bluuebunny/crossref_metadata_2025 huggingface dataset:
Sampling bias minimization in disease frequency estimates
Authors: Shtossel Oshrit , Louzoun Yoram
Published: May 2021

An accurate estimate of the number of infected individuals in any disease is crucial. Current estimates are mainly based on the fraction of positive samples or the total number of positive samples. However, both methods are biased and sensitive to the sampling depth. We here propose an alternative method to use the attributes of each sample to estimate the change in the total number of positive patients in the total population. We present a Bayesian estimator assuming a combination of condition and time-dependent probability of being positive, and mixed implicit-explicit solution for the probability of a person with conditions i at time t of being positive. We use this estimate to predict the total probability of being positive at a given day t.

We show that these estimate results are smooth and not sensitive to the properties of the samples. Moreover, these results are a better predictor of future mortality.
Rare GATA6 variants associated with risk of congenital heart disease phenotypes in 200,000 UK Biobank exomes
Authors: Williams Simon G. , Byrne Dominic , Keavney Bernard D.
Published: May 2021

Several genes have been associated with congenital heart disease (CHD) risk in previous GWAS and sequencing studies, but studies involving larger numbers of case samples remain needed to facilitate further understanding of what remains a complex and largely uncharacterised genetic etiology. Here we use whole exome sequencing data from 200,000 samples in the UK Biobank to assess ultra-rare and potentially pathogenic variation associated with increased risk of CHD. Our findings indicate that rare variants in GATA6, presumably with a lesser effect on gene function than those causing severe CHD phenotypes, or buffered by other genetic and environmental effects during development, are also associated with minor CHD conditions, specifically bicuspid aortic valve, the most common CHD condition.
COVID-19 susceptibility variants associate with blood clots, thrombophlebitis and circulatory diseases
Authors: Papadopoulou Areti , Musa Hanan , Sivaganesan Mathura , McCoy David , Deloukas Panos , Marouli Eirini
Published: May 2021

Objective

Epidemiological studies suggest that individuals with comorbid conditions including diabetes, chronic lung diseases and others, are at higher risk of adverse COVID-19 outcomes. Genome-wide association studies have identified several loci associated with increased susceptibility and severity for COVID-19. However, it is not clear whether these associations are genetically determined or not. We used a Phenome-Wide Association (PheWAS) approach to investigate the role of genetically determined COVID-19 susceptibility on disease related outcomes.

Approach and Results

PheWAS analyses were performed in order to identify traits and diseases related to COVID-19 susceptibility and severity, evaluated through a predictive COVID-19 risk score. We utilised phenotypic data in up to 400,000 individuals from the UK Biobank, including Hospital Episode Statistics and General Practice data. We identified a spectrum of associations between both genetically determined COVID-19 susceptibility and severity with a number of traits. COVID-19 risk was associated with increased risk for phlebitis and thrombophlebitis (OR = 1.11, p = 5.36e-08). We also identified significant signals between COVID-19 susceptibility with blood clots in the leg (OR= 1.1, p = 1.66e-16) and with increased risk for blood clots in the lung (OR = 1.12, p = 1.45 e-10).

Conclusions

Our study identifies significant association of genetically determined COVID-19 with increased blood clot events in leg and lungs. The reported associations between both COVID-19 susceptibility and severity and other diseases adds to the identification and stratification of individuals at increased risk, adverse outcomes and long-term effects.
Vaccination strategies when vaccines are scarce: On conflicts between reducing the burden and avoiding the evolution of escape mutants
Authors: Geoffroy Félix , Traulsen Arne , Uecker Hildegard
Published: May 2021

When vaccine supply is limited but population immunisation urgent, the allocation of the available doses needs to be carefully considered. One aspect of dose allocation is the time interval between the primer and the booster injections in two-dose vaccines. By stretching this interval, more individuals can be vaccinated with the first dose more quickly. Even if the level of immunity of these ‘half-vaccinated’ individuals is lower than that of those who have received both shots, delaying the second injection can be beneficial in reducing case numbers, provided a single dose is sufficiently effective. On the other hand, there has been concern that intermediate levels of immunity in partially vaccinated individuals may favour the evolution of vaccine escape mutants. In that case, a large fraction of half-vaccinated individuals would pose a risk – but only if they encounter the virus. This raises the question whether there is a conflict between reducing the burden and the risk of vaccine escape evolution or not. We develop a minimal model to assess the population-level effects of the timing of the booster dose. We set up an SIR-type model, in which more and more individuals become vaccinated with a two-dose vaccine over the course of a pandemic. As expected, there is no trade-off when vaccine escape evolves at equal probabilities in unvaccinated and half-vaccinated patients. If vaccine escape evolves more easily in half-vaccinated patients, the presence or absence of a trade-off depends on the reductions in susceptibility and transmissibility elicited by the primer dose.
Assessing COVID-19 Pandemic Risk Perception and Response Preparedness in Veterinary and Animal Care Workers
Authors: Dalton Kathryn R. , Guyer Kimberly M. , Schiaffino Francesca , Ferradas Cusi , Falke Jacqueline R. , Beasley Erin A. , Meza Kayla , Laughlin Paige , Agnew Jacqueline , Barnett Daniel J. , Nuzzo Jennifer B. , Davis Meghan F.
Published: May 2021

Veterinary and animal care workers (VACW) perform critical functions in biosecurity and public health, yet little has been done to understand the unique needs and barriers these workers face when responding during a pandemic crisis. This study evaluated VACWs’ perceived risks and roles during COVID-19, and explored barriers and facilitators in their readiness, ability, and willingness to respond during a pandemic. We deployed a survey targeting U.S. veterinary medical personnel, animal shelter and control workers, zoo and wildlife workers, plus other animal care workers. Data were collected on participants’ self-reported job and demographic factors, perceptions of risk and job efficacy, and readiness, ability, and willingness to respond during the pandemic. We found that leadership roles and older age had the strongest association with decreased perceived risk and improved job efficacy and confidence, and that increased reported contact level with others (both co-workers and the public) was associated with increased perceived risk. We determined that older age and serving in leadership positions were associated with improved readiness, willingness, and ability to respond. VACWs’ dedication to public health response, reflected in our findings, will be imperative if more zoonotic vectors of SARS-CoV-2 arise. Response preparedness in VACW can be improved by targeting younger workers not in leadership roles in support programs that center on improving job efficacy and confidence in safety protocols. These findings can be used to target intervention and training efforts to support the most vulnerable within this critical, yet often overlooked, workforce.
Visual Exploratory Data Analysis of COVID-19 Pandemic: One Year After the Outbreak
Authors: Nazir Amril , Ulusoy Suleyman , Lotfi Lujaini
Published: May 2021

Background

Governments across the globe have taken different measures to handle the Covid-19 outbreak since it began in early 2020. Countries implemented various policies and restrictive measures to prevent transmission of the virus, reduce the impacts of the outbreak (i.e., individual, social, and economic), and provide effective control measures. Although it has been over one year since the outbreak started, few studies have examined the long-term effects of the pandemic. Furthermore, researchers need to examine which government intervention variables are the most, and least, effective. Such analysis is critical to determine the best practices in support of policy decisions.

Methods

Visual exploratory data analysis (V-EDA) offers a user-friendly data visualization model to evaluate the impact of the pandemic. It allows one to observe visual patterns of trends. The V-EDA was conducted on one year data for the COVID-19 Pandemic, one year after the outbreak between 1 January and 31 December, 2020. The data were analyzed using the student’s t-test to verify if there was a statistical difference between two independent groups, and the Spearman test was also used to analyze the correlation coefficient between two quantitative datasets and their positive or negative inclination.

Findings

We found that high-testing countries had more cases per million than low-testing countries. For low-testing countries, however, there was a positive correlation between the testing level and the number of cases per million. This suggests that high-testing countries tested in a preventive manner while low-testing countries may have a higher number of cases than those confirmed. The poorest developing countries have reduced testing which can coincide with the reduction in new cases, which we did not observe in the high-testing countries. Among the restrictive measures analyzed, a higher population aged 70 or older and lower GDP per capita was related to a higher case fatality ratio. Restrictive measures reduce the number of new cases after four weeks, indicating the minimum time required for the measures to have a positive effect. Finally, public event cancellation, international travel control, school closing, contact tracing, and facial coverings were the most important measures to reduce virus spread. We observed that countries with the lowest number of cases had a higher stringency index.
Identification of risk and protective human leukocyte antigens in COVID-19 using genotyping and structural modeling
Authors: Shen Yiran , Ostrov David A. , Rananaware Santosh , Jain Piyush K , Nguyen Cuong Q.
Published: May 2021

COVID-19 is caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The severity of COVID-19 is highly variable and related to known (e.g., age, obesity, immune deficiency) and unknown risk factors. Since innate and adaptive immune responses are elicited in COVID-19 patients, we genotyped 94 Florida patients with confirmed COVID-19 and 89 healthy controls. We identified an HLA gene, HLA-DPA1, in which specific alleles were associated with the risk of SARS-CoV-2 positivity and COVID-19 disease. HLA-DPA1*01:03 was associated with reduced incidence of SARS-CoV-2 positivity, whereas HLA-DPA1*03:01 was associated with increased risk of SARS-CoV-2 positivity. These data suggest a model in which COVID-19 severity is influenced by immunodominant peptides derived from SARS-CoV-2 preferentially presented by specific HLA-DP molecules to either protective (for asymptomatic COVID-19) or pathogenic T cells (in severe COVID-19). Although this study is limited to comparing SARS-CoV-2 positive and negative subjects, these data suggest that HLA typing of COVID-19 patients stratified for disease severity may be informative for identifying biomarkers and disease mechanisms in high-risk individuals.
Population-level management of Type 1 diabetes via continuous glucose monitoring and algorithm-enabled patient prioritization: Precision health meets population health
Authors: Ferstad Johannes O. , Vallon Jacqueline J. , Jun Daniel , Gu Angela , Vitko Anastasiya , Morales Dianelys P. , Leverenz Jeannine , Lee Ming Yeh , Leverenz Brianna , Vasilakis Christos , Osmanlliu Esli , Prahalad Priya , Maahs David M , Johari Ramesh , Scheinker David
Published: May 2021

Objective

To develop and scale algorithm-enabled patient prioritization to improve population-level management of type 1 diabetes (T1D) in a pediatric clinic with fixed resources, using telemedicine and remote monitoring of patients via continuous glucose monitor (CGM) data review.

Research Design and Methods

We adapted consensus glucose targets for T1D patients using CGM to identify interpretable clinical criteria to prioritize patients for weekly provider review. The criteria were constructed to manage the number of patients reviewed weekly and identify patients who most needed provider contact. We developed an interactive dashboard to display CGM data relevant for the patients prioritized for review.

Results

The introduction of the new criteria and interactive dashboard was associated with a 60% reduction in the mean time spent by diabetes team members who remotely and asynchronously reviewed patient data and contacted patients, from 3.2±0.20 to 1.3±0.24 minutes per patient per week. Given fixed resources for review, this corresponded to an estimated 147% increase in weekly clinic capacity. Patients who qualified for and received remote review (n=58) have associated 8.8 percentage points (pp) (95% CI = 0.6–16.9pp) greater time-in-range (70-180 mg/dL) glucoses compared to 25 control patients who did not qualify at twelve months after T1D onset.

Conclusions

An algorithm-enabled prioritization of T1D patients with CGM for asynchronous remote review reduced provider time spent per patient and was associated with improved time-in-range.
Teletherapy for children with developmental disorders during the COVID-19 pandemic in the Philippines: a mixed-methods evaluation from the perspectives of parents and therapists
Authors: Eguia Kathlynne F. , Capio Catherine M.
Published: May 2021

Objectives

As a response to the lockdown associated with COVID-19 in the Philippines, therapy services for children with developmental disorders shifted to telehealth (i.e., teletherapy). This study evaluated the delivery of teletherapy from the perspectives of parents and therapists.

Methods

Participants consisted of parents (n = 47) and therapists (n = 102) of children with developmental disorders who were receiving teletherapy during the lockdown. A mixed-methods triangulation design-convergence model was adopted; participants were invited to respond to an online survey with closed- and open-ended questions. Quantitative data were analyzed using descriptive and non-parametric inferential tests, while qualitative data were examined using thematic analysis.

Results

Overall satisfaction with teletherapy was positive, with parents reporting significantly higher satisfaction compared to therapists. Satisfaction was positively associated with the frequency of teletherapy sessions for parents, and with their years of experience for therapists. The top enabling factors were family participation and effective communication. The main challenges were time constraints and difficulty with instruction and monitoring associated with the two-dimensional nature of teletherapy. The benefits included parents’ empowerment and enhanced understanding of their children’s needs.

Discussion

The shift to teletherapy facilitated a heightened focus on family-centered care. The evaluation findings suggest that the general satisfaction with teletherapy and the benefits associated with family-centered care will likely promote teletherapy as a service delivery mode to continue beyond the pandemic.
Impact of National and Regional Lockdowns on Growth of COVID-19 Cases in COVID-Hotspot City of Pune in Western India: A Real-World Data Analysis
Authors: Mave Vidya , Shaikh Arsh , Monteiro Joy Merwin , Bogam Prasad , Pujari Bhalchandra S , Gupte Nikhil
Published: May 2021

Background

Real-world data assessing the impact of lockdowns on COVID-19 cases remain limited from resource-limited settings. We examined growth of incident confirmed COVID-19 cases before, during and after lockdowns in Pune, a city in western India with 3.1 million population that reported the largest COVID-19 burden at the peak of the pandemic.

Methods

Using anonymized individual-level data captured by Pune’s public health surveillance program between February 1st and September 15th 2020, we assessed weekly incident COVID-19 cases, infection rates, and epidemic curves by lockdown status (overall and by sex, age, and population density) and modelled the natural epidemic using the 9-compartmental model INDSCI-SIM. Effect of lockdown on incident cases was assessed using multilevel Poisson regression. We used geospatial mapping to characterize regional spread.

Findings

Of 241,629 persons tested for SARS-CoV-2, the COVID-19 disease rate was 267.0 (95% CI 265.3 – 268.8) per 1000 persons. Epidemic curves and geospatial mapping showed delayed peak of the cases by approximately 8 weeks during the lockdowns as compared to modelled natural epidemic. Compared to a subsequent unlocking period, incident COVID-19 cases 43% lower (IRR 0.57, 95% CI 0.53 – 0.62) during India’s nationwide lockdown and 22% (IRR 0.78, 95% CI 0.73 – 0.84) during Pune’s regional lockdown and was uniform across age groups and population densities.

Conclusion

Lockdowns slowed the growth of COVID-19 cases in population dense, urban region in India. Additional analysis from rural and semi-rural regions of India and other resource-limited settings are needed.
SARS-CoV-2 RNA in urban wastewater samples to monitor the COVID-19 epidemic in Lombardy, Italy (March – June 2020)
Authors: Castiglioni Sara , Schiarea Silvia , Pellegrinelli Laura , Primache Valeria , Galli Cristina , Bubba Laura , Mancinelli Federica , Marinelli Marilisa , Cereda Danilo , Ammoni Emanuela , Pariani Elena , Zuccato Ettore , Binda Sandro
Published: May 2021

Wastewater-based viral surveillance is a promising approach to monitor the circulation of SARS-CoV-2 in the general population. The aim of this study was to develop an analytical method to detect SARS-CoV-2 RNA in urban wastewater, to be implemented in the framework of a surveillance network in the Lombardy region (Northern Italy). This area was the first hotspot of COVID-19 in Europe. Composite 24h samples were collected weekly in eight cities from end-March to mid-June 2020 (first peak of the epidemic). The method developed and optimized, involved virus concentration, using PEG centrifugation, and one-step real-time RT-PCR for analysis. SARS-CoV-2 RNA was identified in 65 (61%) out of 107 samples, and the viral concentrations (up to 2.1 E +05 copies/L) were highest in March-April. By mid-June, wastewater samples tested negative in all the cities. Viral loads were used for inter-city comparison and Brembate, Ranica and Lodi had the highest. The pattern of decrease of SARS-CoV-2 in wastewater was closely comparable to the decline of active COVID-19 cases in the population, reflecting the effect of lock-down. Wastewater surveillance of SARS-CoV-2 can integrate ongoing virological surveillance of COVID-19, providing information from both symptomatic and asymptomatic individuals, and monitoring the effect of health interventions.
The COVID-19 pandemic storm in India
Authors: Nesteruk Igor
Published: May 2021

The sharp increase in the number of new COVID-19 patients in India in the second half of April 2021 has caused alarm around the world. A detailed analysis of this pandemic storm is still ahead. We present the results of anterior analysis using a generalized SIR-model (susceptible-infected-removed). The final size of this pandemic wave and its duration are predicted. Obtained results show that the COVID-19 pandemic will be a problem for mankind for a very long time.
Quantifying the relationship between SARS-CoV-2 viral load and infectiousness
Authors: Marc Aurélien , Kerioui Marion , Blanquart François , Bertrand Julie , Mitjà Oriol , Corbacho-Monné Marc , Marks Michael , Guedj Jérémie
Published: May 2021

The relationship between SARS-CoV-2 viral load and infectiousness is not known. Using data from a prospective cohort of index cases and high-risk contact, we reconstructed by modelling the viral load at the time of contact and the probability of infection. The effect of viral load was particularly large in household contacts, with a transmission probability that increased to as much as 37% when the viral load was greater than 10 log10 copies per mL. The transmission probability peaked at symptom onset in most individuals, with a median probability of transmission of 15%, that hindered large individual variations (IQR: [8, 37]). The model also projects the effects of variants on disease transmission. Based on the current knowledge that viral load is increased by 2 to 4-fold on average, we estimate that infection with B1.1.7 virus could lead to an increase in the probability of transmission by 8 to 17%.
Comparing Patient Reported Outcomes to Objective Measures of Function in patients with Chronic Pain: Using the SF-12, 2 minute walk test and Elevation and Movement Lift test
Authors: Gupta Gaurav , Paquet-Proulx Emilie , Besemann LCol Markus , Burton Kira , Lalonde Sasha , Minerbi Amir
Published: May 2021

Introduction

An Ideal battery of testing for function would be inexpensive, easily administered, standardized and validated for multiple health issues. This would also be sensitive to change over time and able to extrapolate avocational and vocational tasks. The data collection exercise for this study included both subjective and objective measures which include the Short Form Health Survey 12 (SF-12), the 2 minute walk test (2MWT) and a newly developed upper extremity strength/conditioning activity called the Elevation and Movement Lift test (EMLi).

Methods

A convenience sample of 102 patients with chronic pain. They were seen in the Canadian Forces Health Services Unit (CFHSU (O)) Physiatry Clinic between January-September 2019 and were asked to complete the data intake protocol. This included: completing a questionnaire with the Numeric Rating Pain Scale (NRS) covering the previous 7 days, the SF-12, and completed the 2 MWT and EMLi.

Results

For the 2MWT heart rate, perceived exertion and number of steps were all increased for patients with chronic pain compared to the control group. There was no difference noted between patients with upper/lower body pain. In patients with chronic pain SF-12 physical function score negatively correlated with perceived exertion but not performance. As for the EMLI test, all groups had similar perceived exertion and heart rate outcomes but a reduced performance was noted with the upper extremity group.

Discussion

For the 2MWT, the individual’s performance related to effort and not their pain state, PE and SF-12. This suggests a higher capacity for walking then the patients realise. As for the EMLi, individual’s performance was poorer for same level of effort. This correlates to their perceived function as seen on the SF-12 which might measure pain related dysfunction.

Conclusion

The 2MWT performance was effort dependent and not correlated with perceived abilities. Therefore it can be used to challenge patient performance. EMLi performance correlated with perception and upper extremity pain. This could be used to set clinical training targets and monitor each individual’s progress.
Failure to detect mutations inU2AF1due to changes in the GRCh38 reference sequence
Authors: Miller Christopher A. , Walker Jason R. , Jensen Travis L. , Hooper William F. , Fulton Robert S. , Painter Jeffrey S. , Sekeres Mikkael A. , Ley Timothy J. , Spencer David H , Goll Johannes B. , Walter Matthew J.
Published: May 2021

The U2AF1 gene is a core part of mRNA splicing machinery and frequently contains somatic mutations that contribute to oncogenesis in MDS, AML, and other cancers. A change introduced in the GRCh38 version of the human reference build prevents mutations in this gene from being detected by many variant calling pipelines. We describe the problem in detail and show that a modified GRCh38 reference build with unchanged coordinates can be used to ameliorate the issue. This reference is available athttps://zenodo.org/record/4684553(doi:10.5281/zenodo.4684553)
Chord: Identifying Doublets in Single-Cell RNA Sequencing Data by an Ensemble Machine Learning Algorithm
Authors: Xiong Ke-Xu , Zhou Han-Lin , Yin Jian-Hua , Kristiansen Karsten , Yang Huan-Ming , Li Gui-Bo
Published: May 2021

High-throughput single-cell RNA sequencing (scRNA-seq) is a popular method, but it is accompanied by doublet rate problems that disturb the downstream analysis. Several computational approaches have been developed to detect doublets. However, most of these methods have good performance in some datasets but lack stability in others; thus, it is difficult to regard a single method as the gold standard for each scenario, and it is a difficult and time-consuming task for researcher to choose the most appropriate software. To address these issues, we propose Chord which implements a machine learning algorithm that integrates multiple doublet detection methods. Chord had a higher accuracy and stability than the individual approaches on different datasets containing real and synthetic data. Moreover, Chord was designed with a modular architecture port, which has high flexibility and adaptability to the incorporation of any new tools. Chord is a general solution to the doublet detection problem.
Striatin 3 and MAP4K4 cooperate towards oncogenic growth and tissue invasion in medulloblastoma
Authors: Migliavacca Jessica , Züllig Buket , Capdeville Charles , Grotzer Michael , Baumgartner Martin
Published: May 2021

MAP4K4 has been correlated with increased cell motility and reduced proliferation in mammalian cells. Consequences and regulation of this dichotomous functionality of MAP4K4 in tumor cells remained elusive. We find that MAP4K4 interacts with the STRN3 protein in medulloblastoma and that STRN3 and MAP4K4 exert opposing functions in Hippo tumor suppressor signaling and clonal growth. However, depletion of either STRN3 or MAP4K4 reduces migration and tissue invasion, and concomitant loss of both proteins halts tumor cell growth in the cerebellar tissue. Mechanistically, STRN3 couples MAP4K4 to the protein phosphatase 2A, which inactivates growth repressing activities of MAP4K4. In parallel, STRN3 enables growth factor-induced PKCθ activation and the direct phosphorylation of VASPS157by MAP4K4, which are necessary for efficient migration and tissue invasion. Thus, STRN3 controls MAP4K4 functionality in growth factor-activated tumor cells, and the cooperation of the two proteins promotes invasiveness through nPKCs and VASP and increases proliferation via inactivation of Hippo signaling. Targeting of the STRN3-MAP4K4 cooperation could reactivate Hippo signaling and repress invasiveness in growth factor-driven tumors.

Graphical abstract
TMEM106B modifies TDP-43 pathology in human ALS brain and cell-based models of TDP-43 proteinopathy
Authors: Mao Fei , Robinson John , Unger Travis , Posavi Marijan , Amado Defne , Elman Lauren , Grossman Murray , Wolk David , Lee Edward , Van Deerlin Vivianna M. , Porta Sílvia , Lee Virginia , Trojanowski John , Chen-Plotkin Alice S.
Published: May 2021

The neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TAR DNA-binding protein-43 (TDP-43) inclusions (FTLD-TDP) share the neuropathological hallmark of aggregates of TDP-43. However, factors governing the severity and regional distribution of TDP-43 pathology, which may account for the divergent clinical presentations of ALS and FTLD-TDP, are not well-understood. Here, we investigated the influence of genotypes atTMEM106B, a locus associated with risk for FTLD-TDP, and hexanucleotide repeat expansions inC9orf72, a known genetic cause for both ALS and FTLD-TDP, on global TDP-43 pathology and regional distribution of TDP-43 pathology in 899 postmortem cases from a spectrum of neurodegenerative diseases. We found that, among the 110 ALS cases, minor (C)- allele homozygotes at theTMEM106Blocus sentinel SNP rs1990622 had more TDP-43 pathology globally, as well as in select brain regions.C9orf72expansions similarly associated with greater TDP-43 pathology in ALS. However, adjusting forC9orf72expansion status did not affect the relationship betweenTMEM106Bgenotype and TDP-43 pathology. In order to elucidate the direction of causality for this association, we directly manipulatedTMEM106Blevels in an inducible cell system that expresses mislocalized TDP-43 protein. We found that partial knockdown ofTMEM106B, to levels similar to what would be expected in rs1990622 C allele carriers, led to development of more TDP-43 cytoplasmic aggregates, which were more insoluble, in this system. Taken together, our results support a causal role for TMEM106B in modifying the development of TDP-43 proteinopathy.
Dynamic behavioral and molecular changes induced by chronic stress exposure in mice
Authors: Prevot Thomas D. , Chatterjee Dipashree , Knoch Jaime , Codeluppi Sierra , Misquitta Keith A. , Fee Corey J.E. , Newton Dwight , Oh Hyunjung , Sibille Etienne , Banasr Mounira
Published: May 2021

Depression is a leading cause of disabilities around the world, and the underlying mechanisms involved in its pathophysiology are broad and complex. Exposure to chronic stress is a risk factor for developing depressive-symptoms and contributes to cellular and molecular changes precipitating the emergence of symptoms. In the brain, excitatory neurons, inhibitory interneurons and supporting astroglial cells are all sensitive to chronic stress exposure and are known to be impaired in depression.

Using an animal model of chronic stress, we assessed the impact of variable durations of chronic stress on the emergence of behavioral deficits and associated molecular changes in the prefrontal cortex (PFC), brain region highly sensitive to stress and impaired in depression. Mice were exposed to up to 35 days of chronic restraint stress and were assessed weekly on behavioral tests measuring anxiety and anhedonia. PFC Protein and RNA levels of specific markers of excitatory, inhibitory synapses and astroglia were quantified using western blot and qPCR, respectively. Correlation and integrative network analyses were used to investigated the impact of chronic stress on the different compartments.

Results showed that chronic stress induces anxiety-like behaviors within 7 days, while anhedonia-like behaviors were observed only after 35 days. At the molecular level, alterations of many markers were observed, in particular with longer exposure to chronic stress. Finally, correlation analyses and integrative network analyses revealed that male and female mice react differently to chronic stress exposure and that some markers seem to be more correlated to behaviors deficits in males than in females.

Our study demonstrate that chronic induces a dynamic changes that can be observed at the behavioral and molecular levels, and that male and female mice, while exhibiting similar symptoms, have different underlying pathologies.
The neuronal GPCR OCTR-1 mediates temperature effects on longevity by regulating immune response genes inC. elegans
Authors: Wibisono Shawndra , Wibisono Phillip , Chen Chia-Hui , Sun Jingru , Liu Yiyong
Published: May 2021

Researchers have long known that many animals live longer in colder climates than in warmer climates. The inverse relationship between temperature and lifespan was traditionally explained using the rate of living theory, which suggests that higher temperatures increase chemical reaction rates, thus speeding up the aging process. However, recent studies have identified specific molecules, cells and signaling pathways involved in the longevity response to temperature, indicating that such a response is not simply thermodynamic but a regulated process. Here, we report thatCaenorhabditis eleganslacking OCTR-1, a neuronal G protein-couple receptor for the neurotransmitter octopamine, had extended lifespan at warm temperature but shortened lifespan at cool temperature, indicating that OCTR-1 modulates the longevity response to both warm and cool temperatures. We further found that these responses are regulated by the OCTR-1-expressing, chemosensory ASH neurons. Transcriptomic analysis and functional assays revealed that OCTR-1 mediates temperature effects on longevity by regulating a subset of immune response genes. Our study provides cellular and molecular insights into the relationship between temperature and longevity, which could be useful for developing strategies to extend human lifespan in the midst of global warming.
Integrated Genome and Transcriptome Analyses Reveal the Mechanism of Genome Instability in Ataxia with Oculomotor Apraxia 2
Authors: Kanagaraj Radhakrishnan , Mitter Richard , Kantidakis Theodoros , Edwards Matthew M. , Benitez Anaid , Chakravarty Probir , Fu Beiyuan , Becherel Olivier , Yang Fengtang , Lavin Martin F. , Koren Amnon , Stewart Aengus , West Stephen C.
Published: May 2021

Mutations in theSETXgene, which encodes Senataxin, are associated with the progressive neurodegenerative diseases Ataxia with Oculomotor Apraxia 2 (AOA2) and Amyotrophic Lateral Sclerosis 4 (ALS4). To identify the causal defect in AOA2, patient-derived cells andSETXknockouts (human and mouse) were analyzed using integrated genomic and transcriptomic approaches. We observed a genome-wide increase in chromosome instability (gains and losses) within genes and at chromosome fragile sites, resulting in changes to gene expression profiles. Senataxin loss caused increased transcription stress near promoters that correlated with high GCskew and R-loop accumulation at promoter-proximal regions. Notably, the chromosomal regions with gains and losses overlapped with regions of elevated transcription stress. In the absence of Senataxin, we found that Cockayne Syndrome protein CSB was required for the recruitment of the transcription-coupled repair endonucleases (XPG and XPF) and recombination protein RAD52 to target and resolve transcription bubbles containing R-loops, leading to error prone repair and genomic instability. These results show that transcription stress is an important contributor toSETXmutation-associated chromosome fragility and AOA2.
The MAGOH paralogs - MAGOH, MAGOHB and their multiple isoforms
Authors: Rehman Ayushi , Chandra Pratap , Singh Kusum Kumari
Published: May 2021

A central processing event in eukaryotic gene expression is splicing. Concurrent with splicing, the core-EJC proteins, eIF4A3 and RBM8A-MAGOH heterodimer are deposited 24 bases upstream of newly formed exon-exon junctions. One of the core-EJC proteins, MAGOH contains a paralog MAGOHB, and this paralog pair is conserved across vertebrates. Upon analysis of the splice variants of MAGOH-paralogs, we have found the presence of alternate protein isoforms which are also evolutionarily conserved. Further, comparison of the amino acid sequence of the principal and alternate protein isoforms has revealed absence of key amino acid residues in the alternate isoforms. The conservation of principal and alternate isoforms correlates to the importance of MAGOH and MAGOHB across vertebrates.
Vesicle-bound regulatory RNAs are associated with tissue aging
Authors: Kern Fabian , Kuhn Thomas , Ludwig Nicole , Simon Martin , Gröger Laura , Fabis Natalie , Salhab Abdulrahman , Fehlmann Tobias , Hahn Oliver , Engel Annika , Koch Marcus , Koehler Jana , Winek Katarzyna , Soreq Hermona , Fuhrmann Gregor , Wyss-Coray Tony , Meese Eckart , Laschke Matthias W. , Keller Andreas
Published: May 2021

Previous work on murine models and human demonstrated global as well as tissue-specific molecular aging trajectories in solid tissues and body fluids1–8. Extracellular vesicles like exosomes play a crucial role in communication and information exchange in between such systemic factors and solid tissues9,10. We sequenced freely circulating and vesicle-bound small regulatory RNAs in mice at five time points across the average life span from 2 to 18 months. Intriguingly, each small RNA class exhibits unique aging patterns, which showed differential signatures between vesicle-bound and freely circulating molecules. In particular, tRNA fragments showed overall highest correlation with aging which also matched well between sample types, facilitating age prediction with non-negative matrix factorization (86% accuracy). Interestingly, rRNAs exhibited inverse correlation trajectories between vesicles and plasma while vesicle-bound microRNAs (miRNAs) were exceptionally strong associated with aging. Affected miRNAs regulate the inflammatory response and transcriptional processes, and adipose tissues show considerable effects in associated gene regulatory modules. Finally, nanoparticle tracking and electron microscopy suggest a shift from overall many small to fewer but larger vesicles in aged plasma, potentially contributing to systemic aging trajectories and affecting the molecular aging of organs.
Glycolysis/gluconeogenesis specialization in microbes is driven by biochemical constraints of flux sensing
Authors: Schink Severin Josef , Christodoulou Dimitris , Mukherjee Avik , Athaide Edward , Brunner Viktoria , Fuhrer Tobias , Bradshaw Gary Andrew , Sauer Uwe , Basan Markus
Published: May 2021

Central carbon metabolism is highly conserved across microbial species, but can catalyze very different pathways depending on the organism and their ecological niche. Here, we study the dynamic re-organization of central metabolism after switches between the two major opposing pathway configurations of central carbon metabolism, glycolysis and gluconeogenesis inEscherichia coli, Pseudomonas aeruginosaandPseudomonas putida. We combined growth dynamics and dynamic changes of intracellular metabolite levels with a coarse-grained model that integrates fluxes, regulation, protein synthesis and growth and uncovered fundamental limitations of the regulatory network: after nutrient shifts, metabolite concentrations collapse to their equilibrium, rendering the cell unable to sense which direction the flux is supposed to flow through the metabolic network. The cell can partially alleviate this by picking a preferred direction of regulation at the expense of increasing lag times in the opposite direction. Moreover, decreasing both lag times simultaneously comes at the cost of reduced growth rate or higher futile cycling between metabolic enzymes. These three trade-offs can explain why microorganisms specialize for either glycolytic or gluconeogenic substrates and can help elucidate the complex growth patterns exhibited by different microbial species.

Graphical synopsis

Standfirst text

Microbes face a series of fundamental trade-offs that limit their ability to optimize simultaneously for both glycolytic and gluconeogenic growth.

Bullet points

Lag times between glycolysis and gluconeogenesis show asymmetry in many microbes: A long lag in one direction, but a short lag in the other.

Long lag times are caused by an inability to sense fluxes after nutrient shifts.

With existing regulation, lag time asymmetry can only be overcome by reducing either growth rate or increasing futile cycling in metabolism.
Intergenerational adaptations to stress are evolutionarily conserved, stress-specific, and have deleterious trade-offs
Authors: Burton Nicholas O. , Willis Alexandra , Fisher Kinsey , Braukmann Fabian , Price Jon , Stevens Lewis , Ryan Baugh L. , Reinke Aaron , Miska Eric A.
Published: May 2021

Despite reports of parental exposure to stress promoting physiological adaptations in progeny in diverse organisms, there remains considerable debate over the significance and evolutionary conservation of such multigenerational effects. Here, we investigate four independent models of intergenerational adaptations to stress inC. elegans– bacterial infection, eukaryotic infection, osmotic stress and nutrient stress – across multiple species. We found that all four intergenerational physiological adaptations are conserved in at least one other species, that they are stress-specific, and that they have deleterious trade-offs in mismatched environments. By profiling the effects of parental bacterial infection and osmotic stress exposure on progeny gene expression across species we established a core set of 279 highly conserved genes that exhibited intergenerational changes in expression in response to stress in all species tested and provide evidence suggesting that presumed adaptive and deleterious intergenerational effects are molecularly related at the gene expression level. By contrast, we found that these same stresses did not elicit any similarly conserved transgenerational changes in progeny gene expression three generations after stress exposure. We conclude that intergenerational responses to stress play a substantial and evolutionarily conserved role in regulating animal physiology and that the vast majority of the effects of parental stress on progeny gene expression are reversible and not maintained transgenerationally.
Standardized nuclear markers advance metazoan taxonomy
Authors: Dietz Lars , Eberle Jonas , Mayer Christoph , Kukowka Sandra , Bohacz Claudia , Baur Hannes , Espeland Marianne , Huber Bernhard A. , Hutter Carl , Mengual Ximo , Peters Ralph S. , Vences Miguel , Wesener Thomas , Willmott Keith , Misof Bernhard , Niehuis Oliver , Ahrens Dirk
Published: May 2021

Species are the fundamental units of life and their recognition is essential for science and society. DNA barcoding, the use of a single and often mitochondrial gene, has been increasingly employed as a universal approach for the identification of animal species. However, this approach faces several challenges. Here, we demonstrate with empirical data from a number of metazoan animal lineages that multiple nuclear-encoded markers, so called universal single-copy orthologs (USCOs) performs much better than the single barcode gene to discriminate closely related species. Overcoming the general shortcomings of mitochondrial DNA barcodes, USCOs also accurately assign samples to higher taxonomic levels. These loci thus provide a powerful and unifying framework for species delimitation which considerably improves the DNA-based inference of animal species.
Fibrinogen αC-subregions critically contribute blood clot fibre growth, mechanical stability and resistance to fibrinolysis
Authors: McPherson Helen R. , Duval Cédric , Baker Stephen R. , Hindle Matthew S. , Cheah Lih T. , Asquith Nathan L. , Domingues Marco M. , Ridger Victoria C. , Connell Simon D.A , Naseem Khalid M. , Philippou Helen , Ajjan Ramzi A. , Ariëns Robert A.S.
Published: May 2021

Fibrinogen is essential for blood coagulation. The C-terminus of the fibrinogen α-chain (αC-region) is composed of an αC-domain and αC-connector. Two recombinant fibrinogen variants (α390 and α220) were produced to investigate the role of subregions in modulating clot stability and resistance to lysis. The α390 variant, truncated before the αC-domain, produced clots with a denser structure and thinner fibres. In contrast, the α220 variant, truncated at the start of the αC-connector, produced clots that were porous with short stunted fibres and visible fibre ends. These clots were mechanically weak and susceptible to lysis. Our data demonstrate differential effects for the αC-subregions in fibrin polymerisation, clot mechanical strength, and fibrinolytic susceptibility. Furthermore, we demonstrate that the αC-subregions are key for promoting longitudinal fibre growth. Together, these findings highlight critical functions of the αC-subregions in relation to clot structure and stability, with future implications for development of novel therapeutics for thrombosis.
Mathematical Analysis and Topology of SARS-CoV-2, Bonding with Cells and Unbonding
Authors: Srinivasa Rao Arni S.R. , Krantz Steven G.
Published: May 2021

Abstract

We consider the structure of the novel coronavirus (SARS-Cov-2) in terms of the number of spikes that are critical in bonding with the cells in the host. Bonding formation is considered for selection criteria with and without any treatments. Functional mappings from the discrete space of spikes and cells and their analysis are performed. We found that careful mathematical constructions help in understanding the treatment impacts, and the role of vaccines within a host. Smale’s famous 2-D horseshoe examples inspired us to create 3-D visualizations and understand the topological diffusion of spikes from one human organ to another organ. The pharma industry will benefit from such an analysis for designing efficient treatment and vaccine strategies.
The role of epistasis in amikacin, kanamycin, bedaquiline, and clofazimine resistance inMycobacterium tuberculosiscomplex
Authors: Vargas Roger , Freschi Luca , Spitaleri Andrea , Tahseen Sabira , Barilar Ivan , Niemann Stefan , Miotto Paolo , Cirillo Daniella Maria , Köser Claudio U. , Farhat Maha R.
Published: May 2021

Antibiotic resistance among bacterial pathogens poses a major global health threat.M. tuberculosiscomplex (MTBC) is estimated to have the highest resistance rates of any pathogen globally. Given the slow growth rate and the need for a biosafety level 3 laboratory, the only realistic avenue to scale up drug-susceptibility testing (DST) for this pathogen is to rely on genotypic techniques. This raises the fundamental question of whether a mutation is a reliable surrogate for phenotypic resistance or whether the presence of a second mutation can completely counteract its effect, resulting in major diagnostic errors (i.e. systematic false resistance results). To date, such epistatic interactions have only been reported for streptomycin that is now rarely used. By analyzing more than 31,000 MTBC genomes, we demonstrated thateisC-14T promoter mutation, which is interrogated by several genotypic DST assays endorsed by the World Health Organization, cannot confer resistance to amikacin and kanamycin if it coincides with loss-of-function (LoF) mutations in the coding region ofeis. To our knowledge, this represents the first definitive example of antibiotic reversion in MTBC. Moreover, we raise the possibility thatmmpR(Rv0678) mutations are not valid markers of resistance to bedaquiline and clofazimine if these coincide with LoF mutation in the efflux pump encoded bymmpS5(Rv0677c) andmmpL5(Rv0676c).
Molecular competition can shape enhancer activity in the Drosophila embryo
Authors: Waymack Rachel , Gad Mario , Wunderlich Zeba
Published: May 2021

Transgenic reporters allow the measurement of regulatory DNA activityin vivoand consequently have long been useful tools in the study of enhancers. Despite the utility of transgenic reporters, few studies have investigated the potential effects these reporters have on the expression of other transgenic reporters or endogenous genes. A full understanding of the impacts transgenic reporters have on expression is required for accurate interpretation of transgenic reporter data and characterization of gene regulatory mechanisms. Here, we investigate the impact transgenic reporters have on the expression of other transgenic reporters and endogenous genes. By measuring the expression ofKruppel(Kr) enhancer reporters in liveDrosophilaembryos that contain either one or two copies of identical reporters, we find reporters have an inhibitory effect on one another’s expression. Further, expression of a nearby endogenous gene is decreased in the presence of aKrenhancer reporter. Through the use of competitor binding site arrays, we present evidence that reporters, and potentially endogenous genes, are competing for transcription factors (TFs). Increasing the number of competitor Bcd binding sites decreases the peak levels and spatial extent of Bcd-regulated enhancer reporters’ expression. To understand how small numbers of added TF binding sites could impact gene expression to the extent we observe, we develop a simple thermodynamic model of our system. Our model predicts competition of the measured magnitude specifically if TF binding is restricted to distinct nuclear subregions, underlining the importance of the non-homogenous nature of the nucleus in regulating gene expression.