bluuebunny/crossref_metadata_2025 huggingface dataset:
SiCTeC: an inexpensive, easily assembled Peltier device for rapid temperature shifting during single-cell imaging
Authors: Knapp Benjamin D. , Zhu Lillian , Huang Kerwyn Casey
Published: May 2020

Single-cell imaging, combined with recent advances in image analysis and microfluidic technologies, have enabled fundamental discoveries of cellular responses to chemical perturbations that are often obscured by traditional liquid-culture experiments. Temperature is an environmental variable well known to impact growth and to elicit specific stress responses at extreme values; it is often used as a genetic tool to interrogate essential genes. However, the dynamic effects of temperature shifts have remained mostly unstudied at the single-cell level, due largely to engineering challenges related to sample stability, heatsink considerations, and temperature measurement and feedback. Additionally, the few commercially available temperature-control platforms are costly. Here, we report an inexpensive (<$110) and modularSingle-CellTemperatureController (SiCTeC) device for microbial imaging, based on straightforward modifications of the typical slide-sample-coverslip approach to microbial imaging, that controls temperature using a ring-shaped Peltier module and microcontroller feedback. Through stable and precise (±0.15 °C) temperature control, SiCTeC achieves reproducible and fast (1-2 min) temperature transitions with programmable waveforms between room temperature and 45 °C with an air objective. At the device’s maximum temperature of 89 °C, SiCTeC revealed thatEscherichia colicells progressively shrink and lose cellular contents. During oscillations between 30 °C and 37 °C, cells rapidly adapted their response to temperature upshifts. Furthermore, SiCTeC enabled the discovery of rapid morphological changes and enhanced sensitivity to substrate stiffness during upshifts to nonpermissive temperatures in temperature-sensitive mutants of cell-wall synthesis enzymes. Overall, the simplicity and affordability of SiCTeC empowers future studies of the temperature dependence of single-cell physiology.
An extracellular protein regulates patched-related/DAF-6-mediated sensory compartment formation inC. elegans
Authors: Hong Hui , Chen Huicheng , Zhang Yuxia , Wu Zhimao , Zhang Yingying , Zhang Yingyi , Hu Zeng , Zhang Jian , Lin Kun , Hu Jinghua , Wei Qing
Published: May 2020

Coordination of neurite extension with surrounding glia development is critical for neuronal function, but the underlying molecular mechanisms remain poorly understood. Through a genome-wide mutagenesis screen inC. elegans, we identifieddyf-4anddaf-6as two mutants sharing similar defects in dendrite extension. DAF-6 encodes a glia-specific patched-related membrane protein that plays vital roles in glial morphogenesis. We cloneddyf-4and found that DYF-4 encodes a glia-secreted extracellular protein. Intriguingly, DYF-4 colocalizes with DAF-6 along the glial channel. Further investigations revealed that DYF-4 directly interacts with DAF-6 and regulates its proper membrane localization. Notably, reported glial suppressors ofdaf-6could also restore dendrite elongation and ciliogenesis in bothdyf-4anddaf-6mutants. Collectively, our data suggest that secreted DYF-4 likely acts as a novel ligand/regulator for the patched-related receptor DAF-6 which promotes the proper formation of the glial channel and indirectly affects neurite extension and ciliogenesis.
Impact of emerging mutations on the dynamic properties the SARS-CoV-2 main protease: anin silicoinvestigation
Authors: Amamuddy Olivier Sheik , Verkhivker Gennady M. , Bishop Özlem Tastan
Published: May 2020

The new coronavirus (SARS-CoV-2) is a global threat to world health and its economy. Its main protease (Mpro), which functions as a dimer, cleaves viral precursor proteins in the process of viral maturation. It is a good candidate for drug development owing to its conservation and the absence of a human homolog. An improved understanding of the protein behaviour can accelerate the discovery of effective therapies in order to reduce mortality. 100 ns all-atom molecular dynamics simulations of 50 homology modelled mutant Mprodimers were performed at pH 7 from filtered sequences obtained from the GISAID database. Protease dynamics were analysed using RMSD, RMSF, Rg, the averagedbetweenness centralityand geometry calculations. Domains from each Mproprotomer were found to generally have independent motions, while the dimer-stabilising N-finger region was found to be flexible in most mutants. A mirrored interprotomer pocket was found to be correlated to the catalytic site using compaction dynamics, and can be a potential allosteric target. The high number of titratable amino acids of Mpromay indicate an important role of pH on enzyme dynamics, as previously reported for SARS-CoV. Independent coarse-grained Monte Carlo simulations suggest a link between rigidity/mutability and enzymatic function.
AMPK regulates cell shape of cardiomyocytes by modulating turnover of microtubules through CLIP-170
Authors: Yashirogi Shohei , Katayama Toru , Nagao Takemasa , Nishida Yuya , Kioka Hidetaka , Matsui Tsubasa S , Saito Shigeyoshi , Masumura Yuki , Tsukamoto Osamu , Kato Hisakazu , Yazawa Issei , Ueda Hiromichi , Yamaguchi Osamu , Yashiro Kenta , Yamazaki Satoru , Takashima Seiji , Shintani Yasunori
Published: May 2020

AMP-activated protein kinase (AMPK) is a multifunctional kinase that regulates microtubule (MT) dynamic instability through CLIP-170 phosphorylation; however, its physiological relevance in vivo remains to be elucidated. In this study, we identified an active form of AMPK localized at the intercalated discs in the heart, a specific cell-cell junction present between cardiomyocytes. A contractile inhibitor, MYK-461, prevented the localization of AMPK at the intercalated discs, and the effect was reversed by the removal of MYK-461, suggesting that the localization of AMPK is regulated by mechanical stress. Time-lapse imaging analysis revealed that the inhibition of CLIP-170 Ser-311 phosphorylation by AMPK leads to the accumulation of MTs at the intercalated discs. Interestingly, MYK-461 increased the individual cell area of cardiomyocytes in CLIP-170 phosphorylation-dependent manner. Moreover, heart-specific CLIP-170 S311A transgenic mice demonstrated elongation of cardiomyocytes along with accumulated MTs, leading to progressive decline in cardiac contraction. In conclusion, these findings suggest that AMPK regulates the cell shape and aspect ratio of cardiomyocytes by modulating the turnover of MTs through homeostatic phosphorylation of CLIP-170 at the intercalated discs.
The Arp1/11 Minifilament of Dynactin Primes the Endosomal Arp2/3 Complex
Authors: Fokin Artem I. , David Violaine , Oguievetskaia Ksenia , Derivery Emmanuel , Stone Caroline E. , Cao Luyan , Rocques Nathalie , Molinie Nicolas , Henriot Véronique , Aumont-Nicaise Magali , Hinckelmann Maria-Victoria , Saudou Frédéric , Le Clainche Christophe , Carter Andrew P. , Romet-Lemonne Guillaume , Gautreau Alexis M.
Published: May 2020

Dendritic actin networks develop from a first actin filament through branching by the Arp2/3 complex. At the surface of endosomes, the WASH complex activates the Arp2/3 complex and interacts with the Capping Protein for unclear reasons. Here we show that that the WASH complex interacts with Dynactin and uncaps it through its FAM21 subunit. In vitro, the uncapped Arp1/11 minifilament elongates an actin filament, which then primes the WASH-induced Arp2/3 branching reaction. In Dynactin-depleted cells or in cells where the WASH complex is reconstituted with a FAM21 mutant that cannot uncap Dynactin, formation of branched actin at the endosomal surface is impaired. Our results reveal the importance of the WASH complex in coordinating two complexes containing actin-related proteins.

One Sentence Summary

Dendritic actin networks grow in an autocatalytic manner starting from the uncapped minifilament of Dynactin.
Evolutionary design of optimal surface topographies for biomaterials
Authors: Vasilevich Aliaksei , Carlier Aurélie , Winkler David A. , Singh Shantanu , de Boer Jan
Published: May 2020

Natural evolution tackles optimization by producing many genetic variants and exposing these variants to selective pressure, resulting in the survival of the fittest. We use high throughput screening of large libraries of materials with differing surface topographies to probe the interactions of implantable device coatings with cells and tissues. However, the vast size of possible parameter design space precludes a brute force approach to screening all topographical possibilities. Here, we took inspiration from Nature to optimize materials surface topographies using evolutionary algorithms. We show that successive cycles of material design, production, fitness assessment, selection, and mutation results in optimization of biomaterials designs. Starting from a small selection of topographically designed surfaces that upregulate expression of an osteogenic marker, we used genetic crossover and random mutagenesis to generate new generations of topographies.
The representation of women as authors of submissions to ecology journals during the COVID-19 pandemic
Authors: Fox Charles W.
Published: May 2020

Observations made from papers submitted to preprint servers, and the speculation of editors on social media platforms, suggest that women are submitting fewer papers to scholarly journals than are men during the COVID-19 pandemic. Here I examine whether submissions by men and women to six ecology journals (all published by the British Ecological Society) have changed since the start of COVID disruptions. At these six ecology journals there is no evidence of a decline in the proportion of submissions that are authored by women (as either first or submitting author) since the start of the COVID-19 disruptions; the proportion of papers authored by women in the post-COVID period of 2020 has increased relative to the same period in 2019, and is higher than in the period pre-COVID in 2020. There is also no evidence of a change in the geographic pattern of submissions from across the globe.
Dose-dependent response to infection with SARS-CoV-2 in the ferret model: evidence of protection to re-challenge
Authors: Ryan Kathryn A. , Bewley Kevin R. , Fotheringham Susan A. , Brown Phillip , Hall Yper , Marriott Anthony C. , Tree Julia A. , Allen Lauren , Aram Marilyn J. , Brunt Emily , Buttigieg Karen R. , Cavell Breeze E. , Carter Daniel P. , Cobb Rebecca , Coombes Naomi S. , Godwin Kerry J. , Gooch Karen E. , Gouriet Jade , Halkerston Rachel , Harris Debbie J. , Humphries Holly E. , Hunter Laura , Ho Catherine M. K. , Kennard Chelsea L. , Leung Stephanie , Ngabo Didier , Osman Karen L. , Paterson Jemma , Penn Elizabeth J. , Pullan Steven T. , Rayner Emma , Slack Gillian S. , Steeds Kimberley , Taylor Irene , Tipton Tom , Thomas Stephen , Wand Nadina I. , Watson Robert J. , Wiblin Nathan R. , Charlton Sue , Hallis Bassam , Hiscox Julian A. , Funnell Simon , Dennis Mike J. , Whittaker Catherine J. , Catton Michael G. , Druce Julian , Salguero Francisco J. , Carroll Miles W.
Published: May 2020

In December 2019 an outbreak of coronavirus disease (COVID-19) emerged in Wuhan, China. The causative agent was subsequently identified and named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which rapidly spread worldwide causing a pandemic. Currently there are no licensed vaccines or therapeutics available against SARS-CoV-2 but numerous candidate vaccines are in development and repurposed drugs are being tested in the clinic. There is a vital need for authentic COVID-19 animal models to further our understanding of pathogenesis and viral spread in addition to pre-clinical evaluation of candidate interventions.

Here we report a dose titration study of SARS-CoV-2 to determine the most suitable infectious dose to use in the ferret model. We show that a high (5×106pfu) and medium (5×104pfu) dose of SARS-CoV-2 induces consistent upper respiratory tract (URT) viral RNA shedding in both groups of six challenged animals, whilst a low dose (5×102pfu) resulted in only one of six displaying signs of URT viral RNA replication. The URT shedding lasted up to 21 days in the high dose animals with intermittent positive signal from day 14. Sequential culls revealed distinct pathological signs of mild multifocal bronchopneumonia in approximately 5-15% of the lung, observed on day 3 in high and medium dosed animals, with presence of mild broncho-interstitial pneumonia on day 7 onwards. No obvious elevated temperature or signs of coughing or dyspnoea were observed although animals did present with a consistent post-viral fatigue lasting from day 9-14 in the medium and high dose groups. After virus shedding ceased, re-challenged ferrets were shown to be fully protected from acute lung pathology. The endpoints of URT viral RNA replication in addition to distinct lung pathology and post viral fatigue were observed most consistently in the high dose group. This ferret model of SARS-CoV-2 infection presents a mild clinical disease (as displayed by 80% of patients infected with SARS-CoV-2). In addition, intermittent viral shedding on days 14-21 parallel observations reported in a minority of clinical cases.
Temporal evolution and adaptation of SARS-COV-2 codon usage
Authors: Posani Elisa , Dilucca Maddalena , Forcelloni Sergio , Pavlopoulou Athanasia , Georgakilas Alexandros G. , Giansanti Andrea
Published: May 2020

The outbreak of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has caused an unprecedented pandemic. Since the first sequenced whole-genome of SARS-CoV-2 on January 2020, the identification of its genetic variants has become crucial in tracking and evaluating their spread across the globe.

In this study, we compared 134,905 SARS-CoV-2 genomes isolated from all affected countries since the outbreak of this novel coronavirus with the first sequenced genome in Wuhan, China to quantify the evolutionary divergence of SARS-CoV-2. Thus, we compared the codon usage patterns of SARS-CoV-2 genes encoding the membrane protein (M), envelope (E), spike surface glycoprotein (S), nucleoprotein (N), RNA-dependent RNA polymerase (RdRp). The polyproteins ORF1a and ORF1b were examined separately.

We found that SARS-CoV-2 tends to diverge over time by accumulating mutations on its genome and, specifically, on the sequences encoding proteins N and S. Interestingly, different patterns of codon usage were observed among these genes. GenesSandNtend to use a narrower set of synonymous codons that are better optimized to the human host. Conversely, genesEandMconsistently use the broader set of synonymous codons, which does not vary in respect to the reference genome. CAI and SiD time evolutions show a tendency to decrease that emerge for most genes. Forsdyke plots are used to study the nature of mutations and they show a rapid evolutionary divergence of each gene, due to the low values of x-intercepets.
Phosphate and phosphite differentially impact the proteome and phosphoproteome of Arabidopsis suspension cell cultures
Authors: Mehta Devang , Ghahremani Mina , Pérez-Fernández Maria , Tan Maryalle , Schläpfer Pascal , Plaxton William C. , Uhrig R. Glen
Published: May 2020

Phosphorus absorbed in the form of phosphate (H2PO4−) is an essential but limiting macronutrient for plant growth and agricultural productivity. A comprehensive understanding of how plants respond to phosphate starvation is essential to develop more phosphate-efficient crops. Here we employed label-free proteomics and phosphoproteomics to quantify protein-level responses to 48 h of phosphate versus phosphite (H2PO3−) resupply to phosphate-deprivedArabidopsis thalianasuspension cells. Phosphite is similarly sensed, taken up, and transported by plant cells as phosphate, but cannot be metabolized or used as a nutrient. Phosphite is thus a useful tool to delineate between non-specific processes related to phosphate sensing and transport, and specific responses to phosphorus nutrition. We found that responses to phosphate versus phosphite resupply occurred mainly at the level of protein phosphorylation, complemented by limited changes in protein abundance, primarily in protein translation, phosphate transport and scavenging, and central metabolism proteins. Altered phosphorylation of proteins involved in core processes such as translation, RNA splicing, and kinase signalling were especially important. We also found differential phosphorylation in response to phosphate and phosphite in 69 proteins, including splicing factors, translation factors, the PHT1;4 phosphate transporter and the HAT1 histone acetyltransferase—potential phospho-switches signalling changes in phosphorus nutrition. Our study illuminates several new aspects of the phosphate-starvation response and identifies important targets for further investigation and potential crop improvement.
Development Optimization and Validation of RT-LAMP based COVID-19 Facility in Pakistan
Authors: Haq Farhan , Sharif Salmaan , Khurshid Adnan , Shabbir Imran , Salman Muhammad , Badar Nazish , Ikram Aamir , Ahad Abdul , Malik Muhammad Faraz Arshad
Published: May 2020

The pandemic SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2) has created a widespread panic across the globe especially in the developing countries like Pakistan. The lack of resources and technical staff are causing havoc challenges in the detection and prevention of this global outbreak. Therefore, a less expensive and massive screening of suspected individuals for COVID-19 is required. In this study, a user-friendly technique of reverse transcription-loop mediated isothermal amplification (RT-LAMP) was designed and validated to suggest a potential RT-qPCR alternate for rapid testing of COVID-19 suspected individuals. A total of 12 COVID-19 negative and 72 COVID-19 suspected individuals were analyzed. Both RT-qPCR and RT-LAMP assays were performed for all the individuals using open reading frame (ORF 1ab), nucleoprotein (N) and Spike (S) genes. All 12 specimens which were negative using RT-qPCR were also found negative using RT-LAMP assay. Overall 62 out of 72 positive samples (detected using RT-qPCR) were found COVID-19 positive using RT-LAMP assay. Interestingly all samples (45) having Ct values less than 30 showed 100% sensitivity. However, samples with weaker Ct values (i.e., => 35) showed 54% concordance, suggesting potential false negatives or false positives in RT-LAMP or RT-qPCR results, respectively.

Overall comparative assessment showed that RT-LAMP assay showed strong sensitivity and specificity and can be used as an alternative strategy for rapid COVID-19 testing. Hence, based on fast processing time, minimal risk of specimens transfer and utilizing available resources, LAMP based detection of COVID-19 is strongly advocated especially for developing countries.
DiNeR: aDifferential Graphical Model for analysis of co-regulationNetworkRewiring
Authors: Zhang Jing , Liu Jason , Lee Donghoon , Lou Shaoke , Chen Zhanlin , Gürsoy Gamze , Gerstein Mark
Published: May 2020

Background

During transcription, numerous transcription factors (TFs) bind to targets in a highly coordinated manner to control the gene expression. Alterations in groups of TF-binding profiles (i.e. “co-binding changes”) can affect the co-regulating associations between TFs (i.e. “rewiring the co-regulator network”). This, in turn, can potentially drive downstream expression changes, phenotypic variation, and even disease. However, quantification of co-regulatory network rewiring has not been comprehensively studied.

Methods

To address this, we propose DiNeR, a computational method to directly construct a differential TF co-regulation network from paired disease-to-normal ChIP-seq data. Specifically, DiNeR uses a graphical model to capture the gained and lost edges in the co-regulation network. Then, it adopts a stability-based, sparsity-tuning criterion -- by sub-sampling the complete binding profiles to remove spurious edges -- to report only significant co-regulation alterations. Finally, DiNeR highlights hubs in the resultant differential network as key TFs associated with disease.

Results

We assembled genome-wide binding profiles of 104 TFs in the K562 and GM12878 cell lines, which loosely model the transition between normal and cancerous states in chronic myeloid leukemia (CML). In total, we identified 351 significantly altered TF co-regulation pairs. In particular, we found that the co-binding of the tumor suppressor BRCA1 and RNA polymerase II, a well-known transcriptional pair in healthy cells, was disrupted in tumors. Thus, DiNeR successfully extracted hub regulators and discovered well-known risk genes.

Conclusions

Our method DiNeR makes it possible to quantify changes in co-regulatory networks and identify alterations to TF co-binding patterns, highlighting key disease regulators. Our method DiNeR makes it possible to quantify changes in co-regulatory networks and identify alterations to TF co-binding patterns, highlighting key disease regulators.
Rare variant analysis of 4,241 pulmonary arterial hypertension cases from an international consortium implicateFBLN2,PDGFDand rarede novovariants in PAH
Authors: Zhu Na , Swietlik Emilia M. , Welch Carrie L. , Pauciulo Michael W. , Hagen Jacob J. , Zhou Xueya , Guo Yicheng , Karten Johannes , Pandya Divya , Tilly Tobias , Lutz Katie A. , Rosenzweig Erika , Krishnan Usha , Coleman Anna W. , Gonzaga-Juaregiu Claudia , Lawrie Allan , Trembath Richard C. , Wilkins Martin R. ,   Regeneron Genetics Center,   PAH Biobank Enrolling Centers’ Investigators,   NIHR BioResource for Translational Research - Rare Diseases,   National Cohort Study of Idiopathic and Heritable PAH, Morrell Nicholas W. , Shen Yufeng , Gräf Stefan , Nichols William C. , Chung Wendy K.
Published: May 2020

Background

Group 1 pulmonary arterial hypertension (PAH) is a lethal vasculopathy characterized by pathogenic remodeling of pulmonary arterioles leading to increased pulmonary pressures, right ventricular hypertrophy and heart failure. Recent high-throughput sequencing studies have identified additional PAH risk genes and suggested differences in genetic causes by age of onset. However, known risk genes explain only 15-20% of non-familial idiopathic PAH cases.

Methods

To identify new risk genes, we utilized an international consortium of 4,241 PAH cases with 4,175 sequenced exomes (n=2,572 National Biological Sample and Data Repository for PAH; n=469 Columbia University Irving Medical Center, enriched for pediatric trios) and 1,134 sequenced genomes (UK NIHR Bioresource – Rare Diseases Study). Most of the cases were adult-onset disease (93%), and 55% idiopathic (IPAH) and 35% associated with other diseases (APAH). We identified protein-coding variants and performed rare variant association analyses in unrelated participants of European ancestry, including 2,789 cases and 18,819 controls (11,101 unaffected parents from the Simons Powering Autism Research for Knowledge study and 7,718 gnomAD individuals). We analyzedde novovariants in 124 pediatric trios.

Results

Seven genes with rare deleterious variants were significantly associated (false discovery rate <0.1) with IPAH, including three known genes (BMPR2,GDF2, andTBX4), two recently identified candidate genes (SOX17,KDR), and two new candidate genes (FBLN2, fibulin 2;PDGFD, platelet-derived growth factor D). The candidate genes exhibit expression patterns in lung and heart similar to that of known PAH risk genes, and most of the variants occur in conserved protein domains. Variants in known PAH gene,ACVRL1, showed association with APAH. Predicted deleteriousde novovariants in pediatric cases exhibited a significant burden compared to the background mutation rate (2.5x, p=7.0E-6). At least eight novel candidate genes carryingde novovariants have plausible roles in lung/heart development.

Conclusions

Rare variant analysis of a large international consortium identifies two new candidate genes -FBLN2andPDGFD. The new genes have known functions in vasculogenesis and remodeling but have not been previously implicated in PAH. Trio analysis predicts that ~15% of pediatric IPAH may be explained byde novovariants.
Stick-Slip model for actin-driven cell protrusions, cell polarisation and crawling
Authors: Sens Pierre
Published: May 2020

Cell crawling requires the generation of intracellular forces by the cytoskeleton and their transmission to an extracellular substrate through specific adhesion molecules. Crawling cells show many features of excitable systems, such as spontaneous symmetry breaking and crawling in the absence of external cues, and periodic and propagating waves of activity. Mechanical instabilities in the active cytoskeleton network and feedback loops in the biochemical network of activators and repressors of cytoskeleton dynamics have been invoked to explain these dynamical features. Here, we show that the interplay between the dynamics of cell-substrate adhesion and linear cellular mechanics is sufficient to reproduce many non-linear dynamical patterns observed in spreading and crawling cells. Using an analytical formalism of the molecular clutch model of cell adhesion, regulated by local mechanical forces, we show that cellular traction forces exhibit a stick-slip dynamics resulting in periodic waves of protrusion/retraction and propagating waves along the cell edge. This can explain spontaneous symmetry breaking and polarisation of spreading cells, leading to steady crawling or bipedal motion, and bistability, where persistent cell motion requires a sufficiently strong transient external stimulus. The model also highlight the role of membrane tension in providing the long-range mechanical communication across the cell required for symmetry breaking.
The evolution of virulence inPseudomonas aeruginosaduring chronic wound infection
Authors: Vanderwoude Jelly , Fleming Derek , Azimi Sheyda , Trivedi Urvish , Rumbaugh Kendra P. , Diggle Stephen P.
Published: May 2020

Opportunistic pathogens are associated with a number of chronic human infections, yet the evolution of virulence in these organisms during chronic infection remains poorly understood. Here, we tested the evolution of virulence in the human opportunistic pathogenPseudomonas aeruginosain a murine chronic wound model using a two-part serial passage and sepsis experiment, and found that virulence evolved in different directions in each line of evolution. We also assessedP. aeruginosaadaptation to a chronic wound after 42 days of evolution, and found that morphological diversity in our evolved populations was limited compared to that previously described in cystic fibrosis (CF) infections. Using whole genome sequencing, we found that genes previously implicated inP. aeruginosapathogenesis (lasR, pilR, fleQ, rpoN, andpvcA), acquired mutations during the course of evolution in wounds, with some mutations evolving in parallel across all lines of evolution. Our findings highlight that (i)P. aeruginosaheterogeneity may be less extensive in chronic wounds than in CF lungs; (ii) genes involved inP. aeruginosapathogenesis acquire mutations during chronic wound infection; (iii) similar genetic adaptations are employed byP. aeruginosaacross multiple infection environments, and (iv) current models of virulence may not adequately explain the diverging evolutionary trajectories observed in an opportunistic pathogen during chronic wound infection.
A serological assay to detect SARS-CoV-2 antibodies in at-home collected finger-prick dried blood spots
Authors: Karp Donna Grace , Danh Kenneth , Seftel David , Robinson Peter , Tsai Cheng-ting
Published: May 2020

Accurate surveillance of coronavirus disease 2019 (COVID-19) incidence requires large-scale testing of the population. Current testing methods require in-person collection of biospecimens by a healthcare worker, limiting access of individuals who do not have access to testing facilities while placing both the patient and healthcare worker at risk of exposure to infection. We report the development and validation of a at-home finger-prick dried blood spot collection kit and an analysis method. We demonstrated 100% sensitivity and specificity using at-home collected specimens across the US. Such methods may facilitate the conduct of unbiased serosurveys within hard to reach populations and help reduce the sample collection burden of serological testing on both health care systems and individuals alike.
Targeted sequencing of Parkinson’s disease loci genes highlightsSYT11, FGF20and other associations
Authors: Rudakou Uladzislau , Yu Eric , Krohn Lynne , Ruskey Jennifer A. , Asayesh Farnaz , Dauvilliers Yves , Spiegelman Dan , Greenbaum Lior , Fahn Stanley , Waters Cheryl H. , Dupré Nicolas , Rouleau Guy A. , Hassin-Baer Sharon , Fon Edward A. , Alcalay Roy N. , Gan-Or Ziv
Published: May 2020

Genome-wide association studies (GWAS) have identified numerous loci associated with Parkinson’s disease. The specific genes and variants that drive the associations within the vast majority of these loci are unknown. We aimed to perform a comprehensive analysis of selected genes to determine the potential role of rare and common genetic variants within these loci. We fully sequenced 32 genes from 25 loci previously associated with Parkinson’s disease in 2,657 patients and 3,647 controls from three cohorts. Capture was done using molecular inversion probes targeting the exons, exon-intron boundaries and untranslated regions (UTRs) of the genes of interest, followed by sequencing. Quality control was performed to include only high-quality variants. We examined the role of rare variants (minor allele frequency < 0.01) using optimized sequence Kernel association tests (SKAT-O). The association of common variants was estimated using regression models adjusted for age, sex and ethnicity as required in each cohort, followed by a meta-analysis. After Bonferroni correction, we identified a burden of rare variants inSYT11, FGF20andGCH1associated with Parkinson’s disease. Nominal associations were identified in 21 additional genes. Previous reports suggested that theSYT11GWAS association is driven by variants in the nearbyGBAgene. However, the association ofSYT11was mainly driven by a rare 3’ UTR variant (rs945006601) and was independent ofGBAvariants (p=5.23E-05 after exclusion of allGBAvariant carriers). The association ofFGF20was driven by a rare 5’ UTR variant (rs1034608171) located in the promoter region. The previously reported association ofGCH1with Parkinson’s Disease is driven by rare nonsynonymous variants, some of which are known to cause dopamine-responsive dystonia. We also identified twoLRRK2variants, p.Arg793Met and p.Gln1353Lys, in ten and eight controls, respectively, but not in patients. We identified common variants associated with Parkinson’s disease inMAPT, TMEM175, BST1,SNCAandGPNMBwhich are all in strong linkage disequilibrium (LD) with known GWAS hits in their respective loci. A common codingPM20D1variant, p.Ile149Val, was nominally associated with reduced risk of Parkinson’s disease (OR 0.73, 95% CI 0.60-0.89, p=1.161E-03). This variant is not in LD with the top GWAS hits within this locus and may represent a novel association. These results further demonstrate the importance of fine mapping of GWAS loci, and suggest thatSYT11, FGF20, and potentiallyPM20D1, BST1andGPNMBshould be considered for future studies as possible Parkinson’s disease-related genes.
Detection of Circulating Tumor-specific DNA Methylation Markers in the Blood of Patients with Pituitary Tumors
Authors: Wells Michael , Asmaro Karam P. , Sabedot Thais S. , Malta Tathiane M. , Mosella Maritza S. , Nelson Kevin , Snyder James , deCarvalho Ana , Mukherjee Abir , Chitale Dhananjay , Robin Adam , Rosenblum Mark , Mikkelsen Thomas , Poisson Laila M. , Lee Ian Y. , Walbert Tobias , Bhan Arti , Kalkanis Steven , Rock Jack , Noushmehr Houtan , Castro Ana Valeria
Published: May 2020

Genome-wide DNA methylation aberrations are pervasive and associated with clinicopathological features across pituitary tumors (PT) subtypes. The feasibility to detect CpG methylation abnormalities in circulating cell-free DNA (cfDNA) has been reported in central nervous system tumors other than PT. Here, we aimed to profile and identify methylome-based signatures in the serum of patients harboring PT (n =13). Our analysis indicated that serum cfDNA methylome from patients with PT are distinct from the counterparts in patients with other tumors (gliomas, meningiomas, colorectal carcinomas, n =134) and nontumor conditions (n = 4). Furthermore, the serum methylome patterns across PT was associated with functional status and adenohypophyseal cell lineage PT subtypes, recapitulating epigenetic features reported in PT-tissue. A machine learning algorithm using serum PT-specific signatures generated a score that distinguished PT from non-PT conditions with 100% accuracy in our validation set. These preliminary results underpin the potential clinical application of a liquid biopsy-based DNA methylation profiling as a noninvasive approach to identify clinically relevant epigenetic markers that can be used in the management of PT.
Mortality and use of angiotensin converting enzyme inhibitors in Covid 19 disease – a systematic review
Authors: Nunes José Pedro L.
Published: May 2020

Background

Interest exits concerning the use of angiotensin converting enzyme inhibitors (ACEi) in patients with Covid-19 disease.

Objectives

To perform a systematic review on mortality associated to the use of ACEi in patients with Covid 19 disease.

Methods

Search in Medline (PubMed), in ISI Web of Knowledge and in medRxiv database; use of other sources.

Results

A total of 33 articles were evaluated. Concerning the papers used to produce the meta-analyses, seven studies were selected, five of which were used. These five studies involved a total number of 944 patients treated with ACEi and 5173 not treated with ACEi. Increased mortality was seen in association to the use of ACEi in the context of Covid-19 disease (ACEi users versus non-users; odds ratio, 1.48; 95% confidence interval [CI], 1.02 to 2.15; P=0.04). When compared to mortality in patients treated with angiotensin receptor blockers, mortality of patients treated with ACEi was not significantly different (odds ratio, 0.96; 95% confidence interval [CI], 0.76 to 1.21; P=0.74). Concerning the remaining reports, different types of data adjustments were used by several authors, after which increased mortality was not seen in association to the use of ACEi in this context.

Conclusions

ACEi use could act as a marker of increased mortality risk in some but not all Covid-19 disease settings. The data now presented do not prove a causal relation but argue in favor of carrying out clinical trials studying ACEi in Covid-19 patients, in order to establish the safety of ACEi use in this context.
Novel indicators for evaluating topological threats to populations from pandemics applied to COVID-19
Authors: Adachi Shun
Published: May 2020

BACKGROUND

To deal with pandemics, evaluating the temporal status of an outbreak is important. However, prevailing standards in this respect are mostly empirical and arbitrary. As an alternative, we focus on a novel approach which configures indicators that evaluate topological threats to populations due to the COVID-19 pandemic.

METHODS

We extended the current PzDom model to calculate a threshold of the model for accelerated growth, an indicator of growth extent Re(v), covariance Re(s), a topological number E(l), and expected sums of possibly increasing numbers of infected people. We term this the exPzDom model.

RESULTS

The indicators in the exPzDom model adhere well to the empirical dynamics of SARS-CoV-2 infected people and align appropriately with actual policies instituted by the Japanese government.

CONCLUSIONS

The described indicators could be leveraged pursuant of objective evaluation based on mathematics. Further testing of the reliability and robustness of exPzDom model in other pandemic contexts is warranted.
Resting-state network plasticity induced by music therapy after traumatic brain injury
Authors: Martínez-Molina Noelia , Siponkoski Sini-Tuuli , Kuusela Linda , Laitinen Sari , Holma Milla , Ahlfors Mirja , Jordan-Kilkki Päivi , Ala-Kauhaluoma Katja , Melkas Susanna , Pekkola Johanna , Rodriguez-Fornells Antoni , Laine Matti , Ylinen Aarne , Rantanen Pekka , Koskinen Sanna , Cowley Benjamin Ultan , Särkämö Teppo
Published: May 2020

Traumatic brain injury (TBI) is characterized by a complex pattern of abnormalities in resting-state functional connectivity (rsFC) and network dysfunction, which can potentially be ameliorated by rehabilitation. In our previous randomized controlled trial, we found that a 3-month neurological music therapy intervention enhanced executive function (EF) and increased grey matter volume in the right inferior frontal gyrus (IFG) in patients with moderate-to-severe TBI (N=40). Extending this study, we performed longitudinal rsFC analyses of resting-state fMRI data using a ROI-to-ROI approach assessing within-network and between-network rsFC in the frontoparietal (FPN), dorsal attention (DAN), default mode (DMN), and salience (SAL) networks, which all have been associated with cognitive impairment after TBI. We also performed a seed-based connectivity analysis between the right IFG and whole-brain rsFC. The results showed that neurological music therapy increased the coupling between the FPN and DAN as well as between these networks and primary sensory networks. By contrast, the DMN was less connected with sensory networks after the intervention. Similarly, there was a shift towards a less connected state within the FPN and SAL networks, which are typically hyperconnected following TBI. Improvements in EF were correlated with rsFC within the FPN and between the DMN and sensorimotor networks. Finally, in the seed-based connectivity analysis, the right IFG showed increased rsFC with the right inferior parietal and left frontoparietal (Rolandic operculum) regions. Together, these results indicate that the rehabilitative effects of neurological music therapy after TBI are underpinned by a pattern of within- and between-network connectivity changes in cognitive networks as well as increased connectivity between frontal and parietal regions associated with music processing.
Loneliness during lockdown: trajectories and predictors during the COVID-19 pandemic in 35,712 adults in the UK
Authors: Bu Feifei , Steptoe Andrew , Fancourt Daisy
Published: May 2020

There are increasing worries that lockdowns and “stay-at-home” orders due to the COVID-19 pandemic could lead to a rise in loneliness, which is recognised as a major public health concern. But profiles of loneliness during the pandemic and risk factors remain unclear.

Data from 35,712 UK adults in the UCL COVID-19 Social Study (a panel study collecting data weekly during the pandemic) were analysed from 21/03/2020-03/05/2020. The sample was well-stratified and weighted to population proportions of gender, age, ethnicity, education and geographical location. Growth mixture modelling was used to identify the latent classes of loneliness growth trajectories and their predictors.

Analyses revealed four classes, with the baseline loneliness level ranging from low to high. In the first six weeks of lockdown, loneliness levels increased in the highest loneliness group, decreased in the lowest loneliness group, and stayed relatively constant in the middle two groups. Younger adults (OR = 2.17–6.81), women (OR = 1.59), people with low income (OR = 1.3), the economically inactive (OR = 1.3–2.04) and people with mental health conditions (OR = 5.32) were more likely to be in highest loneliness class relative to the lowest. Further, living with others or in a rural area, and having more close friends or greater social support were protective.

Perceived levels of loneliness in the first few weeks of lockdown during COVID-19 were relatively stable in the UK, but for many people these levels were high with no signs of improvement. Results suggest that more efforts are needed to address loneliness, especially amongst young people.
SARS-CoV-2 Seroprevalence Among All Workers in a Teaching Hospital in Spain: Unmasking The Risk
Authors: Isabel Galán M , Velasco María , Luisa Casas M , José Goyanes M , Rodríguez-Caravaca Gil , Emilio Losa Juan , Noguera Carmen , Castilla Virgilio ,   Working Group Alcorcon COVID-19 investigators
Published: May 2020

Background

Health-care workers (HCW) are at increased risk for SARS-CoV-2 infection, but few studies have evaluated prevalence of antibodies against SARS-CoV-2 among them.

Objective

To determine the seroprevalence against SARS-CoV-2 in all HCW.

Methods

Cross-sectional study (April 14th- 27th, 2020) of all HCW at Hospital Universitario Fundación Alcorcón, a second level teaching hospital in Madrid, Spain. SARS-CoV-2 IgG was measured by ELISA. HCW were classified by professional category, working area, and risk for SARS-CoV-2 exposure.

Results

Among 2919 HCW, 2590 (90.5%) were evaluated. Mean age was 43.8 years (SD 11.1) and 73.9% were females. Globally, 818 (31.6%) workers were IgG positive, with no differences for age, sex or previous diseases. Among them, 48.5% did not report previous symptoms. Seropositivity was more frequent in high (33.1%) and medium (33.8%) than in low-risk areas (25.8%, p = 0.007), but no difference was found for hospitalization areas attending COVID-19 and non-COVID-19 patients (35.5 vs 38.3% p = NS). HCW with a previous SARS-CoV2 PCR positive test were IgG seropositive in 90.8%. By multivariate logistic regression analysis, seropositivity was associated with being physicians (OR 2.37, CI95% 1.61–3.49), nurses (OR 1.67, CI95% 1.14–2.46), or nurse- assistants (OR 1.84, CI95% 1.24–2.73), HCW working at COVID-19 hospitalization areas (OR 1.71, CI95% 1.22–2.40), non-COVID-19 hospitalization areas (OR 1.88, CI95% 1.30–2.73), and at the Emergency Room (OR 1.51, CI95% 1.01–2.27)

Conclusions

Seroprevalence uncovered a high rate of infection previously unnoticed among HCW. Patients not suspected of having COVID-19 as well as asymptomatic HCW may be a relevant source for nosocomial SARS-CoV-2 transmission.
Can medication mitigate the need for a strict lock down?: A mathematical study of control strategies for COVID-19 infection
Authors: Ali Mohsin , Imran Mudassar , Khan Adnan
Published: May 2020

We formulate a deterministic epidemic model to study the effects of medication on the transmission dynamics of Corona Virus Disease (COVID-19). We are especially interested in how the availability of medication could change the necessary quarantine measures for effective control of the disease. We model the transmission by extending the SEIR model to include asymptomatic, quarantined, isolated and medicated population compartments. We calculate the basic reproduction number R0 and show that for R0 < 1 the disease dies out and for R0 > 1 the disease is endemic. Using sensitivity analysis we establish that R0 is most sensitive to the rates of quarantine and medication. We also study how the effectiveness and the rate of medication along with the quarantine rate affect R0. We devise optimal quarantine, medication and isolation strategies, noting that availability of medication reduces the duration and severity of the lock-down needed for effective disease control. Our study also reinforces the idea that with the availability of medication, while the severity of the lock downs can be eased over time some social distancing protocols need to be observed, at least till a vaccine is found. We also analyze the COVID-109 outbreak data for four different countries, in two of these, India and Pakistan the curve is still rising, and in he other two, Italy and Spain, the epidemic curve is now falling due to effective quarantine measures. We provide estimates of R0 and the proportion of asymptomatic individuals in the population for these countries.
Serum proteomics in COVID-19 patients: Altered coagulation and complement status as a function of IL-6 level
Authors: D’Alessandro Angelo , Thomas Tiffany , Dzieciatkowska Monika , Hill Ryan C. , Francis Richard O , Hudson Krystalyn E. , Zimring James C. , Hod Eldad A. , Spitalnik Steven L. , Hansen Kirk C.
Published: May 2020

Over 5 million people around the world have tested positive for the beta coronavirus SARS-CoV-2 as of May 29, 2020, a third of which in the United States alone. These infections are associated with the development of a disease known as COVID-19, which is characterized by several symptoms, including persistent dry cough, shortness of breath, chills, muscle pain, headache, loss of taste or smell, and gastrointestinal distress. COVID-19 has been characterized by elevated mortality (over 100 thousand people have already died in the US alone), mostly due to thromboinflammatory complications that impair lung perfusion and systemic oxygenation in the most severe cases. While the levels of pro-inflammatory cytokines such as interleukin-6 (IL-6) have been associated with the severity of the disease, little is known about the impact of IL-6 levels on the proteome of COVID-19 patients. The present study provides the first proteomics analysis of sera from COVID-19 patients, stratified by circulating levels of IL-6, and correlated to markers of inflammation and renal function. As a function of IL-6 levels, we identified significant dysregulation in serum levels of various coagulation factors, accompanied by increased levels of anti-fibrinolytic components, including several serine protease inhibitors (SERPINs). These were accompanied by up-regulation of the complement cascade and antimicrobial enzymes, especially in subjects with the highest levels of IL-6, which is consistent with an exacerbation of the acute phase response in these subjects. Although our results are observational, they highlight a clear increase in the levels of inhibitory components of the fibrinolytic cascade in severe COVID-19 disease, providing potential clues related to the etiology of coagulopathic complications in COVID-19 and paving the way for potential therapeutic interventions, such as the use of pro-fibrinolytic agents.
A model for COVID-19 with isolation, quarantine and testing as control measures
Authors: Aronna M.S. , Guglielmi R. , Moschen L.M.
Published: May 2020

In this article we propose a compartmental model for the dynamics of Coronavirus Disease 2019 (COVID-19). We take into account the presence of asymptomatic infections and the main policies that have been adopted so far to contain the epidemic: isolation (or social distancing) of a portion of the population, quarantine for confirmed cases and testing. We model isolation by separating the population in two groups: one composed by key-workers that keep working during the pandemic and have a usual contact rate, and a second group consisting of people that are enforced/recommended to stay at home. We refer to quarantine as strict isolation, and it is applied to confirmed infected cases.

In the proposed model, the proportion of people in isolation, the level of contact reduction and the testing rate are control parameters that can vary in time, representing policies that evolve in different stages. We obtain an explicit expression for the basic reproduction numberin terms of the parameters of the disease and of the control policies. In this way we can quantify the effect that isolation and testing have in the evolution of the epidemic. We present a series of simulations to illustrate different realistic scenarios. From the expression ofand the simulations we conclude that isolation (social distancing) and testing among asymptomatic cases are fundamental actions to control the epidemic, and the stricter these measures are and the sooner they are implemented, the more lives can be saved. Additionally, we show that people that remain in isolation significantly reduce their probability of contagion, so risk groups should be recommended to maintain a low contact rate during the course of the epidemic.