bluuebunny/crossref_metadata_2025 huggingface dataset:
Sexual selection can partly explain low frequencies of
Segregation Distorter
alleles
Authors: Keaney Thomas A. , Jones Therésa M. , Holman Luke
Published: September 2021

The
Segregation Distorter
(
SD
) allele found in
Drosophila melanogaster
distorts Mendelian inheritance in heterozygous males by causing developmental failure of non-
SD
spermatids, such that greater than 90% of the surviving sperm carry
SD
. This within-individual advantage should cause
SD
to fix, and yet
SD
is typically rare in wild populations. Here, we explore whether this paradox can be resolved by sexual selection, by testing if males carrying three different variants of
SD
suffer reduced pre- or post-copulatory reproductive success. We find that males carrying the
SD
allele are just as successful at securing matings as control males, but that one
SD
variant (
SD-5
) reduces sperm competitive ability and increases the likelihood of female remating. We then used these results to inform a theoretical model; we found that sexual selection could limit
SD
to natural frequencies when sperm competitive ability and female remating rate equalled the values observed for
SD-5
. However, sexual selection was unable to explain natural frequencies of the
SD
allele when the model was parameterized with the values found for two other
SD
variants, indicating that sexual selection alone is unlikely to explain the rarity of
SD
.
Analysis of the antimicrobial resistance gene frequency in whole-genome sequenced Vibrio from Latin American countries
Authors: Vilela Felipe Pinheiro , Falcão Juliana Pfrimer
Published: September 2021

Vibrio

species are important environmental-related bacteria responsible for diverse infections in humans due to consumption of contaminated water and seafood in underdeveloped areas of the world. This study aimed to investigate the frequency of antimicrobial resistance genes in 577 sequenced Vibrio cholerae, Vibrio parahaemolyticus and

Vibrio vulnificus

strains isolated in Latin American countries available at the NCBI Pathogen Detection database and to determine the sequence type (ST) of the strains. Almost all strains studied (99.8%) carried at least one antimicrobial resistance gene, while 54.2 % presented a multidrug-resistance profile. The

Vibrio

strains exhibited genotypic resistance to 11 antimicrobial classes and almG, varG, and catB9, which confer resistance to antibiotic peptides, β-lactams and amphenicols, respectively, were the most detected genes.

Vibrio parahaemolyticus

and

V. vulnificus

showed a broad diversity of STs.

Vibrio cholerae

strains isolated in Haiti after 2010’s earthquake presented the highest diversity and amount of resistance genes in the set of strains analysed and mostly belonged to ST69. In conclusion, the detection of resistance genes from 11 antimicrobial classes and the high number of multidrug-resistant

Vibrio

species strains emphasize that Latin American public health authorities should employ more efficient control measures and that special attention should be given for the rational use of antimicrobials in human therapy and aquaculture, since the consumption of contaminated water and seafood with resistant

Vibrio

may result in human infections difficult to be treated.
Prevalence of SARS-CoV-2: An age-stratified, population-based, sero-epidemiological survey in Islamabad, Pakistan
Authors: Baig Mirza Amir , Ansari Jamil Ahmed , Ikram Aamer , Khan Mumtaz Ali , Salman Muhammad , Hussain Zakir , Baig Mirza Zeeshan Iqbal , Chaudhry Ambreen , Malik Muhammad Wasif , Akram Khurram Shahzad , Saeed Asim , Ranjha Muazzam Abbas , Sultan Faisal , Sabir Sohail
Published: September 2021

Introduction

Serological surveys are valuable tools to evaluate the extent of disease transmission, measuring preventive effectiveness and proportion of asymptomatic individuals. This age-stratified, serological survey was aimed to measure the COVID-19 distribution and determinants in district Islamabad of Pakistan.

Methodology

Three-stage cluster sampling, using population proportionate to size technique, starting with a random number was used. A structured, pretested questionnaire was used after taking informed written consent, to gather demographic, risk factor information.

Results

Seroprevalence was found 16.5% (AR: 16.5%/100,000). The mean age was 35 (±16 Years). The majority were male (64%), self-employed (29%), and had primary level education (33%). The highest seroprevalence was found in the 21-30 years age group (24.8%) while the 41-50 years age group showed the highest attack rate (112.9/100,000 population). The proportion of the population tested that were asymptomatic was 69% (n=711) while the most frequently reported sign/symptom was cough (99%) followed by fever (20%). No known co-morbidity was reported in 86% (n=884) of respondents while hypertension remained the most reported condition (8%). High seroprevalence was observed in urban areas (12.3%) compared to rural union councils (6.4%). Visiting a house where COVID-19 case was isolated (OR 2, CI 1.38-2.84, P< 0.001), history of contact with a known case of COVID-19 (OR 1.42, CI 1.11-1.82, P=0.005), and attending a mass gathering (OR 1.21, CI: 1.02-1.42, p=0.02) were significant risk factors associated with contracting an infection. A Chi-Square test of independence showed significant protection while using regular hand hygiene practices (6.5; p<0.05) and regular usage of face masks (8.6; p<0.05).

Conclusion

Seroprevalence gives a direct estimation of population groups exposed to the virus. A remarkable difference in prevalence is found in urban and rural areas, extreme age groups, and socioeconomic statuses, suggesting targeted public health interventions. Sero-studies are affordable counterparts of molecular testing where quick estimation, prevention effectiveness, and data-driven public health policies are priorities.
Physical Injuries and Burns among Refugees in Lebanon: Implications for Programs and Policies
Authors: Al-Hajj Samar , Moustafa Moustafa , Hechi Majed El , Chahrour Mohamad A. , Nasrallah Ali A. , Kaafarani Haytham
Published: September 2021

Background

Refugees are prone to injury due to often austere living conditions, social and economic disadvantages, and limited access to health care services in host countries. This study systematically quantified the prevalence of physical injuries and burns among the refugee community in Western Lebanon and examined injury characteristics, risk factors and outcomes.

Method

We conducted a cluster-based population survey across 21 camps in the Bekaa region of Lebanon from February to April 2019. A modified version of the ‘Surgeons Overseas Assessment of Surgical Need (SOSAS)’ tool v 3.0 was administered to the head of the refugee household and documented all injuries sustained by family members over the last 12 months. Descriptive and univariate regression analyses were performed to understand the association between variables.

Results

750 heads of household were surveyed. 112 (14.9%) household sustained injuries in the past 12 months, 39 of which (34.9%) reported disabling injuries that affected their work and daily living. Most injuries occurred inside the tent (29.9%). A burn was sustained by at least one household member in 136 (18.1%) households. The majority (63.7%) of burns affected children under 5 years and were mainly due to boiling liquid (50%). Significantly more burns were reported in households where caregivers have the inability to lockout children while cooking (25.6% vs 14.9%, p-value=0.001). Similarly, households with unemployed head significantly had more reported burns (19.7% vs 13.3%, p-value=0.05). Nearly 16.1% of injured refugees were unable to seek health care due to lack of health insurance coverage and financial liability.

Conclusion

Refugees suffer injuries and burns with substantial human and economic repercussions on individuals, their families and the host healthcare system. Resources should be allocated to designing safe camps and implementing educational and awareness programs with special focus on heating and cooking methods.
Population-scale analysis of common and rare genetic variation associated with hearing loss in adults
Authors: Praveen Kavita , Dobbyn Lee , Gurski Lauren , Ayer Ariane H. , Staples Jeffrey , Mishra Shawn , Bai Yu , Kaufman Alexandra , Moscati Arden , Benner Christian , Chen Esteban , Chen Siying , Popov Alexander , Smith Janell ,   GHS-REGN DiscovEHR collaboration,   Regeneron Genetics Center,   Decibel-REGN collaboration, Melander Olle , Jones Marcus , Marchini Jonathan , Balasubramanian Suganthi , Zambrowicz Brian , Drummond Meghan , Baras Aris , Abecasis Goncalo R. , Ferreira Manuel A. , Stahl Eli A. , Coppola Giovanni
Published: September 2021

Understanding the genetic underpinnings of disabling hearing loss, which affects ∼466 million people worldwide, can provide avenues for new therapeutic target development. We performed a genome-wide association meta-analysis of hearing loss with 125,749 cases and 469,497 controls across five cohorts, including UK Biobank, Geisinger DiscovEHR, the Malmö Diet and Cancer Study, Mount Sinai’s BioMe Personalized Medicine Cohort, and FinnGen. We identified 53 loci affecting hearing loss risk, 15 of which are novel, including common coding variants in COL9A3 and TMPRSS3. Through exome-sequencing of 108,415 cases and 329,581 controls from the same cohorts, we identified hearing loss associations with burden of rare coding variants in FSCN2 (odds ratio [OR] = 1.14, P = 1.9 × 10−15) and burden of predicted loss-of-function variants in KLHDC7B (OR = 2.14, P = 5.2 × 10−30). We also observed single-variant and gene-burden associations with 11 genes known to cause Mendelian forms of hearing loss, including an increased risk in heterozygous carriers of mutations in the autosomal recessive hearing loss genes GJB2 (Gly12fs; OR = 1.21, P = 4.2 × 10−11) and SLC26A5 (gene burden; OR = 1.96, P = 2.8 × 10−17). Our results suggest that loss of KLHDC7B function increases risk for hearing loss, and show that Mendelian hearing loss genes contribute to the burden of hearing loss in the adult population, suggesting a shared etiology between common and rare forms of hearing loss. This work illustrates the potential of large-scale exome sequencing to elucidate the genetic architecture of common traits in which risk is modulated by both common and rare variation.
Lexical and acoustic speech features relating to Alzheimer’s disease pathology
Authors: Cho Sunghye , Cousins Katheryn A.Q. , Shellikeri Sanjana , Ash Sharon , Irwin David J. , Liberman Mark , Grossman Murray , Nevler Naomi
Published: September 2021

INTRODUCTION

In this study, we compared digital speech features of AD and lvPPA patients in a biologically confirmed cohort and related them to specific neuropsychiatric test scores and CSF proteins.

METHODS

We extracted language variables with automated lexical and acoustic pipelines from oral picture descriptions of 44 AD and 21 lvPPA patients with autopsy or CSF confirmation of AD pathology. We correlated distinct speech features with MMSE and BNT test scores and CSF p-tau levels.

RESULTS

LvPPA patients produced fewer verbs, adjectives, and more fillers with lower lexical diversity and higher pause rate than AD. Both groups showed some shared language impairments compared with normal speakers.

DISCUSSION

Our speech measures captured differences in speech between the two phenotypes. Also, shared speech markers were linked to the common underlying pathology. This work demonstrates the potential of natural speech analysis in detecting underlying AD pathology.
The Effect of Conflict on Healthcare Workers in Syria: Results of a Qualitative Survey
Authors: Abdelrahman Sarah , Haar Rohini J.
Published: September 2021

The purpose of this study is to understand how the conflict in Syria, having devasted the healthcare system, has affected Syrian healthcare workers (Joseph et al. 2016). We provide a secondary analysis of a summer 2019 survey Physicians for Human Rights (PHR) conducted with 82 Syrian healthcare workers living in neighbouring countries as well as in northeast and northwest Syria. Our descriptive analysis found that 48 participants reported an average of 16.52 hours of work per day, and 40 participants reported caring for an average of 43 patients per day while working in Syria during the conflict. Sixty-eight participants reported facing barriers to perform their work, and 59 participants reported facing risks as a medical professional. Seventy-one participants experienced traumatic events during their work as a medical professional, and 70 participants experienced stress in the month prior to being interviewed.

This analysis illustrates the negative effect an armed conflict has on healthcare workers through disruptions in their workload, training and resources, barriers and risks faced, and mental health and security issues. The study indicates that these factors require long-term consideration in order to protect healthcare workers and improve the health system.
Epidemiological and Clinical Features, Treatment Status, and Economic Burden of Traumatic Spinal Cord Injury in China
Authors: Zhou Hengxing , Lou Yongfu , Chen Lingxiao , Kang Yi , Liu Lu , Cai Zhiwei , Anderson David B , Wang Wei , Zhang Chi , Wang Jinghua , Ning Guangzhi , Gao Yanzheng , He Baorong , Ding Wenyuan , Wang Yisheng , Mei Wei , Song Yueming , Zhou Yue , Xia Maosheng , Wang Huan , Zhao Jie , Yin Guoyong , Zhang Tao , Jing Feng , Zhu Rusen , Meng Bin , Duan Li , Deng Zhongliang , Zhang Zhongmin , Wu Desheng , Liu Yajun , Cai Zhengdong , Huang Lin , Yin Zhanhai , Li Kainan , Lu Shibao , Cao Xu , Feng Shiqing
Published: September 2021

Background

China has the largest population of traumatic spinal cord injury (TSCI), but has not yet performed a national-level study on its epidemiological and clinical features, treatment status, and economic burden.

Methods

A total of 14 754 patients were recruited between January 2013 and December 2018 from 37 hospitals in 11 provinces and municipalities, which represented all geographical divisions of China. The percentage of TSCI in hospitalized patients and the percentage of TSCI in hospitalized patients through the orthopaedic departments were calculated. The treatment status, total and daily costs were collected.

Results

The percentage of TSCI in hospitalized patients and the percentage of TSCI in hospitalized patients through the orthopaedic departments did not change significantly overall (APC= -0.5%, 95% CI: -3.0 to 2.1 and -1.6%, -4.9 to 1.8, respectively). A total of 10 918 (74.0%) patients received surgery after TSCI. However, only 3.0% of patients underwent surgery received surgery less than 24 hours after injury. A total of 2 084 (14.1%) patients were treated with methylprednisolone sodium succinate/methylprednisolone (MPSS/MP) at a high dose (≥500 mg) and 641 (4.3%) patients receiving it within 8 hours. The total costs for acute TSCI decreased (-4.8%, -6.2 to -3.4), while the daily costs did not change significantly (0.5%, -1.2 to 2.2).

Conclusions

This study revealed epidemiological and clinical features, treatment status, and economic burden of TSCI that occurred in China from 2013 to 2018.

Funding

National Key Research and Development Project of Stem Cell and Transformation Research (2019YFA0112100).
Monoclonal antibodies against SARS-CoV-2: potential game-changer still underused
Authors: Gentile Ivan , Maraolo Alberto Enrico , Buonomo Antonio Riccardo , Nobile Mariano , Piscitelli Prisco , Miani Alessandro , Moriello Nicola Schiano
Published: September 2021

Even several months after the start of a massive vaccination campaign against COVID-19, mortality and hospital admission are still in considerable numbers in many nations. Monoclonal antibodies are the ideal complement to vaccination in high-risk subjects who have been infected by SARS-CoV-2 and are at high risk of developing severe disease. Combining data provided by clinal trials and demographics of SARS-CoV-2 infections, this analysis tries to predict the benefits of an extensive use of monoclonal antibodies to reduce hospital admissions, deaths, and costs.
TSABL: Trait Specific Annotation Based Locus Predictor
Authors: Lorenz Kimberly , Thom Christopher S. , Adurty Sanjana , Voight Benjamin F.
Published: September 2021

The majority of GWAS loci fall in the non-coding genome, making causal variants difficult to identify and study. We hypothesized that the regulatory features underlying causal variants are biologically specific, identifiable from data, and that the regulatory architecture that influences one trait is distinct compared to biologically unrelated traits. To better characterize and identify these variants, we used publicly available GWAS loci and genomic annotations to build 17 Trait Specific Annotation Based Locus (TSABL) predictors to identify differences between GWAS loci associated with different phenotypic trait groups. We used a penalized binomial logistic regression model to select trait relevant annotations and tested all models on a holdout set of loci not used for training in any trait. We were able to successfully build models for autoimmune, electrocardiogram, lipid, platelet, red blood cell, and white blood cell trait groups. We used these models both to prioritize variants in existing loci and to identify new genomic regions of interest. We found that TSABL models identified biologically relevant regulatory features, and anticipate their future use to enhance the design and interpretation of genetic studies.
Mucosal antibody response to SARS-CoV-2 in paediatric and adult patients: a longitudinal study
Authors: Chan Renee WY , Chan Kate CC , Lui Grace CY , Tsun Joseph GS , Chan Kathy YY , Yip Jasmine SK , Liu Shaojun , Yu Michelle WL , Ng Rita WY , Chong Kelvin KL , Wang Maggie H , Chan Paul KS , Li Albert M , Lam Hugh S
Published: September 2021

Conjunctival and nasal mucosal antibody responses in thirty-four paediatric and forty-seven adult COVID-19 patients were measured. The mucosal antibody was IgA dominant. In the nasal epithelial lining fluid (NELF) of asymptomatic paediatric patients, SARS-CoV-2 spike protein 1 (S1) specific immunoglobulin A (IgA) was induced early. Their plasma S1-specific IgG levels were higher than symptomatic patients. More adult with mild disease had NELF S1-specific IgA than those with severe/critical illness. Within the first week of diagnosis, higher S1-specific antibodies in NELF and plasma and lower vial loads were detected in paediatric than adult patients with mild disease. The IgA and IgG levels correlated positively with the surrogate neutralization readout. The detectable NELF ‘neutralizing’ S1-specific IgA in the first week after diagnosis correlated with a rapid decline in viral load. This study highlights the effect of nasal IgA in limiting the SARS-CoV-2 replication and provides complementary information to the serum antibody measurements.
Cis-regulatory changes in locomotor genes are associated with the evolution of burrowing behavior
Authors: Hu Caroline K. , York Ryan A. , Metz Hillery C. , Bedford Nicole L. , Fraser Hunter B. , Hoekstra Hopi E.
Published: September 2021

How evolution modifies complex, innate behaviors is largely unknown. Divergence in many morphological traits has been linked, at least in part, to cis-regulatory changes in gene expression, a pattern also observed in some behaviors of recently diverged populations. Given this, we compared the gene expression in the brains of two interfertile sister species of Peromyscus mice, including allele-specific expression (ASE) of their F1 hybrids, that show large and heritable differences in burrowing behavior. Because cis-regulation may contribute to constitutive as well as activity-dependent gene expression, we also captured a molecular signature of burrowing circuit divergence by quantifying gene expression in mice shortly after burrowing. We found that several thousand genes were differentially expressed between the two sister species regardless of behavioral context, with several thousand more showing behavior-dependent differences. Allele-specific expression in F1 hybrids showed a similar pattern, suggesting that much of the differential expression is driven by cis-regulatory divergence. Genes related to locomotor coordination showed the strongest signals of lineage-specific selection on burrowing-induced cis-regulatory changes. By comparing these candidate genes to independent quantitative trait locus (QTL) mapping data, we found that the closest QTL markers to these candidate genes are associated with variation in burrow shape, demonstrating an enrichment for candidate locomotor genes near segregating causal loci. Together, our results provide insight into how cis-regulated gene expression can depend on behavioral context as well as how this dynamic regulatory divergence between species can be integrated with forward genetics to enrich our understanding of the genetic basis of behavioral evolution.
Machine learning modeling of protein-intrinsic features predicts tractability of targeted protein degradation
Authors: Zhang Wubing , Roy Burman Shourya S. , Chen Jiaye , Donovan Katherine A. , Cao Yang , Zhang Boning , Zeng Zexian , Zhang Yi , Li Dian , Fischer Eric S. , Tokheim Collin , Liu X. Shirley
Published: September 2021

Targeted protein degradation (TPD) has rapidly emerged as a therapeutic modality to eliminate previously undruggable proteins by repurposing the cell’s endogenous protein degradation machinery. However, the susceptibility of proteins for targeting by TPD approaches, termed “degradability”, is largely unknown. Recent systematic studies to map the degradable kinome have shown differences in degradation between kinases with similar drug-target engagement, suggesting yet unknown factors influencing degradability. We therefore developed a machine learning model, MAPD (Model-based Analysis of Protein Degradability), to predict degradability from protein features that encompass post-translational modifications, protein stability, protein expression and protein-protein interactions. MAPD shows accurate performance in predicting kinases that are degradable by TPD compounds (auPRC=0.759) and is likely generalizable to independent non-kinase proteins. We found five features with statistical significance to achieve optimal prediction, with ubiquitination potential being the most predictive. By structural modeling, we found that E2-accessible ubiquitination sites, but not lysine residues in general, are particularly associated with kinase degradability. Finally, we extended MAPD predictions to the entire proteome to find 964 disease-causing proteins, including 278 cancer genes, that may be tractable to TPD drug development.
A Mechanism for the Rare Fluctuation that Powers Protein Conformational Change
Authors: Wu Shanshan , Ma Ao
Published: September 2021

Most functional processes of biomolecules are rare events. Key to a rare event is the rare fluctuation that enables the energy activation process, which powers the system across the activation barrier. But the physical nature of this rare fluctuation and how it enables barrier crossing are unknown. With the help of a novel metric, the reaction capacity pC, that rigorously defines the beginning and parameterizes the progress of energy activation, the rare fluctuation was identified as a special phase-space condition that is necessary and sufficient for initiating systematic energy flow from the non-reaction coordinates into the reaction coordinates. The energy activation of a prototype biomolecular isomerization reaction is dominated by kinetic energy transferring into and accumulating in the reaction coordinates, administered by inertial forces alone. The two major reaction coordinates move in precise synergy, with one acting as a gating mechanism on the other. This mechanism is enabled by the structural features of biomolecules and may the cause of their unique functions that are not possible in small molecules.
The architecture of phenotypic flexibility within a complex trait: an empirical case study using avian thermogenic performance
Authors: Stager Maria , Cheviron Zachary A.
Published: September 2021

Reversible modifications to trait values can allow individuals to match their phenotypes to changing environmental conditions, a phenomenon known as phenotypic flexibility. A system’s capacity for flexibility may be determined by its underlying architecture, and these relationships can have important implications for both organismal adaptation and the evolvability of acclimatization responses. Theory provides two possible alternatives to explain the ways in which lower-level traits respond to environmental challenges and contribute to phenotypic flexibility in complex, whole-organism traits: symmorphosis predicts correspondence between structure and demand across all levels of a physiological system, while the alternative predicts that influence is concentrated in select elements of a physiological network. Here we provide a rich dataset — composed of 20 sub-organismal, physiological traits paired with whole-organism metabolic rates for 106 adult Dark-eyed Juncos (Junco hyemalis) — to explore the mechanistic basis of phenotypic flexibility in complex traits. When exposed to synthetic temperature cues, these individuals have previously been shown to increase their thermogenic capacity (Msum) and enhance their ability to maintain their body temperature in the cold. We show that the relationships among a number of the traits that contribute to Msum varied as the environmental context changed. Moreover, variation in Msum in response to temperature acclimation was correlated with only a handful of subordinate phenotypes. As a result, avian thermogenic flexibility does not appear to be a symmorphotic response. If this is generally true of complex traits, it suggests that simple and reversible modifications can significantly impact whole-organism performance, and thus that the evolution of phenotypic flexibility in a single component part could impart flexibility for the entire system.
A machine vision based frailty index for mice
Authors: Hession Leinani E. , Sabnis Gautam S. , Churchill Gary A. , Kumar Vivek
Published: September 2021

1

Chronological aging is uniform, but biological aging is heterogeneous. Clinically, this heterogeneity manifests itself in health status and mortality, and it distinguishes healthy from unhealthy aging. Frailty indexes (FIs) serve as an important tool in gerontology to capture health status. FIs have been adapted for use in mice and are an effective predictor of mortality risk. To accelerate our understanding of biological aging, high-throughput approaches to pre-clinical studies are necessary. Currently, however, mouse frailty indexing is manual and relies on trained scorers, which imposes limits on scalability and reliability. Here, we introduce a machine learning based visual frailty index (vFI) for mice that operates on video data from an open field assay. We generate a large mouse FI dataset of both male and female mice. From video data on these same mice, we use neural networks to extract morphometric, gait, and other behavioral features that correlate with manual FI score and age. We use these features to train a regression model that accurately predicts the normalized FI score within 0.04 ± 0.002 (mean absolute error). We show that features of biological aging are encoded in open-field video data and can be used to construct a vFI that can complement or replace current manual FI methods. We use the vFI data to examine sex-specific aspects of aging in mice. This vFI provides increased accuracy, reproducibility, and scalability, that will enable large scale mechanistic and interventional studies of aging in mice.
Gigantic Genomes of Salamanders Indicate Body Temperature, not Genome Size, is the Driver of Global Methylation and 5-Methylcytosine Deamination in Vertebrates
Authors: Adams Alexander Nichols , Denton Robert Daniel , Mueller Rachel Lockridge
Published: September 2021

Methylation of cytosines at CpG dinucleotide sites silences transposable elements (TEs), sequences that replicate and move throughout genomes. TE abundance drives differences in genome size, but TE silencing variation across genomes of different sizes remains largely unexplored. Salamanders include most of the largest C-values — 9 to 120 Gb. We measured CpG methylation levels in salamanders with genomes ranging from 2N = ~58 Gb to 4N = ~116 Gb. We compared these levels to results from endo- and ectothermic vertebrates with more typical genomes. Salamander methylation levels are ~90%, higher than all endotherms. However, salamander methylation does not differ from the other ectotherms, despite a ~100-fold difference in nuclear DNA content. Because methylation affects the nucleotide compositional landscape through 5-methylcytosine deamination to thymine, we quantified salamander CpG dinucleotide levels and compared them to other vertebrates. Salamanders have comparable CpG levels to other ectotherms, and ectotherm levels are higher than endotherms. These data show no shift in global methylation at the base of salamanders, despite a dramatic increase in TE load and genome size. This result is reconcilable with previous studies by considering endothermy and ectothermy, which may be more important drivers of methylation in vertebrates than genome size.
Lip movements enhance speech representations and effective connectivity in speech dorsal stream and its relationship with neurite architecture
Authors: Zhang Lei , Du Yi
Published: September 2021

Lip movements facilitate speech comprehension, especially under adverse listening conditions, but the neural mechanisms of this perceptual benefit at the phonemic and feature levels remain unclear. This fMRI study addresses this question by quantifying regional multivariate representation and network organization underlying audiovisual speech-in-noise perception. We found that valid lip movements enhanced neural representations of phoneme, place of articulation, or voicing feature of speech differentially in dorsal stream regions, including frontal speech motor areas and supramarginal gyrus. Such local changes were accompanied by strengthened dorsal stream effective connectivity. Moreover, the neurite orientation dispersion of left arcuate fasciculus, a structural basis of speech dorsal stream, predicted the visual enhancements of neural representations and effective connectivity. Our findings provide novel insight to speech science that lip movements promote both local phonemic and feature encoding and network connectivity in speech dorsal pathway and the functional enhancement is mediated by the microstructural architecture of the circuit.
Phylodynamics Of A Regional, Sars-Cov-2 Rapid Spreading Event In Colorado
Authors: Wade Kristen J. , Tisa Samantha , Barrington Chloe , Crooks Kristy R. , Gignoux Chris R. , Almand Austin T. , Steel J. Jordan , Sitko John C. , Rohrer Joseph W. , Wickert Douglas P. , Almand Erin A. , Pollock David D. , Rissland Olivia S.
Published: September 2021

Since the initial reported discovery of SARS-CoV-2 in late 2019, genomic surveillance has been an important tool to understand its transmission and evolution. Here, we describe a case study of genomic sequencing of Colorado SARS-CoV-2 samples collected August through November 2020 at the University of Colorado Anschutz Medical campus in Aurora and the United States Air Force Academy in Colorado Springs. We obtained nearly complete sequences for 44 genomes, inferred ancestral sequences shared among these local samples, and used NextStrain variant and clade frequency monitoring in North America to place the Colorado sequences into their continental context. Furthermore, we describe genomic monitoring of a lineage that likely originated in the local Colorado Springs community and expanded rapidly over the course of two months in an outbreak within the well-controlled environment of the United States Air Force Academy. This variant contained a number of amino acid-altering mutations that may have contributed to its spread, but it appears to have been controlled using extensive contact tracing and strict quarantine protocols. The genome sequencing allowed validation of the transmission pathways inferred by the United States Air Force Academy and provides a window into the evolutionary process and transmission dynamics of a potentially dangerous but ultimately contained variant.

SIGNIFICANCE

SARS-CoV-2 spreads and mutates, negatively impacting containment. In this study, we use long-read sequencing to generate 44 SARS-CoV-2 genomes from COVID-19 patients associated with a rapid-spreading event on the USAFA campus, as well as a neighboring community for reference. We reconstruct the genomic and evolutionary signatures of the rapid-spreading event, and pin-point novel, protein-altering mutations that may have impacted viral fitness. These insights into viral evolutionary dynamics, in the context of contact tracing and a rigorous containment program, help to inform response efforts in the future.
A MUC5Bgene polymorphism, rs35705950-T, confers protective effects in COVID-19 infection
Authors: Verma Anurag , Minnier Jessica , Huffman Jennifer E , Wan Emily S , Gao Lina , Joseph Jacob , Ho Yuk-Lam , Wu Wen-Chih , Cho Kelly , Gorman Bryan R , Rajeevan Nallakkandi , Pyarajan Saiju , Garcon Helene , Meigs James B , Sun Yan V , Reaven Peter D , McGeary John E , Suzuki Ayako , Gelernter Joel , Lynch Julie A , Petersen Jeffrey M , Zekavat Seyedeh Maryam , Natarajan Pradeep , Madison Cecelia J , Dalal Sharvari , Jhala Darshana N , Arjomandi Mehrdad , Gatsby Elise , Lynch Kristine E , Bonomo Robert A , Freiberg Mat , Pathak Gita A , Zhou Jin J , Donskey Curtis J , Madduri Ravi K , Wells Quinn S , Huang Rose DL , Polimanti Renato , Chang Kyong-Mi , Liao Katherine P , Tsao Philip S , Wilson Peter W.F. , Hung Adriana , O’Donnell Christopher J , Gaziano John M , Hauger Richard L , Iyengar Sudha K. , Luoh Shiuh-Wen
Published: September 2021

Rationale

A commonMUC5Bgene polymorphism, rs35705950-T, is associated with idiopathic pulmonary fibrosis, but its role in the SARS-CoV-2 infection and disease severity is unclear.

Objectives

To assess whether rs35705950-T confers differential risk for clinical outcomes associated with COVID-19 infection among participants in the Million Veteran Program (MVP) and COVID-19 Host Genetics Initiative (HGI).

Methods

MVP participants were examined for an association between the incidence or severity of COVID-19 and the presence of aMUC5Brs35705950-T allele. Comorbidities and clinical events were extracted from the electronic health records (EHR). The analysis was performed within each ancestry group in the MVP, adjusting for sex, age, age2,and first twenty principal components followed by a trans-ethnic meta-analysis. We then pursued replication and performed a meta-analysis with the trans-ethnic summary statistics from the HGI. A phenome-wide association study (PheWAS) of the rs35705950-T was conducted to explore associated pathophysiologic conditions.

Measurements and Main Results

A COVID-19 severity scale was modified from the World Health Organization criteria, and phenotypes derived from the International Classification of Disease-9/10 were extracted from EHR. Presence of rs35705950-T was associated with fewer hospitalizations (Ncases=25353, Ncontrols=631,024; OR=0.86 [0.80-0.93], p=7.4 × 10−5) in trans-ethnic meta-analysis within MVP and joint meta-analyses with the HGI (N=1641311; OR=0.89 [0.85-0.93], p =1.9 × 10−6). Moreover, individuals of European Ancestry with at least one copy of rs35705950-T had fewer post-COVID-19 pneumonia events (OR=0.85 [0.76-0.96], p =0.008). PheWAS exclusively revealed pulmonary involvement.

Conclusions

TheMUC5Bvariant rs35705950-T is protective in COVID-19 infection.
A multivariable Mendelian randomization analysis disentangling the causal relations between abdominal obesity, non-alcoholic fatty liver disease and cardiometabolic diseases
Authors: Pelletier William , Gagnon Éloi , Gobeil Émilie , Bourgault Jérôme , Manikpurage Hasanga D. , Maltais-Payette Ina , Abner Erik , Taba Nele , Esko Tõnu , Mitchell Patricia L. , Ghodsian Nooshin , Després Jean-Pierre , Vohl Marie-Claude , Tchernof André , Thériault Sébastien , Arsenault Benoit J.
Published: September 2021

Background

Observational studies have linked obesity and especially abdominal obesity to non-alcoholic fatty liver disease (NAFLD). These traits are also associated with type 2 diabetes (T2D) and coronary artery disease (CAD) but the causal factor(s) underlying these associations remain unexplored.

Methods

We used a multivariable Mendelian randomization (MVMR) study design to determine whether obesity (defined using body mass index [BMI]) and abdominal obesity (defined using waist circumference) were causally associated with NAFLD using publicly available genome-wide association study (GWAS) summary statistics of the UK Biobank (n>450,000) and a GWAS meta-analysis of NAFLD (8434 cases and 770,180 control). A MVMR study design was also used to determine the respective causal contributions of waist circumference and NAFLD to T2D and CAD using additional GWAS summary statistics of the DIAGRAM (74,124 cases and 824,006 controls) and CARDIoGRAMplusC4D (122,733 cases and 424,528 controls) consortia.

Results

In univariable Mendelian randomization analyses, both BMI and waist circumference were associated with NAFLD. NAFLD was not associated with obesity or abdominal obesity. In MVMR analyses, waist circumference was associated with NAFLD when accounting for BMI (OR per 1-standard deviation increase = 2.56 95% CI: 1.39-4.69, p=2.4e-03) and BMI was not associated with NAFLD when accounting for waist circumference (0.81 95% CI: 0.5-1.31, p =3.9e-01). In MVMR analyses accounting for NAFLD, waist circumference remained strongly associated with both T2D (3.25 95% CI: 2.87-3.68, p=5.1e-77) and CAD (1.62 95% CI: 1.48-1.76, p=6.5e-28).

Conclusions

These results identified abdominal obesity as a strong, independent and causal contributor to NAFLD, T2D and CAD, suggesting that interventions targeting abdominal obesity rather than body weight per se should be prioritized for the prevention and management of cardiometabolic diseases.
Predicting hospital-onset COVID-19 infections using dynamic networks of patient contacts: an observational study
Authors: Myall Ashleigh , Price James R , Peach Robert L , Abbas Mohamed , Mookerjee Siddharth , Zhu Nina , Ahmad Isa , Ming Damien , Ramzan Farzan , Teixeira Daniel , Graf Christophe , Weiße Andrea Y , Harbarth Stephan , Holmes Alison , Barahona Mauricio
Published: September 2021

Background

Real-time prediction is key to prevention and control of healthcare-associated infections. Contacts between individuals drive infections, yet most prediction frameworks fail to capture the dynamics of contact. We develop a real-time machine learning framework that incorporates dynamic patient contact networks to predict patient-level hospital-onset COVID-19 infections (HOCIs), which we test and validate on international multi-site datasets spanning epidemic and endemic periods.

Methods

Our framework extracts dynamic contact networks from routinely collected hospital data and combines them with patient clinical attributes and background contextual hospital data to forecast the infection status of individual patients. We train and test the HOCI prediction framework using 51,157 hospital patients admitted to a UK (London) National Health Service (NHS) Trust from 01 April 2020 to 01 April 2021, spanning UK COVID-19 surges 1 and 2. We then validate the framework by applying it to data from a non-UK (Geneva) hospital site during an epidemic surge (40,057 total inpatients) and to data from the same London Trust from a subsequent period post surge 2, when COVID-19 had become endemic (43,375 total inpatients).

Findings

Based on the training data (London data spanning surges 1 and 2), the framework achieved high predictive performance using all variables (AUC-ROC 0·89 [0·88-0·90]) but was almost as predictive using only contact network variables (AUC-ROC 0·88 [0·86-0·90]), and more so than using only hospital contextual (AUC-ROC 0·82 [0·80-0·84]) or patient clinical (AUC-ROC 0·64 [0·62-0·66]) variables. The top three risk factors we identified consisted of one hospital contextual variable (background hospital COVID-19 prevalence) and two contact network variables (network closeness, and number of direct contacts to infectious patients), and together achieved AUC-ROC 0·85 [0·82-0·88]. Furthermore, the addition of contact network variables improved performance relative to hospital contextual variables on both the non-UK (AUC-ROC increased from 0·84 [0·82–0·86] to 0·88 [0·86–0·90]) and the UK validation datasets (AUC-ROC increased from 0·52 [0·49–0·53] to 0·68 [0·64-0·70]).

Interpretation

Our results suggest that dynamic patient contact networks can be a robust predictor of respiratory viral infections spreading in hospitals. Their integration in clinical care has the potential to enhance individualised infection prevention and early diagnosis.

Funding

Medical Research Foundation, World Health Organisation, Engineering and Physical Sciences Research Council, National Institute for Health Research, Swiss National Science Foundation, German Research Foundation.
Persistence of neuropsychiatric symptoms associated with SARS-CoV-2 positivity among a cohort of children and adolescents
Authors: Castro Victor M. , Gunning Faith M. , Perlis Roy H.
Published: September 2021

Background

Post-acute sequelae of COVID-19 are common among adults. The prevalence of such syndromes among community samples of children and adolescents remains less well characterized.

Method

We identified all individuals age 5-18 across 2 New England health systems who had a positive SARS-CoV-2 PCR test between 3/12/2020 and 4/18/2021 and at least 90 days of follow-up visits documented in electronic health records. We identified neuropsychiatric symptoms in intervals prior to, and following, this testing using a previously-derived set of ICD-10 codes and natural language processing terms. Primary analysis examined sociodemographic features associated with presence of at least one incident (i.e., new-onset) neuropsychiatric symptom between 90 and 150 days after an initial positive test for COVID-19.

Results

Among 5058 children (50% female, 2.9% Asian, 6.3% Black, and 63% White; 30% Hispanic; mean age was 12.4 (IQR 8.9-15.6), 366 (7.2%) exhibited at least one new-onset neuropsychiatric symptom between 90 and 150 days following initial SARS-CoV-2 test positivity. The most common incident symptoms at 90-150 days were headache (2.4%), mood and anxiety symptoms (2.4%), cognitive symptoms (2.3%), and fatigue (1.1%). In regression models, older children, girls, those with Hispanic ethnicity, those with public versus private insurance, and those with greater overall burden of medical comorbidity were more likely to exhibit subsequent symptoms.

Conclusion

The prevalence of neuropsychiatric symptoms between 3- and 5-months following SARS-CoV-2 test positivity is similar to that observed in the period prior to infection. Prospective controlled studies will be needed to further refine these estimates.
Excess Deaths associated with the COVID-19 Pandemic in Ukraine in 2020
Authors: Mehta Neil K. , Honchar Ihor , Doroshenko Olena , Brovchenko Igor , Pak Khrystyna , Danyuk Maria , Polikarchuk Pavlo
Published: September 2021

COVID-19 related mortality has been understudied in Ukraine. As part of a World Bank project, we estimated excess mortality in Ukraine during 2020. Data on all deaths registered in government-controlled Ukraine from 2016-2020 (N=2,946,505) were utilized. We predicted deaths in 2020 by five-year age groups, sex, and month and calculated the number of deaths that deviated from expected levels (excess deaths). We compared excess deaths with the number of recorded COVID-19 deaths on death certificates and with published estimates for 30 European countries. We estimated 38,095 excess deaths in 2020 (6% of all deaths). Death rates were above expected levels in February and from June-December and lower in January and March-May. From June-December, we estimated 52,124 excess deaths with a peak in November (16,891 deaths). COVID-19 recorded deaths were approximately one-third of excess deaths in June-December (18,959 vs. 52,124). Higher than expected mortality was detected for all age groups 40-44 years and above and for those ages 0-4, 15-19, and 20-24. Ukraine’s excess mortality was about average compared to 30 other European countries. Excess deaths may be attributed directly to SARS-COV2 infection or indirectly to death causes associated with social and economic upheavals resulting in from the pandemic. Lower than expected mortality during the early part of 2020 is consistent with low influenza activity and reductions in deaths from restricted movement. Further studies are required to examine the causes of death that have contributed to positive excess mortality, particularly among younger aged groups.

Key Messages

Ukraine has experienced sizeable changes in its recent demography and the impact of the COVID-19 pandemic on the country’s aggregate mortality patterns is understudied

Based on recent death trends, we found that Ukraine experienced lower than expected mortality during the early part of 2020 and consistently higher than expected mortality from June-December with peak levels occurring in November

Positive excess mortality was observed for all age groups beginning at ages 40-44 as well as some younger age groups.
Temporal analysis of enhancers during mouse brain development reveals dynamic regulatory function and identifies novel regulators of cerebellar development
Authors: Ramirez Miguel , Badayeva Yuliya , Yeung Joanna , Wu Joshua , Yang Erin ,   FANTOM 5 Consortium, Trost Brett , Scherer Stephen W. , Goldowitz Daniel
Published: September 2021

In this study, we identified active enhancers in the mouse cerebellum at embryonic and postnatal stages establishing the first catalog of enhancers active during embryonic cerebellum development. The majority of cerebellar enhancers have dynamic activity between embryonic and postnatal development. Cerebellar enhancers were enriched for neural transcription factor binding sites with temporally specific expression. Putative gene targets displayed spatially restricted expression patterns, indicating cell-type specific expression regulation. Functional analysis of target genes indicated that enhancers regulate processes spanning several developmental epochs such as specification, differentiation and maturation. We use these analyses to discover one novel regulator and one novel marker of cerebellar development: Bhlhe22 and Pax3, respectively. We identified an enrichment of de novo mutations and variants associated with autism spectrum disorder in cerebellar enhancers. Our study provides insight into the dynamics of gene expression regulation by enhancers in the developing brain and delivers a rich resource of novel gene-enhancer associations providing a basis for future in-depth studies in the cerebellum.
Specific Detection of Endogenous S129 Phosphorylated α-Synuclein in Tissue Using Proximity Ligation Assay
Authors: Arlinghaus Ryan , Iba Michiyo , Masliah Eliezer , Cookson Mark R , Landeck Natalie
Published: September 2021

BACKGROUND

Synucleinopathies are a group of neurodegenerative disorders that are pathologically characterized by the accumulation of protein aggregates called Lewy Bodies. Lewy bodies are primarily composed of α-synuclein (asyn) protein, which is phosphorylated at serine 129 (pS129) when aggregated. Currently available commercial antibodies used to stain for pS129 asyn can cross react with other proteins, thus making it difficult to specifically detect endogenous pS129 asyn and to interpret pS129 asyn staining.

OBJECTIVE

To develop a staining procedure that detects pS129 asyn with high specificity and low background.

METHODS

We use the fluorescent and brightfield in situ Proximity Ligation Assay (PLA) to specifically detect pS129 asyn in cell culture, mouse and human brain sections.

RESULTS

The pS129 asyn PLA specifically stained for endogenous, soluble pS129 asyn in cell culture, mouse brain sections, and human brain tissue without significant cross-reactivity or background signal.

CONCLUSIONS

This PLA method can be used to specifically detect pS129 asyn in order to further explore and understand its role in health and disease.