bluuebunny/crossref_metadata_2025 huggingface dataset:
Gene-environment interaction analysis incorporating sex, cardiometabolic diseases, and multiple deprivation index reveals novel genetic associations with COVID-19 severity
Authors: Westerman Kenneth E. , Lin Joanna , Sevilla-Gonzalez Magdalena , Tadess Beza , Marchek Casey , Manning Alisa K.
Published: August 2021

Increasing evidence indicates that specific genetic variants influence the severity of outcomes after infection with COVID-19. However, it is not clear whether the effect of these genetic factors is independent of the risk due to more established non-genetic demographic and metabolic risk factors such as male sex, poor cardiometabolic health, and low socioeconomic status. We sought to identify interactions between genetic variants and non-genetic risk factors influencing COVID-19 severity via a genome-wide interaction study in the UK Biobank. Of 378,051 unrelated individuals of European ancestry, 2,402 were classified as having experienced severe COVID-19, defined as hospitalization or death due to COVID-19. Exposures included sex, cardiometabolic risk factors (obesity and type 2 diabetes [T2D], tested jointly), and multiple deprivation index. Multiplicative interaction was tested using a logistic regression model, conducting both an interaction test and a joint test of genetic main and interaction effects. Five independent variants reached genome-wide significance in the joint test, one of which also reached significance in the interaction test. One of these, rs2268616 in the PGF gene, showed stronger effects in males and in individuals with T2D. None of the five variants showed effects on a similarly-defined phenotype in a lookup in the COVID-19 Host Genetics Initiative. These results reveal potential additional genetic loci contributing to COVID-19 severity and demonstrate the value of including non-genetic risk factors in an interaction testing approach for genetic discovery.
Multiplex Target-Redundant RT-LAMP for Robust Detection of SARS-CoV-2 Using Fluorescent Universal Displacement Probes
Authors: Kline Enos C , Panpradist Nuttada , Hull Ian T , Wang Qin , Oreskovic Amy K , Han Peter D , Starita Lea M , Lutz Barry R
Published: August 2021

The increasing prevalence of variant lineages during the COVID-19 pandemic has the potential to disrupt molecular diagnostics due to mismatches between primers and variant templates. Point-of-care molecular diagnostics, which often lack the complete functionality of their high throughput laboratory counterparts, are particularly susceptible to this type of disruption, which can result in false negative results. To address this challenge, we have developed a robust Loop Mediated Isothermal Amplification assay with single tube multiplexed multi-target redundancy and an internal amplification control. A convenient and cost-effective target specific fluorescence detection system allows amplifications to be grouped by signal using adaptable probes for pooled reporting of SARS-COV-2 target amplifications or differentiation of the Internal Amplification Control. Over the course of the pandemic, primer coverage of viral lineages by the three redundant sub-assays has varied from assay to assay as they have diverged from the Wuhan-Hu-1 isolate sequence, but aggregate coverage has remained high for all variant sequences analyzed, with a minimum of 97.4% (Variant of Interest: Eta). In three instances (Delta, Gamma, Eta), a high frequency mismatch with one of the three sub-assays was observed, but overall coverage remained high due to multi-target redundancy. When challenged with extracted human samples the multiplexed assay showed 100% sensitivity for samples containing greater than 30 copies of viral RNA per reaction, and 100% specificity. These results are further evidence that conventional laboratory methodologies can be leveraged at the point-of-care for robust performance and diagnostic stability over time.
Preliminary High-Level Modelling Estimates of Impacts of Denicotinisation on Smoking Prevalence in Aotearoa New Zealand
Authors: Wilson Nick , Hoek Janet , Nghiem Nhung , Summers Jennifer , Grout Leah , Edwards Richard
Published: August 2021

Aim

To provide preliminary high-level modelling estimates of the impact of denicotinisation of tobacco on changes in smoking prevalence in Aotearoa New Zealand (NZ).

Methods

An Excel spreadsheet was populated with smoking/vaping prevalence data from the NZ Health Survey and business-as-usual trends projected. Using various parameters from the literature (NZ trial data, NZ EASE-ITC Study results), we modelled the impact of denicotinisation of tobacco (with no other tobacco permitted for sale) out to 2025, the year of this country’s Smokefree Goal. Scenario 1 used estimates from a published expert knowledge elicitation process, and Scenario 2 considered the addition of extra mass media campaign and quitline support to the base case.

Results

With the denicotinisation intervention, adult daily smoking prevalences were all estimated to decline to under 5% in 2025 for non-Māori and in one scenario for Māori (Indigenous population) (2.5% in Scenario 1). However, prevalence did not fall below five percent in the base case for Māori (7.7%) or with Scenario 2 (5.2%). In the base case, vaping was estimated to increase to 7.9% in the adult population in 2025, and up to 10.7% in one scenario (Scenario 1).

Conclusions

This preliminary, high-level modelling suggests a mandated denicotinisation policy for could provide a realistic chance of achieving the NZ Government’s Smokefree 2025 Goal. The probability of success would further increase if supplemented with other interventions such as mass media campaigns with Quitline support (especially if targeted for a predominantly Māori audience). Nevertheless, there is much uncertainty with these preliminary high-level results and more sophisticated modelling is highly desirable.
Effect of kettlebell training on bone mineral density in two older adults with osteoporosis: a multiple-case study from the BELL trial
Authors: Meigh Neil J. , Keogh Justin W.L. , Hing Wayne
Published: August 2021

The purpose of this explanatory retrospective case study was to report clinically significant increases in bone mineral density in a female and a male over 70 years of age with osteoporosis, following 16 weeks of hardstyle kettlebell training. Both case subjects were insufficiently active prior to participating in the BELL trial. Subjects trained five days a week accruing a large training load volume (calculated as kettlebell mass multiplied by repetitions performed) during structured group-based classes (74,872 kg and 110,132 kg, respectively). Regional dual-energy X-ray absorptiometry was used to assess BMD at the hip and lumbar spine. Increases in BMD of 12.7% and 5.9% at the femoral neck and lumbar spine (L2-L4) respectively were observed for the female, and 2.5% and 6.0% respectively for the male. Magnitude of change in BMD (g/cm2) at the lumbar spine was 2.0 and 1.9 times larger than the least significant change for the female and male respectively, and sufficient to advance the female subjects’ status from osteoporosis to osteopenia. Although these results do not show a definitive causal relationship between kettlebell training and increased BMD, further investigation of the effects of kettlebell training on BMD in older adults with osteoporosis and osteopenia is warranted.
Polyautoimmunity Clusters as a New Taxonomy of Autoimmune Diseases
Authors: Rojas Manuel , Ramírez-Santana Carolina , Acosta-Ampudia Yeny , Monsalve Diana M. , Rodriguez-Jimenez Mónica , Zapata Elizabeth , Naranjo-Pulido Angie , Suárez-Avellaneda Ana , Ríos-Serna Lady J. , Prieto Carolina , Zambrano-Romero William , Valero María Alejandra , Mantilla Rubén D. , Zhu Chengsong , Li Quan-Zhen , Toro-Gutiérrez Carlos Enrique , Tobón Gabriel J. , Anaya Juan-Manuel
Published: August 2021

Polyautoimmunity (PolyA) is an emerging concept that may help to develop a better classification of autoimmune diseases (ADs). Thus, we aimed to develop new taxonomy based on PolyA. Two-hundred and fifty-four consecutive patients were included with rheumatoid arthritis (RA, n:146), systemic lupus erythematosus (SLE, n:45), Sjögren’s syndrome (SS, n:29), autoimmune thyroid disease (AITD, n:17) and systemic sclerosis (SSc, n:17). Clinical features, autoantigen array chip, lymphocytes immunophenotype and cytokine profile were assessed simultaneously. The coexistence of two or more ADs with classification criteria was termed “Overt PolyA”, whereas the presence of autoantibodies unrelated to the index AD, without criteria fulfillment, was named “Latent PolyA”. Combination of IgG autoantibodies yielded high accuracy for classification of ADs. In SLE, Histone H2A, Sm/RNP, ssDNA, and dsDNA IgG autoantibodies were the most predictive autoantibodies for this condition. Laminin, Ro/SSA (52 kDa), and U1−snRNP B/B’ for SS; Thyroglobulin for AITD; Ribo Phosphoprotein P1, and CENP-A for SSc. Interestingly, Thyroglobulin and U1−snRNP B/B’ were mutual diagnostic biomarkers in SS and SSc. Latent PolyA showed in nearly 70% of patients, whereas overt PolyA was most common in AITD (82.4%) and SLE (40%). Cluster analysis based on autoantibodies yielded three clusters of which clusters 2 and 3 exhibited high frequency of latent and overt PolyA with distinctive clinical and immunological phenotypes. Combination of autoantibodies demonstrated high performance for classification of ADs. Patients with both latent and overt PolyA cluster together and exhibit differential clinical and immunological features. High prevalence of latent and overt PolyA advocates for routinary surveillance in clinical settings.

One Sentence Summary

This is a proof-of-concept study which allowed a new classification of autoimmune diseases. The results highlight that most patients with both latent and overt polyautoimmunity cluster together, with differential clinical and immunological characteristics.
“Urban Tertiary Care Centre Experience of Characteristics of Severe COVID-19 Pneumonia”
Authors: Shah Nehal M , Khambholja Janakkumar R , Suthar Nilay , Tiwari Hemant , Desai Vandit , Beriwala Vishal
Published: August 2021

Introduction

The global pandemic of novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began in Wuhan, China, in December 2019, and has since spread worldwide.[1] This study attempts to summarize current evidence regarding major inflammatory markers, severity predictors and its impact on outcome, which provide current clinical experience and treatment guidance for this novel coronavirus.

Methods

This is a retrospective observational study done at an urban teaching covid-19 designated hospital. Hospital data were analysed with aim of studying inflammatory markers, predictors and outcome. Patients were classified in Mild, Moderate, Severe & Critical categories of COVID cases. Their clinical parameters, laboratory investigations, radiological findings & Outcome measures were studied. Strength of association & correlation of those parameters with severity and in-hospital mortality were studied.

Results

A total 204 (N) patients were clinically classified into different severity groups, as per MOHFW and qCSI(quick Covid Severity Index) guidelines, as Mild (34), Moderate (56), Severe (39) and Critical (75). The mean(SD) age of the cohort was 55.1+13.2 years; 74.02% were male. Severe COVID-19 illness is seen more in patients more than 50 years of age. COVID-19 patients having IHD develop worse disease with excess early in-hospital mortality. Respiratory rate & Heart Rate on admission are correlated with severe and stormy disease. Among Inflammatory markers, on admission LDH, D-Dimer and CRP are related with severity and excess in-hospital death rate.

Conclusion

Advanced age, male gender, IHD, Respiratory Rate & Heart Rate on admission were associated with severe covid-19 illness. S. Lactate Dehydrogenase & D-dimer was associated with severe covid-19 illness and early in-hospital death.
Macular vascular complexity analysis of diabetes mellitus by swept-source optical coherence tomographic angiography
Authors: Liu Jiahui , Chen Shuhui , Xu Zhiyi , Wang Wei , Wang Dingqiao , Su Yongyue , Zhao Shulun , Li Meichan , Chen Fengling , Zuo Chengguo , Chen Minyu
Published: August 2021

Purpose

To evaluate the associations of retinal vascular complexity features, including fractal dimension (FD) and blood vessel tortuosity (BVT), with the severity of diabetic retinopathy (DR) by using noninvasive optical coherence tomographic angiography (OCTA).

Methods

This prospective cross-sectional study recruited ocular-treatment-naïve patients with type 2 diabetes mellitus (DM) registered in the community of Guangzhou, China. OCTA was used to obtain the measurements of FD and BVT in the superficial capillary plexus (SCP) and the deep capillary plexus (DCP). Univariate and multivariate linear regression was used to analyse the correlation of FD and BVT in different layers with DR severity.

Results

A total of 1282 patients with DM (1282 eyes), with a mean age of 64.2±7.8 years, were included. FD in the DCP decreased and BVT in the DCP increased in DR patients compared to non-DR patients, even after adjusting for confounding factors (P< 0.05). Trend analysis showed a significant decrease in the FD values as the DR progressed, while the BVT progressively increased with worsening DR severity (P< 0.01). The FD in DCP had a statistically significant positive correlation with FD in SCP and a negative correlation with BVT in SCP and BVT in DCP in all of the participants, including the non-DR group, moderate DR group and severe DR group (P< 0.01).

Conclusion

FD and BVT determined using OCTA might be useful parameters for objectively distinguishing DR from non-DR and indicating DR progression.
Differential associations between neocortical tau pathology and blood flow with cognitive deficits in early-onset vs late-onset Alzheimer’s disease
Authors: Visser Denise , Verfaillie Sander CJ , Wolters Emma E , Coomans Emma M , Timmers Tessa , Tuncel Hayel , Boellaard Ronald , Golla Sandeep SV , Windhorst Albert D , Scheltens Philip , van der Flier Wiesje M , van Berckel Bart NM , Ossenkoppele Rik
Published: August 2021

Purpose

Early-onset Alzheimer’s disease (EOAD) and late-onset Alzheimer’s disease (LOAD) differ in neuropathological burden and type of cognitive deficits. Assessing tau pathology and relative cerebral blood flow (rCBF) measured with [18F]flortaucipir PET in relation to cognition may help explain these differences between EOAD and LOAD.

Methods

Seventy-nine amyloid-positive individuals with a clinical diagnosis of AD (EOAD: n=35, age-at-PET=59±5, MMSE=23±4; LOAD: n=44, age-at-PET=71±5, MMSE=23±4) underwent a 130 minutes dynamic [18F]flortaucipir PET scan and extensive neuropsychological assessment. We extracted binding potentials (BPND) and R1(proxy of rCBF) from parametric images using receptor parametric mapping, in medial and lateral temporal, parietal, occipital and frontal regions-of-interest and used nine neuropsychological tests covering memory, attention, language and executive functioning. We first examined differences between EOAD and LOAD in BPNDor R1using ANOVA (region-of-interest analysis) and voxel-wise contrasts. Next, we performed linear regression models to test for potential interaction effects between age-at-onset and BPND/R1on cognition.

Results

Both region-of-interest and voxel-wise contrasts showed higher [18F]flortaucipir BPNDvalues across all neocortical regions in EOAD. By contrast, LOAD patients had lower R1values (indicative of more reduced rCBF) in medial temporal regions. For both tau and flow in lateral temporal, and occipito-parietal regions, associations with cognitive impairment were stronger in EOAD than in LOAD (EOAD BPND-0.76≤stβ≤-0.48 vs LOAD -0.18≤stβ≤-0.02; EOAD R10.37≤stβ≤0.84 vs LOAD -0.25≤stβ≤0.16).

Conclusions

Compared to LOAD, the degree of lateral temporal and occipito-parietal tau pathology and relative cerebral blood-flow is more strongly associated with cognition in EOAD.
Closed Doors: Predictors of Stress, Anxiety, Depression, and PTSD During the Onset of COVID-19 Pandemic in Brazil
Authors: Calegaro Vitor Crestani , Ramos-Lima Luis Francisco , Hoffmann Mauricio Scopel , Zoratto Gustavo , Kerber Natália , Dala Costa Fernanda Coloniese , Picinin Vitor Daniel , Köchler Julia , Rodrigues Leonardo , Maciel Luisa , Braun Luiza Elizabete , Girardi Fernando Leite , Cecatto Gabriel Olerich , Weber Leopoldo Pompeo , Rodrigues Bruna Fragoso , Bertolazi Alessandra Naimaier , de Oliveira Juliana Motta , Negretto Bianca Lorenzi , de Mello Andrea Feijó
Published: August 2021

Background

The rise of mental health problems in the population directly or indirectly by the COVID-19 pandemic is a major concern. The aim of this study was to investigate and compare independent predictors of symptoms of stress, anxiety, depression, and post-traumatic stress disorder (PTSD) in Brazilians, one month after the implementation of measures of social distancing.

Methods

It was a cross-sectional study, performed through a web-based survey. Depression, Anxiety, and Stress Scale (DASS-21) and PTSD Checklist for DSM-5 (PCL-5) were the outcomes. Data were gathered regarding demographics, social distancing, economic problems, exposure to the news of the pandemic, psychiatric history, sleep disturbances, traumatic situations, and substance use. The Alcohol Use Disorders Identification Test - Consumption (AUDIT-C) was also included. Predictors of symptoms were investigated through hierarchical multiple linear regression.

Result

Of a sample of 3,587 participants, approximately two-thirds considered that their mental health worsened after the beginning of the social restriction measures. The most important predictors of the symptoms investigated were the intensity of the distress related to pandemic news, younger age, current psychiatric diagnosis, trouble sleeping, emotional abuse or violence, and economic problems.

Limitations

The convenience sample assessed online may have limited external validity. It does not represent the northern regions of the country and most participants was white wealthier females.

Conclusions

These results confirm the hypothesis that a pandemic would have important impacts on the mental health of the population and indicate the level of distress related to the media as an important predictor of psychological suffering.

Highlights

Distress triggered by news was the main predictor of psychological symptoms

Sleeping problems were strong indicators of mental health problems

People with ongoing psychiatric disorders are especially vulnerable

Measures to prevent interpersonal trauma and financial loss are crucial

Young people may experience great suffering at the onset of the pandemic
“Men are the main COVID-19 transmitters: lessons from couples”
Authors: Silva Monize V. R. , de Castro Mateus V. , Passos-Bueno Maria Rita , Otto Paulo A. , Naslavsky Michel S. , Zatz Mayana
Published: August 2021

Background

COVID-19 has affected millions of people worldwide. Clinical manifestations range from severe cases with a lethal outcome to mild or asymptomatic cases. Although there is the same proportion of infected genders, men are more susceptible to severe COVID-19, with a higher risk of death than women. This sex-bias may be explained by biological pathways.

Methods

We performed an epidemiological survey from July 2020 to July 2021 including 1744 unvaccinated adult Brazilian couples with at least one infected spouse despite living together during the COVID-19 infection without protective measures. The presence or absence of infection was confirmed by RT-PCR and/or serology results. The couples were divided between groups where both partners were infected (concordant couples) or only one spouse remained asymptomatic despite the close contact with the infected one (discordant couples). Statistical analysis of the collected data was performed aiming to verify a differential transmitter potential between genders in household contact.

Results

The combination of our data collected from concordant and discordant couples showed that the man is the first (or the only) affected in the major occurrences when compared to women. Our findings support other published surveys and are in concordance with previous studies of our group.

Conclusions

These observations support the hypothesis according to which male individuals are more efficient virus transmitters than females, independently of the use of protective masks. In short, the present study confirmed the existence of gender differences not only for susceptibility to infection and resistance to COVID-19 but also in the transmission rate.

HIGHLIGHTS

There are sex differences in COVID-19 susceptibility and transmission between couples with direct contact without protective measures;

Men are more efficient virus transmitters than women;

Sex-bias in COVID-19 transmission can be explained by differences in viral load in saliva, immune response and also behavioural protective differences between genders.
COVID-19 related messaging, beliefs, information sources, and mitigation behaviors in Virginia: A cross-sectional survey in the summer of 2020
Authors: Silverman Rachel A. , Short Danielle , Wenzel Sophie , Friesen Mary Ann , Cook Natalie E.
Published: August 2021

Conflicting messages and misinformation related to the coronavirus (COVID-19) pandemic (SARS-CoV-2) have hindered mitigation efforts. To gain insight and inform effective evidence-based public health messaging, we distributed an online cross-sectional survey from May to July, 2020. Among 3,488 respondents, systematic differences were observed in information sources that people trust, events that impacted beliefs and behaviors, and how behaviors changed by socio-demographics, political identity, and geography within Virginia. Characteristics significantly associated (p<0.05) with not wearing a mask in public included identifying as non-Hispanic white, men, Republican, younger age, lower income, not trusting national science and health organizations, believing a non-evidence-based messages, and Southwest Virginia in logistic regression. Similar, lesser in magnitude correlations, were observed for distancing in public. This study can assist decision makers and the public to improve and effectively target public health messaging related to the ongoing COVID-19 pandemic and future public health challenges in Virginia and similar jurisdictions.
Photoreceptor layer thinning is an early biomarker for age-related macular degeneration development: Epidemiological and genetic evidence from UK Biobank optical coherence tomography data
Authors: Zekavat Seyedeh Maryam , Sekimitsu Sayuri , Ye Yixuan , Raghu Vineet , Zhao Hongyu , Elze Tobias , Segrè Ayellet V. , Wiggs Janey L. , Natarajan Pradeep , Priore Lucian Del , Zebardast Nazlee , Wang Jay C.
Published: August 2021

Introduction

Age-related macular degeneration (AMD) is a blinding condition for which there is currently no early-stage clinical biomarker. AMD is characterized by thinning of the outer retina and drusen formation leading to thickening of the Bruch’s membrane and RPE complex, but the timing between these two events, as well as the role of genetic variants in these processes, are unclear. Here, we jointly analyzed genomic, electronic health record, and optical coherence tomography (OCT) data across 44,823 individuals from the UK Biobank to characterize the epidemiological and genetic associations between retinal layer thicknesses and AMD.

Methods

The Topcon Advanced Boundary Segmentation algorithm was used for automated retinal layer segmentation. We associated 9 retinal layer thicknesses with prevalent AMD (present at enrollment) in a logistic regression model, and with incident AMD (diagnosed after enrollment) in a Cox proportional hazards model. Next, we tested the association of AMD-associated genetic alleles, individually and as a polygenic risk score (PRS), with retinal layer thicknesses. All analyses were adjusted for age, age2, sex, smoking status, and principal components of ancestry.

Results

Photoreceptor segment (PS) thinning was observed throughout the lifespan of individuals analyzed and accelerated at age 45, while retinal pigment epithelium and Bruch’s membrane complex (RPE+BM) thickening started after age 57. Each standard deviation (SD) of PS thinning and RPE+BM thickening were associated with prevalent AMD (PS: OR 1.37, 95% CI 1.25-1.49, P=2.5×10−12; RPE+BM: OR=1.34, 95% CI 1.27-1.41, P=8.4×10−28) and incident AMD (PS: HR 1.35, 95% CI 1.23-1.47, P=3.7×10−11; RPE+BM: HR 1.14, 95% CI 1.06-1.22, P=0.00024). An AMD polygenic risk score (PRS) was associated with PS thinning (Beta -0.21 SD per 2-fold genetically increased risk of AMD, 95% CI -0.23 to -0.19, P=2.8×10−74), and its association with RPE+BM was U-shaped (thinning with AMD PRS<92ndpercentile and thickening with AMD PRS>92ndpercentile suggestive of drusen formation). The loci with strongest support were AMD risk-raising variantsCFH:rs570618-T,CFH:10922109-C, andARMS2/HTRA1:rs3750846-C on PS thinning, andSYN3/TIMP3:rs5754227-T on RPE+BM thickening.

Conclusions

Epidemiologically, PS thinning precedes RPE+BM thickening by decades, and is the retinal layer most strongly predictive of future AMD risk. Genetically, AMD risk variants are associated with decreased PS thickness. Overall, these findings support PS thinning as an early-stage clinical biomarker for future AMD development.
Early Precursors of Literacy Development in Simultaneous Bilinguals: A Systematic Review and Meta-Analysis
Authors: Bhalloo Insiya , Molnar Monika
Published: August 2021

Purpose

Literacy precursors are cognitive, linguistic, and oral-language skills that predict future reading skills in children as young as 4 years. Speech-language pathologists and educators utilize these precursors as assessment tools to identify children at risk for reading difficulties. Most current tools are developed based on monolinguals (predominantly in English), despite the significant percentage of bilinguals globally. As such, bilingual children are typically assessed on tools developed for monolinguals in research and clinical settings. Despite this common practice, there is a lack of comprehensive synthesis on whether these precursors are a reliable indicator of reading skills in bilingual children. Our paper examines whether literacy precursors commonly used with monolinguals are associated with literacy development in simultaneous bilinguals.

Method

Following PRISMA and Cochrane guidelines, our review includes four databases (LLBA, ERIC, MLA, and PsycINFO), in addition to gray-literature and manual reference-list searches. To control for age of acquisition and language dominance variability, we included typically-developing simultaneous bilinguals exposed to both languages before age 3 (N=5,942). We analyzed reported statistical associations between code-related or oral-language precursors and reading outcome measures, using correlational meta-analyses.

Results

The 41 reports, that met inclusion/exclusion criteria, were published between 1977-2022. The average age at assessment was 7;5 years (range: 3;0 - 11;0 years), with children speaking over 21 bilingual language combinations. Our meta-analysis demonstrated significant within-language correlations and cross-language transfer effects for code-related (e.g., phonological awareness) and oral-language (e.g., vocabulary, morphological awareness) precursors. Semantic awareness, however, was not a reliable predictor in bilinguals.

Conclusions

Phonological awareness and vocabulary measures – even if originally developed for monolingual children - can form a meaningful component of early literacy assessment in simultaneous bilingual children: these precursors may be used as assessment tools across heritage and societal languages in research and clinical practice. Future research suggestions within this domain are also discussed.
CardioVinci: building blocks for virtual cardiac cells using deep learning
Authors: Khadangi Afshin , Boudier Thomas , Rajagopal Vijay
Published: August 2021

Recent advances in high-throughput microscopy imaging have made it easier to acquire large volumes of cell images. Thanks to electron microscopy (EM) imaging, they provide a high-resolution and sufficient field of view that suits imaging large cell types, including cardiomyocytes. A significant bottleneck with these large datasets is the time taken to collect, extract and statistically analyse 3D changes in cardiac ultrastructures. We address this bottleneck with CardioVinci.
Multi-omics integration and regulatory inference for unpaired single-cell data with a graph-linked unified embedding framework
Authors: Cao Zhi-Jie , Gao Ge
Published: August 2021

With the ever-increasing amount of single-cell multi-omics data accumulated during the past years, effective and efficient computational integration is becoming a serious challenge. One major obstacle of unpaired multi-omics integration is the feature discrepancies among omics layers. Here, we propose a computational framework called GLUE (graph-linked unified embedding), which utilizes accessible prior knowledge about regulatory interactions to bridge the gaps between feature spaces. Systematic benchmarks demonstrated that GLUE is accurate, robust and scalable. We further employed GLUE for various challenging tasks, including triple-omics integration, model-based regulatory inference and multi-omics human cell atlas construction (over millions of cells) and found that GLUE achieved superior performance for each task. As a generalizable framework, GLUE features a modular design that can be flexibly extended and enhanced for new analysis tasks. The full package is available online athttps://github.com/gao-lab/GLUEfor the community.
Temperature increase affects acetate-derived methane production in Alaskan lake sediments and wetland soils
Authors: Dellagnezze BM , Bovio-Winkler P. , Lavergne C. , Menoni D.A. , Mosquillo F. , Cabrol L , Barret M. , Etchebehere C.
Published: August 2021

Under climate change framework, methanogens activity is expected to be strongly affected, eventually resulting in positive feedback on global climate, with higher greenhouse gas (GHG) emissions in the Arctic. This work aimed to evaluate the effect of increasing temperature on methane production rate and archaeal community of lake sediments and wetland soils from Denali to Toolik regions in Alaska (USA). For that, anaerobic acetate-amended microcosms were incubated at 5, 10, 15 and 20 °C. The acetate-derived methanogenic rate was determined and the methanogenic communities were analyzed by qPCR and 16S rRNA sequencing. Warmer temperatures yielded 4-6 times higher methane production rates and organic matter content (OM) showed significant positive correlation to methane production. Different patterns were observed in the archaeal communities after incubation at higher temperatures, with an increase in Methanosarcina abundance for most of the samples and Methanosaeta in one of the lakes tested, showing the adaptation of key acetoclastic groups among different temperatures. Our results demonstrate the impact of increasing temperature on methane production, bringing insights on key drivers involved in the process of acetoclastic methanogenic potential occurring in these ecosystems in Alaska.
Assessing the use of ellipsoidal microparticles for determining lipid membrane viscosity
Authors: Jahl P. E. , Parthasarathy R.
Published: August 2021

The viscosity of lipid membranes sets the timescales of membrane-associated flows and therefore influences the dynamics of a wide range of cellular processes. Techniques to measure membrane viscosity remain sparse, however, and reported measurements to date, even of similar systems, give viscosity values that span orders of magnitude. To address this, we improve a method based on measuring both the rotational and translational diffusion of membrane-anchored microparticles and apply this approach and one based on tracking the motion of phase-separated lipid domains to the same system of phase-separated giant vesicles. We find good agreement between the two methods, with inferred viscosities within a factor of two of each other. Our technique uses ellipsoidal microparticles, and we show that the extraction of physically meaningful viscosity values from their motion requires consideration of their anisotropic shape. The validation of our method on phase-separated membranes makes possible its application to other systems, which we demonstrate by measuring the viscosity of bilayers composed of lipids with different chain lengths ranging from 14 to 20 carbon atoms, revealing a very weak dependence of two-dimensional viscosity on lipid size. The experimental and analysis methods described here should be generally applicable to a variety of membrane systems, both reconstituted and cellular.

Statement of Significance

The lipid bilayers that underlie cellular membranes are two-dimensional fluids whose viscosity sets timescales of flow. Lipid membrane viscosity remains poorly quantified, with a paucity of methods and considerable disagreement between values reported using different techniques. We describe a method based on measuring the Brownian diffusion of ellipsoidal microparticles which we apply to phase-separated membranes alongside a previously established method for determining membrane viscosity, finding good agreement between the two techniques. We further examine homogenous membranes composed of lipids with different chain lengths, not amenable to phase-separationbased methods, revealing a very weak dependence of viscosity on lipid size. Our approach should be applicable to a wide range of membrane systems, both in vitro and in living cells.
Genome-wide development of lncRNA-derived-SSR markers for Dongxiang wild rice (Oryza rufipogon Griff.)
Authors: Yang Wanling , Fan Yuanwei , Chen Yong , Ding Gumu , Liu Hu , Xie Jiankun , Zhang Fantao
Published: August 2021

Dongxiang wild rice (Oryza rufipogon Griff., DXWR) is the northernmost distributed common wild rice found in the world. It contains a large number of agronomically valuable genes, which makes it a natural gene pool for rice breeding. Molecular markers, especially simple repeat sequence (SSR) markers, play important roles in crop breeding. Although a large number of SSR markers have been developed, most of them are derived from the genome coding sequences, rarely from non-coding sequences. Meanwhile, long non-coding RNAs (lncRNAs), which are derived from the transcription of non-coding sequences, play vital roles in plant growth, development and stress responses. In this study, 1878 SSR loci were detected from the lncRNA sequences of DXWR, and 1258 lncRNA-derived-SSR markers were developed on the genome-wide scale. To verify the validity and applicability of these markers, 72 pairs of primers were randomly selected to test 44 rice materials. The results showed that 42 (58.33%) pairs of primers have abundant polymorphism among these rice materials; the polymorphism information content (PIC) values ranged from 0.04 to 0.87 with an average of 0.50; the genetic diversity index of SSR loci varied from 0.04 to 0.88 with an average of 0.56; and the number of alleles per marker ranged from 2 to 11 with an average of 4.36. Thus, we concluded that these lncRNA-derived-SSR markers are a very useful source for future basic and applied research, including genetic diversity analysis, QTL mapping, and molecular breeding programs, to make good use of the elite lncRNA genes from DXWR.
de novogene birth as an inevitable consequence of adaptive evolution
Authors: Mani Somya , Tlusty Tsvi
Published: August 2021

Phylostratigraphy suggests that new genes are continually bornde novofrom non-genic sequences, and the genes that persist found new lineages, contributing to the adaptive evolution of organisms. While recent evidence supports the view thatde novogene birth is frequent and widespread, the mechanisms underlying this process are yet to be discovered. Here we hypothesize and examine a potential general mechanism of gene birth driven by the accumulation of beneficial mutations at non-genic loci. To demonstrate this possibility, we model this mechanism within the boundaries set by current knowledge on mutation effects. Estimates from this analysis are in line with observations of recurrent and extensive gene birth in genomics studies. Thus, we propose that, rather than being inactive and silent, non-genic regions are likely to be dynamic storehouses of potential genes.
Spontaneous Chiral Symmetry Breaking in a Random Driven Chemical System
Authors: Piñeros William D. , Tlusty Tsvi
Published: August 2021

Living systems have evolved to efficiently consume available energy sources using an elaborate circuitry of chemical reactions which, puzzlingly, bear a strict restriction to asymmetric chiral configurations. While autocatalysis is known to promote such chiral symmetry breaking, whether a similar phenomenon may also be induced in a more general class of configurable chemical systems—via energy exploitation—is a sensible yet underappreciated possibility. This work examines this question within a model of randomly generated complex chemical networks. We show that chiral symmetry breaking may occur spontaneously and generically by harnessing energy sources from external environmental drives. Key to this transition are intrinsic fluctuations of achiral-to-chiral reactions and tight matching of system configurations to the environmental drives, which together amplify and sustain diverged enantiomer distributions. These asymmetric states emerge through steep energetic transitions from the corresponding symmetric states and sharply cluster as highly-dissipating states. The results thus demonstrate a generic mechanism in which energetic drives may give rise to homochirality in an otherwise totally symmetrical environment, and from an early-life perspective, might emerge as a competitive, energy-harvesting advantage.
The crystal structure of the varicella zoster Orf24-Orf27 nuclear egress complex spotlights multiple determinants of herpesvirus subfamily specificity
Authors: Schweininger Johannes , Kriegel Mark , Häge Sigrun , Conrad Marcus , Alkhashrom Sewar , Lösing Josephine , Weiler Sigrid , Tillmanns Julia , Egerer-Sieber Claudia , Decker Andrea , Roviš Tihana Lenac , Eichler Jutta , Sticht Heinrich , Marschall Manfred , Muller Yves A.
Published: August 2021

Varicella zoster virus (VZV) is a human pathogen from the α-subfamily of herpesviruses. Here, the crystal structure of the VZV Orf24-Orf27 complex is described, representing the essential viral core nuclear egress complex (NEC) that orchestrates the egress of the preassembled capsids from the nucleus. While previous studies have primarily emphasized the finding that the architecture of core NEC complexes is highly conserved among herpesviruses, the present report focusses on subfamily-specific structural and functional features that help explain the differences in the autologous versus nonautologous interaction patterns observed for NEC formation across herpesviruses. CoIP and confocal imaging data show that Orf24-Orf27 complex formation displays some promiscuity in a herpesvirus subfamily-restricted manner. At the same time, analysis of the NEC formation thermodynamic parameters of three prototypical α-, β- and γ herpesviruses, i.e. VZV, human cytomegalovirus (HCMV) and Epstein-Barr virus (EBV) reveals highly similar binding affinities for the autologous interaction with some specific differences in the enthalpy and entropy terms. Computational alanine scanning and structural comparisons highlight intermolecular interactions shared among α-herpesviruses that are clearly distinct from those seen in β- and γ-herpesviruses. Combined, these data allow to explain the distinct properties of specificity and permissivity so far observed in herpesviral NEC interactions. These findings might prove highly valuable when attempting to target multiple herpesvirus core NECs with selective or broad-acting drug candidates.
Parity-induced changes to mammary epithelial cells control NKT cell expansion and mammary oncogenesis
Authors: Hanasoge Somasundara Amritha V. , Moss Matthew A. , Feigman Mary J. , Chen Chen , Cyrill Samantha L. , Ciccone Michael F. , Trousdell Marygrace C. , Vollbrecht Macy , Li Siran , Kendall Jude , Beyaz Semir , Wilkinson John E. , dos Santos Camila O.
Published: August 2021

Pregnancy reprograms the epigenome of mammary epithelial cells (MECs) in a manner that control responses to pregnancy hormone re-exposure and the rate of carcinoma progression. However, the influence of pregnancy on the tissue microenvironment of the mammary gland is less clear. Here, we used single-cell RNA sequencing to comparatively profile the composition of epithelial and non-epithelial cells in mammary tissue from nulliparous and parous female mice. Our analysis revealed an expansion of γδ Natural Killer T (NKT) immune cells following pregnancy, in association with upregulation of immune signal molecules in post-pregnancy MECs. We show that expansion of NKT cells following pregnancy is due to elevated expression of the antigen presenting molecule CD1d protein, which is known to induce NKT activation. Accordingly, loss of CD1d expression on post-pregnancy MECs, or overall lack of activated NKT cells, accompanied the development of mammary oncogenesis in response to cMYC overexpression and loss of Brca1 function. Collectively, our findings illustrate how pregnancy-induced epigenetic changes modulate the communication between MECs and the mammary immune microenvironment, and establish a causal link between pregnancy, the immune microenvironment, and mammary oncogenesis.
Recruitment and organization of ESCRT-0 and ubiquitinated cargo via condensation
Authors: Banjade Sudeep , Zhu Lu , Jorgensen Jeffrey R. , Suzuki Sho W. , Emr Scott D.
Published: August 2021

The general mechanisms by which ESCRTs are specifically recruited to various membranes, and how ESCRT subunits are spatially organized remain central questions in cell biology. At the endosome and lysosomes, ubiquitination of membrane proteins triggers ESCRT-mediated substrate recognition and degradation. Using the yeast lysosome/vacuole, we define the principles by which substrate engagement by ESCRTs occurs at this organelle. We find that multivalent interactions between ESCRT-0 and polyubiquitin is critical for substrate recognition at yeast vacuoles, with a lower-valency requirement for cargo engagement at endosomes. Direct recruitment of ESCRT-0 induces dynamic foci on the vacuole membrane, and forms fluid condensates in vitro with polyubiquitin. We propose that self-assembly of early ESCRTs induces condensation, an initial step in ESCRT-assembly/nucleation at membranes. This property can be tuned specifically at various organelles by modulating the number of binding interactions.

One-Sentence Summary

Condensation of multivalent ESCRT-0/polyubiquitin assemblies organizes cargo sorting reactions at lysosomes
Prior expectations in visual speed perception predict encoding characteristics of neurons in area MT
Authors: Zhang Ling-Qi , Stocker Alan A.
Published: August 2021

Bayesian inference provides an elegant theoretical framework for understanding the characteristic biases and discrimination thresholds in visual speed perception. However, the framework is difficult to validate due to its flexibility and the fact that suitable constraints on the structure of the sensory uncertainty have been missing. Here, we demonstrate that a Bayesian observer model constrained by efficient coding not only well explains human visual speed perception but also provides an accurate quantitative account of the tuning characteristics of neurons known for rep-resenting visual speed. Specifically, we found that the population coding accuracy for visual speed in area MT (“neural prior”) is precisely predicted by the power-law, slow-speed prior extracted from fitting the Bayesian model to psychophysical data (“behavioral prior”) to the point that the two priors are indistinguishable in a cross-validation model comparison. Our results demonstrate a quantitative validation of the Bayesian observer model constrained by efficient coding at both the behavioral and neural levels.

Significance Statement

Statistical regularities of the environment play an important role in shaping both neural representations and perceptual behavior. Most previous works addressed these two aspects independently. Here we present a quantitative validation of a theoretical framework that makes joint predictions for neural coding and behavior, based on the assumption that neural representations of sensory information are efficient but also optimally used in generating a percept. Specifically, we demonstrate that the neural tuning characteristics for visual speed in brain area MT are precisely predicted by the statistical prior expectations extracted from psychophysical data. As such, our results provide a normative link between perceptual behavior and the neural representation of sensory information in the brain.
Hierarchical Clustering on RNA Dependent RNA Polymerase using Machine Learning.
Authors: Kumar Gudipati Pavan
Published: August 2021

RNA Dependent RNA Polymerase (RdRP) catalyzes the replication of RNA from an RNA template and is mostly found in Viruses. We have collected over 161 viral RdRP FASTA Sequences from the NCBI protein database using python script. Each of these sequences was transformed with TfidfVectorizer using sklearn module, with the one Letter word, because each Letter belongs to one Amino acid. These transformed data were sent to Hierarchical clustering using scipy library and visualized data using Dendrogram. These Machine Learning technique is able to classify or segment similar RdRp into one cluster. Each of these clusters was tested for their multiple sequence alignment with COBALT of NCBI. We observed that these clusters predicted similar RdRP among various viruses. These techniques can be further improved to segment or classify various proteins. These Machine Learning or Artificial Intelligence techniques need more improvement in their algorithms to solve genomics and proteomics.
Converging evidence for differential regulatory control of APOEε4 on African versus European haplotypes
Authors: Nuytemans Karen , Lipkin Marina , Wang Liyong , Van Booven Derek , Griswold Antony J. , Rajabli Farid , Celis Katrina , Oron Oded , Hofmann Natalia , Rolati Sophie , Garcia-Serje Catherine , Zhang Shanshan , Jin Fulai , Argenziano Mariana , Grant Struan F.A. , Chesi Alessandra , Brown Christopher D. , Young Juan I. , Dykxhoorn Derek M. , Pericak-Vance Margaret A. , Vance Jeffery M.
Published: August 2021

INTRODUCTION

The difference in APOEε4 risk for Alzheimer disease (AD) between different populations is associated with APOEε4 local ancestry (LA). We examined LA SNPs with significant frequency differences between African and European/Japanese APOEε4 haplotypes for areas of differential regulation.

METHODS

We performed two enhancer Massively Parallel Reporter Assay (MPRA) approaches, supplemented with single fragment reporter assays. We utilized Capture C analyses to support interactions with the APOE promoter.

RESULTS

The TOMM40 intron 2 and 3 region showed increased enhancer activity in the European/Japanese versus African LA haplotypes in astrocytes and microglia. This region overlaps with APOE promoter interactions as assessed by Capture C analysis. Single variant analyses pinpoints rs2075650/rs157581, and rs59007384 as functionally different on these haplotypes.

DISCUSSION

Both differential regulatory function and Capture C data support an intronic region in TOMM40 as contributing to the differential APOE expression between African and European/Japanese LA.