bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical validation of the quantitative Siemens SARS-CoV-2 spike IgG assay (sCOVG) reveals improved sensitivity and a good correlation with virus neutralization titers
Authors: Irsara Christian , Egger Alexander E. , Prokop Wolfgang , Nairz Manfred , Loacker Lorin , Sahanic Sabina , Pizzini Alex , Sonnweber Thomas , Holzer Barbara , Mayer Wolfgang , Schennach Harald , Loeffler-Ragg Judith , Bellmann-Weiler Rosa , Hartmann Boris , Tancevski Ivan , Weiss Günter , Binder Christoph J. , Anliker Markus , Griesmacher Andrea , Hoermann Gregor
Published: February 2021

Objectives

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infections cause Coronavirus Disease 2019 (COVID-19) and induce a specific antibody response. Serological assays detecting IgG against the receptor binding domain (RBD) of the spike (S) protein are useful to monitor the immune response after infection or vaccination. The objective of our study was to evaluate the clinical performance of the Siemens SARS-CoV-2 IgG (sCOVG) assay.

Methods

Sensitivity and specificity of the Siemens sCOVG test were evaluated on 178 patients with SARS-CoV-2-infection and 160 pre-pandemic samples in comparison with its predecessor test COV2G. Furthermore, correlation with virus neutralization titers was investigated on 134 samples of convalescent COVID-19 patients.

Results

Specificity of the sCOVG test was 99.4% and sensitivity was 90.5% (COV2G assay 78.7%; p<0.0001). S1-RBD antibody levels showed a good correlation with virus neutralization titers (r=0.843; p<0.0001) and an overall qualitative agreement of 98.5%. Finally, median S1-RBD IgG levels increase with age and were significantly higher in hospitalized COVID-19 patients (median levels general ward: 25.7 U/ml; intensive care: 59.5 U/ml) than in outpatients (3.8 U/ml; p<0.0001).

Conclusions

Performance characteristics of the sCOVG assay have been improved compared to the predecessor test COV2G. Quantitative SARS-CoV-2 S1-RBD IgG levels could be used as a surrogate for virus neutralization capacity. Further harmonization of antibody quantification might assist to monitor the humoral immune response after COVID-19 disease or vaccination.
The interaction between lifetime depression severity and BMI is related to altered activation pattern in the right inferior frontal gyrus during food anticipation
Authors: Manelis A , Halchenko YO , Satz S , Ragozzino R , Lucero M , Swartz HA , Levine MD
Published: February 2021

Background

Depression and obesity often co-occur but the underlying neural mechanisms for this bidirectional link are not well understood. Using fMRI, we examined how the relationship between Body Mass Index (BMI) and dimensional lifetime depression severity was associated with brain activation during food anticipation and pleasant/unpleasant rating.

Methods

90 participants (48 healthy controls, 42 with unipolar depression (UD), 69 female, age=28.5±6.6) were fMRI-scanned while performing the Food and Object Cued Encoding task consisting of food/object anticipation and food/object pleasant/unpleasant rating phases.

Results

The analysis across all participants revealed a significant BMI-by-lifetime depression severity interaction on RIFG activation during food anticipation (p<0.0125). Most symptomatic and overweight/obese individuals with UD showed decreased right inferior frontal gyrus (RIFG) activation during food anticipation, while less symptomatic and/or normal-weight individuals with UD showed increased RIFG activation during food anticipation. RIFG activation during food anticipation was negatively correlated with RIFG activation during pleasant/unpleasant rating (r= -0.63, p<0.001). Individuals with UD who showed higher RIFG activation for food items during pleasant/unpleasant rating reported liking or wanting those food items less than those with lower RIFG activation (p<0.05).

Conclusions

The IFG is involved in emotion regulation and response inhibition necessary to control appetitive behavior. Greater RIFG activation during pleasant/unpleasant rating of food coupled with low ratings of food liking and wanting could be associated with inhibition of cognitive and emotional response to food in UD. This process may be cognitively challenging and stressful thus putting affected individuals with UD at risk for weight gain and worsening of depression.
SARS-CoV-2 shedding dynamics across the respiratory tract, sex and disease severity for adult and pediatric COVID-19
Authors: Chen Paul Z. , Bobrovitz Niklas , Premji Zahra , Koopmans Marion , Fisman David N. , Gu Frank X.
Published: February 2021

Background

SARS-CoV-2 shedding dynamics influence the risk of transmission and clinical manifestations of COVID-19. Yet, the relationships between SARS-CoV-2 shedding dynamics in the upper (URT) and lower respiratory tract (LRT) and age, sex and COVID-19 severity remain unclear.

Methods

Using systematic review, we developed a dataset of case characteristics (age, sex and COVID-19 severity) and quantitative respiratory viral loads (rVLs). We then conducted stratified analyses to assess SARS-CoV-2 shedding across disease course, COVID-19 severity, the respiratory tract, sex and age groups (aged 0 to 17 years, 18 to 59 years, and 60 years or older).

Results

The systematic dataset included 1,266 adults and 136 children with COVID-19. In the URT, adults with severe COVID-19 had higher rVLs at 1 day from symptom onset (DFSO) than adults (P = 0.005) or children (P = 0.017) with nonsevere illness. Between 1-10 DFSO, severe adults had comparable rates of SARS-CoV-2 clearance from the URT as nonsevere adults (P = 0.479) and nonsevere children (P = 0.863). In the LRT, severe adults showed higher rVLs post-symptom onset than nonsevere adults (P = 0.006). In the analyzed period (4-10 DFSO), severely affected adults had no significant trend in SARS-CoV-2 clearance from LRT (P = 0.105), whereas nonsevere adults showed a clear trend (P < 0.001). After stratifying for disease severity, sex and age (including child vs. adult) were not predictive of the duration of respiratory shedding. The estimated accuracy for using URT shedding as a prognostic indicator for COVID-19 severity was up to 65%, whereas it was up to 81% for LRT shedding.

Conclusions

High, persistent LRT shedding of SARS-CoV-2 characterized severe COVID-19 in adults. After symptom onset, severe cases tended to have slightly higher URT shedding than their nonsevere counterparts. Disease severity, rather than age or sex, predicted SARS-CoV-2 kinetics. LRT specimens more accurately prognosticate COVID-19 severity than do URT specimens.

Funding

Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant, NSERC Senior Industrial Research Chair and the Toronto COVID-19 Action Fund.
COVID-BioB Cohort Study: the neutralizing antibody response to SARS-CoV-2 in symptomatic COVID-19 is persistent and critical for virus control and survival
Authors: Dispinseri Stefania , Secchi Massimiliano , Pirillo Maria Franca , Tolazzi Monica , Borghi Martina , Brigatti Cristina , De Angelis Maria Laura , Baratella Marco , Bazzigaluppi Elena , Venturi Giulietta , Sironi Francesca , Canitano Andrea , Marzinotto Ilaria , Tresoldi Cristina , Ciceri Fabio , Piemonti Lorenzo , Negri Donatella , Cara Andrea , Lampasona Vito , Scarlatti Gabriella
Published: February 2021

Understanding how antibody to SARS-CoV-2 evolve during infection may provide important insight into therapeutic approaches to prevent fatal COVID-19 illness and vaccines. Here, we profile the antibody response of 162 well-characterized COVID-19 symptomatic patients followed longitudinally for up to eight months from symptom onset. Using two newly developed assays we detect SARS-CoV-2 neutralization and antibodies binding to Spike antigens and nucleoprotein as well as to Spike S2 antigen of seasonal beta-coronaviruses, and to hemagglutinin of the H1N1 flu virus. Presence of neutralizing antibodies withing the first weeks from symptom onset correlates with time to a negative swab result (p=0.002) while lack of neutralization with an increased risk of a fatal disease outcome (HR 2.918, 95%CI 1.321-6.449; p=0.008). Neutralizing antibody titers progressively drop after 5-8 weeks but are still detectable up to 8 months in the majority of recovered patients regardless of age or co-morbidities. IgG to Spike antigens are the best correlate of neutralization. Antibody responses to seasonal coronaviruses are temporary boosted and parallel those to SARS-CoV-2 without dampening the specific response or worsening disease progression. Thus, a compromised immune response to the Spike rather than an enhanced one is a major trait of patients with critical conditions. Patients should be promptly identified and immediately start therapeutic interventions aimed at restoring their immunity.
COVID-19 associated autoimmunity is a feature of severe respiratory disease - a Bayesian analysis
Authors: Trahtemberg Uriel , Rottapel Robert , dos Santos Claudia C , Di Battista Alex P , Slutsky Arthur S. , Baker Andrew J , Fritzler Marvin J
Published: February 2021

Background

Serological and clinical features with similarities to systemic autoimmunity have been reported in severe COVID-19, but there is a lack of studies that include contemporaneous controls who do not have COVID-19.

Methods

Observational cohort study of adult patients admitted to an intensive care unit with acute respiratory failure. Patients were divided into COVID+ and COVID− based on SARS-CoV-2 PCR from nasopharyngeal swabs and/or endotracheal aspirates. No COVID-19 specific interventions were given. The primary clinical outcome was death in the ICU within 3 months; secondary outcomes included in-hospital death and disease severity measures. Measurements including autoantibodies, were done longitudinally. ANOVA and Fisher’s exact test were used with α=0.05, with a false discovery rate of q=0.05. Bayesian analysis was performed to provide credible estimates of the possible states of nature compatible with our results.

Results

22 COVID+ and 20 COVID− patients were recruited, 69% males, median age 60.5 years. Overall, 64% had anti-nuclear antibodies, 38% had antigen-specific autoantibodies, 31% had myositis related autoantibodies, and 38% had high levels of anti-cytokine autoantibodies. There were no statistically significant differences between COVID+ and COVID− for any of the clinical or autoantibody parameters. A specific pattern of anti-nuclear antibodies was associated with worse clinical severity for both cohorts.

Conclusions

Severe COVID+ patients have similar humoral autoimmune features as comparably ill COVID− patients, suggesting that autoantibodies are a feature of critical illness regardless of COVID-19 status. The clinical significance of autoimmune serology and the correlation with severity in critical illness remains to be elucidated.
Host-virus chimeric events in SARS-CoV2 infected cells are infrequent and artifactual
Authors: Yan Bingyu , Chakravorty Srishti , Mirabelli Carmen , Wang Luopin , Trujillo-Ochoa Jorge L. , Chauss Daniel , Kumar Dhaneshwar , Lionakis Michail S. , Olson Matthew R , Wobus Christiane E. , Afzali Behdad , Kazemian Majid
Published: February 2021

Pathogenic mechanisms underlying severe SARS-CoV2 infection remain largely unelucidated. High throughput sequencing technologies that capture genome and transcriptome information are key approaches to gain detailed mechanistic insights from infected cells. These techniques readily detect both pathogen and host-derived sequences, providing a means of studying host-pathogen interactions. Recent studies have reported the presence of host-virus chimeric (HVC) RNA in RNA-seq data from SARS-CoV2 infected cells and interpreted these findings as evidence of viral integration in the human genome as a potential pathogenic mechanism. Since SARS-CoV2 is a positive sense RNA virus that replicates in the cytoplasm it does not have a nuclear phase in its life cycle, it is biologically unlikely to be in a location where splicing events could result in genome integration. Here, we investigated the biological authenticity of HVC events. In contrast to true biological events such as mRNA splicing and genome rearrangement events, which generate reproducible chimeric sequencing fragments across different biological isolates, we found that HVC events across >100 RNA-seq libraries from patients with COVID-19 and infected cell lines, were highly irreproducible. RNA-seq library preparation is inherently error-prone due to random template switching during reverse transcription of RNA to cDNA. By counting chimeric events observed when constructing an RNA-seq library from human RNA and spike-in RNA from an unrelated species, such as fruit-fly, we estimated that ~1% of RNA-seq reads are artifactually chimeric. In SARS-CoV2 RNA-seq we found that the frequency of HVC events was, in fact, not greater than this background “noise”. Finally, we developed a novel experimental approach to enrich SARS-CoV2 sequences from bulk RNA of infected cells. This method enriched viral sequences but did not enrich for HVC events, suggesting that the majority of HVC events are, in all likelihood, artifacts of library construction. In conclusion, our findings indicate that HVC events observed in RNA-sequencing libraries from SARS-CoV2 infected cells are extremely rare and are likely artifacts arising from either random template switching of reverse-transcriptase and/or sequence alignment errors. Therefore, the observed HVC events do not support SARS-CoV2 fusion to cellular genes and/or integration into human genomes.
The unexpected dynamics of COVID-19 in Manaus, Brazil: Was herd immunity achieved?
Authors: He Daihai , Artzy-Randrup Yael , Musa Salihu S. , Gräf Tiago , Naveca Felipe , Stone Lewi
Published: February 2021

In late March 2020, SARS-CoV-2 arrived in Manaus, Brazil, and rapidly developed into a large-scale epidemic that collapsed the local health system, and resulted in extreme death rates. Several key studies reported that ∼76% of residents of Manaus were infected (attack rate AR≃76%) by October 2020, suggesting protective herd immunity had been reached. Despite this, in November an unexpected second wave of COVID-19 struck again, and proved to be larger than the first creating a catastrophe for the unprepared population. It has been suggested that this could only be possible if the second wave was driven by reinfections. Here we use novel methods to model the epidemic from mortality data, evaluate the impact of interventions, in order to provide an alternative explanation as to why the second wave appeared. The method fits a “flexible” reproductive number R0(t) that changes over the epidemic, and found AR≃30-34% by October 2020, for the first wave, which is far less than required for herd immunity, yet in-line with recent seroprevalence estimates. The two-strain model provides an accurate fit to observed epidemic datasets, and finds AR≃70% by March 2021. Using genomic data, the model estimates transmissibility of the new P.1 virus lineage, as 1.9 times as transmissible as the non-P1. The model thus provides a reasonable explanation for the two-wave dynamics in Manaus, without the need to rely on reinfections which until now have only been found in small numbers in recent surveillance efforts.

Significance

This paper explores the concept of herd immunity and approaches for assessing attack rate during the explosive outbreak of COVID-19 in the city of Manaus, Brazil. The event has been repeatedly used to exemplify the epidemiological dynamics of the disease and the phenomenon of herd immunity, as claimed to be achieved by the end of the first wave in October 2020. A novel modelling approach reconstructs these events, specifically in the presence of interventions. The analysis finds herd immunity was far from being attained, and thus a second wave was readily possible, as tragically occurred in reality. Based on genomic data, the multi-strain model gives insights on the new highly transmissible variant of concern P.1 and role of reinfection.
Roadkill islands: carnivore extinction shifts seasonal use of roadside carrion by generalist avian scavenger
Authors: Fielding Matthew W. , Buettel Jessie C. , Brook Barry W. , Stojanovic Dejan , Yates Luke A.
Published: February 2021

Global road networks facilitate habitat modification and are integral to human expansion. Many animals, particularly scavengers, use roads as they provide a reliable source of food, such as carrion left after vehicle collisions. Tasmania is often cited as the ‘roadkill capital of Australia’, with the isolated offshore islands in the Bass Strait experiencing similar, if not higher, levels of roadkill. However, native mammalian predators on the islands are extirpated, meaning the remaining scavengers are likely to experience lower interference competition.

In this study, we use a naturally occurring experiment to examine how the loss of mammalian carnivores within a community impacts roadside foraging behaviour by avian scavengers.

We monitored the locations of roadkill and forest ravens (Corvus tasmanicus), an abundant scavenger species, on eight road transects across the Tasmanian mainland (high scavenging competition) and the Bass Strait islands (low scavenging competition). We represented raven observations as one-dimensional point patterns, using hierarchical Bayesian models to investigate the dependence of raven spatial intensity on habitat, season, distance to roadkill and route location.

We found that roadkill carcasses were a strong predictor of raven presence along road networks. The effect of roadkill was amplified on roads on the Bass Strait islands, where roadside carrion was a predictor of raven presence across the entire year. In contrast, ravens were more often associated with roadkill on Tasmanian mainland roads in the autumn, when other resources were low. This suggests that in the absence of competing mammalian scavengers, ravens choose to feed on roadside carrion throughout the year, even in seasons when other resources are available. This low interference competition could be disproportionately benefiting forest ravens, leading to augmented raven populations and changes to the vertebrate community structure.

Our study provides evidence that scavengers modify their behaviour in response to reduced scavenger species diversity, potentially triggering trophic shifts and highlighting the importance of conserving or reintroducing carnivores within ecosystems.
ClusterMap: multi-scale clustering analysis of spatial gene expression
Authors: He Yichun , Tang Xin , Huang Jiahao , Zhou Haowen , Chen Kevin , Liu Albert , Ren Jingyi , Shi Hailing , Lin Zuwan , Li Qiang , Aditham Abhishek , Shu Jian , Liu Jia , Wang Xiao
Published: February 2021

Quantifying RNAs in their spatial context is crucial to understanding gene expression and regulation in complex tissues.In situtranscriptomic methods generate spatially resolved RNA profiles in intact tissues. However, there is a lack of a unified computational framework for integrative analysis ofin situtranscriptomic data. Here, we present an unsupervised and annotation-free framework, termed ClusterMap, which incorporates physical proximity and gene identity of RNAs, formulates the task as a point pattern analysis problem, and thus defines biologically meaningful structures and groups. Specifically, ClusterMap precisely clusters RNAs into subcellular structures, cell bodies, and tissue regions in both two- and three-dimensional space, and consistently performs on diverse tissue types, including mouse brain, placenta, gut, and human cardiac organoids. We demonstrate ClusterMap to be broadly applicable to variousin situtranscriptomic measurements to uncover gene expression patterns, cell-cell interactions, and tissue organization principles from high-dimensional transcriptomic images.
Brain endothelial CXCL12 attracts protective Natural Killer cells during ischemic stroke
Authors: Wang Shuaiwei , de Fabritus Lauriane , Kumar Praveen Ashok , Werner Yves , Siret Carole , Simic Milesa , Kerdiles Yann M. , Stumm Ralf , van de Pavert Serge A.
Published: February 2021

Innate lymphoid cells (ILCs) have a function in homeostasis and immune responses, but their role in ischemic brain insult is unknown. Here, we report that ILCs are not resident within the mouse brain parenchyma during steady-state conditions, but are attracted after ischemic stroke. Specifically, we identified NK cells, ILC1s, ILC2s and ILC3s within the lesion, the highest influx being observed for NK cells and ILC1s. We further show that Cxcl12 expressed at the blood-brain barrier is essential for NK cells and NKp46+ILC3s to migrate toward the lesion. Complementary,Cxcr4-deficiency in NK cells prevented NK cells from entering the infarct area. The lack of NK cell migration resulted in a higher neurological deficit in the beam-walk sensorimotor test. Our data show a new role for blood-brain barrier-derived Cxcl12 in attracting protective NK cells to ischemic brain lesions and identifies a new Cxcl12/ Cxcr4-mediated component of the innate immune response to stroke.
Deep Learning-Based Approaches for Decoding Motor Intent from Peripheral Nerve Signals
Authors: Luu Diu Khue , Nguyen Anh Tuan , Jiang Ming , Xu Jian , Drealan Markus W. , Cheng Jonathan , Keefer Edward W. , Zhao Qi , Yang Zhi
Published: February 2021

The ultimate goal of an upper-limb neuroprosthesis is to achieve dexterous and intuitive control of individual fingers. Previous literature shows that deep learning (DL) is an effective tool to decode the motor intent from neural signals obtained from different parts of the nervous system. However, it still requires complicated deep neural networks that are inefficient and not feasible to work in real-time. Here we investigate different approaches to enhance the efficiency of the DL-based motor decoding paradigm. First, a comprehensive collection of feature extraction techniques is applied to reduce the input data dimensionality. Next, we investigate two different strategies for deploying DL models: a one-step (1S) approach when big input data are available and a two-step (2S) when input data are limited. With the 1S approach, a single regression stage predicts the trajectories of all fingers. With the 2S approach, a classification stage identifies the fingers in motion, followed by a regression stage that predicts those active digits’ trajectories. The addition of feature extraction substantially lowers the motor decoder’s complexity, making it feasible for translation to a real-time paradigm. The 1S approach using a recurrent neural network (RNN) generally gives better prediction results than all the ML algorithms with mean squared error (MSE) ranges from 10−3to 10−4for all finger while variance accounted for (VAF) scores are above 0.8 for the most degree of freedom (DOF). This result reaffirms that DL is more advantageous than classic ML methods for handling a large dataset. However, when training on a smaller input data set as in the 2S approach, ML techniques offers a simpler implementation while ensuring comparably good decoding outcome to the DL ones. In the classification step, either machine-learning (ML) or DL models achieve the accuracy and F1 score of 0.99. Thanks to the classification step, in the regression step, both types of models result in comparable MSE and VAF scores as those of the 1S approach. Our study outlines the trade-offs to inform the implementation of real-time, low-latency, and high accuracy DL-based motor decoder for clinical applications.
A Combination Adjuvant for the Induction of Potent Antiviral Immune Responses for a Recombinant SARS-CoV-2 Protein Vaccine
Authors: Jangra Sonia , Landers Jeffrey J. , Rathnasinghe Raveen , O’Konek Jessica J. , Janczak Katarzyna W. , Cascalho Marilia , Kennedy Andrew A. , Tai Andrew W. , Baker James R. , Schotsaert Michael , Wong Pamela T.
Published: February 2021

Several SARS-CoV-2 vaccines have received EUAs, but many issues remain unresolved, including duration of conferred immunity and breadth of cross-protection. Adjuvants that enhance and shape adaptive immune responses that confer broad protection against SARS-CoV-2 variants will be pivotal for long-term protection. We developed an intranasal, rationally designed adjuvant integrating a nanoemulsion (NE) that activates TLRs and NLRP3 with an RNA agonist of RIG-I (IVT DI). The combination adjuvant with spike protein antigen elicited robust responses to SARS-CoV-2 in mice, with markedly enhanced TH1-biased cellular responses and high virus-neutralizing antibody titers towards both homologous SARS-CoV-2 and a variant harboring the N501Y mutation shared by B1.1.7, B.1.351 and P.1 variants. Furthermore, passive transfer of vaccination-induced antibodies protected naive mice against heterologous viral challenge. NE/IVT DI enables mucosal vaccination, and has the potential to improve the immune profile of a variety of SARS-CoV-2 vaccine candidates to provide effective cross-protection against future drift variants.
MethReg: estimating the regulatory potential of DNA methylation in gene transcription
Authors: Silva Tiago C. , Young Juan I. , Martin Eden R. , Chen Xi , Wang Lily
Published: February 2021

Epigenome-wide association studies (EWAS) often detect a large number of differentially methylated sites or regions, many are located in distal regulatory regions. To further prioritize these significant sites, there is a critical need to better understand the functional impact of CpG methylation. Recent studies demonstrated CpG methylation-dependent transcriptional regulation is a widespread phenomenon. Here we present MethReg, an R/Bioconductor package that analyzes matched DNA-methylation and gene-expression data, along with external transcription factor (TF) binding information, to evaluate, prioritize, and annotate CpG sites with high regulatory potential. By simultaneous modeling three key elements that contribute to gene transcription (CpG methylation, target gene expression and TF activity), MethReg identifies TF-target gene associations that are present only in a subset of samples with high (or low) methylation levels at the CpG that influences TF activities, which can be missed in analyses that use all samples. Using real colorectal cancer and Alzheimer’s disease datasets, we show MethReg significantly enhances our understanding of the regulatory roles of DNA methylation in complex diseases.
Ultrastructural analysis of dendritic spine necks reveals a continuum of spine morphologies
Authors: Ofer Netanel , Berger Daniel R. , Kasthuri Narayanan , Lichtman Jeff W. , Yuste Rafael
Published: February 2021

Dendritic spines are membranous protrusions, with a bulbous head connected to the dendrite by a thin neck, and receive essentially all excitatory inputs in most mammalian neurons. Spines have a wide variety of morphologies that likely have a significant effect on their biochemical and electrical properties. The question of whether spines belong to distinct morphological or functional subtypes or constitute a continuum is still open. To discern this, it is important to measure spine necks objectively. Recent advances in electron microscopy enable automatic reconstructions of 3D spines with nanometer precision. Analyzing ultrastructural reconstructions from mouse neocortical neurons with computer vision algorithms, we demonstrate that the vast majority of spines can be rigorously separated into head and neck components. Analysis of the head and neck morphologies reveals a continuous distribution of parameters. The spine neck diameter, but not the neck length, was correlated with the head volume. Spines with larger head volumes often had a spine apparatus and pairs of spines in a post-synaptic cell contacted by the same axon had similar head volumes. Our data are consistent with a lack of morphological categories of spines and indicate that the morphologies of the spine neck and head are independently regulated. These results have repercussions for our understanding of the function of dendritic spines in neuronal circuits.
Latching dynamics as a basis for short-term recall
Authors: Ryom Kwang Il , Boboeva Vezha , Soldatkina Oleksandra , Treves Alessandro
Published: February 2021

We discuss simple models for the transient storage in short-term memory of cortical patterns of activity, all based on the notion that their recall exploits the natural tendency of the cortex to hop from state to state – latching dynamics. We show that in one such model, and in simple spatial memory tasks we have given to human subjects, short-term memory can be limited to similar low capacity by interference effects, in tasks terminated by errors, and can exhibit similar sublinear scaling, when errors are overlooked. The same mechanism can drive serial recall if combined with weak order-encoding plasticity. Finally, even when storing randomly correlated patterns of activity the network demonstrates correlation-driven latching waves, which are reflected at the outer extremes of pattern space.
Membrane-binding mechanism of the EEA1 FYVE domain revealed by multi-scale molecular dynamics simulations
Authors: Larsen Andreas Haahr , Tata Lilya , John Laura , Sansom Mark S.P.
Published: February 2021

Early Endosomal Antigen 1 (EEA1) is a key protein in endosomal trafficking and is implicated in both autoimmune and neurological diseases. The C-terminal FYVE domain of EEA1 binds endosomal membranes, which contain phosphatidylinositol-3-phosphate (PI(3)P). Although it is known that FYVE binds PI(3)P specifically, it has not previously been described of how FYVE attaches and binds to endosomal membranes. In this study, we employed both coarse-grained (CG) and atomistic (AT) molecular dynamics (MD) simulations to determine how FYVE binds to PI(3)P-containing membranes. CG-MD showed that the dominant membrane binding mode resembles the crystal structure of EEA1 FYVE domain in complex with inositol-1,3-diphospate (PDB ID 1JOC). FYVE, which is a homodimer, binds the membrane via a hinge mechanism, where the C-terminus of one monomer first attaches to the membrane, followed by the C-terminus of the other monomer. The total binding energy is 70 kJ/mol, of which 50-60 kJ/mol stems from specific PI(3)P-interactions. By AT-MD, we could partition the binding mode into two types: (i) adhesion by electrostatic FYVE-PI(3)P interaction, and (ii) insertion of amphipathic loops. The AT simulations also demonstrated flexibility within the FYVE homodimer between the C-terminal heads and coiled-coil stem, allowing binding via a mechanism resembling that of a suction cup connected to a locally rigid stem via a flexible hinge.
Muscle-specific economy of force generation and efficiency of work production during human running
Authors: Bohm Sebastian , Mersmann Falk , Santuz Alessandro , Schroll Arno , Arampatzis Adamantios
Published: February 2021

Human running features a spring-like interaction of body and ground, enabled by elastic tendons that store mechanical energy and facilitate muscle operating conditions to minimize the metabolic cost. By experimentally assessing the operating conditions of two important muscles for running, the soleus and vastus lateralis, we investigated physiological mechanisms of muscle energy production and muscle force generation. Results showed that the soleus continuously shortened throughout the stance phase, operating as energy generator under conditions that were found to be optimal for work production: high force-length potential and enthalpy efficiency. The vastus lateralis promoted tendon energy storage and contracted nearly isometrically close to optimal length, resulting in a high force-length-velocity potential beneficial for economical force generation. The favorable operating conditions of both muscles were a result of an effective length and velocity-decoupling of fascicles and muscle-tendon unit mostly due to tendon compliance and, in the soleus, marginally by fascicle rotation.
ChEC-seq: a robust method to identify protein-DNA interactions genome-wide
Authors: Bruzzone Maria Jessica , Albert Benjamin , Hafner Lukas , Kubik Slawomir , Lezaja Aleksandra , Mattarocci Stefano , Shore David
Published: February 2021

Mittal et al. (2021; first brought to our attention in May 2019) have raised concerns regarding the Chromatin Endogenous Cleavage-sequencing (ChEC-seq) technique (Zentner et al., 2015) that may create a false impression that this method has fundamental flaws which prevent one from distinguishing between signal and noise. Although Mittal et al. focus on studies of the global co-activators SAGA, TFIID and Mediator that we were not involved in, we feel obliged to highlight here several of our own publications (Albert et al., 2019; Bruzzone et al., 2018; Hafner et al., 2018; Kubik et al., 2019; Kubik et al., 2018), as well as recent unpublished data, that employed ChEC-seq and directly addressed the observation raised by Mittal et al. that cleavage maps for various MNase fusion proteins often qualitatively resemble each other and those generated by “free” (unfused) MNase. Our studies lay out a clear path for determining sites of preferential factor localization by normalization of ChEC-seq experimental data to matched free-MNase controls. They also demonstrate the use of in vivo functional assays to assess ChEC-seq reliability and reveal examples where ChEC-seq identifies functional binding sites missed by conventional ChIP-seq analysis.
So you want to be a Super Researcher
Authors: Rathee Sanjay , Lee Sheah Lin
Published: February 2021

Publishing original scientific research is inherent to the work of a researcher. However, the pressure to maintain productivity and scientific impact can lead to research group publishing excessively, negatively affecting the mental health of a researcher. Ph.D. students and early career researchers are particularly susceptible to this pressure due to the inherent vulnerability of their positions. At present, there are no resources that concisely summarise the publication culture of a research group to help the researcher make an informed decision before joining. In this article, we present the ‘Super Researcher’ app, an R Shiny application(app) with a user-friendly interface. Using text-mining methodology to extract publicly available author data from Scopus, this pilot app has four fundamental functions to provide snapshot information that will help researchers grasp the publication culture of a research group within minutes. The ‘Super Researcher’ app provides information on: 1) institution data, 2) author’s publication, 3) co-author network plots and 4) publication journals.

The ‘Super Researcher’ app is built on R shiny which provides an interactive interface to users. This app utilizes the Big Data framework Apache Spark to mine relevant information from a huge author information database. The author’s information is stored and manipulated using both SQL(SQLite) and NoSQL(HBase) databases. Hbase is used for local data storage and manipulation while SQLite feeds data to the R Shiny interface.

In this paper, we introduce these functionalities and illustrate how this information can help guide a researcher to select a new Principle Investigator (PI) with better compatibility in terms of publication attitude using a case study. Available:https://researchmind.co.uk/super-researcher/
Rotavirus susceptibility of antibiotic-treated mice ascribed to diminished expression of interleukin-22
Authors: Schnepf Daniel , Hernandez Pedro , Mahlakõiv Tanel , Crotta Stefania , Sullender Meagan E. , Peterson Stefan T. , Ohnemus Annette , Michiels Camille , Gentle Ian , Dumoutier Laure , Reis Celso A. , Diefenbach Andreas , Wack Andreas , Baldridge Megan T. , Staeheli Peter
Published: February 2021

The commensal microbiota regulates susceptibility to enteric pathogens by fine-tuning mucosal innate immune responses, but how susceptibility to enteric viruses is shaped by the microbiota remains incompletely understood. Past reports have indicated that commensal bacteria may either promote or repress rotavirus replication in the small intestine of mice. We now report that rotavirus replicated more efficiently in the intestines of germ-free and antibiotic-treated mice compared to animals with an unmodified microbiota. Antibiotic treatment also facilitated rotavirus replication in type I and type III interferon (IFN) receptor-deficient mice, revealing IFN-independent proviral effects. Expression of interleukin-22 (IL-22) was strongly diminished in the intestine of antibiotic-treated mice. Treatment with exogenous IL-22 blocked rotavirus replication in microbiota-depleted wild-type andStat1-/-mice, demonstrating that the antiviral effect of IL-22 in animals with altered microbiome is not dependent on IFN signaling. In antibiotic-treated animals, IL-22-induced a specific set of genes includingFut2, encoding fucosyl-transferase 2 that participates in the biosynthesis of fucosylated glycans which can mediate rotavirus binding. Interestingly, IL-22 also blocked rotavirus replication in antibiotic-treatedFut2-/-mice. Furthermore, IL-22 inhibited rotavirus replication in antibiotic-treated mice lacking key molecules of the necroptosis or pyroptosis pathways of programmed cell death. Taken together, our results demonstrate that IL-22 determines rotavirus susceptibility of antibiotic-treated mice, yet the IL-22-induced effector molecules conferring rotavirus resistance remain elusive.
Biological convolutions improve DNN robustness to noise and generalisation
Authors: Evans Benjamin D. , Malhotra Gaurav , Bowers Jeffrey S.
Published: February 2021

Deep Convolutional Neural Networks (DNNs) have achieved superhuman accuracy on standard image classification benchmarks. Their success has reignited significant interest in their use as models of the primate visual system, bolstered by claims of their architectural and representational similarities. However, closer scrutiny of these models suggests that they rely on various forms of shortcut learning to achieve their impressive performance, such as using texture rather than shape information. Such superficial solutions to image recognition have been shown to make DNNs brittle in the face of more challenging tests such as noise-perturbed or out-of-domain images, casting doubt on their similarity to their biological counterparts. In the present work, we demonstrate that adding fixed biological filter banks, in particular banks of Gabor filters, helps to constrain the networks to avoid reliance on shortcuts, making them develop more structured internal representations and more tolerant to noise. Importantly, they also gained around 20 35% improved accuracy when generalising to our novel out-of-domain test image sets over standard end-to-end trained architectures. We take these findings to suggest that these properties of the primate visual system should be incorporated into DNNs to make them more able to cope with real-world vision and better capture some of the more impressive aspects of human visual perception such as generalisation.
Characterization and tissue localization of zebrafish homologs of the humanABCB1multidrug transporter
Authors: Robey Robert W. , Robinson Andrea N. , Ali-Rahmani Fatima , Huff Lyn M. , Lusvarghi Sabrina , Vahedi Shahrooz , Hotz Jordan , Warner Andrew C. , Butcher Donna , Matta Jennifer , Edmondson Elijah F. , Lee Tobie D. , Roth Jacob S. , Lee Olivia W. , Shen Min , Tanner Kandice , Hall Matthew D. , Ambudkar Suresh V. , Gottesman Michael M.
Published: February 2021

Given its similarities with mammalian systems, the zebrafish has emerged as a potential model to study the blood-brain barrier (BBB). Capillary endothelial cells at the human BBB express high levels of P-glycoprotein (P-gp, encoded by theABCB1gene) and ABCG2 (encoded by theABCG2gene). However, little information has been available about ATP-binding cassette transporters expressed at the zebrafish BBB. In this study, we focus on the characterization and tissue localization of two genes that are similar to humanABCB1, zebrafishabcb4andabcb5. Cytotoxicity assays with stably-transfected cell lines revealed that zebrafish Abcb5 cannot efficiently transport the substrates doxorubicin and mitoxantrone compared to human P-gp and zebrafish Abcb4. Additionally, zebrafish Abcb5 did not transport the fluorescent probes BODIPY-ethylenediamine or LDS 751, while they were readily transported by Abcb4 and P-gp. A high-throughput screen conducted with 90 human P-gp substrates confirmed that zebrafish Abcb4 has overlapping substrate specificity with P-gp. Basal ATPase activity of zebrafish Abcb4 and Abcb5 was comparable to that of human P-gp. In the brain vasculature, RNAscope probes to detectabcb4colocalized with staining by the P-gp antibody C219, whileabcb5was not detected. Zebrafishabcb4also colocalized with claudin-5 expression in brain endothelial cells. Abcb4 and Abcb5 had different tissue localizations in multiple zebrafish tissues, consistent with different functions. The data suggest that zebrafish Abcb4 most closely phenocopies P-gp and that the zebrafish may be a viable model to study the role of the multidrug transporter P-gp at the BBB.
Isolation and characterisation of bacteriophages with activity against invasive non-typhoidalSalmonellacausing bloodstream infection in Malawi
Authors: Rodwell Ella V. , Wenner Nicolas , Pulford Caisey V. , Cai Yueyi , Bowers-Barnard Arthur , Beckett Alison , Rigby Jonathan , Picton David M. , Blower Tim R. , Feasey Nicholas A. , Hinton Jay C. D. , Perez-Sepulveda Blanca M.
Published: February 2021

In recent years, novel lineages of invasive non-typhoidalSalmonella(iNTS) serovars Typhimurium and Enteritidis have been identified in patients with bloodstream infection in sub-Saharan Africa. Here, we isolated and characterised 32 phages capable of infectingS. Typhimurium andS. Enteritidis, from water sources in Malawi and the UK. The phages were classified in three major phylogenetic clusters that were geographically distributed. In terms of host range, Cluster 1 phages were able to infect all bacterial hosts tested, whereas Clusters 2 and 3 had a more restricted profile. Cluster 3 contained two sub-clusters, and 3.b contained the most novel isolates. This study represents the first exploration of the potential for phages to target the lineages ofSalmonellathat are responsible for bloodstream infections in sub-Saharan Africa.
TERRA transcription destabilizes telomere integrity to initiate break-induced replication in human ALT cells
Authors: Silva Bruno , Arora Rajika , Azzalin Claus M.
Published: February 2021

Alternative Lengthening of Telomeres (ALT) is a Break-Induced Replication (BIR)-based mechanism elongating telomeres in a subset of human cancer cells. While the notion that spontaneous DNA damage at telomeres is required for ALT to occur, the molecular triggers of this physiological telomere instability are largely unknown. We previously proposed that the telomeric long noncoding RNA TERRA may represent one such trigger; however, given the lack of tools to suppress TERRA transcription in cells, our hypothesis remained speculative. We have now developed Transcription Activator-Like Effectors able to rapidly inhibit TERRA transcription from multiple chromosome ends in an ALT cell line. TERRA transcription inhibition decreases marks of DNA replication stress and DNA damage at telomeres and impairs ALT activity and telomere length maintenance. We conclude that TERRA transcription actively destabilizes telomere integrity in ALT cells, thereby initiating BIR and supporting telomere elongation. Our data point to TERRA transcription manipulation as a potentially useful target for therapy.
CO2supply modulates lipid remodelling, photosynthetic and respiratory activities inChlorellaspecies
Authors: Cecchin Michela , Paloschi Matteo , Busnardo Giovanni , Cazzaniga Stefano , Cuine Stephan , Li-Beisson Yonghua , Wobbe Lutz , Ballottari Matteo
Published: February 2021

Microalgae represent potential solutions to reduce the atmospheric CO2level through photosynthesis. To boost CO2fixation by microalgae it is essential to understand physiologic and metabolic responses at the base of CO2assimilation and carbon flow. In this work twoTrebouxiophyceaespecies,Chlorella sorokinianaandChlorella vulgaris, were investigated for their metabolic responses to high and low CO2(air level) availability. High CO2availability resulted in an increase in biomass accumulation in both species but with a different chloroplast and mitochondrial responses. InC. sorokinianawe observed increased polar lipids and protein amount and a balanced NADPH redox state and a similar total respiration in the two conditions analysed. In contrast, inC. vulgarishigh CO2level caused an increase in TAG accumulation and a higher NADPH consumption suggesting a CO2dependent increase of reducing power consumption in the chloroplast, which in turn influences the redox state of the mitochondria by lowering total dark respiration. Several rearrangements of the photosynthetic machinery were observed in both species, which differ from those described for the model organismChlamydomonas reinhardtii. In the case ofC. reinhardtii, adaptation of the photosynthetic apparatus to different CO2availability relies on the translational repressor NAB1. NAB1 homologous protein could be identified only inC. vulgarisbut lacked the regulation mechanisms previously described inC. reinhardtii. These findings highlight that the acclimation strategies to cope with a fluctuating inorganic carbon supply are diverse among green microalgae and point to new biotechnological strategies to boost CO2fixation.

One sentence summary

High/low CO2availability induces cell responses as lipids remodelling, adaptations of the photosynthetic apparatus and modulation of mitochondrial respiration not conserved among green algae
Dopaminergic Ric GTPase activity impacts amphetamine sensitivity and sleep quality in a dopamine transporter-dependent manner inDrosophila melanogaster
Authors: Fagan Rita R. , Kearney Patrick J. , Luethi Dino , Bolden Nicholas C. , Sitte Harald H. , Emery Patrick , Melikian Haley E.
Published: February 2021

Dopamine (DA) is required for movement, sleep, and reward, and DA signaling is tightly controlled by the presynaptic DA transporter (DAT). Therapeutic and addictive psychostimulants, including methylphenidate (Ritalin; MPH), cocaine, and amphetamine (AMPH), markedly elevate extracellular DA via their actions as competitive DAT inhibitors (MPH, cocaine) and substrates (AMPH). DAT silencing in mice and invertebrates results in hyperactivity, reduced sleep, and blunted psychostimulant responses, highlighting DAT’s essential role in DA-dependent behaviors. DAT surface expression is not static; rather it is dynamically regulated by endocytic trafficking. PKC-stimulated DAT endocytosis requires the neuronal GTPase, Rit2, and Rit2 silencing in mouse DA neurons impacts psychostimulant sensitivity. However, it is unknown whether or not Rit2-mediated changes in psychostimulant sensitivity are DAT-dependent. Here, we leveragedDrosophila melanogasterto test whether theDrosophilaRit2 ortholog, Ric, impacts dDAT function, trafficking, and DA-dependent behaviors. Orthologous to hDAT and Rit2, dDAT and Ric directly interact, and the constitutively active Ric mutant Q117L increased dDAT surface levels and function in cell lines andex vivo Drosophilabrains. Moreover, DAergic RicQ117L expression caused sleep fragmentation in a DAT-dependent manner but had no effect on total sleep and daily locomotor activity. Importantly, we found that Rit2 is required for AMPH-stimulated DAT internalization in mouse striatum, and that DAergic RicQ117L expression significantly increasedDrosophilaAMPH sensitivity in a DAT-dependent manner, suggesting a conserved impact of Ric-dependent DAT trafficking on AMPH sensitivity. These studies support that the DAT/Rit2 interaction impacts both baseline behaviors and AMPH sensitivity, potentially by regulating DAT trafficking.