Universitätspublikationen
Refine
Year of publication
Document Type
- Article (10976)
- Preprint (1704)
- Doctoral Thesis (1575)
- Working Paper (1440)
- Part of Periodical (569)
- Conference Proceeding (513)
- Report (299)
- Part of a Book (107)
- Review (92)
- Book (60)
Language
- English (17428) (remove)
Has Fulltext
- yes (17428) (remove)
Keywords
- inflammation (95)
- COVID-19 (91)
- SARS-CoV-2 (63)
- Financial Institutions (48)
- climate change (46)
- Germany (45)
- ECB (43)
- aging (43)
- apoptosis (42)
- cancer (42)
Institute
- Medizin (5153)
- Physik (3114)
- Frankfurt Institute for Advanced Studies (FIAS) (1663)
- Wirtschaftswissenschaften (1650)
- Biowissenschaften (1412)
- Informatik (1262)
- Center for Financial Studies (CFS) (1138)
- Sustainable Architecture for Finance in Europe (SAFE) (1066)
- Biochemie und Chemie (858)
- House of Finance (HoF) (702)
Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. While many rare variants in synaptic proteins have been identified in patients with ASD, little is known about their effects at the synapse and their interactions with other genetic variations. Here, following the discovery of two de novo SHANK2 deletions by the Autism Genome Project, we identified a novel 421 kb de novo SHANK2 deletion in a patient with autism. We then sequenced SHANK2 in 455 patients with ASD and 431 controls and integrated these results with those reported by Berkel et al. 2010 (n = 396 patients and n = 659 controls). We observed a significant enrichment of variants affecting conserved amino acids in 29 of 851 (3.4%) patients and in 16 of 1,090 (1.5%) controls (P = 0.004, OR = 2.37, 95% CI = 1.23-4.70). In neuronal cell cultures, the variants identified in patients were associated with a reduced synaptic density at dendrites compared to the variants only detected in controls (P = 0.0013). Interestingly, the three patients with de novo SHANK2 deletions also carried inherited CNVs at 15q11-q13 previously associated with neuropsychiatric disorders. In two cases, the nicotinic receptor CHRNA7 was duplicated and in one case the synaptic translation repressor CYFIP1 was deleted. These results strengthen the role of synaptic gene dysfunction in ASD but also highlight the presence of putative modifier genes, which is in keeping with the "multiple hit model" for ASD. A better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of ASD.
Introduction: Febrile neutropenia is a common and potentially life-threatening complication of treatment for childhood cancer, which has increasingly been subject to targeted treatment based on clinical risk stratification. Our previous meta-analysis demonstrated 16 rules had been described and 2 of them subject to validation in more than one study. We aimed to advance our knowledge of evidence on the discriminatory ability and predictive accuracy of such risk stratification clinical decision rules (CDR) for children and young people with cancer by updating our systematic review.
Methods: The review was conducted in accordance with Centre for Reviews and Dissemination methods, searching multiple electronic databases, using two independent reviewers, formal critical appraisal with QUADAS and meta-analysis with random effects models where appropriate. It was registered with PROSPERO: CRD42011001685.
Results: We found 9 new publications describing a further 7 new CDR, and validations of 7 rules. Six CDR have now been subject to testing across more than two data sets. Most validations demonstrated the rule to be less efficient than when initially proposed; geographical differences appeared to be one explanation for this.
Conclusion: The use of clinical decision rules will require local validation before widespread use. Considerable uncertainty remains over the most effective rule to use in each population, and an ongoing individual-patient-data meta-analysis should develop and test a more reliable CDR to improve stratification and optimise therapy. Despite current challenges, we believe it will be possible to define an internationally effective CDR to harmonise the treatment of children with febrile neutropenia.
Pancreatic resections for advanced M1-pancreatic carcinoma : the value of synchronous metastasectomy
(2010)
Background: For M1 pancreatic adenocarcinomas pancreatic resection is usually not indicated. However, in highly selected patients synchronous metastasectomy may be appropriate together with pancreatic resection when operative morbidity is low.
Materials and Methods: From January 1, 2004 to December, 2007 a total of 20 patients with pancreatic malignancies were retrospectively evaluated who underwent pancreatic surgery with synchronous resection of hepatic, adjacent organ, or peritoneal metastases for proven UICC stage IV periampullary cancer of the pancreas. Perioperative as well as clinicopathological parameters were evaluated.
Results: There were 20 patients (9 men, 11 women; mean age 58 years) identified. The primary tumor was located in the pancreatic head (n=9, 45%), in pancreatic tail (n=9, 45%), and in the papilla Vateri (n=2, 10%). Metastases were located in the liver (n=14, 70%), peritoneum (n=5, 25%), and omentum majus (n=2, 10%). Lymphnode metastases were present in 16 patients (80%). All patients received resection of their tumors together with metastasectomy. Pylorus preserving duodenopancreatectomy was performed in 8 patients, distal pancreatectomy in 8, duodenopancreatectomy in 2, and total pancreatectomy in 2. Morbidity was 45% and there was no perioperative mortality. Median postoperative survival was 10.7 months (2.6–37.7 months) which was not significantly different from a matched-pair group of patients who underwent pancreatic resection for UICC adenocarcinoma of the pancreas (median survival 15.6 months; =.1).
Conclusion: Pancreatic resection for M1 periampullary cancer of the pancreas can be performed safely in well-selected patients. However, indication for surgery has to be made on an individual basis.
Investigations of the micro- and nanostructures and chemical composition of the sponge skeletons as examples for natural structural biocomposites are of fundamental scientific relevance. Recently, we show that some demosponges (Verongula gigantea, Aplysina sp.) and glass sponges (Farrea occa, Euplectella aspergillum) possess chitin as a component of their skeletons. The main practical approach we used for chitin isolation was based on alkali treatment of corresponding external layers of spicules sponge material with the aim of obtaining alkali-resistant compounds for detailed analysis. Here, we present a detailed study of the structural and physicochemical properties of spicules of the glass sponge Rossella fibulata. The structural similarity of chitin derived from this sponge to invertebrate alpha chitin has been confirmed by us unambiguously using physicochemical and biochemical methods. This is the first report of a silica-chitin composite biomaterial found in Rossella species. Finally, the present work includes a discussion related to strategies for the practical application of silica-chitin-based composites as biomaterials.
This thesis has light mesons and their vacuum interactions as its topic. In particular, the work examines the question where the scalar antiquark-quark states are found in the physical spectrum -- in the energy region below or above 1 GeV. Contrary to the naive expectation, the mentioned states are found in the region above 1 GeV. This has consequences for the building of order parameters for the chiral symmetry breaking of Quantum Chromodynamics (QCD).
Functional magnetic resonance imaging (fMRI) has been used for more than a decade to investigate possible supraspinal mechanisms of acupuncture stimulation. More than 60 studies and several review articles have been published on the topic. However, till now some acupuncture-fMRI studies have not adopted all methodological standards applied to most other fMRI studies. In this critical review, we comment on some of the problems including the choice of baseline, interpretation of deactivations, attention control and implications of different group statistics. We illustrate the possible impact of these problems by focussing on some early findings, namely activations of visual and auditory cortical areas, when acupoints were stimulated that are believed to have a therapeutic effect on vision or hearing in traditional Chinese medicine. While we are far from questioning the validity of using fMRI for the study of acupuncture effects, we think that activations reported by some of these studies were probably not a direct result of acupuncture stimulation but rather attributable to one or more of the methodological problems covered here. Finally, we try to offer solutions for these problems where possible.
Background: Panic disorder is common (5% prevalence) and females are twice as likely to be affected as males. The heritable component of panic disorder is estimated at 48%. Glutamic acid dehydrogenase GAD1, the key enzyme for the synthesis of the inhibitory and anxiolytic neurotransmitter GABA, is supposed to influence various mental disorders, including mood and anxiety disorders. In a recent association study in depression, which is highly comorbid with panic disorder, GAD1 risk allele associations were restricted to females.
Methodology/Principal Findings: Nineteen single nucleotide polymorphisms (SNPs) tagging the common variation in GAD1 were genotyped in two independent gender and age matched case-control samples (discovery sample n = 478; replication sample n = 584). Thirteen SNPs passed quality control and were examined for gender-specific enrichment of risk alleles associated with panic disorder by using logistic regression including a genotype×gender interaction term. The latter was found to be nominally significant for four SNPs (rs1978340, rs3762555, rs3749034, rs2241165) in the discovery sample; of note, the respective minor/risk alleles were associated with panic disorder only in females. These findings were not confirmed in the replication sample; however, the genotype×gender interaction of rs3749034 remained significant in the combined sample. Furthermore, this polymorphism showed a nominally significant association with the Agoraphobic Cognitions Questionnaire sum score.
Conclusions/Significance: The present study represents the first systematic evaluation of gender-specific enrichment of risk alleles of the common SNP variation in the panic disorder candidate gene GAD1. Our tentative results provide a possible explanation for the higher susceptibility of females to panic disorder.
The neurexin genes (NRXN1/2/3) encode two families (α and β) of highly polymorphic presynaptic proteins that are involved in excitatory/inhibitory synaptic balance. Recent studies indicate that neuronal activation and memory formation affect NRXN1/2/3α expression and alternative splicing at splice sites 3 and 4 (SS#3/SS#4). Neurons in the biological clock residing in the suprachiasmatic nuclei of the hypothalamus (SCN) act as self-sustained oscillators, generating rhythms in gene expression and electrical activity, to entrain circadian bodily rhythms to the 24 hours day/night cycles. Cell autonomous oscillations in NRXN1/2/3α expression and SS#3/SS#4 exons splicing and their links to rhythms in excitatory/inhibitory synaptic balance in the circadian clock were explored. NRXN1/2/3α expression and SS#3/SS#4 splicing, levels of neurexin-2α and the synaptic scaffolding proteins PSD-95 and gephyrin (representing excitatory and inhibitory synapses, respectively) were studied in mRNA and protein extracts obtained from SCN of C3H/J mice at different times of the 24 hours day/night cycle. Further studies explored the circadian oscillations in these components and causality relationships in immortalized rat SCN2.2 cells. Diurnal rhythms in mNRXN1α and mNRXN2α transcription, SS#3/SS#4 exon-inclusion and PSD-95 gephyrin and neurexin-2α levels were found in the SCN in vivo. No such rhythms were found with mNRXN3α. SCN2.2 cells also exhibited autonomous circadian rhythms in rNRXN1/2 expression SS#3/SS#4 exon inclusion and PSD-95, gephyrin and neurexin-2α levels. rNRXN3α and rNRXN1/2β were not expressed. Causal relationships were demonstrated, by use of specific siRNAs, between rNRXN2α SS#3 exon included transcripts and gephyrin levels in the SCN2.2 cells. These results show for the first time dynamic, cell autonomous, diurnal rhythms in expression and splicing of NRXN1/2 and subsequent effects on the expression of neurexin-2α and postsynaptic scaffolding proteins in SCN across the 24-h cycle. NRXNs gene transcripts may have a role in coupling the circadian clock to diurnal rhythms in excitatory/inhibitory synaptic balance.
Protective ant-plant mutualisms that are exploited by non-defending parasitic ants represent prominent model systems for ecology and evolutionary biology. The mutualist Pseudomyrmex ferrugineus is an obligate plant-ant and fully depends on acacias for nesting space and food. The parasite Pseudomyrmex gracilis facultatively nests on acacias and uses host-derived food rewards but also external food sources. Integrative analyses of genetic microsatellite data, cuticular hydrocarbons and behavioral assays showed that an individual acacia might be inhabited by the workers of several P. gracilis queens, whereas one P. ferrugineus colony monopolizes one or more host trees. Despite these differences in social organization, neither of the species exhibited aggressive behavior among conspecific workers sharing a tree regardless of their relatedness. This lack of aggression corresponds to the high similarity of cuticular hydrocarbon profiles among ants living on the same tree. Host sharing by unrelated colonies, or the presence of several queens in a single colony are discussed as strategies by which parasite colonies could achieve the observed social organization. We argue that in ecological terms, the non-aggressive behavior of non-sibling P. gracilis workers — regardless of the route to achieve this social structure — enables this species to efficiently occupy and exploit a host plant. By contrast, single large and long-lived colonies of the mutualist P. ferrugineus monopolize individual host plants and defend them aggressively against invaders from other trees. Our findings highlight the necessity for using several methods in combination to fully understand how differing life history strategies affect social organization in ants.
Yuanmou Basin of Yunnan, SW China, is a famous locality with hominids, hominoids, mammals and plant fossils. Based on the published megaflora and palynoflora data from Yuanmou Basin, the climate of Late Pliocene is reconstructed using the Coexistence Approach. The results indicate a warm and humid subtropical climate with a mean annual temperature of ca. 16–17°C and a mean annual precipitation of ca. 1500–1600 mm in the Late Pliocene rather than a dry, hot climate today, which may be due to the local tectonic change and gradual intensification of India monsoon. The comparison of Late Pliocene climate in Eryuan, Yangyi, Longling, and Yuanmou Basin of Yunnan Province suggests that the mean annual temperatures generally show a latitudinal gradient and fit well with their geographic position, while the mean annual precipitations seem to be related to the different geometries of the valleys under the same monsoon system.
Background: Dopamine plays an important role in orienting, response anticipation and movement evaluation. Thus, we examined the influence of functional variants related to dopamine inactivation in the dopamine transporter (DAT1) and catechol-O-methyltransferase genes (COMT) on the time-course of motor processing in a contingent negative variation (CNV) task.
Methods: 64-channel EEG recordings were obtained from 195 healthy adolescents of a community-based sample during a continuous performance task (A-X version). Early and late CNV as well as motor postimperative negative variation were assessed. Adolescents were genotyped for the COMT Val158Met and two DAT1 polymorphisms (variable number tandem repeats in the 3′-untranslated region and in intron 8).
Results: The results revealed a significant interaction between COMT and DAT1, indicating that COMT exerted stronger effects on lateralized motor post-processing (centro-parietal motor postimperative negative variation) in homozygous carriers of a DAT1 haplotype increasing DAT1 expression. Source analysis showed that the time interval 500–1000 ms after the motor response was specifically affected in contrast to preceding movement anticipation and programming stages, which were not altered.
Conclusions: Motor slow negative waves allow the genomic imaging of dopamine inactivation effects on cortical motor post-processing during response evaluation. This is the first report to point towards epistatic effects in the motor system during response evaluation, i.e. during the post-processing of an already executed movement rather than during movement programming.
Despite being internal organs, digestive structures are frequently preserved in Cambrian Lagerstätten. However, the reasons for their fossilisation and their biological implications remain to be thoroughly explored. This is particularly true with arthropods--typically the most diverse fossilised organisms in Cambrian ecosystems--where digestive structures represent an as-yet underexploited alternative to appendage morphology for inferences on their biology. Here we describe the phosphatised digestive structures of three trilobite species from the Cambrian Weeks Formation Lagerstätte (Utah). Their exquisite, three-dimensional preservation reveals unique details on trilobite internal anatomy, such as the position of the mouth and the absence of a differentiated crop. In addition, the presence of paired pygidial organs of an unknown function is reported for the first time. This exceptional material enables exploration of the relationships between gut phosphatisation and the biology of organisms. Indeed, soft-tissue preservation is unusual in these fossils as it is restricted to the digestive structures, which indicates that the gut played a central role in its own phosphatisation. We hypothesize that the gut provided a microenvironment where special conditions could develop and harboured a source of phosphorus. The fact that gut phosphatization has almost exclusively been observed in arthropods could be explained by their uncommon ability to store ions (including phosphorous) in their digestive tissues. However, in some specimens from the Weeks Formation, the phosphatisation extends to the entire digestive system, suggesting that trilobites might have had some biological particularities not observed in modern arthropods. We speculate that one of them might have been an increased capacity for ion storage in the gut tissues, related to the moulting of their heavily-mineralised carapace.
Dendritic cells (DCs) and oxLDL play an important role in the atherosclerotic process with DCs accumulating in the plaques during plaque progression. Our aim was to investigate the role of oxLDL in the modulation of the DC homing-receptor CCR7 and endothelial-ligand CCL21. Methods and Results. The expression of the DC homing-receptor CCR7 and its endothelial-ligand CCL21 was examined on atherosclerotic carotic plaques of 47 patients via qRT-PCR and immunofluorescence. In vitro, we studied the expression of CCR7 on DCs and CCL21 on human microvascular endothelial cells (HMECs) in response to oxLDL. CCL21- and CCR7-mRNA levels were significantly downregulated in atherosclerotic plaques versus non-atherosclerotic controls [90% for CCL21 and 81% for CCR7 (P<0.01)]. In vitro, oxLDL reduced CCR7 mRNA levels on DCs by 30% and protein levels by 46%. Furthermore, mRNA expression of CCL21 was significantly reduced by 50% (P<0.05) and protein expression by 24% in HMECs by oxLDL (P<0.05). Conclusions. The accumulation of DCs in atherosclerotic plaques appears to be related to a downregulation of chemokines and their ligands, which are known to regulate DC migration. oxLDL induces an in vitro downregulation of CCR7 and CCL21, which may play a role in the reduction of DC migration from the plaques.
Borrelia burgdorferi evades complement-mediated killing by interacting with complement regulators through distinct complement regulator-acquiring surface proteins (CRASPs). Here, we extend our analyses to the contribution of CRASP-4 in mediating complement resistance of B. burgdorferi and its interaction with human complement regulators. CRASP-4 (also known as ErpC) was immobilized onto magnetic beads and used to capture proteins from human serum. Following Western blotting, factor H (CFH), CFH-related protein 1 (CFHR1), CFHR2, and CFHR5 were identified as ligands of CRASP-4. To analyze the impact of native CRASP-4 on mediating survival of serum-sensitive cells in human serum, a B. garinii strain was generated that ectopically expresses CRASP-4. CRASP-4-producing bacteria bound CFHR1, CFHR2, and CFHR5 but not CFH. In addition, transformed spirochetes deposited significant amounts of lethal complement components on their surface and were susceptible to human serum, thus indicating that CRASP-4 plays a subordinate role in complement resistance of B. burgdorferi.
Background. Leukotriene B4 (LTB4), a proinflammatory lipid mediator correlates well with the acute phase of Acute Respiratory Distress Syndrome (ARDS). Therefore, LTB4-levels were investigated to determine whether they might be a useful clinical marker in predicting pulmonary complications (PC) in multiply traumatized patients. Methods: Plasma levels of LTB4 were determined in 100 patients on admission (ED) and for five consecutive days (daily). Twenty healthy volunteers served as control. LTB4-levels were measured by ELISA. Thirty patients developed PC (pneumonia, respiratory failure, acute lung injury (ALI), ARDS, pulmonary embolism) and 70 had no PC (ØPC). Results. LTB4-levels in the PC-group [127.8 pg/mL, IQR: 104–200pg/ml] were significantly higher compared to the ØPC-group on admission [95.6 pg/mL, IQR: 55–143 pg/mL] or control-group [58.4 pg/mL, IQR: 36–108 pg/mL]. LTB4 continuously declined to basal levels from day 1 to 5 without differences between the groups. The cutoff to predict PC was calculated at 109.6 pg/mL (72% specificity, 67% sensitivity). LTB4 was not influenced by overall or chest injury severity, age, gender or massive transfusion. Patients with PC received mechanical ventilation for a significantly longer period of time, and had prolonged intensive care unit and overall hospital stay. Conclusion. High LTB4-levels indicate risk for PC development in multiply traumatized patients
Statistical analysis on various stocks reveals long range dependence behavior of the stock prices that is not consistent with the classical Black and Scholes model. This memory or nondeterministic trend behavior is often seen as a reflection of market sentiments and causes that the historical volatility estimator becomes unreliable in practice. We propose an extension of the Black and Scholes model by adding a term to the original Wiener term involving a smoother process which accounts for these effects. The problem of arbitrage will be discussed. Using a generalized stochastic integration theory [8], we show that it is possible to construct a self financing replicating portfolio for a European option without any further knowledge of the extension and that, as a consequence, the classical concept of volatility needs to be re-interpreted.
AMS subject classifications: 60H05, 60H10, 90A09.
Integral equations for the mean-square estimate are obtained for the linear filtering problem, in which the noise generating the signal is a fractional Brownian motion with Hurst index h∈(3/4,1) and the noise in the observation process includes a fractional Brownian motion as well as a Wiener process. AMS subject classifications: 93E11, 60G20, 60G35.
Acupuncture is a therapy based on sensory stimulation of the human
body by means of metal needles. The exact underlying mechanisms of
acupuncture have not been clarified so far. Functional magnetic
resonance imaging (fMRI) has become an important tool in
acupuncture research. Standard acupuncture needles, which are made
of ferromagnetic steel, however, are problematic in
acupuncture-fMRI studies for several reasons, such as attraction
by the scanner's magnetic field, significant image distortions and
signal-dropouts, when positioned close to the head or even heating
due to absorption of radio frequency (RF). The aim of this study
was to compare two novel types of acupuncture needles with a
standard needle for their effect on MRI image quality. The
standard needle severely reduced image quality, when located
inside the RF coil. The nonferromagnetic metal needle may pose a
risk due to RF heating, while the plastic needle has a
significantly larger diameter. In conclusion, our recommendations
are: (1) standard needles should not be used in MRI; (2)
Nonferromagnetic metal needles seem to be the best choice for
acupoints outside of the transmitter coil; and (3) only plastic
needles are suited for points inside the coil. Laser acupuncture
may be a safe alternative, too.
P-type ATPases are membrane proteins acting as ion pumps that drive an active transport of cations across the membrane against a concentration gradient. The required energy for the ion transport is provided by binding and hydrolysis of ATP. A reaction mechanism of ion transport and energy transduction is assumed to be common for all P-type ATPases and generally described by the Post-Albers cycle. Transient currents and charge translocation of P-type ATPases were extensively investigated by electrical measurements that apply voltage jumps to initiate the reaction cycle. In this study, we simulate an applied voltage across the membrane by an electric field and perform electrostatic calculations in order to verify the experimentally-driven hypothesis that the energy transduction mechanism is regulated by specific structural elements. Side chain conformational and ionization changes induced by the electric field are evaluated for each transmembrane helix and the selectivity in response is qualitatively analyzed for the Ca2+-ATPase as well as for structural models of the Na+/K+-ATPase. Helix M5 responds with more conformer changes as compared to the other transmembrane helices what is even more emphasized when the stalk region is included. Thus our simulations support experimental results and indicate a crucial role for the highly conserved transmembrane helix M5 in the energy transduction mechanism of P-type ATPases.
In the past, the genetically diabetic-obese diabetes/diabetes (db/db) and obese/obese (ob/ob) mouse strains were used to investigate mechanisms of diabetes-impaired wound healing. Here we determined patterns of skin repair in genetically normal C57Bl/6J mice that were fed using a high fat diet (HFD) to induce a diabetes-obesity syndrome. Wound closure was markedly delayed in HFD-fed mice compared to mice which had received a standard chow diet (CD). Impaired wound tissue of HFD mice showed a marked prolongation of wound inflammation. Expression of vascular endothelial growth factor (VEGF) was delayed and associated with the disturbed formation of wound margin epithelia and an impaired angiogenesis in the reduced granulation tissue. Normal wound contraction was retarded and disordered. Wound disorders in obese C57Bl/6J mice were paralleled by a prominent degradation of the inhibitor of NFκB (IκB-α) in the absence of an Akt activation. By contrast to impaired wound conditions in ob/ob mice, late wounds of HFD mice did not develop a chronic inflammatory state and were epithelialized after 11 days of repair. Thus, only genetically obese and diabetic ob/ob mice finally developed chronic wounds and therefore represent a better suited experimental model to investigate diabetes-induced wound healing disorders.
Treatment of malignant glioma with chemotherapy is limited mostly because of delivery impediment related to the blood-brain tumor barrier (BTB). B1 receptors (B1R), inducible prototypical G-protein coupled receptors (GPCR) can regulate permeability of vessels including possibly that of brain tumors. Here, we determine the extent of BTB permeability induced by the natural and synthetic peptide B1R agonists, LysdesArg9BK (LDBK) and SarLys[DPhe8]desArg9BK (NG29), in syngeneic F98 glioma-implanted Fischer rats. Ten days after tumor inoculation, we detected the presence of B1R on tumor cells and associated vasculature. NG29 infusion increased brain distribution volume and uptake profiles of paramagnetic probes (Magnevist and Gadomer) at tumoral sites (T1-weighted imaging). These effects were blocked by B1R antagonist and non-selective cyclooxygenase inhibitors, but not by B2R antagonist and non-selective nitric oxide synthase inhibitors. Consistent with MRI data, systemic co-administration of NG29 improved brain tumor delivery of Carboplatin chemotherapy (ICP-Mass spectrometry). We also detected elevated B1R expression in clinical samples of high-grade glioma. Our results documented a novel GPCR-signaling mechanism for promoting transient BTB disruption, involving activation of B1R and ensuing production of COX metabolites. They also underlined the potential value of synthetic biostable B1R agonists as selective BTB modulators for local delivery of different sized-therapeutics at (peri)tumoral sites.
Proteomic analysis is the large-scale identification and characterization of proteins including post translational modifications. Proteomics encompasses a number of approaches including bottom-up and top-down workflows which are widely used independently and complementary as tools for the successful study of protein species. However, up to the present day these techniques have not been able to overcome every analytical limitation. Mass spectrometry has played a vital role alongside proteomics in providing the required analytical means of detecting protein amounts down to the atomole range. Soft ionization methods such as matrix assisted laser desorption/ionization (MALDI) and electrospray ionization (ESI) have permitted the transfer of peptides and intact proteins into the gas phase without extensive degradation. The introduction of recent developments in MALDI technology such as the highly sensitive 4-chloro-alpha-cyanocinnamic acid matrix (Cl-CCA) as well as the commercial availability of a MALDI-LTQ-Orbitrap which boosts peptide mass accuracy below 3 parts per million (ppm), have offered new prospective in protein analysis. The aim of the current study is to incorporate these new aspects and provide further advancements in gel-based as well as gel-free proteomic workflows.
Peptides of proteolytically digested proteins are routinely analyzed by means of peptide mass fingerprinting (PMF) often combined with MS/MS analyses to complement and substantiate PMF results by peptide sequence information. The most widely used protease for enzymatic digestion is trypsin, since it exhibits a very specific cleavage behavior limited to C-terminal hydrolyses after basic amino acids. However, less specific enzymes such as chymotrypsin, elastase and pepsin have emerged as useful tools in the analysis of particular protein classes e.g. membrane, cereal, and phosphorylated proteins. In this work a comprehensive bottom-up proteomic investigation including in-solution and in-gel protein digestions of analytes covering small to large, acidic to basic, and hydrophobic to hydrophilic proteins in combination with a series of less specific enzymes are presented in order to show the superiority of the novel MALDI matrix Cl-CCA. The Cl-CCA matrix proved to be highly superior compared to standard α-cyano-4-hydroxycinnamic acid (CHCA) since an average detection of more than 2- to 3-fold peptide amount was possible depending on the used protease and, therefore, resulting in strongly increased sequence coverage. Additionally, protein identification of chymotrypsin and elastase in-gel digested protein standards was evaluated. The MALDI-LTQ-Orbitrap providing peptide mass accuracy below and up to 3 ppm in combination with Cl-CCA as matrix and newly optimized digestion conditions led to unambiguous protein identifications of all chymotryptic digests outperforming its tryptic counterparts in the case of hydrophobic bacteriorhodopsin and α-globin from hemoglobin A (α-HgbA). In addition, significantly higher sequence coverage and increased number of detected peptides was acquired. Moreover, a proposed workaround for elastase digestions was capable of providing a solution for successful identification results.
Apart from digestions of singly separated proteins, solution isoelectic focusing (sIEF) was evaluated. OFFGEL fractionation is an efficient means of fractionating peptides and proteins according to their isoelectric point (pI) values through immobilized pH gel (IPG) strips after which samples are recovered in solution. Consequently, an issue of peptide recovery arises as a category of peptides relatively insoluble to the recovery solution should be present. A method was developed including the scraping of gel matrix from the IPG strips and peptide extraction using acetonitrile as organic solvent in combination with analytical techniques such as nLC-MALDI-MS/MS for peptide identification. The nature of the peptide species remaining in-gel was analysed and attributed to peptide solubility. A general trend in which a high percentage of neutral and hydrophobic peptides remaining entrapped in the IPG gel strip was observed.
The present work also examines a new top-down proteomic workflow involving protein elution from cleavable gels containing the labile crosslinker ethylene-glycol-diacrylate (EDA). Protein amounts of as low as 100 ng loaded onto EDA gels were detected using MALDI-TOF MS in the linear acquisition mode. Proteins from 8.5 up to 78 kDa were successfully measured including a hydrophobic 15 kDa core protein attaining a GRAVY score of +0.079. Additionally, the method was compatible with one dimensional protein separation as well as for 2-D IEF/SDS-PAGE. Lastly, two methods for protein identification were tested and found to be compatible to the proposed technique.
Clathrin-mediated endocytosis (CME) involves spatially and temporally restricted molecular dynamics.
Although protein kinases and the actin cytoskeleton contribute to the process, whether and how
functions of kinases and actin are integrated remains unknown. Here, we demonstrate that neural
Wiskott-Aldrich syndrome protein (N-WASP) and protein kinase CK2 form a complex and localize on
clathrin-coated vesicles (CCVs). N-WASP binds to and is phosphorylated by CK2, thereby reducing the
kinase activity of CK2. By contrast, N-WASP-promoted actin polymerization is decreased upon both
phosphorylation and binding of CK2. Knockdown of N-WASP and CK2, alone or in combination, results
in impaired endocytosis of epidermal growth factor (EGF) and increased cell-surface levels of EGF
receptor (EGFR). In order to rescue the phenotype of N-WASP-CK2 knockdown cells, both N-WASP and
CK2 activities and abilities to assemble in a complex are required. In summary, this study shows that the
N-WASP-CK2 complex integrates in a single circuit different activities contributing to CME of EGFR and
that the interplay between the two proteins optimizes this process.
Towards a THz Bloch laser
(2011)
The realisation of tunable THz laser sources working at room temperature would give
rise to further applications in this range of the electromagnetic spectrum. The THz
Bloch laser could therefore become the basis for a technological breakthrough. Beside
this practical relevance, the physics of the gain mechanism has been investigated
theoretically for a long time and the experimental implementation of a self-starting
laser still has not been achieved.
At the beginning of this thesis the basic principles of Bloch oscillations and the
related Bloch gain are described. The need of a superlattice structure to make Bloch
oscillations possible in a semiconductor material is discussed. In this context, the effect
of negative differential resistance and its influence on the field distribution due to Gunn
domains is explained. The latter lead to an inhomogeneous field which may suppress
the Bloch gain mechanism. The Krömer criterion is introduced and the concept of
field-pinning layers to improve the field homogeneity is deduced. Finally, the design of
the laser material is shown and different types of laser waveguides are compared.
In chapter 3 detailed recipes for the processing of samples are given. Different types of
contacts (ohmic and Schottky), the wafer bonding process required for double-metal
lasers and the application of different photoresists for different purposes are described.
An explanation of the formation of waveguides due to dry etching, wet etching
and ion implantation follows. Dry etching is an established technique in the field
of microstructure processing but the challenge of etching about 20 μm has led to
problems. The high etching depth also makes wet etching difficult but this method
could be improved due to a hard bake of the photoresist. The protection of critical
areas on the surface of the samples with photoresist during ion implantation was
increased by optimising the spin coating process. However, a full implantation of the
active layer between the waveguides was not achieved which was the reason for the
development of the hybrid technology. Here a prior wet etching of about 10 μm is
performed and the rest of the material is implanted.
The experimental setup is shown in chapter 4. An alternative method for the electrical
contacting with the help of a copper bar is introduced. This improves the current
distribution and the risk of an electrical breakdown during the measurements could
therefore be lowered. Devices for THz beam guidance and spectroscopic measurements
are shown and the method of biasing the samples with pulses below 100 ns and
determining the effective voltage applied to the sample is depicted. These short pulses
are required to prevent the samples heating up drastically due to high power.
Chapter 5 contains the current-voltage characterisation of several structures including
I-V-samples, Bloch laser samples and a quantum cascade laser. Different contacts
(ohmic and Schottky) and different techniques for the formation of the ridges have
been used in the processing of these samples (performed at the University of Frankfurt
in all cases) and their influence on the I-V-dependence is discussed. The properties of
the THz emission of the quantum cascade laser are in good agreement with published
results from lasers processed with the same material. Another important result of
this chapter is that the Bloch laser samples show unstable behaviour compared to the
quantum cascade structure even with short pulses (of about 10 ns) where the risk of an
electrical breakdown or the building of filaments is low. THz radiation emitted from
one of the Bloch laser samples could not be observed.
Two aspects that may have prevented the Bloch laser to emit are discussed in
chapter 6. The saturation of the gain for higher amplitudes of the THz wave is
investigated in single mode and multiple mode operation (the latter could occur due
to the Bloch gain being expected to be broadband). In both cases it is shown that
the saturation effect would limit the output power only to values clearly above the
detection limit. In the subsequent section the distribution of the electric field is
simulated with SILVACO software. Structures with transit layer lengths above the
Krömer criterion are compared with structures which include field-pinning layers. It is
shown that the latter are useful to avoid propagating Gunn domains as they build up
in similar structures without field-pinning layers. Nevertheless, the electric field inside
the superlattice regions is not stable. Beside spatial inhomogeneities also temporal
variations of the field magnitude are observed. The lack of a suitable field distribution
is expected to be the main reason for the samples not to work.
Introduction: Efficacy of currently approved anti-HIV drugs is hampered by mutations of the viral enzymes, leading invariably to drug resistance and chemotherapy failure. Recent data suggest that cellular co-factors also represent useful targets for anti-HIV therapy. We have recently provided evidence for the possibility to block HIV-1 replication by targeting its cellular cofactor DDX3.
Material and methods: Molecular modeling and in silico technologies were applied to rationally design small molecules specifically targeting the RNA binding site of human DDX3. Biochemical studies of mutated DDX3 enzymes were also used to identify additional potential drug binding sites.
Results
Optimization of compounds identified by application of a high-throughput docking approach afforded a promising lead compound which proved to inhibit both the helicase and ATPase activity of DDX3 and to reduce the viral load of peripheral blood mononuclear cells (PBMC) infected with HIV-1. A novel interaction site has been also identified in DDX3, which, when blocked, can reduce viral replication, representing an additional target for small molecules inhibitors.
Conclusions: We have identified the first inhibitors of HIV-1 replication targeting the RNA binding site of the cellular cofactor human DDX3. These compounds may offer superior selectivity over the ATP-competitive inhibitors previously developed. In addition, a novel RNA interacting motif specific to DDX3 has been identified, opening new venues for HIV-1 drug development.
We have analysed the microseismic activity within the Rwenzori Mountains area in the western branch of the East African Rift. Seismogram recordings from a temporary array of up to 27 stations reveal approximately 800 events per month with local magnitudes ranging from –0.5 to 5.1. The earthquake distribution is highly heterogeneous. The majority of located events lie within faults zones to the East and West of the Rwenzoris with the highest seismic activity observed in the northeastern area, where the mountains are in contact with the rift shoulders. The hypocentral depth distribution exhibits a pronounced peak of seismic energy release at 15 km depth. The maximum extent of seismicity ranges from 20 to 32 km and correlates well with Moho depths that were derived from teleseismic receiver functions. We observe two general features: (i) beneath the rift shoulders seismicity extends from the surface down to ca. 30 km depth; (ii) beneath the rift valley seismicity is confined to depths greater than 10 km. From the observations there is no indication for a crustal root beneath the Rwenzori Mountains. The magnitude frequency distribution reveals a b-value of 1.1, which is consistent with the hypothesis that part of the seismicity is caused by magmatic processes within the crust. Fault plane solutions of 304 events were derived from P-polarities and SV/P amplitude ratios. More than 70 % of the source mechanisms exhibit pure or predominantly normal faulting. T-axis trends are highly uniform and oriented WNW-ESE, which is perpendicular to the rift axis and in good agreement with kinematic rift models. At the northernmost part of the region we observe a rotation of the T-axis trends to NEN-SWS, which may be indicative of a local perturbation of the regional stress field.
The neuroendocrine substance melatonin is a hormone synthesized rhythmically by the pineal gland under the influence of the circadian system and alternating light/dark cycles. Melatonin has been shown to have broad applications, and consequently becoming a molecule of great controversy. Undoubtedly, however, melatonin plays an important role as a time cue for the endogenous circadian system. This review focuses on melatonin as a regulator in the circadian modulation of memory processing. Memory processes (acquisition, consolidation, and retrieval) are modulated by the circadian system. However, the mechanism by which the biological clock is rhythmically influencing cognitive processes remains unknown. We also discuss, how the circadian system by generating cycling melatonin levels can implant information about daytime into memory processing, depicted as day and nighttime differences in acquisition, memory consolidation and/or retrieval.
Oncolytic effects of a novel Influenza A virus expressing Interleukin-15 from the NS reading frame
(2012)
Oncolytic influenza A viruses with deleted NS1 gene (delNS1) replicate selectively in tumour cells with defective interferon response and/or activated Ras/Raf/MEK/ERK signalling pathway. To develop a delNS1 virus with specific immunostimulatory properties, we used an optimised technology to insert the interleukin-15 (IL-15) coding sequence into the viral NS gene segment (delNS1-IL-15). DelNS1 and delNS1-IL-15 exerted similar oncolytic effects. Both viruses replicated and caused caspase-dependent apoptosis in interferon-defective melanoma cells. Virus replication was required for their oncolytic activity. Cisplatin enhanced the oncolytic activity of delNS1 viruses. The cytotoxic drug increased delNS1 replication and delNS1-induced caspase-dependent apoptosis. Interference with MEK/ERK signalling by RNAi-mediated depletion or the MEK inhibitor U0126 did not affect the oncolytic effects of the delNS1 viruses. In oncolysis sensitive melanoma cells, delNS1-IL-15 (but not delNS1) infection resulted in the production of IL-15 levels ranging from 70 to 1140 pg/mL in the cell culture supernatants. The supernatants of delNS1-IL-15-infected (but not of delNS1-infected) melanoma cells induced primary human natural killer cell-mediated lysis of non-infected tumour cells. In conclusion, we constructed a novel oncolytic influenza virus that combines the oncolytic activity of delNS1 viruses with immunostimulatory properties through production of functional IL-15. Moreover, we showed that the oncolytic activity of delNS1 viruses can be enhanced in combination with cytotoxic anti-cancer drugs.
0 Home ; 1 Editorial ; 2 Do Information Rents in Loan Spreads Persist over the Business Cycle? ; 3 Regulation of Executive Pay in Germany - Perspectives of Optimal Contracting and Managerial Power ; 4 Linking Customer and Financial Metrics to Shareholder Value ; 5 Policy Platform: Recommendations for the Regulation of Shadow Banking ; 6 INTERVIEW – Lars-Hendrik Röller: "Theory Needs to Address the Right Kind of Policy Questions" ; 7 News ; 8 Selected Research and Policy Publications
CD95 co-stimulation blocks activation of naive T cells by inhibiting T cell receptor signaling
(2009)
CD95 is a multifunctional receptor that induces cell death or proliferation depending on the signal, cell type, and cellular context. Here, we describe a thus far unknown function of CD95 as a silencer of T cell activation. Naive human T cells triggered by antigen-presenting cells expressing a membrane-bound form of CD95 ligand (CD95L) or stimulated by anti-CD3 and -CD28 antibodies in the presence of recombinant CD95L had reduced activation and proliferation, whereas preactivated, CD95-sensitive T cells underwent apoptosis. Triggering of CD95 during T cell priming interfered with proximal T cell receptor signaling by inhibiting the recruitment of ζ-chain–associated protein of 70 kD, phospholipase-γ, and protein kinase C-θ into lipid rafts, thereby preventing their mutual tyrosine protein phosphorylation. Subsequently, Ca2+ mobilization and nuclear translocation of transcription factors NFAT, AP1, and NF-κB were strongly reduced, leading to impaired cytokine secretion. CD95-mediated inhibition of proliferation in naive T cells could not be reverted by the addition of exogenous interleukin-2 and T cells primed by CD95 co-stimulation remained partially unresponsive upon secondary T cell stimulation. HIV infection induced CD95L expression in primary human antigeen-presenting cells, and thereby suppressed T cell activation, suggesting that CD95/CD95L-mediated silencing of T cell activation represents a novel mechanism of immune evasion.
The apolipoprotein E4 (ApoE4) is an established risk factor for Alzheimer's disease (AD). Previous work has shown that this allele is associated with functional (fMRI) changes as well structural grey matter (GM) changes in healthy young, middle-aged and older subjects. Here, we assess the diffusion characteristics and the white matter (WM) tracts of healthy young (20-38 years) ApoE4 carriers and non-carriers. No significant differences in diffusion indices were found between young carriers (ApoE4+) and non-carriers (ApoE4-). There were also no significant differences between the groups in terms of normalised GM or WM volume. A feature selection algorithm (ReliefF) was used to select the most salient voxels from the diffusion data for subsequent classification with support vector machines (SVMs). SVMs were capable of classifying ApoE4 carrier and non-carrier groups with an extremely high level of accuracy. The top 500 voxels selected by ReliefF were then used as seeds for tractography which identified a WM network that included regions of the parietal lobe, the cingulum bundle and the dorsolateral frontal lobe. There was a non-significant decrease in volume of this WM network in the ApoE4 carrier group. Our results indicate that there are subtle WM differences between healthy young ApoE4 carriers and non-carriers and that the WM network identified may be particularly vulnerable to further degeneration in ApoE4 carriers as they enter middle and old age.
Striatal dopamine transmission is subtly modified in human A53Tα-synuclein overexpressing mice
(2012)
Mutations in, or elevated dosage of, SNCA, the gene for α-synuclein (α-syn), cause familial Parkinson's disease (PD). Mouse lines overexpressing the mutant human A53Tα-syn may represent a model of early PD. They display progressive motor deficits, abnormal cellular accumulation of α-syn, and deficits in dopamine-dependent corticostriatal plasticity, which, in the absence of overt nigrostriatal degeneration, suggest there are age-related deficits in striatal dopamine (DA) signalling. In addition A53Tα-syn overexpression in cultured rodent neurons has been reported to inhibit transmitter release. Therefore here we have characterized for the first time DA release in the striatum of mice overexpressing human A53Tα-syn, and explored whether A53Tα-syn overexpression causes deficits in the release of DA. We used fast-scan cyclic voltammetry to detect DA release at carbon-fibre microelectrodes in acute striatal slices from two different lines of A53Tα-syn-overexpressing mice, at up to 24 months. In A53Tα-syn overexpressors, mean DA release evoked by a single stimulus pulse was not different from wild-types, in either dorsal striatum or nucleus accumbens. However the frequency responsiveness of DA release was slightly modified in A53Tα-syn overexpressors, and in particular showed slight deficiency when the confounding effects of striatal ACh acting at presynaptic nicotinic receptors (nAChRs) were antagonized. The re-release of DA was unmodified after single-pulse stimuli, but after prolonged stimulation trains, A53Tα-syn overexpressors showed enhanced recovery of DA release at old age, in keeping with elevated striatal DA content. In summary, A53Tα-syn overexpression in mice causes subtle changes in the regulation of DA release in the striatum. While modest, these modifications may indicate or contribute to striatal dysfunction.
The Alpine Region, constituting the Alps and the Dinaric Alps, has played a major role in the formation of current patterns of biodiversity either as a contact zone of postglacial expanding lineages or as the origin of genetic diversity. In our study, we tested these hypotheses for two widespread, sympatric microgastropod taxa - Carychium minimum O.F. Müller, 1774 and Carychium tridentatum (Risso, 1826) (Gastropoda, Eupulmonata, Carychiidae) - by using COI sequence data and species potential distribution models analyzed in a statistical phylogeographical framework. Additionally, we examined disjunct transatlantic populations of those taxa from the Azores and North America. In general, both Carychium taxa demonstrate a genetic structure composed of several differentiated haplotype lineages most likely resulting from allopatric diversification in isolated refugial areas during the Pleistocene glacial periods. However, the genetic structure of Carychium minimum is more pronounced, which can be attributed to ecological constraints relating to habitat proximity to permanent bodies of water. For most of the Carychium lineages, the broader Alpine Region was identified as the likely origin of genetic diversity. Several lineages are endemic to the broader Alpine Region whereas a single lineage per species underwent a postglacial expansion to (re)colonize previously unsuitable habitats, e.g. in Northern Europe. The source populations of those expanding lineages can be traced back to the Eastern and Western Alps. Consequently, we identify the Alpine Region as a significant 'hot-spot' for the formation of genetic diversity within European Carychium lineages. Passive dispersal via anthropogenic means best explains the presence of transatlantic European Carychium populations on the Azores and in North America. We conclude that passive (anthropogenic) transport could mislead the interpretation of observed phylogeographical patterns in general.
Resistance of rhabdomyosarcoma to current therapies remains one of the key issues in pediatric oncology. Since the success of most cytotoxic therapies in the treatment of cancer, for example, chemotherapy, depends on intact signaling pathways that mediate programmed cell death (apoptosis), defects in apoptosis programs in cancer cells may result in resistance. Evasion of apoptosis in rhabdomyosarcoma may be caused by defects in the expression or function of critical mediators of apoptosis or in aberrant expression of antiapoptotic proteins. Therefore, the identification of the molecular mechanisms that confer primary or acquired resistance to apoptosis in rhabdomyosarcoma presents a critical step for the rational development of molecular targeted drugs. This approach will likely open novel perspectives for the treatment of rhabdomyosarcoma.
Betulinic acid is a natural product with a range of biological effects, for example potent antitumor activity. This anticancer property is linked to its ability to induce apoptotic cell death in cancer cells by triggering the mitochondrial pathway of apoptosis. In contrast to the cytotoxicity of betulinic acid against a variety of cancer types, normal cells and tissue are relatively resistant to betulinic acid, pointing to a therapeutic window. Compounds that exert a direct action on mitochondria present promising experimental cancer therapeutics, since they may trigger cell death under circumstances in which standard chemotherapeutics fail. Thus, mitochondrion-targeted agents such as betulinic acid hold great promise as a novel therapeutic strategy in the treatment of human cancers.
Keywords: apoptosis, cancer, betulinic acid, mitochondria
Keywords: AIF, apoptosis inducing factor; Apaf-1, Apoptotic protease activating factor-1; BA, betulinic acid; DIABLO, direct IAP Binding protein with Low PI; HtrA2, high temperature requirement protein A; IAPs, Inhibitor of Apoptosis Proteins; MOMP, mitochondrial outer membrane permeabilization; ROS, reactive oxygen species; PARP, Poly (ADP-ribose) Polymerase; Smac, second mitochondria-derived activator of caspase; TNF, tumor necrosis factor; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; zVAD.fmk, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone
Cells can respond to stress in various ways ranging from the activation of survival pathways to the initiation of cell death that eventually eliminates damaged cells. Whether cells mount a protective or destructive stress response depends to a large extent on the nature and duration of the stress as well as the cell type. Also, there is often the interplay between these responses that ultimately determines the fate of the stressed cell. The mechanism by which a cell dies (i.e., apoptosis, necrosis, pyroptosis, or autophagic cell death) depends on various exogenous factors as well as the cell's ability to handle the stress to which it is exposed. The implications of cellular stress responses to human physiology and diseases are manifold and will be discussed in this review in the context of some major world health issues such as diabetes, Parkinson's disease, myocardial infarction, and cancer.
One of the hallmarks of human cancers is the intrinsic or acquired resistance to apoptosis. Evasion of apoptosis can be part of a cellular stress response to ensure the cell's survival upon exposure to stressful stimuli. Apoptosis resistance may contribute to carcinogenesis, tumor progression, and also treatment resistance, since most current anticancer therapies including chemotherapy as well as radio- and immunotherapies primarily act by activating cell death pathways including apoptosis in cancer cells. Hence, a better understanding of the molecular mechanisms regarding how cellular stress stimuli trigger antiapoptotic mechanisms and how this contributes to tumor resistance to apoptotic cell death is expected to provide the basis for a rational approach to overcome apoptosis resistance mechanisms in cancers.
Autophagy has long been thought to be an essential but unselective bulk degradation pathway. However, increasing evidence suggests selective autophagosomal turnover of a broad range of substrates. Bifunctional autophagy receptors play a key role in selective autophagy by tethering cargo to the site of autophagosomal engulfment. While the identity of molecular components involved in selective autophagy has been revealed at least to some extent, we are only beginning to understand how selectivity is achieved in this process. Here, we summarize the mechanistic and structural basis of receptor-mediated selective autophagy.
For reconstructing environmental change in terrestrial realms the geochemistry of fossil bioapatite in bones and teeth is among the most promising applications. This study demonstrates that alkaline earth elements in enamel of Hippopotamids, in particular Ba and Sr are tracers for water provenance and hydrochemistry. The studied specimens are molar teeth from Hippopotamids found in modern and fossil lacustrine settings of the Western Branch of the East African Rift system (Lake Kikorongo, Lake Albert, and Lake Malawi) and from modern fluvial environments of the Nile River.
Concentrations in enamel vary by ca. two orders of magnitude for Ba (120–9336 μg g−1) as well as for Sr (9–2150 μg g−1). Concentration variations in enamel are partly induced during post-mortem alteration and during amelogenesis, but the major contribution originates from the variable water chemistry in the habitats of the Hippopotamids which is dominated by the lithologies and weathering processes in the watershed areas. Amelogenesis causes a distinct distribution of Ba and Sr in modern and fossil enamel, in that element concentrations increase along profiles from the outer rim towards the enamel-dentin junction by a factor of 1.3–1.5. These elements are well correlated with MgO and Na2O in single specimens, thus suggesting that their distribution is determined by a common, single process. Presuming that the shape of the tooth is established at the end of the secretion process and apatite composition is in equilibrium with the enamel fluid, the maturation process can be modeled by closed system Rayleigh crystallization.
Enamel from many Hippopotamid specimens has Sr/Ca and Ba/Ca which are typical for herbivores, but the compositions extend well into the levels of plants and carnivores. Within enamel from single specimens these element ratios covary and provide a specific fingerprint of the Hippopotamid habitat. All specimens together, however, define subparallel trends with different Ba/Sr ranging from 0.1 to 3. This ratio varies on spatial and temporal scales and traces provenance signals as well as the fractionation of the elements in the hydrological cycle. Thus, Sr concentrations and Ba/Sr in enamel differentiate between habitats having basaltic or Archean crustal rocks as the ultimate sources of Sr and Ba. The provenance signal is modulated by climate change. In Miocene to Pleistocene enamel from the Lake Albert region, Ba/Sr decreases systematically with time from about 2 to 0.5. This trend can be correlated with changes in climate from humid to arid in vegetation from C3 to C4 biomass as well as with increasing evaporation of the lake water. The most plausible explanation is that with time, Ba mobility decreased relative to that of Sr. This can arise if preferential adsorption of Ba to clay and Fe-oxide-hydroxide is related to increasing aridification. Additionally, weathering solutions and lake water can become increasingly alkaline and barite becomes stable. In this case, Ba will be preferentially deposited on the watershed of Lake Albert and rivers with low Ba/Sr will feed the habitats of the Hippopotamids.
Spatial variations of nitrogen trace gas emissions from tropical mountain forests in Nyungwe, Rwanda
(2012)
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. Therefore, 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 positive correlation with free iron and a negative correlation with soil pH (only N2O). 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 benefit from spatially explicit trace gas emission estimates linked to basic soil property data and differentiating between biological and chemical pathways for N trace gas formation.
Orangutans (Pongo) are the only great ape genus with a substantial Pleistocene and Holocene fossil record, demonstrating a much larger geographic range than extant populations. In addition to having an extensive fossil record, Pongo shows several convergent morphological similarities with Homo, including a trend of dental reduction during the past million years. While studies have documented variation in dental tissue proportions among species of Homo, little is known about variation in enamel thickness within fossil orangutans. Here we assess dental tissue proportions, including conventional enamel thickness indices, in a large sample of fossil orangutan postcanine teeth from mainland Asia and Indonesia. We find few differences between regions, except for significantly lower average enamel thickness (AET) values in Indonesian mandibular first molars. Differences between fossil and extant orangutans are more marked, with fossil Pongo showing higher AET in most postcanine teeth. These differences are significant for maxillary and mandibular first molars. Fossil orangutans show higher AET than extant Pongo due to greater enamel cap areas, which exceed increases in enamel-dentine junction length (due to geometric scaling of areas and lengths for the AET index calculation). We also find greater dentine areas in fossil orangutans, but relative enamel thickness indices do not differ between fossil and extant taxa. When changes in dental tissue proportions between fossil and extant orangutans are compared with fossil and recent Homo sapiens, Pongo appears to show isometric reduction in enamel and dentine, while crown reduction in H. sapiens appears to be due to preferential loss of dentine. Disparate selective pressures or developmental constraints may underlie these patterns. Finally, the finding of moderately thick molar enamel in fossil orangutans may represent an additional convergent dental similarity with Homo erectus, complicating attempts to distinguish these taxa in mixed Asian faunas.
Background: Mammalian fossils from the Eppelsheim Formation (Dinotheriensande) have been a benchmark for Neogene vertebrate palaeontology since 200 years. Worldwide famous sites like Eppelsheim serve as key localities for biochronologic, palaeobiologic, environmental, and mammal community studies. So far the formation is considered to be of early Late Miocene age (~9.5 Ma, Vallesian), representing the oldest sediments of the Rhine River. The stratigraphic unity of the formation and of its fossil content was disputed at times, but persists unresolved.
Principal Findings: Here we investigate a new fossil sample from Sprendlingen, composed by over 300 mammalian specimens and silicified wood. The mammals comprise entirely Middle Miocene species, like cervids Dicrocerus elegans, Paradicrocerus elegantulus, and deinotheres Deinotherium bavaricum and D. levius. A stratigraphic evaluation of Miocene Central European deer and deinothere species proof the stratigraphic inhomogenity of the sample, and suggest late Middle Miocene (~12.5 Ma) reworking of early Middle Miocene (~15 Ma) sediments. This results agree with taxonomic and palaeoclimatic analysis of plant fossils from above and within the mammalian assemblage. Based on the new fossil sample and published data three biochronologic levels within the Dinotheriensand fauna can be differentiated, corresponding to early Middle Miocene (late Orleanian to early Astaracian), late Middle Miocene (late Astaracian), and early Late Miocene (Vallesian) ages.
Conclusions/Significance: This study documents complex faunal mixing of classical Dinotheriensand fauna, covering at least six million years, during a time of low subsidence in the Mainz Basin and shifts back the origination of the Rhine River by some five million years. Our results have severe implications for biostratigraphy and palaeobiology of the Middle to Late Miocene. They suggest that turnover events may be obliterated and challenge the proposed ‘supersaturated’ biodiversity, caused by Middle Miocene superstites, of Vallesian ecosystems in Central Europe.
NF-κB is involved in immune responses, inflammation, oncogenesis, cell proliferation and apoptosis. Even though NF-κB can be activated by DNA damage via Ataxia telangiectasia-mutated (ATM) signalling, little was known about an involvement in DNA repair. In this work, we dissected distinct DNA double-strand break (DSB) repair mechanisms revealing a stimulatory role of NF-κB in homologous recombination (HR). This effect was independent of chromatin context, cell cycle distribution or cross-talk with p53. It was not mediated by the transcriptional NF-κB targets Bcl2, BAX or Ku70, known for their dual roles in apoptosis and DSB repair. A contribution by Bcl-xL was abrogated when caspases were inhibited. Notably, HR induction by NF-κB required the targets ATM and BRCA2. Additionally, we provide evidence that NF-κB interacts with CtIP-BRCA1 complexes and promotes BRCA1 stabilization, and thereby contributes to HR induction. Immunofluorescence analysis revealed accelerated formation of replication protein A (RPA) and Rad51 foci upon NF-κB activation indicating HR stimulation through DSB resection by the interacting CtIP-BRCA1 complex and Rad51 filament formation. Taken together, these results define multiple NF-κB-dependent mechanisms regulating HR induction, and thereby providing a novel intriguing explanation for both NF-κB-mediated resistance to chemo- and radiotherapies as well as for the sensitization by pharmaceutical intervention of NF-κB activation
Allogeneic stem cell transplantation (allo-SCT) has become an important treatment modality for patients with high-risk acute myeloid leukemia (AML) and is also under investigation for soft tissue sarcomas. The therapeutic success is still limited by minimal residual disease (MRD) status ultimately leading to patients’ relapse. Adoptive donor lymphocyte infusions based on MRD status using IL-15-expanded cytokine-induced killer (CIK) cells may prevent relapse without causing graft-versus-host-disease (GvHD). To generate preclinical data we developed mouse models to study anti-leukemic- and anti-tumor-potential of CIK cells in vivo. Immunodeficient mice (NOD/SCID/IL-2Rγc−, NSG) were injected intravenously with human leukemic cell lines THP-1, SH-2 and with human rhabdomyosarcoma (RMS) cell lines RH41 and RH30 at minimal doses required for leukemia or tumor engraftment. Mice transplanted with THP-1 or RH41 cells were randomly assigned for analysis of CIK cell treatment. Organs of mice were analyzed by flow cytometry as well as quantitative polymerase chain reaction for engraftment of malignant cells and CIK cells. Potential of CIK cells to induce GvHD was determined by histological analysis. Tissues of the highest degree of THP-1 cell expansion included bone marrow followed by liver, lung, spleen, peripheral blood (PB), and brain. RH30 and RH41 engraftment mainly took place in liver and lung, but was also detectable in spleen and PB. In spite of delayed CIK cell expansion compared with malignant cells, CIK cells injected at equal amounts were sufficient for significant reduction of RH41 cells, whereas against fast-expanding THP-1 cells 250 times more CIK than THP-1 cells were needed to achieve comparable results. Our preclinical in vivo mouse models showed a reliable 100% engraftment of malignant cells which is essential for analysis of anti-cancer therapy. Furthermore our data demonstrated that IL-15-activated CIK cells have potent cytotoxic capacity against AML and RMS cells without causing GvHD.
The correction of hypovolemia with acellular fluids results in acute normovolemic anemia. Whether the choice of the infusion fluid has an impact on the maintenance of oxygen (O2) supply during acute normovolemic anemia has not been investigated so far.
Methods:
Thirty-six anesthetized and mechanically ventilated pigs were hemodiluted to their physiological limit of anemia tolerance, reflected by the individual critical hemoglobin concentration (Hbcrit). Hbcrit was defined as the Hb-concentration corresponding with the onset of supply-dependency of total body O2-consumption (VO2). The hemodilution protocol was randomly performed with either Tetrastarch (6% HES 130/0.4, TS-group, n=9), Gelatin (3.5% urea-crosslinked polygeline, GEL-group, n=9), Hetastarch (6% HES 450/0.7, HS-group, n=9) or Ringer's solution (RS-group, n=9). The primary endpoint was the dimension of Hbcrit, secondary endpoints were parameters of central hemodynamics, O2-transport and tissue oxygenation.
Results:
In each animal, normovolemia was maintained throughout the protocol. Hbcrit was met at 3.7+/-0.6 g/dl (RS), 3.0+/-0.6 g/dl (HS P<0.05 vs. RS), 2.7+/-0.6 g/dl (GEL, P<0.05 vs. RS) and 2.1+/-0.4 g/dl (TS, P<0.05 vs. GEL, HS and RS). Hemodilution with RS resulted in a significant increase of extravascular lung water index (EVLWI) and a decrease of arterial oxygen partial pressure (paO2), O2-extraction ratio was increased, when animals of the TS-, GEL- and HS-groups met their individual Hbcrit.
Conclusions:
The choice of the intravenous (i.v) fluid has an impact on the tolerance of acute normovolemic anemia induced by acellular volume replacement. Third-generation Tetrastarch preparations (e.g., HES 130/0.4) appear most advantageous regarding maintenance of tissue oxygenation during progressive anemia. The underlying mechanism includes a lower degree of extravasation and favourable effects on microcirculatory function.
Background: 15-20% of all patients initially diagnosed with colorectal cancer develop metastatic disease and surgical resection remains the only potentially curative treatment available. Current 5-year survival following R0-resection of liver metastases is 28-39%, but recurrence eventually occurs in up to 70%. To date, adjuvant chemotherapy has not improved clinical outcomes significantly. The primary objective of the ongoing LICC trial (L-BLP25 In Colorectal Cancer) is to determine whether L-BLP25, an active cancer immunotherapy, extends recurrence-free survival (RFS) time over placebo in colorectal cancer patients following R0/R1 resection of hepatic metastases. L-BLP25 targets MUC1 glycoprotein, which is highly expressed in hepatic metastases from colorectal cancer. In a phase IIB trial, L-BLP25 has shown acceptable tolerability and a trend towards longer survival in patients with stage IIIB locoregional NSCLC.
Methods: This is a multinational, phase II, multicenter, randomized, double-blind, placebo-controlled trial with a sample size of 159 patients from 20 centers in 3 countries. Patients with stage IV colorectal adenocarcinoma limited to liver metastases are included. Following curative-intent complete resection of the primary tumor and of all synchronous/metachronous metastases, eligible patients are randomized 2:1 to receive either L-BLP25 or placebo. Those allocated to L-BLP25 receive a single dose of 300 mg/m2 cyclophosphamide (CP) 3 days before first L-BLP25 dose, then primary treatment with s.c. L-BLP25 930 mug once weekly for 8 weeks, followed by s.c. L-BLP25 930 mug maintenance doses at 6-week (years 1&2) and 12-week (year 3) intervals unless recurrence occurs. In the control arm, CP is replaced by saline solution and L-BLP25 by placebo. Primary endpoint is the comparison of recurrence-free survival (RFS) time between groups. Secondary endpoints are overall survival (OS) time, safety, tolerability, RFS/OS in MUC-1 positive cancers. Exploratory immune response analyses are planned. The primary endpoint will be assessed in Q3 2016. Follow-up will end Q3 2017. Interim analyses are not planned.
Discussion: The design and implementation of such a vaccination study in colorectal cancer is feasible. The study will provide recurrence-free and overall survival rates of groups in an unbiased fashion. Trial Registration EudraCT Number 2011-000218-20
Background: Multimorbidity is a phenomenon with high burden and high prevalence in the elderly. Our previous research has shown that multimorbidity can be divided into the multimorbidity patterns of 1) anxiety, depression, somatoform disorders (ADS) and pain, and 2) cardiovascular and metabolic disorders. However, it is not yet known, how these patterns are influenced by patient characteristics. The objective of this paper is to analyze the association of socio-demographic variables, and especially socio-economic status with multimorbidity in general and with each multimorbidity pattern.
Methods: The MultiCare Cohort Study is a multicentre, prospective, observational cohort study of 3.189 multimorbid patients aged 65+ randomly selected from 158 GP practices. Data were collected in GP interviews and comprehensive patient interviews. Missing values have been imputed by hot deck imputation based on Gower distance in morbidity and other variables. The association of patient characteristics with the number of chronic conditions is analysed by multilevel mixed-effects linear regression analyses.
Results: Multimorbidity in general is associated with age (+0.07 chronic conditions per year), gender (-0.27 conditions for female), education (-0.26 conditions for medium and -0.29 conditions for high level vs. low level) and income (-0.27 conditions per logarithmic unit). The pattern of cardiovascular and metabolic disorders shows comparable associations with a higher coefficient for gender (-1.29 conditions for female), while multimorbidity within the pattern of ADS and pain correlates with gender (+0.79 conditions for female), but not with age or socioeconomic status.
Conclusions: Our study confirms that the morbidity load of multimorbid patients is associated with age, gender and the socioeconomic status of the patients, but there were no effects of living arrangements and marital status. We could also show that the influence of patient characteristics is dependent on the multimorbidity pattern concerned, i.e. there seem to be at least two types of elderly multimorbid patients. First, there are patients with mainly cardiovascular and metabolic disorders, who are more often male, have an older age and a lower socio-economic status. Second, there are patients mainly with ADS and pain-related morbidity, who are more often female and equally distributed across age and socio-economic groups.
Because of the imbalance in the supply and demand of red blood cells (RBCs), especially for alloimmunized patients or patients with rare blood phenotypes, extensive research has been done to generate therapeutic quantities of mature RBCs from hematopoietic stem cells of various sources, such as bone marrow, peripheral blood, and cord blood. Since human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) can be maintained indefinitely in vitro, they represent potentially inexhaustible sources of donor-free RBCs. In contrast to other ex vivo stem-cell-derived cellular therapeutics, tumorigenesis is not a concern, as RBCs can be irradiated without marked adverse effects on in vivo function. Here, we provide a comprehensive review of the recent publications relevant to the generation and characterization of hESC- and iPSC-derived erythroid cells and discuss challenges to be met before the eventual realization of clinical usage of these cells.
Adipose tissue as a stem cell source is ubiquitously available and has several advantages compared to other sources. It is easily accessible in large quantities with minimal invasive harvesting procedure, and isolation of adipose-derived mesenchymal stromal/stem cells (ASCs) yields a high amount of stem cells, which is essential for stem-cell-based therapies and tissue engineering. Several studies have provided evidence that ASCs in situ reside in a perivascular niche, whereas the exact localization of ASCs in native adipose tissue is still under debate. ASCs are isolated by their capacity to adhere to plastic. Nevertheless, recent isolation and culture techniques lack standardization. Cultured cells are characterized by their expression of characteristic markers and their capacity to differentiate into cells from meso-, ecto-, and entodermal lineages. ASCs possess a high plasticity and differentiate into various cell types, including adipocytes, osteoblasts, chondrocytes, myocytes, hepatocytes, neural cells, and endothelial and epithelial cells. Nevertheless, recent studies suggest that ASCs are a heterogeneous mixture of cells containing subpopulations of stem and more committed progenitor cells. This paper summarizes and discusses the current knowledge of the tissue localization of ASCs in situ, their characterization and heterogeneity in vitro, and the lack of standardization in isolation and culture methods.
Within the last twenty years, the contraction method has turned out to be a fruitful approach to distributional convergence of sequences of random variables which obey additive recurrences. It was mainly invented for applications in the real-valued framework; however, in recent years, more complex state spaces such as Hilbert spaces have been under consideration. Based upon the family of Zolotarev metrics which were introduced in the late seventies, we develop the method in the context of Banach spaces and work it out in detail in the case of continuous resp. cadlag functions on the unit interval. We formulate sufficient conditions for both the sequence under consideration and its possible limit which satisfies a stochastic fixed-point equation, that allow to deduce functional limit theorems in applications. As a first application we present a new and considerably short proof of the classical invariance principle due to Donsker. It is based on a recursive decomposition. Moreover, we apply the method in the analysis of the complexity of partial match queries in two-dimensional search trees such as quadtrees and 2-d trees. These important data structures have been under heavy investigation since their invention in the seventies. Our results give answers to problems that have been left open in the pioneering work of Flajolet et al. in the eighties and nineties. We expect that the functional contraction method will significantly contribute to solutions for similar problems involving additive recursions in the following years.
European pea crabs - taxonomy, morphology, and host-ecology (Crustacea: Brachyura: Pinnotheridae)
(2010)
Pinnotherids are small crabs symbiotic to a variety of invertebrates. The European species infest bivalves and sea squirts. Their way of life is parasitic and poses a threat to commercially exploited bivalves. While juveniles of both sexes still look very similar - being agile swimmers and partially free living - a metamorphosis takes place in the female after mating and results in a conspicuous sexual dimorphism. Thereafter, the female settles in its host definitely and is morphologically strongly adapted to the parasitic life phase. A very high reproductive output was demonstrated among several pea crab species infesting bivalves. Despite from that, hardly any information is present in the literature on the pinnotherids’ reproductive biology and the underlying morphology.
Due to their cryptic way of life, the sexual dimorphism, and the different morphotypes of the female, the taxonomy of the Pinnotheridae is a serious challenge. Two widely accepted species are recognized on European coasts: Pinnotheres pisum and Nepinnotheres pinnotheres. Pinnotheres pectunculi was so far only known from the bivalve Glycymeris glycymeris in its type locality Roscoff (France), while Pinnotheres ascidicola and Pinnotheres marioni were described as living exclusively in ascidians without careful comparison with the previously described species. In order to produce standardized comparative descriptions, pea crabs were collected and studied from different hosts and localities in the Northeast Atlantic and in the Mediterranean. Nepinnotheres pinnotheres and Pinnotheres pisum were redescribed with consideration to characters of female and male. According to our morphological analysis, Pinnotheres ascidicola and Pinnotheres marioni are junior synonyms of Nepinnotheres pinnotheres, whereas the status of Pinnotheres pectunculi as a valid species was ascertained. Important characters are the mouthparts, the male gonopods, and especially chelipeds that showed consistent characteristics among different crab stages of both sexes.
Based on our sampling, we estimated the host-range of the European species. Nepinnotheres pinnotheres lives in ascidians and in the pen shell Pinna nobilis. Pinnotheres pisum infests numerous bivalve species - Pinna nobilis included. For Pinnotheres pectunculi novel host records are presented, all from the bivalve family Veneridae. Furthermore, feeding of the Pinnotheres-species was observed. They use a setae comb ventrally on the claw to brush mucus (and the accumulated food particles) from the bivalve gills. Feeding strategies and host-ecology will be thoroughly discussed in consideration to other Pinnotheridae.
We investigated the reproductive systems of European pinnotherids by histological methods, scanning and transmission electron microscopy, and confocal laser scanning microscopy.
The Eubrachyura have internal fertilization: paired vaginas enlarge into storage structures, the spermathecae, which are connected to the ovaries by oviducts. Sperm is stored until the oocytes are mature and transported into the spermathecae, where fertilization takes place. In the investigated pinnotherids, the vagina is of the ‘concave pattern’. Musculature is attached alongside flexible parts of the vagina-wall to control the dimension of its lumen. The genital opening is closed by a muscular mobile operculum.
The spermatheca can be divided into two distinct regions by function and morphology. The ventral part includes the connection with vagina and oviduct and is regarded as the zone where fertilization takes place. It is lined with cuticle except where the oviduct enters the spermatheca by the ‘holocrine transfer tissue’. At ovulation, the oocytes have to pass through this multi-layered glandular epithelium, which has a holocrine mode secretion. The dorsal part of the spermatheca is lined by a highly secretory apocrine glandular epithelium, which was to date only found in fiddler crabs of the genus Uca.
The male internal reproductive system consists of paired testes and corresponding vasa deferentia. The sperm morphology of pinnotherids conforms to other thoracotremes, with slight differences between Nepinnotheres pinnotheres and Pinnotheres pisum. Spermatozoa become enveloped into spermatophores in the secretory proximal vas deferens. The medial vas deferens is strongly enlarged and stores spermatophores embedded in seminal plasma. The distal vas deferens holds tubular appendices, which extend into the ventral cephalothorax and slightly into the pleon. These appendices produce and store vast quantities of seminal plasma. The copulatory system of the Brachyura is formed by paired penes and two pairs of gonopods, which function in sperm transfer. In pinnotherids, the long first gonopods transfers the sperm mass to the female. It holds the ejaculatory canal inside, which opens proximally and distally. The second gonopod is solid, short and conical. During copulation, the penis and the second gonopod are inserted into the base of the tubular first gonopod. The second gonopod functions in the transport of the sperm mass inside the ejaculatory canal towards its distal opening. The specific shape of the second gonopod is strongly adapted for a sealing of the tubular first gonopod with longitudinal cuticle foldings that interlock inside the first gonopod. The presented results are discussed concerning their function in reproduction and in respect of the systematic account.
The role of secretion in sperm transfer, storage and fertilization among the Brachyura is still under debate. It is notable that structure and function of secretion are more complex in pinnotherids and probably more efficient than in other brachyuran crabs, which will be discussed, in view of the parasitic way of life and the high fecundity of pinnotherids.
Das geographische Verbreitungsgebiet von Arten ist ein fundamentales Struktur gebendes Merkmal der biologischen Welt. Warum Arten so verteilt sind, wie sie sind ist seit langem eine der zentralen Fragen in Ökologie, Biogeographie und Evolution. Gegenwärtig verändern sich, im Wesentlichen als unbeabsichtigtes Nebenprodukt menschlicher ökonomischen Aktivitäten und Populationsdynamik, die geographischen Verbreitungsgebiete von Arten mit entscheidender Bedeutung für Land- und Forstwirtschaft, als Krankheitsvektoren oder als Teil der biologischen Systeme, die Ökosystemfunktionen bereitstellen. Daher ist es dringend notwendig, dass wir unser Verständnis über die Dynamiken, aus denen die geographische Verbreitung von Arten erwachsen, verbessern. Mit dieser Doktorarbeit versuche ich, in drei Untersuchungen zur Dynamik der Verbreitungsgebiete von Singvögeln einen Beitrag zu unserem in Entwicklung begriffenen Verständnis der multiplen Faktoren die Artverbreitungsgebiete beeinflussen, zu leisten.
1) Zu einem mechanistischeren Verständnis von Artmerkmalen und Verbreitungsgebietsgrößen: Ein wichtiger, ungelöster Fragenkomplex in der Makroökologie ist, die immense interspezifische Variation in der Größe geographischer Verbreitungsgebiete zu verstehen. Während man davon ausgeht, dass Artmerkmale wie Fekundität und Körpergröße einen Effekt auf Verbreitungsgebietsgrößen haben, fehlt ein allgemeines Verständnis davon, wie Verbreitungsgebietsgrößen von mehreren Merkmalen gemeinsam beeinflusst werden. Hier beurteilen wir den Effekt von Lebensgeschichtsmerkmalen (Fekundität, Ausbreitungsfähigkeit), ökologischen Merkmalen (Habitatnische, Nahrungsnische, Zugverhalten, Flexibilität im Zugverhalten) und morphologischen Merkmalen (Körpergröße) auf die globale Verbreitungsgebietsgröße von 165 europäischen Singvögeln. Wir identifizieren Hypothesen zur Beziehung von Artmerkmalen und Verbreitungsgebietsgrößen aus der Literatur und verwenden die Methodik der Pfadanalyse, um sie zu testen. Die Größe der globalen geographischen Verbreitungsgebiete europäischer Singvögel wurde von Lebensgeschichtsmerkmalen (Fekundidtät und Ausbreitungsfähigkeit), ökologischen Merkmalen (Habitatnischenbreite, Nahrungsnischenposition und Zugverhalten) und von Körpergröße beeinflusst. Artmerkmale beeinflussten Verbreitungsgebietsgrößen auf direktem und indirektem Weg. Insbesondere der Einfluss von Körpergröße war komplex mit positiven und negativen Effekten über verschiedene Pfade. Die Größe von Verbreitungsgebieten ist sehr wahrscheinlich auch von anderen Faktoren als von Artmerkmalen abhängig. Wir zeigen, dass es notwendig ist, den direkten und indirekten Einfluss einer Vielzahl von Merkmalen zu entwirren, um die Mechanismen, die makroökologische Beziehungen generieren, aufzuklären.
2) Konkurrenz und Ausbreitungsfähigkeit interagieren bei der Bestimmung der geographischen Verbreitung von Vögeln: Es ist weiterhin eine Herausforderung für Ökologie und Evolutionsbiologie, die Faktoren zu verstehen , die die geographische Verbreitung von Arten beeinflussen. Wir untersuchen wie Konkurrenz, Ausbreitungsfähigkeit, das Alter eines Taxons und Habitatverschiebungen seit dem letzten glazialen Maximum das Ausmaß beeinflussen, in dem Arten der Vogelgattung Sylvia in allen Gegenden mit geeigneten Umweltbedingungen vorkommen (d.h. range filling).
Wir haben range filling in der Vogelgattung Sylvia (Grasmücken) unter Verwendung von Boosted Regression Trees und Ridge-Regression quantifiziert. Mittels multipler Regression haben wir für die Effekte von intragenerischer Konkurrenz, Ausbreitungfähigkeit, Alter des Taxons und Habitatverschiebung seit dem letzten glazialen Maximum auf range filling getestet.
Grasmücken mit hoher Ausbreitungsfähigkeit zeigten höheres range filling, aber nur wenn Konkurrenz in Gebieten mit weniger geeignetem Habitat innerhalb ihres potentiellen Verbreitungsgebietes niedrig war. Das Alter eines Taxon und Habitatverschiebung seit dem letzten glazialen Maximum hatten keinen konsistenten Effekt. Wir zeigen, dass die Verbreitungsgebiete von Grasmücken mit hoher Wahrscheinlichkeit durch den simultanen, interaktiven Effekt von Konkurrenz und Ausbreitungsfähigkeit geformt werden. Wenn biotische Interaktionen wie Konkurrenz generell die Fähigkeit von Arten beeinflussen auf der kontinentalen Skala neue Gebiete zu kolonisieren, wird es eine Herausforderung sein, den Effekt von Klimawandel auf Biodiversität vorherzusagen.
3) Nischenverfügbarkeit in Zeit und Raum: Vogelzug der Grasmücken: Im Kontext neuer Fortschritte in der ökologischen Nischenmodellierung sind sowohl die Umwelt als auch die ökologische Nische einer Art als statische Entitäten behandelt und quantifiziert worden. In der Realität sind aber die Umwelt und die Nischenanforderungen einer Art auf einer Vielzahl von Skalen dynamisch. Wir schlagen ein konzeptionelles System vor das berücksichtigt, wie die realisierte Nische und geographische Verbreitung von Arten durch die entkoppelte raumzeitliche Verfügbarkeit unterschiedlicher Umweltbedingungen und durch Veränderungen der Nischenanforderungen über die Lebenszeit eines Organismus geformt werden. Das Testen von aus dem konzeptionellen System abgeleiteten Vorhersagen am Beispiel des Vogelzugs der Grasmücken ergab neue Erkenntnisse: Das Verfolgen der Klimanische im geographischen Raum war höchstwahrscheinlich nicht die treibende Kraft für Migration in der Gattung und steht potentiell im Konflikt mit dem Verfolgen der Landnutzungsnische. Die Nischen der Grasmücken waren während der Brutsaison schmaler, was zeigt, dass Nischenanforderungen zeitlich dynamisch sein können. Wir legen nahe, dass die Berücksichtigung dynamischer Umwelten und Nischenanforderungen zu einer entscheidenden Verbessserung unseres Verständnisses der treibenden Faktoren hinter der Bewegung von Organismen im Raum und der Dynamik ihrer Nischen und Verbreitungsgebiete führt.
The subject of this thesis aimed at a better understanding of the spectacular X-ray burst. The most likely astrophysical site is a very dense neutron star, which accretes H/He-rich matter from a close companion. While falling towards the neutron star, the matter is heated up and a thermonuclear runaway is ignited. The exact description of this process is dominated by the properties of a few proton-rich radioactive isotopes, which have a low interaction probability, hence a high abundance.
The topic of this thesis was therefore an investigation of the short-lived, proton-rich isotopes 31Cl and 32Ar. The Coulomb dissociation method is the modern technique of choice. Excitations with energies up to 20 MeV can be induced by the Lorentz contracted Coulomb field of a lead target. At the GSI Helmholtzzentrum für Schwerionenforschung GmbH in Darmstadt, Germany, a Ar beam was accelerated to an energy of 825 AMeV and fragmented in a beryllium target. The fragment separator was used to select the desired isotopes with a remaining energy of 650 AMeV. They were subsequently directed onto a 208 Pb target in the ALAND/LAND setup. The measurement was performed in inverse kinematics. All reaction products were detected and inclusive and exclusive measurements of the respective Coulomb dissociation cross sections were possible.
During the analysis of the experiment, it was possible to extract the energy-differential excitation spectrum of 31Cl, and to constrain astrophysically important parameters for the time-reversed 30S(p,γ)31Cl reaction. A single resonance at 0.443(37) MeV dominates the stellar reaction rate, which was also deduced and compared to previous calculations.
The integrated Coulomb dissociation cross section of this resonance was determined to 15(6) mb. The astrophysically important one- and two-proton emission channels were analyzed for 32Ar and energy-differential excitation spectra could be derived. The integrated Coulomb dissociation cross section for two proton emission were determined with two different techniques. The inclusive measurement yields a cross section of 214(29stat)(20sys) mb, whereas the exclusive reconstruction results in a cross section of 226(14stat)(23sys) mb. Both results are in very good agreement. The Coulomb dissociation cross section for the one-proton emission channel is extracted solely from the exclusive measurement and is 54(8stat)(6sys) mb.
Furthermore, the development of the Low Energy Neutron detector Array (LENA) for the upcoming R3B setup is described. The detector will be utilized in charge-exchange reactions to detect the low-energy recoil neutrons from (p,n)-type reactions. These reaction studies are of particular importance in the astrophysical context and can be used to constrain half lifes under stellar conditions. In the frame of this work, prototypes of the detector were built and successfully commissioned in several international laboratories.
The analysis was supported by detailed simulations of the detection characteristics.
In this thesis I use effective models to investigate the properties of QCD-like theories at nonzero temperature and baryon chemical potential. First I construct a PNJL model using a lattice spin model with nearestneighbor interactions for the gauge sector and four-fermion interactions for the quarks in (pseudo)real representations of the gauge group. Calculating the phase diagram in the plane of temperature and quark chemical potential in QCD with adjoint quarks, it is qualitatively confirmed that the critical temperature of the chiral phase transition is much higher than the deconfinement transition temperature. At a chemical potential equal to half of the diquark mass in the vacuum, a diquark Bose–Einstein condensation (BEC) phase transition occurs. In the two-color case, a Ginzburg–Landau expansion is used to study the tetracritical behavior around the intersection point of the deconfinement and BEC transition lines which are both of second order. A compact expression for the expectation value of the Polyakov loop in an arbitrary representation of the gauge group is obtained for any number of colors, which allows us to study Casimir scaling at both nonzero temperature and chemical potential. Subsequently I study the thermodynamics of two-color QCD (QC2D) at high temperature and/or density using ZQCD, a dimensionally reduced superrenormalizable effective theory, formulated in terms of a coarse grained Wilson line. In the absence of quarks, the theory is required to respect the Z2 center symmetry, while the effects of quarks of arbitrary masses and chemical potentials are introduced via soft Z2 breaking operators. Perturbative matching of the effective theory parameters to the full theory is carried out explicitly, and it is argued how the new theory can be used to explore the phase diagram of two-color QCD.
Axonal growth is essential for establishing neuronal circuits during brain development and for regenerative processes in the adult brain. Unfortunately, the extracellular signals controlling axonal growth are poorly understood. Here we report that a reduction in extracellular ATP levels by tissue-nonspecific alkaline phosphatase (TNAP) is essential for the development of neuritic processes by cultured hippocampal neurons. Selective blockade of TNAP activity with levamisole or specific TNAP knockdown with short hairpin RNA interference inhibited the growth and branching of principal axons, whereas addition of alkaline phosphatase (ALP) promoted axonal growth. Neither activation nor inhibition of adenosine receptors affected the axonal growth, excluding the contribution of extracellular adenosine as a potential hydrolysis product of extracellular ATP to the TNAP-mediated effects. TNAP was colocalized at axonal growth cones with ionotropic ATP receptors (P2X7 receptor), whose activation inhibited axonal growth. Additional analyses suggested a close functional interrelation of TNAP and P2X7 receptors whereby TNAP prevents P2X7 receptor activation by hydrolyzing ATP in the immediate environment of the receptor. Furthermore inhibition of P2X7 receptor reduced TNAP expression, whereas addition of ALP enhanced P2X7 receptor expression. Our results demonstrate that TNAP, regulating both ligand availability and protein expression of P2X7 receptor, is essential for axonal development.
We propose a model of the dynamics of organizational communication. Our model specifies the mechanics by which communication impact is fed back to communication inputs and closes the gap between sender and receiver of messages. We draw on language critique, a branch of language philosophy, and derive joint linguistic actions of interlocutors to explain the emergence and adaptation of communication on the group level. The model is framed by Te'eni's cognitive-affective model of organizational communication.
An information system is more than just the information technology; it is the system that emerges from the complex interactions and relationships between the information technology and the organization. However, what impact information technology has on an organization and how organizational structures and organizational change influence information technology remains an open question. We propose a theory to explain how communication structures emerge and adapt to environmental changes. We operationalize the interplay of information technology and organization as language communities whose members use and develop domain-specific languages for communication. Our theory is anchored in the philosophy of language. In developing it as an emergent perspective, we argue that information systems are self-organizing and that control of this ability is disseminated throughout the system itself, to the members of the language community. Information technology influences the dynamics of this adaptation process as a fundamental constraint leading to perturbations for the information system. We demonstrate how this view is separated from the entanglement in practice perspective and show that this understanding has far-reaching consequences for developing, managing, and examining information systems.
Theory building is not only underdeveloped in IT services management research, but in
general in IS. Given the paradigm shift that comes from the development away from a
networked economy towards a network economy, the lack of spending enough attention to
theorizing in IS becomes even more obvious. In the light of other "megatrends" in IS
research, such as the increasing professionalization and use of statistical methods and the
exploitation of extremely large sets of data (often harvested from social media sites), we
might lose interest in theorizing in the presence of the tremendous amount of available
empirical data. In this position paper, the author advocates that services science researchers
should focus on rigor and relevance in their research approaches.
Splicing of pre-mRNA is a critical step in mRNA maturation and disturbances cause several genetic disorders. We apply the synthetic tetracycline (tc)-binding riboswitch to establish a gene expression system for conditional tc-dependent control of pre-mRNA splicing in yeast. Efficient regulation is obtained when the aptamer is inserted close to the 5′splice site (SS) with the consensus sequence of the SS located within the aptamer stem. Structural probing indicates limited spontaneous cleavage within this stem in the absence of the ligand. Addition of tc leads to tightening of the stem and the whole aptamer structure which probably prevents recognition of the 5′SS. Combination of more then one aptamer-regulated intron increases the extent of regulation leading to highly efficient conditional gene expression systems. Our findings highlight the potential of direct RNA–ligand interaction for regulation of gene expression.
The impacts of human activities, notably the conversion of tropical forests into farmland habitat, has profound impacts on biological diversity and ecosystem functions (Millennium Ecosystem Assessment 2005). It is widely debated to what extent human modified landscapes can maintain tropical biodiversity and their ecosystem functionality (e.g. Waltert et al. 2004, Sekercioglu et al. 2007). In this thesis, I have used a huge and temporarily replicated dataset to assess the value of different habitat types differing in land-use intensities for bird communities in tropical East Africa. I investigated bird abundance and species richness along a forest-farmland habitat gradient and assessed spatial and temporal fluctuations of bird assemblages and their food resources.
I could show that forest and farmland habitats harbor distinct bird communities. Moreover, the protection of natural forests merits the highest priority for conserving the high diversity of forest-dependent bird species. My study, however, also shows that farmland habitats in the proximity of natural forest can support a high bird diversity. High bird diversity in tropical farmlands depends on a high structural complexity, such as in small-scale subsistence farmlands. From my findings, I conclude that the conversion of forest to farmland leads to substantial losses in bird diversity, in particular in specialized feeding guilds such as insectivores, while the conversion of structurally heterogeneous subsistence farmlands to sugarcane plantation causes erosion of bird diversity in agricultural ecosystems. Both findings are important for conservation planning in times when tropical forests and agroecosystems are under constantly high pressure due to increasing human population numbers and global demands for biofuel crops (Gibbs et al. 2008). From an ecosystem function perspective, my study demonstrates the potential of agroecosystems in supporting important ecosystem functions, such as seed dispersal by frugivorous birds and pest control by insectivorous birds. I could show that bird abundances in both frugivorous and insectivorous guilds were strongly predicted by their respective food resources, implying that seasonal shifts in fruit and invertebrate abundance at Kakamega forest and surrounding farmlands affect community dynamics and appear to influence local movement patterns of birds. The most interesting finding of this study was that feeding guilds responded idiosyncratically to resource fluctuations. Frugivore richness fluctuated asynchronously in forest and farmland habitats, suggesting foraging movements and fruit tracking across habitat borders. In contrast, I found that insectivores fluctuated synchronously in the two habitat types, suggesting a lack of inter-habitat movements. I therefore predict that insectivorous bird communities in this forest-farmland landscape may be more susceptible to the combined effects of land-use and climate change, due to their narrow habitat niche and limited capacity to track their resources.
The fact that a number of bird species regularly moved across the landscape mosaic in my study system implies that birds are able to provide long-distance seed dispersal across habitat borders. Thus, birds may enhance forest regeneration in human-modified landscapes, such as those in most parts of tropical Africa, given that forest remnants are protected within an agricultural habitat matrix. In order to effectively conserve tropical biodiversity within forest-farmland mosaics, this study advocates for conservation strategies that go beyond forest protection and explicitly integrate farmlands into forest management plans and policies. This should emphasize the retention of keystone habitat elements within tropical farmland landscapes, such as indigenous trees, forest galleries and hedgerows, whose presence enhance species diversity. Such grassroot-level approaches can be operationalized for instance through providing incentives to farmers to maintain their traditional subsistence land-use practices and through community-based livelihood projects aiming at enhancing local habitat heterogeneity and inter-habitat connectivity.
Thermal expansion measurements provide a sensitive tool for exploring a material's thermodynamic
properties in condensed matter physics as they provide useful information
on the electronic, magnetic and lattice properties of a material. In this thesis, thermal
expansion measurements have been carried out both at ambient-pressure and under hydrostatic
pressure conditions. From the materials point of view, the spin-liquid candidate
Kappa-(BEDT-TTF) 2 Cu 2(CN)3 has been studied extensively as a function of temperature and
magnetic field. Azurite, Cu 3 (CO 3) 2 (OH) 2 - a realization of a one-dimensional distorted
Heisenberg chain is also studied both at ambient and hydrostatic pressure to demonstrate
the proper functioning of the newly built setup "thermal expansion under pressure". ...
Seit Anbeginn der Festkörperphysik ist die Frage, warum manche Materialien metallisch sind, andere dagegen isolierend, von zentraler Bedeutung. Eine erste Erklärung wurde durch die Bändertheorie [23, 44] gegeben. Die Elektronen sind dem periodischen Potential der Rumpfatome ausgesetzt, wodurch ein Energiespektrum bestehend aus Bändern erzeugt wird und die Füllung dieser Bänder bestimmt die Leitungseigenschaften des Festkörpers. ...
For millennia, rural West African communities living in or adjacent of savanna ecosystems have been collecting components of local plant species (e.g. fruits, leaves, bark) in order to fulfil essential household subsistence needs (alimentation, medical care, energy demand etc.), to generate cash income and to overcome times of (financial) crisis. Thus, these non-timber forest products (NTFPs) make a considerable contribution to the well-being of local households. However, climate and land use change severely impact West African savanna ecosystems and, consequently, the safe-guarding of dependent rural livelihoods. The conversion of savanna area into cultivated land for subsistence farming owing to the ongoing population growth, as well as the progressive promotion of cash crops (e.g. cotton) is ever-increasing. As a consequence, present land-use management in West Africa has to cope with serious trade-offs. Within this decision-making NTFPs have been constantly understated due to a lack of appropriate economic figures to use within common cost-benefit analysis, and, thus, have been frequently outcompeted by seemingly more profitable land-use options. Therefore, it is crucial to provide appropriate economic data for NTFPs in order to create positive incentives for both decision-makers and NTFP beneficiaries to conserve NTFP-providing trees. The key finding of this analysis is that income from NTFPs accounts for 39 % on average of an annual total household income in Northern Benin, representing the second largest income share next to crop income and proving the respective households to be economically heavily dependent on NTFPs. Thereby, socio-economic characteristics of NTFP users tremendously shape their preferences for woody species. Particularly ethnicity has a major impact on the species used and the economic return obtained by them. Moreover, the study investigated the impacts of climate and land use change on the economic benefits derived from the three economically most important tree species in the region Vitellaria paradoxa, Parkia biglobosa and Adansonia digitata in 2050: Environmental changes will have primarily negative effects on the economic returns from all the three species. At large, the study underpins the economic relevance of NTFPs for rural communities in West African savannas and, consequently, the necessity to appropriately sustain them in order to safe-guard local livelihoods. Providing key figures on the current and future economic benefits obtained from NTFPs can augment common cost-benefit analysis, and, delivering detailed information about peoples’ use preferences for local species, this study clearly contributes to improve the basis of decision-making with reference to local land-use policies.
Interacting ultracold gases in optical lattices: non-equilibrium dynamics and effects of disorder
(2012)
This dissertation aims at giving a theoretical description of various applications of ultracold gases. A particular focus is cast upon the dynamical evolution of bosonic condensates in non-equilibrium by means of the time-dependent Gutzwiller method. Ground state properties of strongly interacting fermionic atoms in box and speckle disordered lattices are investigated via real-space dynamical mean-field theory. ...
The first measurement of the fluctuation of the kaon-to-proton ratio in relativistic heavy-ion collisions is presented. This thesis details the analysis procedure for identifying kaons and protons using the NA49 experiment at CERN-SPS and discusses the results in the context of the current state of the field.
Background: Many disabling human retinal disorders involve the central retina, particularly the macula. However, the commonly used rodent models in research, mouse and rat, do not possess a macula. The purpose of this study was to identify small laboratory rodents with a significant central region as potential new models for macular research.
Methodology/Principal Findings: Gerbillus perpallidus, Meriones unguiculatus and Phodopus campbelli, laboratory rodents less commonly used in retinal research, were subjected to confocal scanning laser ophthalmoscopy (cSLO), fluorescein and indocyanine green angiography, and spectral-domain optical coherence tomography (SD-OCT) using standard equipment (Heidelberg Engineering HRA1 and Spectralis™) adapted to small rodent eyes. The existence of a visual streak-like pattern was assessed on the basis of vascular topography, retinal thickness, and the topography of retinal ganglion cells and cone photoreceptors. All three species examined showed evidence of a significant horizontal streak-like specialization. cSLO angiography and retinal wholemounts revealed that superficial retinal blood vessels typically ramify and narrow into a sparse capillary net at the border of the respective area located dorsal to the optic nerve. Similar to the macular region, there was an absence of larger blood vessels in the streak region. Furthermore, the thickness of the photoreceptor layer and the population density of neurons in the ganglion cell layer were markedly increased in the visual streak region.
Conclusions/Significance: The retinal specializations of Gerbillus perpallidus, Meriones unguiculatus and Phodopus campbelli resemble features of the primate macula. Hence, the rodents reported here may serve to study aspects of macular development and diseases like age-related macular degeneration and diabetic macular edema, and the preclinical assessment of therapeutic strategies.
Background: Human primary monocytes are refractory to infection with the human immunodeficiency virus 1 (HIV-1) or transduction with HIV-1-derived vectors. In contrast, efficient single round transduction of monocytes is mediated by vectors derived from simian immunodeficiency virus of sooty mangabeys (SIVsmmPBj), depending on the presence of the viral accessory protein Vpx.
Methods and Findings: Here we analyzed whether Vpx of SIVsmmPBj is sufficient for transduction of primary monocytes by HIV-1-derived vectors. To enable incorporation of PBj Vpx into HIV-1 vector particles, a HA-Vpr/Vpx fusion protein was generated. Supplementation of HIV-1 vector particles with this fusion protein was not sufficient to facilitate transduction of human monocytes. However, monocyte transduction with HIV-1-derived vectors was significantly enhanced after delivery of Vpx proteins by virus-like particles (VLPs) derived from SIVsmmPBj. Moreover, pre-incubation with Vpx-containing VLPs restored replication capacity of infectious HIV-1 in human monocytes. In monocytes of non-human primates, single-round transduction with HIV-1 vectors was enabled.
Conclusion: Vpx enhances transduction of primary human and even non-human monocytes with HIV-1-derived vectors, only if delivered in the background of SIVsmmPBj-derived virus-like particles. Thus, for accurate Vpx function the presence of SIVsmmPBj capsid proteins might be required. Vpx is essential to overcome a block of early infection steps in primary monocytes.
Aim: Cellular CD81 is a well characterized hepatitis C virus (HCV) entry factor, while the relevance of soluble exosomal CD81 in HCV pathogenesis is poorly defined. We performed a case-control study to investigate whether soluble CD81 in the exosomal serum fraction is associated with HCV replication and inflammatory activity.
Patients and Methods: Four cohorts were investigated, patients with chronic hepatitis C (n = 37), patients with chronic HCV infection and persistently normal ALT levels (n = 24), patients with long term sustained virologic response (SVR, n = 7), and healthy volunteers (n = 23). Concentration of soluble CD81 was assessed semi-quantitatively after differential centrifugation ranging from 200 g to 100,000 g in the fifth centrifugation fraction by immunoblotting and densitometry.
Results: Soluble CD81 was increased in patients with chronic hepatitis C compared to healthy subjects (p = 0.03) and cured patients (p = 0.017). Patients with chronic HCV infection and persistently normal ALT levels and patients with long term SVR had similar soluble CD81 levels as healthy controls (p>0.2). Overall, soluble CD81 levels were associated with ALT levels (r = 0.334, p = 0.016) and severe liver fibrosis (p = 0.027).
Conclusion: CD81 is increased in the exosomal serum fraction in patients with chronic hepatitis C and appears to be associated with inflammatory activity and severity of fibrosis.
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.