Refine
Year of publication
- 2020 (3438) (remove)
Document Type
- Article (1914)
- Part of Periodical (478)
- Doctoral Thesis (235)
- Preprint (169)
- Contribution to a Periodical (160)
- Book (128)
- Working Paper (123)
- Review (104)
- Part of a Book (86)
- Bachelor Thesis (11)
Language
- English (2168)
- German (1132)
- Portuguese (43)
- French (31)
- Turkish (28)
- Multiple languages (17)
- Spanish (13)
- Italian (3)
- slo (3)
Keywords
- taxonomy (88)
- Deutsch (53)
- new species (50)
- Spracherwerb (34)
- Sprachtest (33)
- Capital Markets Union (25)
- Financial Markets (25)
- Literatur (25)
- Übersetzung (25)
- Coronavirus (24)
Institute
- Medizin (744)
- Präsidium (278)
- Physik (267)
- Wirtschaftswissenschaften (220)
- Sustainable Architecture for Finance in Europe (SAFE) (167)
- Biowissenschaften (161)
- Frankfurt Institute for Advanced Studies (FIAS) (150)
- Informatik (116)
- Biochemie, Chemie und Pharmazie (104)
- Neuere Philologien (95)
We estimate the temperature dependence of the bulk viscosity in a relativistic hadron gas. Employing the Green–Kubo formalism in the SMASH (Simulating Many Accelerated Strongly-interacting Hadrons) transport approach, we study different hadronic systems in increasing order of complexity. We analyze the (in)validity of the single exponential relaxation ansatz for the bulk-channel correlation function and the strong influence of the resonances and their lifetimes. We discuss the difference between the inclusive bulk viscosity of an equilibrated, long-lived system, and the effective bulk viscosity of a short-lived mixture like the hadronic phase of relativistic heavy-ion collisions, where the processes whose inverse relaxation rate are larger than the fireball duration are excluded from the analysis. This clarifies the differences between previous approaches which computed the bulk viscosity including/excluding the very slow processes in the hadron gas. We compare our final results with previous hadron gas calculations and confirm a decreasing trend of the inclusive bulk viscosity over entropy density as temperature increases, whereas the effective bulk viscosity to entropy ratio, while being lower than the inclusive one, shows no strong dependence to temperature.
Non-ribosomal peptide synthetases (NRPSs) are the origin of a wide range of natural products, including many clinically used drugs. Engineering of these often giant biosynthetic machineries to produce novel non-ribosomal peptides (NRPs) at high titre is an ongoing challenge. Here we describe a strategy to functionally combine NRPS fragments of Gram-negative and -positive origin, synthesising novel peptides at titres up to 290 mg l-1. Extending from the recently introduced definition of eXchange Units (XUs), we inserted synthetic zippers (SZs) to split single protein NRPSs into up to three independently expressed and translated polypeptide chains. These synthetic type of NRPS (type S) enables easier access to engineering, overcomes cloning limitations, and provides a simple and rapid approach to building peptide libraries via the combination of different NRPS subunits.
Individual differences in perception are widespread. Considering inter-individual variability, synesthetes experience stable additional sensations; schizophrenia patients suffer perceptual deficits in, eg, perceptual organization (alongside hallucinations and delusions). Is there a unifying principle explaining inter-individual variability in perception? There is good reason to believe perceptual experience results from inferential processes whereby sensory evidence is weighted by prior knowledge about the world. Perceptual variability may result from different precision weighting of sensory evidence and prior knowledge. We tested this hypothesis by comparing visibility thresholds in a perceptual hysteresis task across medicated schizophrenia patients (N = 20), synesthetes (N = 20), and controls (N = 26). Participants rated the subjective visibility of stimuli embedded in noise while we parametrically manipulated the availability of sensory evidence. Additionally, precise long-term priors in synesthetes were leveraged by presenting either synesthesia-inducing or neutral stimuli. Schizophrenia patients showed increased visibility thresholds, consistent with overreliance on sensory evidence. In contrast, synesthetes exhibited lowered thresholds exclusively for synesthesia-inducing stimuli suggesting high-precision long-term priors. Additionally, in both synesthetes and schizophrenia patients explicit, short-term priors—introduced during the hysteresis experiment—lowered thresholds but did not normalize perception. Our results imply that perceptual variability might result from differences in the precision afforded to prior beliefs and sensory evidence, respectively.
Background Reward processing has been proposed to underpin atypical social behavior, a core feature of autism spectrum disorder (ASD). However, previous neuroimaging studies have yielded inconsistent results regarding the specificity of atypicalities for social rewards in ASD. Utilizing a large sample, we aimed to assess altered reward processing in response to reward type (social, monetary) and reward phase (anticipation, delivery) in ASD.
Methods Functional magnetic resonance imaging during social and monetary reward anticipation and delivery was performed in 212 individuals with ASD (7.6-30.5 years) and 181 typically developing (TD) participants (7.6-30.8 years).
Results Across social and monetary reward anticipation, whole-brain analyses (p<0.05, family-wise error-corrected) showed hypoactivation of the right ventral striatum (VS) in ASD. Further, region of interest (ROI) analysis across both reward types yielded hypoactivation in ASD in both the left and right VS. Across delivery of social and monetary reward, hyperactivation of the VS in individuals with ASD did not survive correction for multiple comparisons. Reward type by diagnostic group interactions, and a dimensional analysis of autism trait scores were not significant during anticipation or delivery. Levels of attention-deficit/hyperactivity disorder (ADHD) symptoms did not affect reward processing in ASD.
Conclusions Our results do not support current theories linking atypical social interaction in ASD to specific alterations in processing of social rewards. Instead, they point towards a generalized hypoactivity of VS in ASD during anticipation of both social and monetary rewards. We suggest that this indicates attenuated subjective reward value in ASD independent of social content and ADHD symptoms.
Background: Autism Spectrum Disorder (henceforth ‘autism’) is a highly heterogeneous neurodevelopmental condition with few effective treatments for core and associated features. To make progress we need to both identify and validate neural markers that help to parse heterogeneity to tailor therapies to specific neurobiological profiles. Atypical hemispheric lateralization is a stable feature across studies in autism, however its potential of lateralization as a neural stratification marker has not been widely examined.
Methods: In order to dissect heterogeneity in lateralization in autism, we used the large EU-AIMS Longitudinal European Autism Project dataset comprising 352 individuals with autism and 233 neurotypical (NT) controls as well as a replication dataset from ABIDE (513 autism, 691 NT) using a promising approach that moves beyond mean-group comparisons. We derived grey matter voxelwise laterality values for each subject and modelled individual deviations from the normative pattern of brain laterality across age using normative modeling.
Results: Results showed that individuals with autism had highly individualized patterns of both extreme right- and leftward deviations, particularly in language-, motor- and visuospatial regions, associated with symptom severity. Language delay (LD) explained most variance in extreme rightward patterns, whereas core autism symptom severity explained most variance in extreme leftward patterns. Follow-up analyses showed that a stepwise pattern emerged with individuals with autism with LD showing more pronounced rightward deviations than autism individuals without LD.
Conclusion: Our analyses corroborate the need for novel (dimensional) approaches to delineate the heterogeneous neuroanatomy in autism, and indicate atypical lateralization may constitute a neurophenotype for clinically meaningful stratification in autism.
Background: Marked sex differences in autism prevalence accentuate the need to understand the role of biological sex-related factors in autism. Efforts to unravel sex differences in the brain organization of autism have, however, been challenged by the limited availability of female data.
Methods: We addressed this gap by using a large sample of males and females with autism and neurotypical (NT) control individuals (ABIDE; Autism: 362 males, 82 females; NT: 409 males, 166 females; 7-18 years). Discovery analyses examined main effects of diagnosis, sex and their interaction across five resting-state fMRI (R-fMRI) metrics (voxel-level Z > 3.1, cluster-level P < 0.01, gaussian random field corrected). Secondary analyses assessed the robustness of the results to different pre-processing approaches and their replicability in two independent samples: the EU-AIMS Longitudinal European Autism Project (LEAP) and the Gender Explorations of Neurogenetics and Development to Advance Autism Research (GENDAAR).
Results: Discovery analyses in ABIDE revealed significant main effects across the intrinsic functional connectivity (iFC) of the posterior cingulate cortex, regional homogeneity and voxel-mirrored homotopic connectivity (VMHC) in several cortical regions, largely converging in the default network midline. Sex-by-diagnosis interactions were confined to the dorsolateral occipital cortex, with reduced VMHC in females with autism. All findings were robust to different pre-processing steps. Replicability in independent samples varied by R-fMRI measures and effects with the targeted sex-by-diagnosis interaction being replicated in the larger of the two replication samples – EU-AIMS LEAP.
Limitations: Given the lack of a priori harmonization among the discovery and replication datasets available to date, sample-related variation remained and may have affected replicability.
Conclusions: Atypical cross-hemispheric interactions are neurobiologically relevant to autism. They likely result from the combination of sex-dependent and sex-independent factors with a differential effect across functional cortical networks. Systematic assessments of the factors contributing to replicability are needed and necessitate coordinated large-scale data collection across studies.
Competing Interest Statement: ADM receives royalties from the publication of the Italian version of the Social Responsiveness Scale Child Version by Organization Speciali, Italy. JKB has been a consultant to, advisory board member of, and a speaker for Takeda/Shire, Medice, Roche, and Servier. He is not an employee of any of these companies and not a stock shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents, or royalties. CFB is director and shareholder in SBGneuro Ltd. TC has received consultancy from Roche and Servier and received book royalties from Guildford Press and Sage. DM has been a consultant to, and advisory board member, for Roche and Servier. He is not an employee of any of these companies, and not a stock shareholder of any of these companies. TB served in an advisory or consultancy role for Lundbeck, Medice, Neurim Pharmaceuticals, Oberberg GmbH, Shire, and Infectopharm. He received conference support or speakers fee by Lilly, Medice, and Shire. He received royalties from Hogrefe, Kohlhammer, CIP Medien, Oxford University Press; the present work is unrelated to these relationships. JT is a consultant to Roche. The remaining authors declare no competing interests.
Individual differences in perception are widespread. Considering inter-individual variability, synesthetes experience stable additional sensations; schizophrenia patients suffer perceptual deficits in e.g. perceptual organization (alongside hallucinations and delusions). Is there a unifying principle explaining inter-individual variability in perception? There is good reason to believe perceptual experience results from inferential processes whereby sensory evidence is weighted by prior knowledge about the world. Different perceptual phenotypes may result from different precision weighting of sensory evidence and prior knowledge. We tested this hypothesis by comparing visibility thresholds in a perceptual hysteresis task across medicated schizophrenia patients, synesthetes, and controls. Participants rated the subjective visibility of stimuli embedded in noise while we parametrically manipulated the availability of sensory evidence. Additionally, precise long-term priors in synesthetes were leveraged by presenting either synesthesia-inducing or neutral stimuli. Schizophrenia patients showed increased visibility thresholds, consistent with overreliance on sensory evidence. In contrast, synesthetes exhibited lowered thresholds exclusively for synesthesia-inducing stimuli suggesting high-precision long-term priors. Additionally, in both synesthetes and schizophrenia patients explicit, short-term priors – introduced during the hysteresis experiment – lowered thresholds but did not normalize perception. Our results imply that distinct perceptual phenotypes might result from differences in the precision afforded to prior beliefs and sensory evidence, respectively.
Nucleic acid and histone modifications critically depend on central metabolism for substrates and co-factors. Although a few enzymes related to the formation of these required metabolites have been reported in the nucleus, the corresponding metabolic pathways are considered to function elsewhere in the cell. Here we show that a substantial part of the mitochondrial tricarboxylic acid (TCA) cycle, the biosynthetic hub of epigenetic modification factors, is operational also in the nucleus. Using 13C-tracer analysis, we identified activity of glutamine-to-fumarate, citrate-to-succinate, and glutamine-to-aspartate routes in the nuclei of HeLa cells. Proximity labeling mass-spectrometry revealed a spatial vicinity of the involved enzymes with core nuclear proteins, supporting their nuclear location. We further show nuclear localization of aconitase 2 and 2-oxoglutarate dehydrogenase in mouse embryonic stem cells. Together, our results demonstrate operation of an extended metabolic pathway in the nucleus warranting a revision of the canonical view on metabolic compartmentalization and gene expression regulation.
Successful consolidation of associative memories relies on the coordinated interplay of slow oscillations and sleep spindles during non-rapid eye movement (NREM) sleep. This enables the transfer of labile information from the hippocampus to permanent memory stores in the neocortex. During senescence, the decline of the structural and functional integrity of the hippocampus and neocortical regions is paralleled by changes of the physiological events that stabilize and enhance associative memories during NREM sleep. However, the currently available evidence is inconclusive as to whether and under which circumstances memory consolidation is impacted during aging. To approach this question, 30 younger adults (19–28 years) and 36 older adults (63–74 years) completed a memory task based on scene–word associations. By tracing the encoding quality of participants’ individual memory associations, we demonstrate that previous learning determines the extent of age-related impairments in memory consolidation. Specifically, the detrimental effects of aging on memory maintenance were greatest for mnemonic contents of intermediate encoding quality, whereas memory gain of poorly encoded memories did not differ by age. Ambulatory polysomnography (PSG) and structural magnetic resonance imaging (MRI) data were acquired to extract potential predictors of memory consolidation from each participant’s NREM sleep physiology and brain structure. Partial Least Squares Correlation was used to identify profiles of interdependent alterations in sleep physiology and brain structure that are characteristic for increasing age. Across age groups, both the ‘aged’ sleep profile, defined by decreased slow-wave activity (0.5–4.5 Hz), and a reduced presence of slow oscillations (0.5–1 Hz), slow, and fast spindles (9–12.5 Hz; 12.5–16 Hz), as well as the ‘aged’ brain structure profile, characterized by gray matter reductions in the medial prefrontal cortex, thalamus, entorhinal cortex, and hippocampus, were associated with reduced memory maintenance. However, inter-individual differences in neither sleep nor structural brain integrity alone qualified as the driving force behind age differences in sleep-dependent consolidation in the present study. Our results underscore the need for novel and age-fair analytic tools to provide a mechanistic understanding of age differences in memory consolidation.
We studied oscillatory mechanisms of memory formation in 48 younger and 51 older adults in an intentional associative memory task with cued recall. While older adults showed lower memory performance than young adults, we found subsequent memory effects (SME) in alpha/beta and theta frequency bands in both age groups. Using logistic mixed effects models, we investigated whether interindividual differences in structural integrity of key memory regions could account for interindividual differences in the strength of the SME. Structural integrity of inferior frontal gyrus (IFG) and hippocampus was reduced in older adults. SME in the alpha/beta band were modulated by the cortical thickness of IFG, in line with its hypothesized role for deep semantic elaboration. Importantly, this structure–function relationship did not differ by age group. However, older adults were more frequently represented among the participants with low cortical thickness and consequently weaker SME in the alpha band. Thus, our results suggest that differences in the structural integrity of the IFG contribute not only to interindividual, but also to age differences in memory formation.
Based on Eysenck’s pioneering work, CNS arousal has long been considered an encouraging biological candidate that may explain individual differences in human personality. Yet, results from empirical studies remained inconclusive. Notably, the vast majority of published results have been derived from small samples, and EEG alpha power has usually served as exclusive indicator for CNS arousal. In this study, we selected N = 468 individuals of the LIFE-Adult cohort and investigated the associations between the Big Five personality traits and CNS arousal by using the low-resolution electromagnetic tomography-based analysis tool VIGALL. Our analyses revealed that subjects who reported higher levels of extraversion and openness to experience, respectively, exhibited lower levels of CNS arousal in the resting state. Bayesian and frequentist analysis results were especially convincing for openness to experience. Among the lower-order personality traits, we obtained strongest evidence for neuroticism facet ‘impulsivity’ and reduced CNS arousal. We regard these findings as well in line with the postulations of Eysenck and Zuckerman and consistent with the assumptions of the ‘arousal regulation model’. Our results also agree with meta-analytically derived effect sizes in the field of individual differences research, highlighting the need for large studies with at least several hundreds of subjects.
Introduction: In recent years, resource-saving handling of allogeneic blood products and a reduction of transfusion rates in adults has been observed. However, comparable published national data for transfusion practices in pediatric patients are currently not available. In this study, the transfusion rates for children and adolescents were analyzed based on data from the Federal Statistical Office of Germany during the past 2 decades. Methods: Data were queried via the database of the Federal Statistical Office (Destasis). The period covered was from 2005 to 2018, and those in the sample group were children and adolescents aged 0–17 years receiving inpatient care. Operation and procedure codes (OPS) for transfusions, procedures, or interventions with increased transfusion risk were queried and evaluated in detail. Results: In Germany, 0.9% of the children and adolescents treated in hospital received a transfusion in 2018. A reduction in transfusion rates from 1.02% (2005) to 0.9% (2018) was observed for the total collective of children and adolescents receiving inpatient care. Increases in transfusion rates were recorded for 1- to 4- (1.41–1.45%) and 5- to 10-year-olds (1.24–1.33%). Children under 1 year of age were most frequently transfused (in 2018, 40.2% of the children were cared for in hospital). Transfusion-associated procedures such as chemotherapy or machine ventilation and respiratory support for newborns and infants are on the rise. Conclusion: Transfusion rates are declining in children and adolescents, but the reasons for increases in transfusion rates in other groups are unclear. Prospective studies to evaluate transfusion rates and triggers in children are urgently needed.
Background: Plasma transfusions are most commonly used therapeutically for bleeding or prophylactically in non-bleeding patients prior to invasive procedures or surgery. Although plasma transfusions generally seem to decline, plasma usage for indications that lack evidence of efficacy prevail. Summary: There is wide international, interinstitutional, and interindividual variance regarding the compliance with guidelines based on published references, supported by appropriate testing. There is furthermore a profound lack of evidence from randomized controlled trials comparing the effect of plasma transfusion with that of other therapeutic interventions for most indications, including massive bleeding. The expected benefit of a plasma transfusion needs to be balanced carefully against the associated risk of adverse events. In light of the heterogeneous nature of bleeding conditions and their rapid evolvement over time, fibrinogen and factor concentrate therapy, directed at specific phases of coagulation identified by alternative laboratory assays, may offer advantages over conventional blood product ratio-driven resuscitation. However, their outcome benefit has not been demonstrated in well-powered prospective trials. This systematic review will detail the current evidence base for plasma transfusion in adult surgical patients.
Management of decompensated cirrhosis is currently geared towards the treatment of complications once they occur. To date there is no established disease-modifying therapy aimed at halting progression of the disease and preventing the development of complications in patients with decompensated cirrhosis. The design of clinical trials to investigate new therapies for patients with decompensated cirrhosis is complex. The population of patients with decompensated cirrhosis is heterogeneous (i.e., different etiologies, comorbidities and disease severity), leading to the inclusion of diverse populations in clinical trials. In addition, primary endpoints selected for trials that include patients with decompensated cirrhosis are not homogeneous and at times may not be appropriate. This leads to difficulties in comparing results obtained from different trials. Against this background, the LiverHope Consortium organized a meeting of experts, the goal of which was to develop recommendations for the design of clinical trials and to define appropriate endpoints, both for trials aimed at modifying the natural history and preventing progression of decompensated cirrhosis, as well as for trials aimed at managing the individual complications of cirrhosis.
The interaction of microplastics with freshwater biota and their interaction with other stressors is still not very well understood. Therefore, we investigated the ingestion, excretion and toxicity of microplastics in the freshwater gastropod Lymnaea stagnalis.
MP ingestion was analyzed as tissues levels in L. stagnalis after 6–96 h of exposure to 5–90 μm spherical polystyrene (PS) microplastics. To understand the excretion, tissue levels were determined after 24 h of exposure followed by a 12 h–7 d depuration period. To assess the toxicity, snails were exposed for 28 d to irregular PS microplastics (<63 μm, 6.4–100,000 particles mL−1), both alone and in combination with copper as additional stressor. To compare the toxicity of natural and synthetic particles, we also included diatomite particles. Microplastics ingestion and excretion significantly depended on the particle size and the exposure/depuration duration. An exposure to irregular PS had no effect on survival, reproduction, energy reserves and oxidative stress. However, we observed slight effects on immune cell phagocytosis. Exposure to microplastics did not exacerbate the reproductive toxicity of copper. In addition, there was no pronounced difference between the effects of microplastics and diatomite. The tolerance towards microplastics may originate from an adaptation of L. stagnalis to particle-rich environments or a general stress resilience. In conclusion, despite high uptake rates, PS fragments do not appear to be a relevant stressor for stress tolerant freshwater gastropods considering current environmental levels of microplastics.
Functional genomics studies in model organisms and human cell lines provided important insights into gene functions and their context-dependent role in genetic circuits. However, our functional understanding of many of these genes and how they combinatorically regulate key biological processes, remains limited. To enable the SpCas9-dependent mapping of gene-gene interactions in human cells, we established 3Cs multiplexing for the generation of combinatorial gRNA libraries in a distribution-unbiased manner and demonstrate its robust performance. The optimal number for combinatorial hit calling was 16 gRNA pairs and the skew of a library’s distribution was identified as a critical parameter dictating experimental scale and data quality. Our approach enabled us to investigate 247,032 gRNA-pairs targeting 12,736 gene-interactions in human autophagy. We identified novel genes essential for autophagy and provide experimental evidence that gene-associated categories of phenotypic strengths exist in autophagy. Furthermore, circuits of autophagy gene interactions reveal redundant nodes driven by paralog genes. Our combinatorial 3Cs approach is broadly suitable to investigate unexpected gene-interaction phenotypes in unperturbed and diseased cell contexts.
While the liver, specifically hepatocytes, are widely accepted as the main source for hepatitis C virus (HCV) production, the role of the liver/hepatocytes in the clearance of circulating HCV remains largely unknown. Here we evaluated the function of the liver/hepatocytes in clearing virus from the circulation by investigating viral clearance during liver transplantation and from culture medium in vitro. Frequent HCV kinetic data during liver transplantation were recorded from 5 individuals throughout the anhepatic (AH) phase and for 4 hours after reperfusion (RP), along with recordings of fluid balances. Using mathematical modeling, the serum viral clearance rate, c, was estimated. Analogously, we monitored the clearance rate of HCV at 37°C from culture medium in vitro in the absence and presence of chronically infected Huh7 human hepatoma cells. During the AH phase, in 3 transplant cases viral levels remained at pre-AH levels, while in the other 2 cases HCV declined (half-life, t1/2~1h). Immediately post-RP, virus declined in a biphasic manner in Cases 1-4 consisting of an extremely rapid (median t1/2=5min) decline followed by a slower decline (HCV t1/2=67min). In Case 5, HCV remained at the same level post-RP as at the end of AH. Declines in virus level were not explained by adjusting for dilution from IV fluid and blood products. Consistent with what was observed in the majority of patients in the anhepatic phase, the t1/2 of HCV in cell culture was much longer in the absence of chronically HCV-infected Huh7 cells. Therefore, kinetic and modeling results from both in vivo liver transplantation cases and in vitro cell culture studies suggest that the liver plays a major role in clearing HCV from the circulation.
SARS-CoV-2 and stroke characteristics: a report from the Multinational COVID-19 Stroke Study Group
(2020)
Background: Stroke is reported as a consequence of SARS-CoV-2 infection. However, there is a lack of regarding comprehensive stroke phenotype and characteristics
Methods: We conducted a multinational observational study on features of consecutive acute ischemic stroke (AIS), intracranial hemorrhage (ICH), and cerebral venous or sinus thrombosis (CVST) among SARS-CoV-2 infected patients. We further investigated the association of demographics, clinical data, geographical regions, and countries’ health expenditure among AIS patients with the risk of large vessel occlusion (LVO), stroke severity as measured by National Institute of Health stroke scale (NIHSS), and stroke subtype as measured by the TOAST criteria. Additionally, we applied unsupervised machine learning algorithms to uncover possible similarities among stroke patients.
Results: Among the 136 tertiary centers of 32 countries who participated in this study, 71 centers from 17 countries had at least one eligible stroke patient. Out of 432 patients included, 323(74.8%) had AIS, 91(21.1%) ICH, and 18(4.2%) CVST. Among 23 patients with subarachnoid hemorrhage, 16(69.5%) had no evidence of aneurysm. A total of 183(42.4%) patients were women, 104(24.1%) patients were younger than 55 years, and 105(24.4%) patients had no identifiable vascular risk factors. Among 380 patients who had known interval onset of the SARS-CoV-2 and stroke, 144(37.8%) presented to the hospital with chief complaints of stroke-related symptoms, with asymptomatic or undiagnosed SARS-CoV-2 infection. Among AIS patients 44.5% had LVO; 10% had small artery occlusion according to the TOAST criteria. We observed a lower median NIHSS (8[3-17], versus 11 [5-17]; p=0.02) and higher rate of mechanical thrombectomy (12.4% versus 2%; p<0.001) in countries with middle to high-health expenditure when compared to countries with lower health expenditure. The unsupervised machine learning identified 4 subgroups, with a relatively large group with no or limited comorbidities.
Conclusions: We observed a relatively high number of young, and asymptomatic SARS-CoV-2 infections among stroke patients. Traditional vascular risk factors were absent among a relatively large cohort of patients. Among hospitalized patients, the stroke severity was lower and rate of mechanical thrombectomy was higher among countries with middle to high-health expenditure.
Background Stigma has been considered a significant barrier both in treatment, rehabilitation and help-seeking behaviours of people diagnosed with depression. This study aimed to assess the influence of the type of previous experience with depression on depression stigma, identify the effects of previous experience with depression on stigma and to analyse the effects of stigma on help-seeking attitudes.
Methods A total of 1693 participants with a mean age of 47.2 (SD=18.17) completed the Depression Stigma Scale (DSS), the Attitude Toward Seeking Professional Psychological Help (ATSPPH), and a sociodemographic questionnaire. We categorised participants into four comparison groups: no previous experience with depression (n=479), indirect experience with depression (n=661), direct experience with depression (n=137), and both direct and indirect experience with depression (n=416). Data were analysed using SPSS 24.0.
Results Levels of personal stigma were lower in people who had family and friends experiencing depression in comparison with individuals with no history of depression experience. Better attitudes towards help-seeking were evident in those with lower personal stigma, and worse help-seeking attitudes were associated with higher perceived stigma in the indirect previous experience group.
Limitations Duration of participant exposure to depression was not collected.
Conclusions The individual’s experience with depression influences the development of personal stigmatisation towards depression and plays a role in help-seeking behaviours. Addressing people’s experience of depression might be a practical way of reducing depression stigma and improve help-seeking behaviours.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can spread from symptomatic patients with COVID-19, but also from asymptomatic individuals. Therefore, robust surveillance and timely interventions are essential for the control of virus spread within the community. In this regard the frequency of testing and speed of reporting, but not the test sensitivity alone, play a crucial role. In order to reduce the costs and meet the expanding demands in real-time RT-PCR (rRT-PCR) testing for SARS-CoV-2, complementary assays, such as rapid antigen tests, have been developed. Rigorous analysis under varying conditions is required to assess the clinical performance of these tests and to ensure reproducible results. We evaluated the sensitivity and specificity of a recently licensed rapid antigen test using 137 clinical samples in two institutions. Test sensitivity was between 88.2-89.6% when applied to samples with viral loads typically seen in infectious patients. Of 32 rRT-PCR positive samples, 19 demonstrated infectivity in cell culture, and 84% of these samples were reactive with the antigen test. Seven full-genome sequenced SARS-CoV-2 isolates and SARS-CoV-1 were detected with this antigen test, with no cross-reactivity against other common respiratory viruses. Numerous antigen tests are available for SARS-CoV-2 testing and their performance to detect infectious individuals may vary. Head-to-head comparison along with cell culture testing for infectivity may prove useful to identify better performing antigen tests. The antigen test analyzed in this study is easy-to-use, inexpensive, and scalable. It can be helpful in monitoring infection trends and thus has potential to reduce transmission.
The novel coronavirus (SARS-CoV-2), identified in China at the end of December 2019 and causing the disease COVID-19, has meanwhile led to outbreaks all over the globe, with about 571,700 confirmed cases and about 26,500 deaths as of March 28th, 2020. We present here the preliminary results of a mathematical study directed at informing on the possible application or lifting of control measures in Germany. The developed mathematical models allow to study the spread of COVID-19 among the population in Germany and to asses the impact of non-pharmaceutical interventions.
The novel coronavirus (SARS-CoV-2), identified in China at the end of December 2019 and causing the disease COVID-19, has meanwhile led to outbreaks all over the globe with about 2.2 million confirmed cases and more than 150,000 deaths as of April 17, 2020 [37]. In view of most recent information on testing activity [32], we present here an update of our initial work [4]. In this work, mathematical models have been developed to study the spread of COVID-19 among the population in Germany and to asses the impact of non-pharmaceutical interventions. Systems of differential equations of SEIR type are extended here to account for undetected infections, as well as for stages of infections and age groups. The models are calibrated on data until April 5, data from April 6 to 14 are used for model validation. We simulate different possible strategies for the mitigation of the current outbreak, slowing down the spread of the virus and thus reducing the peak in daily diagnosed cases, the demand for hospitalization or intensive care units admissions, and eventually the number of fatalities. Our results suggest that a partial (and gradual) lifting of introduced control measures could soon be possible if accompanied by further increased testing activity, strict isolation of detected cases and reduced contact to risk groups.
Cells maintain membrane fluidity by regulating lipid saturation, but the molecular mechanisms of this homeoviscous adaptation remain poorly understood. We have reconstituted the core machinery for regulating lipid saturation in baker’s yeast to study its molecular mechanism. By combining molecular dynamics simulations with experiments, we uncover a remarkable sensitivity of the transcriptional regulator Mga2 to the abundance, position, and configuration of double bonds in lipid acyl chains, and provide insights into the molecular rules of membrane adaptation. Our data challenge the prevailing hypothesis that membrane fluidity serves as the measured variable for regulating lipid saturation. Rather, we show that Mga2 senses the molecular lipid-packing density in a defined region of the membrane. Our findings suggest that membrane property sensors have evolved remarkable sensitivities to highly specific aspects of membrane structure and dynamics, thus paving the way toward the development of genetically encoded reporters for such properties in the future.
In search for practical silvicultural management tools to identify alternative tree species for predicted Central European climate conditions, a cross-species survey with five evergreen, semi-evergreen, and deciduous Quercus taxa with contrasting morphological leaf traits was performed. Fast chlorophyll fluorescence induction of PSII and relative leaf chlorophyll contents were performed to assess the overall plant vitality at any point in time during two complete vegetation periods in consecutive years (2012 and 2013). Maximum photochemical efficiency of PSII and the performance index on absorption base showed a very conservative relationship to each other and a similar intra-annual progress in all deciduous species, but with a different speed of increase and decrease during leaf development and senescence and thus a different length of vegetation period. The intra-annual variability of OJIP and chlorophyll content parameters is considered with respect to the practicability of measurements in the field for management purposes.
Stabilization exercise (SE) is evident for the management of chronic non-specific low back pain (LBP). The optimal dose-response-relationship for the utmost treatment success is, thus, still unknown. The purpose is to systematically review the dose-response-relationship of stabilisation exercises on pain and disability in patients with chronic non-specific LBP. A systematic review with meta-regression was conducted (Pubmed, Web of Knowledge, Cochrane). Eligibility criteria were RCTs on patients with chronic non-specific LBP, written in English/German and adopting a longitudinal core-specific/stabilising/motor control exercise intervention with at least one outcome for pain intensity and/or disability. Meta-regressions (dependent variable = effect sizes (Cohens d) of the interventions (for pain and for disability), independent variable = training characteristics (duration, frequency, time per session)), and controlled for (low) study quality (PEDro) and (low) sample sizes (n) were conducted to reveal the optimal dose required for therapy success. From the 3,415 studies initially selected, 50 studies (n = 2,786 LBP patients) were included. N = 1,239 patients received SE. Training duration was 7.0 ± 3.3 weeks, training frequency was 3.1 ± 1.8 sessions per week with a mean training time of 44.6 ± 18.0 min per session. The meta-regressions’ mean effect size was d = 1.80 (pain) and d = 1.70 (disability). Total R2 was 0.445 and 0.17. Moderate quality evidence (R2 = 0.231) revealed that a training duration of 20 to 30 min elicited the largest effect (both in pain and disability, logarithmic association). Low quality evidence (R2 = 0.125) revealed that training 3 to 5 times per week led to the largest effect of SE in patients with chronic non-specific LBP (inverted U-shaped association). In patients with non-specific chronic LBP, stabilization exercise with a training frequency of 3 to 5 times per week (Grade C) and a training time of 20 to 30 min per session (Grade A) elicited the largest effect on pain and disability.
In this paper we present a new approach to deterministic modelling of COVID-19 epidemic. Our model dynamics is expressed by a single prognostic variable which satisfies an integro-differential equation. All unknown parameters are described with a single, time-dependent variable R(t). We show that our model has similarities to classic compartmental models, such as SIR, and that the variable R(t) can be interpreted as a generalized effective reproduction number. The advantages of our approach are the simplicity of having only one equation, the numerical stability due to an integral formulation and the reliability since the model is formulated in terms of the most trustable statistical data variable: the number of cumulative diagnosed positive cases of COVID-19. Once this dynamic variable is calculated, other non-dynamic variables, such as the number of heavy cases (hospital beds), the number of intensive-care cases (ICUs) and the fatalities, can be derived from it using a similarly stable, integral approach. The formulation with a single equation allows us to calculate from real data the values of the sample effective reproduction number, which can then be fitted. Extrapolated values of R(t) can be used in the model to make reliable forecasts, though under the assumption that measures for reducing infections are maintained. We have applied our model to more than 15 countries and the ongoing results are available on a web-based platform [1]. In this paper, we focus on the data for two exemplary countries, Italy and Germany, and show that the model is capable of reproducing the course of the epidemic in the past and forecasting its course for a period of four to five weeks with a reasonable numerical stability.
Airborne transmission of SARS-CoV-2 through virus-containing aerosol particles has been established as an important pathway for Covid-19 infection. Suitable measures to prevent such infections are imperative, especially in situations when a high number of persons convene in closed rooms. Here we tested the efficiency and practicability of operating four air purifiers equipped with HEPA filters in a high school classroom while regular classes were taking place. We monitored the aerosol number concentration for particles > 3 nm at two locations in the room, the aerosol size distribution in the range from 10 nm to 10 µm, PM10 and CO2 concentration. For comparison, we performed similar measurements in a neighboring classroom without purifiers. In times when classes were conducted with windows and door closed, the aerosol concentration was reduced by more than 90 % within less than 30 minutes when running the purifiers (air exchange rate 5.5 h-1). The reduction was homogeneous throughout the room and for all particle sizes. The measurements are supplemented by a calculation estimating the maximum concentration levels of virus-containing aerosol from a highly contagious person speaking in a closed room with and without air purifiers. Measurements and calculation demonstrate that air purifiers potentially represent a well-suited measure to reduce the risks of airborne transmission of SARS-CoV-2 substantially. Staying for two hours in a closed room with a highly infective person, we estimate that the inhaled dose is reduced by a factor of six when using air purifiers with a total air exchange rate of 5.7 h-1.
Rhodesain is the lysosomal cathepsin L-like cysteine protease of T. brucei rhodesiense, the causative agent of Human African Trypanosomiasis. The enzyme is essential for the proliferation and pathogenicity of the parasite as well as its ability to overcome the blood-brain barrier of the host. Lysosomal cathepsins are expressed as zymogens with an inactivating pro-domain that is cleaved under acidic conditions. A structure of the uncleaved maturation intermediate from a trypanosomal cathepsin L-like protease is currently not available. We thus established the heterologous expression of T. brucei rhodesiense pro-rhodesain in E. coli and determined its crystal structure. The trypanosomal pro-domain differs from non-parasitic pro-cathepsins by a unique, extended α-helix that blocks the active site and whose interactions resemble that of the antiprotozoal inhibitor K11777. Interdomain dynamics between pro- and core protease domain as observed by photoinduced electron transfer fluorescence correlation spectroscopy increase at low pH, where pro-rhodesain also undergoes autocleavage. Using the crystal structure, molecular dynamics simulations and mutagenesis, we identify a conserved interdomain salt bridge that prevents premature intramolecular cleavage at higher pH values and may thus present a control switch for the observed pH-sensitivity of pro-enzyme cleavage in (trypanosomal) CathL-like proteases.
WaterGAP (Water - Global Assessment and Prognosis) is a tool for modeling global water use and water availability. It participates among other models in the ISIMIP initiative (The Inter-Sectoral Impact Model Intercomparison Project). As part of this initiative, the water temperature should be calculated by participating hydrological models because it plays a vital role in many chemical, physical and biological processes. Therefore, the subject of this master thesis is to implement the physically based surface water temperature computation after VAN BEEK ET AL. (2012) and WANDERS ET AL. (2019) into WaterGAP and compare the results to the statistical regression approach by PUNZET ET AL. (2012). The computation is validated with observed water temperature data obtained from the GEMStat water quality database. The results are good for arctic and temperate latitudes. Surface water temperatures for tropical rivers are overestimated, most likely due to the overestimation of precipitation temperatures, incoming radiation and groundwater temperatures. The comparison with the regression model by PUNZET ET AL. (2012) shows matching results. The regression model even matches with WaterGAP results for most of the simulations of the future under climate change conditions, where the regression model should stop working due to changing environmental parameters. Several assumptions had to be made in order to implement the water temperature calculation in Water-GAP. These include, e.g., discharge temperatures for power plant cooling water, precipitation and surface runoff temperatures. For model improvements, perhaps three different values for the different regions of the world should be used to cool down the precipitation and surface runoff. The model could also be improved by refining the ice formation calculation, especially for the conditions when the ice melts, breaks up and is transported downstream. Furthermore, the feedback to the river channel roughness could be implemented if ice has formed. The WaterGAP model upgraded with the water temperature calculation will help the ISIMIP initiative in the future.
The development of binocular vision is an active learning process comprising the development of disparity tuned neurons in visual cortex and the establishment of precise vergence control of the eyes. We present a computational model for the learning and self-calibration of active binocular vision based on the Active Efficient Coding framework, an extension of classic efficient coding ideas to active perception. Under normal rearing conditions, the model develops disparity tuned neurons and precise vergence control, allowing it to correctly interpret random dot stereogramms. Under altered rearing conditions modeled after neurophysiological experiments, the model qualitatively reproduces key experimental findings on changes in binocularity and disparity tuning. Furthermore, the model makes testable predictions regarding how altered rearing conditions impede the learning of precise vergence control. Finally, the model predicts a surprising new effect that impaired vergence control affects the statistics of orientation tuning in visual cortical neurons.
The spike protein (S) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is required for cell entry and is the primary focus for vaccine development. In this study, we combined cryo–electron tomography, subtomogram averaging, and molecular dynamics simulations to structurally analyze S in situ. Compared with the recombinant S, the viral S was more heavily glycosylated and occurred mostly in the closed prefusion conformation. We show that the stalk domain of S contains three hinges, giving the head unexpected orientational freedom. We propose that the hinges allow S to scan the host cell surface, shielded from antibodies by an extensive glycan coat. The structure of native S contributes to our understanding of SARS-CoV-2 infection and potentially to the development of safe vaccines.
The spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is required for cell entry and is the major focus for vaccine development. We combine cryo electron tomography, subtomogram averaging and molecular dynamics simulations to structurally analyze S in situ. Compared to recombinant S, the viral S is more heavily glycosylated and occurs predominantly in a closed pre-fusion conformation. We show that the stalk domain of S contains three hinges that give the globular domain unexpected orientational freedom. We propose that the hinges allow S to scan the host cell surface, shielded from antibodies by an extensive glycan coat. The structure of native S contributes to our understanding of SARS-CoV-2 infection and the development of safe vaccines. The large scale tomography data set of SARS-CoV-2 used for this study is therefore sufficient to resolve structural features to below 5 Ångstrom, and is publicly available at EMPIAR-10453.
Understanding the nano-architecture of protein machines in diverse subcellular compartments remains a challenge despite rapid progress in super-resolution microscopy. While single-molecule localization microscopy techniques allow the visualization and identification of cellular structures with near-molecular resolution, multiplex-labeling of tens of target proteins within the same sample has not yet been achieved routinely. However, single sample multiplexing is essential to detect patterns that threaten to get lost in multi-sample averaging. Here, we report maS3TORM (multiplexed automated serial staining stochastic optical reconstruction microscopy), a microscopy approach capable of fully automated 3D direct STORM (dSTORM) imaging and solution exchange employing a re-staining protocol to achieve highly multiplexed protein localization within individual biological samples. We demonstrate 3D super-resolution images of 15 targets in single cultured cells and 16 targets in individual neuronal tissue samples with <10 nm localization precision, allowing us to define distinct nano-architectural features of protein distribution within the presynaptic nerve terminal.
The auditory midbrain (inferior colliculus, IC) plays an important role in sound processing, acting as hub for acoustic information extraction and for the implementation of fast audio-motor behaviors. IC neurons are topographically organized according to their sound frequency preference: dorsal IC regions encode low frequencies while ventral areas respond best to high frequencies, a type of sensory map defined as tonotopy. Tonotopic maps have been studied extensively using artificial stimuli (pure tones) but our knowledge of how these maps represent information about sequences of natural, spectro-temporally rich sounds is sparse. We studied this question by conducting simultaneous extracellular recordings across IC depths in awake bats (Carollia perspicillata) that listened to sequences of natural communication and echolocation sounds. The hypothesis was that information about these two types of sound streams is represented at different IC depths since they exhibit large differences in spectral composition, i.e., echolocation covers the high-frequency portion of the bat soundscape (> 45 kHz), while communication sounds are broadband and carry most power at low frequencies (20–25 kHz). Our results showed that mutual information between neuronal responses and acoustic stimuli, as well as response redundancy in pairs of neurons recorded simultaneously, increase exponentially with IC depth. The latter occurs regardless of the sound type presented to the bats (echolocation or communication). Taken together, our results indicate the existence of mutual information and redundancy maps at the midbrain level whose response cannot be predicted based on the frequency composition of natural sounds and classic neuronal tuning curves.
Neural oscillations are at the core of important computations in the mammalian brain. Interactions between oscillatory activities in different frequency bands, such as delta (1-4 Hz), theta (4-8 Hz), or gamma (>30 Hz), are a powerful mechanism for binding fundamentally distinct spatiotemporal scales of neural processing. Phase-amplitude coupling (PAC) is one such plausible and well-described interaction, but much is yet to be uncovered regarding how PAC dynamics contribute to sensory representations. In particular, although PAC appears to have a major role in audition, the characteristics of coupling profiles in sensory and integration (i.e. frontal) cortical areas remain obscure. Here, we address this question by studying PAC dynamics in the frontal-auditory field (FAF; an auditory area in the bat frontal cortex) and the auditory cortex (AC) of the bat Carollia perspicillata. By means of simultaneous electrophysiological recordings in frontal and auditory cortices examining local-field potentials (LFPs), we show that the amplitude of gamma-band activity couples with the phase of low-frequency LFPs in both structures. Our results demonstrate that the coupling in FAF occurs most prominently in delta/high-gamma frequencies (1-4/75-100 Hz), whereas in the AC the coupling is strongest in the theta/low-gamma (2-8/25-55 Hz) range. We argue that distinct PAC profiles may represent different mechanisms for neuronal processing in frontal and auditory cortices, and might complement oscillatory interactions for sensory processing in the frontal-auditory cortex network.
Animals extract behaviorally relevant signals from “noisy” environments. To investigate signal extraction, echolocating provides a rich system testbed. For orientation, bats broadcast calls and assign each echo to the corresponding call. When orienting in acoustically enriched environments or when approaching targets, bats change their spectro-temporal call design. Thus, to assess call adjustments that are exclusively meant to facilitate signal extraction in “noisy” environments, it is necessary to control for distance-dependent call changes. By swinging bats in a pendulum, we tested the influence of acoustic playback on the echolocation behavior of Carollia perspicillata. This paradigm evokes reproducible orientation behavior and allows a precise definition of the influence of the acoustic context. Our results show that bats dynamically switch between different adaptations to cope with sound-based navigation in acoustically contaminated environments. These dynamics of echolocation behavior may explain the large variety of adaptations that have been reported in the bat literature.
It becomes more and more obvious that deregulation of host metabolism play an important role in SARS-CoV-2 pathogenesis with implication for increased risk of severe course of COVID-19. Furthermore, it is expected that COVID-19 patients recovered from severe disease may experience long-term metabolic disorders. Thereby understanding the consequences of SARS-CoV-2 infection on host metabolism can facilitate efforts for effective treatment option. We have previously shown that SARS-CoV-2-infected cells undergo a shift towards glycolysis and that 2-deoxy-D-glucose (2DG) inhibits SARS-CoV-2 replication. Here, we show that also pentose phosphate pathway (PPP) is remarkably deregulated. Since PPP supplies ribonucleotides for SARS-CoV-2 replication, this could represent an attractive target for an intervention. On that account, we employed the transketolase inhibitor benfooxythiamine and showed dose-dependent inhibition of SARS-CoV-2 in non-toxic concentrations. Importantly, the antiviral efficacy of benfooxythiamine was further increased in combination with 2DG.
Endogenous clocks enable organisms to adapt their physiology and behavior to daily variation in environmental conditions. Metabolic processes in cyanobacteria to humans are effected by the circadian clock, and its dysregulation causes metabolic disorders. In mouse and Drosophila were shown that the circadian clock directs translation of factors involved in ribosome biogenesis and synchronizes protein synthesis. However, the role of clocks in Drosophila neurogenesis and the potential impact of clock impairment on neural circuit formation and function is less understood. Here we demonstrate that light stimuli or circadian clock causes a defect in neural stem cell growth and proliferation accompanied by reduced nucleolar size. Further, we define that light and clock independently affect the InR/TOR growth regulatory pathway due to the effect on regulators of protein biosynthesis. Altogether, these data suggest that alterations in growth regulatory pathways induced by light and clock are associated with impaired neural development.
The firing pattern of ventral midbrain dopamine neurons is controlled by afferent and intrinsic activity to generate prediction error signals that are essential for reward-based learning. Given the absence of intracellular in vivo recordings in the last three decades, the subthreshold membrane potential events that cause changes in dopamine neuron firing patterns remain unknown. By establishing stable in vivo whole-cell recordings of >100 spontaneously active midbrain dopamine neurons in anaesthetized mice, we identified the repertoire of subthreshold membrane potential signatures associated with distinct in vivo firing patterns. We demonstrate that dopamine neuron in vivo activity deviates from a single spike pacemaker pattern by eliciting transient increases in firing rate generated by at least two diametrically opposing biophysical mechanisms: a transient depolarization resulting in high frequency plateau bursts associated with a reactive, depolarizing shift in action potential threshold; and a prolonged hyperpolarization preceding slower rebound bursts characterized by a predictive, hyperpolarizing shift in action potential threshold. Our findings therefore illustrate a framework for the biophysical implementation of prediction error and sensory cue coding in dopamine neurons by tuning action potential threshold dynamics.
Genome-wide CRISPR screens are becoming more widespread and allow the simultaneous interrogation of thousands of genomic regions. Although recent progress has been made in the analysis of CRISPR screens, it is still an open problem how to interpret CRISPR mutations in non-coding regions of the genome. Most of the tools concentrate on the interpretation of mutations introduced in gene coding regions. We introduce a computational pipeline that uses epigenomic information about regulatory elements for the interpretation of CRISPR mutations in non-coding regions. We illustrate our approach on the analysis of a genome-wide CRISPR screen in hTERT-RPE-1 cells and reveal novel regulatory elements that mediate chemoresistance against doxorubicin in these cells. We infer links to established and to novel chemoresistance genes. Our approach is general and can be applied on any cell type and with different CRISPR enzymes.
Background: Ever decreasing costs along with advances in sequencing and library preparation technologies enable even small research groups to generate chromosome-level assemblies today. Here we report the generation of an improved chromosome-level assembly for the Siamese fighting fish (Betta splendens) that was carried out during a practical university Master’s course. The Siamese fighting fish is a popular aquarium fish and an emerging model species for research on aggressive behaviour. We updated the current genome assembly by generating a new long-read nanopore-based assembly with subsequent scaffolding to chromosome-level using previously published HiC data.
Findings: The use of nanopore-based long-read data sequenced on a MinION platform (Oxford Nanopore Technologies) allowed us to generate a baseline assembly of only 1,276 contigs with a contig N50 of 2.1 Mbp, and a total length of 441 Mbp. Scaffolding using previously published HiC data resulted in 109 scaffolds with a scaffold N50 of 20.7 Mbp. More than 99% of the assembly is comprised in 21 scaffolds. The assembly showed the presence of 95.8% complete BUSCO genes from the Actinopterygii dataset indicating a high quality of the assembly.
Conclusion: We present an improved full chromosome-level assembly of the Siamese fighting fish generated during a university Master’s course. The use of ~35× long-read nanopore data drastically improved the baseline assembly in terms of continuity. We show that relatively in-expensive high-throughput sequencing technologies such as the long-read MinION sequencing platform can be used in educational settings allowing the students to gain practical skills in modern genomics and generate high quality results that benefit downstream research projects.
Entorhinal-retrosplenial circuits for allocentric-egocentric transformation of boundary coding
(2020)
Spatial navigation requires landmark coding from two perspectives, relying on viewpoint-invariant and self-referenced representations. The brain encodes information within each reference frame but their interactions and functional dependency remains unclear. Here we investigate the relationship between neurons in the rat's retrosplenial cortex (RSC) and entorhinal cortex (MEC) that increase firing near boundaries of space. Border cells in RSC specifically encode walls, but not objects, and are sensitive to the animal’s direction to nearby borders. These egocentric representations are generated independent of visual or whisker sensation but are affected by inputs from MEC that contains allocentric spatial cells. Pharmaco- and optogenetic inhibition of MEC led to a disruption of border coding in RSC, but not vice versa, indicating allocentric-to-egocentric transformation. Finally, RSC border cells fire prospective to the animal’s next motion, unlike those in MEC, revealing the MEC-RSC pathway as an extended border coding circuit that implements coordinate transformation to guide navigation behavior.
Central Europe was affected by a compressional tectonic event in the Late Cretaceous, caused by the convergence of Iberia and Europe. Basement uplifts, inverted graben structures and newly formed marginal troughs are the main expressions of crustal shortening. Although the maximum activity occurred in a short period between 90 and 75 Ma, the exact timing of this event is still unclear. Dating of start and end of basin inversion is very different depending on the applied method. On the basis of borehole data, facies and thickness maps, the timing of basin re-organisation was reconstructed for several basins in Central Europe. The obtained data point to a synchronous start of basin inversion already at 95 Ma (Cenomanian), 5 Million years earlier than commonly assumed. The end of the Late Cretaceous compressional event is more difficult to pinpoint, because regional uplift and salt migration disturb the signal of shifting marginal troughs. Unconformities of Late Campanian to Paleogene age on inverted structures indicate slowly declining uplift rates.
Several studies suggested that transcription factor (TF) binding to DNA may be impaired or enhanced by DNA methylation. We present MeDeMo, a toolbox for TF motif analysis that combines information about DNA methylation with models capturing intra-motif dependencies. In a large-scale study using ChIP-seq data for 335 TFs, we identify novel TFs that are affected by DNA methylation. Overall, we find that CpG methylation decreases the likelihood of binding for the majority of TFs. For a considerable subset of TFs, we show that intra-motif dependencies are pivotal for accurately modelling the impact of DNA methylation on TF binding.
Objectives: An increasing number of treatment-determining biomarkers has been identified in non-small cell lung cancer (NSCLC) and molecular testing is recommended to enable optimal individualized treatment. However, data on implementation of these recommendations in the “real-world” setting are scarce. This study presents comprehensive details on the frequency, methodology and results of biomarker testing of advanced NSCLC in Germany.
Patients and methods: This analysis included 3,717 patients with advanced NSCLC (2,921 non-squamous; 796 squamous), recruited into the CRISP registry at start of systemic therapy by 150 German sites between December 2015 and June 2019. Evaluated were the molecular biomarkers EGFR, ALK, ROS1, BRAF, KRAS, MET, TP53, RET, HER2, as well as expression of PD-L1.
Results: In total, 90.5 % of the patients were tested for biomarkers. Testing rates were 92.2 % (non-squamous), 70.7 % (squamous) and increased from 83.2 % in 2015/16 to 94.2% in 2019. Overall testing rates for EGFR, ALK, ROS1, and BRAF were 72.5 %, 74.5 %, 66.1 %, and 53.0 %, respectively (non-squamous). Testing rates for PD-L1 expression were 64.5 % (non-squamous), and 58.5 % (squamous). The most common testing methods were immunohistochemistry (68.5 % non-squamous, 58.3 % squamous), and next-generation sequencing (38.7 % non-squamous, 14.4 % squamous). Reasons for not testing were insufficient tumor material or lack of guideline recommendations (squamous). No alteration was found in 37.8 % (non-squamous), and 57.9 % (squamous), respectively. Most common alterations in non-squamous tumors (all patients/all patients tested for the respective biomarker): KRAS (17.3 %/39.2 %), TP53 (14.1 %/51.4 %), and EGFR (11.0 %/15.1 %); in squamous tumors: TP53 (7.0 %/69.1 %), MET (1.5 %/11.1 %), and EGFR (1.1 %/4.4 %). Median PFS (non-squamous) was 8.7 months (95 % CI 7.4–10.4) with druggable EGFR mutation, and 8.0 months (95 % CI 3.9–9.2) with druggable ALK alterations.
Conclusion: Testing rates in Germany are high nationwide and acceptable in international comparison, but still leave out a significant portion of patients, who could potentially benefit. Thus, specific measures are needed to increase implementation.
Human lymph nodes play a central part of immune defense against infection agents and tumor cells. Lymphoid follicles are compartments of the lymph node which are spherical, mainly filled with B cells. B cells are cellular components of the adaptive immune systems. In the course of a specific immune response, lymphoid follicles pass different morphological differentiation stages. The morphology and the spatial distribution of lymphoid follicles can be sometimes associated to a particular causative agent and development stage of a disease. We report our new approach for the automatic detection of follicular regions in histological whole slide images of tissue sections immuno-stained with actin. The method is divided in two phases: (1) shock filter-based detection of transition points and (2) segmentation of follicular regions. Follicular regions in 10 whole slide images were manually annotated by visual inspection, and sample surveys were conducted by an expert pathologist. The results of our method were validated by comparing with the manual annotation. On average, we could achieve a Zijbendos similarity index of 0.71, with a standard deviation of 0.07.
Most mammals rely on the extraction of acoustic information from the environment in order to survive. However, the mechanisms that support sound representation in auditory neural networks involving sensory and association brain areas remain underexplored. In this study, we address the functional connectivity between an auditory region in frontal cortex (the frontal auditory field, FAF) and the auditory cortex (AC) in the bat Carollia perspicillata. The AC is a classic sensory area central for the processing of acoustic information. On the other hand, the FAF belongs to the frontal lobe, a brain region involved in the integration of sensory inputs, modulation of cognitive states, and in the coordination of behavioural outputs. The FAF-AC network was examined in terms of oscillatory coherence (local-field potentials, LFPs), and within an information theoretical framework linking FAF and AC spiking activity. We show that in the absence of acoustic stimulation, simultaneously recorded LFPs from FAF and AC are coherent in low frequencies (1-12 Hz). This “default” coupling was strongest in deep AC layers and was unaltered by acoustic stimulation. However, presenting auditory stimuli did trigger the emergence of coherent auditory-evoked gamma-band activity (>25 Hz) between the FAF and AC. In terms of spiking, our results suggest that FAF and AC engage in distinct coding strategies for representing artificial and natural sounds. Taken together, our findings shed light onto the neuronal coding strategies and functional coupling mechanisms that enable sound representation at the network level in the mammalian brain.
Synchronization has been implicated in neuronal communication, but causal evidence remains indirect. We used optogenetics to generate depolarizing currents in pyramidal neurons of cat visual cortex, emulating excitatory synaptic inputs under precise temporal control, while measuring spike output. Cortex transformed constant excitation into strong gamma-band synchronization, revealing the well-known cortical resonance. Increasing excitation with ramps increased the strength and frequency of synchronization. Slow, symmetric excitation profiles revealed hysteresis of power and frequency. Crucially, white-noise input sequences enabled causal analysis of network transmission, establishing that cortical resonance selectively transmits coherent input components. Models composed of recurrently coupled excitatory and inhibitory units uncovered a crucial role of feedback inhibition and suggest that hysteresis can arise through spike-frequency adaptation. The presented approach provides a powerful means to investigate the resonance properties of local circuits and probe how these properties transform input and shape transmission.
The gamma rhythm has been implicated in neuronal communication, but causal evidence remains indirect. We measured spike output of local neuronal networks and emulated their synaptic input through optogenetics. Opsins provide currents through somato-dendritic membranes, similar to synapses, yet under experimental control with high temporal precision. We expressed Channelrhodopsin-2 in excitatory neurons of cat visual cortex and recorded neuronal responses to light with different temporal characteristics. Sine waves of different frequencies entrained neuronal responses with a reliability that peaked for input frequencies in the gamma band. Crucially, we also presented white-noise sequences, because their temporal unpredictability enables analysis of causality. Neuronal spike output was caused specifically by the input’s gamma component. This gamma-specific transfer function is likely an emergent property of in-vivo networks with feedback inhibition. The method described here could reveal the transfer function between the input to any one and the output of any other neuronal group.
The plant family Brassicaceae includes some of the most studied hosts of plant microbiomes, targeting microbial diversity, community assembly rules, and effects on host performance. Compared to bacteria, eukaryotes in the brassicaceous microbiome remain understudied, especially under natural settings. Here, we assessed the impact of host identity and age on the assembly of fungal and oomycete root communities, using DNA metabarcoding of roots and associated soil of three annual co-habiting Brassicaceae collected at two time points. Our results showed that fungal communities are more diverse and structured than those of oomycetes. In both cases, plant identity and sampling time had little influence on community variation, whereas root/soil compartment had a strong effect by exerting control on the entry of soil microorganisms into the roots. The enrichment in roots of specific fungi suggests a specialization towards the asymptomatic colonization of plant tissues, which could be relevant to host’s fitness and health.
Wildfires are relatively rare in subarctic tundra ecosystems, but they can strongly change ecosystem properties. Short-term fire effects on subarctic tundra vegetation are well documented, but long-term vegetation recovery has been studied less. The frequency of tundra fires will increase with climate warming. Understanding the long-term effects of fire is necessary to predict future ecosystem changes.
We used a space-for-time approach to assess vegetation recovery after fire over more than four decades. We studied soil and vegetation patterns on three large fire scars (>44, 28 and 12 years old) in dry, lichen-dominated forest tundra in Western Siberia. On 60 plots, we determined soil temperature and permafrost thaw depth, sampled vegetation and measured plant functional traits. We assessed trends in NDVI to support the field-based results on vegetation recovery.
Soil temperature, permafrost thaw depth and total vegetation cover had recovered to pre-fire levels after >44 years, as well as total vegetation cover. In contrast, after >44 years, functional groups had not recovered to the pre-fire state. Burnt areas had lower lichen and higher bryophyte and shrub cover. The dominating shrub species, Betula nana, exhibited a higher vitality (higher specific leaf area and plant height) on burnt compared with control plots, suggesting a fire legacy effect in shrub growth. Our results confirm patterns of shrub encroachment after fire that were detected before in other parts of the Arctic and Subarctic. In the so far poorly studied Western Siberian forest tundra we demonstrate for the first time, long-term fire-legacies on the functional composition of relatively dry shrub- and lichen-dominated vegetation.
Signal transfer of visual stimuli to V4 occurs in gamma-rhythmic, pulsed information packages
(2020)
Summary Selective visual attention allows the brain to focus on behaviorally relevant information while ignoring irrelevant signals. As a possible mechanism, routing by synchronization was proposed: neural populations sending attended signals align their gamma-rhythmic activities with receiving populations, such that spikes from the senders arrive at excitability peaks of the receivers, enhancing signal transfer. Conversely, the non-attended signals arrive unaligned to the receiver’s oscillation, reducing signal transfer. Therefore, visual signals should be transferred through periodically pulsed information packages, resulting in a modulation of the stimulus content within the receiver’s activity by its gamma phase and amplitude. To test this prediction, we quantified gamma phase-specific stimulus content within neural activity from area V4 of macaques performing a visual attention task. For the attended stimulus we find enhanced stimulus content reaching its maximum near excitability peaks, with effect magnitude increasing with oscillation amplitude, establishing a functional link between selective processing and gamma activity.
No disease modifying therapy is currently available for Parkinson’s disease (PD), the second most common neurodegenerative disease. The long non-motor prodromal phase of PD is a window of opportunity for early detection and intervention. However, we lack the pathophysiological understanding to develop selective biomarkers and interventions. By developing a mutant α-synuclein selective-overexpression mouse model of prodromal PD, we identified a cell-autonomous selective Kv4 channelopathy in dorsal motor nucleus of the vagus (DMV) neurons. This functional remodeling of intact DMV neurons leads to impaired pacemaker function in vitro and in vivo, which in turn reduces gastrointestinal motility which is a common, very early symptom of prodromal PD. We show for the first time a causal chain of events from α-synuclein via a biophysical dysfunction of specific neuronal populations to a clinically relevant prodromal symptom. These findings can facilitate the rational design of clinical biomarkers to identify people at risk for PD.
Learning in the eyes: specific changes in gaze patterns track explicit and implicit visual learning
(2020)
What is the link between eye movements and sensory learning? Although some theories have argued for a permanent and automatic interaction between what we know and where we look, which continuously modulates human information- gathering behavior during both implicit and explicit learning, there exist surprisingly little evidence supporting such an ongoing interaction. We used a pure form of implicit learning called visual statistical learning and manipulated the explicitness of the task to explore how learning and eye movements interact. During both implicit exploration and explicit visual learning of unknown composite visual scenes, eye movement patterns systematically changed in accordance with the underlying statistical structure of the scenes. Moreover, the degree of change was directly correlated with the amount of knowledge the observers acquired. Our results provide the first evidence for an ongoing and specific interaction between hitherto accumulated knowledge and eye movements during both implicit and explicit learning.
To characterize the left-ventral occipito-temporal cortex (lvOT) role during reading in a quantitatively explicit and testable manner, we propose the lexical categorization model (LCM). The LCM assumes that lvOT optimizes linguistic processing by allowing fast meaning access when words are familiar and filter out orthographic strings without meaning. The LCM successfully simulates benchmark results from functional brain imaging. Empirically, using functional magnetic resonance imaging, we demonstrate that quantitative LCM simulations predict lvOT activation across three studies better than alternative models. Besides, we found that word-likeness, which is assumed as input to LCM, is represented posterior to lvOT. In contrast, a dichotomous word/non-word contrast, which is assumed as the LCM’s output, could be localized to upstream frontal brain regions. Finally, we found that training lexical categorization results in more efficient reading. Thus, we propose a ventral-visual-stream processing framework for reading involving word-likeness extraction followed by lexical categorization, before meaning extraction.
Most current models assume that the perceptual and cognitive processes of visual word recognition and reading operate upon neuronally coded domain-general low-level visual representations – typically oriented line representations. We here demonstrate, consistent with neurophysiological theories of Bayesian-like predictive neural computations, that prior visual knowledge of words may be utilized to ‘explain away’ redundant and highly expected parts of the visual percept. Subsequent processing stages, accordingly, operate upon an optimized representation of the visual input, the orthographic prediction error, highlighting only the visual information relevant for word identification. We show that this optimized representation is related to orthographic word characteristics, accounts for word recognition behavior, and is processed early in the visual processing stream, i.e., in V4 and before 200 ms after word-onset. Based on these findings, we propose that prior visual-orthographic knowledge is used to optimize the representation of visually presented words, which in turn allows for highly efficient reading processes.
Most current models assume that the perceptual and cognitive processes of visual word recognition and reading operate upon neuronally coded domain-general low-level visual representations – typically oriented line representations. We here demonstrate, consistent with neurophysiological theories of Bayesian-like predictive neural computations, that prior visual knowledge of words may be utilized to ‘explain away’ redundant and highly expected parts of the visual percept. Subsequent processing stages, accordingly, operate upon an optimized representation of the visual input, the orthographic prediction error, highlighting only the visual information relevant for word identification. We show that this optimized representation is related to orthographic word characteristics, accounts for word recognition behavior, and is processed early in the visual processing stream, i.e., in V4 and before 200 ms after word-onset. Based on these findings, we propose that prior visual-orthographic knowledge is used to optimize the representation of visually presented words, which in turn allows for highly efficient reading processes.
Mental imagery provides an essential simulation tool for remembering the past and planning the future, with its strength affecting both cognition and mental health. Research suggests that neural activity spanning prefrontal, parietal, temporal, and visual areas supports the generation of mental images. Exactly how this network controls the strength of visual imagery remains unknown. Here, brain imaging and transcranial magnetic phosphene data show that lower resting activity and excitability levels in early visual cortex (V1-V3) predict stronger sensory imagery. Further, electrically decreasing visual cortex excitability using tDCS increases imagery strength, demonstrating a causative role of visual cortex excitability in controlling visual imagery. Together, these data suggest a neurophysiological mechanism of cortical excitability involved in controlling the strength of mental images.
Background: Nations are imposing unprecedented measures at large-scale to contain the spread of COVID-19 pandemic. Recent studies indicate that measures such as lockdowns may have slowed down the growth of COVID-19. However, in addition to substantial economic and social costs, these measures also limit the exposure to Ultraviolet-B radiation (UVB). Emerging observational evidence indicate the protective role of UVB and vitamin D in reducing the severity and mortality of COVID-19 deaths. In this observational study, we empirically outline the independent protective roles of lockdown and UVB exposure as measured by ultraviolet index (UVI), whilst also examining whether the severity of lockdown is associated with a reduction in the protective role.
Methods: We apply a log-linear fixed-effects model to a panel dataset of 162 countries over a period of 108 days (n=6049). We use the cumulative number of COVID-19 deaths as the dependent variable and isolate the mitigating influence of lockdown severity on the association between UVI and growth-rates of COVID-19 deaths from time-constant country-specific and time-varying country-specific potentially confounding factors.
Findings: After controlling for time-constant and time-varying factors, we find that a unit increase in UVI and lockdown severity are independently associated with 17% [-1.8 percentage points] and 77% [-7.9 percentage points] decline in COVID-19 deaths growth rate, indicating their respective protective roles. However, the widely utilized and least severe lockdown (recommendation to not leave the house) already fully mitigates the protective role of UVI by 95% [1.8 percentage points] indicating its downside.
Interpretation: We find that lockdown severity and UVI are independently associated with a slowdown in the daily growth rates of cumulative COVID-19 deaths. However, we find consistent evidence that increase in lockdown severity is associated with a significant reduction in the protective role of UVI in reducing COVID-19 deaths. Our results suggest that lockdowns in conjunction with adequate exposure to UVB radiation might have provided even more substantial health benefits, than lockdowns alone. For example, we estimate that there would be 21% fewer deaths on average with sufficient UVB exposure while people were recommended not to leave their house. Therefore, our study outlines the importance of considering UVB exposure, especially while implementing lockdowns and may support policy decision making in countries imposing such measures.
Competing Interest Statement: RKM is a PhD researcher at Goethe University, Frankfurt. He also is an employee of a multinational chemical company involved in vitamin D business and holds the shares of the company. This study is intended to contribute to the ongoing COVID-19 crisis and is not sponsored by his company. All other authors declare no competing interests. The views expressed in the paper are those of the authors and do not represent that of any organization. No other relationships or activities that could appear to have influenced the submitted work.
The clinical and economic value of a successful shutdown during the SARS-CoV-2 pandemic in Germany
(2020)
Background and aim A shutdown of businesses enacted during the SARS-CoV-2 pandemic can serve different goals, e.g., preventing the intensive care unit (ICU) capacity from being overwhelmed (‘flattening the curve’) or keeping the reproduction number substantially below one (‘squashing the curve’). The aim of this study was to determine the clinical and economic value of a shutdown that is successful in ‘flattening’ or ‘squashing the curve’ in Germany.
Methods In the base case, the study compared a successful shutdown to a worst-case scenario with no ICU capacity left to treat COVID-19 patients. To this end, a decision model was developed using, e.g., information on age-specific fatality rates, ICU outcomes, and the herd protection threshold. The value of an additional life year was borrowed from new, innovative oncological drugs, as cancer reflects a condition with a similar morbidity and mortality burden in the general population in the short term as COVID-19.
Results A shutdown that is successful in ‘flattening the curve’ is projected to yield an average health gain between 0.02 and 0.08 life years (0.2 to 0.9 months) per capita in the German population. The corresponding economic value ranges between €1543 and €8027 per capita or, extrapolated to the total population, 4% to 19% of the gross domestic product (GDP) in 2019. A shutdown that is successful in ‘squashing the curve’ is expected to yield a minimum health gain of 0.10 life years (1.2 months) per capita, corresponding to 24% of the GDP in 2019. Results are particularly sensitive to mortality data and the prevalence of undetected cases.
Conclusion A successful shutdown is forecasted to yield a considerable gain in life years in the German population. Nevertheless, questions around the affordability and underfunding of other parts of the healthcare system emerge.
Antimicrobial resistance is a major threat to global health and food security today. Scheduling cycling therapies by targeting phenotypic states associated to specific mutations can help us to eradicate pathogenic variants in chronic infections. In this paper, we introduce a logistic switching model in order to abstract mutation networks of collateral resistance. We found particular conditions for which unstable zero-equilibrium of the logistic maps can be stabilized through a switching signal. That is, persistent populations can be eradicated through tailored switching regimens.
Starting from an optimal-control formulation, the switching policies show their potential in the stabilization of the zero-equilibrium for dynamics governed by logistic maps. However, employing such switching strategies, deserve a specific characterization in terms of limit behaviour. Ultimately, we use evolutionary and control algorithms to find either optimal and sub-optimal switching policies. Simulations results show the applicability of Parrondo’s Paradox to design cycling therapies against drug resistance.
COVID-19 pandemic has underlined the impact of emergent pathogens as a major threat for human health. The development of quantitative approaches to advance comprehension of the current outbreak is urgently needed to tackle this severe disease. In this work, several mathematical models are proposed to represent SARS-CoV-2 dynamics in infected patients. Considering different starting times of infection, parameters sets that represent infectivity of SARS-CoV-2 are computed and compared with other viral infections that can also cause pandemics.
Based on the target cell model, SARS-CoV-2 infecting time between susceptible cells (mean of 30 days approximately) is much slower than those reported for Ebola (about 3 times slower) and influenza (60 times slower). The within-host reproductive number for SARS-CoV-2 is consistent to the values of influenza infection (1.7-5.35). The best model to fit the data was including immune responses, which suggest a slow cell response peaking between 5 to 10 days post onset of symptoms. The model with eclipse phase, time in a latent phase before becoming productively infected cells, was not supported. Interestingly, both, the target cell model and the model with immune responses, predict that virus may replicate very slowly in the first days after infection, and it could be below detection levels during the first 4 days post infection. A quantitative comprehension of SARS-CoV-2 dynamics and the estimation of standard parameters of viral infections is the key contribution of this pioneering work.
Objectives: The aim of the present study was to characterize the cellular reaction to a xenogeneic resorbable collagen membrane of porcine origin using a subcutaneous implantation model in Wistar rats over 30 days.
Materials and methods: Ex vivo, liquid platelet-rich fibrin (PRF), a leukocyte and platelet-rich cell suspension, was used to evaluate the blood cell membrane interaction. The material was implanted subcutaneously in rats. Sham-operated rats without biomaterial displayed physiological wound healing (control group). Histological, immunohistological, and histomorphometric analyses were focused on the inflammatory pattern, vascularization rate, and degradation pattern.
Results: The membrane induced a large number of mononuclear cells over the observation period, including lymphocytes, macrophages, and fibroblasts. After 15 days, multinucleated giant cells (MNGCs) were observed on the biomaterial surface. Their number increased significantly, and they proceeded to the center of the biomaterial on day 30. These cells highly expressed CD-68, calcitonin receptor, and MMP-9, but not TRAP or integrin-ß3. Thus, the membrane lost its integrity and underwent disintegration as a consequence of the induction of MNGCs. The significant increase in MNGC number correlated with a high rate of vascularization, which was significantly higher than the control group. Physiological wound healing in the control group did not induce any MNGCs at any time point. Ex vivo blood cells from liquid-PRF did not penetrate the membrane.
Conclusion: The present study suggests a potential role for MNGCs in biomaterial degradation and questions whether it is beneficial to accept them in clinically approved biomaterials or focus on biomaterials that induce only mononuclear cells. Thus, further studies are necessary to identify the function of biomaterial-induced MNGCs.
Clinical relevance: Understanding the cellular reaction to biomaterials is essential to assess their suitability for specific clinical indications and outline the potential benefit of specific group of biomaterials in the respective clinical indications.
Combining market data with a publicly available monthly snapshot of Deutsche Börse’s index ranking list, I create a model that predicts index changes in the DAX, MDAX, SDAX, and TecDAX from 2010 to 2019 before they are officially announced. Even though I empirically show that index changes are predictable, they still earn sizeable post-announcement 1-day abnormal returns up to 1.42% and − 1.54% for promotions and demotions, respectively. While abnormal returns are larger in smaller stocks, I find no evidence that they are related to funding constraints or additional risk for trading on wrong predictions. A trading strategy that trades according to my model yields an annualized Sharpe ratio of 0.83 while being invested for just 4 days a year.
The severity of the COVID-19 pandemic, caused by the SARS-CoV-2 coronavirus, calls for the urgent development of a vaccine. The primary immunological target is the SARS-CoV-2 spike (S) protein. S is exposed on the viral surface to mediate viral entry into the host cell. To identify possible antibody binding sites not shielded by glycans, we performed multi-microsecond molecular dynamics simulations of a 4.1 million atom system containing a patch of viral membrane with four full-length, fully glycosylated and palmitoylated S proteins. By mapping steric accessibility, structural rigidity, sequence conservation and generic antibody binding signatures, we recover known epitopes on S and reveal promising epitope candidates for vaccine development. We find that the extensive and inherently flexible glycan coat shields a surface area larger than expected from static structures, highlighting the importance of structural dynamics in epitope mapping.
Disordered proteins and nucleic acids can condense into droplets that resemble the membraneless organelles observed in living cells. MD simulations offer a unique tool to characterize the molecular interactions governing the formation of these biomolecular condensates, their physicochemical properties, and the factors controlling their composition and size. However, biopolymer condensation depends sensitively on the balance between different energetic and entropic contributions. Here, we develop a general strategy to fine-tune the potential energy function for molecular dynamics simulations of biopolymer phase separation. We rebalance protein–protein interactions against solvation and entropic contributions to match the excess free energy of transferring proteins between dilute solution and condensate. We illustrate this formalism by simulating liquid droplet formation of the FUS low-complexity domain (LCD) with a rebalanced MARTINI model. By scaling the strength of the nonbonded interactions in the coarse-grained MARTINI potential energy function, we map out a phase diagram in the plane of protein concentration and interaction strength. Above a critical scaling factor of αc ≈ 0.6, FUS-LCD condensation is observed, where α = 1 and 0 correspond to full and repulsive interactions in the MARTINI model. For a scaling factor α = 0.65, we recover experimental densities of the dilute and dense phases, and thus the excess protein transfer free energy into the droplet and the saturation concentration where FUS-LCD condenses. In the region of phase separation, we simulate FUS-LCD droplets of four different sizes in stable equilibrium with the dilute phase and slabs of condensed FUS-LCD for tens of microseconds, and over one millisecond in aggregate. We determine surface tensions in the range of 0.01–0.4 mN/m from the fluctuations of the droplet shape and from the capillary-wave-like broadening of the interface between the two phases. From the dynamics of the protein end-to-end distance, we estimate shear viscosities from 0.001 to 0.02 Pa s for the FUS-LCD droplets with scaling factors α in the range of 0.625–0.75, where we observe liquid droplets. Significant hydration of the interior of the droplets keeps the proteins mobile and the droplets fluid.
Hintergrund: Die Erstversorgung von Wunden und kleinere chirurgische Eingriffe gehören neben der hochspezialisierten Medizin zu den allgemein notwendigen Grundleistungen der Notfallversorgung in den Kliniken. Die Vergütung der ambulanten Notfallleistungen für gesetzlich Versicherte erfolgt derzeit nach dem Einheitlichen Bewertungsmaßstab (EBM), welchem die betriebswirtschaftliche Aufwandserfassung des niedergelassenen Sektors als Kalkulationsgrundlage dient. Krankenhäuser haben im Vergleich zu Arztpraxen wesentlich höhere Vorhaltungskosten.
Ziel der Arbeit: In dieser Arbeit wird das entstehende Kosten-Erlös-Verhältnis der ambulanten Wundversorgung in einer Notaufnahme durch die Vergütung nach EBM analysiert.
Material und Methoden: Die Daten wurden in der Notaufnahme des Universitätsklinikums Frankfurt am Main über 12 Monate erhoben. Eingeschlossen wurden alle Patienten, die in diesem Zeitraum eine Wundversorgung mittels Naht erhielten. Die Kosten wurden der Abrechnung nach EBM 01210 (bzw. 01212) mit der Zusatzpauschale für kleinchirurgische Eingriffe EBM 02301 gegenübergestellt.
Ergebnisse: Im Beobachtungszeitraum wurden 1548 Patienten versorgt; das entspricht 19,52 % aller unfallchirurgischen Fälle. Den Kosten einer Standardwundversorgung in Höhe von 45,40 € steht eine Vergütung von 31,83 € gegenüber. Die Berechnung des Gesamterlöses weist einen Defizitbetrag von 13,57 € pro ambulantem Fall auf; dies entspricht einem Jahresdefizit von 21.006,36 €.
Diskussion: Es konnte gezeigt werden, dass ohne Betrachtung der relevanten Vorhaltekosten in keinem Fall eine Kostendeckung erreicht werden kann.
Die bisherige Vergütung der ambulanten Wundversorgung nach EBM erscheint unzureichend. Eine Anpassung bzw. Zusatzvergütung scheint notwendig, um eine ausreichende Versorgungsqualität in Zukunft sicherstellen zu können.
This paper defends The Transformation of Values into Prices on the Basis of Random Systems, published in EIER, by answering to the Comments made in the same journal by Professors Mori, Morioka and Yamazaki. The clarifications mainly concern the justification of the randomness assumptions, the conditions needed to obtain the equality of total profit with total surplus value in the simplified one-industry system and the invariance of the results to changes in the units of measurement.
Summary We introduce fsbrain, an R package for the visualization of neuroimaging data. The package can be used to visualize vertex-wise and region-wise morphometry data, parcellations, labels and statistical results on brain surfaces in three dimensions (3D). Voxel data can be displayed in lightbox mode. The fsbrain package offers various customization options and produces publication quality plots which can be displayed interactively, saved as bitmap images, or integrated into R notebooks.
Availability and Implementation The software, source code and documentation are available under the MIT license at https://github.com/dfsp-spirit/fsbrain. Releases can be installed directly from the Comprehensive R Archive Network (CRAN).
Visual scene perception is mediated by a set of cortical regions that respond preferentially to images of scenes, including the occipital place area (OPA) and parahippocampal place area (PPA). However, the differential contribution of OPA and PPA to scene perception remains an open research question. In this study, we take a deep neural network (DNN)-based computational approach to investigate the differences in OPA and PPA function. In a first step we search for a computational model that predicts fMRI responses to scenes in OPA and PPA well. We find that DNNs trained to predict scene components (e.g., wall, ceiling, floor) explain higher variance uniquely in OPA and PPA than a DNN trained to predict scene category (e.g., bathroom, kitchen, office). This result is robust across several DNN architectures. On this basis, we then determine whether particular scene components predicted by DNNs differentially account for unique variance in OPA and PPA. We find that variance in OPA responses uniquely explained by the navigation-related floor component is higher compared to the variance explained by the wall and ceiling components. In contrast, PPA responses are better explained by the combination of wall and floor, that is scene components that together contain the structure and texture of the scene. This differential sensitivity to scene components suggests differential functions of OPA and PPA in scene processing. Moreover, our results further highlight the potential of the proposed computational approach as a general tool in the investigation of the neural basis of human scene perception.
Single-particle electron cryo-microscopy (cryoEM) has undergone a `resolution revolution' that makes it possible to characterize megadalton (MDa) complexes at atomic resolution without crystals. To fully exploit the new opportunities in molecular microscopy, new procedures for the cloning, expression and purification of macromolecular complexes need to be explored. Macromolecular assemblies are often unstable, and invasive construct design or inadequate purification conditions and sample-preparation methods can result in disassembly or denaturation. The structure of the 2.6 MDa yeast fatty acid synthase (FAS) has been studied by electron microscopy since the 1960s. Here, a new, streamlined protocol for the rapid production of purified yeast FAS for structure determination by high-resolution cryoEM is reported. Together with a companion protocol for preparing cryoEM specimens on a hydrophilized graphene layer, the new protocol yielded a 3.1 Å resolution map of yeast FAS from 15 000 automatically picked particles within a day. The high map quality enabled a complete atomic model of an intact fungal FAS to be built.
Modular polyketide synthases (PKSs) produce complex, bioactive secondary metabolites in assembly line-like multistep reactions. Longstanding efforts to produce novel, biologically active compounds by recombining intact modules to new modular PKSs have mostly resulted in poorly active chimeras and decreased product yields. Recent findings demonstrate that the low efficiencies of modular chimeric PKSs also result from rate limitations in the transfer of the growing polyketide chain across the non-cognate module:module interface and further processing of the non-native polyketide substrate by the ketosynthase (KS) domain. In this study, we aim at disclosing and understanding the low efficiency of chimeric modular PKSs and at establishing guidelines for modular PKSs engineering. To do so, we work with a bimodular PKS testbed and systematically vary substrate specificity, substrate identity, and domain:domain interfaces of the KS involved reactions. We observe that KS domains employed in our chimeric bimodular PKSs are bottlenecks with regards to both substrate specificity as well as interaction with the ACP. Overall, our systematic study can explain in quantitative terms why early oversimplified engineering strategies based on the plain shuffling of modules mostly failed and why more recent approaches show improved success rates. We moreover identify two mutations of the KS domain that significantly increased turnover rates in chimeric systems and interpret this finding in mechanistic detail.
Inspired by the physiology of neuronal systems in the brain, artificial neural networks have become an invaluable tool for machine learning applications. However, their biological realism and theoretical tractability are limited, resulting in poorly understood parameters. We have recently shown that biological neuronal firing rates in response to distributed inputs are largely independent of size, meaning that neurons are typically responsive to the proportion, not the absolute number, of their inputs that are active. Here we introduce such a normalisation, where the strength of a neuron’s afferents is divided by their number, to various sparsely-connected artificial networks. The learning performance is dramatically increased, providing an improvement over other widely-used normalisations in sparse networks. The resulting machine learning tools are universally applicable and biologically inspired, rendering them better understood and more stable in our tests.
Achieving functional neuronal dendrite structure through sequential stochastic growth and retraction
(2020)
Class I ventral posterior dendritic arborisation (c1vpda) proprioceptive sensory neurons respond to contractions in the Drosophila larval body wall during crawling. Their dendritic branches run along the direction of contraction, possibly a functional requirement to maximise membrane curvature during crawling contractions. Although the molecular machinery of dendritic patterning in c1vpda has been extensively studied, the process leading to the precise elaboration of their comb-like shapes remains elusive. Here, to link dendrite shape with its proprioceptive role, we performed long-term, non-invasive, in vivo time-lapse imaging of c1vpda embryonic and larval morphogenesis to reveal a sequence of differentiation stages. We combined computer models and dendritic branch dynamics tracking to propose that distinct sequential phases of stochastic growth and retraction achieve efficient dendritic trees both in terms of wire and function. Our study shows how dendrite growth balances structure–function requirements, shedding new light on general principles of self-organisation in functionally specialised dendrites.
Achieving functional neuronal dendrite structure through sequential stochastic growth and retraction
(2020)
Class I ventral posterior dendritic arborisation (c1vpda) proprioceptive sensory neurons respond to contractions in the Drosophila larval body wall during crawling. Their dendritic branches run along the direction of contraction, possibly a functional requirement to maximise membrane curvature during crawling contractions. Although the molecular machinery of dendritic patterning in c1vpda has been extensively studied, the process leading to the precise elaboration of their comb-like shapes remains elusive. Here, to link dendrite shape with its proprioceptive role, we performed long-term, non-invasive, in vivo time-lapse imaging of c1vpda embryonic and larval morphogenesis to reveal a sequence of differentiation stages. We combined computer models and dendritic branch dynamics tracking to propose that distinct sequential phases of targeted growth and stochastic retraction achieve efficient dendritic trees both in terms of wire and function. Our study shows how dendrite growth balances structure–function requirements, shedding new light on general principles of self-organisation in functionally specialised dendrites.
Dendrites display a striking variety of neuronal type-specific morphologies, but the mechanisms and principles underlying such diversity remain elusive. A major player in defining the morphology of dendrites is the neuronal cytoskeleton, including evolutionarily conserved actin-modulatory proteins (AMPs). Still, we lack a clear understanding of how AMPs might support developmental phenomena such as neuron-type specific dendrite dynamics. To address precisely this level of in vivo specificity, we concentrated on a defined neuronal type, the class III dendritic arborisation (c3da) neuron of Drosophila larvae, displaying actin-enriched short terminal branchlets (STBs). Computational modelling reveals that the main branches of c3da neurons follow a general growth model based on optimal wiring, but the STBs do not. Instead, model STBs are defined by a short reach and a high affinity to grow towards the main branches. We thus concentrated on c3da STBs and developed new methods to quantitatively describe dendrite morphology and dynamics based on in vivo time-lapse imaging of mutants lacking individual AMPs. In this way, we extrapolated the role of these AMPs in defining STB properties. We propose that dendrite diversity is supported by the combination of a common step, refined by a neuron type-specific second level. For c3da neurons, we present a molecular model of how the combined action of multiple AMPs in vivo define the properties of these second level specialisations, the STBs.
The way in which dendrites spread within neural tissue determines the resulting circuit connectivity and computation. However, a general theory describing the dynamics of this growth process does not exist. Here we obtain the first time-lapse reconstructions of neurons in living fly larvae over the entirety of their developmental stages. We show that these neurons expand in a remarkably regular stretching process that conserves their shape. Newly available space is filled optimally, a direct consequence of constraining the total amount of dendritic cable. We derive a mathematical model that predicts one time point from the previous and use this model to predict dendrite morphology of other cell types and species. In summary, we formulate a novel theory of dendrite growth based on detailed developmental experimental data that optimises wiring and space filling and serves as a basis to better understand aspects of coverage and connectivity for neural circuit formation.
Disordered proteins and nucleic acids can condense into droplets that resemble the membraneless organelles observed in living cells. MD simulations offer a unique tool to characterize the molecular interactions governing the formation of these biomolecular condensates, their physico-chemical properties, and the factors controlling their composition and size. However, biopolymer condensation depends sensitively on the balance between different energetic and entropic contributions. Here, we develop a general strategy to fine-tune the potential energy function for molecular dynamics simulations of biopolymer phase separation. We rebalance protein-protein interactions against solvation and entropic contributions to match the excess free energy of transferring proteins between dilute solution and condensate. We illustrate this formalism by simulating liquid droplet formation of the FUS low complexity domain (LCD) with a rebalanced MARTINI model. By scaling the strength of the nonbonded interactions in the coarse-grained MARTINI potential energy function, we map out a phase diagram in the plane of protein concentration and interaction strength. Above a critical scaling factor of αc ≈ 0.6, FUS LCD condensation is observed, where α = 1 and 0 correspond to full and repulsive interactions in the MARTINI model, respectively. For a scaling factor α = 0.65, we recover the experimental densities of the dilute and dense phases, and thus the excess protein transfer free energy into the droplet and the saturation concentration where FUS LCD condenses. In the region of phase separation, we simulate FUS LCD droplets of four different sizes in stable equilibrium with the dilute phase and slabs of condensed FUS LCD for tens of microseconds, and over one millisecond in aggregate. We determine surface tensions in the range of 0.01 to 0.4mN/m from the fluctuations of the droplet shape and from the capillary-wave-like broadening of the interface between the two phases. From the dynamics of the protein end-to-end distance, we estimate shear viscosities from 0.001 to 0.02Pas for the FUS LCD droplets with scaling factors α in the range of 0.625 to 0.75, where we observe liquid droplets. Significant hydration of the interior of the droplets keeps the proteins mobile and the droplets fluid.
The protein Atg2 has been proposed to form a membrane tether that mediates lipid transfer from the ER to the phagophore in autophagy. However, recent kinetic measurements on the human homolog ATG2A indicated a transport rate of only about one lipid per minute, which would be far too slow to deliver the millions of lipids required to form a phagophore on a physiological time scale. Here, we revisit the analysis of the fluorescence quenching experiments. We develop a detailed kinetic model of the lipid transfer between two membranes bridged by a tether that forms a conduit for lipids. The model provides an excellent fit to the fluorescence experiments, with a lipid transfer rate of about 100 per second and protein. At this rate, Atg2-mediated transfer can supply a significant fraction of the lipids required in autophagosome biogenesis. Our kinetic model is generally applicable to lipid-transfer experiments, in particular to proteins forming organelle contact sites in cells.
Binding of the spike protein of SARS-CoV-2 to the human angiotensin converting enzyme 2 (ACE2) receptor triggers translocation of the virus into cells. Both the ACE2 receptor and the spike protein are heavily glycosylated, including at sites near their binding interface. We built fully glycosylated models of the ACE2 receptor bound to the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. Using atomistic molecular dynamics (MD) simulations, we found that the glycosylation of the human ACE2 receptor contributes substantially to the binding of the virus. Interestingly, the glycans at two glycosylation sites, N90 and N322, have opposite effects on spike protein binding. The glycan at the N90 site partly covers the binding interface of the spike RBD. Therefore, this glycan can interfere with the binding of the spike protein and protect against docking of the virus to the cell. By contrast, the glycan at the N322 site interacts tightly with the RBD of the ACE2-bound spike protein and strengthens the complex. Remarkably, the N322 glycan binds into a conserved region of the spike protein identified previously as a cryptic epitope for a neutralizing antibody. By mapping the glycan binding sites, our MD simulations aid in the targeted development of neutralizing antibodies and SARS-CoV-2 fusion inhibitors.
Active efficient coding explains the development of binocular vision and its failure in amblyopia
(2020)
The development of vision during the first months of life is an active process that comprises the learning of appropriate neural representations and the learning of accurate eye movements. While it has long been suspected that the two learning processes are coupled, there is still no widely accepted theoretical framework describing this joint development. Here we propose a computational model of the development of active binocular vision to fill this gap. The model is based on a new formulation of the Active Efficient Coding theory, which proposes that eye movements, as well as stimulus encoding, are jointly adapted to maximize the overall coding efficiency. Under healthy conditions, the model self-calibrates to perform accurate vergence and accommodation eye movements. It exploits disparity cues to deduce the direction of defocus, which leads to co-ordinated vergence and accommodation responses. In a simulated anisometropic case, where the refraction power of the two eyes differs, an amblyopia-like state develops, in which the foveal region of one eye is suppressed due to inputs from the other eye. After correcting for refractive errors, the model can only reach healthy performance levels if receptive fields are still plastic, in line with findings on a critical period for binocular vision development. Overall, our model offers a unifying conceptual framework for understanding the development of binocular vision.
SARS-CoV-2 infections are rapidly spreading around the globe. The rapid development of therapies is of major importance. However, our lack of understanding of the molecular processes and host cell signaling events underlying SARS-CoV-2 infection hinder therapy development. We employed a SARS-CoV-2 infection system in permissible human cells to study signaling changes by phospho-proteomics. We identified viral protein phosphorylation and defined phosphorylation-driven host cell signaling changes upon infection. Growth factor receptor (GFR) signaling and downstream pathways were activated. Drug-protein network analyses revealed GFR signaling as key pathway targetable by approved drugs. Inhibition of GFR downstream signaling by five compounds prevented SARS-CoV-2 replication in cells, assessed by cytopathic effect, viral dsRNA production, and viral RNA release into the supernatant. This study describes host cell signaling events upon SARS-CoV-2 infection and reveals GFR signaling as central pathway essential for SARS-CoV-2 replication. It provides with novel strategies for COVID-19 treatment.
The survivin suppressant YM155 is a drug candidate for neuroblastoma. Here, we tested YM155 in 101 neuroblastoma cell lines (19 parental cell lines, 82 drug-adapted sublines). 77 cell lines displayed YM155 IC50s in the range of clinical YM155 concentrations. ABCB1 was an important determinant of YM155 resistance. The activity of the ABCB1 inhibitor zosuquidar ranged from being similar to that of the structurally different ABCB1 inhibitor verapamil to being 65-fold higher. ABCB1 sequence variations may be responsible for this, suggesting that the design of variant-specific ABCB1 inhibitors may be possible. Further, we showed that ABCC1 confers YM155 resistance. Previously, p53 depletion had resulted in decreased YM155 sensitivity. However, TP53-mutant cells were not generally less sensitive to YM155 than TP53 wild-type cells in this study. Finally, YM155 cross-resistance profiles differed between cells adapted to drugs as similar as cisplatin and carboplatin. In conclusion, the large cell line panel was necessary to reveal an unanticipated complexity of the YM155 response in neuroblastoma cell lines with acquired drug resistance. Novel findings include that ABCC1 mediates YM155 resistance and that YM155 cross-resistance profiles differ between cell lines adapted to drugs as similar as cisplatin and carboplatin.
SARS-CoV-2 is a novel coronavirus currently causing a pandemic. We show that the majority of amino acid positions, which differ between SARS-CoV-2 and the closely related SARS-CoV, are differentially conserved suggesting differences in biological behaviour. In agreement, novel cell culture models revealed differences between the tropism of SARS-CoV-2 and SARS-CoV. Moreover, cellular ACE2 (SARS-CoV-2 receptor) and TMPRSS2 (enables virus entry via S protein cleavage) levels did not reliably indicate cell susceptibility to SARS-CoV-2. SARS-CoV-2 and SARS-CoV further differed in their drug sensitivity profiles. Thus, only drug testing using SARS-CoV-2 reliably identifies therapy candidates. Therapeutic concentrations of the approved protease inhibitor aprotinin displayed anti-SARS-CoV-2 activity. The efficacy of aprotinin and of remdesivir (currently under clinical investigation against SARS-CoV-2) were further enhanced by therapeutic concentrations of the proton pump inhibitor omeprazole (aprotinin 2.7-fold, remdesivir 10-fold). Hence, our study has also identified anti-SARS-CoV-2 therapy candidates that can be readily tested in patients.
SARS-CoV-2 is the causative agent of COVID-19. Severe COVID-19 disease has been associated with disseminated intravascular coagulation and thrombosis, but the mechanisms underlying COVID-19-related coagulopathy remain unknown. Since the risk of severe COVID-19 disease is higher in males than in females and increases with age, we combined proteomics data from SARS-CoV-2-infected cells with human gene expression data from the Genotype-Tissue Expression (GTEx) database to identify gene products involved in coagulation that change with age, differ in their levels between females and males, and are regulated in response to SARS-CoV-2 infection. This resulted in the identification of transferrin as a candidate coagulation promoter, whose levels increases with age and are higher in males than in females and that is increased upon SARS-CoV-2 infection. A systematic investigation of gene products associated with the GO term “blood coagulation” did not reveal further high confidence candidates, which are likely to contribute to COVID-19-related coagulopathy. In conclusion, the role of transferrin should be considered in the course of COVID-19 disease and further examined in ongoing clinic-pathological investigations.
Einleitung: Begehen zwei Menschen infolge einer gemeinsamen Entscheidung Suizid, wird dies als Doppelsuizid oder gemeinschaftlicher Suizid definiert. Die rechtsmedizinische Begutachtung hängt von den Umständen des konkreten Einzelfalls ab und kann für die rechtliche Würdigung insbesondere bei Konstellationen, bei denen ein Beteiligter überlebt hat, wichtige Hinweise liefern.
Material und Methoden: Für einen 25-Jahres-Zeitraum von 1995 bis 2019 wurden retrospektiv alle Sektionsfälle mit vollendeten und versuchten Doppelsuiziden analysiert und, soweit erhältlich, mit den Ermittlungsakten abgeglichen.
Ergebnisse: Unter den erhobenen 23 Doppelsuizidfällen fanden sich 16 vollendete sowie 7 Fälle mit jeweils einem Überlebenden. In 83 % der Fälle handelte es sich um Ehepaare bzw. eingetragene Lebensgemeinschaften, in 13 % um Personen, die sich zuvor in einer psychiatrischen Einrichtung, und in 4 % um Personen, die sich in einem „Suizidforum“ im Internet kennengelernt hatten. Der Mittelwert des Sterbealters betrug bei den Männern 57,8 und bei den Frauen 63,4 Jahre. In etwa zwei Drittel der Fälle wurden Erkrankungen als vorherrschendes Suizidmotiv angegeben. Als häufigste Methode wurde eine Intoxikation gewählt. Am zweithäufigsten fanden Schusswaffen Anwendung, wobei ausnahmslos der Mann zuerst einen oder mehrere Kopfschüsse auf seine Frau abgab, bevor er sich suizidierte. Der häufigste Sterbe- und Auffindeort war das gemeinsame Bett der Suizidenten.
Diskussion: Im Gegensatz zu Suiziden i. Allg. wurden die Doppelsuizide am häufigsten mittels einer Intoxikation als sogenannte weiche Methode verübt. In Anlehnung an die rechtsmedizinische Literatur werden für einen Doppelsuizid typische Merkmale herausgearbeitet.
Schlussfolgerung: Doppelsuizide stellen seltene Fälle in der rechtsmedizinischen Praxis dar, wobei die Abgrenzung zu einem erweiterten Suizid (Homizid-Suizid) schwierig werden kann und zugleich unabdingbar ist. Hierfür ist eine ganzheitliche Berücksichtigung der Vorgeschichte, der rechtsmedizinisch erhobenen Befunde und der kriminalistischen Umstände erforderlich.
Bei Suizidformen mit mehreren Suizidenten und Opfern werden teilweise in Literatur und Rechtsprechung eine unterschiedliche Nomenklatur und Interpretation der Begrifflichkeiten vorgenommen. Der Beitrag analysiert die Begrifflichkeiten und befasst sich im Speziellen mit dem Phänomen des Doppelsuizids. Historische Fälle von Doppelsuiziden werden angeführt. Anhand von Fallkonstellationen werden rechtliche Bewertungen vorgenommen, die beim einseitig fehlgeschlagenen Doppelsuizid praxisrelevant werden können. Dabei werden die mitunter konträren Auffassungen in der einschlägigen Literatur und der Rechtsprechung dargestellt und Lösungsansätze aufgezeigt. Zudem verdeutlichen die Fallkonstellationen die Relevanz einer umfassenden Tatortarbeit und einer tatnahen Klärung der Motivationslage bei dem Überlebenden bzw. den Verstorbenen.
The 𝒮-cone provides a common framework for cones of polynomials or exponen- tial sums which establish non-negativity upon the arithmetic-geometric inequality, in particular for sums of non-negative circuit polynomials (SONC) or sums of arithmetic- geometric exponentials (SAGE). In this paper, we study the S-cone and its dual from the viewpoint of second-order representability. Extending results of Averkov and of Wang and Magron on the primal SONC cone, we provide explicit generalized second- order descriptions for rational S-cones and their duals.
The aim of this study is to provide a systematic assessment of the influence of the position on the arterial input function (AIF) for perfusion quantification. In 39 patients with a wide range of left ventricular function the AIF was determined using a diluted contrast bolus of a cardiac magnetic resonance imaging in three left ventricular levels (basal, mid, apex) as well as aortic sinus (AoS). Time to peak signal intensities, baseline corrected peak signal intensity and upslopes were determined and compared to those obtained in the AoS. The error induced by sampling the AIF in a position different to the AoS was determined by Fermi deconvolution. The time to peak signal intensity was strongly correlated (r2 > 0.9) for all positions with a systematic earlier arrival in the basal (− 2153 ± 818 ms), the mid (− 1429 ± 928 ms) and the apical slice (− 450 ± 739 ms) relative to the AoS (all p < 0.001). Peak signal intensity as well as upslopes were strongly correlated (r2 > 0.9 for both) for all positions with a systematic overestimation in all positions relative to the AoS (all p < 0.001 and all p < 0.05). Differences between the positions were more pronounced for patients with reduced ejection fraction. The error of averaged MBF quantification was 8%, 13% and 27% for the base, mid and apex. The location of the AIF significantly influences core parameters for perfusion quantification with a systematic and ejection fraction dependent error. Full quantification should be based on obtaining the AIF as close as possible to the myocardium to minimize these errors.
We introduce a novel approach based on elas- tic and inelastic scattering rates to extract the hyper-surface of the chemical freeze-out from a hadronic transport model in the energy range from Elab = 1.23 AGeV to √sNN = 62.4 GeV. For this study, the Ultra-relativistic Quantum Molecular Dynamics (UrQMD) model combined with a coarse-graining method is employed. The chemical freeze- out distribution is reconstructed from the pions through sev- eral decay and re-formation chains involving resonances and taking into account inelastic, pseudo-elastic and string excita- tion reactions. The extracted average temperature and baryon chemical potential are then compared to statistical model analysis. Finally we investigate various freeze-out criteria suggested in the literature. We confirm within this micro- scopic dynamical simulation, that the chemical freeze-out at all energies coincides with ⟨E⟩/⟨N⟩ ≈ 1 GeV, while other criteria, like s/T 3 = 7 and nB +nB ̄ ≈ 0.12 fm−3 are limited to higher collision energies.
Der Tumormarker Sialinsäure
(2020)
Die vorliegende Übersicht zum Tumormarker Sialinsäure wird im Rahmen der Serie „Tumormarker“ des Zentralblatts für Arbeitsmedizin, Arbeitsschutz und Ergonomie publiziert, die sich mit dem immer häufigeren Gebrauch der Bestimmung von spezifischen Markern bei sog. Manager-Vorsorgen und Check-up-Untersuchungen beschäftigt. Sialinsäure eignet sich grundsätzlich nicht für solche Vorsorgen, sondern ist ein Marker zur Therapie‑, Verlaufs- und Rezidivkontrolle von Mundhöhlenkarzinomen. Hier zeigt dieser eine hohe Sensitivität und Spezifität, wobei der Marker aber auf keinen Fall als Screeningparameter zur Frühdiagnostik eingesetzt werden soll.
The production of light (anti-)nuclei and (anti-)hypernuclei in ultra-relativistic heavy-ion collisions, but also in more elementary collisions as proton–proton and proton–nucleus collisions, became recently a focus of interest. In particular, the fact that these objects are all loosely bound compared to the temperature and energies, e.g. the kinetic energies involved, is often stressed out to be special for their production. The binding energies of these (anti-)nuclei is between 130 keV (Λ separation energy in the hypertriton) and about 8 MeV per nucleon. Whereas the connected temperatures are of the order of 100 to 160 MeV. This lead to some difficulties in the interpretation of the usually discussed production models, i.e. coalescence and statistical-thermal models, as will be discussed here. In this brief review we discuss selected highlights of the production of light (anti-)nuclei, such as (anti-)deuteron, (anti-)helium and (anti-)alpha nuclei. In addition, we will discuss the current status of the highly debated lifetime of the (anti-)hypertriton and connected measurements and model results.
The sudden infant death syndrome (SIDS) is one of the leading causes of postneonatal infant death. It has been shown that there exists a complex relationship between SIDS and inherited cardiac disease. Next-generation sequencing and surveillance of cardiac channelopathy and cardiomyopathy genes represent an important tool for investigating the cause of death in SIDS cases. In the present study, targeted sequencing of 80 genes associated with genetic heart diseases in a cohort of 31 SIDS cases was performed. To determine the spectrum and prevalence of genetic heart disease associated mutations as a potential monogenic basis for SIDS, a stringent variant classification was applied and the percentage of rare (minor allele frequency ≤ 0.2%) and ultra-rare variants (minor allele frequency ≤ 0.005%) in these genes was assessed. With a minor allele frequency of ≤ 0.005%, about 20% of the SIDS cases exhibited a variant of uncertain significance (VUS), but in only 6% of these cases, gene variants proved to be “potentially informative.” The present study shows the importance of careful variant interpretation. Applying stringent criteria misinterpretations are avoided, as the results of genetic analyses may have an important impact of the family members involved.
We investigate hadronic particle spectra and flow characteristics of heavy-ion reactions in the FAIR/NICA energy range of 1 AGeV ≤ Elab ≤ 10 AGeV within a relativistic ideal hydrodynamic one-fluid approach. The particlization is realized by sampling the Cooper-Frye distribution for a grand canonical hadron gas on a hypersurface of constant energy density. Results of the hydrodynamic calculations for different underlying equations of state are presented and compared with experimental data and microscopic transport simulations. The sensitivity of the approach to physical model inputs concerning the initial state and the particlization is studied.
Hintergrund: Die Analyse krankheitsspezifischer Kosten gewinnt in einem zunehmend ökonomisch ausgerichteten Gesundheitssystem an Relevanz, wobei vor allem chronische Erkrankungen aufgrund der langen Krankheitsdauer sowie häufiger Hospitalisierung und Arztbesuche von besonderem Interesse sind. Epilepsien stellen eine häufige neurologische Erkrankung dar, welche mit paroxysmal auftretenden epileptischen Anfällen und häufig hiermit assoziierten Verletzungen einhergeht und alle Altersgruppen betrifft.
Ziel: Ziel der Arbeit ist die Aufarbeitung der stationären Behandlungskosten anfallsbedingter Verletzungen sowie die Analyse hinsichtlich relevanter kostenverursachender Faktoren. Mittels alternativer Kalkulation der Versorgungskosten soll zusätzlich der Frage nach potenziellen Vergütungsproblemen im aktuellen DRG-System („diagnosis related groups“) nachgegangen werden.
Methoden: Grundlage dieser monozentrischen, retrospektiven Analyse ist der tatsächliche Erlös der stationären Behandlung von 62 Patienten, die zwischen 01/2010 und 01/2018 im Universitätsklinikum Frankfurt aufgrund von Verletzungen im Rahmen epileptischer Anfälle erfolgte. Die Analyse potenzieller kostenverursachender Faktoren bezog sich auf relevante soziodemographische und klinische Aspekte, die alternative Kalkulation der Versorgungskosten wurde mit gängigen gesundheitsökonomischen Methoden durchgeführt.
Ergebnisse: Der mittlere DRG-Erlös betrug 7408 € (±8993 €, Median 5086 €, Spanne 563–44.519 €), die mittleren kalkulierten Kosten 9423 € (±11.113 €, 5626 €, Spanne 587–49.830 €). Als signifikant kostenverursachender Faktor konnte eine Liegedauer ≥7 Tage (p = 0,014) identifiziert werden. Aufgrund des signifikanten Unterschieds (p < 0,001) zwischen Erlös und kalkulierten Kosten erfolgte eine Analyse nach Faktoren für potenzielle Vergütungsprobleme, welche für eine Aufenthaltsdauer von ≥7 Tagen (p = 0,014) sowie für eine Behandlung auf Intensivstation (p = 0,019) signifikant verblieb.
Schlussfolgerung: Die stationären Versorgungskosten von Patienten mit Frakturen aufgrund epileptischer Anfälle sind hoch und daher gesundheitsökonomisch relevant. Generell scheint die auf Fallpauschalen basierende Vergütung nach G‑DRG die tatsächlichen Kosten zu decken, bei Patienten mit einer langen Liegedauer oder einen Aufenthalt auf Intensivstation können jedoch Vergütungsprobleme bestehen.
Purpose: The primary treatment goals for advanced-stage thumb carpometacarpal (CMC) joint osteoarthritis are complete pain relief and restoration of thumb strength. The purpose of the present study was to introduce a variation of the abductor pollicis longus (APL) suspension arthroplasty using a single looping of a radial slip from the APL tendon around the flexor carpi radialis (FCR) tendon combined with RegJoint™ interposition and to determine its efficacy in the treatment of thumb CMC joint osteoarthritis.
Methods: Between 2015 and 2017, 21 patients were included. The average age was 60.8 years (range 48–79). The mean follow-up was 27.7 months (range 8–50). Evaluation included pain, radial and palmar abduction, tip pinch and grip strength, and Disabilities of the Arm, Shoulder, and Hand (DASH) score.
Results: Pain averaged 0.3 (range 0–4) at rest and 1.4 (range 0–4) on exertion. The radial and palmar abduction were 97% and 99% compared to the contralateral side. The tip pinch and grip strength were 4.1 kg (range 3–6.5) and 22 kg (range 13.3–40), respectively. The DASH score accounted for 18.5 (range 0.8–41.7).
Conclusion: The modified APL suspension interposition arthroplasty was an efficient and simplified option for the treatment of thumb CMC joint osteoarthritis, with results comparable or better than other published procedures. The APL suspension technique was easy to perform avoiding difficult bone tunneling and incision of the FCR tendon. The RegJoint™ interposition as spacer prevented impingement of the first metacarpal base on the second metacarpal base or the trapezoid bone.
Developmental loss of ErbB4 in PV interneurons disrupts state-dependent cortical circuit dynamics
(2020)
GABAergic inhibition plays an important role in the establishment and maintenance of cortical circuits during development. Neuregulin 1 (Nrg1) and its interneuron-specific receptor ErbB4 are key elements of a signaling pathway critical for the maturation and proper synaptic connectivity of interneurons. Using conditional deletions of the ERBB4 gene in mice, we tested the role of this signaling pathway at two developmental timepoints in parvalbumin-expressing (PV) interneurons, the largest subpopulation of cortical GABAergic cells. Loss of ErbB4 in PV interneurons during embryonic, but not late postnatal, development leads to alterations in the activity of excitatory and inhibitory cortical neurons, along with severe disruption of cortical temporal organization. These impairments emerge by the end of the second postnatal week, prior to the complete maturation of the PV interneurons themselves. Early loss of ErbB4 in PV interneurons also results in profound dysregulation of excitatory pyramidal neuron dendritic architecture and a redistribution of spine density at the apical dendritic tuft. In association with these deficits, excitatory cortical neurons exhibit normal tuning for sensory inputs, but a loss of state-dependent modulation of the gain of sensory responses. Together these data support a key role for early developmental Nrg1/ErbB4 signaling in PV interneurons as powerful mechanism underlying the maturation of both the inhibitory and excitatory components of cortical circuits.