bluuebunny/crossref_metadata_2025 huggingface dataset:
Open Access and Altmetrics in the pandemic age: Forescast analysis on COVID-19 literature
Authors: Torres-Salinas Daniel , Robinson-Garcia Nicolas , Castillo-Valdivieso Pedro A.
Published: April 2020

We present an analysis on the uptake of open access on COVID-19 related literature as well as the social media attention they gather when compared with non OA papers. We use a dataset of publications curated by Dimensions and analyze articles and preprints. Our sample includes 11,686 publications of which 67.5% are openly accessible. OA publications tend to receive the largest share of social media attention as measured by the Altmetric Attention Score. 37.6% of OA publications are bronze, which means toll journals are providing free access. MedRxiv contributes to 36.3% of documents in repositories but papers in BiorXiv exhibit on average higher AAS. We predict the growth of COVID-19 literature in the following 30 days estimating ARIMA models for the overall publications set, OA vs. non OA and by location of the document (repository vs. journal). We estimate that COVID-19 publications will double in the next 20 days, but non OA publications will grow at a higher rate than OA publications. We conclude by discussing the implications of such findings on the dissemination and communication of research findings to mitigate the coronavirus outbreak.
flowCut — An R package for precise and accurate automated removal of outlier events and flagging of files based on time versus fluorescence analysis
Authors: Meskas Justin , Wang Sherrie , Brinkman Ryan
Published: April 2020

Technical artifacts that occur during the data acquisition process of cytometry data can result in erroneous data. We showed the presence of these data leads to biased gating analysis. Common technical issues, such as clogging, can cause spurious events and fluorescence intensity shifting. These events should be identified and potentially removed before being passed to the next stage of the gating analysis. flowCut, an R package, automatically detects anomaly events and flags files for flow cytometry experiments. flowCut outperforms existing automated approaches in our evaluation.

flowCut is available as an R package at:https://github.com/jmeskas/flowCut. Test data uploaded to FlowRepository (Repository ID: FR-FCM-ZYPD) along with the manual results.
Joint eQTL mapping and Inference of Gene Regulatory Network Improves Power of Detecting bothcis- andtrans-eQTLs
Authors: Zhou Xin , Cai Xiaodong
Published: April 2020

Motivation

Genetic variations of expression quantitative trait loci (eQTLs) play a critical role in influencing complex traits and diseases development. Two main factors that affect the statistical power of detecting eQTLs are: 1) relatively small size of samples available, and 2) heavy burden of multiple testing due to a very large number of variants to be tested. The later issue is particularly severe when one tries to identifytrans-eQTLs that are far away from the genes they influence. If one can exploit co-expressed genes jointly in eQTL-mapping, effective sample size can be increased. Furthermore, using the structure of the gene regulatory network (GRN) may help to identifytrans-eQTLs without increasing multiple testing burden.

Results

In this paper, we employ the structure equation model (SEM) to model both GRN and effect of eQTLs on gene expression, and then develop a novel algorithm, named sparse SEM, for eQTL mapping (SSEMQ) to conduct joint eQTL mapping and GRN inference. The SEM can exploit co-expressed genes jointly in eQTL mapping and also use GRN to determinetrans-eQTLs. Computer simulations demonstrate that our SSEMQ significantly outperforms eight existing eQTL mapping methods. SSEMQ is further employed to analyze a real dataset of human breast tissues, yielding a number ofcis- andtrans-eQTLs.

Availability

R package ssemQr is available onhttps://github.com/Ivis4ml/ssemQr.git.
Role of the atmospheric pollution in the Covid-19 outbreak risk in Italy
Authors: Fattorini Daniele , Regoli Francesco
Published: April 2020

After the initial outbreak in China, the diffusion in Italy of SARS-CoV-2 is exhibiting a clear regional trend with Northern areas being the most affected in terms of both frequency and severity of cases. Among multiple factors possibly involved in such geographical differences, a role has been hypothesized for atmospheric pollution. We provide additional evidence on the possible influence of air quality, particularly in terms of chronicity of exposure on the spread viral infection in Italian regions. Actual data on COVID-19 outbreak in Italian provinces and corresponding long-term air quality evaluations, were obtained from Italian and European agencies, elaborated and tested for possible interactions. Our elaborations reveal that, beside concentrations, the chronicity of exposure may influence the anomalous variability of SARS-CoV-2 in Italy. Data on distribution of atmospheric pollutants (NO2, O3, PM2.5 and PM10) in Italian regions during the last 4 years, days exceeding regulatory limits, and years of the last decade (2010-2019) in which the limits have been exceeded for at least 35 days, confirmed that Northern Italy has been constantly exposed to chronic air pollution. Long-term air-quality data significantly correlated with cases of Covid-19 in up to 71 Italian provinces (updated 27 April 2020) providing further evidence that chronic exposure to atmospheric contamination may represent a favourable context for the spread of the virus. Pro-inflammatory responses and high incidence of respiratory and cardiac affections are well known, while the capability of this coronavirus to bind particulate matters remains to be established. Atmospheric and environmental pollution should be considered as part of an integrated approach for sustainable development, human health protection and prevention of epidemic spreads but in a long-term and chronic perspective, since adoption of mitigation actions during a viral outbreak could be of limited utility.

Capsule

Chronic exposure to air pollutants might have a role in the spread of COVID-19 in Italian regions. Diffusion of Covid-19 in 71 Italian provinces correlated with long-term air-quality data.
MiBiOmics: An interactive web application for multi-omics data exploration and integration
Authors: Zoppi Johanna , Guillaume Jean-François , Neunlist Michel , Chaffron Samuel
Published: April 2020

Background

Multi-omics experimental approaches are becoming common practice in biological and medical sciences underlying the need to design new integrative techniques and applications to enable the holistic characterization of biological systems. The integrative analysis of heterogeneous datasets generally allows us to acquire additional insights and generate novel hypotheses about a given biological system. However, it can often become challenging given the large size of omics datasets and the diversity of existing techniques. Moreover, visualization tools for interpretation are usually non-accessible to biologists without programming skills.

Results

Here, we present MiBiOmics, a web-based and standalone application that facilitates multi-omics data visualization, exploration, integration, and analysis by providing easy access to dedicated and interactive protocols. It implements advanced ordination techniques and the inference of omics-based (multi-layer) networks to mine complex biological systems, and identify robust biomarkers linked to specific contextual parameters or biological states.

Conclusions

Through an intuitive and interactive interface, MiBiOmics provides easy-access to ordination techniques and to a network-based approach for integrative multi-omics analyses. MiBiOmics is currently available as a Shiny app athttps://shiny-bird.univ-nantes.fr/app/Mibiomicsand as a standalone application athttps://gitlab.univ-nantes.fr/combi-ls2n/mibiomics.
Somatomotor cortical representations are predicted by levels of short-interval intracortical inhibition
Authors: Sigurdsson Hilmar P. , Molloy Katherine , Jackson Stephen R.
Published: April 2020

Transcranial magnetic stimulation (TMS) can be used to probe for the location of cortical somatomotor representations in humans. These somatomotor representations are dynamic and are perturbed following motor training, systematic intervention, and in disease. Evidence suggests that these representations are maintained by the inhibitory neurotransmitter gamma-Aminobutyric acid (GABA). In the current study, we quantified the location, outline, and variability of the first dorsal interosseous (FDI) hand muscle somatomotor representation using a novel rapid-acquisition TMS method in 14 healthy young volunteers. In addition, resting motor thresholds were measured using established protocols. TMS was also used to examine short-interval intracortical inhibition (SICI), which is thought to measure transiently activated cortical gamma-Aminobutyric acid (GABA) interneurons. Using stepwise regression, our results showed that the level of intracortical inhibition was a significant predictor of the FDI somatomotor representation suggesting that greater excitability of the hand area representation is possibly governed by greater activation of transient GABA interneurons.
Primary and recurrent glioma patient-derived orthotopic xenografts (PDOX) represent relevant patient avatars for precision medicine
Authors: Golebiewska Anna , Hau Ann-Christin , Oudin Anaïs , Stieber Daniel , Yabo Yahaya A. , Baus Virginie , Barthelemy Vanessa , Klein Eliane , Bougnaud Sébastien , Keunen Olivier , Wantz May , Michelucci Alessandro , Neirinckx Virginie , Muller Arnaud , Kaoma Tony , Nazarov Petr V. , Azuaje Francisco , De Falco Alfonso , Flies Ben , Richart Lorraine , Poovathingal Suresh , Arns Thais , Grzyb Kamil , Mock Andreas , Herold-Mende Christel , Steino Anne , Brown Dennis , May Patrick , Miletic Hrvoje , Malta Tathiane M. , Noushmehr Houtan , Kwon Yong-Jun , Jahn Winnie , Klink Barbara , Tanner Georgette , Stead Lucy F. , Mittelbronn Michel , Skupin Alexander , Hertel Frank , Bjerkvig Rolf , Niclou Simone P.
Published: April 2020

Patient-derived cancer models are essential tools for studying tumor biology and preclinical interventions. Here, we show that glioma patient-derived orthotopic xenografts (PDOXs) enable long-term propagation of patient tumors and represent clinically relevant patient avatars. We created a large collection of PDOXs from primary and recurrent gliomas with and without mutations inIDH1, which retained histopathological, genetic, epigenetic and transcriptomic features of patient tumors with no mouse-specific clonal evolution. Longitudinal PDOX models recapitulate the limited genetic evolution of gliomas observed in patient tumors following treatment. PDOX-derived standardized tumor organoid cultures enabled assessment of drug responses, which were validated in mice. PDOXs showed clinically relevant responses to Temozolomide and to targeted treatments such as EGFR and CDK4/6 inhibitors in (epi)genetically defined groups, according toMGMTpromoter andEGFR/CDKstatus respectively. Dianhydrogalactitol, a bifunctional alkylating agent, showed promising potential against glioblastoma. Our study underlines the clinical relevance of glioma PDOX models for translational research and personalized treatment studies.
Donut PCR: a rapid, portable, multiplexed, and quantitative DNA detection platform with single-nucleotide specificity
Authors: Khodakov Dmitriy , Li Jiaming , Zhang Jinny X. , Zhang David Yu
Published: April 2020

Current platforms for molecular analysis of DNA markers are either limited in multiplexing (qPCR, isothermal amplification), turnaround time (microarrays, NGS), quantitation accuracy (isothermal amplification, microarray, nanopore sequencing), or specificity against single-nucleotide differences (microarrays, nanopore sequencing). Here, we present the Donut PCR platform that features high multiplexing, rapid turnaround times, single nucleotide discrimination, and precise quantitation of DNA targets in a portable, affordable, and battery-powered instrument using closed consumables that minimize contamination. We built a bread-board instrument prototype and three assays/chips to demonstrate the capabilities of Donut PCR: (1) a 9-plex mammal identification panel, (2) a 15-plex bacterial identification panel, and (3) a 30-plex human SNP genotyping assay. The limit of detection of the platform is under 10 genomic copies in under 30 minutes, and the quantitative dynamic range is at least 4 logs. We envision that this platform would be useful for a variety of applications where rapid and highly multiplexed nucleic acid detection is needed at the point of care.
Leveraging UMLS-driven NLP to enhance identification of influenza predictors derived from electronic medical record data
Authors: Stephens Kari A. , Au Margaret A. , Yetisgen Meliha , Lutz Barry , Suchsland Monica Zigman , Ebell Mark H. , Thompson Matthew
Published: April 2020

Objective

Multiple clinical prediction rules have been developed, but lack validation. This study aims to identify a set of prediction algorithms for influenza, based on electronic health record (EHR) structured data and clinical notes derived data using Unified Medical Language System (UMLS) driven natural language processing (NLP).

Materials and Methods

Data were extracted from an enterprise-wide data warehouse for all patients who tested positive for influenza and were seen in ambulatory care between 2009 and 2019 (N= 7,278). A text processing pipeline was used to analyze chart notes for UMLS terms for symptoms of interest to improve data quality completeness. Three models, which step up complexity of the dataset and predictors, were tested with least absolute shrinkage and selection operator (LASSO)-selected parameters to identify predictors for influenza. Receiver operating characteristic (ROC) curves compared test accuracy across the three models.

Results

Three models identified 7, 8, and 10 predictors, and the most complex model performed best. The addition of the UMLS-driven NLP symptoms data improved data quality (false negatives) and increased the number of significant predictors. NLP also increased the strength of the models, as did the addition of two-way predictor interactions.

Discussion

The EHR is a feasible source for offering rapidly accessible datasets for influenza related prediction research that was used to produce a prediction model for influenza. Combining data collected in routine care with data science methods improved a prediction model for influenza, and in the future, could be used to drive diagnostics at the point of care.
AlphaPart - R implementation of the method for partitioning genetic trends
Authors: Obšteter Jana , Holl Justin , Hickey John M. , Gorjanc Gregor
Published: April 2020

Background

In this paper we present the AlphaPart R package, an open-source software that implements a method for partitioning breeding values and genetic trends to identify sources of genetic gain. Breeding programmes improve populations for a set of traits, which can be measured with a genetic trend calculated from averaged year of birth estimated breeding values of selection candidates. While sources of the overall genetic gain are generally known, their realised contributions are hard to quantify in complex breeding programmes. The aim of this paper is to present the AlphaPart R package and demonstrate it with a simulated pig breeding example.

Results

The package includes the main partitioning function AlphaPart, that partitions the breeding values and genetic trends by analyst defined paths, and a set of functions for handling data and results. The package is freely available from CRAN repository athttp://CRAN.R-project.org/package=AlphaPart. We demonstrate the use of the package by examining the genetic gain in a pig breeding example, in which the multiplier achieved higher breeding values than the nucleus for traits measured and selected in the multiplier. The partitioning analysis revealed that these higher values depended on the accuracy and intensity of selection in the multiplier and the extent of gene flow from the nucleus. For traits measured only in the nucleus, the multiplier achieved comparable or smaller genetic gain than the nucleus depending on the amount of gene flow.

Conclusions

AlphaPart implements a method for partitioning breeding values and genetic trends and provides a useful tool for quantifying the sources of genetic gain in breeding programmes. The use of AlphaPart will help breeders to better understand or improve their breeding programmes.
Gene polymorphism associated with Angiotensinogen(M235T), Endothelial lipase (584C/T) and susceptibility to coronary artery disease: A meta-analysis
Authors: Zhao Hongyan , Hu Shan , Rong Jidong
Published: April 2020

Objective

To explore the association between the variant M235 locus of angiotensinogen (AGT) gene, 584C/T locus of Endothelial lipase (EL) gene, and coronary artery disease (CAD) by meta-analysis.

Methods

The case-control studies on the association between AGT/EL gene polymorphism and CAD were collected through searching PubMed, EMbase, Web of Science, CNKI and Wanfang database up to March 1, 2020. Stata 15.0 software was used for analysis.

Results

A total of 29 articles met the inclusion criteria. After analyzing, it was found that the M235T polymorphism of AGT gene was associated with the occurrence of CAD. In the allele model (T vs. M), OR=1.38 (P < 0.05). In other heredity, there was also statistically significant. Subgroup analysis indicated that except the heterozygous genetic model of the Chinese population, other genetic models of the Caucasian and Chinese population were also statistically significant. The 584C/T polymorphism of EL gene was associated with the occurrence of CAD, with OR=0.83 (P < 0.05) in the allele model (T vs. C) and OR=0.80 (P < 0.05) in the dominant gene model. Also, in the allele model of Caucasian subgroup, OR=0.83 (P < 0.05), while in Asian subgroup, there was no statistically significant genetic model.

Conclusion

AGT M235 and EL 584C/T polymorphisms are associated with CAD susceptibility. The genotype TT, TC or allele T of AGT M235T and genotype CC or allele C of EL 584C/T might be the genetic risk factors for the development of CAD.
Identification of stromal genes differentially expressed in lobular breast cancer highlights role for pregnancy-associated-plasma protein-A
Authors: Gómez-Cuadrado Laura , Zhao Hong , Souleimanova Margarita , Noer Pernille Rimmer , Turnbull Arran K , Oxvig Claus , Bertos Nicholas , Dixon J Michael , Park Morag , Sims Andrew H , Brunton Valerie G
Published: April 2020

Background

Invasive lobular carcinoma (ILC) is the second most common histological subtype of breast cancer and exhibits a number of clinico-pathological characteristics that are distinct from the more common invasive ductal carcinoma (IDC). Despite these differences, ILC is treated in the same way as IDC. We set out to identify alterations in the tumor microenvironment (TME) of ILC with potential clinical significance.

Methods

We used laser-capture microdissection (LCM) to separate tumor epithelium from stroma in 23 ER+ ILC samples. Gene expression analysis was used to identify genes that are enriched in the stroma of ILC, but not IDC or normal breast.

Results

45 genes involved in regulation of the extracellular matrix (ECM) were enriched in the stroma of ILC, but not stroma from ER+ IDC or normal breast. Of these, 10 were expressed in cancer-associated fibroblasts (CAFs) and were increased in ILC compared to IDC in bulk gene expression datasets.PAPPAwas the most enriched in the stroma compared to the tumor epithelial compartment in ILC.PAPPAencodes pregnancy-associated plasma protein-A (PAPP-A), a metalloproteinase that cleaves insulin-like binding protein-4 (IGFBP-4) increasing IGF-1 bioavailability and subsequent downstream signaling. Analysis ofPAPPAandIGF1associated genes identified a paracrine signaling pathway and active PAPP-A was shown to be secreted from primary CAFs. Comprehensive survival analysis across 3000 breast cancers identifiedPAPPAas a potential ILC-specific prognostic marker.

Conclusions

This is the first study to demonstrate molecular differences in the TME between ILC and IDC and identifies PAPP-A, a CAF-derived proteinase, as a potential prognostic marker.
Repeat DNA-PAINT suppresses background and non-specific signals in optical nanoscopy
Authors: Clowsley Alexander H. , Kaufhold William T. , Lutz Tobias , Meletiou Anna , Di Michele Lorenzo , Soeller Christian
Published: April 2020

DNA-PAINT is a versatile optical super-resolution technique relying on the transient binding of fluorescent DNA ‘imagers’ to target epitopes. Its performance in biological samples is often constrained by strong background signals and non-specific binding events, both exacerbated by high imager concentrations. Here we describe Repeat DNA-PAINT, a method that enables a substantial reduction in imager concentration, thus suppressing spurious signals. Additionally, Repeat DNA-PAINT reduces photoinduced target-site loss and can accelerate sampling, all without affecting spatial resolution.
An adjunctive therapy administered with an antibiotic prevents enrichment of antibiotic-resistant clones of a colonizing opportunistic pathogen
Authors: Morley Valerie J. , Kinnear Clare L. , Sim Derek G. , Olson Samantha N. , Jackson Lindsey M. , Hansen Elsa , Usher Grace A. , Showalter Scott A. , Pai Manjunath P. , Woods Robert J. , Read Andrew F.
Published: April 2020

A key challenge in antibiotic stewardship is figuring out how to use antibiotics therapeutically without promoting the evolution of antibiotic resistance. Here, we demonstrate proof of concept for an adjunctive therapy that allows intravenous antibiotic treatment without driving the evolution and onward transmission of resistance. We repurposed the FDA-approved bile sequestrant cholestyramine, which we show binds the antibiotic daptomycin, as an ‘anti-antibiotic’ to disable systemically-administered daptomycin reaching the gut. We hypothesized that adjunctive cholestyramine could enable therapeutic daptomycin treatment in the bloodstream, while preventing transmissible resistance emergence in opportunistic pathogens colonizing the gastrointestinal tract. We tested this idea in a mouse model ofEnterococcus faeciumgastrointestinal tract colonization. In mice treated with daptomycin, adjunctive cholestyramine therapy reduced the fecal shedding of daptomycin-resistantE. faeciumby up to 80-fold. These results provide proof of concept for an approach that could reduce the spread of antibiotic resistance for important hospital pathogens.
Fractal analysis of muscle activity patterns during locomotion: pitfalls and how to avoid them
Authors: Santuz Alessandro , Akay Turgay
Published: April 2020

Time-dependent physiological data, such as electromyogram (EMG) recordings from multiple muscles, is often difficult to interpret objectively. Here, we used EMG data gathered during mouse locomotion to investigate the effects of calculation parameters and data quality on two metrics for fractal analysis: the Higuchi’s fractal dimension (HFD) and the Hurst exponent (H). A curve is fractal if it repeats itself at every scale or, in other words, if its shape remains unchanged when zooming in the curve at every zoom level. Many linear and nonlinear analysis methods are available, each of them aiming at the explanation of different data features. In recent years, fractal analysis has become a powerful nonlinear tool to extract information from physiological data not visible to the naked eye. It can present, however, some dangerous pitfalls that can lead to misleading interpretations. To calculate the HFD and the H, we have extracted muscle synergies from normal and mechanically perturbed treadmill locomotion from the hindlimb of adult mice. Then, we used one set per condition (normal and perturbed walking) of the obtained time-dependent coefficients to create surrogate data with different fluctuations over the original mean signal. Our analysis shows that HFD and H are exceptionally sensitive to the presence or absence of perturbations to locomotion. However, both metrics suffer from variations in their value depending on the parameters used for calculations and the presence of quasi-periodic elements in the time series. We discuss those issues giving some simple suggestions to reduce the chance of misinterpreting the outcomes.

New & Noteworthy

Despite the lack of consensus on how to perform fractal analysis of physiological time series, many studies rely on this technique. Here, we shed light on the potential pitfalls of using the Higuchi’s fractal dimension and the Hurst exponent. We expose and suggest how to solve the drawbacks of such methods when applied to data from normal and perturbed locomotion by combiningin vivorecordings and computational approaches.
InLyl1-/-mice, adipose stem cell vascular niche impairment leads to premature development of fat tissues
Authors: Hussain Abid , Kebriti Leila El , Deleuze Virginie , Glasson Yaël , Pirot Nelly , Mathieu Danièle , Pinet Valérie
Published: April 2020

Lymphoblastic leukemia-derived sequence 1(Lyl1)encodes a hematopoietic- and endothelial-specific transcriptional factor.Lyl1-deficient mice are viable, but they display mild hematopoietic and vascular defects. Here, we report that youngLyl1-/-mice exhibit transient obesity associated with general expansion of adipose tissues and unrelated to food intake. The increased fat tissue development inLyl1-/-mice resulted from an earlier adipocyte differentiation of adipose stem cells (ASCs) through non-cell autonomous mechanisms. Specifically, we found that inLyl1-/-mice, the vascular structures of adipose tissues are unstable, more prone to angiogenesis and, consequently, cannot maintain adipose progenitors in the niche vessel wall. Together, our data show that inLyl1-/-mice, the impaired vascular compartment of the adipose niche promotes uncontrolled ASC activation and differentiation, leading to early adipocyte expansion and premature depletion of ASCs. Our study highlights the major structural role of the adipose tissue vascular niche in coordinating stem cell self-renewal and differentiation into adipocytes.
Dissociable Effects of Emotional Stimuli on Perception and Decision-Making for Time
Authors: Gladhill Keri , Mioni Giovanna , Wiener Martin
Published: April 2020

Previous research has demonstrated that negative emotional faces dilate time perception, however, the mechanisms underlying this phenomenon are not fully understood. Previous attempts focus on the pacemaker-accumulator model of time perception, which includes a clock, memory, and decision-making stage, wherein emotion affects one of these stages; possibly by increasing pacemaker rate via arousal, increasing accumulation rate via attention, or by biasing decision-making. To further investigate the stage(s) that emotion is affecting time perception we conducted a visual temporal bisection task with sub-second intervals while recording 64-channel electroencephalogram (EEG). To separate the influence of face and timing responses the temporal stimulus was preceded and followed by a face stimulus displaying a neutral or negative expression creating three trial-types: Neg→Neut, Neut→Neg, or Neut→Neut. The data revealed a leftward shift in bisection point (BP) in Neg→Neut and Neut→Neg suggesting an overestimation of time. Neurally, we found the face-responsive N170 component was larger for negative faces and the N1 and contingent negative variation (CNV) were larger when preceded by a negative face. We also found an interaction effect between condition and response for the late positive component of timing (LPCt) and a significant difference between response (short/long) in the neutral condition. We conclude that a preceding negative face affects the clock stage leading to more pulses being accumulated, either through attention or arousal, as indexed by a larger N1, CNV, and N170; whereas viewing the negative face second biased decision-making leading to “short” responses being less likely, as evidenced by the LPCt.
On the robustness of graph-based clustering to random network alterations
Authors: Stacey R. Greg , Skinnider Michael A. , Foster Leonard J.
Published: April 2020

Biological functions emerge from complex and dynamic networks of protein-protein interactions. Because these protein-protein interaction networks, or interactomes, represent pairwise connections within a hierarchically organized system, it is often useful to identify higher-order associations embedded within them, such as multi-member protein-complexes. Graph-based clustering techniques are widely used to accomplish this goal, and dozens of field-specific and general clustering algorithms exist. However, interactomes can be prone to errors, especially interactomes that infer interactions using high-throughput biochemical assays. Therefore, robustness to network-level variability is an important criterion for any clustering algorithm that aims to generate robust, reproducible clusters. Here, we tested the robustness of a range of graph-based clustering algorithms in the presence of network-level noise, including algorithms common across domains and those specific to protein networks. We found that the results of all clustering algorithms measured were profoundly sensitive to injected network noise.

Randomly rewiring 1% of network edges yielded up to a 57% change in clustering results, indicating that clustering markedly amplified network-level noise. However, the impact of network noise on individual clusters was not uniform. We found that some clusters were consistently robust to injected network noise while others were not. Therefore, we developed theclust.perturbR package and Shiny web application, which measures the reproducibility of clusters by randomly perturbing the network. We show thatclust.perturbresults are predictive of real-world cluster stability: poorly reproducible clusters as identified byclust.perturbare significantly less likely to be reclustered across experiments. We conclude that quantifying the robustness of a cluster to network noise, as implemented inclust.perturb, provides a powerful tool for ranking the reproducibility of clusters, and separating stable protein complexes from spurious associations.
A splicing isoform of GPR56 mediates microglial synaptic refinement via phosphatidylserine binding
Authors: Li Tao , Chiou Brian , Gilman Casey K , Luo Rong , Koshi Tatsuhiro , Yu Diankun , Oak Hayeon C , Giera Stefanie , Johnson-Venkatesh Erin , Muthukumar Allie K. , Stevens Beth , Umemori Hisashi , Piao Xianhua
Published: April 2020

Developmental synaptic remodeling is important for the formation of precise neural circuitry and its disruption has been linked to neurodevelopmental disorders such as autism and schizophrenia. Microglia prune synapses, but integration of this synapse pruning with overlapping and concurrent neurodevelopmental processes remains elusive. Adhesion G protein-coupled receptor ADGRG1/GPR56 controls multiple aspects of brain development in a cell type-specific manner: in neural progenitor cells, GPR56 regulates cortical lamination, whereas in oligodendrocyte progenitor cells, GPR56 controls developmental myelination and myelin repair. Here, we show that microglial GPR56 maintains appropriate synaptic numbers in several brain regions in a time- and circuit-dependent fashion. Phosphatidylserine (PS) on pre-synaptic elements binds GPR56 in a domain-specific manner, and microglia-specific deletion ofGpr56leads to increased synapses as a result of reduced microglial engulfment of PS+pre-synaptic inputs. Remarkably, a particular alternatively spliced isoform of GPR56 is selectively required for microglia-mediated synaptic pruning. Our present data provide a ligand- and isoform-specific mechanism underlying microglial GPR56-mediated synapse pruning in the context of complex neurodevelopmental processes.
Multi-modal characterization and simulation of human epileptic circuitry
Authors: Buchin Anatoly , de Frates Rebecca , Nandi Anirban , Mann Rusty , Chong Peter , Ng Lindsay , Miller Jeremy , Hodge Rebecca , Kalmbach Brian , Bose Soumita , Rutishauser Ueli , McConoughey Stephen , Lein Ed , Berg Jim , Sorensen Staci , Gwinn Ryder , Koch Christof , Ting Jonathan , Anastassiou Costas A.
Published: April 2020

Temporal lobe epilepsy is the fourth most common neurological disorder with about 40% of patients not responding to pharmacological treatment. Increased cellular loss in the hippocampus is linked to disease severity and pathological phenotypes such as heightened seizure propensity. While the hippocampus is the target of therapeutic interventions such as temporal lobe resection, the impact of the disease at the cellular level remains unclear in humans. Here we show that properties of hippocampal granule cells change with disease progression as measured in living, resected hippocampal tissue excised from epilepsy patients. We show that granule cells increase excitability and shorten response latency while also enlarging in cellular volume, surface area and spine density. Single-cell RNA sequencing combined with simulations ascribe the observed electrophysiological changes to gradual modification in three key ion channel conductances: BK, Cav2.2 and Kir2.1. In a bio-realistic computational network model, we show that the changes related to disease progression bring the circuit into a more excitable state. In turn, we observe that by reversing these changes in the three key conductances produces a less excitable, “early disease-like” state. These results provide mechanistic understanding of epilepsy in humans and will inform future therapies such as viral gene delivery to reverse the course of the disorder.
In silicotools for accurate HLA and KIR inference from clinical sequencing data empower immunogenetics on individual-patient and population scales
Authors: Chen Jieming , Madireddi Shravan , Nagarkar Deepti , Migdal Maciej , Heiden Jason Vander , Chang Diana , Mukhyala Kiran , Selvaraj Suresh , Kadel Edward E. , Brauer Matthew J. , Mariathasan Sanjeev , Hunkapiller Julie , Jhunjhunwala Suchit , Albert Matthew L. , Hammer Christian
Published: April 2020

Immunogenetic variation in humans is important in research, clinical diagnosis and increasingly a target for therapeutic intervention. Two highly polymorphic loci play critical roles, namely the human leukocyte antigen (HLA) system, which is the human version of the major histocompatibility complex (MHC), and the Killer-cell immunoglobulin-like receptors (KIR) that are relevant for responses of Natural Killer (NK) cells and some subsets of T cells. Their accurate classification has typically required the use of dedicated biological specimens and a combination ofin vitroandin silicoefforts. Increased availability of next generation sequencing data has led to the development of ancillary computational solutions. Here, we report an evaluation of recently published algorithms to computationally infer complex immunogenetic variation in the form of HLA alleles and KIR haplotypes from whole-genome or whole-exome sequencing data. For both HLA allele and KIR gene typing, we identified tools that yielded >97% overall accuracy for 4-digit HLA types, and >99% overall accuracy for KIR gene presence, suggesting the readiness of in silico solutions for use in clinical and high-throughput research settings.
“Comparative Analysis of Gut Microbiome in Individuals of the Old Civilization of Caral-Supe Based on Data from 16S rRNA and ITS region”
Authors: Vásquez-Domínguez Andrés , Jaramillo-Valverde Luis , Levano Kelly S. , Novoa-Bellota Pedro , Machaguay-Romero Marco , Garcia-de-la-Guarda Ruth , Cano Raul J. , Solis Ruth Shady , Guio Heinner
Published: April 2020

Genetic and microbiome studies of ancient Caral-Supe civilization have not yet been published. For this reason, the objective of this work is to identify the microorganisms and possible diseases that existed in this ancient civilization using coprolites samples. To do this, two coprolites samples were analyzing through high-throughput sequencing data of 16S rRNA gene and an intergenic region (ITS).
Simultaneous determination of87Sr/86Sr and trace-element data in otoliths and other sclerochronological hard structures
Authors: Hegg Jens C. , Fisher Christopher M. , Vervoort Jeffrey
Published: April 2020

Chronological data from hard structures have been instrumental in reconstructing information about the past across numerous disciplines. Isotopic and trace elemental chronologies from the depositional layers of speleothems, corals, bivalve shells, fish otoliths and other structures are routinely used to reconstruct climate, growth, temperature, geological, archeological and migratory histories. Recentin situanalytical advances have revolutionized the use of these structures. This is particularly true of fish, in which detailed origin, life-history, and migration history can be reconstructed from their otoliths. Specifically, improvements in laser ablation-inductively coupled plasma mass spectrometry (LA-ICPMS) have allowed increases in temporal resolution, precision, and sample throughput. Many studies now combine multiple chemical and isotopic tracers, taking advantage of multivariate statistical methods and multiple trace-elements and isotope systems to glean further information from individual samples. This paper describes a novel laser ablation split-stream (LASS) methodology which allows simultaneous collection of the Sr isotope composition (87Sr/86Sr) and trace-elemental data from chronologically deposited carbonate samples. The study investigates the accuracy and precision of varying laser spot sizes on a marine shell standard and fish otoliths using LASS and presents a comparison to traditional “single stream methods” using pre-existing otolith data on the same samples. Our results indicate that LASS techniques can be used to provide accurate and precise data at the same laser spot sizes as previous otolith studies, thereby doubling analytical throughput, while also providing improved spatially and temporally-matched data reduction using newly developed features for the Iolite data reduction platform.
SARS-CoV-2 Productively Infects Human Gut Enterocytes
Authors: Lamers Mart M. , Beumer Joep , van der Vaart Jelte , Knoops Kèvin , Puschhof Jens , Breugem Tim I. , Ravelli Raimond B.G. , van Schayck J. Paul , Mykytyn Anna Z. , Duimel Hans Q. , van Donselaar Elly , Riesebosch Samra , Kuijpers Helma J.H. , Schipper Debby , van de Wetering Willine J. , de Graaf Miranda , Koopmans Marion , Cuppen Edwin , Peters Peter J. , Haagmans Bart L. , Clevers Hans
Published: April 2020

COVID-19, caused by SARS-CoV-2, is an influenza-like disease with a respiratory route of transmission, yet clinical evidence suggests that the intestine may present another viral target organ. Indeed, the SARS-CoV-2 receptor angiotensin converting enzyme 2 (ACE2) is highly expressed on differentiated enterocytes. In human small intestinal organoids, enterocytes were readily infected by SARS-CoV and SARS-CoV-2 as demonstrated by confocal- and electron-microscopy. Consequently, significant titers of infectious viral particles were measured. mRNA expression analysis revealed strong induction of a generic viral response program. We conclude that intestinal epithelium supports SARS-CoV-2 replication.

One Sentence Summary

SARS-CoV-2 infection of enterocytes in human small intestinal organoids
MMEJ-based Precision Gene Editing for applications in Gene Therapy and Functional Genomics
Authors: Martínez-Gálvez Gabriel , Manduca Armando , Ekker Stephen C.
Published: April 2020

Experiments in gene editing commonly elicit error-prone non-homologous end joining for DNA double-strand break (DSB) repair. Microhomology-mediated end joining (MMEJ) can generate more predictable outcomes for functional genomic and somatic therapeutic applications. MENTHU is a computational tool that predicts nuclease-targetable sites likely to result in MMEJ-repaired, homogeneous genotypes (PreMAs) in zebrafish. We deployed MENTHU on 5,885 distinct Cas9-mediated DSBs in mouse embryonic stem cells, and compared the predictions to those by inDelphi, another DSB repair predictive algorithm. MENTHU correctly identified 46% of all PreMAs available, doubling the sensitivity of inDelphi. We also introduce MENTHU@4, an MENTHU update trained on this large dataset. We trained two MENTHU-based algorithms on this larger dataset and validated them against each other, MENTHU, and inDelphi. Finally, we estimated the frequency and distribution of SpCas9-targetable PreMAs in vertebrate coding regions to evaluate MMEJ-based targeting for gene discovery. 44 out of 54 genes (81%) contained at least one early out-of-frame PreMA and 48 out of 54 (89%) did so when also considering Cas12a. We suggest that MMEJ can be deployed at scale for reverse genetics screenings and with sufficient intra-gene density rates to be viable for nearly all loss-of-function based gene editing therapeutic applications.
Genetic inactivation of the translin/trax microRNA-degrading enzyme phenocopies the robust adiposity induced byTranslin(Tsn) deletion
Authors: Fu Xiuping , Shah Aparna P. , Li Zhi , Li Mengni , Tamashiro Kellie L. , Baraban Jay M.
Published: April 2020

Objective

Deletion ofTranslin(Tsn) from mice induces an unusual metabolic profile characterized by robust adiposity, normal body weight and glucose tolerance. Translin (TN) protein and its partner, trax (TX), form the TN/TX microRNA-degrading enzyme. Since the microRNA system plays a prominent role in regulating metabolism, we reasoned that the metabolic profile displayed byTsnKO mice might reflect dysregulation of microRNA signaling.

Methods

To test this hypothesis, we inserted a mutation, E126A, inTsnax, the gene encoding TX, that abolishes the microRNA-degrading enzymatic activity of the TN/TX complex. In addition, to help define the cell types that drive the adiposity phenotype, we have also generated mice with floxed alleles of Tsn or Tsnax.

Results

Introduction of the E126A mutation inTsnaxdoes not impair expression of TN or TX proteins or their co-precipitation. Furthermore, these mice display selective increases in microRNAs that match those induced byTsndeletion, confirming that this mutation inTsnaxinactivates the microRNA-degrading activity of the TN/TX complex. Mice homozygous for theTsnax(E126A) mutation display a metabolic profile that closely mimics that ofTsnKO mice.

Selective deletion ofTsnorTsnaxfrom either adipocytes or hepatocytes, two candidate cell types, does not phenocopy the elevated adiposity displayed by mice with constitutiveTsndeletion or theTsnax(E126A) mutation. Furthermore, global, conditional deletion ofTsnin adulthood does not elicit increased adiposity.

Conclusion

Taken together, these findings indicate that inactivation of the TN/TX microRNA-degrading enzyme during development is necessary to drive the robust adiposity displayed byTsnKO mice.
International authorship and collaboration across bioRxiv preprints
Authors: Abdill Richard J. , Adamowicz Elizabeth M. , Blekhman Ran
Published: April 2020

As preprints become integrated into conventional avenues of scientific communication, it’s critical to understand who is included and who is not. However, little is known about which countries are participating or how they collaborate with each other. Here, we present an analysis of all 67,885 preprints posted on bioRxiv (through 2019) using the first comprehensive dataset of country-level preprint author affiliations. We find the plurality of preprints (39%) come from the United States, and that countries such as the U.S. and U.K. are overrepresented on bioRxiv relative to their overall scientific output, while countries including China, Russia, and Turkey show lower bioRxiv adoption. We describe a set of “contributor countries” including Uganda, Croatia and Thailand that appear almost exclusively as non-senior authors on international collaborations. Lastly, we find multiple journals that publish a disproportionate number of preprints from some countries, a dynamic that almost always benefits manuscripts from the U.S.
MINERVA: A facile strategy for SARS-CoV-2 whole genome deep sequencing of clinical samples
Authors: Chen Chen , Li Jizhou , Di Lin , Jing Qiuyu , Du Pengcheng , Song Chuan , Li Jiarui , Li Qiong , Cao Yunlong , Xie X. Sunney , Wu Angela R. , Zeng Hui , Huang Yanyi , Wang Jianbin
Published: April 2020

The novel coronavirus disease 2019 (COVID-19) pandemic poses a serious public health risk. Analyzing the genome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from clinical samples is crucial for the understanding of viral spread and viral evolution, as well as for vaccine development. Existing sample preparation methods for viral genome sequencing are demanding on user technique and time, and thus not ideal for time-sensitive clinical samples; these methods are also not optimized for high performance on viral genomes. We have developedMetagenomIc RNAEnRichmentVirAl sequencing (MINERVA), a facile, practical, and robust approach for metagenomic and deep viral sequencing from clinical samples. This approach uses direct tagmentation of RNA/DNA hybrids using Tn5 transposase to greatly simplify the sequencing library construction process, while subsequent targeted enrichment can generate viral genomes with high sensitivity, coverage, and depth. We demonstrate the utility of MINERVA on pharyngeal, sputum and stool samples collected from COVID-19 patients, successfully obtaining both whole metatranscriptomes and complete high-depth high-coverage SARS-CoV-2 genomes from these clinical samples, with high yield and robustness. MINERVA is compatible with clinical nucleic extracts containing carrier RNA. With a shortened hands-on time from sample to virus-enriched sequencing-ready library, this rapid, versatile, and clinic-friendly approach will facilitate monitoring of viral genetic variations during outbreaks, both current and future.
Post-fire changes in plant growth form composition in Andean páramo grassland
Authors: Zomer Maya A. , Ramsay Paul M.
Published: April 2020

Questions

Fire suppression policies have been widely adopted in the páramo grasslands of the northern Andes to protect their biodiversity and ecosystem services. Páramos have been regularly burned for many years, and it is not clear how páramo vegetation will respond to significant changes in their fire regimes. This study investigates differences in plant growth form composition, light levels and soil temperatures in páramo plots representing a range of recovery times since the last fire.

Location

Reserva Ecológica El Ángel and La Bretaña Nature Reserve, Carchi, Northern Ecuador.

Methods

We assessed the frequency of ten páramo growth forms, vegetation height, soil temperature, and light intensity in fifteen fire sites with historical records of fire (<1 – 15 years since fire), and one recently unburned site (at least 40 years since fire). A chronosquence of sites was used to assess potential changes in plant community composition in post-fire succession of páramo.

Results

The recovery of páramo vegetation after fire comprised three phases: initial recruitment with high growth form diversity, followed by reduced diversity, light and soil temperatures in dense tussock vegetation, and ultimately canopy height stratification with a return of diversity. All but one plant growth forms were represented in each of the three phases, and the changes reflected differences in relative abundance.

Conclusions

Post-fire páramo succession is characterized by clear shifts in the relative abundance of plant growth forms, ending with (co-)dominance of upright shrubs. The long-term consequences of such shifts for biodiversity and ecosystem function, given the widespread adoption of fire suppression policies in the páramo need careful, evidence-based consideration.