bluuebunny/crossref_metadata_2025 huggingface dataset:
Pre-pandemic SARS-CoV-2 potential natural immunity among population of the Democratic Republic of Congo
Authors: Souris Marc , Tshilolo Léon , Parzy Daniel , Kamgaing Rachel , Mbongi Destin , Phoba Baltazar , Tshilolo Marie-Anasthasie , Mbungu René , Morand Pierre , Gonzalez Jean-Paul
Published: May 2021

More than a year after the emergence of COVID-19, significant regional differences in terms of morbidity persist, showing lower incidence rates in sub-Saharan Africa, Southeast Asia, and Oceania. Like SARS-CoV-1 and MERS viruses, SARS-CoV-2 is monophyletically positioned with parental species of chiropteran coronavirus. Furthermore, we observe that the spatial distribution of several targeted bat species (i.e., Coronavirus species hosts) overlaps the distribution of countries with low COVID-19 incidence.

The work presented here aims to test the presence of natural immunity among population with a low COVD-19 prevalence, potentially due to a previous exposure to coronavirus antigens of a virus close related to SARS-CoV-2. To identify such pre-existing immunity, an ELISA serological test was used to detect IgG antibodies targeting main SARS-CoV-2 proteins including: the N-protein, the Spike 1 (S1) protein, the receptor binding domain (RBD) of the S1 protein, the N-terminal domain (NTD) of the S1 protein, and the S2 protein.

A total of 574 sera samples collected before 2019 in the population of the Democratic Republic of Congo (DRC) were tested). 189 control sera from blood donors in France were used as control samples.

The results showed a statistically significant difference between the DRC samples and control samples for all antigens (N, S1, S2, NTD) except for RBD. The percentage of positive samples presenting reactive antibodies for S1 antigen was respectively of 19.2% for RDC versus 2.11% for the control, and of 9.3% versus 1.6% for the S2 antigen.

In conclusion, our data showed that the study population has been potentially exposed to a SARS-CoV-2-like virus antigen before the pandemic in the Central African sub-region. Therefore, it is quite legitimate to think that this prior immunity may be protective and responsible for the observed low prevalence of COVID-19. Moreover, we can assume that this not yet identified SARS-CoV-2-like could be associated to a chiropteran species in close contact with the studied population. In order to confirm the presence of SARS-CoV-2-like virus antibodies and ultimately identify the neutralizing potential for the detected antibodies, our study is underway in other African and Asian countries, where the COVID-19 prevalence is limited.
Investigating the causal relationship between allergic disease and mental health
Authors: Budu-Aggrey Ashley , Joyce Sally , Davies Neil M , Paternoster Lavinia , Munafò Marcus R. , Brown Sara J , Evans Jonathan , Sallis Hannah M.
Published: May 2021

Background

Observational studies have reported an association between allergic disease and mental health, but a causal relationship has not been established.

Objective

To use Mendelian Randomization (MR) to investigate a possible causal relationship between atopic disease and mental health phenotypes.

Methods

The observational relationship between allergic disease and mental health was investigated in UK Biobank. The direction of causality was investigated with bidirectional two-sample MR using summary-level data from published genome-wide association studies. A genetic instrument was derived from associated variants for a broad allergic disease phenotype to test for causal relationships with various mental health outcomes. Genetic instruments were also derived for mental health conditions to assess causality in the reverse direction. We also investigated if these relationships were specific to atopic dermatitis (AD), asthma or hay fever.

Results

The broad allergic disease phenotype was phenotypically associated with most measures of mental health, but we found little evidence of causality in either direction. However, we did find evidence of genetic liability for bipolar disorder causally influencing hay fever risk (OR=0.94 per doubling odds of bipolar disorder risk; 95%CI=0.90-0.99;P-value=0.02), but evidence of a phenotypic association was weak.

Conclusions

Few of the phenotypic associations between allergic disease and mental health were replicated. Any causal effects we detected were considerably attenuated compared to the phenotypic association. This suggests that most co-morbidity observed clinically is unlikely to be causal.

Clinical Implication

We found little evidence that genetic predisposition to allergic diseasecausesmental ill-health, andvice versa, which suggests that intervening to prevent onset of allergic disease is unlikely to directly prevent the onset of mental ill-health.

Key Messages

Mendelian randomization effect estimates suggest that the phenotypic association between allergic disease and mental health is likely to be inflated

Causal analysis was unable to corroborate the phenotypic associations observed between allergic disease and mental health phenotypes

Intervening on an individual’s allergic disease is not likely to directly improve their mental health

Capsule summary

Mendelian Randomization suggests that evidence of a causal relationship between allergic disease and mental health phenotypes is weak. It is unlikely that intervening to prevent onset of allergic disease will prevent poor mental health.
Aspirin and NSAID use and the risk of COVID-19
Authors: Drew David A. , Guo Chuan-Guo , Lee Karla A. , Nguyen Long H. , Joshi Amit D. , Lo Chun-Han , Ma Wenjie , Mehta Raaj S. , Kwon Sohee , Astley Christina M. , Song Mingyang , Davies Richard , Capdevila Joan , Lochlainn Mary Ni , Sudre Carole H. , Graham Mark S. , Varsavsky Thomas , Gomez Maria F. , Kennedy Beatrice , Fitipaldi Hugo , Wolf Jonathan , Spector Tim D. , Ourselin Sebastien , Steves Claire J. , Chan Andrew T.
Published: May 2021

Early reports raised concern that use of non-steroidal anti-inflammatory drugs (NSAIDs) may increase risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19). Users of the COVID Symptom Study smartphone application reported use of aspirin and other NSAIDs between March 24 and May 8, 2020. Users were queried daily about symptoms, COVID-19 testing, and healthcare seeking behavior. Cox proportional hazards regression was used to determine the risk of COVID-19 among according to aspirin or non-aspirin NSAID users. Among 2,736,091 individuals in the U.S., U.K., and Sweden, we documented 8,966 incident reports of a positive COVID-19 test over 60,817,043 person-days of follow-up. Compared to non-users and after stratifying by age, sex, country, day of study entry, and race/ethnicity, non-aspirin NSAID use was associated with a modest risk for testing COVID-19 positive (HR 1.23 [1.09, 1.32]), but no significant association was observed among aspirin users (HR 1.13 [0.92, 1.38]). After adjustment for lifestyle factors, comorbidities and baseline symptoms, any NSAID use was not associated with risk (HR 1.02 [0.94, 1.10]). Results were similar for those seeking healthcare for COVID-19 and were not substantially different according to lifestyle and sociodemographic factors or after accounting for propensity to receive testing. Our results do not support an association of NSAID use, including aspirin, with COVID-19 infection. Previous reports of a potential association may be due to higher rates of comorbidities or use of NSAIDs to treat symptoms associated with COVID-19.

One Sentence Summary

NSAID use is not associated with COVID-19 risk.
Opioids, Needle Exchange, and Barriers to Care in the Rural Context: Interviews with Law Enforcement and Emergency Medical Personnel
Authors: Lawton Ralph , Leland John , Leland William
Published: May 2021

Background

The large increase in opioid use, subsequent addiction and related death has come to be known as a national epidemic in the United States, particularly affecting rural areas. The crisis has been met with an increase in attempts to address the large overdose rates. In many of these strategies, first responders such as police and emergency services personnel are placed on the front lines. The input and opinions of these individuals, and the communication with them from agency leadership during program implementation can dramatically affect the success of drug related policies. However, there is a paucity of research focused on the attitudes of primary responders, particularly in rural settings. This study conducts a geographically-focused investigation into the attitudes of rural EMS and law enforcement personnel in regards to opioid treatment in a location that was currently implementing a major substance use policy.

Methods

Qualitative semi-structured interviews were conducted with 24 members of law enforcement and 22 emergency medical providers within a single rural county in North Carolina. Interviews spanned three sections: demographics, barriers to opioid treatment and county-specific programs.

Results

The largest barriers to care cited were lack of local treatment resources, the stigma against drug use and a perception that people who use opioids did not want to change. A multi-agency approach to the crisis was supported by EMS personnel and law enforcement. However, first responders’ awareness of an active multiagency county-wide initiative was very limited. This was very surprising, as first responders were expected to implement the program, and this phenomena resulted in very low program efficacy to that point. This result underscored the importance of communication between and within agencies, particularly in environments that are resource-constrained.

Conclusions

This study is unique in comparing attitudes of rural EMS and law enforcement regarding substance use treatment. This paper provides insight into the viewpoints of rural first responders, with clear implications for rural drug policy. This paper further underscores opportunities for maximizing effective opioid policy in rural settings, particularly emphasizing clear communication between agencies.
Serum Neurofilament Light is Elevated in COVID-19 Positive Adults in the ICU and is Associated with Co-Morbid Cardiovascular Disease, Neurological Complications, and Acuity of Illness
Authors: Hay Meredith , Ryan Lee , Huentelman Matthew , Konhilas John , Hoyer-Kimura Christina , Beach Thomas G. , Serrano Geidy E. , Reiman Eric M. , Blennow Kaj , Henrik Zetterberg , Parthasarathy Sairam
Published: May 2021

In critically ill COVID-19 patients, the risk of long-term neurological consequences is just beginning to be appreciated. While recent studies have identified that there is an increase in structural injury to the nervous system in critically ill COVID-19 patients, there is little known about the relationship of COVID-19 neurological damage to the systemic inflammatory diseases also observed in COVID-19 patients. The purpose of this pilot observational study was to examine the relationships between serum neurofilament light protein (NfL, a measure of neuronal injury) and co-morbid cardiovascular disease (CVD) and neurological complications in COVID-19 positive patients admitted to the intensive care unit (ICU). In this observational study of one-hundred patients who were admitted to the ICU in Tucson, Arizona between April and August 2020, 89 were positive for COVID-19 (COVID-pos) and 11 were COVID-negative (COVID-neg). A healthy control group (n=8) was examined for comparison. The primary outcomes and measures were subject demographics, serum NfL, presence and extent of CVD, diabetes, sequential organ failure assessment score (SOFA), presence of neurological complications, and blood chemistry panel data. COVID-pos patients in the ICU had significantly higher mean levels of Nfl (229.6±163 pg/ml) compared to COVID-neg ICU patients (19.3±5.6 pg/ml), Welch’s t-test, p =.01 and healthy controls (12.3±3.1 pg/ml), Welch’s t-test p =.005. Levels of Nfl in COVID-pos ICU patients were significantly higher in patients with concomitant CVD and diabetes (n=35, log Nfl 1.6±.09), and correlated with higher SOFA scores (r=.5, p =.001). These findings suggest that in severe COVID-19 disease, the central neuronal and axonal damage in these patients may be driven, in part, by the level of systemic cardiovascular disease and peripheral inflammation. Understanding the contributions of systemic inflammatory disease to central neurological degeneration in these COVID-19 survivors will be important to the design of interventional therapies to prevent long-term neurological and cognitive dysfunction.
Top-down inhibition of irrelevant information indexed by alpha rhythms is disrupted in migraine
Authors: Masson Rémy , ElShafei Hesham A. , Demarquay Geneviève , Fornoni Lesly , Lévêque Yohana , Caclin Anne , Bidet-Caulet Aurélie
Published: May 2021

Abstract

There is growing evidence that migraine is associated with attentional abnormalities, both during and outside migraine attacks, which would impact the cognitive processing of sensory stimulation. However, these attention alterations are poorly characterized and their neurophysiological basis is still unclear. Nineteen migraineurs without aura and nineteen healthy participants were recruited to perform a task which used visually-cued auditory targets and distracting sounds to evaluate conjointly top-down and bottom-up attention mechanisms. Magnetoencephalography (MEG) signals were recorded. We investigated anticipatory alpha activity (power increase and decrease) and distractor-induced gamma activity as markers for top-down (inhibition and facilitation) and bottom-up attention, respectively. Compared to healthy participants, migraineurs presented a significantly less prominent alpha power increase in visual areas in anticipation of the auditory target, indexing a reduced inhibition of task-irrelevant visual areas. However, there was no significant group difference regarding the alpha power decrease in the relevant auditory cortices in anticipation of the target, nor regarding the distractor-induced gamma power increase in the ventral attention network. These results in the alpha band suggest that top-down inhibitory processes in the visual cortices are deficient in migraine but there is no clear evidence supporting a disruption of top-down facilitatory attentional processes. This relative inability to suppress irrelevant sensory information may be underlying the self-reported increased distractibility and contribute to sensory disturbances in migraine.
Evidence for the utility of cfDNA plasma concentrations to predict disease severity in COVID-19
Authors: Hoeter Katharina , Neuberger Elmo , Fischer Susanne , Herbst Manuel , Juškevičiūtė Ema , Rossmann Heidi , Sprinzl Martin F. , Simon Perikles , Bodenstein Marc , Schäfer Michael K.E.
Published: May 2021

COVID-19 is a pandemic caused by the highly infective SARS-CoV-2. There is a need for biomarkers not only for overall prognosis but also for predicting the response to treatments and thus for improvements in the clinical management of patients with COVID-19. Circulating cell-free DNA (cfDNA) has emerged as a promising biomarker in the assessment of various disease conditions. The aim of this retrospective and observational pilot study was to examine the potential value of cfDNA plasma concentrations as a correlative biomarker in hospitalized COVID-19 patients. Lithium-Heparin plasma samples were obtained from twenty-one COVID-19 patients during hospitalization in the University Medical Center of Mainz, Germany, and the cfDNA concentrations were determined by quantitative PCR yielding amplicons of long interspersed nuclear elements (LINE-1). cfDNA plasma concentrations of COVID-19 patients ranged between 247.5 and 6346.25 ng/ml and the mean concentrations were 1831 ± 1388 ng/ml (± standard deviation). Correlations were found between cfDNA levels and the occurrence of acute respiratory distress symptom (ARDS), acute kidney injury (AKI), myositis, neurological complications, bacterial superinfection and disease severity as defined by sepsis-related organ failure assessment score (SOFA) score. D-Dimer and C-reactive-protein (CRP), determined by clinical laboratory analysis, showed the highest correlations with cfDNA levels. The results of this observational study suggest that cfDNA plasma concentrations may serve as a predictive biomarker of disease severity in COVID-19. Prospective studies enrolling larger patient cohorts are ongoing to test this hypothesis.
Women’s Awareness of Obstetric Fistula and its Associated Factors Among Reproductive-Age Women in Ethiopia: A Multilevel Analysis Based on National Survey Data
Authors: Alemnew Wallelign , Mulat Bezawit , Shitu Kegnie
Published: May 2021

Objective

This study aimed to determine the magnitude and associated factors of women’s awareness of obstetric fistula (OF).

Methods

This community based crossectional study was conducted among 15,683 reproductive-aged women. A multi-level multivariable logistic regression analysis employed. A 95% CI and p-value < 0.05 were used to declare statistical significance.

Result

The magnitude of women’s awareness of OF was 38% [95%CI: 0.37, 0.39]. Individual level variables such as being in the age group 20-25 [AOR=1.17; 95%CI:1.02, 1.35], 26-30 [AOR=1.50; 95%CI: 1.27, 1.76] and >30 [AOR=1.76; 95%CI: 1.50, 2.07], being Muslim religion follower [AOR = 0.83; 95%CI: 0.73, 0.94], attending primary education [AOR=1.70; 95%CI: 1.53, 1.89], attending secondary education [AOR=3.43; 95%CI: 2.95, 3.99] and attending higher education [AOR=5.88; 95%CI: 4.66, 7.42], history of pregnancy termination [AOR=1.31; 95%CI: 1.13, 1.51], media exposure at least once a week [AOR= 1.33; 95%CI: 1.2, 1.49], internet use [AOR= 2.25; 95%CI: 1.84, 2.75], medium house hold wealth [AOR=1.17; 95%CI: 1.02, 1.34], rich house hold wealth [AOR=1.50; 95%CI:1.31, 1.72] and community level factors including high community media exposure [AOR = 1.30; 95%CI: 1.05, 1.61], high community ANC rate [AOR=1.66; 95%CI: 1.37, 2.02] and low health facility distance problem [AOR=1.49; 95%CI: 1.23, 1.81] were significantly associated with awareness of OF.

Conclusion

The magnitude of women’s awareness of OF was very low in Ethiopia. Maternal age, religion, being educated, media exposure, being from a wealthier household, low health facility distance problem, and high community ANC rate were significantly and positively associated factors with awareness of OF.
Executive functioning in Body Dysmorphic Disorder and Obsessive-Compulsive Disorder
Authors: Chen Long Long , Flygare Oskar , Wallert John , Enander Jesper , Ivanov Volen Z. , Rück Christian , Djurfeldt Diana
Published: May 2021

Objective

To assess executive functions in patients with Body Dysmorphic Disorder (BDD) and Obsessive-Compulsive Disorder (OCD) compared with healthy controls.

Methods

Adults diagnosed with BDD (n=26) or OCD (n=29) according to DSM-5, and healthy controls (n=28) underwent validated and computerized neuropsychological tests; spatial working memory (SWM), Intra- extra dimensional set shifting (IED) and Stop signal task (SST), from the Cambridge Neuropsychological Test Automated Battery (CANTAB). Test performance was compared between groups, and correlated to standardized symptom severity of BDD and OCD. Significance level was set to p<0.05.

Results

There were no statistically significant between-group differences on key outcome measures in SWM, IED, or SST. There was a weak positive correlation between symptom severity and test errors on SWM and IED in both OCD and BDD groups; increased clinical severity were associated with more errors in these tests. Further, there was a negative correlation between symptom severity and SST in the BDD group.

Conclusions

Patients with BDD or OCD did not differ from healthy control subjects in terms of test performance, however there were several statistically significant correlations between symptom severity and performance in those with BDD or OCD. More studies on EF in BDD and OCD are required to elucidate if there are differences in EF between these two disorders.
Association of depression screening with diagnostic and treatment-related outcomes among youth
Authors: Riehm Kira E. , Brignone Emily , Stuart Elizabeth A. , Gallo Joseph J. , Mojtabai Ramin
Published: May 2021

Background and Objectives

The goals of depression screening, which is universally recommended in primary care settings in the U.S., are to identify adolescents with depression and connect them to treatment. However, little is known about how depression screening affects the likelihood of being diagnosed with a mental disorder or accessing mental health care over time.

Methods

This longitudinal cohort study used insurance claims data from 57,732 adolescents who had at least one routine well-visit between 2014 and 2017. Using propensity score matching, we compared adolescents who were screened for depression to similar adolescents who were not screened for depression during the well-visit. Diagnostic and treatment-related outcomes were examined over 6-month follow-up and included depression diagnoses, mood-related diagnoses, antidepressant prescriptions, any mental health-related prescriptions, and psychotherapy. We also examined heterogeneity of associations by sex.

Results

Compared to adolescents who were not screened for depression, adolescents screened for depression were 30% more likely to be diagnosed with depression (RR=1.30, 95% CI=1.11-1.52) and 17% more likely to receive a mood-related diagnosis (RR=1.17, 95% CI=1.08-1.27), but were not more likely to be treated with an antidepressant prescription (RR=1.11, 95% CI=0.82-1.51), any mental health prescription (RR=1.15, 95% CI=0.87-1.53), or psychotherapy (RR=1.13, 95% CI=0.98-1.31). In general, associations were stronger among females.

Conclusions

Adolescents who were screened for depression during a well-visit were more likely to receive a diagnosis of depression or a mood-related disorder in the six months following screening. Future research should explore methods for increasing access to treatment and treatment uptake following screening.

Clinical Trial Registration (if any)

N/A

Table of Contents Summary

Insurance claims data were used to explore associations between depression screening during routine well-visits and depression diagnoses, psychiatric prescriptions, and psychotherapy among adolescents.

What’s Known on This Subject

Depression screening is increasingly viewed as a key strategy for addressing depression among adolescents. To inform clinical guidelines, the United States Preventive Services Task Force has called for research to examine the diagnostic and treatment-related outcomes of depression screening.

What This Study Adds

In a sample of 57,732 adolescents, adolescents who were screened for depression during a well-visit were more likely to receive a depression or mood-related diagnosis over 6-month follow-up, but were not more likely to be treated with medication or psychotherapy.
A tissue-level phenome-wide network map of colocalized genes and phenotypes in the UK Biobank
Authors: Rocheleau Ghislain , Forrest Iain S. , Duffy Áine , Bafna Shantanu , Dobbyn Amanda , Verbanck Marie , Won Hong-Hee , Jordan Daniel M. , Do Ron
Published: May 2021

Background

Phenome-wide association studies conducted in electronic health record (EHR)-linked biobanks have uncovered a large number of genomic loci associated with traits and diseases. However, interpretation of the complex relationships of associated genes and phenotypes is challenging.

Results

We constructed a tissue-level phenome-wide network map of colocalized genes and phenotypes. First, we generated colocalized expression quantitative trait loci from 48 tissues of the Genotype-Tissue Expression project and from publicly available genome-wide association study summary statistics from the UK Biobank. We identified 9,151 colocalized genes for 1,411 phenotypes across 48 tissues. Then, we constructed a bipartite network using the colocalized signals to establish links between genes and phenotypes in each tissue. The majority of links are observed in a single tissue whereas only a few are present in all tissues. Finally, we applied the biLouvain clustering algorithm in each tissue-specific bipartite network to identify co-clusters of non-overlapping genes and phenotypes. The majority of co-clusters contains a small number of genes and phenotypes, and 88.6% of co-clusters are found in only one tissue. To demonstrate functionality of the phenome-wide map, we tested if these co-clusters were enriched with known biological and functional gene classes and observed several significant enrichments. Furthermore, we observed that tissue-specific co-clusters are enriched with reported drug side effects for the corresponding drug target genes in clinical trial data.

Conclusions

The phenome-wide map provides links between genes, phenotypes and tissues across a wide spectrum of biological classes and can yield biological and clinical discoveries. The phenome-wide map is publicly available athttps://rstudio-connect.hpc.mssm.edu/biPheMap/.
Minimal phrase composition revealed by intracranial recordings
Authors: Murphy Elliot , Woolnough Oscar , Rollo Patrick S. , Roccaforte Zachary , Segaert Katrien , Hagoort Peter , Tandon Nitin
Published: May 2021

The ability to comprehend phrases is an essential integrative property of the brain. Here we evaluate the neural processes that enable the transition from single word processing to a minimal compositional scheme. Previous research has reported conflicting timing effects of composition, and disagreement persists with respect to inferior frontal and posterior temporal contributions. To address these issues, 19 patients (10 male, 19 female) implanted with penetrating depth or surface subdural intracranial electrodes heard auditory recordings of adjective-noun, pseudoword-noun and adjective-pseudoword phrases and judged whether the phrase matched a picture. Stimulus-dependent alterations in broadband gamma activity, low frequency power and phase-locking values across the language-dominant left hemisphere were derived. This revealed a mosaic located in the posterior superior temporal sulcus (pSTS), in which closely neighboring cortical sites displayed exclusive sensitivity to either lexicality or phrase structure, but not both. Distinct timings were found for effects of phrase composition (210–300 ms) and pseudoword processing (approximately 300–700 ms), and these were localized to neighboring electrodes in pSTS. The pars triangularis and temporal pole encode anticipation of composition in broadband low frequencies, and both regions exhibit greater functional connectivity with pSTS during phrase composition. Our results suggest that the pSTS is a highly specialized region comprised of sparsely interwoven heterogeneous constituents that encodes both lower and higher level linguistic features. This hub in pSTS for minimal phrase processing may form the neural basis for the human-specific computational capacity for forming hierarchically organized linguistic structures.

Significance

Linguists have claimed that the integration of multiple words into a phrase demands a computational procedure distinct from single word processing. Here, we provide intracranial recordings from a large patient cohort, with high spatiotemporal resolution, to track the cortical dynamics of phrase composition. Epileptic patients volunteered to participate in a task in which they listened to phrases (“red boat”), word-pseudoword or pseudoword-word pairs (e.g., “red fulg”). At the onset of the second word in phrases, greater broadband high gamma activity was found in posterior superior temporal sulcus in electrodes that exclusively indexed phrasal meaning, and not lexical meaning. These results provide direct, high-resolution signatures of minimal phrase composition in humans, a potentially species-specific computational capacity.
Novel AT1R-Allosteric Ligands Mask the Preeclampsia Auto-antibody Epitope and Decrease Angiotensin-induced Vasoconstriction
Authors: Singh Khuraijam Dhanachandra , Jara Zaira P. , Harford Terri , Saha Prasenjit Prasad , Pardhi Triveni R. , Desnoyer Russell , Karnik Sadashiva S.
Published: May 2021

Maternal blood pressure regulation by the hormone angiotensin II (AngII) sustains fetal growth through feto-placental circulation. AngII binding to orthosteric pocket in the angiotensin type 1 receptor (AT1R) induces G protein and β-arrestin signaling. AT1R blocking drugs and β-arrestin biased ligands also bind to the orthosteric pocket but evoke different inactive and active states1–6. AT1R-directed auto-antibodies observed in preeclampsia bound outside the orthosteric pocket to extracellular loop-2 (ECL2) of AT1R7–9. How auto-antibodies modulate AT1R activity causing preeclampsia pathogenesis is unknown. Here we report a druggable cryptic allosteric pocket encompassing the preeclampsia epitope on ECL2. Using structure based high-throughput small molecule screening we discovered 18 ligands specific for AT1R’s allosteric pocket. After procuring these ligands we validated inhibition of preeclampsia epitope-specific antibody binding. We characterize their inhibitory effect on antibody and AngII-signaling in cells and vasoconstrictionex vivo. These novel AT1R allosteric ligands, thus act as dual action negative modulators of auto-antibody action and vasoconstriction. Our study demonstrates that positive allosteric modulator action of auto-antibody causes a disease linked to AT1R. We anticipate our findings to kindle structure-based discovery of AT1R allosteric ligands for intervention in maladies such as preeclampsia7–10, rejection of organ transplants11, vasodilatory shock12, 13and metabolic syndrome14.
Development of an open source program to identify the size of objects using bright-field microscopy - an automated calibration tool
Authors: Glowacki Gerard , Gkantiragas Alexis , Brett-Holt Brooke , Mihalik Daniel , He Peter
Published: May 2021

In light microscopy, eyepiece graticules are commonly used to gauge the size of objects at the micron scale. While this is a relatively simple tool to use, not all microscopes possess this feature. Furthermore, calibrating an eyepiece graticule with a stage micrometer can be time-consuming, particularly for inexperienced microscopists. Similarly, calculating the size of individual objects may also take some time. We present an open-source program to determine the size of objects under a microscope using Python and OpenCV. Taking photos of a stage micrometer under a microscope, we identify gradations on the micrometer and calculate the distance between lines on the micrometer in pixels. From this, we can infer the size of objects from bright-field microscopy images. We believe this will improve access to quantitative microscopy techniques and increase the speed at which samples may be analyzed by light microscopy. Future studies may aim to integrate this with machine learning for object identification.
Adolescents’ dietary habits and meal patterns influence school performance in the Northern Finland Birth Cohort 1986: mendelian randomisation study
Authors: Zagkos Loukas , Drenos Fotios , Emmett Pauline , Blakemore Alexandra I. , Nordstrom Tanja , Hurtig Tuula , Jarvelin Marjo-Riitta , Dovey Terence M.
Published: May 2021

Several observational studies indicate that dietary habits in children and adolescents are associated with school performance. These associations are heavily confounded by socio-economic characteristics, such as household income and parents’ educational attainment, amongst other factors. In this study, we report observational and causal effects of habitual diet on school performance, using individual level data for 9,220 adolescents in the Northern Finland Birth Cohort 1986. For this purpose, we derived principal components for the dietary variables, meal patterns and school performance variables. The observational study showed a significant association of consumption of foods that are high in fat, salt and sugar (HFSS) with poor performance in all school subjects, and an association of consumption of healthy foods and traditional foods with good school performance in general subjects, science and physical education (PE). Moreover, a positive association was observed between not skipping breakfast and good performance in all school subjects. Mendelian randomisation analysis confirmed a negative effect of HFSS on school performance in general/science subjects (−0.080, −0.128 to −0.033) and a positive effect of healthy food on school performance in general/science subjects (0.071, 0.024 to 0.119) and PE (0.065, 0.021 to 0.110). To conclude, we identified compelling evidence that HFSS foods and healthy foods were causally affecting school performance.
Transcriptomics reveals the putative mycoparasitic strategy of the mushroomEntoloma abortivumon species of the mushroomArmillaria
Authors: Koch Rachel A. , Herr Joshua R.
Published: May 2021

During mycoparasitism, a fungus—the host—is parasitized by another fungus—the mycoparasite. The genetic underpinnings of these relationships have been best characterized in ascomycete fungi. However, within basidiomycete fungi, there are rare instances of mushroom-forming species parasitizing the reproductive structures, or sporocarps, of other mushroom-forming species, which have been rarely investigated on a genetic level. One of the most enigmatic of these occurs betweenEntoloma abortivumand species ofArmillaria, where hyphae ofE. abortivumare hypothesized to disrupt the development ofArmillariasporocarps, resulting in the formation of carpophoroids. However, it remains unknown whether carpophoroids are the direct result of a mycoparasitic relationship. To address the nature of this unique interaction, we analyzed gene expression of field-collectedArmillariaandE. abortivumsporocarps and carpophoroids. Transcripts in the carpophoroids are primarily fromE. abortivum, supporting the hypothesis that this species is parasitizingArmillaria. Most notably, we identified differentially upregulatedE. abortivumβ-trefoil-type lectins in the carpophoroid, which we hypothesize bind toArmillariacell wall galactomannoproteins, thereby mediating recognition between the mycoparasite and the host. The most differentially upregulatedE. abortivumtranscripts in the carpophoroid code for oxalate decarboxylases—enzymes that degrade oxalic acid. Oxalic acid is a virulence factor in many plant pathogens, includingArmillariaspecies, however,E. abortivumhas evolved a sophisticated strategy to overcome this defense mechanism. The number of gene models and genes that code for carbohydrate-active enzymes in theE. abortivumtranscriptome were reduced compared to other closely related species, perhaps as a result of the specialized nature of this interaction.

IMPORTANCE

By studying fungi that parasitize other fungi, we can understand the basic biology of these unique interactions. Studies focused on the genetic mechanisms regulating mycoparasitism between host and parasite have thus far concentrated on a single fungal lineage within the Ascomycota. The work presented here expands our understanding of mycoparasitic relationships to the Basidiomycota and represents the first transcriptomic study to our knowledge that examines fungal-fungal relationships in their natural setting. The results presented here suggest that even distantly related mycoparasites utilize similar mechanisms to parasitize their host. Given that species of the mushroom-forming pathogenArmillariacause plant root-rot diseases in many agroecosystems, an enhanced understanding of this interaction may contribute to better control of these diseases through biocontrol applications.
In heart failure reactivation of RNA-binding proteins drives the transcriptome into a fetal state
Authors: D’Antonio Matteo , Nguyen Jennifer P. , Arthur Timothy D. , Matsui Hiroko , Donovan Margaret K.R. , D’Antonio-Chronowska Agnieszka , Frazer Kelly A.
Published: May 2021

Transcriptome-wide expression changes occur during heart failure, including reactivation of fetal-specific isoforms. However, the underlying molecular mechanisms and the extent to which a fetal gene program switch occurs remains unclear. Limitations hindering transcriptome-wide analyses of alternative splicing differences (i.e. isoform switching) in cardiovascular system (CVS) tissues between fetal and adult (healthy and diseased) stages have included both cellular heterogeneity across bulk RNA-seq samples and limited availability of fetal tissue for research. To overcome these limitations, we have deconvoluted the cellular compositions of 996 RNA-seq samples representing heart failure, healthy adult (heart and arteria), and fetal-like (iPSC-derived cardiovascular progenitor cells) CVS tissues. Comparison of the expression profiles revealed that RNA-binding proteins (RBPs) are highly overexpressed in fetal-like compared with healthy adult and are reactivated in heart failure, which results in expression of thousands fetal-specific isoforms. Of note, isoforms for 20 different RBPs were among those that reverted in heart failure to the fetal-like expression pattern. We determined that, compared with adult-specific isoforms, fetal-specific isoforms are more likely to bind RBPs, have canonical sequences at their splice sites and encode proteins with more functions. Our findings suggest targeting RBP fetal-specific isoforms could result in novel therapeutics for heart failure.
Multimodal brain features at preschool age and the relationship with pre-reading measures one year later: an exploratory study
Authors: Manning Kathryn Y. , Reynolds Jess E. , Long Xiangyu , Llera Alberto , Dewey Deborah , Lebel Catherine
Published: May 2021

Pre-reading language skills develop rapidly in early childhood and are related to brain structure and function in young children prior to formal education. However, the early neurobiological development that support these skills is not well understood and has not been assessed longitudinally using multiple imaging approaches. Here we acquired anatomical, diffusion tensor imaging (DTI) and resting state functional MRI (rs-fMRI) from 35 children at 3.5 years of age. Children were assessed for pre-reading abilities using the NEPSY-II subtests one year later (4.5 years). We applied a data-driven linked independent component analysis to explore the shared co-variation of grey and white matter measures. Two sources of structural variation at 3.5 years of age demonstrated a weak relationship with Speeded Naming scores at 4.5 years of age. The first imaging component involved volumetric variability in reading-related cortical regions alongside microstructural features of the superior longitudinal fasciculus. The second component was dominated by cortical volumetric variations within the cerebellum and visual association area. In a subset of children with rs-fMRI data, we evaluated the inter-network functional connectivity of the left-lateralized fronto-parietal language (FPL) network and its relationship with pre-reading measures. Higher functional connectivity between the FPL functional network and the default mode and visual networks at 3.5 years predicted better Phonological Processing scores at 4.5 years. Together, these results suggest that the integration of functional networks, as well as the co-development of white and grey matter brain structures in early childhood, may support the emergence of pre-reading measures in preschool children.
Precision neoantigen discovery using large-scale immunopeptidomes and composite modeling of MHC peptide presentation
Authors: Pyke Rachel Marty , Mellacheruvu Datta , Dea Steven , Abbott Charles , Zhang Simo V. , Phillips Nick A. , Harris Jason , Bartha Gabor , Desai Sejal , McClory Rena , West John , Snyder Michael P. , Chen Richard , Boyle Sean Michael
Published: May 2021

Major histocompatibility complex (MHC)-bound peptides that originate from tumor-specific genetic alterations, known as neoantigens, are an important class of anti-cancer therapeutic targets. Accurately predicting peptide presentation by MHC complexes is a key aspect of discovering therapeutically relevant neoantigens. Technological improvements in mass-spectrometry-based immunopeptidomics and advanced modeling techniques have vastly improved MHC presentation prediction over the past two decades. However, improvement in the sensitivity and specificity of prediction algorithms is needed for clinical applications such as the development of personalized cancer vaccines, the discovery of biomarkers for response to checkpoint blockade and the quantification of autoimmune risk in gene therapies. Toward this end, we generated allele-specific immunopeptidomics data using 25 mono-allelic cell lines and createdSystematic HLA Epitope Ranking Pan Algorithm(SHERPA™), a pan-allelic MHC-peptide algorithm for predicting MHC-peptide binding and presentation. In contrast to previously published large-scale mono-allelic data, we used an HLA-null K562 parental cell line and a stable transfection of HLA alleles to better emulate native presentation. Our dataset includes five previously unprofiled alleles that expand MHC binding pocket diversity in the training data and extend allelic coverage in underprofiled populations. To improve generalizability, SHERPA systematically integrates 128 mono-allelic and 384 multi-allelic samples with publicly available immunoproteomics data and binding assay data. Using this dataset, we developed two features that empirically estimate the propensities of genes and specific regions within gene bodies to engender immunopeptides to represent antigen processing. Using a composite model constructed with gradient boosting decision trees, multiallelic deconvolution and 2.15 million peptides encompassing 167 alleles, we achieved a 1.44 fold improvement of positive predictive value compared to existing tools when evaluated on independent mono-allelic datasets and a 1.15 fold improvement when evaluating on tumor samples. With a high degree of accuracy, SHERPA has the potential to enable precision neoantigen discovery for future clinical applications.
Simplifying the development of portable, scalable, and reproducible workflows
Authors: Piccolo Stephen R. , Ence Zachary E. , Anderson Elizabeth C. , Chang Jeffrey T. , Bild Andrea H.
Published: May 2021

Command-line software plays a critical role in biology research. However, processes for installing and executing software differ widely. The Common Workflow Language (CWL) is a community standard that addresses this problem. Using CWL, tool developers can formally describe a tool’s inputs, outputs, and other execution details in a manner that fosters use of shared computational methods and reproducibility of complex analyses. CWL documents can include instructions for executing tools inside software containers—isolated, operating-system environments. Accordingly, CWL tools are portable—they can be executed on diverse computers—including personal workstations, high-performance clusters, or the cloud. This portability enables easier adoption of bioinformatics pipelines. CWL supports workflows, which describe dependencies among tools and using outputs from one tool as inputs to others. To date, CWL has been used primarily for batch processing of large datasets, especially in genomics. But it can also be used for analytical steps of a study. This article explains key concepts about CWL and software containers and provides examples for using CWL in biology research. CWL documents are text-based, so they can be created manually, without computer programming. However, ensuring that these documents confirm to the CWL specification may prevent some users from adopting it. To address this gap, we created ToolJig, a Web application that enables researchers to create CWL documents interactively. ToolJig validates information provided by the user to ensure it is complete and valid. After creating a CWL tool or workflow, the user can create “input-object” files, which store values for a particular invocation of a tool or workflow. In addition, ToolJig provides examples of how to execute the tool or workflow via a workflow engine.
Generation of fate patterns via intercellular forces
Authors: Nunley Hayden , Xue Xufeng , Fu Jianping , Lubensky David K.
Published: May 2021

Studies of fate patterning during development typically emphasize cell-cell communication via diffusible signals. Recent experiments on monolayer stem cell colonies, however, suggest that mechanical forces between cells may also play a role. These findings inspire a model of mechanical patterning: fate affects cell contractility, and pressure in the cell layer biases fate. Cells at the colony boundary, more contractile than cells at the center, seed a pattern that propagates via force transmission. In agreement with previous observations, our model implies that the width of the outer fate domain depends only weakly on colony diameter. We further predict and confirm experimentally that this same width varies non-monotonically with substrate stiffness. This finding supports the idea that mechanical stress can mediate patterning in a manner similar to a morphogen; we argue that a similar dependence on substrate stiffness can be achieved by a chemical signal only if strong constraints on the signaling pathway’s mechanobiology are met.
CRISPR-Cas-mediated tethering recruits the yeastHMRmating-type locus to the nuclear periphery but fails to silence gene expression
Authors: Cliff Emily R. , Kirkpatrick Robin L. , Cunningham-Bryant Daniel , Fernandez Brianna , Zalatan Jesse G.
Published: May 2021

To investigate the relationship between genome structure and function, we have developed a programmable CRISPR-Cas system for nuclear peripheral recruitment in yeast. We benchmarked this system at theHMRandGAL2loci, both well-characterized model systems for localization to the nuclear periphery. Using microscopy and gene silencing assays, we demonstrate that CRISPR-Cas-mediated tethering can recruit theHMRlocus but does not silence reporter gene expression. A previously reported Gal4-mediated tethering system does silence gene expression, and we demonstrate that the silencing phenotype has an unexpected dependence on the structure of the protein tether. The CRISPR-Cas system was unable to recruitGAL2to the nuclear periphery. Our results reveal potential challenges for synthetic genome structure perturbations and suggest that distinct functional effects can arise from subtle structural differences in how genes are recruited to the periphery.
TransposonUltimate: software for transposon classification, annotation and detection
Authors: Riehl Kevin , Riccio Cristian , Miska Eric A. , Hemberg Martin
Published: May 2021

Motivation

Most genomes harbor a large number of transposons, and they play an important role in evolution and gene regulation. They are also of interest to clinicians as they are involved in several diseases, including cancer and neurodegeneration. Although several methods for transposon identification are available, they are often highly specialised towards specific tasks or classes of transposons, and they lack common standards such as a unified taxonomy scheme and output file format. Moreover, many methods are difficult to install, poorly documented, and difficult to reproduce.

Results

We present TransposonUltimate, a powerful bundle of three modules for transposon classification, annotation, and detection of transposition events. TransposonUltimate comes as a Conda package under the GPL-3.0 licence, is well documented and it is easy to install. We benchmark the classification module on the largeTransposonDBcovering over 891,051 sequences to demonstrate that it outperforms the currently best existing solutions. The annotation and detection modules combine sixteen existing softwares, and we illustrate its use by annotatingCaenorhabditis elegans,Rhizophagus irregularisandOryza sativa subs. japonicagenomes. Finally, we use the detection module to discover 29,554 transposition events in the genomes of twenty wild type strains ofCaenorhabditis elegans.

Availability

Running software and source code available onhttps://github.com/DerKevinRiehl/TransposonClassifierRFSB. Databases, assemblies, annotations and further findings can be downloaded fromhttps://cellgeni.cog.sanger.ac.uk/browser.html?shared=transposonultimate.