bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeted DamID inC. elegansreveals a role for LIN-22 and NHR-25 in epidermal cell differentiation
Authors: Katsanos Dimitris , Barkoulas Michalis
Published: December 2020

Transcription factors are key players in gene networks controlling cell fate specification during development. In multicellular organisms, they can display complex patterns of expression and binding to their targets, which necessitates tissue-specific characterisation of transcription factor-target interactions. Here, we focus onC. elegansseam cell development, which is used as a model of robust epidermal stem cell patterning. Despite our knowledge of multiple transcription factors playing a role in epidermal development, the composition of the gene network underlying cell fate patterning remains largely unknown. We introduce Targeted DamID (TaDa) that allows tissue-specific transcription factor target identification in intactC. elegansanimals without cell isolation. We employ this method to recover putative targets in the epidermis for two transcription factors, the HES1 homologue LIN-22 and the NR5A1/2 nuclear hormone receptor NHR-25. Using single-molecule FISH (smFISH), we validate TaDa predictions and reveal a role for these transcription factors in promoting cell differentiation, as well as an unusual link between a HES factor and the Wnt signalling pathway.

Our results expand our understanding of the epidermal gene network and highlight the power of TaDa to dissect the architecture of tissue-specific gene regulatory networks.
BLOCKADE OF M4 MUSCARINIC RECEPTORS ON STRIATAL CHOLINERGIC INTERNEURONS NORMALIZES STRIATAL DOPAMINE RELEASE IN A MOUSE MODEL OFTOR1ADYSTONIA
Authors: Downs Anthony M. , Donsante Yuping , Jinnah H.A. , Hess Ellen J.
Published: December 2020

Trihexyphenidyl (THP), a non-selective muscarinic receptor (mAChR) antagonist, is commonly used for the treatment of dystonia associated withTOR1A, otherwise known asDYT1dystonia. A better understanding of the mechanism of action of THP is a critical step in the development of better therapeutics with fewer side effects. We previously found that THP normalizes the deficit in striatal dopamine (DA) release in a mouse model ofTOR1Adystonia (Tor1a+/ΔEknockin (KI) mice), revealing a plausible mechanism of action for this compound, considering that abnormal DA neurotransmission is consistently associated with many forms of dystonia. However, the mAChR subtype(s) that mediate the rescue of striatal dopamine release remain unclear. In this study we used a combination of pharmacological challenges and cell-type specific mAChR conditional knockout mice of either sex to determine which mAChR subtypes mediate the DA release-enhancing effects of THP. We determined that THP acts in part at M4 mAChR on striatal cholinergic interneurons to rescue DA release in bothTor1a+/+andTor1a+/ΔEKI mice. Further, we found that the subtype selective M4 antagonist VU6021625 recapitulates the effects of THP. These data implicate a principal role for M4 mAChR located on striatal cholinergic interneurons in the mechanism of action of THP and suggest that subtype selective M4 mAChR antagonists may be effective therapeutics with fewer side effects than THP for the treatment ofTOR1Adystonia.
Probing T-cell response by sequence-based probabilistic modeling
Authors: Bravi Barbara , Balachandran Vinod P. , Greenbaum Benjamin D. , Walczak Aleksandra M. , Mora Thierry , Monasson Rémi , Cocco Simona
Published: December 2020

With the increasing ability to use high-throughput next-generation sequencing to quantify the diversity of the human T cell receptor (TCR) repertoire, the ability to use TCR sequences to infer antigen-specificity could greatly aid potential diagnostics and therapeutics. Here, we use a machine-learning approach known as Restricted Boltzmann Machine to develop a sequence-based inference approach to identify antigen-specific TCRs. Our approach combines probabilistic models of TCR sequences with clone abundance information to extract TCR sequence motifs central to an antigen-specific response. We use this model to identify patient personalized TCR motifs that respond to individual tumor and infectious disease antigens, and to accurately discriminate specific from non-specific responses. Furthermore, the hidden structure of the model results in an interpretable representation space where TCRs responding to the same antigen cluster, correctly discriminating the response of TCR to different viral epitopes. The model can be used to identify condition specific responding TCRs. We focus on the examples of TCRs reactive to candidate neoantigens and selected epitopes in experiments of stimulated TCR clone expansion.

Author Summary

Large repertoires of immune cells, such as T cells, are increasingly made available by high-throughput sequencing. Exploiting such datasets to infer how T-cell respond to antigens could help design vaccines and adoptive T-cell therapies. We here propose an approach based on probabilistic machine learning to identify and characterize responding T cells. After learning, this approach is able to distinguish clones that specifically respond to different antigen stimulations. The model parameters and the low-dimensional representations of the T-cell sequences identify sequence motifs underlying T-cell recognition at the molecular level. The approach is illustrated on repertoire data describingin vitrostimulation of T cells by cancer-related neoantigens, as well as on data for common infectious diseases.
Megadepth: efficient coverage quantification for BigWigs and BAMs
Authors: Wilks Christopher , Ahmed Omar , Baker Daniel N. , Zhang David , Collado-Torres Leonardo , Langmead Ben
Published: December 2020

Motivation

A common way to summarize sequencing datasets is to quantify data lying within genes or other genomic intervals. This can be slow and can require different tools for different input file types.

Results

Megadepth is a fast tool for quantifying alignments and coverage for BigWig and BAM/CRAM input files, using substantially less memory than the next-fastest competitor. Megadepth can summarize coverage within all disjoint intervals of the Gencode V35 gene annotation for more than 19,000 GTExV8 BigWig files in approximately one hour using 32 threads. Megadepth is available both as a command-line tool and as an R/Bioconductor package providing much faster quantification compared to the rtracklayer package.

Availability

https://github.com/ChristopherWilks/megadepth,https://bioconductor.org/packages/megadepth.

Contact

chris.wilks@jhu.edu
Application of the anatomical fiducials framework to a clinical dataset of patients with Parkinson’s disease
Authors: Abbass Mohamad , Gilmore Greydon , Taha Alaa , Chevalier Ryan , Jach Magdalena , Peters Terry M. , Khan Ali R. , Lau Jonathan C.
Published: December 2020

Establishing spatial correspondence between subject and template images is necessary in neuroimaging research and clinical applications such as brain mapping and stereotactic neurosurgery. Our anatomical fiducials (AFIDs) framework has recently been validated to serve as a quantitative measure of image registration based on salient anatomical features. In this study, we sought to apply the AFIDs protocol to the clinic, focusing on structural magnetic resonance images obtained from patients with Parkinson’s Disease (PD). We confirmed AFIDs could be placed to millimetric accuracy in the PD dataset with results comparable to those in normal control subjects. We evaluated subject-to-template registration using this framework by aligning the clinical scans to standard template space using a robust open preprocessing workflow. We found that registration errors measured using AFIDs were higher than previously reported, suggesting the need for optimization of image processing pipelines for clinical grade datasets. Finally, we examined the utility of using point-to-point distances between AFIDs as a morphometric biomarker of PD, finding evidence of reduced distances between AFIDs that circumscribe regions known to be affected in PD including the substantia nigra. Overall, we provide evidence that AFIDs can be successfully applied in a clinical setting and utilized to provide localized and quantitative measures of registration error. AFIDs provide clinicians and researchers with a common, open framework for quality control and validation of spatial correspondence and the location of anatomical structures, facilitating aggregation of imaging datasets and comparisons between various neurological conditions.
The chaperonin GroESL facilitatesCaulobacter crescentuscell division by supporting the function of the actin homologue FtsA
Authors: Schroeder Kristen , Heinrich Kristina , Neuwirth Ines , Jonas Kristina
Published: December 2020

The highly conserved chaperonin GroESL performs a crucial role in protein folding, however the essential cellular pathways that rely on this chaperone are underexplored. Loss of GroESL leads to severe septation defects in diverse bacteria, suggesting the folding function of GroESL may be integrated with the bacterial cell cycle at the point of cell division. Here, we describe new connections between GroESL and the bacterial cell cycle, using the model organismCaulobacter crescentus. Using a proteomics approach, we identify candidate GroESL client proteins that become insoluble or are degraded specifically when GroESL folding is insufficient, revealing several essential proteins that participate in cell division and peptidoglycan biosynthesis. We demonstrate that other cell cycle events such as DNA replication and chromosome segregation are able to continue when GroESL folding is insufficient, and find that deficiency of the bacterial actin homologue FtsA function mediates the GroESL-dependent block in cell division. Our data suggest that a GroESL-FtsA interaction is required to maintain normal dynamics of the FtsZ scaffold and divisome functionality inC. crescentus. In addition to supporting FtsA function, we show that GroESL is required to maintain the flow of peptidoglycan precursors into the growing cell wall. Linking a chaperone to cell division may be a conserved way to coordinate environmental and internal cues that signal when it is safe to divide.

Importance

All organisms depend on mechanisms that protect proteins from misfolding and aggregation. GroESL is a highly conserved molecular chaperone that functions to prevent protein aggregation in organisms ranging from bacteria to humans. Despite detailed biochemical understanding of GroESL function, thein vivopathways that strictly depend on this chaperone remain poorly defined in most species. This study provides new insights into how GroESL is linked to the bacterial cell division machinery, a crucial target of current and future antimicrobial agents. We identify a functional interaction between GroESL and FtsA, a conserved bacterial actin homologue, suggesting that as in eukaryotes, some bacteria exhibit a connection between cytoskeletal actin proteins and chaperonins. Our work further defines how GroESL is integrated with cell wall synthesis, and illustrates how highly conserved folding machines ensure the functioning of fundamental cellular processes during stress.
Risk of thrombotic complications in influenza versus COVID-19 hospitalized patients
Authors:   Dutch COVID & Thrombosis Coalition (DCTC), Huisman MV , Stals Milou AM , Grootenboers Marco JJH , van Guldener Coen , Kaptein Fleur HJ , Braken Sander JE , Chen Qingui , Chu Gordon , van Driel Erik M , Iglesias del Sol Antonio , de Jonge Evert , Kant K Merijn , Pals Fleur , Toorop Myrthe MA , Cannegieter Suzanne C , Klok Frederikus A
Published: December 2020

Background

Whereas accumulating studies on COVID-19 patients report high incidences of thrombotic complications, large studies on clinically relevant thrombosis in patients with other respiratory tract infections are lacking. How this high risk in COVID-19 patients compares to those observed in hospitalized patients with other viral pneumonias such as influenza is unknown.

Objectives

To assess the incidence of venous and arterial thrombotic complications in hospitalized influenza patients as opposed to that observed in hospitalized COVID-19 patients.

Methods

Retrospective cohort study; we used data from Statistics Netherlands (study period: 2018) on thrombotic complications in hospitalized influenza patients. In parallel, we assessed the cumulative incidence of thrombotic complications – adjusted for competing risk of death - in patients with COVID-19 in three Dutch hospitals (February 24th - April 26th 2020).

Results

Of the 13.217 hospitalized influenza patients, 437 (3.3%) were diagnosed with thrombotic complications, versus 66 (11%) of the 579 hospitalized COVID-19 patients. The 30-day cumulative incidence of any thrombotic complication in influenza was 11% (95%CI 9.4-12) versus 25% (95%CI 18-32) in COVID-19. For venous thrombotic complications (VTE) and arterial thrombotic complications alone, these numbers were respectively 3.6% (95%CI 2.7-4.6) and 7.5% (95%CI 6.3-8.8) in influenza versus 23% (95%CI 16-29) and 4.4% (95%CI 1.9-8.8) in COVID-19.

Conclusions

The incidence of thrombotic complications in hospitalized influenza patients was lower than in hospitalized COVID-19 patients. This difference was mainly driven by a high risk of VTE complications in the COVID-19 patients admitted to ICU. Remarkably, influenza patients were more often diagnosed with arterial thrombotic complications.

Essentials

It is unknown how COVID-19 compares to patients with other virus infections regarding thrombosis.

Hospitalized patients with influenza and COVID-19 were evaluated and compared to each other.

30-day cumulative incidence of thrombosis was lower in influenza (11%) than in COVID-19 (25%).

Difference was mainly driven by a high risk of VTE in COVID-19 patients admitted to the ICU.
The COSEVAST Study: Unravelling the role of Arterial Stiffness in COVID-19 Disease severity
Authors: Kumar Sanjeev , Kumar Neeraj , Kumar Abhyuday , Bhushan Divendu , Kumar Amarjeet , Kumar Ajeet , Singh Veena , Singh Prabhat Kumar
Published: December 2020

Background

Based on the detailed review of available research and case studies reported in reputed international journals, it can be concluded that endothelial damage (En-dotheliitis) both in small and large arteries may be an important factor of morbidity and mortality in COVID-19 patients. Arterial stiffness due to Endothelial Dysfunction has been established as an independent and specific marker of various chronic cardiovascular diseases.

Objective

Our objective was to examine functional impairment of the arteries in COVID-19 disease and establish the non-invasive measurement of Arterial Stiffness as an independent marker of disease severity.

Methods

We recorded the Arterial Stiffness of 23 Mild, 21 Moderate and 20 Severe COVID-19 patients grouped on latest NIH severity criteria. We observed Arterial Stiffness of COVID-19 patients with standard parameters like non-invasive Carotid-Femoral Pulse Wave velocity (cfPWV), Age-Normalized increase in cfPWV (ANI_cfPWV).

Results

Moderate and Severe COVID-19 patients have extremely elevated arterial stiffness than Mild patients. In Mild patients, cfPWV (829.1 ± 139.2 cm/s) was extremely significantly lower than both Moderate (1067 ± 152.5 cm/s, P< 0.0001) and Severe (1416 ± 253.9 cm/s, P < 0.0001) patients. ANI_cfPWV in Moderate and Severe patients was significantly higher than Mild patients. (Mild: 101.2 ± 126.1 cm/s; Moderate: 279 ± 114.4 cm/s; Severe: 580.1 ± 216.4 cm/s; intergroup P <0.0001). Conclusion: Our findings strongly suggest that arterial stiffness can be an independent and accurate marker for objective risk stratification and therapeutic alleviation of the acute cardiovascular complications like MODS in COVID-19.
Impact of MEK inhibitor therapy on neurocognition in neurofibromatosis type 1
Authors: Walsh Karin S. , Wolters Pamela L. , Widemann Brigitte C. , del Castillo Allison A. , Sady Maegan D. , Inker Tess , Roderick Marie Claire , Martin Staci , Toledo-Tamula Mary Anne , Struemph Kari , Paltin Iris , Collier Victoria , Mullin Kathy , Fisher Michael J. , Packer Roger J.
Published: December 2020

Objective

NF1-associated cognitive impairments carry significant life-long morbidity. The lack of targeted biologic treatments remains a significant unmet need. We examine changes in cognition in patients with NF1 in the first 48 weeks of MEK inhibitor (MEKi) treatment.

Methods

59 NF1 patients ages 5-27 on a MEKi clinical trial treating plexiform neurofibroma underwent pre-treatment and follow-up cognitive assessments over 48-weeks of treatment. Performance tasks (Cogstate) and observer-reported functioning (BRIEF) were primary outcomes. Group-level (pairedt-tests) and individual-level analyses (reliable change index; RCI) were used.

Results

Analysis showed statistically significant improvements on BRIEF compared to baseline (24-week BRI:t(58)=3.03,p=.004,d=0.24; 48-week MCI:t(39)=2.70,p=.01,d=0.27). RCI indicated more patients had clinically significant improvement at 48-weeks than expected by chance (Chi Square=11.95,p=.001, OR=6.3). Group-level analyses indicated stable performance on Cogstate (p>.05). RCI statistics showed high proportions of improved working memory (24-weeksChi Square=8.36,p=.004, OR=4.6 and 48-weeksChi Square=9.34,p=.004, OR=5.3) but not visual learning/memory. Patients with baseline impairments on BRIEF were more likely to show significant improvement than non-impaired patients (24-weeks 46% v. 8%;Chi Square=9.54,p=.008, OR=9.22; 48-weeks 63% v. 16%;Chi Square=7.50,p=.02, OR=9.0).

Interpretation

Our data shows no evidence of neurotoxicity in 48-weeks of treatment with a MEKi and a potential clinical signal supporting future research of MEKi as a cognitive intervention.
SARS-CoV-2 infection, risk perception, behaviour, and preventive measures at schools in Berlin, Germany, during the early post-lockdown phase: A cross-sectional study
Authors: Hommes Franziska , Loon Welmoed van , Thielecke Marlene , Abramovich Igor , Lieber Sascha , Hammerich Ralf , Gehrke-Beck Sabine , Linzbach Elisabeth , Schuster Angela , von dem Busche Katja , Theuring Stefanie , Gertler Maximilian , Martinez Gabriela Equihua , Richter Joachim , Bergmann Clara , Bölke Alisa , Böhringer Falko , Mall Marcus A. , Rosen Alexander , Krannich Alexander , Keller Jan , Bethke Norma , Kurzmann Marco , Kurth Tobias , Kirchberger Valerie , Seybold Joachim , Mockenhaupt Frank P.
Published: December 2020

Background

Briefly before the first peak of the COVID-19 pandemic in Berlin, Germany, schools closed in mid-March 2020 for six weeks. Following re-opening, schools gradually resumed operation at a reduced level for nine weeks preceding the summer holidays.

Aim

During this phase, we conducted a situational assessment in schools among students and teachers as to infection status, symptoms, affective, behavioural, educational issues, and preventive measures.

Methods

At twenty-four randomly selected primary and secondary schools, one class each was examined. Oro-nasopharyngeal swabs and capillary blood samples were collected to assess SARS-CoV-2 infection (PCR) and specific IgG (ELISA), respectively. Medical history, household and schooling characteristics, leisure time activities, fear of infection, risk perception, hand hygiene, physical distancing, and facemask wearing were assessed.

Results

Among 535 participants (385 students, 150 staff), one teenager was SARS-CoV-2 infected (0.2%), and seven individuals exhibited specific IgG (1.3%); 16% reported symptoms upon examination, and 48% in the preceding 14 days. Compared to before the pandemic, the proportion of leisure time spent as screen-time increased, and the majority of primary school students reported reduced physical activity. Fear of infection and risk perception were relatively low, but acceptance of adapted health behaviours was high. Governmental preventive measures were adequately implemented, with primary schools performing better than secondary schools.

Conclusion

In this phase of rare infection and low seroreactivity, individual and school-level infection prevention and control measures were largely adhered to. Nevertheless, vigilance, continued and proactive preventive measures, and well-rehearsed reaction options are essential to cope with increasing pandemic activity.
Spatial Allocation of Scarce COVID-19 Vaccines*†‡
Authors: Castonguay François M. , Blackwood Julie C. , Howerton Emily , Shea Katriona , Sims Charles , Sanchirico James N.
Published: December 2020

The COVID-19 Vaccines Global Access (COVAX) is an initiative led by the World Health Organization (WHO) and other partners that aims for an equitable access of COVID-19 vaccines. Despite a potential heterogeneous disease burden across space, countries receiving allotments of vaccines via COVAX may want to follow WHO’s allocation rule and distribute vaccines to their jurisdictions based on the jurisdictions’ relative population size. Utilizing economic–epidemiological modeling, we benchmark the performance of thisad hocallocation rule by comparing it to the rule that minimizes the economic damages and expenditures over time, including a penalty cost representing the social costs of deviating from thead hocallocation. Under different levels of vaccine scarcity and different demographic characteristics, we consider scenarios where length of immunity and compliance to travel restrictions vary, and consider the robustness of the rules when assumptions regarding these factors are incorrect. The benefits from deviating are especially high when immunity is permanent, when there is compliance to travel restrictions, when the supply of vaccine is low, and when there is heterogeneity in demographic characteristics. Interestingly, a lack of compliance to travel restrictions pushes the optimal allocations of vaccine towards thead hocand improves the relative robustness of thead hocrule, as the mixing of the populations reduces the spatial heterogeneity in disease burden.

JEL Classification

C61, H12, H84, I18, Q54
The impact of the first UK Covid-19 lockdown on carers and people living with low prevalence dementia: results from the Rare Dementia Support survey
Authors: Suárez-González Aida , Harding Emma , Zimmerman Nikki , Hoare Zoe , Brotherhood Emilie , Crutch Sebastian
Published: December 2020

Introduction

The public health measures imposed to contain Covid-19 during the first UK lockdown resulted in significant changes in the provision of community support and care for people with dementia. People with low prevalence and young-onset dementias often experience non-memory, behavioural or neuropsychiatric symptoms that require specialised support.

Objective

We explored the impact of the first Covid-19 lockdown on people living with low prevalence and young-onset dementia and their carers in the UK.

Method

An online survey, including eleven questions about the impact of the lockdown on both the person with dementia and their family caregivers was conducted. Participants were people living with dementia and caregivers who are members of the UK national-reach organisation Rare Dementia Support.

Results

184 carers and 24 people with dementia completed the survey. People with dementia experienced worsening of cognitive symptoms (70%), ability to do things (62%) and well-being (57%) according to their carers. Carers also reported a reduction in the support received for caring (55%). 93% of carers of people living in care homes reported a reduction in their ability to provide care. 26% of carers reported changes in the medication of the person with dementia during the lockdown. 74% of people with dementia reported decreased ability to connect with people socially.

Conclusions

People with dementia experienced a worsening of dementia symptoms, removal of support and increased difficulty to connect with other people socially during the 1st wave of Covid-19. Carers encountered barriers to both receiving and providing support and a decline in their own mental health and well-being.

Key points

70 % of carers reported cognitive symptoms getting worse during the lockdown (e.g., the person with dementia being more disoriented and finding it more difficult to communicate).

26 % of carers reported a change (initiation or increase) in medication in the person with dementia during the lockdown.

79 % carers reported their own physical or mental health getting worse due to the lockdown. This increased to 93% when considering responses only from family carers of people living in care homes.

93 % of family carers of people living in care homes found it harder to continue providing care and support for their relative due to Covid-19.
Common X-chromosome variants are associated with Parkinson’s disease risk
Authors: Guen Yann Le , Napolioni Valerio , Belloy Michael E. , Yu Eric , Krohn Lynne , Ruskey Jennifer A. , Gan-Or Ziv , Kennedy Gabriel , Eger Sarah J. , Greicius Michael D.
Published: December 2020

Objective

Identify genetic variants on the X-chromosome associated with Parkinson’s disease (PD) risk.

Methods

We performed an X-chromosome-wide association study (XWAS) of PD risk by meta-analyzing results from sex-stratified analyses. To avoid spurious associations, we designed a specific harmonization pipeline for the X-chromosome and focused on a European ancestry sample. We included 11,324 cases, 280,060 controls, and 5,379 proxy cases, based on parental history of PD. Additionally, we tested the association of significant variants with: (i) PD risk in an independent replication with 1,564 cases and 2,467 controls, and (ii) putamen volume in 33,360 individuals from the UK Biobank.

Results

In the discovery meta-analysis, we identified: rs7066890 (OR=1.10 [1.06-1.14]; P=2.2×10−9) intron of GPM6B, and rs28602900 (OR=1.10 [1.07-1.14]; P=1.6×10−8) in a high gene density region including RPL10, ATP6A1, FAM50A, PLXNA3. The rs28602900 association with PD was replicated (OR=1.16 [1.03-1.30]; P=0.016) and shown to colocalize with a significant expression quantitative locus (eQTL) regulating RPL10 expression in the putamen and other brain tissues in GTEx. Additionally, the rs28602900 locus was found to be associated with reduced brain putamen volume. No results reached genome-wide significance in the sex-stratified analyses.

Interpretation

We report the first XWAS of PD and identify two genome-wide significant loci. The rs28602900 association replicated in an independent PD dataset and showed concordant effects in its association with putamen volume. Critically, rs26802900 is a significant eQTL of RPL10.These results support a role for ribosomal proteins in PD pathogenesis and show that the X-chromosome contributes to PD genetic risk.
Common variants at 21q22.3 locus influenceMX1gene expression and susceptibility to severe COVID-19
Authors: Andolfo Immacolata , Russo Roberta , Lasorsa Alessandro Vito , Cantalupo Sueva , Rosato Barbara Eleni , Bonfiglio Ferdinando , Frisso Giulia , Pasquale Abete , Cassese Gian Marco , Servillo Giuseppe , Esposito Gabriella , Gentile Ivan , Piscopo Carmelo , Villani Romolo , Fiorentino Giuseppe , Cerino Pellegrino , Buonerba Carlo , Pierri Biancamaria , Zollo Massimo , Iolascon Achille , Capasso Mario
Published: December 2020

The COVID-19 disease, caused by the SARS-Cov-2, presents a heterogeneous clinical spectrum. The risk factors do not fully explain the wide spectrum of disease manifestations, so it is possible that genetic factors could account for novel insights into its pathogenesis.

In our previous study, we hypothesized that common variants on chromosome 21, nearTMPRSS2andMX1genes, may be genetic risk factors associated to the different clinical manifestations of COVID-19. Here, we performed an in-depth genetic analysis of chromosome 21 exploiting the genome-wide association study data including 6,406 individuals hospitalized for COVID-19 and 902,088 controls with European genetic ancestry from COVID-19 Host Genetics Initiative. We found that five single nucleotide polymorphisms (SNPs) withinTMPRSS2and nearMX1gene show suggestive associations (P≤1×10−5) with severe COVID-19. All five SNPs replicated the association in two independent cohorts of Asian subjects while two and one out of the 5 SNPs replicated in African and Italian populations, respectively (P≤0.05). The minor alleles of these five SNPs correlated with a reduced risk of developing severe COVID-19 and increased level ofMX1expression in blood.

Our findings provide further evidence that host genetic factors can contribute to determine the different clinical presentations of COVID-19 and that MX1, an antiviral effector of type I and III interferon pathway, may be a potential therapeutic target.
Effects of obesity on serum levels of SARS-CoV-2-specific antibodies in COVID-19 patients
Authors: Frasca Daniela , Reidy Lisa , Cray Carolyn , Diaz Alain , Romero Maria , Kahl Kristin , Blomberg Bonnie B.
Published: December 2020

SARS-CoV-2 (Severe Acute Respiratory Syndrome Corona Virus-2), cause of COVID-19 (Coronavirus Disease of 2019), represents a significant risk to people living with pre-existing conditions associated with exacerbated inflammatory responses and consequent dysfunctional immunity. In this paper, we have evaluated the effects of obesity, a condition associated with chronic systemic inflammation, on the secretion of SARS-CoV-2-specific IgG antibodies in the blood of COVID-19 patients. Results have shown that SARS-CoV-2 IgG antibodies are negatively associated with Body Mass Index (BMI) in COVID-19 obese patients, as expected based on the known effects of obesity on humoral immunity. Antibodies in COVID-19 obese patients are also negatively associated with serum levels of pro-inflammatory and metabolic markers of inflammaging and pulmonary inflammation, such as SAA (serum amyloid A protein), CRP (C-reactive protein) and ferritin, but positively associated with NEFA (nonesterified fatty acids). These results altogether could help to identify an inflammatory signature with strong predictive value for immune dysfunction that could be targeted to improve humoral immunity in individuals with obesity as well as with other chronic inflammatory conditions.
De novo identification and visualization of important cell populations for classic Hodgkin lymphoma using flow cytometry and machine learning
Authors: Simonson Paul D. , Wu Yue , Wu David , Fromm Jonathan R. , Lee Aaron Y.
Published: December 2020

Objectives

Automated classification of flow cytometry data has the potential to reduce errors and accelerate flow cytometry interpretation. We desired a machine learning approach that is accurate, intuitively easy to understand, and highlights the cells that are most important in the algorithm’s prediction for a given case.

Methods

We developed an ensemble of convolutional neural networks (CNNs) for classification and visualization of impactful cell populations in detecting classic Hodgkin lymphoma, using two-dimensional (2D) histograms. Data from 977 and 245 clinical flow cytometry cases were used for training and testing, respectively. 78 non-gated 2D histograms were created per flow cytometry file. SHAP values were calculated to determine the most impactful 2D histograms and regions within the histograms. The SHAP values from all 78 histograms were then projected back to the original cells data for gating and visualization using standard flow cytometry software.

Results

The algorithm achieved 67.7% recall (sensitivity), 82.4 % precision, and 0.92 AUROC. Visualization of the important cell populations in making individual predictions demonstrated correlations with known biology.

Conclusions

The method presented enables model explainability while highlighting important cell populations in individual flow cytometry specimens, with potential applications in both diagnosis and discovery of previously overlooked key cell populations.
Autonomous sensing the insulin peptide by an olfactory G protein coupled receptor modulates glucose metabolism
Authors: Cheng Jie , Yang Zhao , Ge Xiao-Yan , Gao Ming-Xin , Meng Ran , Lin Jing-Yu , Tian Zhao-Mei , Xu Yun-Fei , Yang Fan , Sun Jin-Peng , Yu Xiao
Published: December 2020

Along with functionally intact insulin, diabetes-associated insulin peptides are secreted by β cells(1-3). By screening the expression and functional characterization of olfactory receptors in pancreatic islets, we identified Olfr109 as the receptor to detect insulin peptides. Engagement of one insulin peptide, insB:9-23, with Olfr109 diminished insulin secretion through Gi-cAMP signalling and promoted macrophage proliferation. Remarkably, Olfr109 deficiency alleviated intra-islet inflammatory responses and improved glucose homeostasis in Akita- and HFD-fed mice. We further determined the binding mode between the insB:9-23 and Olfr109. A pepducin-based Olfr109 antagonist improved glucose homeostasis in diabetic and obese mouse models. Collectively, we found that pancreatic β cells use Olfr109 to autonomously detect self-secreted insulin peptides and this detection arrests insulin secretion and crosstalk with macrophages to increase intra-islet inflammation.
Memory precision of object-location binding is unimpaired inAPOEε4-carriers with spatial navigation deficits
Authors: Gellersen Helena M. , Coughlan Gillian , Hornberger Michael , Simons Jon S.
Published: December 2020

Research suggests that tests of memory fidelity, feature binding and spatial navigation are promising for early detection of subtle behavioural changes related to Alzheimer’s disease (AD). In the absence of longitudinal data, one way of testing the early detection potential of cognitive tasks is through the comparison of individuals at different genetic risk for AD. Most studies have done so using samples aged 70 years or older. Here, we tested whether memory fidelity of long-term object-location binding may be a sensitive marker even among cognitively healthy individuals in their mid-60s by comparing participants at low and higher risk based on presence of the ε4-allele of the apolipoprotein gene (n=26 ε3ε3,n=20 ε3ε4 carriers). We used a continuous report paradigm in a visual memory task that required participants to recreate the spatial position of objects in a scene. We employed mixture modelling to estimate the two distinct memory processes that underpin the trial-by-trial variation in localisation errors: retrieval success which indexes the proportion of trials where participants recalled any information about an object’s position and the precision with which participants retrieved this information. Prior work has shown that these memory paradigms that separate retrieval success from precision are capable of detecting subtle differences in mnemonic fidelity even when retrieval success could not. Nonetheless, a Bayesian analysis found good evidence that ε3ε4 carriers did not remember fewer object locations (F(1, 42)=.450,p=.506, BF01=3.02), nor was their precision for the spatial position of objects reduced compared to ε3ε3 carriers (F(1, 42)=.12,p=.726, BF01=3.19). Because the participants in the sample presented here were a subset of a study onAPOEeffects on spatial navigation in the Sea Hero Quest game (Coughlan et al., 2019.PNAS, 116(9)), we obtained these data to contrastAPOEeffects on the two tasks within the same sample (n=33). Despite the smaller sample size, wayfinding deficits among ε3ε4 could be replicated (F(1, 33)=5.60,p=.024,BF10=3.44). Object-location memory metrics and spatial navigation scores were not correlated (allr<.25,p>.1, 0<BF10<3). These findings show spared object-location binding in the presence of a detrimentalAPOEε4 effect on spatial navigation. This suggests that the sensitivity of memory fidelity and binding tasks may not extend to individuals with one ε4-allele in their early to mid-60s. The results provide further support to prior proposals that spatial navigation may be a sensitive marker for the earliest AD-dependent cognitive changes, even before episodic memory.
Pollen sterols are associated with phylogenetics and environment but not with pollinators
Authors: Zu Pengjuan , Koch Hauke , Schwery Orlando , Pironon Samuel , Phillips Charlotte , Ondo Ian , Farrell Iain W. , Nes W. David , Moore Elynor , Wright Geraldine A. , Farman Dudley I. , Stevenson Philip C.
Published: December 2020

Phytosterols are primary plant metabolites that have fundamental structural and regulatory functions. They are also essential nutrients for phytophagous insects, including pollinators, that cannot synthesize sterols. Despite the well-described composition and diversity in vegetative plant tissues, few studies have examined phytosterol diversity in pollen.

We quantified 25 pollen phytosterols in 122 plant species (105 genera, 51 families) to determine their composition and diversity across plant taxa. We searched literature and databases for plant phylogeny, environmental conditions, and pollinator guilds of the species to examine the relationships with pollen sterols.

24-methylenecholesterol, sitosterol and isofucosterol were the most common and abundant pollen sterols. We found phylogenetic clustering of twelve individual sterols, total sterol content and sterol diversity, and of sterol groupings that reflect their underlying biosynthesis pathway (24 carbon alkylation, ring B desaturation). Plants originating in tropical-like climates (higher mean annual temperature, lower temperature seasonality, higher precipitation in wettest quarter) were more likely to record higher pollen sterol content. However, pollen sterol composition and content showed no clear relationship with pollinator guilds.

Our study is the first to show that pollen sterol diversity is phylogenetically clustered and that pollen sterol content may adapt to environmental conditions.
Single-cell transcriptomics and cell-specific proteomics reveals molecular signatures of sleep
Authors: Jha Pawan K. , Valekunja Utham K. , Ray Sandipan , Nollet Mathieu , Reddy Akhilesh B.
Published: December 2020

Every day, we sleep for a third of the day. Sleep is important for cognition, brain waste clearance, metabolism, and immune responses. The molecular mechanisms governing sleep are largely unknown. Here, we used a combination of single cell RNA sequencing and cell-type specific proteomics to interrogate the molecular underpinnings of sleep. Different cell types in three important brain regions for sleep (brainstem, cortex, and hypothalamus) exhibited diverse transcriptional responses to sleep need. Sleep restriction modulates astrocyte-neuron crosstalk and sleep need enhances expression of specific sets of transcription factors in different brain regions. In cortex, we also interrogated the proteome of two major cell types: astrocytes and neurons. Sleep deprivation differentially alters the expression of proteins in astrocytes and neurons. Similarly, phosphoproteomics revealed large shifts in cell-type specific protein phosphorylation. Our results indicate that sleep need regulates transcriptional, translational, and post-translational responses in a cell-specific manner.
Maternal reactivity of ewes at lambing is genetically linked to their behavioral reactivity in an arena test
Authors: Hazard Dominique , Kempeneers Amandine , Delval Eric , Bouix Jacques , Foulquie Didier , Boissy Alain
Published: December 2020

In sheep, the bond between the dam and her lambs is established during the first hours of a lamb s life. Genetic variability for behavioral reactivity of ewes assessed in an arena test performed 24 h after lambing has already been reported. However, there is no evidence that this reactivity represents the ewe s maternal reactivity at lambing in outdoor conditions. The objective of this study was to investigate whether or not the behavioral reactivity of ewes in the arena test is genetically related to their maternal reactivity measured at lambing. A total of 935 Romane ewes were studied. The maternal reactivity of ewes at the outdoor lambing site was recorded in response to a human approach and to the handling of the lambs. Their behavioral reactivity was also recorded 24 h post-lambing in the arena test that involved a separation from the litter and a human presence. Flight distance, aggressive reaction, time to restore contact with the litter at the lambing site and maternal behavior scores were moderately heritable (0.18 to 0.34), and vocalizations were slightly heritable (0.16). All of these behaviors were genetically correlated with the behavioral reactivity in the arena test. The highest genetic correlations (from 0.60 to 0.90) were found for maternal behavioral scores, flight distance and high-pitched bleats. In conclusion, behavioral reactivity in the arena test can be used to assess early maternal reactivity in standardized conditions. Such phenotyping could be used for genetic improvement of maternal behavior in sheep.
Development of an optimized and scalable method for isolation of umbilical cord blood-derived small extracellular vesicles for future clinical use
Authors: Cardoso R.M.S. , Rodrigues S.C. , Gomes C. F. , Duarte F.V. , Romao M. , Leal E.C. , Freire P.C. , Neves R. , Simões-Correia J.
Published: December 2020

Extracellular vesicles (EV) are a promising therapeutic tool in regenerative medicine. These particles were shown to accelerate wound healing, through delivery of regenerative mediators, such as microRNAs. Herein we describe an optimized and up-scalable process for the isolation of EV smaller than 200 nm (sEV), secreted by umbilical cord blood mononuclear cells (UCB-MNC) under ischemic conditions and propose quality control thresholds for the isolated vesicles, based on the thorough characterization of their protein, lipid and RNA content.

Ultrafiltration and size exclusion chromatography (UF/SEC) optimized methodology proved superior to traditional ultracentrifugation (UC), regarding production time, standardization, scalability, and vesicle yield. Using UF/SEC, we were able to recover approximately 400 times more sEV per mL of media than with UC, and up-scaling this process further increases EV yield by about 3-fold. UF/SEC-isolated sEV display many of the sEV/exosomes classical markers and are enriched in molecules with anti-inflammatory and regenerative capacity, such as hemopexin and miR-150. Accordingly, treatment with sEV promotes angiogenesis and extracellular matrix remodeling,in vitro. In vivo, UCB-MNC-sEV significantly accelerate skin regeneration in a mouse model of delayed wound healing.

The proposed isolation protocol constitutes a significant improvement compared to UC, the gold-standard in the field. Isolated sEV maintain their regenerative properties, whereas downstream contaminants are minimized. The use of UF/SEC allows for the standardization and up-scalability required for mass production of sEV to be used in a clinical setting.
Modeling population size independent tissue epigenomes by ChIL-seq with single-thin sections
Authors: Maehara Kazumitsu , Tomimatsu Kosuke , Harada Akihito , Tanaka Kaori , Sato Shoko , Okada Seiji , Handa Tetsuya , Kurumizaka Hitoshi , Kimura Hiroshi , Ohkawa Yasuyuki
Published: December 2020

Recent advances in omics studies have enabled analysis at the single-cell level; however, methods for analyzing the whole cell of large organs and tissues remain challenging. Here, we developed a method named tsChIL to understand the diverse cellular dynamics at the tissue level using high-depth epigenomic data. tsChIL allowed the analysis of a single tissue section and could reproducibly acquire epigenomic profiles from several types of tissues, based on the distribution of target epigenomic states, tissue morphology, and number of cells. The proposed method enabled the independent evaluation of changes in cell populations and gene activation of cells in regenerating skeletal muscle tissues, using a statistical model of RNA polymerase II distribution on gene loci. Thus, the integrative analysis by tsChIL can elucidatein vivocell-type dynamics of tissues.
Meta-analytic evidence for downregulation of the amygdala during working memory maintenance
Authors: de Voogd Lycia D. , Hermans Erno J.
Published: December 2020

The amygdala is a region critically implicated in affective processes. Downregulation of the amygdala is therefore one of the hallmarks of successful emotion regulation. Downregulation is thought to be established through top-down control of the executive control network over the amygdala. Such a reciprocal relationship, however, is not exclusive to cognitive regulation of emotion. It has recently been noted that any cognitively demanding task may downregulate the amygdala, including a standard working memory task. Here, using a coordinate-based meta-analysis based on an activation likelihood estimation (ALE), we examined whether a standard working memory task (i.e., a 2-back task) downregulates the amygdala similarly to a cognitive reappraisal task. Following the PRISMA guidelines, we included a total of 66 studies using a 2-back working memory task and 65 studies using a cognitive reappraisal task. We found that a standard 2-back working memory task indeed systematically downregulates the amygdala, and that deactivated clusters strongly overlap with those observed during a cognitive reappraisal task. This finding has important consequences for the interpretation of the underlying mechanism of the effects of cognitive reappraisal on amygdala activity: downregulation of amygdala during cognitive reappraisal might be due to the cognitively demanding nature of the task and not per se by the act of the reappraisal itself. Moreover, it raises the possibility of applying working memory tasks in a clinical setting as an alternative emotion regulation strategy.
Cell patterning by secretion-induced plasma membrane flows
Authors: Gerganova Veneta , Lamas Iker , Rutkowski David M. , Vještica Aleksandar , Castro Daniela Gallo , Vincenzetti Vincent , Vavylonis Dimitrios , Martin Sophie G
Published: December 2020

Cells self-organize using reaction-diffusion and fluid-flow principles. Whether bulk membrane flows contribute to cell patterning has not been established. Here, using mathematical modelling, optogenetics and synthetic probes, we show that polarized exocytosis causes lateral membrane flows away from regions of membrane insertion. Plasma membrane-associated proteins with sufficiently low diffusion and/or detachment rates couple to the flows and deplete from areas of exocytosis. In rod-shaped fission yeast cells, zones of Cdc42 GTPase activity driving polarized exocytosis are limited by GTPase activating proteins (GAPs). We show that membrane flows pattern the GAP Rga4 distribution and coupling of a synthetic GAP to membrane flows is sufficient to establish the rod shape. Thus, membrane flows induced by Cdc42-dependent exocytosis form a negative feedback restricting the zone of Cdc42 activity.

One Sentence Summary

Exocytosis causes bulk membrane flows that drag associated proteins and form a negative feedback restricting the exocytic site.