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Phenytoin (PHT), valproic acid, and modern antiepileptic drugs (AEDs), eg, remacemide, loreclezole, and safinamide, are only effective within a maximum of 70%-80% of epileptic patients, and in many cases the clinical use of AEDs is restricted by their side effects. Therefore, a continuous need remains to discover innovative chemical entities for the development of active and safer AEDs. Ligands targeting central histamine H3 receptors (H3Rs) for epilepsy might be a promising therapeutic approach. To determine the potential of H3Rs ligands as new AEDs, we recently reported that no anticonvulsant effects were observed for the (S)-2-(4-(3-(piperidin-1-yl)propoxy)benzylamino)propanamide (1). In continuation of our research, we asked whether anticonvulsant differences in activities will be observed for its R-enantiomer, namely, (R)-2-(4-(3-(piperidin-1-yl)propoxy)benzylamino)propaneamide (2) and analogs thereof, in maximum electroshock (MES)-, pentylenetetrazole (PTZ)-, and strychnine (STR)-induced convulsion models in rats having PHT and valproic acid (VPA) as reference AEDs. Unlike the S-enantiomer (1), the results show that animals pretreated intraperitoneally (ip) with the R-enantiomer 2 (10 mg/kg) were moderately protected in MES and STR induced models, whereas proconvulsant effect was observed for the same ligand in PTZ-induced convulsion models. However, animals pretreated with intraperitoneal doses of 5, 10, or 15 mg/kg of structurally bulkier (R)-enantiomer (3), in which 3-piperidinopropan-1-ol in ligand 2 was replaced by (4-(3-(piperidin-1-yl)propoxy)phenyl)methanol, and its (S)-enantiomer (4) significantly and in a dose-dependent manner reduced convulsions or exhibited full protection in MES and PTZ convulsions model, respectively. Interestingly, the protective effects observed for the (R)-enantiomer (3) in MES model were significantly greater than those of the standard H3R inverse agonist/antagonist pitolisant, comparable with those observed for PHT, and reversed when rats were pretreated with the selective H3R agonist R-(α)-methyl-histamine. Comparisons of the observed antagonistic in vitro affinities among the ligands 1-6 revealed profound stereoselectivity at human H3Rs with varying preferences for this receptor subtype. Moreover, the in vivo anticonvulsant effects observed in this study for ligands 1-6 showed stereoselectivity in different convulsion models in male adult rats.
Abstract: The hallmarks of Alzheimer’s disease (AD) are characterized by cognitive decline and behavioral changes. The most prominent brain region affected by the progression of AD is the hippocampal formation. The pathogenesis involves a successive loss of hippocampal neurons accompanied by a decline in learning and memory consolidation mainly attributed to an accumulation of senile plaques. The amyloid precursor protein (APP) has been identified as precursor of Aβ-peptides, the main constituents of senile plaques. Until now, little is known about the physiological function of APP within the central nervous system. The allocation of APP to the proteome of the highly dynamic presynaptic active zone (PAZ) highlights APP as a yet unknown player in neuronal communication and signaling. In this study, we analyze the impact of APP deletion on the hippocampal PAZ proteome. The native hippocampal PAZ derived from APP mouse mutants (APP-KOs and NexCreAPP/APLP2-cDKOs) was isolated by subcellular fractionation and immunopurification. Subsequently, an isobaric labeling was performed using TMT6 for protein identification and quantification by high-resolution mass spectrometry. We combine bioinformatics tools and biochemical approaches to address the proteomics dataset and to understand the role of individual proteins. The impact of APP deletion on the hippocampal PAZ proteome was visualized by creating protein-protein interaction (PPI) networks that incorporated APP into the synaptic vesicle cycle, cytoskeletal organization, and calcium-homeostasis. The combination of subcellular fractionation, immunopurification, proteomic analysis, and bioinformatics allowed us to identify APP as structural and functional regulator in a context-sensitive manner within the hippocampal active zone network.
Author Summary: More than 20 years ago, the amyloid precursor protein (APP) was identified as the precursor protein of the Aβ peptide, the main component of senile plaques in brains affected by Alzheimer’s disease. However, little is known about the physiological function of amyloid precursor protein. Allocating APP to the proteome of the structurally and functionally dynamic presynaptic active zone highlights APP as a hitherto unknown player within the presynaptic network. The hippocampus is the most prominent brain region for learning and memory consolidation, and a vulnerable target for neurodegenerative disease, e. g. Alzheimer’s disease. Therefore, our experimental design is focused on the hippocampal neurotransmitter release site. Currently, the underlying mechanism of how APP acts within presynaptic networks is still elusive. Within the scope of this research article, we constructed a network of APP within the presynaptic active zone and how deletion of APP affects these individual networks. We combine bioinformatics tools and biochemical approaches to address the dataset provided by proteomics. Furthermore, we could unravel that APP executes regulatory functions within the synaptic vesicle cycle, cytoskeletal rearrangements and Ca2+-homeostasis. Taken together, our findings offer a new perspective on the physiological function of APP in the central nervous system and may provide a molecular link to the pathogenesis of Alzheimer’s disease.
One of important consequences of Hagedorn statistical bootstrap model is the prediction of limiting temperature Tcrit for hadron systems colloquially known as Hagedorn temperature. According to Hagedorn, this effect should be observed in hadron spectra obtained in infinite equilibrated nuclear matter rather than in relativistic heavy-ion collisions. We present results of microscopic model calculations for the infinite nuclear matter, simulated by a box with periodic boundary conditions. The limiting temperature indeed appears in the model calculations. Its origin is traced to strings and many-body decays of resonances.
The growth of aerosol due to the aqueous phase oxidation of sulfur dioxide by ozone was measured in laboratory-generated clouds created in the Cosmics Leaving OUtdoor Droplets (CLOUD) chamber at the European Organization for Nuclear Research (CERN). Experiments were performed at 10 and −10 °C, on acidic (sulfuric acid) and on partially to fully neutralised (ammonium sulfate) seed aerosol. Clouds were generated by performing an adiabatic expansion – pressurising the chamber to 220 hPa above atmospheric pressure, and then rapidly releasing the excess pressure, resulting in a cooling, condensation of water on the aerosol and a cloud lifetime of approximately 6 min. A model was developed to compare the observed aerosol growth with that predicted using oxidation rate constants previously measured in bulk solutions. The model captured the measured aerosol growth very well for experiments performed at 10 and −10 °C, indicating that, in contrast to some previous studies, the oxidation rates of SO2 in a dispersed aqueous system can be well represented by using accepted rate constants, based on bulk measurements. To the best of our knowledge, these are the first laboratory-based measurements of aqueous phase oxidation in a dispersed, super-cooled population of droplets. The measurements are therefore important in confirming that the extrapolation of currently accepted reaction rate constants to temperatures below 0 °C is correct.
Despite the high significance of the Western Siberian grain belt for crop production in Russia, its weed communities are largely unknown. In this region spring wheat is grown on fertile Chernozem soils with large field sizes but land-use intensity per area is low compared to Central Europe. By using a randomized sampling design we studied arable weed assemblages in the northern forest-steppe zone of Tyumen region on 99 within-field sampling plots of 100 m² size. Surprisingly, with average of 9.8 ± 3.8 species 100 m-2 species richness was low when compared with low-input farming in Central Europe and did not differ between areas of different land-use intensity. Against expectations species composition was not predominantly controlled by soil characteristics and climate, most likely due to short natural gradients. Instead, management factors such as fertilization and tillage intensity seemed to be important factors. Except for two species the Tyumen weed flora consisted mainly of species that are widespread throughout the temperate zone. We found only 10 species with an origin or core area in North Asia or Eastern Europe. The species pool was generally small and with 26% the proportion of non-native species (archaeophytes) was low, when compared to Central European weed communities. Given that weed communities with higher species richness are described from neighboring Bashkiria, we conclude that arable land-use intensity in Tyumen region is high enough to reduce community species richness within arable fields estimated by a randomized sampling design. Since measured soil nutrient values did not affect species richness, herbicide use is most likely the crucial management factor. Furthermore, species-richness was vitally restricted by the small species pool. The low proportion of thermophilous arable weed species that originate from the Mediterranean or Middle-Eastern area and contribute signif-icantly to the Central European weed diversity indicate that climatic dispersal limitations may be re-sponsible for the small number of weed species in the Tyumen flora. An additional constraint was the short history of arable farming in Western Siberia, where considerable arable land use was started only by the end of the 17th century.
19(S)-hydroxy-eicosatetraenoic acid (19(S)-HETE) belongs to a family of arachidonic acid metabolites produced by cytochrome P450 enzymes, which play critical roles in the regulation of cardiovascular, renal and pulmonary functions. Although it has been known for a long time that 19(S)-HETE has vascular effects, its mechanism of action has remained unclear. In this study we show that 19(S)-HETE induces cAMP accumulation in the human megakaryoblastic leukemia cell line MEG-01. This effect was concentration-dependent with an EC50 of 520 nM, insensitive to pharmacological inhibition of COX-1/2 and required the expression of the G-protein Gs. Systematic siRNA-mediated knock-down of each G-protein coupled receptor (GPCR) expressed in MEG-01 followed by functional analysis identified the prostacyclin receptor (IP) as the mediator of the effects of 19(S)-HETE, and the heterologously expressed IP receptor was also activated by 19(S)-HETE in a concentration-dependent manner with an EC50 of 567 nM. Pretreatment of isolated murine platelets with 19(S)-HETE blocked thrombin-induced platelets aggregation, an effect not seen in platelets from mice lacking the IP receptor. Furthermore, 19(S)-HETE was able to relax mouse mesenteric artery- and thoracic aorta-derived vessel segments. While pharmacological inhibition of COX-1/2 enzymes had no effect on the vasodilatory activity of 19(S)-HETE these effects were not observed in vessels from mice lacking the IP receptor. These results identify a novel mechanism of action for the CYP450-dependent arachidonic acid metabolite 19(S)-HETE and point to the existence of a broader spectrum of naturally occurring prostanoid receptor agonists.
Background: Environmental tobacco smoke (ETS) is associated with human morbidity and mortality, particularly chronic obstructive pulmonary disease (COPD and lung cancer. Although direct DNA-damage is a leading pathomechanism in active smokers, passive smoking is enough to induce bronchial asthma, especially in children. Particulate matter (PM) demonstrably plays an important role in this ETS-associated human morbidity, constituting a surrogate parameter for ETS exposure.
Methods: Using an Automatic Environmental Tobacco Smoke Emitter (AETSE) and an in-house developed, non-standard smoking regime, we tried to imitate the smoking process of human smokers to demonstrate the significance of passive smoking. Mean concentration (Cmean) and area under the curve (AUC) of particulate matter (PM2.5) emitted by 3R4F reference cigarettes and the popular filter-tipped and non-filter brand cigarettes “Roth-Händle” were measured and compared. The cigarettes were not conditioned prior to smoking. The measurements were tested for Gaussian distribution and significant differences.
Results: Cmean PM2.5 of the 3R4F reference cigarette: 3911 µg/m3; of the filter-tipped Roth-Händle: 3831 µg/m3; and of the non-filter Roth-Händle: 2053 µg/m3. AUC PM2.5 of the 3R4F reference cigarette: 1,647,006 µg/m3·s; of the filter-tipped Roth-Händle: 1,608,000 µg/m3·s; and of the non-filter Roth-Händle: 858,891 µg/m3·s.
Conclusion: The filter-tipped cigarettes (the 3R4F reference cigarette and filter-tipped Roth-Händle) emitted significantly more PM2.5 than the non-filter Roth-Händle. Considering the harmful potential of PM, our findings note that the filter-tipped cigarettes are not a less harmful alternative for passive smokers. Tobacco taxation should be reconsidered and non-smoking legislation enforced.
Natural Killer (NK) cells are active against Aspergillus fumigatus, which in turn is able to impair the host defense. Unfortunately, little is known on the mutual interaction of NK cells and A. fumigatus. We coincubated human NK cells with A. fumigatus hyphae and assessed the gene expression and protein concentration of selected molecules. We found that A. fumigatus up-regulates the gene expression of pro-inflammatory molecules in NK cells, but inhibited the release of these molecules resulting in intracellular accumulation and limited extracellular availability. A. fumigatus down-regulatedmRNA levels of perforin in NK cells, but increased its intra- and extracellular protein concentration. The gene expression of stress related molecules of A. fumigatus such as heat shock protein hsp90 was up-regulated by human NK cells. Our data characterize for the first time the immunosuppressive effect of A. fumigatus on NK cells and may help to develop new therapeutic antifungal strategies.
This study aims to assess the skill of regional climate models (RCMs) at reproducing the climatology of Mediterranean cyclones. Seven RCMs are considered, five of which were also coupled with an oceanic model. All simulations were forced at the lateral boundaries by the ERA-Interim reanalysis for a common 20-year period (1989–2008). Six different cyclone tracking methods have been applied to all twelve RCM simulations and to the ERA-Interim reanalysis in order to assess the RCMs from the perspective of different cyclone definitions. All RCMs reproduce the main areas of high cyclone occurrence in the region south of the Alps, in the Adriatic, Ionian and Aegean Seas, as well as in the areas close to Cyprus and to Atlas mountains. The RCMs tend to underestimate intense cyclone occurrences over the Mediterranean Sea and reproduce 24–40 % of these systems, as identified in the reanalysis. The use of grid nudging in one of the RCMs is shown to be beneficial, reproducing about 60 % of the intense cyclones and keeping a better track of the seasonal cycle of intense cyclogenesis. Finally, the most intense cyclones tend to be similarly reproduced in coupled and uncoupled model simulations, suggesting that modeling atmosphere–ocean coupled processes has only a weak impact on the climatology and intensity of Mediterranean cyclones.
This paper is a contribution to the special issue on Med-CORDEX, an international coordinated initiative dedicated to the multi-component regional climate modelling (atmosphere, ocean, land surface, river) of the Mediterranean under the umbrella of HyMeX, CORDEX, and Med-CLIVAR and coordinated by Samuel Somot, Paolo Ruti, Erika Coppola, Gianmaria Sannino, Bodo Ahrens, and Gabriel Jordà.
Ataxin-2 (Atxn2)-knock-out mice show branched chain amino acids and fatty acids pathway alterations
(2016)
Human Ataxin-2 (ATXN2) gene locus variants have been associated with obesity, diabetes mellitus type 1,and hypertension in genome-wide association studies, whereas mouse studies showed the knock-out of Atxn2 to lead to obesity, insulin resistance, and dyslipidemia. Intriguingly, the deficiency of ATXN2 protein orthologs in yeast and flies rescues the neurodegeneration process triggered by TDP-43 and Ataxin-1 toxicity. To understand the molecular effects of ATXN2 deficiency by unbiased approaches, we quantified the global proteome and metabolome of Atxn2-knock-out mice with label-free mass spectrometry. In liver tissue, significant downregulations of the proteins ACADS, ALDH6A1, ALDH7A1, IVD, MCCC2, PCCA, OTC, together with bioinformatic enrichment of downregulated pathways for branched chain and other amino acid metabolism, fatty acids, and citric acid cycle were observed. Statistical trends in the cerebellar proteome and in the metabolomic profiles supported these findings. They are in good agreement with recent claims that PBP1, the yeast ortholog of ATXN2, sequestrates the nutrient sensor TORC1 in periods of cell stress. Overall, ATXN2 appears to modulate nutrition and metabolism, and its activity changes are determinants of growth excess or cell atrophy.
Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominantly inherited neurodegenerative disorder with preferential affection of Purkinje neurons, which are known as integrators of calcium currents. The expansion of a polyglutamine (polyQ) domain in the RNA-binding protein ataxin-2 (ATXN2) is responsible for this disease, but the causal roles of deficient ATXN2 functions versus aggregation toxicity are still under debate. Here, we studied mouse mutants with Atxn2 knockout (KO) regarding their cerebellar global transcriptome by microarray and RT-qPCR, in comparison with data from Atxn2-CAG42-knock-in (KIN) mouse cerebellum. Global expression downregulations involved lipid and growth signaling pathways in good agreement with previous data. As a novel effect, downregulations of key factors in calcium homeostasis pathways (the transcription factor Rora, transporters Itpr1 and Atp2a2, as well as regulator Inpp5a) were observed in the KO cerebellum, and some of them also occurred subtly early in KIN cerebellum. The ITPR1 protein levels were depleted from soluble fractions of cerebellum in both mutants, but accumulated in its membrane-associated form only in the SCA2 model. Coimmunoprecipitation demonstrated no association of ITPR1 with Q42-expanded or with wild-type ATXN2. These findings provide evidence that the physiological functions and protein interactions of ATXN2 are relevant for calcium-mediated excitation of Purkinje cells as well as for ATXN2-triggered neurotoxicity. These insights may help to understand pathogenesis and tissue specificity in SCA2 and other polyQ ataxias like SCA1, where inositol regulation of calcium flux and RORalpha play a role.
This article analyzes the representation of linguistic variation in the Finnish translations of four Swedish coming-of-age stories depicting migrant or minority perspectives: Mikael Niemi’s 2000 Popular Music from Vittula, Jonas Hassen Khemiri’s 2003 Ett öga rött, Marjaneh Bakhtiari’s 2005 Kalla det vad fan du vill, and Susanna Alakoski’s 2006 Svinalängorna. Through an analysis of speech and thought representation techniques and focalization, the article explores the role played by literature and translation in the materialization of dialects and sociolects as bounded entities. The paper argues that linguistic and social hybridity, on which the reception of minority and migrant literatures often focuses, is accompanied by the reification of new varieties conceived as authentic expressions of migrant and minority experience. Literature and translation are active agents in such processes, which are largely based on cultural, discursive, and cognitive constraints that condition the interpretation of each text.
Recently, several magnetic resonance imaging contrast mechanisms have been shown to distinguish cortical substructure corresponding to selected cortical layers. Here, we investigate cortical layer and area differentiation by automatized unsupervised clustering of high-resolution diffusion MRI data. Several groups of adjacent layers could be distinguished in human primary motor and premotor cortex. We then used the signature of diffusion MRI signals along cortical depth as a criterion to detect area boundaries and find borders at which the signature changes abruptly. We validate our clustering results by histological analysis of the same tissue. These results confirm earlier studies which show that diffusion MRI can probe layer-specific intracortical fiber organization and, moreover, suggests that it contains enough information to automatically classify architecturally distinct cortical areas. We discuss the strengths and weaknesses of the automatic clustering approach and its appeal for MR-based cortical histology.
Autophagy can act either as a tumor suppressor or as a survival mechanism for established tumors. To understand how autophagy plays this dual role in cancer, in vivo models are required. By using a highly heterogeneous C. elegans germline tumor, we show that autophagy-related proteins are expressed in a specific subset of tumor cells, neurons. Inhibition of autophagy impairs neuronal differentiation and increases tumor cell number, resulting in a shorter life span of animals with tumors, while induction of autophagy extends their life span by impairing tumor proliferation. Fasting of animals with fully developed tumors leads to a doubling of their life span, which depends on modular changes in transcription including switches in transcription factor networks and mitochondrial metabolism. Hence, our results suggest that metabolic restructuring, cell-type specific regulation of autophagy and neuronal differentiation constitute central pathways preventing growth of heterogeneous tumors.
High shares of intermittent renewable power generation in a European electricity system will require flexible backup power generation on the dominant diurnal, synoptic, and seasonal weather timescales. The same three timescales are already covered by today’s dispatchable electricity generation facilities, which are able to follow the typical load variations on the intra-day, intra-week, and seasonal timescales. This work aims to quantify the changing demand for those three backup flexibility classes in emerging large-scale electricity systems, as they transform from low to high shares of variable renewable power generation. A weather-driven modelling is used, which aggregates eight years of wind and solar power generation data as well as load data over Germany and Europe, and splits the backup system required to cover the residual load into three flexibility classes distinguished by their respective maximum rates of change of power output. This modelling shows that the slowly flexible backup system is dominant at low renewable shares, but its optimized capacity decreases and drops close to zero once the average renewable power generation exceeds 50% of the mean load. The medium flexible backup capacities increase for modest renewable shares, peak at around a 40% renewable share, and then continuously decrease to almost zero once the average renewable power generation becomes larger than 100% of the mean load. The dispatch capacity of the highly flexible backup system becomes dominant for renewable shares beyond 50%, and reach their maximum around a 70% renewable share. For renewable shares above 70% the highly flexible backup capacity in Germany remains at its maximum, whereas it decreases again for Europe. This indicates that for highly renewable large-scale electricity systems the total required backup capacity can only be reduced if countries share their excess generation and backup power.
Infectious diseases remain a remarkable health threat for humans and animals. In the past, the epidemiology, etiology and pathology of infectious agents affecting humans and animals have mostly been investigated in separate studies. However, it is evident, that combined approaches are needed to understand geographical distribution, transmission and infection biology of “zoonotic agents”. The genus Bartonella represents a congenial example of the synergistic benefits that can arise from such combined approaches: Bartonella spp. infect a broad variety of animals, are linked with a constantly increasing number of human diseases and are transmitted via arthropod vectors. As a result, the genus Bartonella is predestined to play a pivotal role in establishing a One Health concept combining veterinary and human medicine.
As current classical Hodgkin lymphoma (cHL) treatment strategies have pronounced side-effects, specific inhibition of signaling pathways may offer novel strategies in cHL therapy. Basal autophagy, a regulated catabolic pathway to degrade cell's own components, is in cancer linked with both, tumor suppression or promotion. The finding that basal autophagy enhances tumor cell survival would thus lead to immediately testable strategies for novel therapies. Thus, we studied its contribution in cHL.We found constitutive activation of autophagy in cHL cell lines and primary tissue. The expression of key autophagy-relevant proteins (e.g. Beclin-1, ULK1) and LC3 processing was increased in cHL cells, even in lymphoma cases. Consistently, cHL cells exhibited elevated numbers of autophagic vacuoles and intact autophagic flux. Autophagy inhibition with chloroquine or inactivation of ATG5 induced apoptosis and reduced proliferation of cHL cells. Chloroquine-mediated inhibition of basal autophagy significantly impaired HL growth in-vivo in NOD SCID γc-/- (NSG) mice. We found that basal autophagy plays a pivotal role in sustaining mitochondrial function.We conclude that cHL cells require basal autophagy for growth, survival and sustained metabolism making them sensitive to autophagy inhibition. This suggests basal autophagy as useful target for new strategies in cHL treatment.
This study investigated laypersons’ perception of invasive alien plant species (IAPS) and attitudes towards their management with the help of a written questionnaire in the cities of Zurich, Geneva, and Lugano, Switzerland. Survey participants (n = 720) judged attractiveness from certain species on visual contact (eight IAPS were shown as photographs). Trachycarpus fortunei and Ludwigia grandiflora were liked most, while Ambrosia artemisiifolia was clearly disliked most. With the exception of Trachycarpus fortunei, all plant species were perceived as rather ordinary, familiar and native to Switzerland, and feelings of ordinariness, familiarity and nativeness were positively correlated. Few participants could correctly identify the species depicted. Knowledge of an IAPS (ability to identify it) and desire to have it around were negatively correlated. Participants agreed most with the eradication of IAPS that cause serious costs and problems. However, people were rather unwilling to remove Buddleja davidii, Solidago canadensis, and Trachycarpus fortunei which are already widely established ornamentals in settlement areas or gardens. Overall, willingness to remove an IAPS and to report it to the authorities decreased with increasing desirability (and thus beauty) of a species.
Gastric cancer is one of the most common malignancies and a leading cause of cancer death worldwide. The prognosis of stomach cancer is generally poor as this cancer is not very sensitive to commonly used chemotherapies. Epigenetic modifications play a key role in gastric cancer and contribute to the development and progression of this malignancy. In order to explore new treatment options in this target area we have screened a library of epigenetic inhibitors against gastric cancer cell lines and identified inhibitors for the BET family of bromodomains as potent inhibitors of gastric cancer cell proliferations. Here we show that both the pan-BET inhibitor (+)-JQ1 as well as a newly developed specific isoxazole inhibitor, PNZ5, showed potent inhibition of gastric cancer cell growth. Intriguingly, we found differences in the antiproliferative response between gastric cancer cells tested derived from Brazilian patients as compared to those from Asian patients, the latter being largely resistant to BET inhibition. As BET inhibitors are entering clinical trials these findings provide the first starting point for future therapies targeting gastric cancer.
Beyond radicalism and resignation: the competing logics for public participation in policy decisions
(2016)
Participation – like justice or freedom – is a term that can be constructed in multiple ways. However, existing typologies of participation pay little attention to the alternative logics for public participation in policy decisions: either they assume one particular normative bias or categorise by institutional design features without reference to the broader ideology that informs the use of these designs. This paper outlines an alternative approach that connects the variety in participatory practices to competing theories of democracy and public administration. It identifies four archetypes of participation: knowledge transfer; collective decision-making; choice and voice; and arbitration and oversight.
A variety of joint action studies show that people tend to fall into synchronous behavior with others participating in the same task, and that such synchronization is beneficial, leading to greater rapport, satisfaction, and performance. It has been noted that many of these task environments require simple interactions that involve little planning of action coordination toward a shared goal. The present study utilized a complex joint construction task in which dyads were instructed to build model cars while their hand movements and heart rates were measured. Participants built these models under varying conditions, delimiting how freely they could divide labor during a build session. While hand movement synchrony was sensitive to the different tasks and outcomes, the heart rate measure did not show any effects of interpersonal synchrony. Results for hand movements show that the more participants were constrained by a particular building strategy, the greater their behavioral synchrony. Within the different conditions, the degree of synchrony was predictive of subjective satisfaction and objective product outcomes. However, in contrast to many previous findings, synchrony was negatively associated with superior products, and, depending on the constraints on the interaction, positively or negatively correlated with higher subjective satisfaction. These results show that the task context critically shapes the role of synchronization during joint action, and that in more complex tasks, not synchronization of behavior, but rather complementary types of behavior may be associated with superior task outcomes.
Biallelic mutations in TMEM126B cause severe complex i deficiency with a variable clinical phenotype
(2016)
Complex I deficiency is the most common biochemical phenotype observed in individuals with mitochondrial disease. With 44 structural subunits and over 10 assembly factors, it is unsurprising that complex I deficiency is associated with clinical and genetic heterogeneity. Massively parallel sequencing (MPS) technologies including custom, targeted gene panels or unbiased whole-exome sequencing (WES) are hugely powerful in identifying the underlying genetic defect in a clinical diagnostic setting, yet many individuals remain without a genetic diagnosis. These individuals might harbor mutations in poorly understood or uncharacterized genes, and their diagnosis relies upon characterization of these orphan genes. Complexome profiling recently identified TMEM126B as a component of the mitochondrial complex I assembly complex alongside proteins ACAD9, ECSIT, NDUFAF1, and TIMMDC1. Here, we describe the clinical, biochemical, and molecular findings in six cases of mitochondrial disease from four unrelated families affected by biallelic (c.635G>T [p.Gly212Val] and/or c.401delA [p.Asn134Ilefs∗2]) TMEM126B variants. We provide functional evidence to support the pathogenicity of these TMEM126B variants, including evidence of founder effects for both variants, and establish defects within this gene as a cause of complex I deficiency in association with either pure myopathy in adulthood or, in one individual, a severe multisystem presentation (chronic renal failure and cardiomyopathy) in infancy. Functional experimentation including viral rescue and complexome profiling of subject cell lines has confirmed TMEM126B as the tenth complex I assembly factor associated with human disease and validates the importance of both genome-wide sequencing and proteomic approaches in characterizing disease-associated genes whose physiological roles have been previously undetermined.
Allostery is a phenomenon observed in many proteins where binding of a macromolecular partner or a small-molecule ligand at one location leads to specific perturbations at a site not in direct contact with the region where the binding occurs. The list of proteins under allosteric regulation includes AGC protein kinases. AGC kinases have a conserved allosteric site, the phosphoinositide-dependent protein kinase 1 (PDK1)-interacting fragment (PIF) pocket, which regulates protein ATP-binding, activity, and interaction with substrates. In this study, we identify small molecules that bind to the ATP-binding site and affect the PIF pocket of AGC kinase family members, PDK1 and Aurora kinase. We describe the mechanistic details and show that although PDK1 and Aurora kinase inhibitors bind to the conserved ATP-binding site, they differentially modulate physiological interactions at the PIF-pocket site. Our work outlines a strategy for developing bidirectional small-molecule allosteric modulators of protein kinases and other signaling proteins.
BACKGROUND: Polyclonal anti-thymocyte globulins (ATGs) are immunosuppressive drugs widely used in induction of immunosuppression and treatment of acute rejection after solid organ transplantation. We have previously demonstrated that ATGs bind to endothelial cells in vitro, and are able to modulate ECs. The aim of this study was to investigate the binding of ATGs to endothelial cells under in vivo conditions.
MATERIAL AND METHODS: Muscle biopsies from extremities of cynomolgus monkeys were obtained after ischemia/reperfusion at 4°C. ATGs (Thymoglobulin, Sanofi-Aventis, France; 1 mg/kg) were added to the blood 30 min prior to the reperfusion. Biopsies (n=10) of patients undergoing heart transplantation and preoperatively treated with ATGs (Thymoglobulin, Sanofi-Aventis, France; 1.5 mg/kg) as induction therapy were also analyzed 6 hours and 7 days after induction. Binding of ATGs to ECs was analyzed with an anti-rabbit IgG antibody by means of immunohistochemistry.
RESULTS: Binding of ATGs to endothelial cells could be demonstrated in vivo in our animal experiments 4 hours after reperfusion, as well as in the clinical biopsies 6 hours after induction of immunosuppression in heart transplant patients, showing a preferred localization in post-capillary veins. No expression of ATGs on the endothelial surface could be observed after 7 days, suggesting that ATGs may be washed out from the endothelial surface in a time-dependent manner.
CONCLUSIONS: Our results show that ATGs are able to bind to endothelial cells in an experimental model and in clinical practice, supporting preconditioning strategies with ATGs in solid organ transplantation.
Biological control of introduced weeds in the 22 Pacific island countries and territories (PICTs) began in 1911, with the lantana seed-feeding fly introduced into Fiji and New Caledonia from Hawaii. To date, a total of 62 agents have been deliberately introduced into the PICTs to control 21 weed species in 17 countries. A further two agents have spread naturally into the region. The general impact of the 36 biocontrol agents now established in the PICTs ranges from none to complete control of their target weed(s). Fiji has been most active in weed biocontrol, releasing 30 agents against 11 weed species. Papua New Guinea, Guam, and the Federated States of Micronesia have also been very active in weed biocontrol. For some weeds such as Lantana camara, agents have been released widely, and can now be found in 15 of the 21 PICTs in which the weed occurs. However, agents for other commonly found weeds, such as Sida acuta, have been released in only a few countries in which the weed is present. There are many safe and effective biocontrol agents already in the Pacific that could be utilised more widely, and highly effective agents that have been released elsewhere in the world that could be introduced following some additional host specificity testing. This paper discusses the current status of biological control efforts against introduced weeds in the 22 PICTs and reviews options that could be considered by countries wishing to initiate weed biological control programmes.
In a recent Discussion Paper, Hoffmann and Courchamp (2016) posed the question: are biological invasions and natural colonisations that different? This apparently simple question resonates at the core of the biological study of human-induced global change, and we strongly believe that the answer is yes: biological invasions and natural colonisations differ in processes and mechanisms in ways that are crucial for science, management, and policy. Invasion biology has, over time, developed into the broader transdisciplinary field of invasion science. At the heart of invasion science is the realisation that biological invasions are not just a biological phenomenon: the human dimension of invasions is a fundamental component in the social-ecological systems in which invasions need to be understood and managed.
We argue that human-mediated invasions are part of the spectrum of species movements, not a unique phenomenon, because species self-dispersing into novel environments are subject to the same barriers of survival, reproduction, dispersal and further range expansion as those assisted by people. Species changing their distributions by human-mediated and non-human mediated modes should be of identical scientific interest to invasion ecology and ecology. Distinctions between human-mediated invasions and natural colonisations are very valid for management and policy, but we argue that these are value-laden distinctions and not necessarily an appropriate division for science, which instead should focus on distinctions based on processes and mechanisms. We propose an all-encompassing framework of species range expansion. This does not detract from the importance of invasion biology as a discipline, but instead will help bring together research being conducted on multiple taxa, and by multiple disciplines, including epidemiology, that are often focused on an identical phenomenon: colonisation.
To improve data availability and exchange in the area of the WAP complex, West Africa’s largest continuous area of reserves, we set up a citizen science project on the iNaturalist platform, allowing contribution of observations, ideally documented by photographs and/or sounds. Along with the project we created a number of online field guides for the local flora. Within only two months, 852 observations of 312 species have been assembled. We expect this dataset to further grow in the future and complement existing data sets from scientific collections and surveys.
Biotic interchange after the connection of previously independently evolving floras and faunas is thought to be one of the key factors that shaped global biodiversity as we see it today. However, it was not known how biotic interchange develops over longer time periods of several million years following the secondary contact of different biotas. Here we present a novel method to investigate the temporal dynamics of biotic interchange based on a phylogeographical meta-analysis by calculating the maximal number of observed dispersal events per million years given the temporal uncertainty of the underlying time-calibrated phylogenies. We show that biotic influx from mainland Asia onto the Indian subcontinent after Eocene continental collision was not a uniform process, but was subject to periods of acceleration, stagnancy and decrease. We discuss potential palaeoenvironmental causes for this fluctuation.
As legislation, research and management of invasive alien species (IAS) are not fully coordinated across countries or different stakeholder groups, one approach leading to more or less standardized activities is based on producing lists of prominent IAS that attain high level of concern and are a subject of priority monitoring and management. These so-called Black, Grey and Watch (alert) Lists represent a convenient starting point for setting priorities in prevention, early warning and management systems. It is important that these lists be based on transparent and robust criteria so as to accommodate interests and perception of impacts by groups of concerned authorities and stakeholders representing sectors as diverse as, e.g. forestry, horticulture, aquaculture, hunting, and nature conservation, and to justify possible trade restrictions. The principles for blacklisting need to be general enough to accommodate differences among taxonomic groups (plants, invertebrates, vertebrates) and invaded environments (e.g. aquatic, terrestrial, urban, suburban, seminatural), and must take into account invasion dynamics, the impact the IAS pose, and management strategies suitable for each particular invader. With these assumptions in mind, we synthesize available information to present Black, Grey and Watch Lists of alien species for the Czech Republic, with recommended categorized management measures for land managers, policy makers and other stakeholders. We took into account differences in the listed species’ distribution, invasion status, known or estimated environmental impact, as well as possible management options, and apply these criteria to both plants and animals. Species with lower impact, but for which some level of management and regulation is desirable, are included on the Grey List. Some potentially dangerous species occurring in European countries with comparable climatic conditions, as well as those introduced in the past but without presently known wild populations in the Czech Republic, are listed on the Watch list. In total, there are 78 plant and 39 animal species on the Black List, 47 and 16 on the Grey List, and 25 and 27, respectively, on the Watch List. The multilayered approach to the classification of alien species, combining their impacts, population status and relevant management, can serve as a model for other countries that are in process of developing their Black Lists.
Background: Patients with Ph-negative myeloproliferative neoplasms (MPN), such as polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are at increased risk for thrombosis/thromboembolism and major bleeding. Due to the morbidity and mortality of these events, antiplatelet and/or anticoagulant agents are commonly employed as primary and/or secondary prophylaxis. On the other hand, disease-related bleeding complications (i.e., from esophageal varices) are common in patients with MPN. This analysis was performed to define the frequency of such events, identify risk factors, and assess antiplatelet/anticoagulant therapy in a cohort of patients with MPN.
Methods: The MPN registry of the Study Alliance Leukemia is a non-interventional prospective study including adult patients with an MPN according to WHO criteria (2008). For statistical analysis, descriptive methods and tests for significant differences as well as contingency tables were used to identify the odds of potential risk factors for vascular events.
Results: MPN subgroups significantly differed in sex distribution, age at diagnosis, blood counts, LDH levels, JAK2V617F positivity, and spleen size (length). While most thromboembolic events occurred around the time of MPN diagnosis, one third of these events occurred after that date. Splanchnic vein thrombosis was most frequent in post-PV-MF and MPN-U patients. The chance of developing a thromboembolic event was significantly elevated if patients suffered from post-PV-MF (OR 3.43; 95 % CI = 1.39–8.48) and splenomegaly (OR 1.76; 95 % CI = 1.15–2.71). Significant odds for major bleeding were previous thromboembolic events (OR = 2.71; 95 % CI = 1.36–5.40), splenomegaly (OR = 2.22; 95 % CI 1.01–4.89), and the administration of heparin (OR = 5.64; 95 % CI = 1.84–17.34). Major bleeding episodes were significantly less frequent in ET patients compared to other MPN subgroups.
Conclusions: Together, this report on an unselected "real-world" cohort of German MPN patients reveals important data on the prevalence, diagnosis, and treatment of thromboembolic and major bleeding complications of MPN.
We compared outcomes from a single-arm study of blinatumomab in adult patients with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia (R/R ALL) with a historical data set from Europe and the United States. Estimates of complete remission (CR) and overall survival (OS) were weighted by the frequency distribution of prognostic factors in the blinatumomab trial. Outcomes were also compared between the trial and historical data using propensity score methods. The historical cohort included 694 patients with CR data and 1112 patients with OS data compared with 189 patients with CR and survival data in the blinatumomab trial. The weighted analysis revealed a CR rate of 24% (95% CI: 20–27%) and a median OS of 3.3 months (95% CI: 2.8–3.6) in the historical cohort compared with a CR/CRh rate of 43% (95% CI: 36–50%) and a median OS of 6.1 months (95% CI: 4.2–7.5) in the blinatumomab trial. Propensity score analysis estimated increased odds of CR/CRh (OR=2.68, 95% CI: 1.67–4.31) and improved OS (HR=0.536, 95% CI: 0.394–0.730) with blinatumomab. The analysis demonstrates the application of different study designs and statistical methods to compare novel therapies for R/R ALL with historical data.
Background: Use of blood oxygenation level-dependent cardiovascular magnetic resonance (BOLD-CMR) to assess perfusion in the lower limb has been hampered by poor reproducibility and a failure to reliably detect post-revascularization improvements in patients with critical limb ischemia (CLI).
Objectives: This study sought to develop BOLD-CMR as an objective, reliable clinical tool for measuring calf muscle perfusion in patients with CLI.
Methods: The calf was imaged at 3-T in young healthy control subjects (n = 12), age-matched control subjects (n = 10), and patients with CLI (n = 34). Signal intensity time curves were generated for each muscle group and curve parameters, including signal reduction during ischemia (SRi) and gradient during reactive hyperemia (Grad). BOLD-CMR was used to assess changes in perfusion following revascularization in 12 CLI patients. Muscle biopsies (n = 28), obtained at the level of BOLD-CMR measurement and from healthy proximal muscle of patients undergoing lower limb amputation (n = 3), were analyzed for capillary-fiber ratio.
Results: There was good interuser and interscan reproducibility for Grad and SRi (all p < 0.0001). The ischemic limb had lower Grad and SRi compared with the contralateral asymptomatic limb, age-matched control subjects, and young control subjects (p < 0.001 for all comparisons). Successful revascularization resulted in improvement in Grad (p < 0.0001) and SRi (p < 0.0005). There was a significant correlation between capillary-fiber ratio (p < 0.01) in muscle biopsies from amputated limbs and Grad measured pre-operatively at the corresponding level.
Conclusions: BOLD-CMR showed promise as a reliable tool for assessing perfusion in the lower limb musculature and merits further investigation in a clinical trial.
Background: Highlighted text in the Internet (i.e., hypertext) is predominantly blue and underlined. The perceptibility of these hypertext characteristics was heavily questioned by applied research and empirical tests resulted in inconclusive results. The ability to recognize blue text in foveal and parafoveal vision was identified as potentially constrained by the low number of foveally centered blue light sensitive retinal cells. The present study investigates if foveal and parafoveal perceptibility of blue hypertext is reduced in comparison to normal black text during reading.
Methods: A silent-sentence reading study with simultaneous eye movement recordings and the invisible boundary paradigm, which allows the investigation of foveal and parafoveal perceptibility, separately, was realized (comparing fixation times after degraded vs. un-degraded parafoveal previews). Target words in sentences were presented in either black or blue and either underlined or normal.
Results: No effect of color and underlining, but a preview benefit could be detected for first pass reading measures. Fixation time measures that included re-reading, e.g., total viewing times, showed, in addition to a preview effect, a reduced fixation time for not highlighted (black not underlined) in contrast to highlighted target words (either blue or underlined or both).
Discussion: The present pattern reflects no detectable perceptual disadvantage of hyperlink stimuli but increased attraction of attention resources, after first pass reading, through highlighting. Blue or underlined text allows readers to easily perceive hypertext and at the same time readers re-visited highlighted words longer. On the basis of the present evidence, blue hypertext can be safely recommended to web designers for future use.
Purpose: Advanced Ewing sarcomas have poor prognosis. They are defined by early relapse (<24 months after diagnosis) and/or by metastasis to multiple bones or bone marrow (BM). We analyzed risk factors, toxicity and survival in advanced Ewing sarcoma patients treated with the MetaEICESS vs. EICESS92 protocols.
Design: Of 44 patients, 18 patients were enrolled into two subsequent MetaEICESS protocols between 1992 and 2014, and compared to outcomes of 26 advanced Ewing sarcoma patients treated with EICESS 1992 between 1992 and 1996. MetaEICESS 1992 consisted of induction chemotherapy, whole body imaging directed radiotherapy to the primary tumor and metastases, tandem high-dose chemotherapy and autologous rescue. In MetaEICESS 2007 this treatment was complemented by allogeneic stem cell transplantation. EICESS 1992 comprised induction chemotherapy, local therapy to the primary tumor only followed by consolidation chemotherapy.
Results: In MetaEICESS 8/18 patients survived in complete remission vs. 2/26 in EICESS 1992 (p<0.05). Survival did not differ between MetaEICESS 2007 and MetaEICESS 1992. Three MetaEICESS patients died of complications, all in MetaEICESS 1992. After exclusion of patients succumbing to treatment related complications (n=3), 7/10 patients survived without BM involvement, in contrast to 0/5 patients with BM involvement. This was confirmed in a multivariate analysis. There was no correlation between BM involvement and the number of metastases at diagnosis.
Conclusion: The MetaEICESS protocols yield long-term disease-free survival in patients with advanced Ewing sarcoma. Allogeneic stem cell transplantation was not associated with increased death of complications. Bone marrow involvement is a risk factor distinct from multiple bone metastases.
The presence of cerebral lesions in patients with neurosensory alterations provides a unique window into brain function. Using a fuzzy logic based combination of morphological information about 27 olfactory-eloquent brain regions acquired with four different brain imaging techniques, patterns of brain damage were analyzed in 127 patients who displayed anosmia, i.e., complete loss of the sense of smell (n = 81), or other and mechanistically still incompletely understood olfactory dysfunctions including parosmia, i.e., distorted perceptions of olfactory stimuli (n = 50), or phantosmia, i.e., olfactory hallucinations (n = 22). A higher prevalence of parosmia, and as a tendency also phantosmia, was observed in subjects with medium overall brain damage. Further analysis showed a lower frequency of lesions in the right temporal lobe in patients with parosmia than in patients without parosmia. This negative direction of the differences was unique for parosmia. In anosmia, and also in phantosmia, lesions were more frequent in patients displaying the respective symptoms than in those without these dysfunctions. In anosmic patients, lesions in the right olfactory bulb region were much more frequent than in patients with preserved sense of smell, whereas a higher frequency of carriers of lesions in the left frontal lobe was observed for phantosmia. We conclude that anosmia, and phantosmia, are the result of lost function in relevant brain areas whereas parosmia is more complex, requiring damaged and intact brain regions at the same time.
Bromodomain-containing protein 4 (BRD4) is a member of the bromo- and extraterminal (BET) domain-containing family of epigenetic readers which is under intensive investigation as a target for anti-tumor therapy. BRD4 plays a central role in promoting the expression of select subsets of genes including many driven by oncogenic transcription factors and signaling pathways. However, the role of BRD4 and the effects of BET inhibitors in non-transformed cells remain mostly unclear. We demonstrate that BRD4 is required for the maintenance of a basal epithelial phenotype by regulating the expression of epithelial-specific genes including TP63 and Grainy Head-like transcription factor-3 (GRHL3) in non-transformed basal-like mammary epithelial cells. Moreover, BRD4 occupancy correlates with enhancer activity and enhancer RNA (eRNA) transcription. Motif analyses of cell context-specific BRD4-enriched regions predicted the involvement of FOXO transcription factors. Consistently, activation of FOXO1 function via inhibition of EGFR-AKT signaling promoted the expression of TP63 and GRHL3. Moreover, activation of Src kinase signaling and FOXO1 inhibition decreased the expression of FOXO/BRD4 target genes. Together, our findings support a function for BRD4 in promoting basal mammary cell epithelial differentiation, at least in part, by regulating FOXO factor function on enhancers to activate TP63 and GRHL3 expression.
Cancer research has become a global enterprise, and the number of researchers, as well as the cost for their activities, has skyrocketed. The budget for the National Cancer Institute of the United States National Institutes of Health alone was US$5.2 billion in 2015. Since most of the research is funded by public money, it is perfectly legitimate to ask if these large expenses are worth it. In this brief commentary, we recapitulate some of the breakthroughs that mark the history of breast cancer research over the past decades and emphasize the resulting benefits for afflicted women. In 1971, only 40% of women diagnosed with breast cancer would live another 10 years. Today, nearly 80% of women reach that significant milestone in most developed countries. This dramatic change has afforded breast cancer patients many productive years and a better quality of life. Progress resulted largely from advances in the understanding of the molecular details of the disease and their translation into innovative, rationally designed therapies. These developments are founded on the revolution in molecular and cellular biology, an entirely new array of methods and technologies, the enthusiasm, optimism, and diligence of scientists and clinicians, and the considerable funding efforts from public and private sources. We were lucky to be able to spend our productive years in a period of scientific upheaval in which methods and concepts were revolutionized and that allowed us to contribute, within the global scientific community, to the progress in basic science and clinical practice.
Bridging markets
(2016)
Under physiological conditions, endothelial cells and the endothelial nitric oxide (NO) synthase (eNOS) are the main source of NO in the cardiovascular system. However, several other cell types have also been implicated in the NO-dependent regulation of cell function, including erythrocytes. NO derived from red blood cells has been proposed to regulate erythrocyte membrane fluidity, inhibit platelet activation and induce vasodilation in hypoxic areas, but these proposals are highly controversial. In the current issue of Cell Communication and Signaling, an elegant study by Gambaryan et al., assayed NO production by erythrocytes by monitoring the activation of the platelet intracellular NO receptor, soluble guanylyl cyclase, and its downstream kinase protein kinase G. After systematically testing different combinations of erythrocyte/platelet suspensions, the authors found no evidence for platelet soluble guanylyl cyclase/protein kinase G activation by erythrocytes and conclude that erythrocytes do not release biologically active NO to inhibit platelet activation.
Background: Multidrug-resistant Gram-negative bacteria (MRGN) and the infections they cause are a serious threat and a challenge to the healthcare system. This particularly applies to carbapenem-resistant Gram-negative bacteria (CRGN). Currently, the introduction of a nationwide mandatory notification system for CRGN in Germany is under consideration. Against this background, this paper presents an analysis of the mandatory reporting system for CRGN in effect since November 2011 in the federal state of Hesse (Germany).
Materials and methods: All carbapenem-resistant Gram-negative bacteria and the detected carbapenemases reported to the public health department of the city of Frankfurt am Main, Hesse, Germany, on the basis of the mandatory notification system were analyzed.
Results: 827 CRGN cases were reported to the public health department of Frankfurt/Main between April 2012 and December 2015. The following bacterial species were reported: Pseudomonas spp. (n=268), Acinetobacter spp. (n=183), Klebsiella spp. (n=195), Enterobacter spp. (n=77), Escherichia coli (n=75) and others (n=29). Between 2012 and 2015, a reduction of the CRGN reports was noticed, mainly due to changes in the reporting of Pseudomonas spp. Between 2012 and 2015, the total number of notifications decreased slightly, although the number of reported CRGN in screening samples increased, thus giving no indication of a decreased testing frequency. For 10.5% of the patients, the place of residence was not Germany, 18.0% of the patients had previously stayed in hospitals abroad, often in countries with a high CRGN prevalence. CRGN bacteria were reported from all of Frankfurt’s hospitals, and 3.9% were reported from out-patient care facilities. Carbapenemases were detected and reported in 251 CRGN bacteria, including 73 OXA-48, 76 OXA-23, 56 NDM subtypes, and 21 KPC subtypes. There have been no major epidemiological signs of outbreak scenarios.
Discussion: CRGN bacteria are already widespread in patients from hospitals and out-patient care facilities. Clearly, infection control measurements should therefore not only include hospital patients but also those receiving out-patient care. Screening strategies focused on patients from foreign countries with high MRGN prevalence is not sufficient, as only 10.5% of MRGN patients resided in those countries, and only 18% of the patients had been previously treated in a foreign hospital. In a public health context, infection control measures should therefore encompass broader screening strategies.
A three-dimensional gridded climatology of carbon monoxide (CO) has been developed by trajectory mapping of global MOZAIC-IAGOS in situ measurements from commercial aircraft data. CO measurements made during aircraft ascent and descent, comprising nearly 41 200 profiles at 148 airports worldwide from December 2001 to December 2012, are used. Forward and backward trajectories are calculated from meteorological reanalysis data in order to map the CO measurements to other locations and so to fill in the spatial domain. This domain-filling technique employs 15 800 000 calculated trajectories to map otherwise sparse MOZAIC-IAGOS data into a quasi-global field. The resulting trajectory-mapped CO data set is archived monthly from 2001 to 2012 on a grid of 5° longitude × 5° latitude × 1 km altitude, from the surface to 14 km altitude.
The mapping product has been carefully evaluated, firstly by comparing maps constructed using only forward trajectories and using only backward trajectories. The two methods show similar global CO distribution patterns. The magnitude of their differences is most commonly 10 % or less and found to be less than 30 % for almost all cases. Secondly, the method has been validated by comparing profiles for individual airports with those produced by the mapping method when data from that site are excluded. While there are larger differences below 2 km, the two methods agree very well between 2 and 10 km with the magnitude of biases within 20 %. Finally, the mapping product is compared with global MOZAIC-IAGOS cruise-level data, which were not included in the trajectory-mapped data set, and with independent data from the NOAA aircraft flask sampling program. The trajectory-mapped MOZAIC-IAGOS CO values show generally good agreement with both independent data sets.
Maps are also compared with version 6 data from the Measurements Of Pollution In The Troposphere (MOPITT) satellite instrument. Both data sets clearly show major regional CO sources such as biomass burning in Central and southern Africa and anthropogenic emissions in eastern China. While the maps show similar features and patterns, and relative biases are small in the lowermost troposphere, we find differences of ∼ 20 % in CO volume mixing ratios between 500 and 300 hPa. These upper-tropospheric biases are not related to the mapping procedure, as almost identical differences are found with the original in situ MOZAIC-IAGOS data. The total CO trajectory-mapped MOZAIC-IAGOS column is also higher than the MOPITT CO total column by 12–16 %.
The data set shows the seasonal CO cycle over different latitude bands and altitude ranges as well as long-term trends over different latitude bands. We observe a decline in CO over the northern hemispheric extratropics and the tropics consistent with that reported by previous studies using other data sources.
We anticipate use of the trajectory-mapped MOZAIC-IAGOS CO data set as an a priori climatology for satellite retrieval and for air quality model validation and initialization.
Atrial fibrillation (AF) is one of the most common arrhythmias in adults and is associated with a high incidence of stroke and heart failure (HF). Despite the advance of AF catheter ablation during the past decades, the high reoccurrence rate of AF after catheter ablation urges improvements of diagnostic approaches, therapies, and technologies. P. D. Dallaglio et al. reviewed the role of adenosine in pulmonary vein isolation in a meta-analysis of 11 studies. The analysis revealed that adenosine is useful to unmask dormant connection (DC) after a first ablation procedure and further ablation at sites of DC would reduce the rate of redo procedures for postablation AF recurrence. The authors also suggested that the use of adenosine should be accompanied by sufficient waiting time. ...
Objectives: Assessment of the clinical severity of Fabry disease (FD), an X-linked, rare, progressive disorder based on a genetic defect in alpha-galactosidase is challenging, especially regarding cardiac involvement. The aim of the study was to evaluate the diagnostic value of cardiac troponin I (cTnI) in discriminating FD patients with cardiac involvement in a large FD patient cohort.
Methods: cTnI levels were measured with a contemporary sensitive assay in plasma samples taken routinely from FD patients. The assay was calibrated to measure cTnI levels ≥0.01 ng/ml. Elevated cTnI values (cut-off ≥0.04 ng/ml) were correlated with clinical data.
Results: cTnI was assessed in 62 FD patients (median age: 47 years, males: 36%). Elevated cTnI levels were detected in 23 (37%) patients. Patients with a cTnI elevation were older (median 55 years versus 36 years, p<0.001). Elevated cTnI levels were associated with the presence of a LVH (16/23 versus 1/39; OR 65.81, CI: 6.747–641.859; p<0.001). In almost all patients with a left ventricular hypertrophy (LVH) elevated cTnI levels were detected (16/17, 94%). Absolute cTnI levels in patients with LVH were higher than in those without (median 0.23 ng/ml versus 0.02 ng/ml; p<0.001). A cTnI level <0.04ng/ml had a high negative predictive value regarding the presence of a LVH (38/39, 97%). In a control group of non-FD patients (n = 17) with LVH (due to hypertension) none showed cTnI levels ≥0.01 ng/ml.
Conclusions: Elevated cTnI levels are common in FD patients, reflecting cardiac involvement. FD patients might benefit from a continuous cTnI monitoring.
A 79 year old female patient was admitted to our emergency department with a fracture of the right medial femoral neck six days after a fall on her right side and a cemented hemiprosthesis was implanted. Five days later, she developed a hemorrhagic shock and was diagnosed with a delayed splenic rupture and the spleen was resected. Histopathological examination showed a delayed rupture of an otherwise normal spleen without signs of an underlying pathology. The outcome was fatal: In the postoperative course she developed pneumonia, three weeks later she succumbed due to multiple organ failure.
Even careful reevaluation of the case did not provide any clues to expect an injury of the spleen according to trauma mechanism.
This case shows that delayed splenic rupture of a normal spleen may occur even after a low energy trauma. Injury of the spleen should therefore always be considered, even with an uncharacteristic anamnesis. Physical examination after trauma should therefore always include a careful clinical evaluation. The clinical threshold for a FAST examination should be low.
The coincidence of a femoral neck fracture and a splenic rupture after a low energy trauma has not been reported before.
Scientometric results on publication trends in clinical psychology, which refer to publication type and methodology of case studies/reports, are presented. Absolute and relative frequencies of clinical case studies are identified for the segment “mental and behavioral disorders” in MEDLINE (ICD-10 Chapter V [F]) as well as for clinical psychology publications documented in PsycINFO and PSYNDEX in 40 publication years (1975-2014). Results show an increase of the absolute number of published case studies documented in MEDLINE and PsycINFO (but not in PSYNDEX), which is highly correlated with the total increase of clinical psychology publications in both databases. Relative frequencies show another picture, namely a drop of the percentage of case studies on mental and behavioral disorders in MEDLINE, and a sharp drop in PSYNDEX since the 1980s. The trend for the relative frequency of case studies within all publications on clinical psychology documented in PsycINFO is V-shaped with 6% in the 1970s, 3% in the early 1990s, and 4-5% after the millennium. Pros and cons of case studies in clinical psychology research and education are discussed. Qualitative and quantitative case study methodologies are distinguished with respect to the phases of clinical trials and observational studies in evidence-based and empirically supported psychotherapy. Subsequently, methodological constraints are balanced with specific values in clinical training, applied research, and innovative research on the symptomatology, etiology, and classification of mental disorders as well as on combined and/or integrative treatment techniques and methods.
We have developed a new in vitro skin irritation test based on an open source reconstructed epidermis (OS-REp) with openly accessible protocols for tissue production and test performance. Due to structural, mechanistic and procedural similarity, a blinded catch-up validation study for skin irritation according to OECD Performance Standards (PS) was conducted in three laboratories to promote regulatory acceptance, with OS-REp models produced at a single production site only. While overall sensitivity and predictive capacity met the PS requirements, overall specificity was only 57%. A thorough analysis of the test results led to the assumption that some of the false-positive classifications could have been evoked by volatile skin-irritating chemicals tested in the same culture plate as the non-irritants falsely predicted as irritants. With GC/MS and biological approaches the cross-contamination effect was confirmed and the experimental set-up adapted accordingly. Retesting of the affected chemicals with the improved experimental set-up and otherwise identical protocol resulted in correct classifications as non-irritants. Taking these re-test results into account, 93% overall sensitivity, 70% specificity and 82% accuracy was achieved, which is in accordance with the OECD PS. A sufficient reliability of the method was indicated by a within-laboratory-reproducibility of 85–95% and a between-laboratory-reproducibility of 90%.
Measurements of charged jet production as a function of centrality are presented for p-Pb collisions recorded at sNN−−−√=5.02 TeV with the ALICE detector. Centrality classes are determined via the energy deposit in neutron calorimeters at zero degree, close to the beam direction, to minimise dynamical biases of the selection. The corresponding number of participants or binary nucleon-nucleon collisions is determined based on the particle production in the Pb-going rapidity region. Jets have been reconstructed in the central rapidity region from charged particles with the anti-kT algorithm for resolution parameters R=0.2 and R=0.4 in the transverse momentum range 20 to 120 GeV/c. The reconstructed jet momentum and yields have been corrected for detector effects and underlying-event background. In the five centrality bins considered, the charged jet production in p-Pb collisions is consistent with the production expected from binary scaling from pp collisions. The ratio of jet yields reconstructed with the two different resolution parameters is also independent of the centrality selection, demonstrating the absence of major modifications of the radial jet structure in the reported centrality classes.
We report on the measurement of freeze-out radii for pairs of identical-charge pions measured in Pb--Pb collisions at sNN−−−√=2.76 TeV as a function of collision centrality and the average transverse momentum of the pair kT. Three-dimensional sizes of the system (femtoscopic radii), as well as direction-averaged one-dimensional radii are extracted. The radii decrease with kT, following a power-law behavior. This is qualitatively consistent with expectations from a collectively expanding system, produced in hydrodynamic calculations. The radii also scale linearly with ⟨dNch/dη⟩1/3. This behaviour is compared to world data on femtoscopic radii in heavy-ion collisions. While the dependence is qualitatively similar to results at smaller sNN−−−√, a decrease in the Rout/Rside ratio is seen, which is in qualitative agreement with specific predictions from hydrodynamic models. The results provide further evidence for the production of a collective, strongly coupled system in heavy-ion collisions at the LHC.
The pseudorapidity density of charged particles (dNch/dη) at mid-rapidity in Pb-Pb collisions has been measured at a center-of-mass energy per nucleon pair of sNN−−−√ = 5.02 TeV. It increases with centrality and reaches a value of 1943±54 in |η|<0.5 for the 5% most central collisions. A rise in dNch/dη as a function of sNN−−−√ for the most central collisions is observed, steeper than that observed in proton-proton collisions and following the trend established by measurements at lower energy. The centrality dependence of dNch/dη as a function of the average number of participant nucleons, ⟨Npart⟩, calculated in a Glauber model, is compared with the previous measurement at lower energy. A constant factor of about 1.2 describes the increase in 2⟨Npart⟩⟨dNch/dη⟩ from sNN−−−√ = 2.76 TeV to sNN−−−√ = 5.02 TeV for all centrality intervals, within the measured range of 0-80% centrality. The results are also compared to models based on different mechanisms for particle production in nuclear collisions.
Transverse momentum (pT) spectra of pions, kaons, and protons up to pT=20 GeV/c have been measured in Pb-Pb collisions at sNN−−−√=2.76 TeV using the ALICE detector for six different centrality classes covering 0-80%. The proton-to-pion and the kaon-to-pion ratios both show a distinct peak at pT≈3 GeV/c in central Pb-Pb collisions that decreases towards more peripheral collisions. For pT>10 GeV/c, the nuclear modification factor is found to be the same for all three particle species in each centrality interval within systematic uncertainties of 10-20%. This suggests there is no direct interplay between the energy loss in the medium and the particle species composition in the hard core of the quenched jet. For pT<10 GeV/c, the data provide important constraints for models aimed at describing the transition from soft to hard physics.
The inclusive production of the ψ(2S) charmonium state was studied as a function of centrality in p-Pb collisions at the nucleon-nucleon center of mass energy sNN−−−√ = 5.02 TeV at the CERN LHC. The measurement was performed with the ALICE detector in the center of mass rapidity ranges −4.46<ycms<−2.96 and 2.03<ycms<3.53, down to zero transverse momentum, by reconstructing the ψ(2S) decay to a muon pair. The ψ(2S) production cross section σψ(2S) is presented as a function of the collision centrality, which is estimated through the energy deposited in forward rapidity calorimeters. The relative strength of nuclear effects on the ψ(2S) and on the corresponding 1S charmonium state J/ψ is then studied by means of the double ratio of cross sections [σψ(2S)/σJ/ψ]pPb/[σψ(2S)/σJ/ψ]pp between p-Pb and pp collisions, and by the values of the nuclear modification factors for the two charmonium states. The results show a large suppression of ψ(2S) production relative to the J/ψ at backward (negative) rapidity, corresponding to the flight direction of the Pb-nucleus, while at forward (positive) rapidity the suppressions of the two states are comparable. Finally, comparisons to results from lower energy experiments and to available theoretical models are presented.
The centrality dependence of the charged-particle pseudorapidity density measured with ALICE in Pb–Pb collisions at √sNN=2.76 TeV over a broad pseudorapidity range is presented. This Letter extends the previous results reported by ALICE to more peripheral collisions. No strong change of the overall shape of charged-particle pseudorapidity density distributions with centrality is observed, and when normalised to the number of participating nucleons in the collisions, the evolution over pseudorapidity with centrality is likewise small. The broad pseudorapidity range (−3.5<η<5) allows precise estimates of the total number of produced charged particles which we find to range from 162±22(syst.) to 17170±770(syst.) in 80–90% and 0–5% central collisions, respectively. The total charged-particle multiplicity is seen to approximately scale with the number of participating nucleons in the collision. This suggests that hard contributions to the charged-particle multiplicity are limited. The results are compared to models which describe dNch/dη at mid-rapidity in the most central Pb–Pb collisions and it is found that these models do not capture all features of the distributions.
The article deals with Finnish translations of varieties of spoken language in fiction from the late 19th century to the beginning of the 2000s. It presents the central findings of a comprehensive study on the changes and developments of translational norms in Finnish literature. The study is based on a corpus consisting of 200 literary works (the original and its translations are counted as one work), representing various genres: literary fiction, young-adult fiction, as well as genre fiction (romance and crime). During this 100-year period, the use of colloquial variants in translations has strongly increased, influenced by the changing literary and linguistic norms of original Finnish literature. The norms of different literary genres, however, vary, and rich, non-standard variation can be found in translated works from different periods.
Characterization of blunt chest trauma in a long-term porcine model of severe multiple trauma
(2016)
Chest trauma has a significant relevance on outcome after severe trauma. Clinically, impaired lung function typically occurs within 72 hours after trauma. However, the underlying pathophysiological mechanisms are still not fully elucidated. Therefore, we aimed to establish an experimental long-term model to investigate physiological, morphologic and inflammatory changes, after severe trauma. Male pigs (sus scrofa) sustained severe trauma (including unilateral chest trauma, femur fracture, liver laceration and hemorrhagic shock). Additionally, non-injured animals served as sham controls. Chest trauma resulted in severe lung damage on both CT and histological analyses. Furthermore, severe inflammation with a systemic increase of IL-6 (p = 0.0305) and a local increase of IL-8 in BAL (p = 0.0009) was observed. The pO2/FiO2 ratio in trauma animals decreased over the observation period (p < 0.0001) but not in the sham group (p = 0.2967). Electrical Impedance Tomography (EIT) revealed differences between the traumatized and healthy lung (p < 0.0001). In conclusion, a clinically relevant, long-term model of blunt chest trauma with concomitant injuries has been developed. This reproducible model allows to examine local and systemic consequences of trauma and is valid for investigation of potential diagnostic or therapeutic options. In this context, EIT might represent a radiation-free method for bedside diagnostics.
Premise of the study: Polymorphic microsatellite markers were developed for the lichen species Cetraria aculeata (Parmeliaceae) to study fine-scale population diversity and phylogeographic structure.
Methods and Results: Using Illumina HiSeq and MiSeq, 15 fungus-specific microsatellite markers were developed and tested on 81 specimens from four populations from Spain. The number of alleles ranged from four to 13 alleles per locus with a mean of 7.9, and average gene diversities varied from 0.40 to 0.73 over four populations. The amplification rates of 10 markers (CA01– CA10) in populations of C. aculeata exceeded 85%. The markers also amplified across a range of closely related species, except for locus CA05, which did not amplify in C. australiensis and C. "panamericana," and locus CA10 which did not amplify in C. australiensis.
Conclusions: The identified microsatellite markers will be used to study the genetic diversity and phylogeographic structure in populations of C. aculeata in western Eurasia.
Knowledge about mass discrimination effects in a chemical ionization mass spectrometer (CIMS) is crucial for quantifying, e.g., the recently discovered extremely low volatile organic compounds (ELVOCs) and other compounds for which no calibration standard exists so far. Here, we present a simple way of estimating mass discrimination effects of a nitrate-based chemical ionization atmospheric pressure interface time-of-flight (CI-APi-TOF) mass spectrometer. Characterization of the mass discrimination is achieved by adding different perfluorinated acids to the mass spectrometer in amounts sufficient to deplete the primary ions significantly. The relative transmission efficiency can then be determined by comparing the decrease of signals from the primary ions and the increase of signals from the perfluorinated acids at higher masses. This method is in use already for PTR-MS; however, its application to a CI-APi-TOF brings additional difficulties, namely clustering and fragmentation of the measured compounds, which can be treated with statistical analysis of the measured data, leading to selfconsistent results. We also compare this method to a transmission estimation obtained with a setup using an electrospray ion source, a high-resolution differential mobility analyzer and an electrometer, which estimates the transmission of the instrument without the CI source. Both methods give different transmission curves, indicating non-negligible mass discrimination effects of the CI source. The absolute transmission of the instrument without the CI source was estimated with the HR-DMA method to plateau between the m=z range of 127 and 568 Th at around 1.5 %; however, for the CI source included, the depletion method showed a steady increase in relative transmission efficiency from the m=z range of the primary ion (mainly at 62 Th) to around 550 Th by a factor of around 5. The main advantages of the depletion method are that the instrument is used in the same operation mode as during standard measurements and no knowledge of the absolute amount of the measured substance is necessary, which results in a simple setup.
We report on measurements of a charge-dependent flow using a novel three-particle correlator with ALICE in Pb-Pb collisions at the LHC, and discuss the implications for observation of local parity violation and the Chiral Magnetic Wave (CMW) in heavy-ion collisions. Charge-dependent flow is reported for different collision centralities as a function of the event charge asymmetry. While our results are in qualitative agreement with expectations based on the CMW, the nonzero signal observed in higher harmonics correlations indicates a possible significant background contribution. We also present results on a differential correlator, where the flow of positive and negative charges is reported as a function of the mean charge of the particles and their pseudorapidity separation. We argue that this differential correlator is better suited to distinguish the differences in positive and negative charges expected due to the CMW and the background effects, such as local charge conservation coupled with strong radial and anisotropic flow.
Children’s interpretations of sentences containing focus particles do not seem adult-like until school age. This study investigates how German 4-year-old children comprehend sentences with the focus particle ‘nur’ (only) by using different tasks and controlling for the impact of general cognitive abilities on performance measures. Two sentence types with ‘only’ in either pre-subject or pre-object position were presented. Eye gaze data and verbal responses were collected via the visual world paradigm combined with a sentence-picture verification task. While the eye tracking data revealed an adult-like pattern of focus particle processing, the sentence-picture verification replicated previous findings of poor comprehension, especially for ‘only’ in pre-subject position. A second study focused on the impact of general cognitive abilities on the outcomes of the verification task. Working memory was related to children’s performance in both sentence types whereas inhibitory control was selectively related to the number of errors for sentences with ‘only’ in pre-subject position. These results suggest that children at the age of 4 years have the linguistic competence to correctly interpret sentences with focus particles, which–depending on specific task demands–may be masked by immature general cognitive abilities.
Purpose: To determine the value of the 2D multiple-echo data image combination (MEDIC) sequence relative to the short-tau inversion recovery (STIR) sequence regarding the depiction of chondral lesions in the patellofemoral joint.
Materials and methods: During a period of 6 month patients with acute pain at the anterior aspect of the knee, joint effusion and suspected chondral lesion defect in the patellofemoral joint underwent MRI including axial MEDIC and STIR imaging. Patients with chondral lesions in the patellofemoral joint on at least one sequence were included. The MEDIC and STIR sequence were quantitatively compared regarding the patella cartilage-to-effusion contrast-to-noise ratio (CNR) and qualitatively regarding the depiction of chondral lesions independently scored by two radiologists on a 3-point scale (1 = not depicted; 2 = blurred depicted; 3 = clearly depicted) using the Wilcoxon-Mann-Whitney-Test. For the analysis of inter-observer agreement the Cohen's Weighted Kappa test was used.
Results: 30 of 58 patients (male: female, 21:9; age: 44 ± 12 yrs) revealed cartilage lesions (fissures, n = 5 including fibrillation; gaps, n = 15; delamination, n = 7; osteoarthritis, n = 3) and were included in this study. The STIR-sequence was significantly (p < 0.001) superior to the MEDIC-sequence regarding both, the patella cartilage-to-effusion CNR (mean CNR: 232 ± 61 vs. 40 ± 16) as well as the depiction of chondral lesion (mean score: 2.83 ± 0.4 vs. 1.75 ± 0.7) with substantial inter-observer agreement in the rating of both sequences (κ = 0.76–0.89).
Conclusion: For the depiction of chondral lesions in the patellofemoral joint, the axial STIR-sequence should be chosen in preference to the axial MEDIC-sequence.
OBJECTIVES: Identification of sufficiently trustworthy top 5 list recommendations from the US Choosing Wisely campaign.
SETTING: Not applicable.
PARTICIPANTS: All top 5 list recommendations available from the American Board of Internal Medicine Foundation website.
MAIN OUTCOME MEASURES/INTERVENTIONS: Compilation of US top 5 lists and search for current German highly trustworthy (S3) guidelines. Extraction of guideline recommendations, including grade of recommendation (GoR), for suggestions comparable to top 5 list recommendations. For recommendations without guideline equivalents, the methodological quality of the top 5 list development process was assessed using criteria similar to that used to judge guidelines, and relevant meta-literature was identified in cited references. Judgement of sufficient trustworthiness of top 5 list recommendations was based either on an 'A' GoR of guideline equivalents or on high methodological quality and citation of relevant meta-literature.
RESULTS: 412 top 5 list recommendations were identified. For 75 (18%), equivalents were found in current German S3 guidelines. 44 of these recommendations were associated with an 'A' GoR, or a strong recommendation based on strong evidence, and 26 had a 'B' or a 'C' GoR. No GoR was provided for 5 recommendations. 337 recommendations had no equivalent in the German S3 guidelines. The methodological quality of the development process was high and relevant meta-literature was cited for 87 top 5 list recommendations. For a further 36, either the methodological quality was high without any meta-literature citations or meta-literature citations existed but the methodological quality was lacking. For the remaining 214 recommendations, either the methodological quality was lacking and no literature was cited or the methodological quality was generally unsatisfactory.
CONCLUSIONS: 131 of current US top 5 list recommendations were found to be sufficiently trustworthy. For a substantial number of current US top 5 list recommendations, their trustworthiness remains unclear. Methodological requirements for developing top 5 lists are recommended.
Peptidyl arginine deiminase 4 (PAD4) is a nuclear enzyme that converts arginine residues to citrulline. Although increasingly implicated in inflammatory disease and cancer, the mechanism of action of PAD4 and its functionally relevant pathways remains unclear. E2F transcription factors are a family of master regulators that coordinate gene expression during cellular proliferation and diverse cell fates. We show that E2F-1 is citrullinated by PAD4 in inflammatory cells. Citrullination of E2F-1 assists its chromatin association, specifically to cytokine genes in granulocyte cells. Mechanistically, citrullination augments binding of the BET (bromodomain and extra-terminal domain) family bromodomain reader BRD4 (bromodomain-containing protein 4) to an acetylated domain in E2F-1, and PAD4 and BRD4 coexist with E2F-1 on cytokine gene promoters. Accordingly, the combined inhibition of PAD4 and BRD4 disrupts the chromatin-bound complex and suppresses cytokine gene expression. In the murine collagen-induced arthritis model, chromatin-bound E2F-1 in inflammatory cells and consequent cytokine expression are diminished upon small-molecule inhibition of PAD4 and BRD4, and the combined treatment is clinically efficacious in preventing disease progression. Our results shed light on a new transcription-based mechanism that mediates the inflammatory effect of PAD4 and establish the interplay between citrullination and acetylation in the control of E2F-1 as a regulatory interface for driving inflammatory gene expression.
Peptidyl arginine deiminase 4 (PAD4) is a nuclear enzyme that converts arginine residues to citrulline. Although increasingly implicated in inflammatory disease and cancer, the mechanism of action of PAD4 and its functionally relevant pathways remains unclear. E2F transcription factors are a family of master regulators that coordinate gene expression during cellular proliferation and diverse cell fates. We show that E2F-1 is citrullinated by PAD4 in inflammatory cells. Citrullination of E2F-1 assists its chromatin association, specifically to cytokine genes in granulocyte cells. Mechanistically, citrullination augments binding of the BET (bromodomain and extra-terminal domain) family bromodomain reader BRD4 (bromodomain-containing protein 4) to an acetylated domain in E2F-1, and PAD4 and BRD4 coexist with E2F-1 on cytokine gene promoters. Accordingly, the combined inhibition of PAD4 and BRD4 disrupts the chromatin-bound complex and suppresses cytokine gene expression. In the murine collagen-induced arthritis model, chromatin-bound E2F-1 in inflammatory cells and consequent cytokine expression are diminished upon small-molecule inhibition of PAD4 and BRD4, and the combined treatment is clinically efficacious in preventing disease progression. Our results shed light on a new transcription-based mechanism that mediates the inflammatory effect of PAD4 and establish the interplay between citrullination and acetylation in the control of E2F-1 as a regulatory interface for driving inflammatory gene expression.
Aims: To investigate real-world clinical and patient-related variables associated with initiating GLP-1 receptor agonist (GLP-1RA) treatment relative to initiation of other glucose-lowering therapies in type 2 diabetes (T2D) patients of primary care in Germany.
Methods: Data for 938 T2D patients who started therapy with a GLP-1RA within 823 practices of primary care throughout Germany were retrospectively analyzed (Disease Analyser: 01/2011–03/2014). 5,197 T2D patients who initiated other non-GLP-1RA antidiabetic therapies were selected as controls. Multivariate logistic regression analyses were applied to identify factors associated with GLP-1RA initiation in primary care.
Results: Mean age (SD) of GLP-1RA users was 57.8 (11.8) years (males: 55.5%) and the average BMI was 36.1 (6.7) kg/m2. 22.8% were in diabetologist care and 12.0% had private health insurance. In multivariate regression, choice of GLP-1RA therapy instead of a different glucose-lowering drug class was associated with obesity (odds ratio: 1.68; 95% CI: 1.34–2.10), private health insurance (2.42; 1.89–3.09), younger age (0.94; 0.93–0.95 per year), male sex (0.85; 0.73–0.99), diabetologist care (2.11; 1.73–2.57), and geographic practice location (East vs. West-Germany; 1.25; 1.05–1.49). Among co-medication, angiotensin II antagonists (increased) and non-steroidal antirheumatic agents (decreased) were related to GLP-1RA prescriptions (both p<0.001).
Conclusions: Consistent with German guidelines, GLP-1RA is mainly prescribed preferentially in T2D patients who are obese. GLP-1RA drugs were more frequently used than other options in privately health insured patients and in patients seeing a diabetologist.
Purpose: To evaluate the efficacy of the virtual reality training simulator Eyesi to prepare surgeons for performing pars plana vitrectomies and its potential to predict the surgeons’ performance.
Methods: In a preparation phase, four participating vitreoretinal surgeons performed repeated simulator training with predefined tasks. If a surgeon was assigned to perform a vitrectomy for the management of complex retinal detachment after a surgical break of at least 60 hours it was randomly decided whether a warmup training on the simulator was required (n = 9) or not (n = 12). Performance at the simulator was measured using the built-in scoring metrics. The surgical performance was determined by two blinded observers who analyzed the video-recorded interventions. One of them repeated the analysis to check for intra-observer consistency. The surgical performance of the interventions with and without simulator training was compared. In addition, for the surgeries with simulator training, the simulator performance was compared to the performance in the operating room.
Results: Comparing each surgeon’s performance with and without warmup trainingshowed a significant effect of warmup training onto the final outcome in the operating room. For the surgeries that were preceeded by the warmup procedure, the performance at the simulator was compared with the operating room performance. We found that there is a significant relation. The governing factor of low scores in the simulator were iatrogenic retinal holes, bleedings and lens damage. Surgeons who caused minor damage in the simulation also performed well in the operating room.
Conclusions: Despite the large variation of conditions, the effect of a warmup training as well as a relation between the performance at the simulator and in the operating room was found with statistical significance. Simulator training is able to serve as a warmup to increase the average performance.
BACKGROUND: We retrospectively evaluated the efficacy and toxicity of gross tumor volume (GTV) mean-dose-optimized and real-time motion-compensated robotic stereotactic body radiation therapy (SBRT) in the treatment of liver metastases.
METHODS: Between March 2011 and July 2015, 52 patients were treated with SBRT for a total of 91 liver metastases (one to four metastases per patient) with a median GTV volume of 12 cc (min 1 cc, max 372 cc). The optimization of mean GTV dose was prioritized during treatment planning at the potential cost of planning target volume (PTV) coverage reduction while adhering to safe normal tissue constraints. The delivered median GTV biological effective dose (BED10) was 142.1 Gy10 (range, 60.2 Gy10 -165.3 Gy10) and the prescribed PTV BED10 ranged from 40.6 Gy10 to 112.5 Gy10 (median, 86.1 Gy10). We analyzed local control (LC), progression-free interval (PFI), overall survival (OS), and toxicity.
RESULTS: Median follow-up was 17 months (range, 2-49 months). The 2-year actuarial LC, PFI, and OS rates were 82.1, 17.7, and 45.0 %, and the median PFI and OS were 9 and 23 months, respectively. In univariate analysis histology (p < 0.001), PTV prescription BED10 (HR 0.95, CI 0.91-0.98, p = 0.002) and GTV mean BED10 (HR 0.975, CI 0.954-0.996, p = 0.011) were predictive for LC. Multivariate analysis showed that only extrahepatic disease status at time of treatment was a significant factor (p = 0.033 and p = 0.009, respectively) for PFI and OS. Acute nausea or fatigue grade 1 was observed in 24.1 % of the patients and only 1 patient (1.9 %) had a side effect of grade ≥ 2.
CONCLUSIONS: Robotic real-time motion-compensated SBRT is a safe and effective treatment for one to four liver metastases. Reducing the PTV prescription dose and keeping a high mean GTV dose allowed the reduction of toxicity while maintaining a high local control probability for the treated lesions.
Infections of the central nervous system (CNS) are infrequently diagnosed in immunocompetent patients, but they do occur in a significant proportion of patients with hematological disorders. In particular, patients undergoing allogeneic hematopoietic stem-cell transplantation carry a high risk for CNS infections of up to 15%. Fungi and Toxoplasma gondii are the predominant causative agents. The diagnosis of CNS infections is based on neuroimaging, cerebrospinal fluid examination and biopsy of suspicious lesions in selected patients. However, identification of CNS infections in immunocompromised patients could represent a major challenge since metabolic disturbances, side-effects of antineoplastic or immunosuppressive drugs and CNS involvement of the underlying hematological disorder may mimic symptoms of a CNS infection. The prognosis of CNS infections is generally poor in these patients, albeit the introduction of novel substances (e.g. voriconazole) has improved the outcome in distinct patient subgroups. This guideline has been developed by the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO) with the contribution of a panel of 14 experts certified in internal medicine, hematology/oncology, infectious diseases, intensive care, neurology and neuroradiology. Grades of recommendation and levels of evidence were categorized by using novel criteria, as recently published by the European Society of Clinical Microbiology and Infectious Diseases.
IKZF1 deletion (ΔIKZF1) is an important predictor of relapse in childhood B-cell precursor acute lymphoblastic leukemia. Because of its clinical importance, we previously mapped breakpoints of intragenic deletions and developed a multiplex PCR assay to detect recurrent intragenic ΔIKZF1. Since the multiplex PCR was not able to detect complete deletions (IKZF1 Δ1-8), which account for ~30% of all ΔIKZF1, we aimed at investigating the genomic scenery of IKZF1 Δ1-8. Six samples of cases with IKZF1 Δ1-8 were analyzed by microarray assay, which identified monosomy 7, isochromosome 7q, and large interstitial deletions presenting breakpoints within COBL gene. Then, we established a multiplex ligation-probe amplification (MLPA) assay and screened copy number alterations within chromosome 7 in 43 diagnostic samples with IKZF1 Δ1-8. Our results revealed that monosomy and large interstitial deletions within chromosome 7 are the main causes of IKZF1 Δ1-8. Detailed analysis using long distance inverse PCR showed that six patients (16%) had large interstitial deletions starting within intronic regions of COBL at diagnosis, which is ~611 Kb downstream of IKZF1, suggesting that COBL is a hotspot for ΔIKZF1. We also investigated a series of 25 intragenic deletions (Δ2–8, Δ3–8 or Δ4–8) and 24 relapsed samples, and found one IKZF1-COBL tail-to-tail fusion, thus supporting that COBL is a novel hotspot for ΔIKZF1. Finally, using RIC score methodology, we show that breakpoint sequences of IKZF1 Δ1-8 are not analog to RAG-recognition sites, suggesting a different mechanism of error promotion than that suggested for intragenic ΔIKZF1.
Orange lily Lilium bulbiferum subsp. bulbiferum occurs in the mountains of Western and Central Europe. Within almost the entire area of distribution, it is considered to be rare and endangered. The main purpose of the present study is to analyse the variability of environmental conditions of sites of the orange lily that are considered natural on its north-eastern border of occurrence. Using vegetation databases from Poland, the Czech Republic and Slovakia and our material collected during field work in the Western Carpathians and the Sudetes, we analysed the variability of species composition within communities with the occurrence of L. bulbiferum subsp. bulbiferum. The classification was performed using a modified TWINSPAN algorithm in the JUICE software. Ecological analysis was performed on the basis of Ellenberg indicator values with a Zelený-Schaffers modified permutation test. In general, the findings indicate that in the study area there are at least seven plant communities, within three separate classes, with the occurrence of the orange lily. All vegetation units distinguished here are semi-natural communities, which are maintained through extensive and traditional agricultural practices. Microclimatic conditions, which indicate a narrow ecological tolerance of the species to light availability and temperature, may have a crucial effect on the distribution of L. bulbiferum subsp. bulbiferum on the north-eastern border of its range in Europe. These factors significantly reduce the possibility of penetration of the species into forest or scrub communities. On the other hand, owing to far wider ranges of tolerance to moisture conditions and soil reaction than previously considered typical of the species, the orange lily can occur in different light-demanding communities, from acidic pastures up to calcareous thermophilous grasslands. An almost exclusive presence of L. bulbiferum subsp. bulbiferum in semi-natural habitats suggests that active management and protection are crucial to protect its full genetic variation on the European continent.
Established populations of non-natives may collapse without a clear causal mechanism. Hypothetically, fluctuations in habitat structural complexity may influence dynamics of invaders and the biotic resistance offered by predators. Herein I report observations of the collapse of a reproducing population of the nonnative African jewelfish (Hemichromis letourneuxi) in a Florida lake concurrent with an unusual low-water period. I test the hypothesis that predation may have played a key role in the collapse using a combination of field surveys of habitat and fish abundance and predator-prey experiments. Habitat complexity was high before and after the low water period but virtually nonexistent during low water. The abundance of African jewelfish and native juvenile bluegill (Lepomis macrochirus) and eastern mosquitofish (Gambusia holbrooki) declined concurrently with decreasing complexity but the native species rebounded when lake levels increased. Large-bodied natives such as largemouth bass (Micropterus salmoides) and adult bluegill showed no pattern of fluctuation related to habitat complexity. African jewelfish survival was 1.6 times greater at high versus low complexity and over 7 times higher versus no complexity in the presence of largemouth bass. Conversely, eastern mosquitofish, a species that exerts strong effects on small-bodied fishes in structurally complex habitats had no effect on African jewelfish survival. Predation effects on susceptible non-natives should be considered as a potential control action. Population collapse is understudied but may provide insights into long-term dynamics of invaders and information useful for management of problematic species.
Within the SEASTAR project at RIKEN-RIBF, 66Cr and 70,72Fe have been produced via protonknockout reactions, and their first excited 2+ and 4+ states have been discovered. The combination of the liquid-hydrogen target and TPC system MINOS has been used in combination with the DALI2 detector array for the first time. A 345 MeV/u 238U beam with a mean intensity of about 12 pnA impinged on a Be target. Fission fragments were separated and identified using the BigRIPS spectrograph, and reaction products were analyzed using the ZeroDegree spectrograph. A plateau of excitation energies, with a small change in the systematic trends past N = 44, reveals an extension of the N = 40 region of collectivity toward N = 50. Hence, the isotopes of interest are located within the N = 40 island of inversion. An interpretation of the observed trends is offered through large scale shell model calculations.
Background: Community acquired viruses (CRVs) may cause severe disease in cancer patients. Thus, efforts should be made to diagnose CRV rapidly and manage CRV infections accordingly.
Methods: A panel of 18 clinicians from the Infectious Diseases Working Party of the German Society for Haematology and Medical Oncology have convened to assess the available literature and provide recommendations on the management of CRV infections including influenza, respiratory syncytial virus, parainfluenza virus, human metapneumovirus and adenovirus.
Results: CRV infections in cancer patients may lead to pneumonia in approximately 30% of the cases, with an associated mortality of around 25%. For diagnosis of a CRV infection, combined nasal/throat swabs or washes/aspirates give the best results and nucleic acid amplification based-techniques (NAT) should be used to detect the pathogen. Hand hygiene, contact isolation and face masks have been shown to be of benefit as general infection management. Causal treatment can be given for influenza, using a neuraminidase inhibitor, and respiratory syncytial virus, using ribavirin in addition to intravenous immunoglobulins. Ribavirin has also been used to treat parainfluenza virus and human metapneumovirus, but data are inconclusive in this setting. Cidofovir is used to treat adenovirus pneumonitis.
Conclusions: CRV infections may pose a vital threat to patients with underlying malignancy. This guideline provides information on diagnosis and treatment to improve the outcome.
Background: Dengue virus infection is the most rapidly spreading vector-borne disease in the world. Essential research on dengue virus transmission and its prevention requires community participation. Therefore, it is crucial to understand the factors that are associated with the willingness of communities in high prevalence areas to participate in dengue research. The aim of this study was to explore factors associated with the willingness of healthy community members in Aceh province, Indonesia, to participate in dengue research that would require phlebotomy.
Methodology/Principal Findings: A community-based cross-sectional study was carried out in nine regencies and municipalities of Aceh from November 2014 to March 2015. Interviews using a set of validated questionnaires were conducted to collect data on demography, history of dengue infection, socioeconomic status, and knowledge, attitude and practice regarding dengue fever. Two-step logistic regression and Spearman’s rank correlation (rs) analysis were used to assess the influence of independent variables on dependent variables. Among 535 participants, less than 20% had a good willingness to participate in the dengue study. The factors associated with good willingness to participate were being female, working as a civil servant, private employee or entrepreneur, having a high socioeconomic status and good knowledge, attitude and practice regarding dengue. Good knowledge and attitude regarding dengue were positive independent predictors of willingness to participate (OR: 2.30 [95% CI: 1.36–3.90] and 3.73 [95% CI: 2.24–6.21], respectively).
Conclusion/Significance: The willingness to participate in dengue research is very low among community members in Aceh, and the two most important associated factors are knowledge and attitude regarding dengue. To increase participation rate, efforts to improve the knowledge and attitude of community members regarding dengue fever and dengue-related research is required before such studies are launched.
Cat’s claw creeper vine, Dolichandra unguis-cati (L.) Lohmann (syn. Macfadyena unguis-cati (L.) Gentry) (Bignoniaceae), is a major environmental weed in Australia. Two distinct forms of this weed (‘long’ and ‘short’ pod), with differences in leaf morphology and fruit size, occur in Australia. The long pod form has only been reported in less than fifteen localities in the whole of south-east Queensland, while the short pod form is widely distributed in Queensland and New South Wales. This study sought to compare growth traits such as specific leaf area, relative growth rate, stem length, shoot/root ratio, tuber biomass and branching architecture between these forms. These traits were monitored under glasshouse conditions over a period of 18 months. Short pod exhibited higher values of relative growth rates, stem length, number of tubers and specific leaf area than long pod, but only after 10 months of plant growth. Prior to this, long and short pod did not differ significantly. Higher values for these traits have been described as characteristics of successful colonizers. Results from this study could partly explain why the short pod form is more widely distributed in Australia while long pod is confined to a few localities.
Binary nucleation of sulphuric acid-water particles is expected to be an important process in the free troposphere at low temperatures. SAWNUC (Sulphuric Acid Water Nucleation) is a model of binary nucleation that is based on laboratory measurements of the binding energies of sulphuric acid and water in charged and neutral clusters. Predictions of SAWNUC are compared for the first time comprehensively with experimental binary nucleation data from the CLOUD chamber at European Organization for Nuclear Research. The experimental measurements span a temperature range of 208–292 K, sulphuric acid concentrations from 1·106 to 1·109 cm−3, and distinguish between ion-induced and neutral nucleation. Good agreement, within a factor of 5, is found between the experimental and modeled formation rates for ion-induced nucleation at 278 K and below and for neutral nucleation at 208 and 223 K. Differences at warm temperatures are attributed to ammonia contamination which was indicated by the presence of ammonia-sulphuric acid clusters, detected by an Atmospheric Pressure Interface Time of Flight (APi-TOF) mass spectrometer. APi-TOF measurements of the sulphuric acid ion cluster distributions (math formula with i = 0, 1, ..., 10) show qualitative agreement with the SAWNUC ion cluster distributions. Remaining differences between the measured and modeled distributions are most likely due to fragmentation in the APi-TOF. The CLOUD results are in good agreement with previously measured cluster binding energies and show the SAWNUC model to be a good representation of ion-induced and neutral binary nucleation of sulphuric acid-water clusters in the middle and upper troposphere.
Type I interferons (IFNs), including IFN-α, upregulate an array of IFN-stimulated genes (ISGs) and potently suppress Human immunodeficiency virus type 1 (HIV-1) infectivity in CD4(+) T cells, monocyte-derived macrophages, and dendritic cells. Recently, we and others identified ISG myxovirus resistance 2 (MX2) as an inhibitor of HIV-1 nuclear entry. However, additional antiviral blocks exist upstream of nuclear import, but the ISGs that suppress infection, e.g., prior to (or during) reverse transcription, remain to be defined. We show here that the HIV-1 CA mutations N74D and A105T, both of which allow escape from inhibition by MX2 and the truncated version of cleavage and polyadenylation specific factor 6 (CPSF6), as well as the cyclophilin A (CypA)-binding loop mutation P90A, all increase sensitivity to IFN-α-mediated inhibition. Using clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 technology, we demonstrate that the IFN-α hypersensitivity of these mutants in THP-1 cells is independent of MX2 or CPSF6. As expected, CypA depletion had no additional effect on the behavior of the P90A mutant but modestly increased the IFN-α sensitivity of wild-type virus. Interestingly, the infectivity of wild-type or P90A virus could be rescued from the MX2-independent IFN-α-induced blocks in THP-1 cells by treatment with cyclosporine (Cs) or its nonimmunosuppressive analogue SDZ-NIM811, indicating that Cs-sensitive host cell cyclophilins other than CypA contribute to the activity of IFN-α-induced blocks. We propose that cellular interactions with incoming HIV-1 capsids help shield the virus from recognition by antiviral effector mechanisms. Thus, the CA protein is a fulcrum for the dynamic interplay between cell-encoded functions that inhibit or promote HIV-1 infection.
Mapping a public discourse with the tools of computational text analysis comes with many contingencies in the areas of corpus curation, data processing and analysis, and visualisation. However, the complexity of algorithmic assemblies and the beauty of resulting images give the impression of ‘objectivity’. Instead of concealing uncertainties and artefacts in order to tell a coherent and all-encompassing story, retaining the variety of alternative assemblies may actually strengthen the method. By utilising the mobility of digital devices, we could create mutable mobiles that allow access to our laboratories and enable challenging rearrangements and interpretations.
Orientation: Lack in congruence amongst industrial and organisational psychologists (IOPs) as to the conceptualisation of its profession poses a significant risk as to the relevance, longevity and professional identity of the profession within the South African context. Research purpose: This study aimed to explore the professional identity of IOPs within the South African context. Specifically, the aim of this study was four-fold: (1) to develop a contemporary definition for IOP, (2) to investigate IOP roles, (3) to determine how the profession should be labelled and (4) to differentiate IOP from human resource management (HRM) from IOPs’ perspectives within South Africa. Motivation for the study: IOPs do not enjoy the same benefits in stature or status as other professions such as medicine, finances and engineering in the world of work. IOPs need to justify its relevance within organisational contexts as a globally shared understanding of ‘what it is’, ‘what it does’ and ‘what makes it different from other professions’, which is non-existent. In order to enhance its perceived relevance, clarity as to IOPs professional identity is needed. Research design, approach and method: A post-positivistic qualitative content analytic and descriptive research design was employed in this study. Data from practising industrial and organisational psychology (IOP) within South Africa (N = 151) were gathered through an electronic web-based survey and were analysed through thematic content analysis. Main findings: The results indicate that IOP in South Africa seeks to optimise the potential of individuals, groups, organisations and the community by implementing scientific processes to support both individual and organisational wellness and sustainability. ‘Work Psychology’ was considered a more fitting professional designation or label than industrial and/or organisational psychology. The industrial psychologist’s major roles related to the well-being and development of employees. A clear distinction between a more dynamic, pro-active approach of IOP compared to a more transactional approach of HRM was also evident. IOP within South Africa appears to have a community development function. Practical/managerial implications: The longevity, relevance and impact of IOP as a profession requires alignment amongst practitioners as to shared common professional identity. Contribution/value-add: This study provides a contemporary understanding of the roles, functions, labels and unique value proposition of industrial and organisational psychology within the South African context.
Chronic hepatitis C is a major reason for development of cirrhosis and hepatocellular carcinoma and a leading cause for liver transplantation. The development of direct-acting antiviral agents lead to (pegylated) interferon-alfa free antiviral therapy regimens with a remarkable increase in sustained virologic response (SVR) rates and opened therapeutic options for patients with advanced cirrhosis and liver graft recipients. This concise review gives an overview about most current prospective trials and cohort analyses for treatment of patients with liver cirrhosis and liver graft recipients. In patients with compensated cirrhosis Child-Pugh-Turcotte (CTP) class A, all approved agents are safe and SVR rates do not significantly differ from patients without cirrhosis in general. In patients with decompensated cirrhosis CTP class B or C, daclastasvir, ledipasvir, velpatasvir, and sofosbuvir are approved, and SVR rates higher than 90% can be achieved. Especially for patients with a model of end stage liver disease score higher than 15 and therefore eligible for liver transplantation, data is scarce. Reported SVR rates in patients with cirrhosis CTP class C are lower compared to patients with a less severe liver disease. In liver transplant recipients with a maximum of CTP class A, SVR rates are comparable to patients without LT. Patients with decompensated graft cirrhosis should be treated on an individual basis.
The Anthropocene Epoch is characterized by novel and increasingly complex dependencies between the environment and human civilization, with many challenges of biodiversity management emerging as wicked problems. Problems arising from the management of biological invasions can be either tame (with simple or obvious solutions) or wicked, where difficulty in appropriately defining the problem can make complete solutions impossible to find. We review four case studies that reflect the main goals in the management of biological invasions – prevention, eradication, and impact reduction – assessing the drivers and extent of wickedness in each. We find that a disconnect between the perception and reality of how wicked a problem is can profoundly influence the likelihood of successful management. For example, managing species introductions can be wicked, but shifting from species-focused to vector-focused risk management can greatly reduce the complexity, making it a tame problem. The scope and scale of the overall management goal will also dictate the wickedness of the problem and the achievability of management solutions (cf. eradication and ecosystem restoration). Finally, managing species that have both positive and negative impacts requires engagement with all stakeholders and scenario-based planning. Effective management of invasions requires either recognizing unavoidable wickedness, or circumventing it by seeking alternative management perspectives.
In the mouse retina, three different types of photoreceptors provide input to 14 bipolar cell (BC) types. Classically, most BC types are thought to contact all cones within their dendritic field; ON-BCs would contact cones exclusively via so-called invaginating synapses, while OFF-BCs would form basal synapses. By mining publically available electron microscopy data, we discovered interesting violations of these rules of outer retinal connectivity: ON-BC type X contacted only ~20% of the cones in its dendritic field and made mostly atypical non-invaginating contacts. Types 5T, 5O and 8 also contacted fewer cones than expected. In addition, we found that rod BCs received input from cones, providing anatomical evidence that rod and cone pathways are interconnected in both directions. This suggests that the organization of the outer plexiform layer is more complex than classically thought.
Optimizing spike-sorting algorithms is difficult because sorted clusters can rarely be checked against independently obtained “ground truth” data. In most spike-sorting algorithms in use today, the optimality of a clustering solution is assessed relative to some assumption on the distribution of the spike shapes associated with a particular single unit (e.g., Gaussianity) and by visual inspection of the clustering solution followed by manual validation. When the spatiotemporal waveforms of spikes from different cells overlap, the decision as to whether two spikes should be assigned to the same source can be quite subjective, if it is not based on reliable quantitative measures. We propose a new approach, whereby spike clusters are identified from the most consensual partition across an ensemble of clustering solutions. Using the variability of the clustering solutions across successive iterations of the same clustering algorithm (template matching based on K-means clusters), we estimate the probability of spikes being clustered together and identify groups of spikes that are not statistically distinguishable from one another. Thus, we identify spikes that are most likely to be clustered together and therefore correspond to consistent spike clusters. This method has the potential advantage that it does not rely on any model of the spike shapes. It also provides estimates of the proportion of misclassified spikes for each of the identified clusters. We tested our algorithm on several datasets for which there exists a ground truth (simultaneous intracellular data), and show that it performs close to the optimum reached by a support vector machine trained on the ground truth. We also show that the estimated rate of misclassification matches the proportion of misclassified spikes measured from the ground truth data.
Pathogenicity of many microbes relies on their capacity to resist innate immunity, and to survive and persist in an immunocompetent human host microbes have developed highly efficient and sophisticated complement evasion strategies. Here we show that different human pathogens including Gram-negative and Gram-positive bacteria, as well as the fungal pathogen Candida albicans, acquire the human terminal complement regulator vitronectin to their surface. By using truncated vitronectin fragments we found that all analyzed microbial pathogens (n = 13) bound human vitronectin via the same C-terminal heparin-binding domain (amino acids 352–374). This specific interaction leaves the terminal complement complex (TCC) regulatory region of vitronectin accessible, allowing inhibition of C5b-7 membrane insertion and C9 polymerization. Vitronectin complexed with the various microbes and corresponding proteins was thus functionally active and inhibited complement-mediated C5b-9 deposition. Taken together, diverse microbial pathogens expressing different structurally unrelated vitronectin-binding molecules interact with host vitronectin via the same conserved region to allow versatile control of the host innate immune response.
Predictions of popular cosmic ray interaction models for some basic characteristics of cosmic ray-induced extensive air showers are analyzed in view of experimental data on proton-proton collisions, obtained at the Large Hadron Collider. The differences between the results are traced down to different approaches for the treatment of hadronic interactions, implemented in those models. Potential measurements by LHC and cosmic ray experiments, which could be able to discriminate between the alternative approaches, are proposed.
This article explores the uses and functions of dialogue in Frank McCourt’s memoir Angela’s Ashes. Taking conversational dialogue and fictional dialogue as points of comparison, the article argues that dialogue in autobiographical writing is essentially constructed, albeit not in the same way as fictional dialogue is. Dialogue as a means of dramatisation raises questions regarding factuality and fictionality. In McCourt’s memoir, dialogue is shown to serve numerous functions: characterisation and stereotyping; selfpositioning and indirect stance-marking; the creation of verisimilitude, humour and reader involvement.
Smac mimetics antagonize IAP proteins, which are highly expressed in several cancers. Recent reports indicate that Smac mimetics trigger a broad cytokine response and synergize with immune modulators to induce cell death. Here, we identify a differential requirement of TRAIL or TNFα as mediators of IFNα/Smac mimetic-induced cell death depending on the cellular context. Subtoxic concentrations of Smac mimetics cooperate with IFNα to induce cell death in various solid tumor cell lines in a highly synergistic manner as determined by combination index. Mechanistic studies show that IFNα/BV6 cotreatment promotes the formation of a caspase-8-activating complex together with the adaptor protein FADD and RIP1. Assembly of this RIP1/FADD/caspase-8 complex represents a critical event, since RIP1 silencing inhibits IFNα/BV6-induced cell death. Strikingly, pharmacological inhibition of paracrine/autocrine TNFα signaling by the TNFα scavenger Enbrel rescues HT-29 colon carcinoma cells, but not A172 glioblastoma cells from IFNα/BV6-induced cell death. By comparison, A172 cells are significantly protected against IFNα/BV6 treatment by blockage of TRAIL signaling through genetic silencing of TRAIL or its cognate receptor TRAIL receptor 2 (DR5). Despite this differential requirement of TNFα and TRAIL signaling, mRNA and protein expression is increased by IFNα/BV6 cotreatment in both cell lines. Interestingly, A172 cells turn out to be resistant to exogenously added recombinant TNFα even in the presence of BV6, whereas they display a high sensitivity towards TRAIL/BV6. In contrast, BV6 efficiently sensitizes HT-29 cells to TNFα while TRAIL only had limited efficacy. This demonstrates that a differential sensitivity towards TRAIL or TNFα determines the dependency on either death receptor ligand for IFNα/Smac mimetic-induced cell death. Thus, by concomitant stimulation of both death receptor systems IFNα/Smac mimetic combination treatment is an effective strategy to induce cell death in TNFα- or TRAIL-responsive cancers.
Correlated activity of cortical neurons survives extensive removal of feedforward sensory input
(2016)
A fundamental property of brain function is that the spiking activity of cortical neurons is variable and that some of this variability is correlated between neurons. Correlated activity not due to the stimulus arises from shared input but the neuronal circuit mechanisms that result in these noise correlations are not fully understood. Here we tested in the visual system if correlated variability in mid-level area V4 of visual cortex is altered following extensive lesions of primary visual cortex (V1). To this end we recorded longitudinally the neuronal correlations in area V4 of two behaving macaque monkeys before and after a V1 lesion while the monkeys fixated a grey screen. We found that the correlations of neuronal activity survived the lesions in both monkeys. In one monkey, the correlation of multi-unit spiking signals was strongly increased in the first week post-lesion, while in the second monkey, correlated activity was slightly increased, but not greater than some week-by-week fluctuations observed. The typical drop-off of inter-neuronal correlations with cortical distance was preserved after the lesion. Therefore, as V4 noise correlations remain without feedforward input from V1, these results suggest instead that local and/or feedback input seem to be necessary for correlated activity.
Correlated event-by-event fluctuations of flow harmonics in Pb–Pb collisions at √sNN = 2.76 TeV
(2016)
We report the measurements of correlations between event-by-event fluctuations of amplitudes of anisotropic flow harmonics in nucleus-nucleus collisions, obtained for the first time using a new analysis method based on multiparticle cumulants in mixed harmonics. This novel method is robust against systematic biases originating from non-flow effects and by construction any dependence on symmetry planes is eliminated. We demonstrate that correlations of flow harmonics exhibit a better sensitivity to medium properties than the individual flow harmonics. The new measurements are performed in Pb-Pb collisions at the centre-of-mass energy per nucleon pair of sNN−−−√=2.76 TeV by the ALICE experiment at the Large Hadron Collider (LHC). The centrality dependence of correlation between event-by-event fluctuations of the elliptic, v2, and quadrangular, v4, flow harmonics, as well as of anti-correlation between v2 and triangular, v3, flow harmonics are presented. The results cover two different regimes of the initial state configurations: geometry-dominated (in mid-central collisions) and fluctuation-dominated (in the most central collisions). Comparisons are made to predictions from MC-Glauber, viscous hydrodynamics, AMPT and HIJING models. Together with the existing measurements of individual flow harmonics the presented results provide further constraints on initial conditions and the transport properties of the system produced in heavy-ion collisions.
The authors inserted an incorrect figure in Oswalt et al. (2015) that was printed as Fig. 2. The mapped species represented in Oswalt et al. (2015) is Triadica sebifera or Chinese tallow. The correct Fig. 2, representing Imperata cylindrica, is reproduced below. The correction does not alter the conclusions of Oswalt et al. (2015).
Periods of rhythmic slow-wave activity during physiological slow-wave sleep or induced by anesthesia are characterized by a waxing and waning of spontaneous neuronal firing coordinated between cortex and thalamus. This activity is generated in the cortex but influences neuronal excitability and stimulus–response properties of neuronal networks throughout the brain (Steriade et al., 1993; Stroh et al., 2013; McGinley et al., 2015b). The corresponding low-frequency component of field potential recordings reflects alternating active states, in which cells are depolarized and synaptic activity is high, and silent states with hyperpolarized membrane potentials and low synaptic activity (Steriade et al., 2001; Timofeev et al., 2001). In contrast, waking is generally associated with continuous depolarization of cortical neurons, resulting in persistent activity (Destexhe et al., 2007; Sheroziya and Timofeev, 2015) and suppression of silent states (Steriade et al., 2001; McGinley et al., 2015b). In their recent study, Sheroziya and Timofeev (2015) demonstrated that moderate cortical cooling (to 29–31°C) of lightly ketamine/xylazin (ket/xyl) anesthetized or non-anesthetized mice reversibly diminished silent states and induced a persistent active state of the cortex. Mild heating (to 39–40°C), in contrast, increased rhythmicity of slow waves. Under deep ket/xyl anesthesia, cortical cooling disrupted slow waves and promoted bursts of activity correlated with thalamic firing. Local cooling of somatosensory cortex was shown to be sufficient to induce a shift from slow-wave to wide-spread persistent cortical activity, extending to the thalamus as well as the contralateral hemisphere. These results suggest that cortical temperature change can be used as a bidirectional and reversible tool for investigating global brain state fluctuations, and provide evidence that the thalamocortical network rapidly reacts upon local depolarization of a small neuronal population with wide-spread shifts of brain state. ...
I review the state-of-the-art concerning the treatment of high energy cosmic ray interactions in the atmosphere, discussing in some detail the underlying physical concepts and the possibilities to constrain the latter by current and future measurements at the Large Hadron Collider. The relation of basic characteristics of hadronic interactions tothe properties of nuclear-electromagnetic cascades induced by primary cosmic rays in the atmosphere is addressed.
New experimental data for dissociation of relativistic 17Ne projectiles incident on targets of lead, carbon, and polyethylene targets at GSI are presented. Special attention is paid to the excitation and decay of narrow resonant states in 17Ne. Distributions of internal energy in the three-body system have been determined together with angular and partial-energy correlations between the decay products in different energy regions. The analysis was done using existing experimental data on 17Ne and its mirror nucleus 17N. The isobaric multiplet mass equation is used for assignment of observed resonances and their spins and parities. A combination of data from the heavy and light targets yielded cross sections and transition probabilities for the Coulomb excitations of the narrow resonant states. The resulting transition probabilities provide information relevant for a better understanding of the 17Ne structure.
ATP-binding cassette (ABC) transporters, a superfamily of integral membrane proteins, catalyse the translocation of substrates across the cellular membrane by ATP hydrolysis. Here we demonstrate by nucleotide turnover and binding studies based on 31P solid-state NMR spectroscopy that the ABC exporter and lipid A flippase MsbA can couple ATP hydrolysis to an adenylate kinase activity, where ADP is converted into AMP and ATP. Single-point mutations reveal that both ATPase and adenylate kinase mechanisms are associated with the same conserved motifs of the nucleotide-binding domain. Based on these results, we propose a model for the coupled ATPase-adenylate kinase mechanism, involving the canonical and an additional nucleotide-binding site. We extend these findings to other prokaryotic ABC exporters, namely LmrA and TmrAB, suggesting that the coupled activities are a general feature of ABC exporters.
We present the prototype of a regional climate system model based on the COSMO-CLM regional climate model coupled with several model components, analyze the performance of the couplings and present a strategy to find an optimum configuration with respect to computational costs and time to solution.
The OASIS3-MCT coupler is used to couple COSMO-CLM with two land surface models (CLM and VEG3D), a regional ocean model for the Mediterranean Sea (NEMO-MED12), two ocean models for the North and Baltic Sea (NEMO-NORDIC and TRIMNP+CICE) and the atmospheric component of an earth system model (MPI-ESM). We present a unified OASIS3-MCT interface which handles all couplings in a similar way, minimizes the model source code modifications and describes the physics and numerics of the couplings. Furthermore, we discuss solutions for specific regional coupling problems like handling of different domains, multiple usage of MCT interpolation library and efficient exchange of 3D fields.
A series of real-case simulations over Europe has been conducted and the computational performance of the couplings has been analyzed. The usage of the LUCIA tool of the OASIS3-MCT coupler enabled separation of the direct costs of: coupling, load imbalance and additional computations. The resulting limits for time to solution and costs are shown and the potential of further improvement of the computational efficiency is summarized for each coupling.
It was found that the OASIS3-MCT coupler keeps the direct coupling costs of communication and horizontal interpolation small in comparison with the costs of the additional computations and load imbalance for all investigated couplings. For the first time this could be demonstrated for an exchange of approximately 450 2D fields per time step necessary for the atmosphere-atmosphere coupling between COSMO-CLM and MPI-ESM.
A procedure for finding an optimum configuration for each of the couplings was developed considering the time to solution and costs of the simulations. The optimum configurations are presented for sequential and concurrent coupling layouts. The procedure applied can be regarded as independent on the specific coupling layout and coupling details.
CRISPR/Cas9-mediated knockout of p22phox leads to loss of Nox1 and Nox4, but not Nox5 activity
(2016)
The NADPH oxidases are important transmembrane proteins producing reactive oxygen species (ROS). Within the Nox family, different modes of activation can be discriminated. Nox1-3 are dependent on different cytosolic subunits, Nox4 seems to be constitutively active and Nox5 is directly activated by calcium. With the exception of Nox5, all Nox family members are thought to depend on the small transmembrane protein p22phox. With the discovery of the CRISPR/Cas9-system, a tool to alter genomic DNA sequences has become available. So far, this method has not been widely used in the redox community. On such basis, we decided to study the requirement of p22phox in the Nox complex using CRISPR/Cas9-mediated knockout. Knockout of the gene of p22phox, CYBA, led to an ablation of activity of Nox4 and Nox1 but not of Nox5. Production of hydrogen peroxide or superoxide after knockout could be rescued with either human or rat p22phox, but not with the DUOX-maturation factors DUOXA1/A2. Furthermore, different mutations of p22phox were studied regarding the influence on Nox4-dependent H2O2 production. P22phox Q130* and Y121H affected maturation and activity of Nox4. Hence, Nox5-dependent O2•- production is independent of p22phox, but native p22phox is needed for maturation of Nox4 and production of H2O2.
Critical Theory is the key-word representing all the universe of thought commonly known as „Frankfurt School”. Within it, Theodor Wiesengrund Adorno and Herbert Marcuse are not so far each other, as instead are Max Horkheimer and Marcuse – considering what I in this paper define as the conservative turn of the director of the Institut für Sozialforschung. Whereas Adorno refuses any engagement in the political and lives as an obsession the theory-praxis relation, Marcuse is closer to a certain critical Marxism and to the student movements of Sixities and Seventhies. The crucial issue of the theory-praxis relation comes back clearly in the distance between Marcuse and the other two maîtres à penser, about their judgment on the ’68 movement.
Congenital sensory deprivation can lead to reorganization of the deprived cortical regions by another sensory system. Such cross-modal reorganization may either compete with or complement the “original“ inputs to the deprived area after sensory restoration and can thus be either adverse or beneficial for sensory restoration. In congenital deafness, a previous inactivation study documented that supranormal visual behavior was mediated by higher-order auditory fields in congenitally deaf cats (CDCs). However, both the auditory responsiveness of “deaf” higher-order fields and interactions between the reorganized and the original sensory input remain unknown. Here, we studied a higher-order auditory field responsible for the supranormal visual function in CDCs, the auditory dorsal zone (DZ). Hearing cats and visual cortical areas served as a control. Using mapping with microelectrode arrays, we demonstrate spatially scattered visual (cross-modal) responsiveness in the DZ, but show that this did not interfere substantially with robust auditory responsiveness elicited through cochlear implants. Visually responsive and auditory-responsive neurons in the deaf auditory cortex formed two distinct populations that did not show bimodal interactions. Therefore, cross-modal plasticity in the deaf higher-order auditory cortex had limited effects on auditory inputs. The moderate number of scattered cross-modally responsive neurons could be the consequence of exuberant connections formed during development that were not pruned postnatally in deaf cats. Although juvenile brain circuits are modified extensively by experience, the main driving input to the cross-modally (visually) reorganized higher-order auditory cortex remained auditory in congenital deafness.