bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetically predicted serum vitamin D and COVID-19: a Mendelian randomization study
Authors: Patchen Bonnie K , Clark Andrew G , Hancock Dana B , Gaddis Nathan , Cassano Patricia A
Published: February 2021

Objectives

To investigate causality of the association of serum vitamin D with the risk and severity of COVID-19 infection.

Design

Two-sample Mendelian randomization study.

Setting

Summary data from genome-wide analyses in the population-based UK Biobank and SUNLIGHT Consortium, applied to meta-analyzed results of genome-wide analyses in the COVID-19 Host Genetics Initiative.

Participants

17,965 COVID-19 cases including 11,085 laboratory or physician confirmed cases, 7,885 hospitalized cases, and 4,336 severe respiratory cases, and 1,370,547 controls, primarily of European ancestry.

Exposures

Genetically predicted variation in serum vitamin D status, based on genome-wide significant single nucleotide polymorphisms (SNPs) associated with serum vitamin D or risk of vitamin D deficiency/insufficiency.

Main outcome measures

Susceptibility to and severity of COVID-19 infection, including severe respiratory infection and hospitalization.

Results

Mendelian randomization analysis, powered to detect moderate effects comparable to those seen in observational studies, provided little to no evidence for an effect of genetically predicted serum vitamin D on susceptibility to or severity of COVID-19 infection. Using SNPs in loci related to vitamin D metabolism as proxies for serum vitamin D concentration, the odds ratio for a standard deviation increase in serum vitamin D was 1.04 (95% confidence interval 0.92 to 1.18) for any COVID-19 infection versus population controls, 1.05 (0.84-1.31) for hospitalized COVID-19 versus population controls, 0.96 (0.64 to 1.43) for severe respiratory COVID-19 versus population controls, 1.15 (0.99 to 1.35) for COVID-19 positive versus COVID-19 negative, and 1.44 (0.75 to 2.78) for hospitalized COVID-19 versus non-hospitalized COVID-19. Results were similar in analyses that used all SNPs with genome-wide significant associations with serum vitamin D (i.e., including SNPs in loci with no known relationship to vitamin D metabolism) and in analyses using SNPs with genome-wide significant associations with risk of vitamin D deficiency or insufficiency.

Conclusions

These findings suggest that genetically predicted differences in long-term vitamin D nutritional status do not causally affect susceptibility to and severity of COVID-19 infection, and that associations observed in previous studies may have been driven by confounding. These results do not exclude the possibility of low-magnitude causal effects, nor do they preclude potential causal effects of acute responses to therapeutic doses of vitamin D. Future directions include extension of this work to non-European ancestry populations, and high-risk populations, for example persons with comorbid disease.
Relative humidity predicts day-to-day variations in COVID-19 cases in the city of Buenos Aires
Authors: Pineda Rojas Andrea L. , Cordo Sandra M. , Saurral Ramiro I. , Jimenez Jose L. , Marr Linsey C. , Kropff Emilio
Published: February 2021

Possible links between the transmission of COVID-19 and meteorology have been investigated by comparing positive cases across geographical regions or seasons. Little is known, however, about the degree to which environmental conditions modulate the daily dynamics of COVID-19 spread at a given location. One reason for this is that individual waves of the disease are typically too abrupt, making it hard to isolate the contribution of meteorological cycles. To overcome this shortage, we here present a case study of the first wave of the outbreak in the city of Buenos Aires, which had a slow evolution of the case load extending along most of 2020. We found that humidity plays a prominent role in modulating the variation of COVID-19 positive cases through a negative-slope linear relationship, with an optimal lag of 9 days between the meteorological observation and the positive case report. This relationship is specific to winter months, when relative humidity predicts up to half of the variance in positive cases. Our results provide a tool to anticipate local surges in COVID-19 cases after events of low humidity. More generally, they add to accumulating evidence pointing to dry air as a facilitator of COVID-19 transmission.
Pelvic Pain: what are the symptoms and predictors for surgery, endometriosis and endometriosis severity?
Authors: Conroy Isabelle , Mooney Samantha S , Kavanagh Shane , Duff Michael , Jakab Ilona , Robertson Katharine , Fitzgerald Amy L , Mccutchan Alexandra , Madden Siana , Maxwell Sarah , Nair Shweta , Origanti Nimita , Quinless Alish , Mirowska-Allen Kelly , Sewell Megan , Grover Sonia R
Published: February 2021

Background

Chronic pelvic pain (CPP) is a common condition which significantly impacts the quality of life and wellbeing of many women.

Laparoscopy with histopathology is recommended for investigation of pelvic pain and identification of endometriosis with concurrent removal. Never-the-less, the association between endometriosis and pelvic pain is challenging, with endometriosis identified in only 30-50% of women with pain.

Aims

To explore the predictors for undergoing surgery, for identifying endometriosis and endometriosis severity in a cohort of women with CPP.

Materials and Methods

This study forms part of the Persistent Pelvic Pain project, a prospective observational cohort study (ANZCTR:ACTRN12616000150448). Women referred to a public gynaecology clinic with pain were randomised to one of 2 gynaecology units for routine care and followed for 36-months with 6-monthly surveys assessing demographics, medical history, quality of life, and pain symptoms measured on a Likert scale. Operative notes were reviewed, and endometriosis staged.

Results

Of 471 women recruited, 102 women underwent laparoscopy or laparotomy, of whom 52 had endometriosis (n=37 stage I-II; n=15 stage III-IV). Gynaecology unit, pelvic pain intensity and lower parity were all predictors of surgery (Odds ratio (OR) 0.342; 95%CI 0.209-0.561; OR 1.303; 95%CI: 1.079-1.573; OR 0.767; 95%CI: 0.620-0.949 respectively). There were no predictors identified for endometriosis diagnosis and the only predictor of severity was increasing age (OR 1.155; 95%CI: 1.047-1.310).

Conclusions

Pain intensity and gynaecology unit were key predictors of undergoing laparoscopy, however, pain severity did not predict endometriosis diagnosis or staging. These findings indicate the need to review current frameworks guiding practice towards surgery for pelvic pain.
Characterization of cognitive-motor function in women who have experienced intimate partner violence-related brain injury
Authors: Maldonado-Rodriguez Naomi , Val Crocker Clara , Taylor Edward , Jones K. Elisabeth , Rothlander Krystal , Smirl Jon , Wallace Colin , van Donkelaar Paul
Published: February 2021

Intimate partner violence (IPV) affects at least 1 in 3 women worldwide and up to 92% report symptoms consistent with brain injury (BI). Although a handful of studies have examined different aspects of brain structure and function in this population, none has characterized potential deficits in cognitive-motor function. This knowledge gap was addressed in the current study by having participants who had experienced IPV complete the bimanual Object Hit & Avoid (OHA) task on a Kinarm End-Point Lab. BI load, as assessed by the Brain Injury Severity Assessment (BISA) tool as well as measures of comorbidities (PTSD, anxiety, depression, substance use, history of abuse) were also collected. Results demonstrated BI load accounted for a significant amount of variability in the number of targets hit and average hand speed. PTSD, anxiety, and depression also contributed significantly to the variability in these measures as well as to the number and proportion of distractor hits, and the object processing rate. Taken together, these findings suggest IPV-related BI, as well as comorbid PTSD, anxiety, and depression, disrupt the processing required to quickly and accurately hit targets while avoiding distractors. This pattern of results reflects the complex interaction between the physical injuries induced by the episodes of IPV and the resulting impacts these experiences have on mental health.
Small size of recorded neuronal structures confines the accuracy in direct axonal voltage measurements
Authors: Oláh Viktor János , Tarcsay Gergely , Brunner János
Published: February 2021

Patch-clamp instruments including amplifier circuits and pipettes affect the recorded voltage signals. We hypothesized that realistic and completein silicorepresentation of recording instruments together with detailed morphology and biophysics of small recorded structures will precisely reveal signal distortions and provides a tool that predicts native signals from distorted voltage recordings. Therefore, we built a model that was verified by small axonal recordings. The model accurately recreated actual action potential measurements with typical recording artefacts and predicted the native electrical behavior. The simulations verified that recording instruments substantially filter voltage recordings. Moreover, we revealed that instrumentation directly interferes with local signal generation depending on the size of the recorded structures, which complicates the interpretation of recordings from smaller structures, such as axons. However, our model offers a straightforward approach that predicts the native waveforms of fast voltage signals and the underlying conductances even from the smallest neuronal structures.
MDM-TASK-web: MD-TASK and MODE-TASK web server for analyzing protein dynamics
Authors: Amamuddy Olivier Sheik , Glenister Michael , Bishop Özlem Tastan
Published: February 2021

MDM-TASK-web is the web server for the MD-TASK and MODE-TASK software suites. It simplifies the set-up required to perform and visualize results from dynamic residue network analysis, perturbation-response scanning, dynamic cross-correlation, essential dynamics and normal mode analysis. In a nutshell, the server gives access to updated versions of the tool suites, and offers new functionalities and integrated 2D/3D visualization. An embedded work-flow, integrated documentation and visualization tools shortens the number of steps to follow, starting from calculations to result visualization. The web server (available athttps://mdmtaskweb.rubi.ru.ac.za/) is powered by Django and a MySQL database, and is compatible with all major web browsers. All scripts implemented in the web platform are freely available athttps://github.com/RUBi-ZA/MD-TASK/tree/mdm-task-webandhttps://github.com/RUBi-ZA/MODE-TASK/tree/mdm-task-web.

Highlights

MDM-TASK-web is the web server for highly utilized MD-TASK and MODE-TASK with updates

Eight residue network centrality metrics are available to analyze static and dynamic proteins

Novel comparative essential dynamics is established to compare independent MD simulations

Communication propensity tool to evaluate residue communication efficiency is implemented.

Normal mode analysis from static and protein MD simulations is provided
Chemogenetic activation of nigrostriatal dopamine neurons in freely moving common marmosets
Authors: Mimura Koki , Nagai Yuji , Inoue Ken-ichi , Matsumoto Jumpei , Hori Yukiko , Sato Chika , Kimura Kei , Okauchi Takashi , Hirabayashi Toshiyuki , Nishijo Hisao , Yahata Noriaki , Takada Masahiko , Suhara Tetsuya , Higuchi Makoto , Minamimoto Takafumi
Published: February 2021

To interrogate particular neuronal pathways in non-human primates under natural and stress-free conditions, we applied designer receptors exclusively activated by designer drugs (DREADDs) technology to common marmosets. We injected adeno-associated virus vectors expressing the excitatory DREADD hM3Dq into the unilateral substantia nigra in three marmosets. Using multi-tracer positron emission tomography imaging, we detected DREADD expression in vivo, which was confirmed in nigrostriatal dopamine neurons by immunohisto-chemistry, and assessed activation of the substantia nigra and dopamine release following agonist administration. The marmosets rotated in a contralateral direction relative to the activated side 30–90 min after consuming food containing the highly potent DREADD agonist deschloroclozapine (DCZ), but not on the following days without DCZ. These results indicate that non-invasive and reversible DREADD manipulation will extend the utility of marmoset as a primate model for linking neuronal activity and natural behavior in various contexts.
Management of altered metabolic activity inDrosophilamodel of Huntington’s disease by curcumin
Authors: Aditi Kumari , Singh Akanksha , Shakarad Mallikarjun N , Agrawal Namita
Published: February 2021

Huntington’s disease (HD) is a devastating polyglutamine (polyQ) disorder characterized by extensive neurodegeneration and metabolic abnormalities at systemic, cellular and intracellular levels. Metabolic alterations in HD manifest as abnormal body weight, dysregulated biomolecule levels, impaired adipocyte functions and defective energy state which exacerbate disease progression and pose acute threat to the health of challenged individuals in form of insulin resistance, cardiovascular disease and energy crisis. To colossally mitigate disease symptoms, we tested the efficacy of curcumin inDrosophilamodel of HD. Curcumin is bioactive component of turmeric (Curcuma longaLinn), well-known for its ability to modulate metabolic activities. We found that curcumin effectively managed abnormal body weight, dysregulated lipid content and carbohydrate level in HD flies. In addition, curcumin administration lowered elevated reactive-oxygen-species (ROS) levels in adult adipose tissue of diseased flies, and improved survival and locomotor function in HD flies at advanced disease stage. Altogether, these findings clearly suggest that curcumin efficiently attenuates metabolic derangements in HD flies and can prove beneficial in alleviating the complexities associated with HD. Phytochemicals like curcumin that can regulate multiple targets in complex diseases like HD, with least side-effects and maximum benefits, provide a better hope for the treatment of terminally-ill HD patients.
Effect of urbanization and its environmental stressors on the intraspecific variation of flight functional traits in two bumblebee species
Authors: Tommasi Nicola , Pioltelli Emiliano , Biella Paolo , Labra Massimo , Casiraghi Maurizio , Galimberti Andrea
Published: February 2021

The way urbanization shapes the intraspecific variation of pollinator functional traits is little understood. However, this topic is relevant for investigating ecosystem services and pollinator health. Here, we studied how urbanization affects the functional traits of workers in two bumblebee species (Bombus terrestrisandB. pascuorum) sampled in 37 sites along a gradient of urbanization in North Italy (an area of 1800 km2including the metropolitan context of Milan and other surrounding capital districts). Namely, we investigated the role played by land-use composition, configuration, temperature, flower resource abundance, and air pollutants on the variation of traits related to flight performance (i.e., body size, wing shape and size fluctuating asymmetry). These traits are relevant because they are commonly used as indicators of stress during insect development. The functional traits of the two bumblebees responded idiosyncratically to urbanization. Urban temperatures were associated with smaller wing sizes inB. pascuorumand with more accentuated fluctuating asymmetry of wing size inB. terrestris. Moreover, flower abundance correlated with bigger wings inB. terrestrisand with less asymmetric wing sizes inB. pascuorum. Other traits did not vary significantly and other urban variables played minor effects. These patterns highlight that environmental stressors linked to urbanization negatively impact traits related to flight performance and development stability of these species with possible consequences on the pollination service they provide.

Overall, this study found species-specific variation patterns in syntopic taxa, expanding our understanding about the effects of anthropic disturbance in shaping relevant functional traits of pollinator model species.
Just-in-time: gaze guidance in natural behavior
Authors: Keshava Ashima , Nezami Farbod Nosrat , Neumann Henri , Izdebski Krzysztof , Schüler Thomas , König Peter
Published: February 2021

Natural eye movements have primarily been studied for over-learned activities such as tea-making, sandwich-making, and hand-washing, which have a fixed sequence of associated actions. These studies indicate a sequential activation of low-level cognitive schemas facilitating task completion. However, it is unclear if these action schemas are activated in the same pattern when a task is novel and a sequence of actions must be planned in the moment. Here, we recorded gaze and body movements in a naturalistic task to study action-oriented gaze behavior. In a virtual environment, subjects moved objects on a life-size shelf to achieve a given order. In order to compel cognitive planning, we added complexity to the sorting tasks. Fixations aligned with the action onset showed gaze as tightly coupled with the action sequence, and task complexity moderately affected the proportion of fixations on the task-relevant regions. Our analysis further revealed that the gaze was allocated to action-relevant targets just in time. Planning behavior predominantly corresponded to a greater visual search for task-relevant objects before the action onset. The results support the idea that natural behavior relies very little on working memory, and humans refrain from encoding objects in the environment to plan long-term actions. Instead, they prefer just-in-time planning by searching for action-relevant items in the moment, directing their body and hand to it, monitoring the action until it is terminated, and moving on to the next action.

Author Summary

Eye movements in the natural environment have primarily been studied for over-learned and habitual everyday activities (tea-making, sandwich-making, hand-washing) with a fixed sequence of associated actions. These studies show eye movements correspond to a specific order of actions learned over time. In this study, we were interested in how humans plan and execute actions for tasks that do not have an inherent action sequence. To that end, we asked subjects to sort objects based on object features on a life-size shelf in a virtual environment as we recorded their eye and body movements. We investigated the general characteristics of gaze behavior while acting under natural conditions. Our paper provides a comprehensive approach to preprocess naturalistic gaze data in virtual reality. Furthermore, we provide a data-driven method of analyzing the different action-oriented functions of gaze. The results show that bereft of a predefined action sequence, humans prefer to plan only their immediate actions where eye movements are used to search for the target object to immediately act on, then to guide the hand towards it, and to monitor the action until it is terminated. Such a simplistic approach ensures that humans choose sub-optimal behavior over planning under sustained cognitive load.
Experimental sexual selection reveals rapid evolutionary divergence in sex-specific transcriptomes and their interactions following mating
Authors: Veltsos Paris , Porcelli Damiano , Fang Yongxiang , Cossins Andrew R. , Ritchie Michael G. , Snook Rhonda R.
Published: February 2021

Postcopulatory interactions between the sexes in internally fertilizing species elicits both sexual conflict and sexual selection. Macroevolutionary and comparative studies have linked these processes to rapid transcriptomic evolution in sex-specific tissues and substantial transcriptomic postmating responses in females, patterns of which are altered when mating between reproductively isolated species. Here we test multiple predictions arising from sexual selection and conflict theory about the evolution of sex-specific and tissue-specific gene expression and the postmating response at the microevolutionary level. Following over 150 generations of experimental evolution under either reduced (enforced monogamy) or elevated (polyandry) sexual selection inDrosophila pseudoobscura, we found a substantial effect of sexual selection treatment on transcriptomic divergence in virgin male and female reproductive tissues (testes, male accessory glands, the female reproductive tract and ovaries). Sexual selection treatment also had a dominant effect on the postmating response, particularly in the female reproductive tract – the main arena for sexual conflict - compared to ovaries. This affect was asymmetric with monandry females typically showing more postmating responses than polyandry females, with enriched gene functions varying across treatments. The evolutionary history of the male partner had a larger effect on the postmating response of monandry females, but females from both sexual selection treatments showed unique patterns of gene expression and gene function when mating with males from the alternate treatment. Our microevolutionary results mostly confirm comparative macroevolutionary predictions on the role of sexual selection on transcriptomic divergence and altered gene regulation arising from divergent coevolutionary trajectories between sexual selection treatments.
Functional inactivation of pulmonary MAIT cells following 5-OP-RU treatment of non-human primates
Authors: Sakai Shunsuke , Lora Nickiana E. , Kauffman Keith D. , Dorosky Danielle E. , Oh Sangmi , Namasivayam Sivaranjani , Gomez Felipe , Fleegle Joel D. ,   Tuberculosis Imaging Program, Lindestam Arlehamn Cecilia S. , Sette Alessandro , Sher Alan , Freeman Gordon J. , Via Laura E. , Barry Clifton E. , Barber Daniel L.
Published: February 2021

Targeting MAIT cells holds promise for the treatment of different diseases and infections. We previously showed that treatment ofMycobacterium tuberculosisinfected mice with 5-OP-RU, a major antigen for MAIT cells, expands MAIT cells and enhances bacterial control. Here we treatedM. tuberculosisinfected rhesus macaques with 5-OP-RU intratracheally but found no clinical or microbiological benefit inM. tuberculosisinfected macaques. In fact, after 5-OP-RU treatment MAIT cells did not expand, but rather upregulated PD-1 and lost the ability to produce multiple cytokines, a phenotype resembling T cell exhaustion. Furthermore, we show that vaccination of uninfected macaques with 5-OP-RU+CpG instillation into the lungs also drives MAIT cell dysfunction, and PD-1 blockade during vaccination partly prevents the loss of MAIT cell function without facilitating their expansion. Thus, in rhesus macaques MAIT cells are prone to the loss of effector functions rather than expansion after TCR stimulationin vivo, representing a significant barrier to therapeutically targeting these cells.
Modeling Vertical Migrations of Zooplankton Based on Maximizing Fitness
Authors: Kuzenkov O. , Ryabova E. , Garcia A. , Degtyarev A.
Published: February 2021

The purpose of the work is to calculate the evolutionarily stable strategy of zooplankton diel vertical migrations from known data of the environment using principles of evolutionary optimality and selection.

At the first stage of the research, the fitness function is identified using artificial neural network technologies. The training sample is formed based on empirical observations. It includes pairwise comparison results of the selective advantages of a certain set of species. Key parameters of each strategy are calculated: energy gain from ingested food, metabolic losses, energy costs on movement, population losses from predation and unfavorable living conditions. The problem of finding coefficients of the fitness function is reduced to a classification problem. The single-layer neural network is built to solve this problem. The use of this technology allows one to construct the fitness function in the form of a linear convolution of key parameters with identified coefficients.

At the second stage, an evolutionarily stable strategy of the zooplankton behavior is found by maximizing the identified fitness function. The maximization problem is solved using optimal control methods. A feature of this work is the use of piecewise linear approximations of environmental factors: the distribution of food and predator depending on the depth. As a result of the study, mathematical and software tools have been created for modeling and analyzing the hereditary behavior of living organisms in an aquatic ecosystem. Mathematical modeling of diel vertical migrations of zooplankton in Saanich Bay has been carried out.
Proton egress pathway during the S1–S2transition of the Oxygen Evolving Complex of Photosystem II
Authors: Kaur Divya , Zhang Yingying , Reiss Krystle M. , Mandal Manoj , Brudvig Gary W. , Batista Victor S. , Gunner M. R.
Published: February 2021

Photosystem II uses water as the ultimate electron source of the photosynthetic electron transfer chain. Water is oxidized to dioxygen at the Oxygen Evolving Complex (OEC), a Mn4CaO5inorganic core embedded in the lumenal side of PSII. Water-filled channels are thought to bring in substrate water molecules to the OEC, remove the substrate protons to the lumen, and may transport the product oxygen. Three water-filled channels, denoted large, narrow, and broad, that extend from the OEC towards the aqueous surface more than 15 Å away are seen. However, the actual mechanisms of water supply to the OEC, the removal of protons to the lumen and diffusion of oxygen away from the OEC have yet to be established. Here, we combine Molecular Dynamics (MD), Multi Conformation Continuum Electrostatics (MCCE) and Network Analysis to compare and contrast the three potential proton transfer paths during the S1to S2transition of the OEC. Hydrogen bond network analysis shows that the three channels are highly interconnected with similar energetics for hydronium as calculated for all paths near the OEC. The channels diverge as they approach the lumen, with the water chain in the broad channel better interconnected that in the narrow and large channels, where disruptions in the network are observed at about 10 Å from the OEC. In addition, the barrier for hydronium translocation is lower in the broad channel, suggesting that a proton from the OEC could access the paths near the OEC, and likely exit to the lumen via the broad channel, passing through PsbO.
DRscDB: A single-cell RNA-seq resource for data mining and data comparison across species
Authors: Hu Yanhui , Tattikota Sudhir Gopal , Liu Yifang , Comjean Aram , Gao Yue , Forman Corey , Kim Grace , Rodiger Jonathan , Papatheodorou Irene , dos Santos Gilberto , Mohr Stephanie E. , Perrimon Norbert
Published: February 2021

With the advent of single-cell RNA sequencing (scRNA-seq) technologies, there has been a spike in studies involving scRNA-seq of several tissues across diverse species includingDrosophila.Although a few databases exist for users to query genes of interest within the scRNA-seq studies, search tools that enable users to find orthologous genes and their cell type-specific expression patterns across species are limited. Here, we built a new search database, called DRscDB (https://www.flyrnai.org/tools/single_cell/web/) to address this need. DRscDB serves as a comprehensive repository for published scRNA-seq datasets forDrosophilaand the relevant datasets from human and other model organisms. DRscDB is based on manual curation ofDrosophilascRNA-seq studies of various tissue types and their corresponding analogous tissues in vertebrates including zebrafish, mouse, and human. Of note, our search database provides most of the literature-derived marker genes, thus preserving the original analysis of the published scRNA-seq datasets. DRscDB serves as a web-based user interface that allows users to mine, utilize and compare gene expression data pertaining to scRNA-seq datasets from the published literature.
Functional dynamic genetic effects on gene regulation are specific to particular cell types and environmental conditions
Authors: Findley Anthony S , Monziani Alan , Richards Allison L , Rhodes Katie , Ward Michelle C , Kalita Cynthia A , Alazizi Adnan , Pazokitoroudi Ali , Sankararaman Sriram , Wen Xiaoquan , Lanfear David E , Pique-Regi Roger , Gilad Yoav , Luca Francesca
Published: February 2021

Genetic effects on gene expression and splicing can be modulated by cellular and environmental factors; yet interactions between genotypes, cell type and treatment have not been comprehensively studied together. We used an induced pluripotent stem cell system to study multiple cell types derived from the same individuals and exposed them to a large panel of treatments. Cellular responses involved different genes and pathways for gene expression and splicing processes, and were also highly variable across cell types and treatments. For thousands of genes, we identified variable allelic expression across contexts, and characterized different types of gene-environment interactions. Many of these G×E genes are associated with complex traits. We characterized promoter functional and evolutionary features that distinguish genes with elevated allelic imbalance mean and variance. More than 47% of the genes with dynamic regulatory interactions were missed by GTEx, but we identified them using a suitable allelic imbalance study design. This indicates the importance of exploring multiple treatments to reveal previously unrecognized regulatory loci that may be important for disease.
Morphological Metrics of Magnetic Resonance Imaging of Glioblastoma as Biomarkers of Prognosis
Authors: Curtin Lee , Whitmire Paula , White Haylye , Mrugala Maciej M. , Hu Leland S. , Swanson Kristin R.
Published: February 2021

Morphological characteristics have been linked to outcomes across a variety of cancers. Lacunarity is a quantitative morphological measure of how shapes fill space while fractal dimension is a morphological measure of the complexity of pixel arrangement. Glioblastoma is the most aggressive primary brain tumor with a short expected survival given the current standard-of-care treatment. Due to the sensitive location of the tumor, there is a heavy reliance on imaging to assess the state of the disease in the clinic. In this project, we computed lacunarity and fractal dimension values for glioblastoma-induced abnormalities on gadolinium-enhanced T1-weighted magnetic resonance imaging (T1Gd MRI) as well as T2-weighted (T2) and fluid-attenuated inversion recovery (FLAIR) MRIs. In our patient cohort (n=402), we aim to connect these morphological metrics calculated on pretreatment MRI with the survival of patients with GBM. We calculated lacunarity and fractal dimension across all MRI slices on necrotic regions (n=390) and abnormalities on T1Gd MRI (n=402), as well as on enhancing abnormalities present on T2/FLAIR MRI (n=257). We also explored the relationship between these metrics and age at diagnosis, as well as abnormality volume. We found statistically significant relationships to outcome across all three imaging subtypes, with the shape of T2/FLAIR abnormalities showing the strongest relationship with overall survival. The link between morphological and survival metrics could be driven by underlying biological phenomena, tumor location or microenvironmental factors that should be further explored.
Functional and comparative genome analysis reveals clade-specific genome innovations in the killer fungusCandida auris
Authors: Narayanan Aswathy , Vadnala Rakesh Netha , Ganguly Promit , Selvakumar Pavitra , Rudramurthy Shivaprakash M , Prasad Rajendra , Chakrabarti Arunaloke , Siddharthan Rahul , Sanyal Kaustuv
Published: February 2021

The thermotolerant multidrug-resistant ascomyceteCandida aurisrapidly emerged since 2009 and simultaneously evolved in different geographical zones worldwide, causing superficial as well as systemic infections. The molecular events that orchestrated this sudden emergence of the killer fungus remain mostly elusive. Here, we identify centromeres inC. aurisand related species, using a combined approach of chromatin immunoprecipitation and comparative genomic analyses. We find thatC. aurisand multiple other species in theClavispora/Candidaclade shared a conserved small regional centromere landscape lacking pericentromeres. Further, a centromere inactivation event led to karyotypic alterations in this species complex. Inter-species genome analysis identified several structural chromosomal changes around centromeres. In addition, centromeres are found to be rapidly evolving loci among the different geographical clades of the same species ofC. auris. Finally, we reveal an evolutionary trajectory of the unique karyotype associated with clade 2 that consists of the drug susceptible isolates ofC. auris.
Diagnostic accuracy of Panbio™ rapid antigen tests on oropharyngeal swabs for detection of SARS-CoV-2
Authors: Ngo Nsoga Marie Thérèse , Kronig Ilona , Perez Rodriguez Francisco Javier , Sattonnet-Roche Pascale , Da Silva Diogo , Helbling Javan , Sacks Jilian A. , de Vos Margaretha , Boehm Erik , Gayet-Ageron Angèle , Berger Alice , Jacquerioz-Bausch Frédérique , Chappuis François , Kaiser Laurent , Schibler Manuel , Renzoni Adriana , Eckerle Isabella
Published: February 2021

Background

Antigen-detecting rapid diagnostic tests (Ag-RDTs) for the detection of SARS-CoV-2 offer new opportunities for testing in the context of the COVID-19 pandemic. Nasopharyngeal swabs (NPS) are the reference sample type, but oropharyngeal swabs (OPS) may be a more acceptable sample type in some patients.

Methods

We conducted a prospective study in a single screening center to assess the diagnostic performance of the Panbio™ COVID-19 Ag Rapid Test (Abbott) on OPS compared with reverse-transcription quantitative PCR (RT-qPCR) using NPS.

Results

402 outpatients were enrolled in a COVID-19 screening center, of whom 168 (41.8%) had a positive RT-qPCR test. The oropharyngeal Ag-RDT sensitivity compared to nasopharyngeal RT-qPCR was 81% (95%CI: 74.2-86.6). Two false positives were noted out of the 234 RT-qPCR negative individuals, which resulted in a specificity of 99.1% (95%CI: 96.9-99.9) for the Ag-RDT.

For cycle threshold values ≤ 26.7 (≥ 1E6 SARS-CoV-2 genomes copies/mL, a presumed cut-off for infectious virus), 96.3% sensitivity (95%CI: 90.7-99.0%) was obtained with the Ag-RDT using OPS.

Interpretation

Based on our findings, the diagnostic performance of the Panbio™ Covid-19 RDT with OPS samples meet the criteria required by the WHO for Ag-RDTs (sensitivity≥80% and specificity ≥97%).
Integrating primary care and social services for older adults with multimorbidity: A qualitative study
Authors: Dambha-Miller Hajira , Simpson Glenn , Hobson Lucy , Olaniyan Doyinsola , Hodgson Sam , Roderick Paul , Fraser Simon DS , Little Paul , Everitt Hazel , Santer Miriam
Published: February 2021

Background

Growing demand from an ageing population, chronic preventable disease and multimorbidity has resulted in complex health and social care needs requiring more integrated services. Integrating primary care with social services could more efficiently utilise resources, and improve experiences for patients, their families and carers. There is limited evidence on progress including key barriers and drivers of integration to inform large-scale national change.

Aim

To elicit stakeholder views on drivers and barriers of integrated primary care and social services. and highlight opportunities for successful implementation.

Design and setting

A qualitative interview study.

Method

Semi-structured interviews with maximum variation sampling to capture stakeholder views across services and professions.

Results

Thirty-seven interviews were conducted across England including GPs, nurses, social care staff, commissioners, local government, voluntary and private sectors, patients and carers. Drivers of integration included groups of like-minded individuals supported by good leadership, expanded interface roles to bridge gaps between systems and co-location of services. Barriers included structural and interdisciplinary tension between professions, organisational self-interest and challenges in record-sharing.

Conclusions

Drivers and barriers to integration identified in other contexts are also present in primary care and social services. Benefits of integration are unlikely to be realised if these are not addressed in the design and execution of new initiatives. Efforts should go beyond local and professional level change to include wider systems and policy-level initiatives. This will support a more systems-wide approach to integrated care reform, which is necessary to meet the complex and growing needs of an ageing multimorbid population.
Understanding soaring coronavirus cases and the effect of contagion policies in the UK
Authors: Durán-Olivencia Miguel A. , Kalliadasis Serafim
Published: February 2021

The number of new daily SARS-CoV-2 infections is frantically rising in almost every country of the EU. The phenomenological explanation offered is a new mutation of the virus, first identified in the UK. We use publicly available data in combination with a controlled SIR model, which captures the effects of preventive measures on the active cases, to show that the current wave of infections is consistent with a single transmission rate. This suggests that the new SARS-CoV-2 variant is as transmissible as previous strains. Our findings indicate that the relaxation of preventive measures is closely related with the ongoing surge in cases. We simulate the effects of new restrictions and vaccination campaigns in 2021, demonstrating that lockdown policies are not fully effective to flatten the curve. For effective mitigation, it is critical that the public keeps on high alert until vaccination reaches a critical threshold.
Single Dose Vaccination in Healthcare Workers Previously Infected with SARS-CoV-2
Authors: Saadat Saman , Tehrani Zahra Rikhtegaran , Logue James , Newman Michelle , Frieman Matthew B. , Harris Anthony D. , Sajadi Mohammad M.
Published: February 2021

Coronavirus disease 2019 (COVID-19) vaccine shortages have led some experts and countries to consider untested dosing regimens. We studied antibody responses to a single dose of the Pfizer-BioNTech or Moderna vaccines in healthcare workers (HCW) with laboratory-confirmed COVID-19 infection and compared to them to antibody responses of HCW who were IgG negative to SARS-CoV-2 spike protein. HCW with prior COVID-19 showed clear secondary antibody responses to vaccination with IgG spike binding titers rapidly increasing by 7 days and peaking by days 10 and 14 post-vaccination. At all time points tested, HCW with prior COVID-19 infection showed statistically significant higher antibody titers of binding and functional antibody compared to HCW without prior COVID-19 infection (p<.0001for each of the time points tested). In times of vaccine shortage, and until correlates of protection are identified, our findings preliminarily suggest the following strategy as more evidence-based: a) a single dose of vaccine for patients already having had laboratory-confirmed COVID-19; and b) patients who have had laboratory-confirmed COVID-19 can be placed lower on the vaccination priority list.
Retinol Depletion in Severe COVID-19
Authors: Sarohan Aziz Rodan , Akelma Hakan , Araç Eşref , Aslan Özgür
Published: February 2021

Background and Purpose

Vitamin A is depleted during infections. Vitamin A has been used successfully in measles, RSV and AIDS patients and is an effective vaccine adjuvant. In this study, low retinol levels were found in patients with severe COVID-19. Retinoid signaling impairment in COVID-19 disrupts Type-I interferon synthesis.

Material and Method

Two groups were formed in the study. The patient group consisted of 27 (Group 1) severe COVID-19 patients hospitalized in the intensive care unit with respiratory failure, and the control group consisted of 23 (Group 2) patients without COVID-19 symptoms. Serum retinol levels were analyzed by ELIZA and HPLC in both groups.

Findings

Retinol levels were found to be significantly lower in the patient group (P <0.001). There was no difference in retinol between two different age groups in the patient group (P> 0.05). There was no significant difference in retinol between men and women (P> 0.05). Comorbidity did not affect serum retinol levels (P >0.05).

Conclusion

Serum retinol levels were low in patients with severe COVID-19. Drugs preventing retinol excretion were not stopped in the patient group. Some patients took vitamin A externally. Despite this, retinol was low in COVID-19 patients. Retinol depletion impairs Type-I interferon synthesis by impairing retinoid signaling. Retinoid signaling may be the main pathogenetic disorder in COVID-19. This pathogenesis can serve as a guide for adjuvants, drug targets, and candidate drugs. Retinol, retinoic acid derivatives, and some CYP450 inhibitors may work on COVID-19.
piRNAs Coordinate poly(UG) Tailing to Prevent Aberrant and Permanent Gene Silencing
Authors: Shukla Aditi , Perales Roberto , Kennedy Scott
Published: February 2021

Noncoding RNAs have emerged as mediators of transgenerational epigenetic inheritance (TEI) in a number of organisms. A robust example of RNA-directed TEI is the inheritance of gene silencing states following RNA interference (RNAi) in the metazoan C. elegans. During RNAi inheritance, gene silencing is transmitted by a self-perpetuating cascade of siRNA-directed poly(UG) tailing of mRNA fragments (pUGylation), followed by siRNA synthesis from poly(UG)-tailed mRNA templates (termed pUG RNA/siRNA cycling). Despite the self-perpetuating nature of pUG RNA/siRNA cycling, RNAi inheritance is finite, suggesting that systems likely exist to prevent permanent RNAi-triggered gene silencing. Here we show that, in the absence of Piwi-interacting RNAs (piRNAs), an animal-specific class of small noncoding RNA, RNAi-based gene silencing can become essentially permanent, lasting at near 100% penetrance for more than five years and hundreds of generations. This permanent gene silencing is mediated by perpetual activation of the pUG RNA/siRNA TEI pathway. Further, we find that piRNAs coordinate endogenous RNAi pathways to prevent germline-expressed genes, which are not normally subjected to TEI, from entering a state of permanent and irreversible epigenetic silencing also mediated by perpetual activation of pUG RNA/siRNA cycling. Together, our results show that one function of C. elegans piRNAs is to insulate germline-expressed genes from aberrant and runaway inactivation by the pUG RNA/siRNA epigenetic inheritance system.
Expected 10-anonymity of HyperLogLog sketches for federated queries of clinical data repositories
Authors: Tao Ziye , Weber Griffin M. , Yu Yun William
Published: February 2021

Motivation

The rapid growth in of electronic medical records provide immense potential to researchers, but are often silo-ed at separate hospitals. As a result, federated networks have arisen, which allow simultaneously querying medical databases at a group of connected institutions. The most basic such query is the aggregate count—e.g. How many patients have diabetes? However, depending on the protocol used to estimate that total, there is always a trade-off in the accuracy of the estimate against the risk of leaking confidential data. Prior work has shown that it is possible to empirically control that trade-off by using the HyperLogLog (HLL) probabilistic sketch.

Results

In this article, we prove complementary theoretical bounds on the k-anonymity privacy risk of using HLL sketches, as well as exhibit code to efficiently compute those bounds.

Availability

https://github.com/tzyRachel/K-anonymity-Expectation

Contact

ywyu@math.toronto.edu

Supplementary information

N/A
Probing individual-level structural atrophy in frontal glioma patients
Authors: Zhang Guobin , Huang Huawei , Zhang Xiaokang , Wang Yonggang , Li Haoyi , Duan Yunyun , Chen Hongyan , Liu Yaou , Jing Bin , Lin Song
Published: February 2021

Although every glioma patient varies in tumor size, location, histological grade and molecular biomarkers, structural abnormalities are commonly conducted in a group-level, leading to the miss of individual structural atrophy. In this study, we introduced an individual-level structural abnormality detection method for glioma patients and proposed several novel abnormality indexes to depict the individual atrophy pattern. Forty-five glioma patients in frontal lobe and fifty-two age-matched healthy controls participated in the study. All patients underwent neurocognitive test and molecular examinations, including 1p/19q co-deletion, isocitrate dehydrogenase (IDH) mutation, telomerase reverse transcriptase (TERT) promoter mutation and O6-methylguanine-DNA methyltransferase (MGMT) promotor methylation. Individual structural abnormality maps for every glioma patient were calculated from the preoperative T1 images, and the individual abnormality index were further computed and explored the associations with clinical indicators. The results manifested that: 1. Every glioma patient show unique atrophy pattern; 2. Glioma patients also share consistent atrophy regions; 3. The atrophy pattern is influenced by some molecular biomarkers. Our study provides an effective way to access the individual structural abnormalities in glioma patients, and displays great potentials in individualized precision medicine for glioma patients.
Sense of Agency for Mental Actions: Insights from a Belief-Based Action-Effect Paradigm
Authors: Lopez-Sola Edmundo , Moreno-Bote Rubén , Arsiwalla Xerxes D.
Published: February 2021

A substantial body of research in the past few decades has converged on the idea that the so-called “sense of agency”, the feeling of being in control of our own actions, arises from the integration of multiple sources of information at different levels. In this study, we investigated whether a measurable sense of agency can be detected for mental actions, without the contribution of motor components. We used a fake action-effect paradigm, where participants were led to think that a motor action or a particular thought could trigger a sound. Results showed that the high-level sense of agency, measured through explicit reports, was of comparable strength for motor and mental actions. The ‘intentional binding’ effect, a phenomenon typically associated with the experience of agency, was also observed for both motor and mental actions, with the only exception of short action-effect delays. Furthermore, a consistent relationship between explicit reports of agency and intentional binding was found. Taken together, our results provide novel insights into the specific role of intentional cues in instantiating a sense of agency, even in the absence of motor signals. These results may have important implications for future brain-computer interfaces as well as for the study of pathological disruptions of agency.