food processing-, electroplating-, paper-recycling- and printing ink factories) were analyzed. The highest mean TMDD concentrations were found in the effluents of municipal WWTPs that have paper-recycling (71.3 μg/L) and printing ink factories (138 μg/L) as indirect industrial dischargers. These results were confirmed by analyzing process wastewater of three paper-recycling factories located in Germany. High TMDD concentrations were detected and fluctuated between 1.83 μg/L and 113 μg/L. TMDD was also analyzed in the wastewater of a non-recycling-paper factory but its concentration was much lower (0.066 μg/L) indicating that TMDD is introduced into the processing water during the papermaking process due to the use of waste paper. Analyses of wastewater samples from different parts of the sewage pipes of a municipal WWTP in Hesse, which receives the wastewater from a printing ink factory, were carried out. The TMDD concentration in the wastewater sample from the sewage pipe of the printing ink factory was much higher (3,300 μg/L) than the TMDD concentration detected in the other wastewater samples from the sewage system (0.030 μg/L – 0.89 g/L). These results confirm the printing ink production as one of the principal sources of TMDD in the sewage. Analysis of surface water samples of the River Modau downstream from the effluent of the WWTP Nieder-Ramstadt showed TMDD concentrations of up to 28.0 μg/L. These high TMDD concentrations might be caused by the indirect wastewater discharges of a paint factory connected to the municipal sewage system. These results indicate that TMDD is introduced into the municipal WWTPs principally by indirect industrial dischargers and they are mainly paint and printing ink factories. The paper-recycling factories also represent an important source of TMDD in municipal WWTPs but indirectly. According to statements given by the representatives of two paper recycling factories neither TMDD or any other TMDD containing product is used or added during the papermaking process. Therefore, TMDD is washed out from the printing inks of the coloured waste paper and concentrated in the process wastewater in the closed water circuits of paper-recycling factories reaching rivers and municipal WWTPs. The occurrence and distribution of TMDD in surface waters in Germany was also studied. The results showed that TMDD is widely distributed across different rivers systems in the federal states of Hesse, North-Rhine-Westphalia, Bavaria, Baden-Wuerttemberg and Rhineland-Palatinate. In Hesse, TMDD was detected in the some of main rivers with mean concentrations of 812 ng/L (Schwarzbach, Hessian Ried), 374 ng/L (Kinzig), 393 ng/L (Main, at Frankfurt), 539 ng/L (Werra), 326 ng/L (Fulda), 151 ng/L (Emsbach) and 161 ng/L (Nidda). In small rivers (creeks) the mean TMDD concentrations varied between <LOQ (Diemel, Urselbach) and 1890 ng/L (Darmbach). The results showed that the TMDD concentrations in creeks are highly influenced by both effluents of WWTPs and by the distance between the sampling point and the nearest WWTP. Surface samples from sampling locations downstream from WWTPs dischargers showed higher TMDD concentrations (mean 518 ng/L) than sampling locations upstream from WWTPs dischargers (mean 35.1 ng/L). The behavior of TMDD during bank filtration was investigated at two locations, at a water utility company at the Lower River Rhine (urban area) and at the Oderbruch polder (rural area). The results indicated that TMDD is removed from the surface water by bank filtration at both sampling locations. The removal process is probably carried out in the first meters of the aquifer (hyporheic zone) by biodegradation processes, since TMDD does not tend to be absorbed by sediments and it was not found in the groundwater of monitoring wells. In groundwater samples from the Hessian Ried (n=23) TMDD was found only in five samples and the highest TMDD concentration was 135 ng/L. According to these results, TMDD does not represent a concern for drinking water in Germany, since it does not reach the groundwater with high concentrations and it has a low toxicity potential. The input of TMDD into the North Sea was estimated to be 60.7 t/a by considering the mean transported loads of TMDD by the River Rhine at Wesel (58.3 t/a) and Meuse in the Netherlands (2.40 t/a). The estimated discharge of TMDD by German municipal WWTPs (8.19 t/a) and paper-recycling factories (9.24 t/a) into rivers seems to be too low considering that the mean TMDD load in the River Rhine downstream from Wesel is 58.3 t/a. However, due to the high density of population and industries at the Lower Rhine it is expected that more relevant sources of TMDD are located along the Rhine River increasing the transported load. According to the results of this PhD project TMDD is a non-ionic surfactant contained in products, which are applied on surfaces (printing inks and paints) and has the potential to reach the aquatic environment. Therefore, TMDD should fulfill the requirement of a biodegradability of 80% established by the “Law on the Environmental Impact of Detergents and Cleaning Products” in Germany. However, due to the partial elimination rates of TMDD obtained in municipal WWTPs (between 33% and 68%) and to the absence of information about the execution of the biodegradation test on TMDD, it is unknown if TMDD is in accordance with this law. Otherwise, its use as surfactant in such products is questionable.
Menschliche Aktivitäten beeinflussen beinahe alle Bereiche des Lebens auf der Erde (MEA 2005a; UNEP 2007). Die Zerstörung und Veränderung natürlicher Lebensräume sind als Hauptursache für den weltweiten Biodiversitätsverlust identifiziert (Harrison and Bruna 1999; Dale et al. 2000; Foley et al. 2005; MEA 2005a). Zusammen mit dem Klimawandel wird die Landnutzungsveränderung daher als einflussreichster Aspekt anthropogen verursachten globalen Wandels betrachtet (MEA 2005a). Landnutzungsveränderung schließt sowohl die Umwandlung natürlicher Habitate in Agrarland oder Siedlungen als auch die Landnutzungsintensivierung in bereits kultivierten Landschaften mit ein. Diese Veränderungen haben weitreichende Konsequenzen für die Artenvielfalt und resultieren häufig in dem Verlust von Arten mit zunehmender Intensität der Landnutzung (Scholes and Biggs 2005).
Biodiversität und Ökosysteme stellen viele verschiedene Funktionen zur Verfügung, wie z. B. die Sauerstoffproduktion, die Reinigung von Wasser und die Bestäubung von Nutzpflanzen.
Einige dieser Funktionen sind hilfreich, andere wichtig und wieder andere notwendig für das menschliche Wohlergehen (MEA 2005b; UNEP 2007). Mittlerweile sind Ökosystemfunktionen und die vielen Nutzen, die sie erbringen, zu einem zentralen Thema der interdisziplinären Forschung von Sozialwissenschaften und Naturwissenschaften geworden (Barkmann et al. 2008 und darin enthaltene Referenzen). Dadurch bedingt ist es zu einiger Verwirrung bezüglich der verwendeten Begriffe der "Ökosystemfunktion" (engl. "ecosystem function") und dem der "Ökosystemdienstleistung" (engl. "ecosystem service") gekommen (deGroot et al. 2002). Da der Fokus meiner Arbeit auf grundlegenden Funktionen von Ökosystemen liegt, verwende ich im Folgenden den Begriff der Ökosystemfunktion.
Für viele Ökosystemfunktionen ist noch sehr unzureichend bekannt, wie diese von externen Störungen beeinflusst werden (Kremen and Ostfeld 2005; Balvanera et al. 2006). Ökosystemfunktionen werden selten von nur einer einzigen Art aufrechterhalten, sondern meist von einer ganzen Reihe unterschiedlicher taxonomischer Gruppen – alle mit ihren ganz eigenen Ansprüchen. Diese Arten, wie auch deren intra- und interspezifischen Interaktionen, können durchaus nterschiedlich auf die gleiche Störungsquelle oder Störungsintensität reagieren. Dies kann Vorhersagen zum Verhalten von Ökosystemfunktionen extrem erschweren. ...
We provide a mathematical framework to model continuous time trading in limit order markets of a small investor whose transactions have no impact on order book dynamics. The investor can continuously place market and limit orders. A market order is executed immediately at the best currently available price, whereas a limit order is stored until it is executed at its limit price or canceled. The limit orders can be chosen from a continuum of limit prices.
In this framework we show how elementary strategies (hold limit orders with only finitely many different limit prices and rebalance at most finitely often) can be extended in a suitable
way to general continuous time strategies containing orders with infinitely many different limit prices. The general limit buy order strategies are predictable processes with values in the set of nonincreasing demand functions (not necessarily left- or right-continuous in the price variable). It turns out that this family of strategies is closed and any element can be approximated by a sequence of elementary strategies.
Furthermore, we study Merton’s portfolio optimization problem in a specific instance of this framework. Assuming that the risky asset evolves according to a geometric Brownian
motion, a proportional bid-ask spread, and Poisson execution times for the limit orders of the small investor, we show that the optimal strategy consists in using market orders to keep the
proportion of wealth invested in the risky asset within certain boundaries, similar to the result for proportional transaction costs, while within these boundaries limit orders are used to profit from the bid-ask spread.
Ende der 70ger Jahre, fünf Jahre nach der Einführung des ersten kommerziellen, medizinischen Computertomographen wurde die Tomographie am Los Alamos Scientific Laboratory zum ersten Mal für die Diagnose von Teilchenstrahlen angewendet. Bei der Tomographie wird aus eindimensionalen Projektionen, sogenannten Profilen, welche in möglichst vielen Winkeln um ein Objekt herum aufgenommen werden, ein zweidimensionales Abbild der Dichteverteilung (Slice oder Scheibe) approximiert. Dies ist möglich durch das bereits 1917 von Johann Radon eingeführte Fourier-Scheiben-Theorem. In der Theorie kann die zwei-dimensionale Dichteverteilung exakt ermittelt werden, wenn Projektionen mit einer unendlich feinen Auflösung über unendlich viele Winkel um ein Objekt herum in die Rekonstruktion einbezogen werden. Durch die Rekonstruktion vieler Scheiben kann ein drei-dimensionales Abbild der Dichteverteilung in einem Objekt, in diesem Fall einem Ionenstrahl, berechnet werden, sofern dieses nicht optisch dicht ist.
Die Profile in der nicht-invasiven Strahldiagnose entstehen durch CCD-Kameraaufnahmen von strahlinduzierter Fluoreszenz, welche durch den Einlass von Restgas hervorgerufen wird. Es sind aber auch Profile, welche aus anderen Methoden gewonnen werden (z.B. Gittermessungen) denkbar. An Orten mit hoher Energie ist jedoch eine nicht-invasive Form der Profilaufnahme sowohl für die Qualität des Strahls, wie auch den Schutz der Messgeräte unabdingbar.
In den letzten 40 Jahren wurden im Bereich der Strahltomographie viele wichtige Fortschritte erzielt:
1. Anfangs standen nur sehr wenige Profile zur Verfügung, so dass die Methode der gefilterten Rückprojektion(FBP), welche sich direkt aus dem Fourier-Scheiben-Theorem ableitet und welches auch in der Medizin verwendet wird, nicht angewendet werden kann. Um dieses Problem zu lösen wurden iterative Methoden wie die Algebraische Rekonstruktion (ART) und die Methode der Maximalen Entropie (MEM) für die Strahltomographie erschlossen, so dass auch mit sehr geringer Profilanzahl eine Rücktransformation möglich wurde.
2. Neben der Ortsraumtomographie wurde die Phasenraumtomografie entwickelt, so dass mittlerweile eine Rekonstruktion des sechs-dimensionalen Phasenraumes möglich ist, mit welchem ein Ionenstrahl in seiner Gesamtheit beschrieben werden kann.
3. Die Projektionen wurden lange Zeit durch Aufnahmen von mehreren festen Anschlüssen aus gewonnen (Multi-Port-Technik). Auf diese Weise ist die Anzahl der möglichen Projektionen sehr begrenzt. So entwickelte man später eine Methode welche den Strahl mit Hilfe von Quadrupolen dreht (Quad-Scan-Technik), so dass auf diese Weise von einem Anschluss aus viele Projektionen gemessen werden konnten, so dass sogar die FBP angewendet werden konnte.
4. Die meisten Bestrebungen zielten darauf ab, die Tomographie für eine nicht-invasive Emittanzmessmethode zu nutzen, welches bis heute aufgrund der großen und noch immer zunehmenden Energien in modernen Beschleunigern ein wichtiges Problem ist. Um die Tomographie zur Emittanzmessung zu verwenden, führt man eine Rekonstruktion des Phasenraumes durch. Das Problem ist, dass hierfür das a priori Wissen über die Strahltransportmatrix in die Tomographie mit einfließt, die berechnete Strahltransportmatrix
jedoch nicht mit dem tatsächlichen Strahltransport übereinstimmt, da dieser bei hohen Energien durch auftretende Raumladung nicht-linear verändert wird. Hierzu wurden gute Fortschritte in der Abschätzung der tatsächlichen Transportmatrix gemacht um die Phasenraumtomographie trotzdem mit hinreichend gutem Ergebnis durchführen zu können.
Trotz all dieser Fortschritte und Entwicklungen ist die Tomographie bis heute keine weitverbreitete Methode in der Strahldiagnose. Der Grund ist, dass das Einrichten einer Tomografie eine komplexe Abfolge etlicher Entscheidungen und weitgestreutes Wissen aus vielen unterschiedlichen Bereichen erfordert, dieser nicht zu unterschätzende Mehraufwand jedoch auch durch einen signifikanten Nutzen gerechtfertigt sein muss. Der große Nutzen der Tomographie für die Strahldiagnose und Untersuchung der Strahldynamik ist bis heute allerdings weitgehend unerkannt und weiterhin reduziert auf die Entwicklung einer nicht-invasiven Methode für die Emittanzbestimmung. Ein zweites Hindernis stellte bisher auch die Diskrepanz zwischen Genauigkeit und Platzaufwand dar (hohe Genauigkeit durch viele Projektionen mit Quad-Scan-Technik auf mehreren Metern oder niedrige Genauigkeit durch wenig Projektionen mit Multi-Port-Technik auf weniger als einem Meter). Die Tomografie kann großen Nutzen leisten für die Online-Überwachung wichtiger Maschineneparameter im Strahlbetrieb (Monitoring) als auch für detaillierte Analysen zur Strahldynamik (Modellierung) weit über die Implementierung einer nicht-invasiven Emittanzmessmethode hinaus.
Um dies zu gewährleisten Bedarf es Zweierlei. Zum einen muss die Diskrepanz zwischen Genauigkeit und Platzaufwand aufgehoben werden. Hierzu wurde im Rahmen dieser Arbeit eine rotierbare Vakuumkammer entwickelt die nach dem Vorbild medizinischer Tomographen in mehr als 5000 Winkelschritten um den Strahl herum fahren kann, dabei ein Vakuum von mindestens 10-7mbar aufrecht erhält und einen Platzbedarf von weniger als 400 mm in der Strahlstrecke einnimmt. Zum anderen muss die Implementierung der Tomografie durch eine Angabe von schematischen Schritten und Entscheidungen vereinfacht werden. Eine Strahltomographie muss immer auf ihren jeweiligen Zweck hin implementiert werden, da Einzelelemente der Tomografie wie beispielsweise Messvorrichtung und dadurch die Profilanzahl, zu verwendender Tomographiealgorithmus, zu bestimmende Parameter sich je nach Einsatz unterscheiden können. Jedoch können die dazu nötigen Entscheidungen in ein Schema eingeordnet werden, welches die Implementierung der Tomographie vereinfacht und beschleunigt. Hierzu wurde in dieser Arbeit eine Diagnosepipeline und ein Entscheidungsschema eingeführt, sowie die Implementierung nach diesem Schema am Beispiel einer Strahltomographie für die Frankfurter Neutronenquelle (FRANZ) demonstriert und die entsprechenden Fragen und Entscheidungen diskutiert. Es wird gezeigt, wie sich aus den Messdaten über die Aufbereitung der Daten durch die Tomografie die erforderlichen Standardstrahlparameter für ein Monitoring gewinnen lassen. Zusätzlich wird ein Ebenen-Modell eingeführt, über welches nicht-Standardparameter oder neu modellierte Strahlparameter für detaillierte Analysen der Strahldynamik über die Standardparameter hinaus entwickelt werden können. Diese Arbeit soll ein grundlegendes Konzept für die routinemäßige Implementierung der Tomographie in der Strahldiagnose zur Verfügung stellen. Für die Verwendung zum Monitoring im Strahlbetrieb muss die Bestimmung von Standardparametern noch wesentlich im Zeitaufwand verbessert werden. Die Verwendung der Phasenraumtomographie benötigt noch eine Idee um den arcustangensförmigen Verlauf der berechneten Phasenraumrotationswinkel mit der Forderung der FBP nach äquidistanten Projektionswinkeln verträglicher zu machen.
The calculus CHF models Concurrent Haskell extended by concurrent, implicit futures. It is a process calculus with concurrent threads, monadic concurrent evaluation, and includes a pure functional lambda-calculus which comprises data constructors, case-expressions, letrec-expressions, and Haskell’s seq. Futures can be implemented in Concurrent Haskell using the primitive unsafeInterleaveIO, which is available in most implementations of Haskell. Our main result is conservativity of CHF, that is, all equivalences of pure functional expressions are also valid in CHF. This implies that compiler optimizations and transformations from pure Haskell remain valid in Concurrent Haskell even if it is extended by futures. We also show that this is no longer valid if Concurrent Haskell is extended by the arbitrary use of unsafeInterleaveIO.
We show how Sestoft’s abstract machine for lazy evaluation of purely functional programs can be extended to evaluate expressions of the calculus CHF – a process calculus that models Concurrent Haskell extended by imperative and implicit futures. The abstract machine is modularly constructed by first adding monadic IO-actions to the machine and then in a second step we add concurrency. Our main result is that the abstract machine coincides with the original operational semantics of CHF, w.r.t. may- and should-convergence.
Lipid-laden alveolar macrophages and pH monitoring have been used in the diagnosis of chronic aspiration in children with gastroesophageal reflux (GER). This study was conducted to prove a correlation between the detection of alimentary pulmonary fat phagocytosis and an increasing amount of proximal gastroesophageal reflux. It was assumed that proximal gastroesophageal reflux better correlates with aspiration than distal GER. Patients from 6 months to 16 years with unexplained recurrent wheezy bronchitis and bronchial hyperreactivity, or recurrent pneumonia with chronic cough underwent 24-hour double-channel pH monitoring and bronchoscopy with bronchoalveolar lavage (BAL). Aspiration of gastric content was determined by counting lipid laden alveolar macrophages from BAL specimens. There were no correlations between any pH-monitoring parameters and counts of lipid-laden macrophages in the whole study population, even when restricting analysis to those with abnormal reflux index expressing clinically significant GER. Quantifying lipid-laden alveolar macrophages from BAL in children with gastroesophageal-related respiratory disorders does not have an acceptable specificity to prove chronic aspiration as an underlying etiology. Therefore, research for other markers of pulmonary aspiration is needed.
During the last years, chemopreventive activity of NSAIDs against a great variety of tumors was highly investigated. COX-2 seemingly plays a major part in tumorigensis and tumor development, underlined by several studies in animals and humans. At first, NSAIDs were thought to accomplish chemoprevention by inhibition of COX-2 as their so far known mode of action comprises unselective inhbition of COX-enzymes. However, further studies revealed COX-independent mechanisms. Sulindac is known as a well established drug used to treat inflammation and pain exerting the most prominent chemopreventive action, mainly in colorectal cancer or FAP and can be classified into the group of NSAIDs inhibting both COX-isoformes. As interference with the AA metabolism is evident, it was speculated whether Ssi has targets other than COX-enzymes providing evidence and explanation of its beneficial side effect profile and its ability to reduce tumor growth. 5-LO is another master enzyme in the AA cascade which produces inflammatory lipid mediators (LTs) upon stimulation in inflamed tissues. The present work should answer the question if Ssi targets the 5-LO pathway and should examine the molecular mechanisms behind Ssi-mediated 5-LO inhibiton. As COX-2 is upregulated during carcinogenesis and is inhibited by Ssi, further investigations should show regulatory effects of Ssi on 5-LO gene expression in MM6-cells and whether Sp1 as a common transcriptional factor is involved in such a regulation. As the use of NO-NSAIDs seem to be a promising strategy concerning their chemopreventive and gastroprotective effects compared to the parent NSAIDs, a possible interaction with the 5-LO pathway as a second, potent target should additionally be elucidated. In the first section it was demonstrated that the pharmacologically active metabolite of sulindac, Ssi, targets 5-LO. Ssi inhibited 5-LO in ionophore A23187- and LPS/fMLP-stimulated human PMNL (IC50 ≈ 8 -10 μM). Importantly, Ssi efficiently suppressed 5-LO in human whole blood at clinically relevant plasma levels (IC50 = 18.7 μM). Ssi was 5-LO-selective as no inhibition of related lipoxygenases (12-LO, 15-LO) was observed. The sulindac prodrug and the other metabolite, sulindac sulfone, failed to inhibit 5-LO. Mechanistic analysis demonstrated that Ssi directly suppresses 5-LO with an IC50 of 20 μM. Together, these findings may provide a novel molecular basis to explain the COX-independent pharmacological effects of sulindac under therapy. In the second part of the work dealing with the analysis of Ssi’s inhibitory mechanism on 5-LO it was presented that Ssi shows a lack of potency in cellular systems where membrane constituents are existent. The addition of microsomal fractions of PMNLto crude 5-LO enzyme were able to recover enzyme activity to ~ 100 %. Selectively 5-LO activity stimulating lipids like PC, participating in 5-LO membrane interactions within the regulatory C2-like domain of 5-LO, counteracted the Ssimediated inhibition on 5-LO-wt in a concentration-dependent manner. Lastly, a protein mutant lacking three trp resudies essential for linking the enzyme to nuclear membranes and deploying catalytic activity was not influenced by Ssi and shows enzyme activity in a cell-free assay. Ssi displays the first 5-LO inhibitor on the market interacting with the C2-like domain of the enzyme and therfore can stand for a novel lead structure of 5-LO inhibitors. An influence on 5-LO gene expression by Ssi could be detected in differentiated MM6-cells, described in the results chapter 3 (4.3). Ssi downregulated the 5-LO mRNA level after 72 hrs of incubation in differentiated MM6-cells to ~ 20 % of output control at concentrations of 10 μM. Concomitantly, mRNA levels of Sp1 were suppressed. Reporter gene studies revealed Sp1 most probably as a regulating agent involved in the Ssi-mediated 5-LO mRNA downregulation as co-transfection of increasing amounts of Sp1 could abrogate the effect. A ChIP assay could identify Sp1 as a critical transcriptional factor as Sp1 binding to the 5-LO promoter decreased in presence of Ssi. Lastly, three NO-NSADIs (NO-sulindac, NOnaproxen, NO-aspirin) were tested for the ability of 5-LO product inhibition. In intact PMNL, all compounds showed effective inhibition of 5-LO activity and NO-sulindac was most potent with an IC50 value of ~ 3 μM. NO-ASA inhibited 5-LO with IC50 values of ~ 30 μM and showed a non-competitive mode of action in cell-based assays. On human recombinant 5-LO all compounds again showed inhibitory potency whereas NO-sulindac again suppressed LT biosynthesis with an IC50 vaue comparable to intact cellular systems. Unfortunately, all inhibitors showed a loss of potency when tested for inhibition of 5-LO product synthesis in human whole blood as higher concentrations up to 100 μM were needed to reach at least 55 % enzyme inhibition. However, this strategy of 5-LO inhibition seems promising and needs further experimental approaches to gain more insight into the mechanism of 5-LO inhibition by NONSAIDs.
5-lipoxygenase (5-LO) catalyzes the first two steps in leukotriene (LT) biosynthesis. In a two step reaction the enzyme oxygenates arachidonic acid (AA) to form the highly unstable epoxide leukotriene A4 (LTA4) in dehydrating a hydroperoxide intermediate (20). LTA4 can then be further metabolized by two terminal synthases yielding either the potent chemoattractant leukotriene B4 (LTB4) or the cysteinyl leukotrienes (CysLTs). 5-LO enzyme expression is primarily found in mature leukocytes (22) where it can either reside in the cytoplasm or in the nucleus associated with euchromatin (29). Its enzymatic activity is embedded in a complicated network in intact cells regulating LT synthesis by various factors dependent on the cell type and nature of stimulus. Factors such as the amount of free AA released by phospholipase A2 enzymes, levels of enzymes involved, catalytic activity per enzyme molecule and availability of different small molecules influence 5-LO activity (36).
The 5-LO derived LTs are lipid mediators which were shown to primarily mediate inflammatory and allergic reactions and their role in the pathogenesis of asthma is well defined. CysLTs are among the most potent bronchoconstrictors yet studied in man and play an important role in airway remodeling. LTB4 has no bronchoconstrictory effects in healthy and asthmatic humans but displays potent chemoattractant properties on neutrophils and increases leukocyte adhesion to the vessel wall endothelium (22). Therefore, LTB4 enhances the capacity of macrophages and neutrophils to ingest and kill microbes. In concert with LTB4, histamine and prostaglandin E2 (PGE2) CysLTs are thought to maintain the tone of the human airways (82).
Besides their well studied role in asthma, 5-LO derived LTs have also been implicated to play a role in cardiovascular diseases and cancer. In contrast to healthy tissues, LT pathway enzymes and receptors were found to be abundantly expressed in cancer tissues, atherosclerotic lesions in the aorta, heart and carotid artery (86). Pharmacological inhibition of 5-LO potently suppressed tumour cell growth by inducing cell cycle arrest and triggering cell death via the intrinsic apoptotic pathway (92, 93). In several studies LTs were found to exhibit cardiovascular actions by promotion of plasma leakage in postcapillary venules, coronary artery vasoconstriction and impaired ventricular contraction leading to reduced coronary blood flow and cardiac output (24). Unfortunately, the precise molecular mechanisms through which LTs influence carcinogenesis and cardiovascular diseases are still incompletely understood.
In contrast, an increasing number of studies questions the correlation between 5-LO and cancer (95-97) since extreme LT concentrations were applied to induce proliferative effects in the majority of the publications. A few studies exist which show susceptibility towards 5-LO products in physiological concentrations or achieve anti-proliferation by applying low concentrations of 5-LO inhibitors (98) ...
The aim of this study is a better understanding of radiation processes in regional climate models (RCMs) in order to quantify their impact and to reduce possible errors. A first important task in finding an answer to this question was to examine the accuracy of the components of the radiation budget in regional climate simulations. To this end, the simulated radiation budgets of two regional climate simulations for Europe were compared with a satellite-based reference. In the simulations with the RCM COSMO-CLM there were some serious under- and overestimations of short- and long-wave net radiation in Europe. However, taking into account the differences in the reference datasets, the results of the COSMO-CLM were quite satisfactory.
Using statistical methods, the influence of potential sources of uncertainties was estimated. Uncertainties in the cloud cover and surface albedo had a significant impact on uncertainties in short-wave net radiation, the explained variance of uncertainties in cloud cover was two to three times higher than that of uncertainties in surface albedo. Uncertainties in the cloud cover resulted in significant errors in the net long-wave radiation. However, the influence of uncertainties in soil temperature on errors in the long-wave radiation budget was low or even negligible. These results were confirmed in a comparison with simulations of the REMO and ALADIN regional climate models. It is reasonable to expect that a better parameterization of relatively simple parameters such as cloud cover and surface albedo is a means of significantly improving the simulation of radiation budget components in the COSMO-CLM.
An important question for the application of RCMs is to examine whether the results of radiation uncertainties and their impact factors are comparable if the model is applied in a region that is not the one for which it was originally created. Comparisons of the simulated radiation budgets of different RCMs for West Africa showed that problems in the simulation of short- and long-wave radiation fluxes were a widespread problem. Most of the tested models showed some considerable under- or overestimation of the short- and long-wave radiation fluxes.
Similar to Europe uncertainties in cloud cover were also in the simulations for Africa a significant factor affecting uncertainties in the simulated radiation fluxes. However, for the African simulations uncertainties in the parameterization of surface albedo were much more important than in Europe. On average, overland uncertainties in the cloud cover and surface albedo were of similar importance. Uncertainties in soil temperature simulations were of higher importance in Africa, and reached overland similar values of the mean explained variance (R2 ≈ 0.2) such as uncertainties in the cloud cover. This indicates a geographical dependence of the model error. This study confirmed the assumption that an improved parameterization of relatively simple parameters such as the surface albedo in RCMs leads to a significant improvement in the modeled radiation budget, particularly in Africa.
The influence of errors in the simulated radiation budget components on the simulation of climate processes, such as the West-African monsoon (WAM), was investigated in a next step. The evaluation of ERA-Interim and ECHAM5 driven COSMO-CLM simulations for Africa showed that the main features of the WAM were well reproduced by the model, but there were only slight improvements compared to the driving data. The index of convective activity in the model simulations was much too high and precipitation was underestimated in large parts of tropical Africa. The partly considerable differences between the ERA-Interim and ECHAM5 driven simulations demonstrated the sensitivity of the RCM to the boundary conditions and in particular to the sea surface temperature. An excessive northwards shift of the monsoon in the model was influenced by the land-sea temperature gradient and the strength of the Saharan heat low. Consequently, a part of the error was due to the driving data and the model itself produced another part.
By modifying the parameterization of the bare soil albedo the errors in the radiation budget and 2 m temperature in the Sahara region were significantly reduced. Similarly, the overesti-mation of precipitation and convection has been reduced in the Sahel. The effect of this modifi-cation on the examined WAM area was low. This confirmed that especially in desert regions, errors in the surface albedo were a driving factor for errors in the radiation budget. However, there are other important factors not yet sufficiently understood that have a strong influence on the quality of the simulation of the WAM.
The analysis of the actual state, the quantification of error sources and the highlighting of connections made it possible to find means to reduce uncertainties in the simulated radiation in RCMs and to have a better understanding of radiation processes. However, the magnitude of the errors found, the number of possible influencing factors, and the complexity of interactions, indicate that there is still a need for further research in this area.
Background and Purpose: Targeted drugs have augmented the cancer treatment armamentarium. Based on the molecular specificity, it was initially believed that these drugs had significantly less side effects. However, currently it is accepted that all of these agents have their specific side effects. Based on the given multimodal approach, special emphasis has to be placed on putative interactions of conventional cytostatic drugs, targeted agents and other modalities. The interaction of targeted drugs with radiation harbours special risks, since the awareness for interactions and even synergistic toxicities is lacking. At present, only limited is data available regarding combinations of targeted drugs and radiotherapy. This review gives an overview on the current knowledge on such combined treatments.
Material and methods: Using the following MESH headings and combinations of these terms pubmed database was searched: Radiotherapy AND cetuximab / trastuzumab / panitumumab / nimotuzumab, bevacizumab, sunitinib / sorafenib / lapatinib / gefitinib / erlotinib / sirolimus, thalidomide / lenalidomide as well as erythropoietin. For citation crosscheck the ISI web of science database was used employing the same search terms.
Results: Several classes of targeted substances may be distinguished: Small molecules including kinase inhibitors and specific inhibitors, antibodies, and anti-angiogenic agents. Combination of these agents with radiotherapy may lead to specific toxicities or negatively influence the efficacy of RT. Though there is only little information on the interaction of molecular targeted radiation and radiotherapy in clinical settings, several critical incidents are reported.
Conclusions: The addition of molecular targeted drugs to conventional radiotherapy outside of approved regimens or clinical trials warrants a careful consideration especially when used in conjunction in hypo-fractionated regimens. Clinical trials are urgently needed in order to address the open question in regard to efficacy, early and late toxicity.
In situ measurements of ice crystal size distributions in tropical upper troposphere/lower stratosphere (UT/LS) clouds were performed during the SCOUT-AMMA campaign over West Africa in August 2006. The cloud properties were measured with a Forward Scattering Spectrometer Probe (FSSP-100) and a Cloud Imaging Probe (CIP) operated aboard the Russian high altitude research aircraft M-55 Geophysica with the mission base in Ouagadougou, Burkina Faso. A total of 117 ice particle size distributions were obtained from the measurements in the vicinity of Mesoscale Convective Systems (MCS). Two to four modal lognormal size distributions were fitted to the average size distributions for different potential temperature bins. The measurements showed proportionately more large ice particles compared to former measurements above maritime regions. With the help of trace gas measurements of NO, NOy, CO2, CO, and O3 and satellite images, clouds in young and aged MCS outflow were identified. These events were observed at altitudes of 11.0 km to 14.2 km corresponding to potential temperature levels of 346 K to 356 K. In a young outflow from a developing MCS ice crystal number concentrations of up to (8.3 ± 1.6) cm−3 and rimed ice particles with maximum dimensions exceeding 1.5 mm were found. A maximum ice water content of 0.05 g m−3 was observed and an effective radius of about 90 μm. In contrast the aged outflow events were more diluted and showed a maximum number concentration of 0.03 cm−3, an ice water content of 2.3 × 10−4 g m−3, an effective radius of about 18 μm, while the largest particles had a maximum dimension of 61 μm.
Close to the tropopause subvisual cirrus were encountered four times at altitudes of 15 km to 16.4 km. The mean ice particle number concentration of these encounters was 0.01 cm−3 with maximum particle sizes of 130 μm, and the mean ice water content was about 1.4 × 10−4 g m−3. All known in situ measurements of subvisual tropopause cirrus are compared and an exponential fit on the size distributions is established for modelling purposes.
A comparison of aerosol to ice crystal number concentrations, in order to obtain an estimate on how many ice particles may result from activation of the present aerosol, yielded low ratios for the subvisual cirrus cases of roughly one cloud particle per 30 000 aerosol particles, while for the MCS outflow cases this resulted in a high ratio of one cloud particle per 300 aerosol particles.
According to the World Health Organization (WHO) bacterial resistance to antibiotic drug therapy is emerging as a major public health problem around the world. Infectious diseases seriously threaten the health and economy of all countries. Hence, the preservation of the effectiveness of antibiotics is a world wide priority. The key to preserving the power of antibiotics lies in maintaining their diversity. Many microorganisms are capable of producing these bioactive products, the so called antibiotics. Specifically in microorganisms, polyketide synthases (PKS) and non-ribosomal peptide synthases (NRPS) produce these natural bioactive compounds. Besides being used as antibiotics these non-ribosomal peptides and polyketides display an even broader spectrum of biological activities, e.g. as antivirals, immunosuppressants or in antitumor therapy. The wide functional spectrum of the peptides and ketides is due to their structural diversity. Mostly they are cyclic or branched cyclic compounds, containing non-proteinogenic amino acids, small heterocyclic rings and other unusual modifications such as epimerization, methylation, N‐formylation or heterocyclization. It is has been shown that these modifications are important for biological activity, but little is known about their biosynthetic origin.
PKS and NRPS are multidomain protein assembly lines which function by sequentially elongating a growing polyketide or peptide chain by incorporating acyl units or amino acids, respectively. The growing product is attached via a thioester linkage to the 4’-phosphopantetheine (4’-Ppant) arm of a holo acyl carrier protein (ACP) in PKSs or holo peptidyl carrier protein (PCP) in NRPSs and is passed from one module to another along the chain of reaction centers. The modular arrangement makes PKS and NRPS systems an interesting target for protein engineering. More than 200 novel polyketide compounds have already been created by module swapping, gene deletion or other specific manipulations. Unfortunately, however, engineered PKS often fail to produce significant amounts of the desired products. Structural studies may faciliate yield improvement from engineered systems by providing a more complete understanding of the interface between the different domains. While some information about domain-domain interactions, involving the most common enzymatic modules, ketosynthase and acyltransferase, is starting to emerge, little is known about the interaction of ACP domains with other modifying enzymes such as methyltransferases, epimerases or halogenases.
To further improve the understanding of domain-domain interactions this work focuses on the curacin A assembly line. Curacin A, which exhibits anti-mitotic activity, is from the marine cyanobacterium Lyngbya majuscula. This outstanding natural product contains a cyclopropane ring, a thiazoline ring, an internal cis double bond and a terminal alkene. The biosynthesis of curacin A is performed by a 2.2 Mega Dalton (MDa) hybrid PKS-NRPS cluster. A 10-enzyme assembly catalyzes the formation of the cyclopropane moiety as the first building block of the final product. Interestingly, for these enzymes the substrate is presented by an unusual cluster of three consecutive ACPs (ACPI,II,III). Little is known about the function of multiple ACPs which are supposed to increase the overall flux for enhanced production of secondary metabolites.
The first task in this work was to elucidate the structural effect of the triplet ACP repetition by nuclear magnetic resonance (NMR). The initial data show that the excised ACPI, ACPII or ACPIII proteins resulted in [15N, 1H]-TROSY spectra with strong chemical shift perturbations (CSPs), suggesting an effect on the structure. The triplet ACP domains display a high sequence identity (93- 100%) making structural investigation using usual NMR techniques due to high peak overlap impossible. To enable the investigation of the triplet ACP in its native composition we developed a powerful method, the three fragment ligation. Segmental labeling allows incorporating isotopes into one single domain in its multidomain context. As a result we could prepare the triplet ACP with only one domain isotopically labeled and therefore assign the full length protein. In this way our method paved the way to study the structural effects of the triplet ACP repetition. We could show unexpectedly, that, despite the fact that the triplet repeat of CurA ACPI,II,III has a synergistic effect in the biosynthesis of CurA, the domains are structurally independent.
In the second part of this work, we studied the structure of the isolated ACPI domain. Our results show that the CurA ACPI undergoes no major conformational changes upon activation via phosphopantetheinylation and therefore contradicts the conformational switching model which has been proposed for PCPs. Further we report the NMR solution structures of holo-ACPI and 3-hydroxyl-3-methylglutaryl (HMG)-ACPI. Data obtained from filtered nuclear overhauser effect (NOE) experiments indicate that the substrate HMG is not sequestered but presented on the ACP surface.
In the third part of this work we focussed on the protein-protein interactions of the isolated ACPI with its cognate interaction partners. We were especially interested in the interaction with the halogenase (Cur Hal), the first enzyme within the curacin A sub-cluster, acting on the initial hydroxyl-methyl-glutaryl (HMG) attached to ACPI. Primarily we studied the interaction using NMR titration and fluorescence anisotropy measurements. Surprisingly no complex between ACPI and Cur Hal could be detected. The combination of an activity assay using matrix-assisted laser desorption/ionization (MALDI) mass spectroscopy and mutational analysis revealed several amino acids of ACPI that strongly decrease the activity of CurA Hal. Mapping these mutations according to their effect on the Cur Hal activity onto the structure of HMG-ACPI displays that these amino acids surround the substrate and form a consecutive surface. These results suggest that this surface is important for Cur Hal recognition and selectivity. Our research presented herein is an excellent example for protein-protein interactions in PKS systems underlying a specific recognition process.
Proceedings of 4th International Workshop "Critical Point and Onset of Deconfinement", July 9-13, 2007, Darmstadt, Germany: The multiplicity fluctuations of hadrons are studied within the statistical hadron-resonance gas model in the large volume limit. The role of quantum statistics and resonance decay effects are discussed. The microscopic correlator method is used to enforce conservation of three charges - baryon number, electric charge, and strangeness - in the canonical ensemble. In addition, in the micro-canonical ensemble energy conservation is included. An analytical method is used to account for resonance decays. The multiplicity distributions and the scaled variances for negatively and positively charged hadrons are calculated for the sets of thermodynamical parameters along the chemical freeze-out line of central Pb+Pb (Au+Au) collisions from SIS to LHC energies. Predictions obtained within different statistical ensembles are compared with the preliminary NA49 experimental results on central Pb+Pb collisions in the SPS energy range. The measured fluctuations are significantly narrower than the Poisson ones and clearly favor expectations for the micro-canonical ensemble. Thus, this is a first observation of the recently predicted suppression of the multiplicity fluctuations in relativistic gases in the thermodynamical limit due to conservation laws.
Bioapatite in mammalian teeth is readily preserved in continental sediments and represents a very important archive for reconstructions of environment and climate evolution. This project provides a comprehensive data base of major, minor and trace element and isotope tracers for tooth apatite using a variety of microanalytical techniques. The aim is to identify specific sedimentary environments and to improve our understanding on the interaction between internal metabolic processes during tooth formation and external nutritional control and secondary alteration effects. Here, we use the electron microprobe to determine the major and minor element contents of fossil and modern molar enamel, cement and dentin from Hippopotamids. Most of the studied specimens are from different ecosystems in Eastern Africa, representing modern and fossil lacustrine (Lake Kikorongo, Lake Albert, and Lake Malawi) and modern fluvial environments of the Nile River system. Secondary alteration effects - in particular FeO, MnO, SO3 and F concentrations – are 2 to 10 times higher in fossil than in modern enamel; the secondary enrichment of these components in fossil dentin and cement is even higher. In modern and fossil enamel, along sections perpendicular to the enamel-dentin junction (EDJ) or along cervix-apex profiles, P2O5 and CaO contents and the CaO/P2O5 ratios are very constant (StdDev ∼1%). Linear regression analysis reveals tight control of the MgO (R2∼0.6), Na2O and Cl variation (for both R2>0.84) along EDJ-outer enamel rim profiles, despite large concentration variations (40% to 300%) across the enamel. These minor elements show well defined distribution patterns in enamel, similar in all specimens regardless of their age and origin, as the concentration of MgO and Na2O decrease from the enamel-dentin junction (EDJ) towards the outer rim, whereas Cl displays the opposite trend. Fossil enamel from Hippopotamids which lived in the saline Lake Kikorongo have a much higher MgO/Na2O ratio (∼1.11) than those from the Neogene fossils of Lake Albert (MgO/Na2O∼0.4), which was a large fresh water lake like those in the western Branch of the East African Rift System today. Similarly, the MgO/Na2O ratio in modern enamel from the White Nile River (∼0.36), which has a Precambrian catchment of dominantly granites and gneisses and passes through several saline zones, is higher than that from the Blue Nile River, whose catchment is the Neogene volcanic Ethiopian Highland (MgO/Na2O∼0.22). Thus, particularly MgO/Na2O might be a sensitive fingerprint for environments where river and lake water have suffered strong evaporation. Enamel formation in mammals takes place at successive mineralization fronts within a confined chamber where ion and molecule transport is controlled by the surrounding enamel organ. During the secretion and maturation phases the epithelium generates different fluid composition, which in principle, should determine the final composition of enamel apatite. This is supported by co-linear relationships between MgO, Cl and Na2O which can be interpreted as binary mixing lines. However, if maturation starts after secretion is completed, the observed element distribution can only be explained by equilibration of existing and addition of new apatite during maturation. It appears the initial enamel crystallites precipitating during secretion and the newly formed bioapatite crystals during maturation equilibrate with a continuously evolving fluid. During crystallization of bioapatite the enamel fluid becomes continuously depleted in MgO and Na2O, but enriched in Cl which results in the formation of MgO, and Na2O-rich, but Cl-poor bioapatite near the EDJ and MgO- and Na2O-poor, but Cl-rich bioapatite at the outer enamel rim. The linkage between lake and river water compositions, bioavailability of elements for plants, animal nutrition and tooth formation is complex and multifaceted. The quality and limits of the MgO/Na2O and other proxies have to be established with systematic investigations relating chemical distribution patterns to sedimentary environment and to growth structures developing as secretion and maturation proceed during tooth formation.
Globally, tropical forest soils represent the second largest source of N2O and NO. However, there is still considerable uncertainty on the spatial variability and soil properties controlling N trace gas emission. To investigate how soil properties affect N2O and NO emission, we carried out an incubation experiment with soils from 31 locations in the Nyungwe tropical mountain forest in southwestern Rwanda. All soils were incubated at three different moisture levels (50, 70 and 90% water filled pore space (WFPS)) at 17 °C. Nitrous oxide emission varied between 4.5 and 400 μg N m−2 h−1, while NO emission varied from 6.6 to 265 μg N m−2 h−1. Mean N2O emission at different moisture levels was 46.5 ± 11.1 (50% WFPS), 71.7 ± 11.5 (70% WFPS) and 98.8 ± 16.4 (90% WFPS) μg N m−2 h−1, while mean NO emission was 69.3 ± 9.3 (50% WFPS), 47.1 ± 5.8 (70% WFPS) and 36.1 ± 4.2 (90% WFPS) μg N m−2 h−1. The latter suggests that climate (i.e. dry vs. wet season) controls N2O and NO emissions. Positive correlations with soil carbon and nitrogen indicate a biological control over N2O and NO production. But interestingly N2O and NO emissions also showed a negative correlation (only N2O) with soil pH and a positive correlation with free iron. The latter suggest that chemo-denitrification might, at least for N2O, be an important production pathway. In conclusion improved understanding and process based modeling of N trace gas emission from tropical forests will not only benefit from better spatial explicit trace gas emission and basic soil property monitoring, but also by differentiating between biological and chemical pathways for N trace gas formation.
Background: Due to constantly rising air pollution levels as well as an increasing awareness of the hazardousness of air pollutants, new laws and rules have recently been passed. Although there has been a large amount of research on this topic, bibliometric data is still to be collected. Thus this study provides a scientometric approach to the material published on this subject so far.
Methods: For this purpose, data retrieved from the "Web of Science" provided by the Thomson Scientific Institute was analyzed and visualized both with density-equalizing methods and classic data-processing methods such as tables and charts.
Results: For the time span between 1955 and 2006, 26,253 items were listed and related to the topic of air pollution, published by 124 countries in 24 different languages. General citation activity has been constantly increasing since the beginning of the examined period. However, beginning with the year 1991, citation levels have been rising exponentially each year, reaching 39,220 citations in the year 2006. The United States, the UK and Germany were the three most productive countries in the area, with English and German ranked first and second in publishing languages, followed by French. An article published by Dockery, Pope, Xu et al. was both the most cited in total numbers and in average citation rate. J. Schwartz was able to claim the highest total number of citations on his publications, while D.W. Dockery has the highest citation rate per publication. As to the subject areas the items are assigned with, the most item were published in Environmental Sciences, followed by Meteorology & Atmospheric Sciences and Public, Environmental & Occupational Health. Nine out of the ten publishing journals with more than 300 entries dealt with environmental interests and one dealt with epidemiology.
Conclusions: Using the method of density-equalizing mapping and further common data processing procedures, it can be concluded that scientific work concerning air pollution and related topics enjoys unbrokenly growing scientific interest. This can be observed both in publication numbers and in citation activity.
Background: Leishmaniasis is a chronic disease that is found in various countries of the world. The aim of the current study was to investigate the impact of leishmaniasis on the world's research output. The present study assessed benchmarking of research output for the period between 1957 and 2006. Using large database analyses, research in the field of leishmaniasis was evaluated. Furthermore, cooperation between different countries was identified.
Results: The number of publications increased with time. Most publications came from Western countries such as the US, UK or Germany. Interestingly, countries like Brazil and India had a high research output. We found a substantial amount of cooperation between countries.
Conclusion: Although leishmaniasis is of limited geographic distribution it attracts a wide research interest. The central hub of research cooperation is the USA.
Environmental tobacco smoke (ETS) is a major contributor to indoor air pollution. Since decades it is well documented that ETS can be harmful to human health and cause premature death and disease. In comparison to the huge research on toxicological substances of ETS, less attention was paid on the concentration of indoor ETS-dependent particulate matter (PM). Especially, investigation that focuses on different tobacco products and their concentration of deeply into the airways depositing PM-fractions (PM10, PM2.5 and PM1) must be stated. The tobacco smoke particles and indoor air quality study (ToPIQS) will approach this issue by device supported generation of indoor ETS and simultaneously measurements of PM concentration by laser aerosol spectrometry. Primarily, the ToPIQ study will conduct a field research with focus on PM concentration of different tobacco products and within various microenvironments. It is planned to extend the analysis to basic research on influencing factors of ETS-dependent PM concentration.
Calibration of TCCON column-averaged CO₂: the first aircraft campaign over European TCCON sites
(2011)
The Total Carbon Column Observing Network (TCCON) is a ground-based network of Fourier Transform Spectrometer (FTS) sites around the globe, where the column abundances of CO2, CH4, N2O, CO and O2 are measured. CO2 is constrained with a precision better than 0.25% (1-σ). To achieve a similarly high accuracy, calibration to World Meteorological Organization (WMO) standards is required. This paper introduces the first aircraft calibration campaign of five European TCCON sites and a mobile FTS instrument. A series of WMO standards in-situ profiles were obtained over European TCCON sites via aircraft and compared with retrievals of CO2 column amounts from the TCCON instruments. The results of the campaign show that the FTS measurements are consistently biased 1.1% ± 0.2% low with respect to WMO standards, in agreement with previous TCCON calibration campaigns. The standard a priori profile for the TCCON FTS retrievals is shown to not add a bias. The same calibration factor is generated using aircraft profiles as a priori and with the TCCON standard a priori. With a calibration to WMO standards, the highly precise TCCON CO2 measurements of total column concentrations provide a suitable database for the calibration and validation of nadir-viewing satellites
Background: Current prognostic gene signatures for breast cancer mainly reflect proliferation status and have limited value in triple-negative (TNBC) cancers. The identification of prognostic signatures from TNBC cohorts was limited in the past due to small sample sizes.
Methodology/Principal Findings: We assembled all currently publically available TNBC gene expression datasets generated on Affymetrix gene chips. Inter-laboratory variation was minimized by filtering methods for both samples and genes. Supervised analysis was performed to identify prognostic signatures from 394 cases which were subsequently tested on an independent validation cohort (n = 261 cases).
Conclusions/Significance: Using two distinct false discovery rate thresholds, 25% and <3.5%, a larger (n = 264 probesets) and a smaller (n = 26 probesets) prognostic gene sets were identified and used as prognostic predictors. Most of these genes were positively associated with poor prognosis and correlated to metagenes for inflammation and angiogenesis. No correlation to other previously published prognostic signatures (recurrence score, genomic grade index, 70-gene signature, wound response signature, 7-gene immune response module, stroma derived prognostic predictor, and a medullary like signature) was observed. In multivariate analyses in the validation cohort the two signatures showed hazard ratios of 4.03 (95% confidence interval [CI] 1.71–9.48; P = 0.001) and 4.08 (95% CI 1.79–9.28; P = 0.001), respectively. The 10-year event-free survival was 70% for the good risk and 20% for the high risk group. The 26-gene signatures had modest predictive value (AUC = 0.588) to predict response to neoadjuvant chemotherapy, however, the combination of a B-cell metagene with the prognostic signatures increased its response predictive value. We identified a 264-gene prognostic signature for TNBC which is unrelated to previously known prognostic signatures.
Fibroblast growth factor receptor substrate 2 (FRS2α) is a signaling adaptor protein that regulates downstream signaling of many receptor tyrosine kinases. During signal transduction, FRS2 can be both tyrosine and threonine phosphorylated and forms signaling complexes with other adaptor proteins and tyrosine phosphatases. We have here identified flotillin-1 and the cbl-associated protein/ponsin (CAP) as novel interaction partners of FRS2. Flotillin-1 binds to the phosphotyrosine binding domain (PTB) of FRS2 and competes for the binding with the fibroblast growth factor receptor. Flotillin-1 knockdown results in increased Tyr phosphorylation of FRS2, in line with the inhibition of ERK activity in the absence of flotillin-1. CAP directly interacts with FRS2 by means of its sorbin homology (SoHo) domain, which has previously been shown to interact with flotillin-1. In addition, the third SH3 domain in CAP binds to FRS2. Due to the overlapping binding domains, CAP and flotillin-1 appear to compete for the binding to FRS2. Thus, our results reveal a novel signaling network containing FRS2, CAP and flotillin-1, whose successive interactions are most likely required to regulate receptor tyrosine kinase signaling, especially the mitogen activated protein kinase pathway.
The development of insecticides requires valid risk assessment procedures to avoid causing harm to beneficial insects and especially to pollinators such as the honeybee Apis mellifera. In addition to testing according to current guidelines designed to detect bee mortality, tests are needed to determine possible sublethal effects interfering with the animal's vitality and behavioral performance. Several methods have been used to detect sublethal effects of different insecticides under laboratory conditions using olfactory conditioning. Furthermore, studies have been conducted on the influence insecticides have on foraging activity and homing ability which require time-consuming visual observation. We tested an experimental design using the radiofrequency identification (RFID) method to monitor the influence of sublethal doses of insecticides on individual honeybee foragers on an automated basis. With electronic readers positioned at the hive entrance and at an artificial food source, we obtained quantifiable data on honeybee foraging behavior. This enabled us to efficiently retrieve detailed information on flight parameters. We compared several groups of bees, fed simultaneously with different dosages of a tested substance. With this experimental approach we monitored the acute effects of sublethal doses of the neonicotinoids imidacloprid (0.15–6 ng/bee) and clothianidin (0.05–2 ng/bee) under field-like circumstances. At field-relevant doses for nectar and pollen no adverse effects were observed for either substance. Both substances led to a significant reduction of foraging activity and to longer foraging flights at doses of ≥0.5 ng/bee (clothianidin) and ≥1.5 ng/bee (imidacloprid) during the first three hours after treatment. This study demonstrates that the RFID-method is an effective way to record short-term alterations in foraging activity after insecticides have been administered once, orally, to individual bees. We contribute further information on the understanding of how honeybees are affected by sublethal doses of insecticides.
Calibration of TCCON column-averaged CO₂: the first aircraft campaign over European TCCON sites
(2011)
The Total Carbon Column Observing Network (TCCON) is a ground-based network of Fourier Transform Spectrometer (FTS) sites around the globe, where the column abundances of CO2, CH4, N2O, CO and O2 are measured. CO2 is constrained with a precision better than 0.25 %. To achieve a similarly high accuracy, calibration to World Meteorological Organization (WMO) standards is required. This paper introduces the first aircraft calibration campaign of five European TCCON sites and a mobile FTS instrument. A series of WMO standards in-situ profiles were obtained over European TCCON sites via aircraft and compared with retrievals of CO2 column amounts from the TCCON instruments. The results of the campaign show that the FTS measurements are consistently biased 1.0 % ± 0.2 % low with respect to WMO standards, in agreement with previous TCCON calibration campaigns. The standard a priori profile for the TCCON FTS retrievals is shown to not add a bias. The same calibration factor is generated using aircraft profiles as a priori and with the TCCON standard a priori. With a calibration to WMO standards, the highly precise TCCON CO2 measurements of total column concentrations provide a suitable database for the calibration and validation of nadir-viewing satellites.
Die vorliegende Arbeit beschäftigt sich mit der zeitstetigen Portfoliooptimierung sowie mit Themen aus dem Bereich des Kreditrisikos. Das Ziel der Portfoliooptimierung ist es, zu einem gegebenen Anfangskapital die bestmöglichen Konsum- und Investmentstrategien zu finden. In dieser Arbeit wird dabei vor allem der Einfluss von Einkommen auf diese Entscheidungen untersucht. Da einerseits jedoch der zukünftige Einkommensstrom vom Zufall bestimmt ist und es andererseits keine Finanzprodukte gibt, die diesen replizieren können, stellt die Einbindung von Einkommen in die Portfoliooptimierung ein großes Problem dar. Es führt dazu, dass die Annahmen eines vollständigen Marktes nicht weiter gelten, so dass die Standardmethoden zur Lösung nicht angewendet werden können. Diese Arbeit analysiert mehrere Ausprägungen dieses Problems und geht auf verschiedene Verfahren zur Lösung ein. Weiterhin untersucht diese Studie den Einfluss des Kreditrisikos einer Firma auf die jeweilige Firmenrendite. Dabei wird vor allem auf eine Anomalie, die bereits umfassend in der Literatur diskutiert wurde, Bezug genommen. Diese Anomalie besagt, dass Firmen mit hohen Ausfallwahrscheinlichkeiten geringere Renditen erwirtschaften als Firmen mit kleineren Ausfallwahrscheinlichkeiten. Eine weitere Frage, die in den Bereich des Kreditrisikos fällt, ist die Frage, inwieweit Modelle dazu in der Lage sind, strukturierte Produkte zu bewerten und abzusichern. Diese Arbeit versucht Antworten darauf zu geben.
The objective of this work is twofold. First, we explore the performance of the density functional theory (DFT) when it is applied to solids with strong electronic correlations, such as transition metal compounds. Along this direction, particular effort is put into the refinement and development of parameterization techniques for deriving effective models on a basis of DFT calculations. Second, within the framework of the DFT, we address a number of questions related to the physics of Mott insulators, such as magnetic frustration and electron-phonon coupling (Cs2CuCl4 and Cs2CuBr4), high-temperature superconductivity (BSCCO) and doping of Mott insulators (TiOCl). In the frustrated antiferromagnets Cs2CuCl4 and Cs2CuBr4, we investigate the interplay between strong electronic correlations and magnetism on one hand and electron-lattice coupling on the other as well as the effect of this interplay on the microscopic model parameters. Another object of our investigations is the oxygen-doped cuprate superconductor BSCCO, where nano-scale electronic inhomogeneities have been observed in scanning tunneling spectroscopy experiments. By means of DFT and many-body calculations, we analyze the connection between the structural and electronic inhomogeneities and the superconducting properties of BSCCO. We use the DFT and molecular dynamic simulations to explain the microscopic origin of the persisting under doping Mott insulating state in the layered compound TiOCl.
Regulation of dissimilatory sulfur oxidation in the purple sulfur bacterium Allochromatium vinosum
(2011)
In the purple sulfur bacterium Allochromatium vinosum, thiosulfate oxidation is strictly dependent on the presence of three periplasmic Sox proteins encoded by the soxBXAK and soxYZ genes. It is also well documented that proteins encoded in the dissimilatory sulfite reductase (dsr) operon, dsrABEFHCMKLJOPNRS, are essential for the oxidation of sulfur that is stored intracellularly as an obligatory intermediate during the oxidation of thiosulfate and sulfide. Until recently, detailed knowledge about the regulation of the sox genes was not available. We started to fill this gap and show that these genes are expressed on a low constitutive level in A. vinosum in the absence of reduced sulfur compounds. Thiosulfate and possibly sulfide lead to an induction of sox gene transcription. Additional translational regulation was not apparent. Regulation of soxXAK is probably performed by a two-component system consisting of a multi-sensor histidine kinase and a regulator with proposed di-guanylate cyclase activity. Previous work already provided some information about regulation of the dsr genes encoding the second important sulfur-oxidizing enzyme system in the purple sulfur bacterium. The expression of most dsr genes was found to be at a low basal level in the absence of reduced sulfur compounds and enhanced in the presence of sulfide. In the present work, we focused on the role of DsrS, a protein encoded by the last gene of the dsr locus in A. vinosum. Transcriptional and translational gene fusion experiments suggest a participation of DsrS in the post-transcriptional control of the dsr operon. Characterization of an A. vinosum ΔdsrS mutant showed that the monomeric cytoplasmic 41.1-kDa protein DsrS is important though not essential for the oxidation of sulfur stored in the intracellular sulfur globules.
Forest fragmentation and selective logging are two main drivers of global environmental change and modify biodiversity and environmental conditions in many tropical forests. The consequences of these changes for the functioning of tropical forest ecosystems have rarely been explored in a comprehensive approach. In a Kenyan rainforest, we studied six animal-mediated ecosystem processes and recorded species richness and community composition of all animal taxa involved in these processes. We used linear models and a formal meta-analysis to test whether forest fragmentation and selective logging affected ecosystem processes and biodiversity and used structural equation models to disentangle direct from biodiversity-related indirect effects of human disturbance on multiple ecosystem processes. Fragmentation increased decomposition and reduced antbird predation, while selective logging consistently increased pollination, seed dispersal and army-ant raiding. Fragmentation modified species richness or community composition of five taxa, whereas selective logging did not affect any component of biodiversity. Changes in the abundance of functionally important species were related to lower predation by antbirds and higher decomposition rates in small forest fragments. The positive effects of selective logging on bee pollination, bird seed dispersal and army-ant raiding were direct, i.e. not related to changes in biodiversity, and were probably due to behavioural changes of these highly mobile animal taxa. We conclude that animal-mediated ecosystem processes respond in distinct ways to different types of human disturbance in Kakamega Forest. Our findings suggest that forest fragmentation affects ecosystem processes indirectly by changes in biodiversity, whereas selective logging influences processes directly by modifying local environmental conditions and resource distributions. The positive to neutral effects of selective logging on ecosystem processes show that the functionality of tropical forests can be maintained in moderately disturbed forest fragments. Conservation concepts for tropical forests should thus include not only remaining pristine forests but also functionally viable forest remnants.
Members of the genus Xenorhabdus are entomopathogenic bacteria that associate with nematodes. The nematode-bacteria pair infects and kills insects, with both partners contributing to insect pathogenesis and the bacteria providing nutrition to the nematode from available insect-derived nutrients. The nematode provides the bacteria with protection from predators, access to nutrients, and a mechanism of dispersal. Members of the bacterial genus Photorhabdus also associate with nematodes to kill insects, and both genera of bacteria provide similar services to their different nematode hosts through unique physiological and metabolic mechanisms. We posited that these differences would be reflected in their respective genomes. To test this, we sequenced to completion the genomes of Xenorhabdus nematophila ATCC 19061 and Xenorhabdus bovienii SS-2004. As expected, both Xenorhabdus genomes encode many anti-insecticidal compounds, commensurate with their entomopathogenic lifestyle. Despite the similarities in lifestyle between Xenorhabdus and Photorhabdus bacteria, a comparative analysis of the Xenorhabdus, Photorhabdus luminescens, and P. asymbiotica genomes suggests genomic divergence. These findings indicate that evolutionary changes shaped by symbiotic interactions can follow different routes to achieve similar end points.
Chickpea (Cicer arietinum L.) is the third most important cool season food legume, cultivated in arid and semi-arid regions of the world. The goal of this study was to develop novel molecular markers such as microsatellite or simple sequence repeat (SSR) markers from bacterial artificial chromosome (BAC)-end sequences (BESs) and diversity arrays technology (DArT) markers, and to construct a high-density genetic map based on recombinant inbred line (RIL) population ICC 4958 (C. arietinum)×PI 489777 (C. reticulatum). A BAC-library comprising 55,680 clones was constructed and 46,270 BESs were generated. Mining of these BESs provided 6,845 SSRs, and primer pairs were designed for 1,344 SSRs. In parallel, DArT arrays with ca. 15,000 clones were developed, and 5,397 clones were found polymorphic among 94 genotypes tested. Screening of newly developed BES-SSR markers and DArT arrays on the parental genotypes of the RIL mapping population showed polymorphism with 253 BES-SSR markers and 675 DArT markers. Segregation data obtained for these polymorphic markers and 494 markers data compiled from published reports or collaborators were used for constructing the genetic map. As a result, a comprehensive genetic map comprising 1,291 markers on eight linkage groups (LGs) spanning a total of 845.56 cM distance was developed (http://cmap.icrisat.ac.in/cmap/sm/cp/thudi/). The number of markers per linkage group ranged from 68 (LG 8) to 218 (LG 3) with an average inter-marker distance of 0.65 cM. While the developed resource of molecular markers will be useful for genetic diversity, genetic mapping and molecular breeding applications, the comprehensive genetic map with integrated BES-SSR markers will facilitate its anchoring to the physical map (under construction) to accelerate map-based cloning of genes in chickpea and comparative genome evolution studies in legumes.
In an ongoing clinical phase I/II study, 16 pediatric patients suffering from high risk leukemia/tumors received highly purified donor natural killer (NK) cell immunotherapy (NK-DLI) at day (+3) +40 and +100 post haploidentical stem cell transplantation. However, literature about the influence of NK-DLI on recipient's immune system is scarce. Here we present concomitant results of a noninvasive in vivo monitoring approach of recipient's peripheral blood (PB) cells after transfer of either unstimulated (NK-DLI(unstim)) or IL-2 (1000 U/ml, 9–14 days) activated NK cells (NK-DLI(IL-2 stim)) along with their ex vivo secreted cytokine/chemokines. We performed phenotypical and functional characterizations of the NK-DLIs, detailed flow cytometric analyses of various PB cells and comprehensive cytokine/chemokine arrays before and after NK-DLI. Patients of both groups were comparable with regard to remission status, immune reconstitution, donor chimerism, KIR mismatching, stem cell and NK-DLI dose. Only after NK-DLI(IL-2 stim) was a rapid, almost complete loss of CD56(bright)CD16(dim/−) immune regulatory and CD56(dim)CD16(+) cytotoxic NK cells, monocytes, dendritic cells and eosinophils from PB circulation seen 10 min after infusion, while neutrophils significantly increased. The reduction of NK cells was due to both, a decrease in patients' own CD69(−) NCR(low)CD62L(+) NK cells as well as to a diminishing of the transferred cells from the NK-DLI(IL-2 stim) with the CD56(bright)CD16(+/−)CD69(+)NCR(high)CD62L(−) phenotype. All cell counts recovered within the next 24 h. Transfer of NK-DLI(IL-2 stim) translated into significantly increased levels of various cytokines/chemokines (i.e. IFN-γ, IL-6, MIP-1β) in patients' PB. Those remained stable for at least 1 h, presumably leading to endothelial activation, leukocyte adhesion and/or extravasation. In contrast, NK-DLI(unstim) did not cause any of the observed effects. In conclusion, we assume that the adoptive transfer of NK-DLI(IL-2 stim) under the influence of ex vivo and in vivo secreted cytokines/chemokines may promote NK cell trafficking and therefore might enhance efficacy of immunotherapy.
Temporal information processing in short- and long-term memory of patients with schizophrenia
(2011)
Cognitive deficits of patients with schizophrenia have been largely recognized as core symptoms of the disorder. One neglected factor that contributes to these deficits is the comprehension of time. In the present study, we assessed temporal information processing and manipulation from short- and long-term memory in 34 patients with chronic schizophrenia and 34 matched healthy controls. On the short-term memory temporal-order reconstruction task, an incidental or intentional learning strategy was deployed. Patients showed worse overall performance than healthy controls. The intentional learning strategy led to dissociable performance improvement in both groups. Whereas healthy controls improved on a performance measure (serial organization), patients improved on an error measure (inappropriate semantic clustering) when using the intentional instead of the incidental learning strategy. On the long-term memory script-generation task, routine and non-routine events of everyday activities (e.g., buying groceries) had to be generated in either chronological or inverted temporal order. Patients were slower than controls at generating events in the chronological routine condition only. They also committed more sequencing and boundary errors in the inverted conditions. The number of irrelevant events was higher in patients in the chronological, non-routine condition. These results suggest that patients with schizophrenia imprecisely access temporal information from short- and long-term memory. In short-term memory, processing of temporal information led to a reduction in errors rather than, as was the case in healthy controls, to an improvement in temporal-order recall. When accessing temporal information from long-term memory, patients were slower and committed more sequencing, boundary, and intrusion errors. Together, these results suggest that time information can be accessed and processed only imprecisely by patients who provide evidence for impaired time comprehension. This could contribute to symptomatic cognitive deficits and strategic inefficiency in schizophrenia.
Background: Oral anticoagulant therapy (OAT) with warfarin is the standard of stroke prevention in patients with atrial fibrillation. Approximately 30% of patients with cardioembolic strokes are on OAT at the time of symptom onset. We investigated whether warfarin exacerbates the risk of thrombolysis-associated hemorrhagic transformation (HT) in a mouse model of ischemic stroke.
Methods: 62 C57BL/6 mice were used for this study. To achieve effective anticoagulation, warfarin was administered orally. We performed right middle cerebral artery occlusion (MCAO) for 3 h and assessed functional deficit and HT blood volume after 24 h.
Results: In non-anticoagulated mice, treatment with rt-PA (10 mg/kg i.v.) after 3 h MCAO led to a 5-fold higher degree of HT compared to vehicle-treated controls (4.0±0.5 µl vs. 0.8±0.1, p<0.001). Mice on warfarin revealed larger amounts of HT after rt-PA treatment in comparison to non-anticoagulated mice (9.2±3.2 µl vs. 2.8±1.0, p<0.05). The rapid reversal of anticoagulation by means of prothrombin complex concentrates (PCC, 100 IU/kg) at the end of the 3 h MCAO period, but prior to rt-PA administration, neutralized the exacerbated risk of HT as compared to sham-treated controls (3.8±0.7 µl vs. 15.0±3.8, p<0.001).
Conclusion: In view of the vastly increased risk of HT, it seems to be justified to withhold tPA therapy in effectively anticoagulated patients with acute ischemic stroke. The rapid reversal of anticoagulation with PCC prior to tPA application reduces the risk attributed to warfarin pretreatment and may constitute an interesting therapeutic option.
Recent work has demonstrated that the formation of platelet neutrophil complexes (PNCs) affects inflammatory tissue injury. Vasodilator-stimulated phosphoprotein (VASP) is crucially involved into the control of PNC formation and myocardial reperfusion injury. Given the clinical importance of hepatic IR injury we pursued the role of VASP during hepatic ischemia followed by reperfusion. We report here that VASP−/− animals demonstrate reduced hepatic IR injury compared to wildtype (WT) controls. This correlated with serum levels of lactate dehydrogenase (LDH), aspartate (AST) and alanine (ALT) aminotransferase and the presence of PNCs within ischemic hepatic tissue and could be confirmed using repression of VASP through siRNA. In studies employing bone marrow chimeric mice we identified hematopoietic VASP to be of crucial importance for the extent of hepatic injury. Phosphorylation of VASP on Ser153 through Prostaglandin E1 or on Ser235 through atrial natriuretic peptide resulted in a significant reduction of hepatic IR injury. This was associated with a reduced presence of PNCs in ischemic hepatic tissue. Taken together, these studies identified VASP and VASP phosphorylation as crucial target for future hepatoprotective strategies.
Accumulating evidence indicates that increased generation of reactive oxygen species (ROS) contributes to the development of exaggerated pain hypersensitivity during persistent pain. In the present study, we investigated the antinociceptive efficacy of the antioxidants vitamin C and vitamin E in mouse models of inflammatory and neuropathic pain. We show that systemic administration of a combination of vitamins C and E inhibited the early behavioral responses to formalin injection and the neuropathic pain behavior after peripheral nerve injury, but not the inflammatory pain behavior induced by Complete Freund's Adjuvant. In contrast, vitamin C or vitamin E given alone failed to affect the nociceptive behavior in all tested models. The attenuated neuropathic pain behavior induced by the vitamin C and E combination was paralleled by a reduced p38 phosphorylation in the spinal cord and in dorsal root ganglia, and was also observed after intrathecal injection of the vitamins. Moreover, the vitamin C and E combination ameliorated the allodynia induced by an intrathecally delivered ROS donor. Our results suggest that administration of vitamins C and E in combination may exert synergistic antinociceptive effects, and further indicate that ROS essentially contribute to nociceptive processing in special pain states.