bluuebunny/crossref_metadata_2025 huggingface dataset:
Spectrum of Genetic Disorders and Gene Variants in the United Arab Emirates National Population: Insights from the CTGA Database
Authors: Bizzari Sami , Nair Pratibha , Hana Sayeeda , Deepthi Asha , Al-Ali Mahmoud Taleb , Al-Gazali Lihadh , El-Hayek Stephany
Published: March 2023

Like many other Arab countries, the United Arab Emirates (UAE) has a relatively high prevalence of genetic disorders. Here we present the first review and analysis of all genetic disorders and gene variants reported in Emirati nationals and hosted on the Catalogue for Transmission Genetics in Arabs (CTGA), an open-access database hosting bibliographic data on human gene variants associated with inherited or heritable phenotypes in Arabs. To date, CTGA hosts 665 distinct genetic conditions that have been described in Emiratis, 621 of which follow a clear Mendelian inheritance. Strikingly, over half of these are extremely rare according to global prevalence rates, predominantly with an autosomal recessive mode of inheritance. This is likely due to the relatively high consanguinity rates within the Emirati population. The 665 conditions include disorders that are unique to the Emirati population, as well as clearly monogenic disorders that have not yet been mapped to a causal genetic locus. We also describe 1,365 gene variants reported in Emiratis, most of which are substitutions and over half are classified as likely pathogenic or pathogenic. Of these, 235 had not been reported on the international databases dbSNP and Clinvar, as of December 2022. Further analysis of this Emirati variant dataset allows a comparison of clinical significance as reported by Clinvar and CTGA, where the latter is derived from the study cited. A total of 307 pathogenic/likely pathogenic variants from CTGA’s Emirati dataset, were classified as benign, variants of uncertain significance, or were missing a clinical significance or had not been reported by Clinvar. In conclusion, we present here the spectrum of genetic disorders and gene variants reported in Emiratis. This review emphasizes the importance of ethnic databases such as CTGA in addressing the underrepresentation of Arab variant data in international databases and documenting population - specific discrepancies in variant interpretation, reiterating the value of such repositories for clinicians and researchers, especially when dealing with rare disorders.
Improving the impact of pharmacy interventions in hospitals
Authors: Baptista Rafael , Williams Mary , Price Jayne
Published: March 2023

The interventions of pharmacy professionals are considered impactful inputs towards optimised patient care and safety, by rationalising prescriptions, enhancing therapeutic choices and reducing and preventing medication errors and adverse effects. Between October 2020 and October 2021, the community hospitals at Powys Teaching Health Board recorded 158 interventions, corresponding to 0.4 interventions per pharmacy staff per week. Predominantly, only two members of the team were recording these pharmacy interventions (PIs). Poor indicative PIs can result in lost opportunities for medication optimisation and prescribing rationalisation, increased costs and unidentified education and training potentials.

The aims of this project were (1) to record 180 interventions between 22/11/2021 and 08/04/2022 (20 weeks), corresponding to an average 3-fold increase, compared to the interventions recorded between October 2020 and October 2021 (52 weeks); (2) to have all hospital pharmacy staff recording at least one intervention during the same period.

The number of interventions recorded and the number of pharmacy staff recording each intervention were two process measures. The project was completed through two Plan-Do-Study-Act (PDSA) cycles and applied theory on managing change in healthcare.

The most successful intervention influencing positively the process measures was the implementation of a newPharmacy InterventionRecordTool (xPIRT) toolkit that included an online recording tool (xPIRT) and an interactive panel with up-to-date results from all interventions recorded (xPIRT Dashboard). Motivating change was proven to be one of the best determinants of user satisfaction and engagement that contributed to meet the project’s targets. xPIRT Dashboard provided staff the capacity to act on possible personal motivators and the possibility to improving care with medicines on their wards. The implementation of xPIRT toolkit was able to increase the representativity and significance of PIs recorded by the hospital pharmacy team and it is expected to be used for personal professional development, demonstrating team activity and impact, service planning, prescribing practice optimisation, and to identify education/training needs. This toolkit can be easily applied and adapted to other health organisations, settings and services.
Effects of Race on Chronic Pain in a Randomized Clinical Trial of Integrative Medical Group Visits
Authors: Polcari Justin J. , Incollingo Rodriguez Angela C. , Nephew Benjamin C. , Melican Veronica , King Jean A. , Gardiner Paula
Published: March 2023

Chronic pain is one of the most common reasons adults seek medical care in the US, with estimates of prevalence ranging from 11% to 40% and relatively higher rates in diverse populations. Mindfulness meditation has been associated with significant improvements in pain, depression, physical and mental health, sleep, and overall quality of life. Group medical visits are increasingly common and are effective at treating myriad illnesses including chronic pain. Integrative Medical Group Visits (IMGV) combine mindfulness techniques, evidence based integrative medicine, and medical group visits and can be used as adjuncts to medications, particularly in diverse underserved populations with limited access to non-pharmacological therapies. The objective of the present study was to assess the effects of race on the primary pain outcomes and evaluate potential relationships between race and additional patient characteristics in data from a randomized clinical trial of IMGV in socially diverse, marginalized patients suffering from chronic pain and depression. It was hypothesized that there would be racial differences in the effects of IMGV on pain outcomes. Our analyses identified significant racial differences in the response to IMGV. Black subjects had increased pain severity throughout the duration of the 21-week study but were less likely to respond to the pain intervention compared to White subjects. These results may be related to differential comorbidity rates, catastrophizing, and digital health literacy among these participant groups. To improve patient outcomes in similar studies, interactions between pain outcomes and these factors require further investigation to affect levels and trajectory of pain severity and enhance the response to complimentary interventions.
N-MYC regulates Cell Survival via eIF4G1 in inv(16) Acute Myeloid Leukemia
Authors: Peramangalam Philomina Sona , Surapally Sridevi , Zheng Shikan , Burns Robert , Zhu Nan , Rao Sridhar , Muller-Tidow Carsten , Pulikkan John A.
Published: March 2023

c-MYC and N-MYC are critical regulators of hematopoietic stem cell activity. While the role of c-MYC deregulation is studied in detail in hematological malignancies, the importance of N-MYC deregulation in leukemogenesis remains elusive. Here we demonstrate that N-MYC is overexpressed in acute myeloid leukemia (AML) cells with chromosome inversion inv(16) and crucial to the survival and maintenance of inv(16) leukemia. We identified a novelMYCNenhancer, active in multiple AML subtypes, essential for MYCN mRNA levels and survival in inv(16) AML cells. We also identified eukaryotic translation initiation factor 4 gamma 1 (eIF4G1) as a key N-MYC target that sustains leukemic survival in inv(16) AML cells. Ours is the first report to demonstrate the oncogenic role of eIF4G1 in AML. Our results reveal a mechanism whereby N-MYC drives a leukemic transcriptional program and provide a rationale for the therapeutic targeting of the N-MYC/eIF4G1 axis in myeloid leukemia.
Medieval social landscape through the genetic history of Cambridgeshire before and after the Black Death
Authors: Hui Ruoyun , Scheib Christiana L. , D’Atanasio Eugenia , Inskip Sarah A. , Cessford Craig , Biagini Simone A. , Wohns Anthony W. , Ali Muhammad Q.A. , Griffith Samuel J. , Solnik Anu , Niinemäe Helja , Ge Xiangyu Jack , Rose Alice K. , Beneker Owyn , O’Connell Tamsin C. , Robb John E. , Kivisild Toomas
Published: March 2023

The extent of the devastation of the Black Death pandemic (1346-53) on European populations is known from documentary sources and its bacterial source illuminated by studies of ancient pathogen DNA. What has remained less understood is the effect of the pandemic on human mobility and genetic diversity at local scale in the context of the social stratification of medieval communities. Here we study 275 newly reported ancient genomes from later medieval and post-medieval Cambridgeshire, from individuals buried before, during, and after the Black Death. The majority of individuals examined had local genetic ancestries. Consistent with the function of the institutions, we found a lack of close relatives among the friars and the inmates of the hospital in contrast to their abundance in general urban and rural parish communities. Accounting for the genetic component for height accentuates the disparities between social groups in stature estimated from long bones, as a proxy for health and the quality of life. While we detect long-term shifts in local genetic ancestry in Cambridgeshire that either pre- or postdate the Black Death, we find no evidence of major changes in genetic ancestry nor, in contrast to recent claims, higher differentiation of immune loci between cohorts living before and after the Black Death.
Prognostic Significance of Different Ventricular Ectopic Burdens During Exercise in Asymptomatic UK Biobank Subjects
Authors: van Duijvenboden Stefan , Ramírez Julia , Orini Michele , Doherty Aiden , Tinker Andrew , Munroe Patricia B. , Lambiase Pier D.
Published: March 2023

Background and Aims

The consequences of exercise-induced premature ventricular contractions (PVCs) in asymptomatic individuals remain unclear. This study aimed to assess the association between PVC burdens during stress testing and major adverse cardiovascular events (MACE; myocardial infarction (MI), life-threatening ventricular arrhythmia (LTVA), and heart failure (HF)), and all-cause mortality. Additional end-points were: MI, LTVA, HF and cardiovascular mortality.

Methods

A neural network was developed to count PVCs from ECGs recorded during exercise (6 min) and recovery (1 min) in 48,502 asymptomatic participants from UK Biobank. Associations were estimated using multivariable Cox proportional hazard models.

Results

Mean age was 56.8 (+/-8.2 years); 51.1% were female, and median follow-up was 11.5 years. Low PVC counts during exercise and recovery were both associated with MACE risk, independently from clinical factors: adjusted hazard ratio [HR]: 1.2 (2-4 exercise PVCs, p = 0.022) and HR 1.2, (1 recovery PVC, p = 0.031). Risk increased with increasing PVC count: HR 1.8 (>25 exercise PVCs, p<0.001) and HR 1.5 (≥5 recovery PVCs, p < 0.001). A similar trend was observed for all-cause mortality, although associations were only significant for higher PVC burdens: HRs: 1.4 (11-25 exercise PVCs, p = 0.007) and 1.5 (≥5 recovery PVCs, p < 0.001). Complex PVCs rhythms were associated with higher risk compared to PVC count alone. PVCs were also strongly associated with incident HF, LTVA, and cardiovascular mortality, but not MI.

Conclusion

PVC count during exercise and recovery are both associated with MACE, all-cause mortality, HF, LTVAs and cardiovascular mortality, independent of clinical and exercise stress test factors, indicating a “dose response” between PVC count and risk. Complex PVCs rhythms are associated with higher risk compared to PVC count alone.
BrcaDx: Precise identification of breast cancer from expression data using a minimal set of features
Authors: Muthamilselvan Sangeetha , Palaniappan Ashok
Published: March 2023

Background

Breast cancer is the foremost cancer in worldwide incidence, surpassing lung cancer notwithstanding the gender bias. One in four cancer cases among women are attributable to cancers of the breast, which are also the leading cause of death in women. Reliable options for early detection of breast cancer are needed.

Methods

Using public-domain datasets, we screened transcriptomic profiles of breast cancer samples, and identified progression-significant linear and ordinal model genes using stage-informed models. We then applied a sequence of machine learning techniques, namely feature selection, principal components analysis, and k-means clustering, to train a learner to discriminate ‘cancer’ from ‘normal’ based on expression levels of identified biomarkers.

Results

Our computational pipeline yielded an optimal set of nine biomarker features for training the learner, namely NEK2, PKMYT1, MMP11, CPA1, COL10A1, HSD17B13, CA4, MYOC, and LYVE1. Validation of the learned model on an internal testset yielded a performance of 99.5% accuracy. Blind validation on an external dataset yielded a balanced accuracy of 95.5%, demonstrating that the model has effectively reduced the dimensionality of the problem, and learnt the solution. The model was rebuilt using the full dataset, and then deployed as a web app for non-profit purposes at:https://apalania.shinyapps.io/brcadx/. To our knowledge, this is the best-performing freely available tool for the high-confidence diagnosis of breast cancer, and represents a promising aid to medical diagnosis.
Testing the neural noise account: an investigation of visual temporal precision in Tourette syndrome
Authors: Slack Hannah R. , Jackson Georgina M. , Jackson Stephen R.
Published: March 2023

Tourette syndrome (TS) is a neurological disorder of childhood onset characterised by the occurrence of vocal and motor tics. The pathophysiology of TS has been linked to dysfunction within cortical-striatal-thalamic-cortical (CSTC) brain circuits and alterations in gamma-aminobutyric acid (GABA) signalling within the striatum. Recently, it has been proposed that increased neural noise, leading to decreased signal-to-noise, may be responsible for dysfunctional information processing in TS. Importantly, increased neural noise could impact all stages of the sensorimotor processing, including sensation, action planning, and action execution, and it currently remains to be determined whether this ‘increased neural noise account’ of TS refers to all aspects of information processing, or is specific to particular stages of information processing. We hypothesised that if TS was associated with decreased signal-to-noise when processing visual stimuli, then this might be reflected in a reduction in the precision of their perceptual timing estimates. To examine this, we investigated the precision of perceptual timing in a group of individuals with tic disorder using a visual temporal-order-judgement (TOJ) task.
Association of NOTCH3 with Elastic Fiber Dispersion in the Infrarenal Abdominal Aorta of Cynomolgus Monkeys
Authors: Ito Sohei , Amioka Naofumi , Franklin Michael K. , Wang Pengjun , Liang Ching-Ling , Katsumata Yuriko , Cai Lei , Temel Ryan E. , Daugherty Alan , Lu Hong S. , Sawada Hisashi
Published: March 2023

Background

The regional heterogeneity of vascular components and transcriptomes is an important determinant of aortic biology. This notion has been explored in multiple mouse studies. In the present study, we examined the regional heterogeneity of aortas in non-human primates.

Methods

Aortic samples were harvested from the ascending, descending, suprarenal, and infrarenal regions of young control monkeys and adult monkeys provided with high fructose for 3 years. The regional heterogeneity of aortic structure and transcriptomes was examined by histological and bulk RNA sequencing analyses.

Results

Immunostaining of CD31 and αSMA revealed that endothelial and smooth muscle cells were distributed homogeneously across the aortic regions. In contrast, elastic fibers were less abundant and dispersed in the infrarenal aorta compared to other regions and associated with collagen deposition. Bulk RNA sequencing identified a distinct transcriptome related to the Notch signaling pathway in the infrarenal aorta with significantly increasedNOTCH3mRNA compared to other regions. Immunostaining revealed that NOTCH3 protein was increased in the media of the infrarenal aorta. The abundance of medial NOTCH3 was positively correlated with the dispersion of elastic fibers. Adult cynomolgus monkeys provided with high fructose displayed vascular wall remodeling, such as smooth muscle cell loss and elastic fiber disruption, predominantly in the infrarenal region. The correlation between NOTCH3 and elastic fiber dispersion was enhanced in these monkeys.

Conclusions

Aortas of young cynomolgus monkeys display regional heterogeneity of their transcriptome and the structure of elastin and collagens. Elastic fibers in the infrarenal aorta are dispersed along with upregulation of medial NOTCH3.

HIGHLIGHTS

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The present study determined the regional heterogeneity of aortas from cynomolgus monkeys.

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Aortas of young cynomolgus monkeys displayed region-specific aortic structure and transcriptomes.

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Elastic fibers were dispersed in the infrarenal aorta along with increased NOTCH3 abundance in the media.

GRAPHIC ABSTRACT
Optimization of somatic embryogenesis inEuterpe edulisMartius using auxin analogs and atomic force microscopy
Authors: de Mello Tamyris , Taliuli Yanara dos Santos , Silva Tatiane Dulcineia , Zanardo Tadeu Ériton Caliman , Hegedus Clovis Eduardo Nunes , Anjos Breno Benvindo dos , Schmildt Edilson Romais , Ferreira Adésio , Lourenço Maicon Pierre , Pinheiro Patricia Fontes , Aquije Glória Maria de Farias Viégas , Lopes José Carlos , Otoni Wagner Campos , Alexandre Rodrigo Sobreira
Published: March 2023

Euterpe edulisMartius is an endangered species of the Atlantic Forest, whose fruits have high antioxidant potential, and propagated exclusively by seeds. The present study assessed the ability of different auxin inducers and picloram analogs to trigger somatic embryogenesis inE. edulis. Immature seeds were harvested, and their zygotic embryos were excised and grown in MS culture medium supplemented with 2,4-D dichlorophenoxyacetic acid (2,4-D) or picloram at 150, 300, 450, 600 µM. The activity of picloram analogs triclopyr and clopyralid was evaluated in semisolid MS medium. At maturation and germination, picloram-derived calli and somatic embryos isolated from triclopyr-grown cultures were first transferred to pre-maturation medium and, after 30 days, to basal MS or MS medium supplemented with either 5 µM abscisic acid or 0.53 µM 1-naphthaleneacetic acid plus 12.3 µM 2-isopentenyladenine. Finally, somatic embryos with root protrusions were transferred to MS medium devoid of sucrose for 30 days and then acclimatized ex vitro. Scanning, transmission, and atomic force microscopy revealed that picloram was superior to 2,4-D but less effective than triclopyr (100 µM) in inducing embryogenesis. Maturation and germination of somatic embryos in E. edulis can be maximized by 5 µM abscisic acid, and selecting calli via atomic force microscopy.

Highlight

This work opens novel roads for embryogenic induction, using a new and more efficient inducer than the usual ones, and an innovative evaluation technique based on AFM.
Mutations in S2 subunit of SARS-CoV-2 Omicron spike strongly influence its conformation, fusogenicity and neutralization sensitivity
Authors: Kumar Sahil , Delipan Rathina , Chakraborty Debajyoti , Kanjo Kawkab , Singh Randhir , Singh Nittu , Siddiqui Samreen , Tyagi Akansha , Jha Sujeet , Thakur Krishan G. , Pandey Rajesh , Varadarajan Raghavan , Ringe Rajesh P.
Published: March 2023

SARS-CoV-2 has remarkable ability to respond to and evolve against the selection pressure by host immunity exemplified by emergence of Omicron lineage. Here, we characterized the functional significance of mutations in Omicron spike. By systematic transfer of mutations in WT spike we assessed neutralization sensitivity, fusogenicity, and TMPRSS2-dependence for entry. The data revealed that the mutations in both S1 and S2 complement to make Omicron highly resistant. Strikingly, the mutations in Omicron S2 modulated the neutralization sensitivity to NTD- and RBD-antibodies, but not to S2 specific neutralizing antibodies, suggesting that the mutations in S2 were primarily acquired to gain resistance to S1-antibodies. Although all six mutations in S2 appeared to act in concert, D796Y showed greatest impact on neutralization sensitivity and rendered WT virus >100-fold resistant to S309, COVA2-17, and 4A8. S2 mutations greatly reduced the antigenicity for NAbs due to reduced exposure of epitopes. In terms of the entry pathway, S1 or S2 mutations only partially altered the entry phenotype of WT and required both sets of mutations for complete switch to endosomal route and loss of syncytia formation. In particular, N856K and L981F in Omicron reduced fusion capacity and explain why subsequent Omicron variants lost them to regain fusogenicity.
Seagrass genomes reveal a hexaploid ancestry facilitating adaptation to the marine environment
Authors: Ma Xiao , Vanneste Steffen , Chang Jiyang , Ambrosino Luca , Barry Kerrie , Bayer Till , Bobrov Alexander A. , Boston LoriBeth , Campbell Justin E , Chen Hengchi , Chiusano Maria Luisa , Dattolo Emanuela , Grimwood Jane , He Guifen , Jenkins Jerry , Khachaturyan Marina , Marín-Guirao Lázaro , Mesterházy Attila , Muhd Danish-Daniel , Pazzaglia Jessica , Plott Chris , Rajasekar Shanmugam , Rombauts Stephane , Ruocco Miriam , Scott Alison , Tan Min Pau , Van de Velde Jozefien , Vanholme Bartel , Webber Jenell , Wong Li Lian , Yan Mi , Sung Yeong Yik , Novikova Polina , Schmutz Jeremy , Reusch Thorsten , Procaccini Gabriele , Olsen Jeanine , Van de Peer Yves
Published: March 2023

Seagrasses comprise the only submerged marine angiosperms, a feat of adaptation from three independent freshwater lineages within the Alismatales. These three parallel lineages offer the unique opportunity to study convergent versus lineage-specific adaptation to a fully marine lifestyle. Here, we present chromosome-level genome assemblies from a representative species of each of the seagrass lineages -Posidonia oceanica(Posidoniaceae),Cymodocea nodosa(Cymodoceaceae), andThalassia testudinum(Hydrocharitaceae)-along with an improved assembly forZostera marina(Zosteraceae). We also include a draft genome ofPotamogeton acutifolius, a representative of Potamogetonaceae, the freshwater sister lineage to the Zosteraceae. Genome analysis reveals that all seagrasses share an ancient whole genome triplication (WGT) event, dating to the early evolution of the Alismatales. An additional whole genome duplication (WGD) event was uncovered forC. nodosaandP. acutifolius. Dating of ancient WGDs and more recent bursts of transposable elements correlate well with major geological and recent climatic events, supporting their role as rapid generators of genetic variation. Comparative analysis of selected gene families suggests that the transition from the submerged-freshwater to submerged-marine environment did not require revolutionary changes. Major gene losses related to, e.g., stomata, volatiles, defense, and lignification, are likely a consequence of the submerged lifestyle rather than the cause (‘use it or lose it’). Likewise, genes, often retained from the WGD and WGT, were co-opted for functions requiring the alignment of many small adaptations (‘tweaking’), e.g., osmoregulation, salinity, light capture, carbon acquisition, and temperature. Our ability to manage and conserve seagrass ecosystems depends on our understanding of the fundamental processes underpinning their resilience. These new genomes will accelerate functional studies and are expected to contribute to transformative solutions — as continuing worldwide losses of the ‘savannas of the sea’ are of major concern in times of climate change and loss of biodiversity.
FARL-11 (STRIP1/2) is Required for Sarcomere and Sarcoplasmic Reticulum Organization inC. elegans
Authors: Martin Sterling C.T. , Qadota Hiroshi , Oberhauser Andres F. , Hardin Jeff , Benian Guy M.
Published: March 2023

Protein phosphatase 2A (PP2A) functions in a variety of cellular contexts. PP2A can assemble into four different complexes based on the inclusion of different regulatory or targeting subunits. The B’’’ regulatory subunit “striatin” forms the STRIPAK complex consisting of striatin, a catalytic subunit (PP2AC), striatin interacting protein 1 (STRIP1), and MOB family member 4 (MOB4). In yeast andC. elegans,STRIP1 is required for formation of the endoplasmic reticulum (ER). Since the sarcoplasmic reticulum (SR) is the highly organized muscle-specific version of ER, we sought to determine the function of the STRIPAK complex in muscle usingC. elegans. CASH-1 (striatin) and FARL-11 (STRIP1/2) form a complexin vivo, and each protein is localized to SR. Missense mutations and single amino acid losses infarl-11andcash-1each result in similar sarcomere disorganization. A missense mutation infarl-11shows no detectable FARL-11 protein by immunoblot, disruption of SR organization around M-lines, and altered levels of the SR Ca+2release channel UNC-68.

Protein phosphatase 2A forms a STRIPAK complex when it includes the targeting B’’’ subunit “striatin” and STRIP1. STRIP1 is required for formation of ER. We show that in muscle STRIP1 is required for organization of SR and sarcomeres.
Massively parallel characterization of transcriptional regulatory elements in three diverse human cell types
Authors: Agarwal Vikram , Inoue Fumitaka , Schubach Max , Martin Beth K. , Dash Pyaree Mohan , Zhang Zicong , Sohota Ajuni , Noble William Stafford , Yardimci Galip Gürkan , Kircher Martin , Shendure Jay , Ahituv Nadav
Published: March 2023

The human genome contains millions of candidatecis-regulatory elements (CREs) with cell-type-specific activities that shape both health and myriad disease states. However, we lack a functional understanding of the sequence features that control the activity and cell-type-specific features of these CREs. Here, we used lentivirus-based massively parallel reporter assays (lentiMPRAs) to test the regulatory activity of over 680,000 sequences, representing a nearly comprehensive set of all annotated CREs among three cell types (HepG2, K562, and WTC11), finding 41.7% to be functional. By testing sequences in both orientations, we find promoters to have significant strand orientation effects. We also observe that their 200 nucleotide cores function as non-cell-type-specific ‘on switches’ providing similar expression levels to their associated gene. In contrast, enhancers have weaker orientation effects, but increased tissue-specific characteristics. Utilizing our lentiMPRA data, we develop sequence-based models to predict CRE function with high accuracy and delineate regulatory motifs. Testing an additional lentiMPRA library encompassing 60,000 CREs in all three cell types, we further identified factors that determine cell-type specificity. Collectively, our work provides an exhaustive catalog of functional CREs in three widely used cell lines, and showcases how large-scale functional measurements can be used to dissect regulatory grammar.
Split-Transformer Impute (STI): A Transformer Framework for Genotype Imputation
Authors: Mowlaei Mohammad Erfan , Li Chong , Jamialahmadi Oveis , Dias Raquel , Chen Junjie , Jamialahmadi Benyamin , Rebbeck Timothy Richard , Carnevale Vincenzo , Kumar Sudhir , Shi Xinghua
Published: March 2023

Motivation

Despite recent advances in sequencing technologies, genome-scale datasets continue to have missing bases and genomic segments. Such incomplete datasets can undermine downstream analyses, such as disease risk prediction and association studies. Consequently, the imputation of missing information is a common pre-processing step for which many methodologies have been developed. However, the imputation of genotypes of certain genomic regions and variants, including large structural variants, remains a challenging problem.

Results

Here, we present a transformer-based deep learning framework, called a split-transformer impute (STI) model, for accurate genome-scale genotype imputation. Empowered by the attention-based transformer model, STI can be trained for any collection of genomes automatically using self-supervision. STI handles multi-allelic genotypes naturally, unlike other models that need special treatments. STI models automatically learned genome-wide patterns of linkage disequilibrium (LD), evidenced by much higher imputation accuracy in high LD regions. Also, STI models trained through sporadic masking for self-supervision performed well in imputing systematically missing information. Our imputation results on the human 1000 Genomes Project show that STI can achieve high imputation accuracy, comparable to the state-of-the-art genotype imputation methods, with the additional capability to impute multi-allelic structural variants and other types of genetic variants. Moreover, STI showed excellent performance without needing any special presuppositions about the patterns in the underlying data when applied to a collection of yeast genomes, pointing to easy adaptability and application of STI to impute missing genotypes in any species.
Biological representation disentanglement of single-cell data
Authors: Piran Zoe , Cohen Niv , Hoshen Yedid , Nitzan Mor
Published: March 2023

Due to its internal state or external environment, a cell’s gene expression profile contains multiple signatures, simultaneously encoding information about its characteristics. Disentangling these factors of variations from single-cell data is needed to recover multiple layers of biological information and extract insight into the individual and collective behavior of cellular populations. While several recent methods were suggested for biological disentanglement, each has its limitations; they are either task-specific, cannot capture inherent nonlinear or interaction effects, cannot integrate layers of experimental data, or do not provide a general reconstruction procedure. We presentbiolord, a deep generative framework for disentangling known and unknown attributes in single-cell data. Biolord exposes the distinct effects of different biological processes or tissue structure on cellular gene expression. Based on that, biolord allows generating experimentally-inaccessible cell states by virtually shifting cells across time, space, and biological states. Specifically, we showcase accurate predictions of cellular responses to drug perturbations and generalization to predict responses to unseen drugs. Further, biolord disentangles spatial, temporal, and infection-related attributes and their associated gene expression signatures in a single-cell atlas ofPlasmodiuminfection progression in the mouse liver. Biolord can handle partially labeled attributes by predicting a classification for missing labels, and hence can be used to computationally extend an infected hepatocyte population identified at a late stage of the infection to earlier stages. Biolord applies to diverse biological settings, is implemented using the scvi-tools library, and is released as open-source software athttps://github.com/nitzanlab/biolord.
Evaluating Effects of Resting-State Electroencephalography Data Pre-Processing on a Machine Learning Task for Parkinson’s Disease
Authors: Vlieger Robin , Daskalaki Elena , Apthorp Deborah , Lueck Christian J. , Suominen Hanna
Published: March 2023

Resting-state electroencephalography (RSEEG) is a method under consideration as a potential biomarker that could support early and accurate diagnosis of Parkinson’s disease (PD). RSEEG data is often contaminated by signals arising from other electrophysiological sources and the environment, necessitating pre-processing of the data prior to applying machine learning methods for classification. Importantly, using differing degrees of pre-processing will lead to different classification results. This study aimed to examine this by evaluating the difference in experimental results when using re-referenced data, data that had undergone filtering and artefact rejection, and data without muscle artefact. The results demonstrated that, using a Random Forest Classifier for feature selection and a Support Vector Machine for disease classification, different levels of pre-processing led to markedly different classification results. In particular, the presence of muscle artefact was associated with inflated classification accuracy, emphasising the importance of its removal as part of pre-processing.
Association of magnesium depletion score with cardiovascular disease and its association with longitudinal mortality in cardiovascular disease patients
Authors: Ye Liu , Zhang Cheng , Duan Qin , Shao Yue , Zhou Jianzhong
Published: March 2023

Background

Dietary magnesium and serum magnesium play an important part in cardiovascular disease (CVD). However, the correlation between magnesium depletion score (MDS) and the development and CVD prognosis remains unclear. This analysis examines the cross-sectional relationship between MDS and CVD, and the longitudinal correlation between MDS and all-cause and cardiovascular mortality in CVD individuals.

Methods

In all, 42,711 individuals were selected from the National Health and Nutrition Examination Survey, including 5,015 subjects with CVD. The correlation between MDS and total and individual CVD was examined using the survey-weighted multiple logistic regression analysis. Among 5,011 CVD patients, 2,285 and 927 participants were recorded with all-cause and cardiovascular deaths, respectively. We applied survey-weighted Cox proportional hazards regression analyses to investigate the impact of MDS on the mortality of CVD individuals.

Results

CVD group had higher MDS levels than the non-CVD groups. After controlling all confounding factors, individuals with MDS scored 1-2, and ≥3 had higher odds of total CVD and specific CVD than those with MDS scored 0. The relationship between MDS and total CVD was stable and significant in all subgroups. The fully adjusted Cox regression model presented that the risk of all-cause and cardiovascular deaths increased 2.41 and 2.00 times in participants with MDS≥3 compared to those with MDS scored 0.

Conclusions

MDS is a vital risk factor for CVD’s prevalence and all-cause and cardiovascular deaths.

What is new?

MDS is a significant positive correlation with CVD’s prevalence in US adults.

High MDS markedly elevated the risk of all-cause and cardiovascular deaths among participants with CVD.

What are the clinical implications?

MDS can be used to evaluate the prevention and prognosis of cardiovascular diseases.
Prevalence of overweight and its associated factors among Malaysian adults: findings from a nationally representative survey
Authors: Tat Chong Chean , Kent Lai Wai , Sallehuddin Syafinaz Mohd , Ganapathy Shubash Shander
Published: March 2023

The World Health Organization has reported that the prevalence of overweight is a growing problem in many countries, including middle- and lower-income countries like Malaysia. This study aimed to determine the prevalence of overweight and its associated factors among Malaysian adults. A total of 9782 Malaysian adults aged 18 and above were included in this study, representing states and federal territories from the National Health and Morbidity Survey 2019. Sociodemographic data (sex, locality, age, marital status, ethnicity, educational level, income level, and health literacy), non-communicable disease status (hypertension, diabetes, and hypercholesterolemia), and lifestyle behaviours (physical activity level, smoking status, and also fruit and vegetable consumption) were collected and analysed to identify factors associated with overweight. The study found that the prevalence of overweight among Malaysian adults was 50.1%. Multivariate analyses showed that several factors, including female gender, ages 30-59 years, being Malay, Indian or other Bumiputeras, being married, and having adequate health literacy, were significantly associated with an increased risk of overweight. Additionally, overweight individuals had a significantly higher risk of non-communicable diseases such as diabetes and hypertension. The study suggests that intervention programs should be implemented in an equitable and cost-effective manner to target these high-risk populations and address the burden of overweight in Malaysia.
Mind the viscous modulus: The mechanotransductive response to the viscous nature of isoelastic matrices regulates stem cell chondrogenesis
Authors: Walker Matthew , Pringle Eonan William , Ciccone Giuseppe , Tassieri Manlio , Gourdon Delphine , Cantini Marco
Published: March 2023

The design of hydrogels as mimetics of tissues’ matrices typically disregards the viscous nature of native tissues and focuses only on their elastic properties. In the case of stem cell chondrogenesis, this has led to contradictory results, likely due to unreported changes of the matrices’ viscous modulus. Here, by employing isoelastic matrices with a Young’s modulus of ~12 kPa, we demonstrate that variations in viscous properties alone (i.e., loss tangent between 0.1-0.25) are sufficient to drive efficient growth factor-free chondrogenesis of human mesenchymal stem cells, both in 2D and 3D cultures. The increase of the viscous component of RGD-functionalised polyacrylamide or polyethylene glycol maleimide hydrogels promotes a phenotype with reduced adhesion, alters mechanosensitive signalling, and boosts cell-cell contacts. In turn, this upregulates the chondrogenic transcription factor SOX9 and supports neocartilage formation, demonstrating that the mechanotransductive response to the viscous nature of the matrix can be harnessed to direct cell fate.
Water chlorination increases the relative abundance of an antibiotic resistance marker in developing sourdough starters
Authors: Lau Pearson , Jain Swapan , Perron Gabriel G.
Published: March 2023

Multiple factors explain the proper development of sourdough starters. While the role of raw ingredients and geography, among other things, have been widely studied recently, the possible effect of water chlorination on the overall bacterial communities associated with sourdough remains to be explored. Here, using16s rRNAamplicon sequencing, we show that water chlorination at levels commonly found in drinking water systems has a limited impact on the overall bacterial communities developing in sourdough starters. However, using targeted sequencing, we found that the abundance of integron 1, a genetic mechanism responsible for the horizontal exchange of antibiotic resistance genes in spoilage and pathogenic bacteria, increased significantly with the level of water chlorination. While our results suggest that water chlorination might not impact sourdough starters at a deep phylogenetic level, they indicate that it can favor the growth of key spoilage bacteria.
Stuck in the weeds: Invasive grasses reduce tiger snake movement
Authors: Cornelis Jari , Cooper Christine E , Lettoof Damian C , Mayer Martin , Marshall Benjamin M
Published: March 2023

Wetlands are particularly vulnerable to degradation in urban environments, partially due to the introduction of non-native plants. Invasive weeds in wetlands can replace native plants leading to alterations in habitat composition and vegetation, in turn, animal movements and ultimately population dynamics might be affected. Here we investigate how home range size and movements of western tiger snakes (Notechis scutatus occidentalis) differ in wetlands dominated by invasive kikuyu grass (Cenchrus clandestinus) compared to wetlands dominated by native vegetation to understand if and how the movement ecology of this top-order predator is altered by vegetation homogenization. To do so, we used Autocorrelated Kernel Density Estimators (AKDE) to estimate home range size, dynamic Brownian Bridge Movement Models to document movement trajectory confidence areas, and compared movement distances using a Bayesian regression model. Home range sizes by tiger snakes were 14.59 ± 9.35 ha smaller in areas dominated by invasive versus native vegetation. Moreover, within-day movement distances tended to be smaller in areas dominated by invasive versus native vegetation (mean ± SD: 9 ± 3 m versus 18 ± 6 m), but there was considerable overlap between the 95% credible intervals between these two groups. Smaller home ranges by tiger snakes in areas dominated by invasive kikuyu grass were likely driven by thermoregulation, with snakes moving vertically between basking locations on top of kikuyu and shelter sites at the base, rather than travelling horizontally along the ground to open basking areas in sites dominated by native vegetation. Additionally, fragmentation of sites dominated by invasive vegetation might have contributed to the comparatively smaller home ranges of snakes there. These findings add to our understanding how changes in habitat composition driven by invasive vegetation can affect animal space use and emphasise the need for further studies to understand how these changes affect population dynamics.
Efficient clathrin-mediated entry of enteric adenoviruses in human duodenal cells
Authors: Becker Miriam , Dorma Noemi , Conca Dario Valter , Mistry Nitesh , Bally Marta , Arnberg Niklas , Gerold Gisa
Published: March 2023

Enteric adenovirus types F40 and 41 (EAdVs) are a leading cause of diarrhea and diarrhea-associated death in young children and have recently been proposed to cause acute hepatitis in children. Unlike other adenoviruses, EAdVs exhibit hitherto a strict tropism for gastrointestinal tissues with, to date, unknown infection mechanism and target cells. In this study, we turn to potentially limiting host factors by comparison of EAdV entry in cell lines with respiratory and intestinal origin by cellular perturbation, virus particle tracking and transmission electron microscopy. Our analyses highlight kinetic advantages in duodenal HuTu80 cell infection and reveal a larger fraction of mobile particles, faster virus uptake and infectious particle entry in intestinal cells. Moreover, EAdVs display a dependence on clathrin- and dynamin-dependent pathways in intestinal cells. Detailed knowledge of virus entry routes and host factor requirements is essential to understand pathogenesis and develop new countermeasures. Hence, this study provides novel insights into the entry mechanisms of a medically important virus with emerging tropism in a physiologically relevant cell line.

Author Summary

Enteric adenoviruses have historically been difficult to grow in cell culture, which resulted in lack of knowledge of host factors and pathways required for infection of these medically relevant viruses. Previous studies in non-intestinal cell lines showed slow infection kinetics and generated comparatively low virus yields compared to other adenovirus types. We suggest duodenum derived HuTu80 cells as a superior cell line for studies to complement efforts using complex intestinal tissue models. We show that viral host cell factors required for virus entry differ between cell lines from distinct origins and demonstrate the importance of clathrin-mediated endocytosis.
The minimal intrinsic stochasticity of constitutively expressed eukaryotic genes is sub-Poissonian
Authors: Weidemann Douglas E. , Singh Abhyudai , Grima Ramon , Hauf Silke
Published: March 2023

Stochastic variation in gene products (“noise”) is an inescapable by-product of gene expression. Noise must be minimized to allow for the reliable execution of cellular functions. However, noise cannot be suppressed beyond an intrinsic lower limit. For constitutively expressed genes, this limit is believed to be Poissonian, meaning that the variance in mRNA numbers cannot be lower than their mean. Here, we show that several cell division genes in fission yeast have mRNA variances significantly below this limit, which cannot be explained by the classical gene expression model for low-noise genes. Our analysis reveals that multiple steps in both transcription and mRNA degradation are essential to explain this sub-Poissonian variance. The sub-Poissonian regime differs qualitatively from previously characterized noise regimes, a hallmark being that cytoplasmic noise is reduced when the mRNA export rate increases. Our study re-defines the lower limit of eukaryotic gene expression noise and identifies molecular requirements for ultra-low noise which are expected to support essential cell functions.
The role of size in biostability of DNA tetrahedra
Authors: Vilcapoma Javier , Patel Akul , Chandrasekaran Arun Richard , Halvorsen Ken
Published: March 2023

The potential for using DNA nanostructures for drug delivery applications requires understanding and ideally tuning their biostability. Here we investigate how biological degradation varies with size of a DNA nanostructure. We designed DNA tetrahedra of three edge lengths ranging from 13 to 20 bp and analyzed nuclease resistance for two nucleases and biostability in fetal bovine serum. We found that DNase I had similar digestion rates across sizes but appeared to incompletely digest the smallest tetrahedron, while T5 exonuclease was notably slower to digest the largest tetrahedron. In fetal bovine serum, the 20 bp tetrahedron was degraded ~four times faster than the 13 bp. These results show that DNA nanostructure size can influence nuclease degradation, but suggest a complex relationship that is nuclease specific.
Tat-fimbriae (“tafi”) – novel type of haloarchaeal surface structures
Authors: Galeva Anna V. , Syutkin Alexey S. , Zhao Dahe , Kireev Igor I. , Surin Alexey K. , Pavlova Elena Yu. , Liu Jingfang , Xiang Hua , Pyatibratov Mikhail G.
Published: March 2023

In present study, we describe “tat-fimbriae (tafi)” – a novel type of archaeal surface appendages isolated from haloarchaeonHaloarcula hispanica. Thesefilamental structures are unique because they are formed of protein subunits secreted through thetwin-arginine translocation pathway (Tat-pathway), in contrast to well-known archaeal surface filamentous structures secreted by the general secretory pathway (Sec-pathway). No cases of the role of Tat-pathway in the assembly of archaeal and bacterial filamentous structures have been described to date. “Tafi” are the first example of such structures. The precursor of the major tafi protein subunit TafA contains the N-terminal signal peptide carrying a twin-arginine consensus motif and fimbria-forming mature TafA lacks this signal peptide. We analyzed the gene neighborhood of thetafAhomologues in the known haloarchaeal genomes and found a conservative cluster of seven associated genestafA, B, C, D, E, F, G. We assume that all of them take part in the tafi synthesis. TafC and TafE proteins, whose precursor sequences also contain twin-arginine motifs, were detected as minor components of tafi. TafE protein is structurally similar to TafA, while TafC contains a TafA-like N-terminal domain and a C-terminal “laminin G-like” domain capable of functioning as an adhesin. TafD is annotated as a signal peptidase I. The functions of TafB, TafF and TafG are not known yet. This study demonstrated that ΔtafAand ΔtafDdeletion mutant strains synthesized archaella and not tafi, and only tafi were detected in ΔarlK(gene of common archaellin/pilin signal peptidase) deletion strain. It was shown that the expression of completeHar. hispanica taf-gene cluster in a heterologous hostHaloferax volcaniithat does not have similar genes leads to synthesis of recombinant tafi structures similar to the native ones. The tafi function remains elusive, but our preliminary data suggest that these structures may be involved in cell adhesion to different surfaces or substrates.