bluuebunny/crossref_metadata_2025 huggingface dataset:
Development and validation of a tool to appraise guidelines on SARS-CoV-2 infection prevention strategies in healthcare workers
Authors: Subramaniam Ashwin , Reddy Mallikarjuna , Zubarev Alexander , Kadam Umesh , Lim Zhengjie , Anstey Chris , Bihari Shailesh , HAji Jumana , Karunanithi Subhathra , Ramanathan Kollengode , Luo Jinghang , Mara Neil , Mitra Saikat , Rajamani Arvind , Rubulotta Francesca , Svensk Erik , Shekar Kiran
Published: June 2020

Background

Clinical guidelines on infection prevention strategies in healthcare workers (HCWs) play an important role in protecting them during the SARS-CoV-2 pandemic. Poorly constructed guidelines that are not comprehensive and are ambiguous may compromise HCWs’ safety. We aimed to develop and validate a tool to appraise guidelines on infection prevention strategies in HCWs.

Methods

A 3-stage, web-based, Delphi consensus-building process among a panel of diverse HCWs and healthcare managers was utilised. We validated the tool by appraising 40 international, specialty-specific and procedure-specific guidelines along with national guidelines from countries with a wide range of gross national income.

Results

Overall consensus (≥75%) was reached at the end of three rounds for all six domains included in the tool. The chosen domains allowed appraisal of guidelines in relation to general characteristics (domain-1), recommendations on engineering (domain-2) and administrative aspects (domain 4-6) of infection prevention, as well as personal protection equipment (PPE) use (domain-3). The appraisal tool performed well across all domains and inter-rater agreement was excellent. All included guidelines performed relatively better in domains 1-3 compared with domains 4-6 and this was more evident in guidelines originating from lower income countries.

Conclusion

The guideline appraisal tool was robust and easy to use. Recommendations on engineering aspects of infection prevention, administrative measures that promote optimal PPE use and HCW wellbeing were generally lacking in assessed guidelines. This tool may enable health systems to adopt high quality HCW infection prevention guidelines during SARS-CoV-2 pandemic and may also provide a framework for future guideline development.

Funding

No funding received.

Key Summary

We developed and validated a guideline-appraisal tool by appraising 40 different guidelines from countries with varying GNI. This tool may help healthcare systems to adopt high-quality HCW infection-prevention guidelines during COVID-19 pandemic and may also provide a guideline development framework.
The inevitability of Covid-19 related distress among healthcare workers: findings from a low caseload country under lockdown
Authors: Hawari Feras Ibrahim , Obeidat Nour Ali , Dodin Yasmeen Izzat , Albtoosh Asma Salameh , Manasrah Rasha Mohammad , Alaqeel Ibrahim Omar , Mansour Asem Hamza
Published: June 2020

Objectives

To characterize psychological distress and factors associated with distress in healthcare practitioners working during a stringent lockdown in a country (Jordan) with one of the lowest incidence rates of Covid-19 globally.

Methods

A cross-sectional online survey sent to physicians, nurses and technicians, and pharmacists working in various hospitals and community pharmacies. Demographic, professional and psychological characteristics (distress using Kessler-6 questionnaire, anxiety, depression, burnout, sleep issues, exhaustion) were measured as were potential sources of fear. Descriptive and multivariable statistics were performed using level of distress as the key outcome.

Results

We surveyed 1,006 practitioners (55.3% females). Approximately 63%, 13%, 17% and 7% were nurses/technicians, physicians, pharmacists, and other nonmedical personnel (respectively). 32% suffered from high distress while 20% suffered from severe distress. Exhaustion, anxiety, depression, and sleep disturbances were reported (in past seven days) by approximately 34%, 34%, 19%, and 29% of subjects (respectively). Being older or male, perception of effective protective institutional measures, and being satisfied at work, were significantly associated with lower distress. Conversely, suffering burnout; reporting sleep-related functional problems; exhaustion; being a pharmacist (relative to a physician) and working in a cancer center; harboring fear about virus spreading; fear that the virus threatened life; fear of alienation from family/friends; and fear of workload increases, were significantly associated with higher distress.

Conclusion

Despite low caseloads, Jordanian practitioners still experienced high levels of distress. Identified demographic, professional and psychological factors influencing distress should inform interventions to improve medical professionals’ resilience and distress likelihood, regardless of the variable Covid-19 situation.
Assessing the burden of COVID-19 in Canada
Authors: Bignami-Van Assche Simona , Van Assche Ari
Published: June 2020

Background

The burden of COVID-19 in Canada is unequally distributed geographically, with the largest number of cases and fatalities recorded in Québec and Ontario while other provinces experienced limited outbreaks. To date, however, no study has assessed how provincial epidemics have unfolded in a comparative perspective. This is essential to calibrate projections of the future course of the epidemic and plan health care resources for the second wave of infections.

Methods

Using newly released individual-level data collected by the Public Health Agency of Canada, we assess COVID-19-related morbidity and mortality across age and gender groups at the provincial level through a combination of demographic and survival analyses.

Results

Québec has the highest absolute and per capita number of COVID-19 confirmed positive cases, hospitalizations and fatalities in all age groups. In each province, a higher number of women than men test positive for the disease, especially above age 80. Yet consistently across age groups, infected men are more likely to be hospitalized and enter intensive care than women do. These gender differences in hospitalisation rates account for the higher case fatality risk due to COVID-19 among men compared to women.

Interpretation

Although health care capacity across provinces has been sufficient to treat severe cases, we find that the main factor accounting for gender differences in COVID-19-related mortality is the need for hospitalization and intensive care, especially above age 80. This suggests a selection effect of severe cases requiring to be treated in a hospital setting that needs to be further investigated.
Critical Complications of COVID-19: A systematic Review and Meta-Analysis study
Authors: Vakili Kimia , Fathi Mobina , Sayehmiri Fatemeh , Mohamadkhani Ashraf , Hajiesmaeili Mohammadreza , Rezaei-Tavirani Mostafa , Pezeshgi Aiyoub
Published: June 2020

Background

Coronavirus disease 2019 (COVID-19) is a novel coronavirus infection that has spread worldwide in a short period and caused a pandemic. The goal of this meta-analysis is to evaluate the prevalence of most common symptoms and complications of COVID-19.

Methods

All related studies assessing the clinical complications of COVID-19 have been identified through web search databases (PubMed and Scopus). Relevant data were extracted from these studies and analyzed by stata (ver 14) random-effects model. The heterogeneity of studies were assessed byI2index. The publication bias was examined by Funnel plots and Egger’s test.

Results

30 studies were in our meta-analysis including 6 389 infected patients. The prevalence of most common symptoms were: fever 84.30% (95% CI: 77.13-90.37; I2=97.74%), cough 63.01% (95% CI: 57.63-68.23; I2=93.73%), dyspnea 37.16% (95% CI: 27.31-47.57%; I2=98.32%), fatigue 34.22% (95% CI: 26.29-42.62; I2=97.29%) and diarrhea 11.47 %(95% CI: 6.96-16.87; I2=95.58%), respectively. The most prevalent complications were acute respiratory distress syndrome (ARDS) 33.15% (95% CI: 23.35-43.73; I2=98.56%), acute cardiac injury 13.77% (95% CI: 9.66-18.45; I2=91.36%), arrhythmia 16.64% (95% CI: 9.34-25.5; I2=92.29%), heart failure 11.50% (95% CI: 3.45-22.83; I2=89.48%), and acute kidney injury (AKI) 8.40 %(95% CI: 5.15-12.31; I2=95.22%, respectively. According to our analysis, mortality rate of COVID-19 patients were 12.29% (95% CI: 6.20-19.99; I2=98.29%).

Conclusion

We assessed the prevalence of the main clinical complications of COVID-19 and found that after respiratory complications, cardiac and renal complications are the most common clinical complications of COVID-19.

Highlights

▪

The most prevalent complication among critical cases of COVID-19 is ARDS.

▪

After pulmonary complications, cardiovascular complications (like arrhythmia, heart failure and acute cardiac injury) are the most important threats for COVID-19 patients.

▪

Renal complications (like AKI) happen as a result of COVID-19, but they are less prevalent than pulmonary and cardiovascular complications.
Resilience and green spaces: association with stress among contact centre agents in the Philippines
Authors: Villanueva Celine P. , Labao Richard Braulio J. , Tran Katherine Regine Anne G. , Gonzalez Nathaniel Reihann B. , Luna Joseph M. , Ochava Kristine Mallory R. , Capio Catherine M.
Published: June 2020

The work environment in Philippine contact centres had been shown to expose employees to factors that contribute to work-related stress; health promotion strategies that could mitigate the impacts are needed. With the framework that stress is experienced as a result of the interactions of an individual with the environment, this study examined the relationship of stress with individual resilience and the presence of urban green spaces (UGS) in the environment. The study involved employees (N = 186) from six contact centres in the capital region of the Philippines, where a large number of contact centre service providers are located. A two-stage survey was administered online using standardised instruments to measure stress (10-item Perceived Stress Scale) and resilience (Connor-Davidson Resilience Scale), customised questions to gather demographic information, and open-ended questions to probe on participants’ insights. Google Earth Pro was used to conduct satellite mapping of UGS, followed by on-site ocular inspection. This study revealed that participants’ average stress level was categorised as high. The percentages of UGS in the vicinity of the study sites were categorised as low. Linear regression revealed that amongst individual and environment factors, resilience, household income, and awareness of UGS in the vicinity were significant predictors of the participants’ stress levels. Health promotion in Philippine contact centres could consider strategies that include resilience building, enhancing income security, and promoting the awareness of UGS within the workplace vicinity.
Neural representation of linguistic feature hierarchy reflects second-language proficiency
Authors: Di Liberto Giovanni M. , Nie Jingping , Yeaton Jeremy , Khalighinejad Bahar , Shamma Shihab A. , Mesgarani Nima
Published: June 2020

Acquiring a new language requires a simultaneous and gradual learning of multiple levels of linguistic attributes. Here, we investigated how this process changes the neural encoding of natural speech by assessing the encoding of the linguistic feature hierarchy in second-language listeners. Electroencephalography (EEG) signals were recorded during English story listening from native Mandarin speakers with varied English proficiency and from native English speakers. We measured the temporal response functions (TRF) for acoustic, phonemic, phonotactic, and semantic features in individual participants and found a main effect of proficiency on the linguistic encoding. This effect of second-language proficiency was particularly prominent on the neural encoding of phonemes, showing stronger encoding of “new” phonemic contrasts (i.e. English contrasts that do not exist in Mandarin) with increasing proficiency. Overall, we found that linguistic feature representation in nonnative listeners progressively converged to that of native listeners with proficiency, which enabled accurate decoding of language proficiency. This detailed view advances our understanding of the cortical processing of linguistic information in second-language learners and provides an objective measure of language proficiency.
Robustness in spiking networks: a geometric perspective
Authors: Calaim Nuno , Dehmelt Florian Alexander , Gonçalves Pedro J. , Machens Christian K.
Published: June 2020

Neural systems are remarkably robust against various perturbations, a phenomenon that still requires a clear explanation. Here, we graphically illustrate how neural networks can become robust. We study spiking networks that generate low-dimensional representations, and we show that the neurons’ subthreshold voltages are confined to a convex region in a lower-dimensional voltage subspace, which we call a ‘bounding box.’ Any changes in network parameters (such as number of neurons, dimensionality of inputs, firing thresholds, synaptic weights, or transmission delays) can all be understood as deformations of this bounding box. Using these insights, we show that functionality is preserved as long as perturbations do not destroy the integrity of the bounding box. We suggest that the principles underlying robustness in these networks—low-dimensional representations, heterogeneity of tuning, and precise negative feedback—may be key to understanding the robustness of neural systems at the circuit level.
Nuclear and cellular, micro and nano calcification in Alzheimer’s disease patients and correlation to phosphorylated Tau
Authors: Tsolaki Elena , Csincsik Lajos , Xue Jing , Lengyel Imre , Bertazzo Sergio
Published: June 2020

Brain calcification (calcium phosphate mineral formation) has been reported in the past 100 years in the brains of Alzheimer’s disease (AD) patients. However, the association between calcification and AD, the triggers for calcification, and its role within the disease are not clear. On the other hand, hyperphosphorylated tau protein (pTau) tangles have been widely studied and recognized as an essential factor in developing AD. In this work, calcification in the brains of AD patients is characterized by advanced electron microscopy and fluorescence microscopy. Results are then compared to samples from cognitively healthy, age-matched donors, and the colocalization of calcification and pTau is investigated. Here, we show that AD patients’ brains present microcalcification associated with the neural cell nuclei and cell projections, and that these are strongly related to the presence of pTau. The link between microcalcification and pTau suggests a potential new mechanism of brain cell damage. Together with the formation of amyloid plaques and neurofibrillary tangles, microcalcification in neuronal cells adds to a better understanding of the pathology of AD. Finally, the presence of microcalcification in the neuronal cells of AD patients may assist in AD diagnosis, and may open new avenues for developing intervention strategies based on inhibition of calcification.
Recombinant T cell receptors specific for HLA-A*02:01-restricted neoepitopes containing KRAS codon 12 hotspot mutations
Authors: Rive Craig M. , Yung Eric , Hughes Christopher S. , Brown Scott D. , Sharma Govinda , Dreolini Lisa , Mawji Nasrin M. , Warren Cassia , Karasinska Joanna M. , Loree Jonathan M. , Yapp Donald T. , Morin Gregg B. , Renouf Daniel J. , Schaeffer David F. , Turcotte Simon , Holt Robert A.
Published: June 2020

KRAS codon 12 mutations are among the most common hotspot mutations in human cancer. Using a functional screening platform we set out to identify αβ T-cell receptors (TCRs) as potential targeting reagents for KRASG12Dand/or KRASG12Vneoepitopes presented by the prevalent HLA-A*02:01 allele. Here we describe isolation and characterization of three distinct CD8+T cell clones from a pre-treated 76 year old patient with pancreatic ductal adenocarcinoma (PDAC). One clone was KRASG12Vreactive and two clones were KRASG12Dreactive. Tetramer staining showed high specificity of each T cell clone for its cognate HLA-A*02:01 restricted KRASG12Vor KRASG12Dneoepitope (>98% tetramer positive) without appreciable cross-reactivity to wild-type KRAS (<2% tetramer positive). We amplified and sequenced the full-length TCR alpha and beta chains from each of the three T cell clones and determined that these three TCRs comprised distinct combinations of two different TCR alpha chains and two distinct TCR beta chains. We resynthesized these TCR alpha and beta chain nucleotide sequences and reconstituted the original pairs in healthy donor CD8+T cells by lentiviral transduction, substituting the human αβ TCR constant gene segments with murine αβ TCR constant gene segments to prevent mispairing with endogenous TCR subunits. Tetramer analysis and IFN-γ ELISpot analysis confirmed the specificity of each reconstituted TCR for its cognate HLA-A*02:01 restricted KRAS neoepitope. To test cytolytic activity TCR-transduced healthy donor CD8+T cells were co-cultured with KRASG12V, KRASG12Dor KRASwtpeptide-pulsed K562-HLA-A*02:01 antigen presenting cells at an effector to target cell ratio of 4:1. Under these conditions we observed neoepitope-specific killing of 16.5% to 19.0% of target cell populations. To assessin vivoactivity we developed a KRASG12V/A*02:01 patient-derived xenograft (PDX) mouse model. Over a 56-day period, PDX bearing mice infused with human TCR-transduced T cells had significantly reduced tumor growth and longer survival compared to mice infused with non-transduced control T cells. In conjunction with other therapeutic approaches, immune effector cell therapies expressing these TCRs may improve outcomes for HLA-A*02:01 patients with KRASG12Vand/or KRASG12Dpositive tumors.
Do carbonated beverages reduce bleeding from gill injuries in angled Northern Pike?: In Prep for North American Journal of Fisheries Management
Authors: Trahan Alexandria , Chhor Auston , Lawrence Michael J. , Brownscombe Jacob W. , Glassman Daniel , Reid Connor H. , Abrams Alice E.I. , Danylchuk Andy J. , Cooke Steven J.
Published: June 2020

The premise of catch-and-release angling is that most fish survive fisheries interactions. Therefore, it is common for anglers, management agencies, and other organizations to share information on handling practices and other strategies that are believed to improve fish welfare and survival. Recent media coverage has sensationalized the use of carbonated beverages to treat bleeding fish, an intervention that is purported to stop bleeding but has yet to be validated scientifically. We captured Northern Pike (Esox lucius) via hook and line, experimentally injured their gills in a standardized manner, and treated them with either Mountain Dew, Coca Cola, or carbonated lake water and observed the duration and intensity of bleeding, as well as overall blood loss (using gill colour as a proxy) while the fish was held in a lake water bath. As a control, we had a group of experimentally injured fish that did not have liquid poured over their gills before the observation period. All treatments and the control were conducted at two different water temperatures (11-18 °C and 24-27 °C) to determine if the effects of pouring carbonated beverages over injured gills is temperature dependent. When compared to the control, we found that the duration and intensity of bleeding increased regardless of the type of carbonated beverages used in this study, and there was no effect of water temperature. Use of chilled versus ambient temperature beverages similarly had no influence on outcomes. As such, there is no scientific evidence to support the use of carbonated beverages for reducing or stopping blood loss for fish that have had their gills injured during recreational angling based on the context studied here. This study reinforced the need to scientifically test angler anecdotes and theories when it comes to best practices for catch-and-release fishing.
Immune Selection Pressure Contributes to Pancreatic Cancer Immune Evasion
Authors: Ajina Reham , Zuo Annie , Wang Shangzi , Moussa Maha , Cooper Connor J. , Shen Yue , Johnson Quentin R. , Parks Jerry M. , Smith Jeremy C. , Catalfamo Marta , Fertig Elana J. , Jablonski Sandra A. , Weiner Louis M.
Published: June 2020

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in the United States. Pancreatic tumors are minimally infiltrated by T cells and are largely refractory to immunotherapy. Accordingly, the role of T cell immunity in pancreatic cancer has been somewhat overlooked. Here, we hypothesized that immune evasion in pancreatic cancer is induced in response to T cell-based immune selection pressure, and that understanding how pancreatic tumors respond to immune attack may facilitate the development of more effective therapeutic strategies. We now provide the first evidence that T cell-dependent host immune responses induce a PDAC-derived myeloid mimicry phenomenon and stimulate immune evasion. mT3-2D cells derived from aKras+/LSL-G12D;Trp53+/LSL-R172H;Pdx1-Cre(KPC) mouse model of pancreatic cancer were grown in immunocompetent and immunodeficient C57BL/6 mice, and analyzed to determine the impacts of adaptive immunity specifically on malignant epithelial cells as well as on whole tumors. We found that immune selection pressure, via signal transducer and activator of transcription 1 (STAT1), stimulates malignant epithelial pancreatic cells to induce the expression of genes typically expressed by myeloid cells and alters intratumoral immunosuppressive myeloid cell profiles. Targeting the Janus Kinase (JAK)/STAT signaling pathway using the FDA approved drug, ruxolitinib, overcomes these tumor-protective responses and improves anti-PD1 antibody therapeutic efficacy. These findings provide future directions for treatments that specifically disable this mechanism of resistance in PDAC.
Deep Learning for Non-Invasive Cortical Potential Imaging
Authors: Razorenova Alexandra , Yavich Nikolay , Malovichko Mikhail , Fedorov Maxim , Koshev Nikolay , Dylov Dmitry V.
Published: June 2020

Electroencephalography (EEG) is a well-established non-invasive technique to measure the brain activity, albeit with a limited spatial resolution. Variations in electric conductivity between different tissues distort the electric fields generated by cortical sources, resulting in smeared potential measurements on the scalp. One needs to solve an ill-posed inverse problem to recover the original neural activity. In this article, we present a generic method of recovering the cortical potentials from the EEG measurement by introducing a new inverse-problem solver based on deep Convolutional Neural Networks (CNN) in paired (U-Net) and unpaired (DualGAN) configurations. The solvers were trained on synthetic EEG-ECoG pairs that were generated using a head conductivity model computed using the Finite Element Method (FEM). These solvers are the first of their kind, that provide robust translation of EEG data to the cortex surface using deep learning. Providing a fast and accurate interpretation of the tracked EEG signal, our approach promises a boost to the spatial resolution of the future EEG devices.
Characterization and validation of 16 α-synuclein conformation-specific antibodies using well-characterized preparations of α-synuclein monomers, fibrils and oligomers with distinct structures and morphology: How specific are the conformation-specific α-synuclein antibodies?
Authors: Kumar Senthil T. , Jagannath Somanath , Francois Cindy , Vanderstichele Hugo , Stoops Erik , Lashuel Hilal A.
Published: June 2020

Increasing evidence suggests that alpha-synuclein (α-syn) oligomers are obligate intermediates in the pathway involved in α-syn fibrillization and Lewy body (LB) formation, and may also accumulate within LBs in Parkinson’s disease (PD) and other synucleinopathies. Therefore, the development of tools and methods to detect and quantify α-syn oligomers has become increasingly crucial for mechanistic studies to understand the role of these oligomers in PD, and to develop new diagnostic methods and therapies for PD and other synucleinopathies. The majority of these tools and methods rely primarily on the use of aggregation state-specific or conformation-specific antibodies. Given the impact of the data and knowledge generated using these antibodies on shaping the foundation and directions of α-syn and PD research, it is crucial that these antibodies are thoroughly characterized, and their specificity or ability to capture diverse α-syn species is tested and validated. Herein, we describe an antibody characterization and validation pipeline that allows a systematic investigation of the specificity of α-syn antibodies using well-defined and well-characterized preparations of various α-syn species, including monomers, fibrils, and different oligomer preparations that are characterized by distinct morphological, chemical and secondary structure properties. This pipeline was used to characterize 18 α-syn antibodies, 16 of which have been reported as conformation- or oligomer-specific antibodies, using an array of techniques, including immunoblot analysis (slot blot and Western blot), a digital ELISA assay using single molecule array technology and surface plasmon resonance. Our results show that i) none of the antibodies tested are specific for one particular type of α-syn species, including monomers, oligomers or fibrils; ii) all antibodies that were reported to be oligomer-specific also recognized fibrillar α-syn; and iii) a few antibodies showed high specificity for oligomers and fibrils but did not bind to monomers. These findings suggest that the great majority of α-syn aggregate-specific antibodies do not differentiate between oligomers and fibrils, thus highlighting the importance of exercising caution when interpreting results obtained using these antibodies. Our results also underscore the critical importance of the characterization and validation of antibodies before their use in mechanistic studies and as diagnostic and therapeutic agents. This will not only improve the quality and reproducibility of research and reduce costs but will also reduce the number of therapeutic antibody failures in the clinic.
DILS: Demographic Inferences with Linked Selection by using ABC
Authors: Fraïsse Christelle , Popovic Iva , Mazoyer Clément , Spataro Bruno , Delmotte Stéphane , Romiguier Jonathan , Loire Étienne , Simon Alexis , Galtier Nicolas , Duret Laurent , Bierne Nicolas , Vekemans Xavier , Roux Camille
Published: June 2020

We present DILS, a deployable statistical analysis platform for conducting demographic inferences with linked selection from population genomic data using an Approximate Bayesian Computation framework. DILS takes as input single-population or two-population datasets (multilocus fasta sequences) and performs three types of analyses in a hierarchical manner, identifying: 1) the best demographic model to study the importance of gene flow and population size change on the genetic patterns of polymorphism and divergence, 2) the best genomic model to determine whether the effective sizeNeand migration rateN.mare heterogeneously distributed along the genome (implying linked selection) and 3) loci in genomic regions most associated with barriers to gene flow. Also availableviaa web interface, an objective of DILS is to facilitate collaborative research in speciation genomics. Here, we show the performance and limitations of DILS by using simulations, and finally apply the method to published data on a divergence continuum composed by 28 pairs ofMytilusmussel populations/species.
The Effect of Between-Probe Variability in Haptic Feedback on Stiffness Perception and Grip Force Adjustment
Authors: Kossowsky Hanna , Farajian Mor , Milstein Amit , Nisky Ilana
Published: June 2020

When interacting with objects, haptic information is used to create perception of the object stiffness and to regulate grip force. Studies have shown that introducing noise into sensory inputs can create uncertainty in those sensory channels, yet a method of creating haptic uncertainty without distorting the haptic information has yet to be discovered. Toward this end, we investigated the effect of between-probe haptic variability on stiffness perception and grip force control. In a stiffness discrimination task, we added different levels of between-probe haptic variability by changing the stiffness of the force fields between consecutive probes. Unlike the low and high variability levels, the medium level created perceptual haptic uncertainty. Additionally, we ascertained that participants calculated a weighted average of the different stiffness levels applied by a given force field. Examining participants’ grip force showed that the modulation of the grip force with the load force decreased with repeated exposure to the force field, whereas no change in the baseline was observed. These results were observed in all the variability levels and suggest that between-probe variability created haptic uncertainty that affected the grip force control. Overall, the medium variability level can be effective in inducing uncertainty in both perception and action.
Mapping RNA dependent RNA polymerase activity and immune gene expression using PRO-seq
Authors: Mahajan Lakshmi S. , Kim Grace Eunyoo , Kwak Hojoong
Published: June 2020

Positive strand, single strand RNA viruses ((+)ssRNA viruses) are viruses with an RNA genome that have broad impacts on a wide range of hosts, including SARS-CoV-2 human respiratory infections. Their replication and gene expression are driven by RNA dependent RNA polymerases (RdRp). Detecting active RNA synthesis by RdRp is critical for assessing the infectivity and pathogenicity of (+)ssRNA viruses. Current approaches rely on viral RNA detection, which cannot distinguish viral titer from RdRp activity. Precision Run-On sequencing (PRO-seq) is a nuclear run-on based nascent RNA sequencing method, widely used to map eukaryotic RNA polymerases by using labeled nucleotide analogues. Here we provide evidence that PRO-seq also detects RdRp activity and can serve as a highly sensitive RdRp mapping method. Coupled to PRO-seq in human blood samples, we propose to use PRO-seq as a single package method to detect (+)ssRNA virus RdRp activity and its interaction with host immune response through transcriptome-wide profiling of leukocyte gene expressions at once.
Exposure to artemisinin at the trophozoite stage increases sexual conversion rates in the malaria parasite Plasmodium falciparum
Authors: Portugaliza Harvie P. , Miyazaki Shinya , Geurten Fiona J.A. , Pell Christopher , Rosanas-Urgell Anna , Janse Chris J. , Cortés Alfred
Published: June 2020

Malaria transmission is dependent on formation of gametocytes in the human blood. The sexual conversion rate, the proportion of asexual parasites that convert into gametocytes at each multiplication cycle, is variable and reflects the relative parasite investment between transmission and maintaining the infection. The impact of environmental factors such as drugs on sexual conversion rates is not well understood. We developed a robust assay using gametocyte-reporter parasite lines to accurately measure the impact of drugs on conversion rates, independently from their gametocytocidal activity. We found that exposure to subcurative doses of the frontline antimalarial drug dihydroartemisinin (DHA) at the trophozoite stage resulted in a ~4-fold increase in sexual conversion. In contrast, no increase was observed when ring stages were exposed or in cultures in which sexual conversion was stimulated by choline depletion. Our results reveal a complex relationship between antimalarial drugs and sexual conversion, with potential public health implications.
Cumulative effect of aging and SARS-CoV2 infection on poor prognosis in the elderly: Insights from transcriptomic analysis of lung and blood
Authors: Bhattacharyya Upasana , Thelma B K
Published: June 2020

Introduction

The ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 2) has affected millions of people worldwide and with notable heterogeneity in its clinical presentation. Probability of contracting this highly contagious infection is similar across age groups but disease severity and fatality among aged patients with or without comorbidities are higher. We hypothesized that SARS-CoV-2 infection may augment aging-related gene expression alterations resulting in severe outcomes in elderly patients.

Methodology

We performed a comparative analysis of publicly available transcriptome data from Broncho Alveolar Lavage Fluid (BALF)/lung/blood of healthy aging group with i) COVID-19 patients; and ii) data of host genes interacting with SARS-CoV-2 proteins.

Results

We observed i) a significant overlap of gene expression profiles of patients’ BALF and blood with lung and blood of the healthy group respectively; ii) a more pronounced overlap in blood compared to lung; and iii) a similar overlap between host genes interacting with SARS-CoV-2 and aging blood transcriptome.

Conclusions

Pathway enrichment analysis of overlapping gene sets suggests that infection alters expression of genes already dysregulated in the elderly, which together may lead to poor prognosis. eQTLs in these genes may also confer poor outcome in young patients worsening with age and co-morbidities. Furthermore, the pronounced overlap observed in blood may explain clinical symptoms including blood clots, strokes, heart attack, multi-organ failure etc. in severe cases. This model based on a limited patient dataset seems robust and holds promise for testing larger tissue specific datasets from patients with varied severity and across populations.
Visually-evoked choice behavior driven by distinct population computations with non-sensory neurons in visual cortical areas
Authors: Osako Yuma , Ohnuki Tomoya , Tanisumi Yuta , Shiotani Kazuki , Manabe Hiroyuki , Sakurai Yoshio , Hirokawa Junya
Published: June 2020

It is widely assumed that variability in visual detection performance is attributed to the fidelity of the visual responses in visual cortical areas, which could be modulated by fluctuations of internal states such as vigilance and behavioral history. However, it is not clear what neural ensembles represent such different internal states. Here, we utilized a visual detection task, which distinguishes perceptual states to identical stimuli, while recording neurons simultaneously from the primary visual cortex (V1) and the posterior parietal cortex (PPC). We found distinct population dynamics segregating hit responses from misses despite no clear differences in visual responses. The population-level computation was significantly contributed by heterogenous non-sensory neurons in V1, whereas the contribution from non-neurons with the previous outcome selectivity was prominent in PPC. These results indicate different contributions of non-sensory neurons in V1 and PPC for the population-level computation that enables behavioral responses from visual information.
μSPIM: A Software Platform for Selective Plane Illumination Microscopy
Authors: Saska Daniel , Pichler Paul , Qian Chen , Pegasiou Chrysia , Buckley Christopher L. , Lagnado Leon
Published: June 2020

Selective Plane Illumination Microscopy (SPIM) is a fluorescence imaging technique that allows volumetric imaging at high spatio-temporal resolution to monitor neural activity in live organisms such as larval zebrafish. A major challenge in the construction of a custom SPIM microscope is the control and synchronization of the various hardware components. Here we present a control toolset, μSPIM, built around the open-source MicroManager platform that has already been widely adopted for the control of microscopy hardware. Installation of μSPIM is relatively straightforward, involving a single C++ executable and a Java-based extension to Micro-Manager. Imaging protocols are defined through the μSPIM extension to Micro-Manager. The extension then synchronizes the camera shutter with the galvanometer mirrors to create a light-sheet that is scanned in the z-dimension, in synchrony with the imaging objective, to produce volumetric recordings. A key advantage of μSPIM is that a series of calibration procedures optimizes acquisition for a given set-up making it relatively independent of the optical design of the microscope, or the hardware used to build it. Two laser illumination arms can be used while also allowing for the introduction of illumination masks. μSPIM allows imaging of calcium activity throughout the brain of larval zebrafish at rates of 100 planes per second with single cell resolution as well as slower imaging to reconstruct cell populations, for example, in the cleared brains of mice.
Dynamics of Tpm1.8 domains on actin filaments with single molecule resolution
Authors: Bareja Ilina , Wioland Hugo , Janco Miro , Nicovich Philip R. , Jégou Antoine , Romet-Lemonne Guillaume , Walsh James , Böcking Till
Published: June 2020

Tropomyosins regulate dynamics and functions of the actin cytoskeleton by forming long chains along the two strands of actin filaments that act as gatekeepers for the binding of other actin-binding proteins. The fundamental molecular interactions underlying the binding of tropomyosin to actin are still poorly understood. Using microfluidics and fluorescence microscopy, we observed the binding of fluorescently labelled tropomyosin isoform Tpm1.8 to unlabelled actin filaments in real time. This approach in conjunction with mathematical modeling enabled us to quantify the nucleation, assembly and disassembly kinetics of Tpm1.8 on single filaments and at the single molecule level. Our analysis suggests that Tpm1.8 decorates the two strands of the actin filament independently. Nucleation of a growing tropomyosin domain proceeds with high probability as soon as the first Tpm1.8 molecule is stabilised by the addition of a second molecule, ultimately leading to full decoration of the actin filament. In addition, Tpm1.8 domains are asymmetrical, with enhanced dynamics at the edge oriented towards the barbed end of the actin filament. The complete description of Tpm1.8 kinetics on actin filaments presented here provides molecular insight into actin-tropomyosin filament formation and the role of tropomyosins in regulating actin filament dynamics.
Phase dynamics of cerebral blood flow in subarachnoid haemorrhage in response to sodium nitrite infusion
Authors: Ezra Martyn , Garry Payashi , Rowland Matthew J , Mitsis Georgios D , Pattinson Kyle TS
Published: June 2020

Aneurysmal subarachnoid haemorrhage (SAH) is a devastating subset of stroke. One of the major determinates of morbidity is the development of delayed cerebral ischemia (DCI). Disruption of the nitric oxide (NO) pathway and consequently the control of cerebral blood flow (CBF), known as cerebral autoregulation, is believed to play a role in its pathophysiology. Through the pharmacological manipulation ofin vivoNO levels using an exogenous NO donor we sought to explore this relationship.

Phase synchronisation index (PSI), an expression of the interdependence between CBF and arterial blood pressure (ABP) and thus cerebral autoregulation, was calculated before and during sodium nitrite administration in 10 high-grade SAH patients acutely postrupture. In patients that did not develop DCI, there was a significant increase in PSI around 0.1 Hz during the administration of sodium nitrite (33%; p-value 0.006). In patients that developed DCI, PSI did not change significantly.

Synchronisation between ABP and CBF at 0.1 Hz has been proposed as a mechanism by which organ perfusion is maintained, during periods of physiological stress. These findings suggest that functional NO depletion plays a role in impaired cerebral autoregulation following SAH, but the development of DCI may have a distinct pathophysiological aetiology.
Demonstration of re-epithelialization in a bioprinted human skin equivalent wound model
Authors: Jara Carlos Poblete , Catarino Carolina Motter , Lei Yuguo , Velloso Lício Augusto , Karande Pankaj , Velander William H. , de Araujo Eliana Pereira
Published: June 2020

Objective

The development of an in vitro platform for modeling human skin injury and the re-epithelization process.

Approach

A fibrin provisional matrix (FPM) was installed into a wound facsimile of a bioprinted human skin equivalent (HSE). A mixture of plasma-derived fibrinogen-containing factor XIII, fibronectin, thrombin, and macrophages (an FPM “bioink”) was extruded into the wound site. The surroundingin vitrotissue culture became a source of keratinocytes to achieve wound closure by a re-epithelialization process signaled by the FPM.

Results

Anin vitroanalog of wound closure and re-epithelialization by keratinocytes occurred over the FPM after a normal migration initiation at 3 days.

Innovation

A physiologic mixture of macrophage/fibrinogen/fibronectin that supports macrophage differentiation was applied to a mechanically wounded, bioprinted dermal tissue. We developed a transitional culture medium to mimic the changing microenvironment during the initial phases of wound healing. As a reference, we temporally compared ourin vitromodel with a murine skin wound healing.

Conclusion

This co-culture model was shown to temporally synchronize a re-epithelization process for initiation of keratinocyte migration from a surrounding tissue and the migration process over the top of an FPM. A future study of the analogous subepithelial healing pathway is envisioned using the samein vitrobioprinted tissue study platform for co-culture of keratinocytes, melanocytes, fibroblasts, endothelial cells, and macrophages using more specialized FPMs.
Categorical judgments do not modify sensory information in working memory
Authors: Luu Long , Stocker Alan A.
Published: June 2020

Categorical judgments can systematically bias the perceptual interpretation of stimulus features. However, it remained unclear whether categorical judgments directly modify working memory representations or, alternatively, generate these biases via an inference process down-stream from working memory. To address this question we ran two novel psychophysical experiments in which human subjects had to revert their categorical judgments about a stimulus feature, if incorrect based on feedback, before providing an estimate of the feature. If categorical judgments indeed directly altered sensory representations in working memory, subjects’ estimates should reflect some aspects of their initial (incorrect) categorical judgment in those trials.

We found no traces of the initial categorical judgment. Rather, subjects seem to be able to flexibly switch their categorical judgment if needed and use the correct corresponding categorical prior to properly perform feature inference. A cross-validated model comparison also revealed that feedback may lead to selective memory recall such that only memory samples that are consistent with the categorical judgment are accepted for the inference process. Our results suggest that categorical judgments do not modify sensory information in working memory but rather act as top-down expectation in the subsequent sensory recall and inference process down-stream from working memory.
Genetic Variation Regulates Opioid-Induced Respiratory Depression in Mice
Authors: Bubier Jason A. , He Hao , Philip Vivek M. , Roy Tyler , Hernandez Christian Monroy , Donohue Kevin D. , O’Hara Bruce F. , Chesler Elissa J.
Published: June 2020

In the U.S., opioid prescription for treatment of pain nearly quadrupled from 1999 to 2014, leading to an epidemic in addiction and overdose deaths. The most common cause of opioid overdose and death is opioid-induced respiratory depression (OIRD), a life-threatening depression in respiratory rate thought to be caused by stimulation of opioid receptors in the inspiratory-generating regions of the brain. Studies in mice have revealed that variation in opiate lethality is associated with strain differences, suggesting that sensitivity to OIRD is genetically determined. We first tested the hypothesis that genetic variation in inbred strains of mice influences the innate variability in opioid-induced responses in respiratory depression, recovery time and survival time. Using the founders of the advanced, high-diversity mouse populations, the Collaborative Cross (CC) and Diversity Outbred (DO), we found substantial sex and genetic effects on respiratory sensitivity and opiate lethality. To define genetic modifiers of OIRD, we then used the high precision DO population treated with morphine to map and identify quantitative trait loci (QTL) for respiratory depression, recovery time and survival time. Trait mapping and integrative functional genomic analysis in GeneWeaver has allowed us to implicateGalnt11, an N-acetylgalactosaminyltransferase, as a candidate gene that regulates OIRD.
STACAS: Sub-Type Anchor Correction for Alignment in Seurat to integrate single-cell RNA-seq data
Authors: Andreatta Massimo , Carmona Santiago J.
Published: June 2020

Computational tools for the integration of single-cell transcriptomics data are designed to correct batch effects between technical replicates or different technologies applied to the same population of cells. However, they have inherent limitations when applied to heterogeneous sets of data with moderate overlap in cell states or sub-types. STACAS is a package for the identification of integration anchors in the Seurat environment, optimized for the integration of datasets that share only a subset of cell types. We demonstrate that byi)correcting batch effects while preserving relevant biological variability across datasets,ii)filtering aberrant integration anchors with a quantitative distance measure, andiii)constructing optimal guide trees for integration, STACAS can accurately align scRNA-seq datasets composed of only partially overlapping cell populations. We anticipate that the algorithm will be a useful tool for the construction of comprehensive single-cell atlases by integration of the growing amount of single-cell data becoming available in public repositories.

Code availability

R package:https://github.com/carmonalab/STACAS

Docker image:https://hub.docker.com/repository/docker/mandrea1/stacas_demo