bluuebunny/crossref_metadata_2025_split huggingface dataset:
White matter microstructural abnormality precedes cortical volumetric decline in Alzheimer’s disease: evidence from data-driven disease progression modelling
Authors: Parker CS , Weston PSJ , Zhang H , Oxtoby NP ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: July 2022

AbstractSequencing the regional progression of neurodegeneration in Alzheimer’s disease (AD) informs disease mechanisms and facilitates identification and staging of individuals at greatest risk of imminent cognitive decline, which may aid the development of early therapeutic interventions. Previous attempts to sequence neurodegeneration have analysed measures of regional volume and identified the initial sites of atrophy. However, focal microstructural alterations in white matter have also been reported in early AD. Yet, the temporal ordering of abnormality in measures of white matter microstructure relative to grey matter volume has not been established. In this study we used event-based modelling of disease progression (EBM) to provide a data-driven evaluation of the temporal sequence of abnormality in markers of white matter microstructure relative to grey matter volume. Regional microstructural metrics derived from diffusion tensor imaging (DTI) and regional volumes from Freesurfer cortical parcellation were obtained from the Alzheimer’s disease Neuroimaging Initiative (ADNI) database for 441 amyloid-positive participants (81 AD-dementia, 159 mild cognitive impairment, 201 cognitively normal). The estimated sequence shows a series of abnormalities in markers of white matter microstructure, followed by sequential grey matter volumetric decline, with no overlap between the two. Analysis of positional variance and cross-validation supports the robustness of our findings. These results provide the first data-driven evidence that markers of white matter microstructural degeneration precede those of cortical volumetric decline in the AD cascade. This prompts a re-evaluation of the view that regional volumetric decline can be used to characterise the very earliest stages of AD neurodegeneration. Instead, we suggest that white matter microstructural markers provide an earlier window into AD neurodegeneration. An early staging system of AD neurodegeneration based on measures of brain microstructure may find application in selecting AD subjects with early but minimal brain damage for clinical trials that aim to prevent cognitive decline.
Integrative genome-scale analyses reveal post-transcriptional signatures of early human small intestinal development in a directed differentiation organoid model
Authors: Hung Yu-Han , Capeling Meghan , Villanueva Jonathan W. , Kanke Matt , Shanahan Michael T. , Huang Sha , Cubitt Rebecca L. , Rinaldi Vera D. , Schimenti John C. , Spence Jason R. , Sethupathy Praveen 
Published: July 2022

AbstractMicroRNAs (miRNAs) are important post-transcriptional gene regulators in organ development. To explore candidate roles for miRNAs in prenatal SI lineage specification in humans, we used a multi-omic analysis strategy in a directed differentiation model that programs human pluripotent stem cells toward the SI lineage. We leveraged small RNA-seq to define the changing miRNA landscape, and integrated chromatin run-on sequencing (ChRO-seq) and RNA-seq to define genes subject to significant post-transcriptional regulation across the different stages of differentiation. Our analyses showed that the elevation of miR-182 and reduction of miR-375 are key events during SI lineage specification. We demonstrated that loss of miR-182 leads to an increase in the foregut marker SOX2. We also used single-cell analyses in murine adult intestinal crypts to support a life-long role for miR-375 in the regulation of Zfp36l2. Finally, we uncovered opposing roles of SMAD4 and WNT signaling in regulating miR-375 expression during SI lineage specification. Beyond the mechanisms highlighted in this study, we also present a web-based application for exploration of post-transcriptional regulation and miRNA-mediated control in the context of early human SI development.Graphical Abstract
School-going learners are more likely to access HIV and contraceptive care at locations with friendly providers, Wi-Fi and other value-added services: Findings from a discrete choice experiment among learners in Gauteng, South Africa
Authors: Govathson Caroline , Long Lawrence , Moolla Aneesa , Mngadi-Ncube Sithabile , Ngcobo Nkosinathi , Mongwenyana Constance , Lince-Deroche Naomi , Pascoe Sophie 
Published: July 2022

AbstractBackgroundMany Adolescents in Sub-Saharan Africa don’t access HIV and reproductive health services optimally. To improve uptake of these services, it is important to understand the students’ preferences for how services are delivered so that implementation strategies can reflect this.MethodsA discrete choice experiment (DCE) was used to elicit preferences. The DCE was conducted in 10 high schools situated in neighbourhoods of varying socio-economic status (SES) in Gauteng (South Africa). Students aged ≥15 years (Grades 9-12) were consented and enrolled in the DCE. Conditional logistic regression was used to determine preferred attributes for HIV and contraceptive service delivery. Results were stratified by gender and neighbourhood SES quintile. (1=Lowest SES; 5=Highest SES).ResultsThe DCE was completed between 07/2018-09/2019; 805 students were enrolled (67% female; 66% 15-17 years; 51% in grades 9-10). 54% of students in quintile 1 schools had no monthly income; 38% in quintile 5 schools had access to USD7 per month. Preferences were similar for male and female students. Students strongly preferred services provided by friendly, non-judgmental staff (Odds ratio 1.63; 95% Confidence Interval: 1.55-1.72) where confidentiality was ensured (1.33; 1.26-1.40). They preferred services offered after school (1.14; 1.04-1.25) with value-added services like free Wi-Fi (1.19; 1.07-1.32), food (1.23; 1.11-1.37) and youth-only waiting areas (1.18; 1.07-1.32). Students did not have a specific location preference, but preferred not to receive services within the community (0.82; 0.74-0.91) or school (0.88; 0.80-0.96). Students attending schools in high SES neighbourhoods expressed a preference for private care (1.15; 0.98-1.35). Costs to access services were a deterrent for most students irrespective of school neighbourhood; female students were deterred by costs ≥USD3 (0.79; 0.70-0.91); males by costs ≥USD7 (0.86; 0.74-1.00)ConclusionsPreferences that encourage utilisation of services do not significantly differ by gender or school neighbourhood SES. Staff attitude and confidentiality are key issues affecting students’ decisions to access HIV and contraceptive services. Addressing how healthcare providers respond to young people seeking sexual and reproductive health services is critical for improving adolescents’ uptake of these services.
SARS-CoV-2 infections during Omicron (BA.1) dominant wave and subsequent population immunity in Gauteng, South Africa
Authors: Madhi Shabir A. , Kwatra Gaurav , Myers Jonathan E. , Jassat Waasila , Dhar Nisha , Mukendi Christian K. , Blumberg Lucille , Welch Richard , Izu Alane , Mutevedzi Portia C. 
Published: July 2022

ABSTRACTBackgroundThe B.1.1.529 (Omicron BA.1) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global resurgence of coronavirus disease 2019 (Covid-19). The contribution of BA.1 infection to population immunity and its effect on subsequent resurgence of B.1.1.529 sub-lineages warrant investigation.MethodsWe conducted an epidemiologic survey to determine the sero-prevalence of SARS-CoV-2 IgG from March 1 to April 11, 2022, after the BA.1-dominant wave had subsided in Gauteng (South Africa), and prior to a resurgence of Covid-19 dominated by the BA.4 and BA.5 (BA.4/BA.5) sub-lineages. Population-based sampling included households in an earlier survey from October 22 to December 9, 2021 preceding the BA.1 dominant wave. Dried-blood-spot samples were quantitatively tested for IgG against SARS-CoV-2 spike protein and nucleocapsid protein. Epidemiologic trends in Gauteng for cases, hospitalizations, recorded deaths, and excess deaths were evaluated from the inception of the pandemic to the onset of the BA.1 dominant wave (pre-BA.1), during the BA.1 dominant wave, and for the BA.4/BA.5 dominant wave through June 6, 2022.ResultsThe 7510 participants included 2420 with paired samples from the earlier survey. Despite only 26.7% (1995/7470) of individuals having received a Covid-19 vaccine, the overall sero-prevalence was 90.9% (95% confidence interval [CI], 90.2 to 91.5), including 89.5% in Covid-19 unvaccinated individuals. Sixty-four percent (95%CI, 61.8-65.9) of individuals with paired samples had serological evidence of SARS-CoV-2 infection during the BA.1 dominant wave. Of all cumulative recorded hospitalisations and deaths, 14.1% and 5.9% were contributed by the BA.1 dominant wave, and 5.1% and 1.6% by the BA.4/BA.5 dominant wave. The SARS-CoV-2 infection fatality risk was lower in the BA.1 compared with pre-BA.1 waves for recorded deaths (0.02% vs. 0.33%) and Covid-19 attributable deaths based on excess mortality estimates (0.03% vs. 0.67%).ConclusionsGauteng province experienced high levels of infections in the BA.1 -dominant wave against a backdrop of high (73%) sero-prevalence. Covid-19 hospitalizations and deaths were further decoupled from infections during BA.4/BA.5 dominant wave than that observed during the BA.1 dominant wave.(Funded by the Bill and Melinda Gates Foundation.)
Semantic and phonetic markers in schizophrenia-spectrum disorders; a combinatory machine learning approach
Authors: Voppel A.E. , de Boer J.N. , Brederoo S.G. , Schnack H.G. , Sommer I.E.C. 
Published: July 2022

AbstractIntroductionSpeech is a promising marker for schizophrenia-spectrum disorder diagnosis, as it closely reflects symptoms. Previous approaches have made use of different feature domains of speech in classification, including semantic and phonetic features. However, an examination of the relative contribution and accuracy per domain remains an area of active investigation. Here, we examine these domains (i.e. phonetic and semantic) separately and in combination.MethodsUsing a semi-structured interview with neutral topics, speech of 94 schizophrenia-spectrum subjects (SSD) and 73 healthy controls (HC) was recorded. Phonetic features were extracted using a standardized feature set, and transcribed interviews were used to assess word connectedness using a word2vec model. Separate cross-validated random forest classifiers were trained on each feature domain. A third, combinatory classifier was used to combine features from both domains.ResultsThe phonetic domain random forest achieved 81% accuracy in classifying SSD from HC. For the semantic domain, the classifier reached an accuracy of 80% with a sparse set of features with 10-fold cross-validation. Joining features from the domains, the combined classifier reached 85% accuracy, significantly improving on models trained on separate domains. Top features were fragmented speech for phonetic and variance of connectedness for semantic, with both being the top features for the combined classifier.DiscussionBoth semantic and phonetic domains achieved similar results compared with previous research. Combining these features shows the relative value of each domain, as well as the increased classification performance from implementing features from multiple domains. Explainability of models and their feature importance is a requirement for future clinical applications.
COVID-19 pandemic surges can induce bias in trials using response adaptive randomization: A simulation study
Authors: Yarnell Christopher J , Fowler Robert A , Sung Lillian , Tomlinson George 
Published: July 2022

AbstractResponse-adaptive randomization is being used in COVID-19 trials, but it is unknown whether outcome rate changes during surges of COVID-19 will lead to bias in trial results. In response-adaptive randomization, allocation ratios are adjusted according to interim analyses to assign more patients to promising interventions. Although it is known that response-adaptive randomization may give biased estimates if outcome rates drift over time, observed mortality fluctuations in the COVID-19 pandemic are more extreme than any previously tested in simulation. We hypothesized that pandemic surges induce bias in trials using response-adaptive randomization, and that adjustment for time will alleviate that bias. Bayesian 4-arm superiority trials with a mortality outcome were simulated to investigate bias in treatment effect, comparing complete and response-adaptive randomization under different pandemic scenarios based on data from New York, Spain, and Italy. Relative bias in the odds ratio associated with treatment ranged from 0.3% to 11% and was largest in trials with a surge and an effective intervention that did not adjust for time. Bias was attenuated by adjustment for time without compromising the false-positive rate. Trials using response-adaptive randomization were more likely to identify effective interventions but were slower to drop ineffective interventions. Even with variation in outcome rates similar to observed pandemic surges, COVID-19 trials using response-adaptive randomization that adjust for time can provide accurate estimates of treatment effects.
Factors Associated with COVID-19 Breakthrough Infection in the Pre-Omicron Era Among Vaccinated Patients with Rheumatic Diseases: A Cohort Study
Authors: Patel Naomi J. , Wang Xiaosong , Fu Xiaoqing , Kawano Yumeko , Cook Claire , Vanni Kathleen M.M. , Qian Grace , Banasiak Emily , Kowalski Emily , Zhang Yuqing , Sparks Jeffrey A. , Wallace Zachary S. 
Published: July 2022

AbstractObjectiveRheumatic disease patients on certain immunomodulators are at increased risk of impaired humoral response to SARS-CoV-2 vaccines. We aimed to identify factors associated with breakthrough infection among patients with rheumatic diseases.MethodsWe identified patients with rheumatic diseases being treated with immunomodulators in a large healthcare system who received at least two doses of either the mRNA-1273 (Moderna) or BNT162b2 (Pfizer-BioNTech) vaccines or one dose of the Johnson & Johnson-Janssen (J&J) vaccine. We followed patients until SARS-CoV-2 infection, death, or December 15, 2021, when the Omicron variant became dominant in our region. We estimated the association of baseline characteristics with the risk of breakthrough infection using multivariable Cox regression.ResultsWe analyzed 11,468 patients (75% female, mean age 60 years). Compared to antimalarial monotherapy, multiple immunomodulators were associated with higher risk of infection: anti-CD20 monoclonal antibodies (aHR 5.20, 95% CI: 2.85, 9.48), CTLA-4 Ig (aHR 3.52, 95% CI: 1.90, 6.51), mycophenolate (aHR 2.31, 95% CI: 1.25, 4.27), IL-6 inhibitors (aHR 2.15, 95% CI: 1.09, 4.24), JAK inhibitors (aHR 2.02, 95% CI: 1.01, 4.06), and TNF inhibitors (aHR 1.70, 95% CI: 1.09, 2.66). mRNA-1273 recipients had a lower risk of breakthrough infection compared to BNT162b2 recipients (aHR 0.66, 95% CI: 0.50, 0.86). There was no association of sex, body mass index, smoking status, race, or ethnicity with risk of breakthrough infection.ConclusionAmong patients with rheumatic diseases, multiple immunomodulators were associated with increased risk of breakthrough infection. These results highlight the need for additional mitigation strategies in this vulnerable population.
Intrinsic linking of chromatin fiber in human cells
Authors: Borodzik Maciej , Denkiewicz Michał , Spaliński Krzysztof , Winnicka-Sztachelska Kamila , Sengupta Kaustav , Pilipczuk Marcin , Pilipczuk Michał , Ruan Yijun , Plewczynski Dariusz 
Published: July 2022

AbstractMotivationWe propose a practical algorithm based on graph theory, with the purpose of identifying CTCF-mediated chromatin loops that are linked in 3D space. Our method is based finding clique minors in graphs constructed from pairwise chromatin interaction data obtained from the ChIA-PET experiments. We show that such a graph structure, representing a particular arrangement of loops, mathematically necessitates linking, if co-occurring in an individual cell. The presence of these linked structures can advance our understanding of the principles of spatial organization of the genome.ResultsWe apply our method to graphs created from in situ ChIA-PET data for GM12878, H1ESC, HFFC6 and WTC11 cell lines, and from long-read ChIA-PET data. We look at these datasets as divided into CCDs - closely interconnected regions defined based on CTCF loops. We find numerous candidate regions with minors, indicating the presence of links. The graph-theoretic characteristics of these linked regions, including betweenness and closeness centrality, differ from regions without, in which no minors were found, which supports their non-random nature. We also look at the position of the linked regions with respect to chromatin compartments.AvailabilityThe implementation of the algorithm is available at https://github.com/SFGLab/cKNOTsContactDariusz.Plewczynski@pw.edu.pl
Effect of Histidine Covalent Modification on Strigolactone Receptor Activation and Selectivity
Authors: Chen Jiming , Shukla Diwakar 
Published: July 2022

AbstractThe parasitic weed Striga has led to billions of dollars’ worth of agricultural productivity loss worldwide. Striga detects host plants using the plant hormone strigolactone. Early steps in the strigolactone signaling pathway involve substrate binding and hydrolysis followed by a conformational change to an “active” or “closed” state, after which it associates with a MAX2-family downstream signaling partner. The structures of the inactive and active states of strigolactone receptors are known through X-ray crystallography, and the transition pathway of from the inactive to active state in apo receptors has previously been characterized using molecular dynamics simulations. However, it also has been suggested that a covalent butenolide modification of the receptor on the catalytic histidine through substrate hydrolysis promotes formation of the active state. Using molecular dynamics simulations, we show that the presence of the covalent butenolide enhances activation in both At D14 and ShHTL7, but the enhancement is ∼50 times greater in ShHTL7. We also show that several conserved interactions with the covalent butenolide modification promote transition to the active state in both At D14 (non-parasite) and ShHTL7 (parasite). Finally, we demonstrate that the enhanced activation of ShHTL7 likely results from disruption of ShHTL7-specific histidine interactions that inhibited activation in the apo case.
Lokatt: A hybrid DNA nanopore basecaller with an explicit duration hidden Markov model and a residual LSTM network
Authors: Xu Xuechun , Bhalla Nayanika , Ståhl Patrik , Jaldén Joakim 
Published: July 2022

AbstractBackgroundBasecalling long DNA sequences is a crucial step in nanopore-based DNA sequencing protocols. In recent years, the CTC-RNN model has become the leading basecalling model, supplanting preceding hidden Markov models (HMMs) that relied on pre-segmenting ion current measurements. However, the CTC-RNN model operates independently of prior biological and physical insights.ResultsWe present a novel basecaller namedLokatt: explicit duration Markov model and residual-LSTM network. It leverages an explicit duration HMM (EDHMM) designed to model the nanopore sequencing processes. Trained on a newly generated library with methylation-free Ecoli samples and MinION R9.4.1chemistry, the Lokatt basecaller achieves basecalling performances with a median single read identity score of0.930, a genome coverage ratio of99.750%, on par with existing state-of-the-art structure when trained on the same datasets.ConclusionOur research underlines the potential of incorporating prior knowledge into the basecalling processes, particularly through integrating HMMs and recurrent neural networks. The Lokatt basecaller showcases the efficacy of a hybrid approach, emphasizing its capacity to achieve high-quality basecalling performance while accommodating the nuances of nanopore sequencing. These outcomes pave the way for advanced basecalling methodologies, with potential implications for enhancing the accuracy and efficiency of nanopore-based DNA sequencing protocols.Supplementary informationSupplementary data are available online.
Heteroplasmic Mitochondrial Genetic Variation in the Human Heart
Authors: Xue Liying , Sun Xianbang , Moreira Jesse D. , Li Yi , Smith Karan Kacy , Padera Robert F. , Lenburg Marc E. , Levy Daniel , Benjamin Emelia J. , Gopal Deepa M. , Liu Chunyu , Fetterman Jessica L. 
Published: July 2022

ABSTRACTWhether heteroplasmic mitochondrial genetic variants in readily accessible tissues (blood, skeletal muscle) reflect those in the human heart (atrial appendage, left ventricle) is unknown. Using next generation sequencing data from paired tissue samples (n=233) collected postmortem in the Genotype-Tissue Expression project, we identified 558 unique heteroplasmic mitochondrial genetic variants across the four tissues, of which only 13% were shared across all four tissue sites. Between the two cardiac sites, 61% of heteroplasmic mitochondrial genetic variants were unique to one site. A greater proportion of the heteroplasmic variants were non-synonymous or frameshift variants in the muscle sites compared to blood or those variants shared across all four tissues. Compared to blood, the total number of heteroplasmic variants was higher in cardiac tissue, which was associated with advancing age. Our findings suggest that human cardiac tissue has unique heteroplasmic mtDNA variants and may be relevant to aging-related diseases.