julilili42/papers huggingface dataset:
Human adenovirus binding to host cell receptors: a structural view
2019-11-29

Abstract Human Adenoviruses (HAdVs) are a family of clinically and therapeutically relevant viruses. A precise understanding of their host cell attachment and entry mechanisms can be applied in inhibitor design and the construction of targeted gene delivery vectors. In this article, structural data on adenovirus attachment and entry are reviewed. HAdVs engage two types of receptors: first, an attachment receptor that is bound by the fibre knob protein protruding from the icosahedral capsid, and next, an integrin entry receptor bound by the pentameric penton base at the capsid vertices. Adenoviruses use remarkably diverse attachment receptors, five of which have been studied structurally in the context of HAdV binding: Coxsackie and Adenovirus Receptor, CD46, the glycans GD1a and polysialic acid, and desmoglein-2. Together with the integrin entry receptors, they display both symmetrical and asymmetrical modes of binding to the virus as demonstrated by the structural analyses reviewed here. The diversity of HAdV receptors contributes to the broad tropism of these viruses, and structural studies are thus an important source of information on HAdV-host cell interactions. The imbalance in structural data between the more and less extensively studied receptors remains to be addressed by future research.
Potent Antitumor Activity of Liposomal Irinotecan in an Organoid- and CRISPR-Cas9-Based Murine Model of Gallbladder Cancer
2019-11-29

Gallbladder cancer is associated with a dismal prognosis, and accurate in vivo models will be elemental to improve our understanding of this deadly disease and develop better treatment options. We have generated a transplantation-based murine model for gallbladder cancer that histologically mimics the human disease, including the development of distant metastasis. Murine gallbladder–derived organoids are genetically modified by either retroviral transduction or transfection with CRISPR/Cas9 encoding plasmids, thereby allowing the rapid generation of complex cancer genotypes. We characterize the model in the presence of two of the most frequent oncogenic drivers—Kras and ERBB2—and provide evidence that the tumor histology is highly dependent on the driver oncogene. Further, we demonstrate the utility of the model for the preclinical assessment of novel therapeutic approaches by showing that liposomal Irinotecan (Nal-IRI) is retained in tumor cells and significantly prolongs the survival of gallbladder cancer–bearing mice compared to conventional irinotecan.
Magnetic resonance imaging of obesity and metabolic disorders: Summary from the 2019 ISMRM Workshop
2019-11-29

More than 100 attendees from Australia, Austria, Belgium, Canada, China, Germany, Hong Kong, Indonesia, Japan, Malaysia, the Netherlands, the Philippines, Republic of Korea, Singapore, Sweden, Switzerland, the United Kingdom, and the United States convened in Singapore for the 2019 ISMRM‐sponsored workshop on MRI of Obesity and Metabolic Disorders. The scientific program brought together a multidisciplinary group of researchers, trainees, and clinicians and included sessions in diabetes and insulin resistance; an update on recent advances in water–fat MRI acquisition and reconstruction methods; with applications in skeletal muscle, bone marrow, and adipose tissue quantification; a summary of recent findings in brown adipose tissue; new developments in imaging fat in the fetus, placenta, and neonates; the utility of liver elastography in obesity studies; and the emerging role of radiomics in population‐based “big data” studies. The workshop featured keynote presentations on nutrition, epidemiology, genetics, and exercise physiology. Forty‐four proffered scientific abstracts were also presented, covering the topics of brown adipose tissue, quantitative liver analysis from multiparametric data, disease prevalence and population health, technical and methodological developments in data acquisition and reconstruction, newfound applications of machine learning and neural networks, standardization of proton density fat fraction measurements, and X‐nuclei applications. The purpose of this article is to summarize the scientific highlights from the workshop and identify future directions of work.
Post‐stroke cognitive deficits rarely come alone: Handling co‐morbidity in lesion‐behaviour mapping
2019-11-29

Abstract Post‐stroke behavioural symptoms often correlate and systematically co‐occur with each other, either because they share cognitive processes, or because their neural correlates are often damaged together. Thus, neuropsychological symptoms often share variance. Many previous lesion‐behaviour mapping studies aimed to methodologically consider this shared variance between neuropsychological variables. A first group of studies controlled the behavioural target variable for the variance explained by one or multiple other variables to obtain a more precise mapping of the target variable. A second group of studies focused on the shared variance of multiple variables itself with the aim to map neural correlates of cognitive processes that are shared between the original variables. In the present study, we tested the validity of these methods by using real lesion data and both real and simulated data sets. We show that the variance that is shared between post‐stroke behavioural variables is ambiguous, and that mapping procedures that consider this variance are prone to biases and artefacts. We discuss under which conditions such procedures could still be used and what alternative approaches exist.
Plant traits are poor predictors of long-term ecosystem functioning
2019-11-29

ABSTRACT Earth is home to over 350,000 vascular plant species 1 that differ in their traits in innumerable ways. Yet, a handful of functional traits can help explaining major differences among species in photosynthetic rate, growth rate, reproductive output and other aspects of plant performance 2–6 . A key challenge, coined “the Holy Grail” in ecology, is to upscale this understanding in order to predict how natural or anthropogenically driven changes in the identity and diversity of co-occurring plant species drive the functioning of ecosystems 7, 8 . Here, we analyze the extent to which 42 different ecosystem functions can be predicted by 41 plant traits in 78 experimentally manipulated grassland plots over 10 years. Despite the unprecedented number of traits analyzed, the average percentage of variation in ecosystem functioning that they jointly explained was only moderate (32.6%) within individual years, and even much lower (12.7%) across years. Most other studies linking ecosystem functioning to plant traits analyzed no more than six traits, and when including either only six random or the six most frequently studied traits in our analysis, the average percentage of explained variation in across-year ecosystem functioning dropped to 4.8%. Furthermore, different ecosystem functions were driven by different traits, with on average only 12.2% overlap in significant predictors. Thus, we did not find evidence for the existence of a small set of key traits able to explain variation in multiple ecosystem functions across years. Our results therefore suggest that there are strong limits in the extent to which we can predict the long-term functional consequences of the ongoing, rapid changes in the composition and diversity of plant communities that humanity is currently facing.
Metagenomic- and cultivation-based exploration of anaerobic chloroform biotransformation in hypersaline sediments as natural source of chloromethanes
2019-11-29

Abstract Chloroform (CF) is an environmental contaminant that can be naturally formed in various environments ranging from forest soils to salt lakes. Here we investigated CF removal potential in sediments obtained from hypersaline lakes in Western Australia. Reductive dechlorination of CF to dichloromethane (DCM) was observed in enrichment cultures derived from sediments of Lake Strawbridge, which has been reported as a natural source of CF. The lack of CF removal in the abiotic control cultures without artificial electron donors indicated that the observed CF removal is a biotic process. Metabolite analysis with 13 C labelled CF in the sediment-free enrichment cultures (pH 8.5, salinity 5%) revealed that increasing the vitamin B 12 concentration from 0.04 to 4 μM enhanced CF removal, reduced DCM formation, and increased 13 CO 2 production, which is likely a product of CF oxidation. Known organohalide-respiring bacteria and reductive dehalogenase genes were neither detected by quantitative PCR nor metagenomic analysis. Rather, members of the order Clostridiales , known to co-metabolically transform CF to DCM and CO 2 , were detected in the enrichment cultures. Genome-resolved metagenome analysis indicated that their genomes encode enzymatic repertoires for the Wood-Ljungdahl pathway and cobalamin biosynthesis that are known to be involved in co-metabolic CF transformation. Importance More than 90% of the global CF emission to the atmosphere originates from natural sources, including saline environments such as salt lake sediments. However, knowledge about the microbial metabolism of CF in such extreme environments is lacking. Here we showed CF transformation potential in a hypersaline lake that was reported as a natural source of CF production. Application of interdisciplinary approaches of microbial cultivation, stable isotope labelling, and metagenomics aided in defining potential chloroform transformation pathways. This study indicates that microbiota may act as a filter to reduce CF emission from hypersaline lakes to the atmosphere, and expands our knowledge of halogen cycling in extreme hypersaline environments.
Regional specificity of cathodal transcranial direct current stimulation (tDCS) effects on spatial‐numerical associations: Comparison of four stimulation sites
2019-11-29

Abstract Based on a theory of impulsive and reflective human behavior, we test the effects of transcranial direct current stimulation (tDCS) targeting either prefrontal or parietal cortex in either hemisphere. In a confirmatory registered report, cathodal tDCS is administered to conceptually reproduce tDCS modulations of implicit spatial‐numerical associations, numerical distance effects, and response inhibition. Those cognitive operations are hypothesized to draw on left prefrontal, parietal, and right prefrontal activations, respectively, thereby susceptible to inhibitory, cathodal tDCS across those regions. Vice versa, the mutual regional and behavioral specificity of tDCS effects on these behavioral indices is examined and expected to produce double dissociations. In a mixed within‐subjects (baseline, during tDCS, post‐tDCS) and between‐subjects (target electrode: left/right prefrontal cortex/posterior parietal cortex, or sham tDCS) design, we collect (a) confirmatory data on the robustness of cathodal tDCS effects on three behavioral effects and (b) differential data on the specificity of regional targets in male and female human participants. Results will provide crucial tests of theories of cortical organization implied by implicit associations and explicit regulation, which can direct future brain stimulation studies.
Taming future mobilities: biopolitics and data behaviourism in the European Travel Information and Authorisation System (ETIAS)
2019-11-30

In this paper, I critically engage with the European Travel Authorisation and Information System (ETIAS), looking at the rationalities underlying its introduction, its system architecture and its proposed functionalities. Tracing the biopolitical problematisation of the border that led to ETIAS, I argue that the system embodies a shift towards data behaviourism in the regime of truth underlying the biopolitical regulation of the EU border. Data behaviourism establishes a new way of seeing conduct, adding a potential future layer to it. Taming future mobilities through data-mining and future-oriented algorithmic processing, ETIAS imagines mobile subjects in terms of their motility and thereby produces dividuals and blurs the spatio-temporal boundedness of the EU border. ETIAS thereby complicates resistance by avoiding fixed identities and instead rarefies subjects through seeing them as being constantly emergent through new correlations.
17q21.31 sub-haplotypes underlying H1-associated risk for Parkinson’s disease are associated with LRRC37A/2 expression in astrocytes
2019-11-30

ABSTRACT Parkinson’s disease (PD) is genetically associated with the H1 haplotype of the MAPT 17q.21.31 locus, although the causal gene and variants underlying this association have not been identified. To better understand the genetic contribution of this region to PD, we fine-mapped the 17q21.31 locus in order to identify novel mechanisms conferring risk for the disease. We identified three novel H1 sub-haplotype blocks across the 17q21.31 locus associated with PD risk. Protective sub-haplotypes were associated with increased LRRC37A/2 copy number and expression in human brain tissue. We found that LRRC37A/2 is a membrane-associated protein that plays a role in cellular migration, chemotaxis and astroglial inflammation. In human substantia nigra, LRRC37A/2 was primarily expressed in astrocytes, interacted directly with soluble α-synuclein, and co-localized with Lewy bodies in PD brain tissue. These data indicate that a novel candidate gene, LRRC37A/2 , contributes to the association between the 17q21.31 locus and PD via its interaction with α-synuclein and its effects on astrocytic function and inflammatory response. These data are the first to associate the genetic association at the 17q21.31 locus with PD pathology, and highlight the importance of variation at the 17q21.31 locus in the regulation of multiple genes other than MAPT and KANSL1 , as well as its relevance to non-neuronal cell types.
Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma
2019-12-01

Abstract Immune-checkpoint blockade (ICB) has demonstrated efficacy in many tumor types, but predictors of responsiveness to anti-PD1 ICB are incompletely characterized. In this study, we analyzed a clinically annotated cohort of patients with melanoma ( n = 144) treated with anti-PD1 ICB, with whole-exome and whole-transcriptome sequencing of pre-treatment tumors. We found that tumor mutational burden as a predictor of response was confounded by melanoma subtype, whereas multiple novel genomic and transcriptomic features predicted selective response, including features associated with MHC-I and MHC-II antigen presentation. Furthermore, previous anti-CTLA4 ICB exposure was associated with different predictors of response compared to tumors that were naive to ICB, suggesting selective immune effects of previous exposure to anti-CTLA4 ICB. Finally, we developed parsimonious models integrating clinical, genomic and transcriptomic features to predict intrinsic resistance to anti-PD1 ICB in individual tumors, with validation in smaller independent cohorts limited by the availability of comprehensive data. Broadly, we present a framework to discover predictive features and build models of ICB therapeutic response.
Pseudo-chromosome–length genome assembly of a double haploid “Bartlett” pear (Pyrus communis L.)
2019-12-01

Abstract Background We report an improved assembly and scaffolding of the European pear (Pyrus communis L.) genome (referred to as BartlettDHv2.0), obtained using a combination of Pacific Biosciences RSII long-read sequencing, Bionano optical mapping, chromatin interaction capture (Hi-C), and genetic mapping. The sample selected for sequencing is a double haploid derived from the same “Bartlett” reference pear that was previously sequenced. Sequencing of di-haploid plants makes assembly more tractable in highly heterozygous species such as P. communis. Findings A total of 496.9 Mb corresponding to 97% of the estimated genome size were assembled into 494 scaffolds. Hi-C data and a high-density genetic map allowed us to anchor and orient 87% of the sequence on the 17 pear chromosomes. Approximately 50% (247 Mb) of the genome consists of repetitive sequences. Gene annotation confirmed the presence of 37,445 protein-coding genes, which is 13% fewer than previously predicted. Conclusions We showed that the use of a doubled-haploid plant is an effective solution to the problems presented by high levels of heterozygosity and duplication for the generation of high-quality genome assemblies. We present a high-quality chromosome-scale assembly of the European pear Pyrus communis and demostrate its high degree of synteny with the genomes of Malus x Domestica and Pyrus x bretschneideri.
A rapidly prototyped lung-on-a-chip model using 3D-printed molds
2019-12-01

Organ-on-a-chip is a microfluidic cell culture model that replicates key organ-specific microarchitecture and pathophysiology in vitro. The current methods to fabricate these devices rely on softlithography, which is usually tedious, laborious, and requires adroit users as well as cleanroom facilities. Recently, the use of 3D-printing technologies for the rapid fabrication of molds for polydimethylsiloxane (PDMS) casting is on the rise. However, most of the 3D-printed materials are unsuitable for PDMS casting. To address this issue, we have improved the existing techniques and introduced a modified protocol for the surface treatment of 3D-printed molds, making them ideal for repeated long-term PDMS casting. Using this protocol, we have fabricated a simple open well lung-on-a-chip model to simulate the in vivo environment of airway at air-liquid interface under dynamic condition. To validate the functionality of the developed chip, Calu-3 cells were cultured in the chip and maintained at an air-liquid interface. The model demonstrated that the cultured cells replicated the 3D culture-specific-morphology, maintained excellent barrier integrity, secreted mucus, and expressed cell surface functional P-glycoprotein; all indicative of a promising in vitro model for permeability assays, toxicological tests, and pulmonary drug delivery studies. To validate the suitability of this lung-on-a-chip in vitro model, the effects of cigarette smoke extract (CSE) on Interleukin-6 (IL-6) and Interleukin-8 (IL-8) release from cultured Calu-3 cells were examined. CSE treated cells showed significantly higher secretion of IL-6 and IL-8 over 24 h compared to the cells treated with both CSE and Budesonide, an anti-inflammatory drug. Moreover, our results illustrated that CSE reduced the expression of E-cadherin as an adherent junctional protein. In conclusion, the proposed protocol demonstrated an easy and low-cost fabrication technique which will allow a biologist with minimal technical skills to rapidly prototype molds for different/versatile organ-on-a-chip models.
Therapy of Type 2 Diabetes
2019-12-01

The practical recommendations of the German Diabetes Society/Deutsche Diabetes Gesellschaft (DDG) together with the German Society for Internal Medicine/Deutschen Gesellschaft für Innere Medizin (DGIM) are based on the contents of the National Treatment Guideline (Nationale Versorgungsleitlinie NVL) "Therapy of Type 2 Diabetes" [1]. The modifications in therapy and their justifications made in the present DDG practical recommendations were updated on the basis of new randomized controlled trials (RCTs) and meta-analyses and were consented by the DDG and the DGIM.
SCN2A channelopathies: Mechanisms and models
2019-12-01

Summary Variants in the SCN 2A gene, encoding the voltage‐gated sodium channel Na V 1.2, cause a variety of neuropsychiatric syndromes with different severity ranging from self‐limiting epilepsies with early onset to developmental and epileptic encephalopathy with early or late onset and intellectual disability ( ID ), as well as ID or autism without seizures. Functional analysis of channel defects demonstrated a genotype‐phenotype correlation and suggested effective treatment options for one group of affected patients carrying gain‐of‐function variants. Here, we sum up the functional mechanisms underlying different phenotypes of patients with SCN 2A channelopathies and present currently available models that can help in understanding SCN 2A ‐related disorders.
Power Flow Approximation Based on Graph Convolutional Networks
2019-12-01

In this article we develop a graph convolutional neural network (GCN) for the approximation of the AC power flow in electrical power grids. The proposed architecture is fully generic and purely data driven, such that no information about the actual underlying physical topology of the power grid is required. This gives the opportunity to apply this approach to a wide range of multivariate regression problems. We test our architecture on 3 datasets of different sizes, two of which are real world type power grids containing up to 5488 nodes. We show that the proposed method allows an accurate approximation of the power flow specifically in the case of large power grids. The GCN architecture implies intrinsic extrapolation, allowing a reasonable reduction of the number of trainable parameters as well as training samples. In contrast, classical approaches based on fully connected networks are shown to face difficulties when fitting such high dimensional functions.
High-resolution and low-background $$^{163}$$Ho spectrum: interpretation of the resonance tails
2019-12-01

Abstract The determination of the effective electron neutrino mass via kinematic analysis of beta and electron capture spectra is considered to be model-independent since it relies on energy and momentum conservation. At the same time the precise description of the expected spectrum goes beyond the simple phase space term. In particular for electron capture processes, many-body electron-electron interactions lead to additional structures besides the main resonances in calorimetrically measured spectra. A precise description of the <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:msup><mml:mrow /><mml:mn>163</mml:mn></mml:msup></mml:math> Ho spectrum is fundamental for understanding the impact of low intensity structures at the endpoint region where a finite neutrino mass affects the shape most strongly. We present a low-background and high-energy resolution measurement of the <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:msup><mml:mrow /><mml:mn>163</mml:mn></mml:msup></mml:math> Ho spectrum obtained in the framework of the ECHo experiment. We study the line shape of the main resonances and multiplets with intensities spanning three orders of magnitude. We discuss the need to introduce an asymmetric line shape contribution due to Auger–Meitner decay of states above the auto-ionisation threshold. With this we determine an enhancement of count rate at the endpoint region of about a factor of 2, which in turn leads to an equal reduction in the required exposure of the experiment to achieve a given sensitivity on the effective electron neutrino mass.