bluuebunny/crossref_metadata_2025 huggingface dataset:
Multi-tract multi-symptom relationships in pediatric concussion
Authors: Guberman Guido I. , Stojanovski Sonja , Nishat Eman , Ptito Alain , Bzdok Danilo , Wheeler Anne , Descoteaux Maxime
Published: April 2021

The heterogeneity of white matter damage and symptoms in concussion has been identified as a major obstacle to therapeutic innovation. In contrast, most diffusion MRI (dMRI) studies on concussion have traditionally relied on group-comparison approaches that average out heterogeneity. To leverage, rather than average out, concussion heterogeneity, we combined dMRI and multivariate statistics to characterize multi-tract multi-symptom relationships. Using cross-sectional data from 306 previously-concussed children aged 9-10 from the Adolescent Brain Cognitive Development Study, we built connectomes weighted by classical and emerging diffusion measures. These measures were combined into two informative indices, the first representing microstructural complexity, the second representing axonal density. We deployed pattern-learning algorithms to jointly decompose these connectivity features and 19 symptom measures. We found multivariate connectivity-symptom correspondences that were stronger than all single-tract single-symptom associations. Expression of multi-tract features was not driven by sociodemographic and injury-related variables. In a replication dataset, the expression of multi-tract features predicted psychiatric diagnoses after accounting for other psychopathology-related variables. These clinically-informative, cross-demographic multi-tract multi-symptom relationships recapitulated well-known findings from the concussion literature and revealed new insights about white matter structure/symptom relationships. These results may pave the way for the development of improved stratification strategies and the development of predictive biomarkers for personalized concussion management approaches.
Evaluating the Risk of Psilocybin for the Treatment of Bipolar Depression: A Review of the Research Literature and Published Case Studies
Authors: Gard David E. , Pleet Mollie M. , Bradley Ellen R. , Penn Andrew , Gallenstein Matthew L. , Riley Lauren S. , DellaCrosse Meghan , Garfinkle Emily , Michalak Erin E. , Woolley Joshua D.
Published: April 2021

Growing evidence suggests that psilocybin, the active ingredient in hallucinogenic mushrooms, can rapidly and durably improve symptoms of depression, leading to recent breakthrough status designation by the FDA and legalization for mental health treatment in some jurisdictions. Depression in bipolar disorder is associated with significant morbidity and has few effective treatments. However, there is little available scientific data on the risk of psilocybin use in people with bipolar disorder. Individuals with bipolar disorder have been excluded from modern clinical trials, out of understandable concerns of activating mania or worsening the illness course. As psilocybin becomes more available, people with these disorders will likely seek psilocybin treatment for depression and have likely already been doing so in unregulated settings. Our goal here is to summarize the known risks of psilocybin use (and similar substances) in bipolar disorder and to systematically evaluate examples of published case history data, in order to critically evaluate the relative risk of psilocybin as a treatment for bipolar depression. We found 17 cases suggesting that there is potential risk for activating a manic episode, thereby warranting caution. Nonetheless, the relative lack of systematic data or common case examples indicating risk appears to show that a cautious trial, using modern trial methods focusing on appropriate ‘set’ and ‘setting’, targeted at those lowest at risk for mania in the bipolar spectrum (e.g., bipolar 2 disorder), is very much needed, especially given the degree to which depression impacts this population.
Genomic Sequencing of SARS-CoV-2 in Rwanda: evolution and regional dynamics
Authors: Butera Yvan , Mukantwari Enatha , Artesi Maria , D’Arc Umuringa Jeanne , O’Toole Áine Niamh , Hill Verity , Rooke Stefan , Hong Samuel Leandro , Dellicour Simon , Majyambere Onesphore , Bontems Sebastien , Boujemla Bouchra , Quick Josh , Resende Paola Cristina , Loman Nick , Umumararungu Esperance , Kabanda Alice , Murindahabi Marylin Milumbu , Tuyisenge Patrick , Gashegu Misbah , Rwabihama Jean Paul , Sindayiheba Reuben , Gikic Djordje , Souopgui Jacob , Ndifon Wilfred , Rutayisire Robert , Gatare Swaibu , Mpunga Tharcisse , Ngamije Daniel , Bours Vincent , Rambaut Andrew , Nsanzimana Sabin , Baele Guy , Durkin Keith , Mutesa Leon , Rujeni Nadine
Published: April 2021

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for coronavirus disease 19 (COVID-19), is a single-stranded positive-sense ribonucleic acid (RNA) virus that typically undergoes one to two single nucleotide mutations per month. COVID-19 continues to spread globally, with case fatality and test positivity rates often linked to locally circulating strains of SARS-CoV-2. Furthermore, mutations in this virus, in particular those occurring in the spike protein (involved in the virus binding to the host epithelial cells) have potential implications in current vaccination efforts. In Rwanda, more than twenty thousand cases have been confirmed as of March 14th 2021, with a case fatality rate of 1.4% and test positivity rate of 2.3% while the recovery rate is at 91.9%. Rwanda started its genomic surveillance efforts, taking advantage of pre-existing research projects and partnerships, to ensure early detection of SARS-CoV-2 variants and to potentially contain the spread of variants of concern (VOC). As a result of this initiative, we here present 203 SARS-CoV-2 whole genome sequences analyzed from strains circulating in the country from May 2020 to February 2021. In particular, we report a shift in variant distribution towards the newly emerging sub-lineage A.23.1 that is currently dominating. Furthermore, we report the detection of the first Rwandan cases of the VOCs, B.1.1.7 and B.1.351, among incoming travelers tested at Kigali International Airport. We also discuss the potential impact of COVID-19 control measures established in the country to control the spread of the virus. To assess the importance of viral introductions from neighboring countries and local transmission, we exploit available individual travel history metadata to inform spatio-temporal phylogeographic inference, enabling us to take into account infections from unsampled locations during the time frame of interest. We uncover an important role of neighboring countries in seeding introductions into Rwanda, including those from which no genomic sequences are currently available or that no longer report positive cases. Our results point to the importance of systematically screening all incoming travelers, regardless of the origin of their travels, as well as regional collaborations for durable response to COVID-19.
Impact of a nighttime curfew on overnight mobility
Authors: Ghasemi Amir , Daneman Nick , Berry Isha , Buchan Sarah A. , Soucy Jean-Paul , Sturrock Shelby , Brown Kevin A.
Published: April 2021

Background

Among non-pharmaceutical interventions, individual movement restrictions have been among the most impactful methods for controlling COVID-19 case growth. While nighttime curfews to control COVID-19 case growth have been implemented in certain regions and cities, few studies have examined their impacts on mobility or COVID-19 incidence. In the second wave of COVID-19, Canada’s two largest and adjacent provinces implemented lockdown restrictions with (Quebec) and without (Ontario) a nighttime curfew, providing a natural experiment to study the association between curfews and mobility.

Methods

This study spanned from December 1, 2020 to January 23, 2021 and included the populations of Ontario (including Toronto) and Quebec (including Montreal). The intervention of interest was a nighttime curfew implemented across Quebec on January 9, 2021. Unadjusted and adjusted difference-in-differences models (DID) were used to measure the incremental impact of the curfew on nighttime mobility in Quebec as compared to Ontario.

Results

The implementation of the curfew was associated with an immediate reduction in nighttime mobility. The adjusted DID analysis indicated that Quebec experienced a 31% relative reduction in nighttime mobility (95%CI: -36% to -25%) compared to Ontario, and that Montreal experienced a 39% relative reduction compared to Toronto (95%CI: -43, -34).

Discussion

However, this natural experiment among two neighbouring provinces provides useful evidence that curfews lead to an immediate and substantial decrease nighttime mobility, particularly in these provinces’ largest urban areas hardest hit by COVID-19.
Quantification of specific antibodies against SARS-CoV-2 in breast milk of lactating women vaccinated with an mRNA vaccine
Authors: Esteve-Palau Erika , Gonzalez-Cuevas Araceli , Guerrero M. Eugenia , Garcia-Terol Clara , Alvarez M. Carmen , Garcia-Aranda Geneva , Casadevall David , Diaz-Brito Vicens
Published: April 2021

The recent approval of vaccines against COVID-19 has generated great concern among breastfeeding women, since these patients were excluded from vaccination clinical trials. The present study aimed to analyze the levels of specific SARS-CoV-2 antibodies in breast milk of mRNA-vaccinated women across time and their correlation with serum antibody levels.

Methods

prospective study including lactating women aged over 18 who were vaccinated against SARS-CoV-2 with the Pfizer-BioNTech® COVID-19 vaccine (BNT162b2). Paired serum and breast milk samples were simultaneously taken from each participant at three timepoints after receiving the vaccine: 2 weeks after 1st dose, 2 weeks after 2nd dose and 4 weeks after 2nd dose (Timepoints 1, 2 and 3, respectively). Levels of IgG antibodies against the spike protein (S1 subunit) were determined for each sample (Architect, Abbott®).

Results

we collected and analyzed 52 serum and 52 milk samples from the first 18 study participants. Median (interquartile range) IgG(S1) levels for serum – milk pairs at each timepoint were 410 (208-606) - 1.7 (0-2.9) AU/ml at Timepoint 1, 11505 (8933 - 21184) – 52.2 (34.1-113) at Timepoint 2 and 8311 (5578-17419) – 41.7 (24.8-75.3) at Timepoint 3. Pearson’s correlation coefficient between breast milk and serum IgG(S1) levels was 0.71. No major adverse reactions were observed in mothers or infants.

Conclusions

Breast milk from women vaccinated with mRNA-based Pfizer-BioNTech® vaccine contains specific anti-SARS-CoV-2 IgG(S1) antibodies, with levels increasing considerably after second dose. IgG(S1) levels in breast milk are positively correlated with corresponding serum levels.
Systematic Review: Recommendations for Rehabilitation in ASD and ID from Clinical Practice Guidelines
Authors: Wickstrom Jordan , Dell’Armo Kristin , Salzman Emma , Hooker Jessica L. , Delehanty Abigail , Bishop Somer , Tassé Marc J. , Wetherby Amy M. , Piergies Antonia M. H. , Damiano Diane , Rauch Alexandra , Thurm Audrey
Published: April 2021

Objective

Autism spectrum disorder (ASD) and intellectual disability (ID) were selected for inclusion in the development of a Package of Interventions for Rehabilitation for the World Health Organization (WHO). Here, we describe results of a search of guidelines for these conditions.

Methods

A literature search for clinical practice guidelines was performed for ASD and ID. Using the Appraisal of Guidelines for Research and Evaluation instrument and other inclusion and exclusion criteria, guidelines were identified for abstraction of recommendations, which were collated into categories based on diagnosis, patient age, type and target of service, valence, and level of evidence.

Results

Six guidelines remained after screening. Four ASD guidelines focused on diagnosis, management and support, and two ID guidelines covered the prevention, assessment, and management of challenging behavior and mental health problems, with 386 and 138 recommendations resulting for each group, respectively. Out of 524 total recommendations, 212 ASD and 58 ID recommendations focused on intervention. The primary type of intervention pertained to pharmacology for each group (27% ASD, 29% ID), followed by psychosocial (21%) and biomedical (23%) for ASD and behavioral (14%) and psychological (14%) for ID. Regarding target of intervention, recommendations primarily focused on coexisting conditions for each group (56% ASD, 93% ID) and core symptoms for ASD (26%), whereas adaptive functioning received little attention (11% ASD, 7% ID).

Conclusions

Although these six guidelines provided many recommendations for comorbid and specific problems in ASD and ID, very few recommendations targeted core symptoms, and many were based on expert opinion. A vital next step includes identifying relevant interventions from the guidelines or that are missing to be included in the WHO Package of Interventions for Rehabilitation.
No Evidence of Infectious SARS-CoV-2 in Human Milk: Analysis of a Cohort of 110 Lactating Women
Authors: Krogstad Paul , Contreras Deisy , Ng Hwee , Tobin Nicole , Chambers Christina D. , Bertrand Kerri , Bode Lars , Aldrovandi Grace
Published: April 2021

Background

SARS-CoV-2 infections of infants and toddlers are usually mild but can result in life-threatening disease. SARS-CoV-2 RNA been detected in the breast milk of lactating women, but the potential role of breastfeeding in transmission to infants has remained uncertain.

Methods

Breast milk specimens were examined for the presence of the virus by RT-PCR and/or culture. Specimens that contained viral RNA (vRNA) were examined for the presence of subgenomic coronavirus RNA (sgRNA), a putative marker of infectivity. Culture methods were used to determine the thermal stability of SARS-CoV-2 in human milk.

Results

Breast milk samples from 110 women (65 confirmed with a SARS-CoV-2 diagnostic test, 36 with symptoms but without tests, and 9 with symptoms but a negative SARS-CoV-2 diagnostic test) were tested by RT-PCR (285 samples) and/or viral culture (160 samples). Although vRNA of SARS-CoV-2 was detected in the milk of 7 of 110 (6%) women with either a confirmed infection or symptomatic illness, and in 6 of 65 (9%) of women with a positive SARS-CoV-2 diagnostic test, virus was not detected in any culture. None of the 7 milk specimens with detectable vRNA contained sgRNA. Notably, when artificially added to human milk in control experiments, infectious SARS-CoV-2 could be cultured despite several freeze-thaw cycles, as occurs in the storage and usage of human milk.

Conclusions

SARS-CoV-2 RNA can be found infrequently in the breastmilk of women with recent infection, but we found no evidence that breastmilk contains infectious virus or that breastfeeding represents a risk factor for transmission of infection to infants.

Key Points

Question

SARS-CoV-2 RNA has been detected in a small number of human milk samples collected from recently infected women. The role of breastfeeding in transmission of the virus to infants has remained uncertain due to the small number of specimens analyzed in any study published thus far.

Findings

In a total study group of 110 women, SARS-CoV-2 RNA was detected in milk from 6 of 65 women (9.2%) with recent confirmed infection. Neither infectious virus nor subgenomic RNA (a marker of virus infectivity) were detected in any of the samples.

Meaning

We found no evidence that infectious SARS-CoV-2 is present milk from recently infected women, even if SARS-CoV-2 PCR tests are positive, providing reassurance of the safety of breastfeeding.
Statistical Modeling of deaths due to COVID-19 influenced by social isolation in Latin American countries
Authors: da Silva Rafael André , de Souza Ferreira Luiz Philipe , Sampaio Leite Jean Michel Rocha , Tiraboshi Fernanda Assunção , Valente Thiago Maciel , de Paiva Roda Vinicius Moraes , Duarte Sanchez Jeniffer Johana
Published: April 2021

Social isolation is extremely important to minimize the effects of a pandemic. Latin American (LA) countries have similar socioeconomic characteristics and health system infrastructures. These countries face difficulties to deal with the COVID-19 pandemic and some of them had very high death rates. Government stringency index (GSI) of twelve LA countries was gathered from the Oxford COVID-19 Government Response Tracker (OxCGRT) project. GSI is calculated considering nine metrics of social distancing and isolation measures. Population data from the United Nations Population Fund and number of deaths data was collected from the dashboard of the World Health Organization (WHO). We performed an analysis of the period March-December using a mixed linear model approach. Peru, Brazil, Chile, Bolivia, Colombia, Argentina and Ecuador had the highest death rates with an increasing trend over time, while Suriname, Venezuela, Uruguay, Paraguay and Guyana had the lowest ones, which remained steady. GSI in most countries followed the same pattern during the analyzed months. i.e., high indices at the beginning of the pandemic and lower ones in the last evaluated months, while the number of deaths increased over the whole period. Almost no country kept its GSI high for a long time, especially from October to December. Time and GSI as well as their interaction were highly significant. As their interaction increases, death rate decreases. In conclusion, a higher GSI at the start of the pandemic COVID-19 would impact on the decrease in the number of deaths over time, in LA countries.
A Consensus Definition of Misophonia: Using a Delphi Process to Reach Expert Agreement
Authors: Swedo Susan , Baguley David M. , Denys Damiaan , Dixon Laura J. , Erfanian Mercede , Fioretti Alessandra , Jastreboff Pawel J. , Kumar Sukhbinder , Rosenthal M. Zachary , Rouw Romke , Schiller Daniela , Simner Julia , Storch Eric A. , Taylor Steven , Werff Kathy R. Vander , Raver Sylvina M.
Published: April 2021

Misophonia is a disorder of decreased tolerance to specific sounds or their associated stimuli that has been characterized using different language and methodologies. The absence of a common understanding or foundational definition of misophonia hinders progress in research to understand the disorder and develop effective treatments for individuals suffering from misophonia. From June 2020 through January 2021, a project was conducted to determine whether a committee of experts with diverse expertise related to misophonia could develop a consensus definition of misophonia. An expert committee used a modified Delphi method to evaluate candidate definitional statements that were identified through a systematic review of the published literature. Over four rounds of iterative voting, revision, and exclusion, the committee made decisions to include, exclude, or revise these statements in the definition based on the currently available scientific and clinical evidence. A definitional statement was included in the final definition only after reaching consensus at 80% or more of the committee agreeing with its premise and phrasing. The results of this rigorous consensus-building process were compiled into a final definition of misophonia that is presented here. This definition will serve as an important step to bring cohesion to the growing field of researchers and clinicians who seek to better understand and support individuals experiencing misophonia.
Ageing impairs the airway epithelium defence response to SARS-CoV-2
Authors: Capraro Alexander , Wong Sharon L , Adhikari Anurag , Allan Katelin M , Patel Hardip R , Zhong Ling , Raftery Mark , Jaffe Adam , Yeang Malinna , Aggarwal Anupriya , Wu Lindsay , Pandzic Elvis , Whan Renee M , Turville Stuart , Vittorio Orazio , Bull Rowena A , Kaakoush Nadeem , Rawlinson William D , Tedla Nicodemus , Vafaee Fatemeh , Waters Shafagh A
Published: April 2021

Age-dependent differences in the clinical response to SARS-CoV-2 infection is well-documented1–3however the underlying molecular mechanisms involved are poorly understood. We infected fully differentiated human nasal epithelium cultures derived from healthy children (1-12 years old), young adults (26-34 years old) and older adults (56-62 years old) with SARS-COV-2 to identify age-related cell-intrinsic differences that may influence viral entry, replication and host defence response. We integrated imaging, transcriptomics, proteomics and biochemical assays revealing age-related changes in transcriptional regulation that impact viral replication, effectiveness of host responses and therapeutic drug targets. Viral load was lowest in infected older adult cultures despite the highest expression of SARS-CoV-2 entry and detection factors. We showed this was likely due to lower expression of hijacked host machinery essential for viral replication. Unlike the nasal epithelium of young adults and children, global host response and induction of the interferon signalling was profoundly impaired in older adults, which preferentially expressed proinflammatory cytokines mirroring the “cytokine storm” seen in severe COVID-194,5.In silicoscreening of our virus-host-drug network identified drug classes with higher efficacy in older adults. Collectively, our data suggests that cellular alterations that occur during ageing impact the ability for the host nasal epithelium to respond to SARS-CoV-2 infection which could guide future therapeutic strategies.
Murine monoclonal antibodies against RBD of SARS-CoV-2 neutralize authentic wild type SARS-CoV-2 as well as B.1.1.7 and B.1.351 viruses and protectin vivoin a mouse model in a neutralization dependent manner
Authors: Amanat Fatima , Strohmeier Shirin , Lee Wen-Hsin , Bangaru Sandhya , Ward Andrew B. , Coughlan Lynda , Krammer Florian
Published: April 2021

After first emerging in December 2019 in China, severe acute respiratory syndrome 2 (SARS-CoV-2) has since caused a pandemic leading to millions of infections and deaths worldwide. Vaccines have been developed and authorized but supply of these vaccines is currently limited. With new variants of the virus now emerging and spreading globally, it is essential to develop therapeutics that are broadly protective and bind conserved epitopes in the receptor binding domain (RBD) or the whole spike of SARS-CoV-2. In this study, we have generated mouse monoclonal antibodies (mAbs) against different epitopes on the RBD and assessed binding and neutralization against authentic SARS-CoV-2. We have demonstrated that antibodies with neutralizing activity, but not non-neutralizing antibodies, lower viral titers in the lungs when administered in a prophylactic settingin vivoin a mouse challenge model. In addition, most of the mAbs cross-neutralize the B.1.351 as well as the B.1.1.7 variantsin vitro.

Importance

Crossneutralization of SARS-CoV-2 variants by RBD-targeting antibodies is still not well understood and very little is known about the potential protective effect of non-neutralizing antibodiesin vivo. Using a panel of mouse monoclonal antibodies, we investigate both of these aspects.
Impacts of Morally Distressing Experiences on the Mental Health of Canadian Health Care Workers During the COVID-19 Pandemic
Authors: Plouffe Rachel A. , Nazarov Anthony , Forchuk Callista A. , Gargala Dominic , Deda Erisa , Le Tri , Bourret-Gheysen Jesse , Jackson Brittni , Soares Vanessa , Hosseiny Fardous , Smith Patrick , Roth Maya , MacDougall Arlene G. , Marlborough Michelle , Jetly Rakesh , Heber Alexandra , Albuquerque Joy , Lanius Ruth , Balderson Ken , Dupuis Gabrielle , Mehta Viraj , Richardson J. Don
Published: April 2021

Objective

Research is urgently needed to understand health care workers’ (HCWs’) experiences of moral-ethical dilemmas encountered throughout the COVID-19 pandemic, and their associations with organizational perceptions and personal well-being. The purpose of this research is to evaluate associations between workplace experiences during COVID-19, moral distress, and the psychological well-being of Canadian HCWs.

Method

A total of 1383 French- and English-speaking Canadian HCWs employed during the COVID-19 pandemic were recruited to participate in an online survey. Participants completed measures reflecting moral distress, perceptions of organizational response to the pandemic, burnout, and symptoms of psychological disorders, including depression, anxiety, and posttraumatic stress disorder.

Results

Structural equation modeling showed that when organizational predictors were considered together, resource adequacy, positive work life impact, and ethical work environment negatively predicted severity of moral distress, whereas COVID-19 risk perception positively predicted severity of moral distress. Moral distress also significantly and positively predicted symptoms of depression, anxiety, PTSD, and burnout.

Conclusions

Our findings highlight an urgent need for HCW organizations to implement strategies designed to prevent long-term moral and psychological distress within the workplace. Ensuring availability of adequate resources, reducing HCW risk of contracting COVID-19, providing organizational support regarding individual priorities, and upholding ethical considerations are crucial to reducing severity of moral distress in HCWs.
Physiotherapists perceived role in managing anxiety in patients with Relapsing-Remitting Multiple Sclerosis: a mixed-methods study
Authors: Lucas Lauren , Parker Jack
Published: April 2021

Objectives

To explore how physiotherapists manage anxiety in patients with RRMS in community and outpatient settings. To identify further training and research to better develop physiotherapy practice.

Design

A mixed-methods design, combining a cross-sectional survey and semi-structured interviews with UK-physiotherapists.

Participants

Sixteen UK-registered physiotherapists: 11 in the survey, 5 in the interviews.

Methods

To inform the qualitative study, a cross-sectional survey collected data from physiotherapists working in neurology to understand the impact and management of anxiety in people with MS (PwMS) during rehabilitation. Analysis used descriptive statistics and the findings formed the interview guide. Semi-structured interviews with specialist physiotherapists explored barriers and facilitators to managing anxiety, physiotherapy training needs and offered suggestions to develop physiotherapy research and practice. Themes were derived inductively.

Results

The survey suggested how PwMS present with anxiety, its impact during rehabilitation, physiotherapy management practices, and physiotherapist skills and training needs. Five semi-structured interviews with specialist physiotherapists expanded on the survey findings and identified five main themes: Understanding the MS journey, modifying assessment and treatment, anxiety management toolbox, lagging behind Musculoskeletal Physiotherapy, and gaining knowledge and skills.

Conclusion

Physiotherapists encounter anxiety in PwMS in community and outpatient rehabilitation and perceive they have a role in managing it as it presents. Facilitators included communication, listening skills and opportunities to develop strong therapeutic relationships. Poor training and support, lack of clinical guidelines and limited research evidence were considered barriers. Clinically relevant learning opportunities, interprofessional working, and greater support through clinical supervision is recommended to better develop physiotherapy practice.

Contribution of the paper

Key messages

Physiotherapists perceive they have a role in managing anxiety and psychological wellbeing in PwMS as it presents in community and outpatient neurorehabilitation settings.

Opportunities to build strong therapeutic relationships through effective communication and listening skills are considered important in being able to manage patient anxiety effectively.

Poor training and support and a lack of clinical guidelines continue to be barriers in this area.

New knowledge

Online CPD facilitated through the CSP website and iCSP learning platform may be beneficial to increase competence in this area.

Further research to understand the MS illness experience in relation to rehabilitation is required to better inform physiotherapy practice and identify appropriate psychologically informed physiotherapy interventions.
Exercise and training regulation of autophagy markers in human and rodent skeletal muscle
Authors: Botella Javier , Jamnick Nicholas A. , Granata Cesare , Genders Amanda J. , Perri Enrico , Jabar Tamim , Garnham Andrew , Lazarou Michael , Bishop David J.
Published: April 2021

Autophagy is a key intracellular mechanism by which cells degrade old or dysfunctional proteins and organelles. In skeletal muscle, evidence suggests that exercise increases autophagosome content and autophagy flux. However, the exercise-induced response seems to differ between rodents and humans, and little is known about how different exercise prescription parameters may affect these results. The present study utilised skeletal muscle samples obtained from four different experimental studies using rats and humans. Here we show that following exercise, in the soleus muscle of Wistar rats, there is an increase in LC3B-I protein levels (+ 109%) immediately after exercise, and a subsequent increase in LC3B-II protein levels (+ 97%) 3 hours into the recovery. Conversely, in human skeletal muscle, there is an immediate exercise-induced decrease in LC3B-II protein levels (− 24%), independent of whether exercise is performed below or above the maximal lactate steady state, which returns to baseline 3.5 hours following recovery, while no change in LC3B-I protein levels is observed. p62 protein levels did not change in neither rats nor humans following exercise. By employing anex vivoautophagy flux assay previously used in rodents we demonstrate that the exercise-induced decrease in LC3B-II protein levels in humans does not reflect a decreased autophagy flux. Instead, effect size analyses suggest a modest-to-large increase in autophagy flux following exercise that lasts up to 24 hours. Our findings suggest that exercise-induced changes in autophagosome content markers differ between rodents and humans, and that exercise-induced decrease in LC3B-II protein levels do not reflect autophagy flux level.
Uneven growth of SARS-CoV-2 clones evidenced by more than 500,000 whole-genome sequences
Authors: Zeng Hong-Li , Liu Yue , Thorell Kaisa , Nordén Rickard , Aurell Erik
Published: April 2021

We have computed the frequencies of the alleles of the “UK variant” (B.1.1.7) and “South Africa variant” (B.1.351) of SARS-CoV-2 from the large GISAID repository. We find that the frequencies of the mutations in UK variant overall rose towards the end of 2020, as widely reported in the literature and in the general press. However, we also find that these frequencies vary in different patterns rather than in concert. For South Africa variant we find a more complex scenario with frequencies of some mutations rising and some remaining close to zero. Our results point to that what is generally reported as one variant is in fact a collection of variants with different genetic characteristics.
Can Deep Convolutional Neural Networks Learn Same-Different Relations?
Authors: Puebla Guillermo , Bowers Jeffrey S.
Published: April 2021

Same-different visual reasoning is a basic skill central to abstract combinatorial thought. This fact has lead neural networks researchers to test same-different classification on deep convolutional neural networks (DCNNs), which has resulted in a controversy regarding whether this skill is within the capacity of these models. However, most tests of same-different classification rely on testing on images that come from the same pixel-level distribution as the testing images, yielding the results inconclusive. In this study we tested relational same-different reasoning DCNNs. In a series of simulations we show that DCNNs are capable of visual same-different classification, but only when the test images are similar to the training images at the pixel-level. In contrast, even when there are only subtle differences between the testing and training images, the performance of DCNNs could drop to chance levels. This is true even when DCNNs’ training regime included a wide distribution of images or when they were trained in a multi-task setup in which training included an additional relational task with test images from the same pixel-level distribution.
Identification of Structures for Ion Channel Kinetic Models
Authors: Mangold Kathryn E. , Wang Wei , Johnson Eric K. , Bhagavan Druv , Moreno Jonathan D. , Nerbonne Jeanne M. , Silva Jonathan R.
Published: April 2021

Markov models of ion channel dynamics have evolved as experimental advances have improved our understanding of channel function. Past studies have examined various topologies for Markov models of channel dynamics. We present a systematic method for identification of all possible Markov model topologies using experimental data for two types of native voltage-gated ion channel currents: mouse atrial sodium and human left ventricular fast transient outward potassium currents. In addition to optional biophysically inspired restrictions on the number of connections from a state and elimination of long-range connections, this study further suggests successful models have more than minimum number of connections for set number of states. When working with topologies with more than the minimum number of connections, the topologies with three and four connections to the open state tend to serve well as Markov models of ion channel dynamics.

Significance Statement

Here, we present a computational routine to thoroughly search for Markov model topologies for simulating whole-cell currents given an experimental dataset. We test this method on two distinct types of voltage-gated ion channels that function in the generation of cardiac action potentials. Particularly successful models have more than one connection between an open state and the rest of the model, and large models may benefit from having even more connections between the open state and the rest of the other states.
Activation of the autophagy pathway affects Dengue virus infection inAedes aegypti
Authors: Chen Tse-Yu , Smartt Chelsea T.
Published: April 2021

Mosquito-borne Dengue virus (DENV) has caused major disease worldwide, impacting 50 to 100 million people every year, and is spread by the major mosquito vectorAedes aegypti. Understanding mosquito physiology and developing new control strategies becomes an important issue to eliminate DENV. We focused on autophagy, a pathway suggested as having a positive influence on virus replication in humans, as a potential anti-viral target in the mosquito. To understand the role played by autophagy inAe. aegypti, we examined the expression of the pathwayin vitro(Aag-2 cell) andin vivo(Ae. aegypti). The results indicated that DENV infection in Aag-2 cells caused the microtubule-associated protein light chain 3-phosphatidylethanolamine conjugate (LC3-II) protein levels to increase which indicated the activation of the autophagy pathway. Rapamycin and 3-Methyladenine were used to activate or suppress the autophagy pathway, respectively. Rapamycin treatment decreased the virus titer in the Aag-2 cells, but the 3-Methyladenine treatment did not affect DENV titer. InAe. aegypti, microinjected rapamycin increased the DENV titer after one-day infection and was significantly different compared to the control group titer. Two ATG genes, ATG4 and ATG12, were expressed differentially under the rapamycin treatments. Although the results differed betweenin vitroandin vivostudies, findings from both support the interaction between autophagy and DENV. Our studies revealed the activation of the autophagy pathway through rapamycin could be related to DENV infection in the mosquito. The possibility of autophagy being associated with different antiviral mechanisms at different extrinsic incubation times and tissues inAe. aegyptiis discussed.

Author Summary

Dengue virus (DENV) has been a great threat to public health and has not developed an efficient method to stop the transmission. To understand the complex interaction between virus and mosquito, we investigate the autophagy pathway and its role during the infection process. We noticed the induction of autophagy pathways from DENV infection in Aag-2 cells and blood meal fromAe. aegypti. Moreover, activation of the autophagy pathway from rapamycin could alter the DENV titer. Our results indicated the autophagy pathway is associated with DENV and could be crucial during the DENV infection. Furthermore, we proved the practicality of small molecules in altering the autophagy pathway in mosquitoes, and thus the usage of small molecules as possible mosquito pathogen vaccines should be evaluated.
The lysine-rich intracellular loop and cell type-specific co-factors are required for IFITM3 antiviral immunity in hematopoietic stem cells
Authors: Unali G. , Giordano A.M.S , Cuccovillo I. , Alezz M. Abou , Apolonia L. , Merelli I. , Malim M. H. , Petrillo C. , Kajaste-Rudnitski A.
Published: April 2021

The interferon-induced transmembrane protein 3 (IFITM3) inhibits lentiviral gene therapy vector entry into hematopoietic stem cells and can be overcome by Cyclosporine H (CsH), but underlying mechanisms remain unclear. Here, we show that mutating the evolutionarily conserved lysines of the IFITM3 intracellular loop abolishes its antiviral activity without affecting either its localization or its degradation by CsH through non-canonical lysosomal pathways. When confined to the plasma membrane, the lysine-competent IFITM3 lost restriction against VSV-G pseudotyped viral vectors but gained antiviral activity against vectors that fuse directly at the plasma membrane. Interestingly, altering the lysines did not alter IFITM3 homodimerization but impacted higher-order protein complex formation, suggesting loss of interaction with cellular co-factors. In agreement, IFITM3 expression was not sufficient to restrict viral vectors in myeloid K562 cells as opposed to promonocytic THP1 or primary HSC. We exclude the involvement of previously identified factors affecting IFITM3 biology and propose a novel model for IFITM3 restriction that depends on the presence of cellular co-factor(s) that may interact with IFITM3 through the intracellular loop lysine residues. Overall, our work provides significant insight into the mechanisms of action of IFITM3 and CsH that can be exploited for improved gene therapies and broadly acting antiviral strategies.
Integrative structural modelling of macromolecular complexes using Assembline
Authors: Rantos Vasileios , Karius Kai , Kosinski Jan
Published: April 2021

Integrative modelling enables structure determination of macromolecular complexes by combining data from multiple experimental sources such as X-ray crystallography, electron microscopy (EM), or crosslinking mass spectrometry (XL-MS). It is particularly useful for complexes not amenable to high-resolution EM—complexes that are flexible, heterogenous, or imaged in cells with cryo-electron tomography. We have recently developed an integrative modelling protocol that allowed us to model multi-megadalton complexes as large as the nuclear pore complex. Here, we describe the Assembline software package, which combines multiple programs and libraries with our own algorithms in a streamlined modelling pipeline. Assembline builds ensembles of models satisfying data from atomic structures or homology models, EM maps and other experimental data, and provides tools for their analysis. Comparing to other methods, Assembline enables efficient sampling of conformational space through a multi-step procedure, provides new modeling restraints, and includes a unique configuration system for setting up the modelling project. Our protocol achieves exhaustive sampling in less than 100 – 1,000 CPU-hours even for complexes in the megadalton range. For larger complexes, resources available in institutional or public computer clusters are needed and sufficient to run the protocol. We also provide step-by-step instructions for preparing the input, running the core modelling steps, and assessing modelling performance at any stage.
Plasma microbiome in COVID-19 subjects: an indicator of gut barrier defects and dysbiosis
Authors: Prasad Ram , Patton Michael John , Floyd Jason L , Vieira Cristiano Pedrozo , Fortmann Seth , DuPont Mariana , Harbour Angie , Jeremy Chen See , Wright Justin , Lamendella Regina , Stevens Bruce R. , Grant Maria B.
Published: April 2021

The gut is a well-established route of infection and target for viral damage by SARS-CoV-2. This is supported by the clinical observation that about half of COVID-19 patients exhibit gastrointestinal (GI) symptoms. We asked whether the analysis of plasma could provide insight into gut barrier dysfunction in patients with COVID-19 infection. Plasma samples of COVID-19 patients (n=30) and healthy control (n=16) were collected during hospitalization. Plasma microbiome was analyzed using 16S rRNA sequencing, metatranscriptomic analysis, and gut permeability markers including FABP-2, PGN and LPS in both patient cohorts. Almost 65% (9 out 14) COVID-19 patients showed abnormal presence of gut microbes in their bloodstream. Plasma samples contained predominatelyProteobacteria, Firmicutes,andActinobacteria. The abundance of gram-negative bacteria (Acinetobacter, Nitrospirillum, Cupriavidus, Pseudomonas, Aquabacterium, Burkholderia, Caballeronia, Parabhurkholderia, Bravibacterium,andSphingomonas) was higher than the gram-positive bacteria (StaphylococcusandLactobacillus) in COVID-19 subjects. The levels of plasma gut permeability markers FABP2 (1282±199.6vs838.1±91.33; p=0.0757), PGN (34.64±3.178vs17.53±2.12; p<0.0001), and LPS (405.5±48.37vs249.6±17.06; p=0.0049) were higher in COVID-19 patients compared to healthy subjects. These findings support that the intestine may represent a source for bacteremia and may contribute to worsening COVID-19 outcomes. Therapies targeting the gut and prevention of gut barrier defects may represent a strategy to improve outcomes in COVID-19 patients.
The Mechanism of Activation of Monomeric B-Raf V600E
Authors: Maloney Ryan C. , Zhang Mingzhen , Jang Hyunbum , Nussinov Ruth
Published: April 2021

Oncogenic mutations in the serine/threonine kinase B-Raf, particularly the V600E mutation, are frequent in cancer, making it a major drug target. Although much is known about B-Raf’s active and inactive states, questions remain about the mechanism by which the protein changes between these two states. Here, we utilize molecular dynamics to investigate both wild-type and V600E B-Raf to gain mechanistic insights into the impact of the Val to Glu mutation. The results show that the wild-type and mutant follow similar activation pathways involving an extension of the activation loop and an inward motion of the αC-helix. The V600E mutation, however, destabilizes the inactive state by disrupting hydrophobic interactions present in the wild-type structure while the active state is stabilized through the formation of a salt bridge between Glu600 and Lys507. Additionally, when the activation loop is extended, the αC-helix is able to move between an inward and outward orientation as long as the DFG motif adopts a specific orientation. In that orientation Phe595 rotates away from the αC-helix, allowing the formation of a salt bridge between Lys483 and Glu501. These mechanistic insights have implications for the development of new Raf inhibitors.
Captive-breeding and catch-and-release’s effects on the reproductive success of Atlantic salmon (Salmo salarL.)
Authors: Bouchard R. , Wellband K. , Lecomte L. , Bernatchez L. , April J.
Published: April 2021

Captive-breeding programs as well as and catch-and-release are among the most commonly adopted conservation practices in recreational fisheries. However, risks and benefits associated with their implementation are rarely evaluated. In the case of Atlantic Salmon, while previous studies revealed that captive-bred fish show reduced fitness compared to their wild counterparts in nature. Yet, few examined the extent and causes of their reduced reproductive success or directly compared their contribution to enhance genetic diversity to that of wild fish, including mature male parr. Furthermore, only one study specifically measured the reproductive success of caught and released Atlantic salmon in natural settings, and no study to date evaluated if released salmon are able to reproduce when released at temperature above 20°C which is known to increase post-release mortality. Here, we use high-throughput microsatellite sequencing of 38 loci to accurately assign 2500 offspring to a comprehensive set of possible parents from a supplemented Atlantic salmon population in Québec, Canada. The resolved molecular pedigree provided informative insight on the reproductive pattern of both captive-bred salmon and caught-and-released salmon. Captive-bred salmon had fewer partners than their wild conspecifics which lead to a significant reduction of reproductive success relative to that of their wild counterparts. Supplementation of captive-bred salmon significantly contributed to increase genetic diversity but mature male parr did so to an even greater extent and significantly inflated the number of alleles found among offspring. Moreover, our results showed that that at least 83% of caught-and-released salmon did successfully reproduced although caught-and-released female salmon have a significantly reduced reproductive success, averaging 73% of the reproductive output of non-caught salmon. Reproductive success of released salmon was not influenced by water temperature over 20°C which suggests either that the studied population is locally adapted to warm waters or that they behaviorally regulated body temperature by accessing nearby thermal refugia. Our results should help refining managers’ ability to analyze the risks and benefits associated with captive-breeding and catch-and-release, and thus, optimize conservation practices used for the preservation of Atlantic salmon populations.
Heritable variation in locomotion, reward sensitivity and impulsive behaviors in a genetically diverse inbred mouse panel
Authors: Bailey Lauren S. , Bagley Jared R. , Dodd Rainy , Olson Ashley , Bolduc Mikayla , Philip Vivek M. , Reinholdt Laura G. , Sukoff Rizzo Stacey J. , Gagnon Leona , Chesler Elissa J. , Jentsch J. David
Published: April 2021

Drugs of abuse, including alcohol and stimulants like cocaine, produce effects that are subject to individual variability, and genetic variation accounts for at least a portion of those differences. Notably, research in both animal models and human subjects point towards reward sensitivity and impulsivity as being trait characteristics that predict relatively greater positive subjective responses to stimulant drugs. Here we describe use of the eight Collaborative Cross (CC) founder strains and multiple CC strains to examine the heritability of reward sensitivity and impulsivity traits, as well as genetic correlations between these measures and existing addiction-related phenotypes.Methods. Strains were all tested for activity in an open field and reward sensitivity (intake of chocolate BOOST®). Mice were then divided into two counterbalanced groups and underwent reversal learning (impulsive action and waiting impulsivity) or delay discounting (impulsive choice).Results. CC and founder mice demonstrate significant heritability for impulsive action, impulsive choice, waiting impulsivity, locomotor activity, and reward sensitivity, with each impulsive phenotype determined to be non-correlating, independent traits. This research was conducted within the broader, inter-laboratory effort of the Center for Systems Neurogenetics of Addiction (CSNA) to characterize CC and DO mice for multiple, cocaine abuse related traits. These data will facilitate the discovery of genetic correlations between predictive traits, which will then guide discovery of genes and genetic variants that contribute to addictive behaviors.