bluuebunny/crossref_metadata_2025_split huggingface dataset:
High-throughput splicing assays identify known and novelWT1exon 9 variants in nephrotic syndrome
Authors: Smith Cathy , Burugula Bala Bharathi , Dunn Ian , Aradhya Swaroop , Kitzman Jacob O. , Yee Jennifer Lai 
Published: March 2023

AbstractFrasier Syndrome (FS) is a rare Mendelian form of nephrotic syndrome caused by variants which disrupt the proper splicing ofWT1. This key transcription factor gene is alternatively spliced at exon 9 to produce two isoforms (“KTS+” and “KTS-”), which are normally expressed in the kidney at a ∼2:1 (KTS+:KTS-) ratio. FS results from variants that reduce this ratio by disrupting the splice donor of the KTS+ isoform. FS is extremely rare, and it is unclear whether any variants beyond the eight already known could cause FS. To prospectively identify other splicing-disruptive variants, we leveraged a massively parallel splicing assay. We tested every possible single nucleotide variant (n=519) in and aroundWT1exon 9 for effects upon exon inclusion and KTS+/- ratio. Splice disruptive variants made up 11% of the tested point variants overall, and were tightly concentrated near the canonical acceptor and the KTS+/- alternate donors. Our map successfully identified all eight known FS or focal segmental glomerulosclerosis variants and 16 additional novel variants which were comparably disruptive to these known pathogenic variants. We also identified 19 variants that, conversely, increased the KTS+/KTS- ratio, of which two are observed in unrelated individuals with 46,XX ovotesticular disorder of sex development (46,XX OTDSD). This splicing effect map can serve as functional evidence to guide the clinical interpretation of newly observed variants in and aroundWT1exon 9.
First-in-human immunoPET imaging of COVID-19 convalescent patients using dynamic total-body PET and a CD8-targeted minibody
Authors: Omidvari Negar , Jones Terry , Price Pat M , Ferre April L , Lu Jacqueline , Abdelhafez Yasser G , Sen Fatma , Cohen Stuart H , Schmiedehausen Kristin , Badawi Ramsey D , Shacklett Barbara L , Wilson Ian , Cherry Simon R 
Published: March 2023

AbstractWith the majority of CD8+T cells residing and functioning in tissue, not blood, developing noninvasive methods forin vivoquantification of their biodistribution and kinetics in humans offers the means for studying their key role in adaptive immune response and memory. This study is the first report on using positron emission tomography (PET) dynamic imaging and compartmental kinetic modeling forin vivomeasurement of whole-body biodistribution of CD8+T cells in human subjects. For this, a89Zr-labeled minibody with high affinity for human CD8 (89Zr-Df-Crefmirlimab) was used with total-body PET in healthy subjects (N=3) and in COVID-19 convalescent patients (N=5). The high detection sensitivity, total-body coverage, and the use of dynamic scans enabled the study of kinetics simultaneously in spleen, bone marrow, liver, lungs, thymus, lymph nodes, and tonsils, at reduced radiation doses compared to prior studies. Analysis and modeling of the kinetics was consistent with T cell trafficking effects expected from immunobiology of lymphoid organs, suggesting early uptake in spleen and bone marrow followed by redistribution and delayed increasing uptake in lymph nodes, tonsils, and thymus. Tissue-to-blood ratios from the first 7 h of CD8-targeted imaging showed significantly higher values in the bone marrow of COVID-19 patients compared to controls, with an increasing trend between 2 and 6 months post-infection, consistent with net influx rates obtained by kinetic modeling and flow cytometry analysis of peripheral blood samples. These results provide the platform for using dynamic PET scans and kinetic modelling to study total-body immunological response and memory.
Leveraging Electronic Medical Records and Knowledge Networks to Predict Disease Onset and Gain Biological Insight Into Alzheimer’s Disease
Authors: Tang Alice , Rankin Katherine P. , Cerono Gabriel , Miramontes Silvia , Mills Hunter , Roger Jacquelyn , Zeng Billy , Nelson Charlotte , Soman Karthik , Woldemariam Sarah , Li Yaqiao , Lee Albert , Bove Riley , Glymour Maria , Oskotsky Tomiko , Miller Zachary , Allen Isabel , Sanders Stephan J. , Baranzini Sergio , Sirota Marina 
Published: March 2023

AbstractEarly identification of Alzheimer’s Disease (AD) risk can aid in interventions before disease progression. We demonstrate that electronic health records (EHRs) combined with heterogeneous knowledge networks (e.g., SPOKE) allow for (1) prediction of AD onset and (2) generation of biological hypotheses linking phenotypes with AD. We trained random forest models that predict AD onset with mean AUROC of 0.72 (-7 years) to .81 (-1 day). Top identified conditions from matched cohort trained models include phenotypes with importance across time, early in time, or closer to AD onset. SPOKE networks highlight shared genes between top predictors and AD (e.g., APOE, IL6, TNF, and INS). Survival analysis of top predictors (hyperlipidemia and osteoporosis) in external EHRs validates an increased risk of AD. Genetic colocalization confirms hyperlipidemia and AD association at the APOE locus, and AD with osteoporosis colocalize at a locus close to MS4A6A with a stronger female association.
Plasma Plasmin Generation and its Determinants in Third Trimester of Pregnancy
Authors: Okoye Helen Chioma , Nwagha Theresa Ukamaka , Enebe Joseph Tochukwu , Efobi Chilota , Nnachi Oluomachi Charity , Okwor Chikaodili J 
Published: March 2023

AbstractBackgroundPregnancy, especially in the third trimester, is associated with changes in the fibrinolytic system that supports clot formation and reduces hemorrhagic risk. Imbalance in the system may occur and can be assessed by plasmin generation (PG). Certain factors are known to affect PG.AimTo assess PG and its determinants during pregnancy using plasma D-dimer and plasmin-antiplasmin (PAP) complex levels.MethodsHealthy pregnant women in the third trimester of pregnancy were systematically recruited. Using the ELISA method, venous blood samples were taken to assess D-Dimer and PAP complex plasma levels. IBM Statistical Package for Social Sciences (SPSS) version 21 was used for statistical analysis.ResultsWe studied a total of 41 subjects with a mean age ±SD and gestational age ±SD of 30.68±4.69years and 34.78±3.34weeks, respectively. The mean ± SD values of the D-Dimer and PAP complex were 194 ± 24 ng/mL and 175 ± 11 ng/mL, respectively. D-Dimer and PAP complex positively correlated with age, GA, and BMI classification. However, only age was statistically significant (p-value 0.032 and 0.016, respectively). In addition, the multiple linear regression model showed that with every unit increase in age, D-Dimer and PAP complex increased by 2.0 (95% CI 0.4 – 3.6) ng/mL and 0.8 (95% CI 0.1 – 1.5) ng/mL respectively, after controlling for GA and BMI.ConclusionD-Dimer and PAP levels increased with increasing age during the third trimester of pregnancy, showing that the woman’s age is an independent determinant of PG in the third trimester.
A methodology of phenotyping ICU patients from EHR data: high-fidelity, personalized, and interpretable phenotypes estimation
Authors: Wang Yanran , Stroh J.N. , Hripcsak George , Low Wang Cecilia C. , Bennett Tellen D. , Wrobel Julia , Der Nigoghossian Caroline , Mueller Scott , Claassen Jan , Albers D.J. 
Published: March 2023

AbstractObjectiveComputing phenotypes that provide high-fidelity, time-dependent characterizations and yield personalized interpretations is challenging, especially given the complexity of physiological and healthcare systems and clinical data quality. This paper develops a methodological pipeline to estimate unmeasured physiological parameters and produce high-fidelity, personalized phenotypes anchored to physiological mechanics from electronic health record (EHR).MethodsA methodological phenotyping pipeline is developed that computes new phenotypes defined with unmeasurable computational biomarkers quantifying specific physiological properties in real time. Working within the inverse problem framework, this pipeline is applied to the glucose-insulin system for ICU patients using data assimilation to estimate an established mathematical physiological model with stochastic optimization. This produces physiological model parameter vectors of clinically unmeasured endocrine properties, here insulin secretion, clearance, and resistance, estimated for individual patient. These physiological parameter vectors are used as inputs to unsupervised machine learning methods to produce phenotypic labels and discrete physiological phenotypes. These phenotypes are inherently interpretable because they are based on parametric physiological descriptors. To establish potential clinical utility, the computed phenotypes are evaluated with external EHR data for consistency and reliability and with clinician face validation.ResultsThe phenotype computation was performed on a cohort of 109 ICU patients who received no or short-acting insulin therapy, rendering continuous and discrete physiological phenotypes as specific computational biomarkers of unmeasured insulin secretion, clearance, and resistance on time windows of three days. Six, six, and five discrete phenotypes were found in the first, middle, and last three-day periods of ICU stays, respectively. Computed phenotypic labels were predictive with an average accuracy of 89%. External validation of discrete phenotypes showed coherence and consistency in clinically observable differences based on laboratory measurements and ICD 9/10 codes and clinical concordance from face validity. A particularly clinically impactful parameter, insulin secretion, had a concordance accuracy of 83%±27%.ConclusionThe new physiological phenotypes computed with individual patient ICU data and defined by estimates of mechanistic model parameters have high physiological fidelity, are continuous, time-specific, personalized, interpretable, and predictive. This methodology is generalizable to other clinical and physiological settings and opens the door for discovering deeper physiological information to personalize medical care.
TheCucumis sativuskinome: Identification, annotation, and expression patterns in response to powdery mildew infection
Authors: Costa Francisco Cleilson Lopes , Pereira Welison Andrade 
Published: March 2023

AbstractIt is widely known that protein kinases (PKs) play a fundamental role in regulating various metabolic processes in plants, from development to response to the environment. However, a detailed characterization of this superfamily is still lacking for several species, such as cucumber (Cucumis sativus), especially regarding their involvement in the response to Powdery Mildew (PM) caused byPodosphaera xanthii. This study aimed to characterize the cucumber PK family, shedding light on its genomic distribution, classification, and expression patterns triggered byP. xanthii. The hidden Markov models (HMMs) analysis uncovered 835 PKs in the cucumber kinome, distributed across its seven chromosomes, and categorized into 20 distinct groups and 123 families, with the RLK group being the most abundant. Evidence of tandem duplication of PK genes was also observed, enriching our understanding of cucumber PKs. To investigate the expression profiles of PK genes in cucumber, we analyzed the transcription levels of all 835 PK genes in RNA-seq data from leaves of resistant and susceptible cultivars of cucumber toP. xanthii, which were artificially inoculated. Depending on the treatment, DEGs ranged from 319 to 1,690, with PK DEGs ranging from 8 to 105. The number of PK DEGs varied between the different contrasts analyzed. Notably, we observed a greater number of PK DEGs in susceptible genotypes when challenged by the pathogen. Our findings indicate the role of specific cucumber PKs in regulating metabolic processes in the context of plant-pathogen interactions and pave the way for further research into the intricate mechanisms underlying cucumber responses to Powdery Mildew.Graphical Abstract
Benchmarking of deep neural networks for predicting personal gene expression from DNA sequence highlights shortcomings
Authors: Sasse Alexander , Ng Bernard , Spiro Anna E. , Tasaki Shinya , Bennett David A. , Gaiteri Christopher , De Jager Philip L. , Chikina Maria , Mostafavi Sara 
Published: March 2023

Introductory ParagraphDeep learning methods have recently become the state-of-the-art in a variety of regulatory genomic tasks1–6including the prediction of gene expression from genomic DNA. As such, these methods promise to serve as important tools in interpreting the full spectrum of genetic variation observed in personal genomes. Previous evaluation strategies have assessed their predictions of gene expression across genomic regions, however, systematic benchmarking is lacking to assess their predictions across individuals, which would directly evaluates their utility as personal DNA interpreters. We used paired Whole Genome Sequencing and gene expression from 839 individuals in the ROSMAP study7to evaluate the ability of current methods to predict gene expression variation across individuals at varied loci. Our approach identifies a limitation of current methods to correctly predict the direction of variant effects. We show that this limitation stems from insufficiently learnt sequence motif grammar, and suggest new model training strategies to improve performance.
Conditionally deleterious mutation load accumulates in genomic islands but can be purged with sufficient genotypic redundancy
Authors: Mee Jonathan A. , Carson Bryce , Yeaman Sam 
Published: March 2023

AbstractLocal adaptation frequently evolves in patches or environments that are connected via migration. In these cases, genomic regions that are linked to an adaptive locus experience reduced effective migration rates. Via individual-based simulations of a two-patch system, we show that this reduced effective migration results in the accumulation of conditionally deleterious mutations, but not universally deleterious mutations, adjacent to adaptive loci. When there is redundancy in the genetic basis of local adaptation (i.e. genotypic redundancy), turnover of adaptive loci allows conditionally deleterious mutation load to be purged. The amount of mutational load that accumulates adjacent to adaptive loci is dependent on redundancy, recombination rate, migration rate, population size, strength of selection, and the phenotypic effect size of adaptive alleles. Our results highlight the need to be cautious when interpreting patterns of local adaptation at the level of phenotype or fitness, as the genetic basis of local adaptation can be transient, and evolution may confer a degree of maladaptation to non-local environments.
Characterization of popcorn temperate and tropical populations and GWAS for zeins and starch contents
Authors: Gotardi Leonardo Fioravante , Viana José Marcelo Soriano , Ribeiro Matheus Pereira , de Castro Raissa Barbosa , Ramos Humberto Josué de Oliveira , Fietto Juliana Lopes Rangel 
Published: March 2023

AbstractBecause measuring expansion volume (EV) is simple and inexpensive, popcorn breeders have developed high-quality single crosses ignoring the contents of zeins, starch, lipids, and cellular wall components in selection. However, some methods of quantification of these quality-related traits can be applied to popcorn breeding, increasing the selection efficacy for quality. The objectives of this study were assess methods of quantification of zeins and starch that can be used in popcorn breeding, characterize a temperate and a tropical populations for zeins and starch contents, and identify candidate genes for these quality-related traits. We genotyped and phenotyped 286 plants. For quantification of total zeins and zein subunits we choose the ‘lab-on-a-chip’ microfluidic electrophoresis. For quantification of starch and amylose/amylopectin we choose the Megazyme’s Amylose/Amylopectin kit assay. The temperate population has superior EV (+36%), a higher level (+32%) of the 19 kDa zein subunit, and lower levels of the 21, 22, and 27 kDa subunits (−1543, −40 and −47%, respectively). Although there are statistical differences between the two populations regarding starch, amylose, and amylose/amylopectin ratio, the differences are not significant (−2 to 8%). Six candidate genes were identified for the 19 and 22 kDa zeins, one for the 21 kDa zein, one for total zeins, two for starch, and four for amylose, with emphasis on three genes from the Z1C subfamily, coding for the 19 and 22 kDa alpha-zeins, located on chromosome 4. The evaluated quantification methods can be used in popcorn breeding programs, with the potential to revolutionize the breeding for quality.Key messageThe protein chip and the Amylose/Amylopectin kit assay for zein and starch quantification, respectively, can be effectively used in popcorn breeding, with the potential to revolutionize the breeding for quality.
WALLFLOWER, a RLK, simultaneously localizes to opposite sides of root hair cells & functions to position hairs
Authors: Toth Jessica N. , Rodriguez-Furlan Cecilia , Van Norman Jaimie M. 
Published: March 2023

ABSTRACTPolarized cells are frequently partitioned into subdomains with unique features or functions. As plant cells are surrounded by walls, polarized cell shape and protein polarity in the plasma membrane are particularly important for normal physiology and development. We have identified WALLFLOWER (WFL), a transmembrane receptor kinase that is asymmetrically distributed at the inner face of epidermal cells and this localization is maintained independent of cell type. In epidermal hair (H) cells in the elongation and differentiation zones, WFL exhibits a dual polar localization, accumulating at the inner domain as well as at the root hair initiation domain (RHID). Furthermore, overexpression of WFL leads to a downward shift in root hair (RH) position suggesting WFL operates in a signaling pathway that functions across H cells to inform RH position. WFL asymmetric distribution and function is affected by deletion of the intracellular domains resulting in its mislocalization to the outer polar domain of H cells and exclusion from RHIDs and bulges. Thus, our results demonstrate that in epidermal H cells the WFL intracellular domains are required to direct its dual polar localization and influence RH position.ONE SENTENCE SUMMARYA receptor kinase with dual polar localization, to the inner polar domain and root hair initiation domain, in root epidermal cells, requires its intracellular domain for localization and function.
The first proof of concept demonstration of nanowarming in coral tissue
Authors: Daly Jonathan , Bouwmeester Jessica , Perry Riley , Page Chris , Khosla Kanav , Kangas Joseph , Lager Claire , Hardy Katherine , Bischof John C. , Hagedorn Mary 
Published: March 2023

ABSTRACTClimate change is causing ocean acidification and warming, resulting in mass bleaching and death of corals globally. Cryopreservation and biobanking to secure the genetics of threatened populations is currently limited to coral sperm and larvae, which are only available during brief annual spawning events and are impacted by ocean warming, so there is an urgent need for methods to enable biobanking activities year-round. Here, we used vitrification and nanowarming to successfully recover adult coral tissues in a novel sample type, the single-polyp microfragment (SPMF). Fluorescence and confocal microscopy showed clearly defined tissues and green fluorescent protein fluorescence around the polyp mouth post-warming in 43.3% of SPMFs at 24 hours post-warming, and 30.0% at one month. These advances provide a basis for continued research and development of a field-ready protocol for cryopreservation of adult coral tissues, to permit biobanking of threatened coral species throughout the year and support reef restoration efforts.
Identification of selective sweeps in bacteria
Authors: Avram Oren , Levy Karin Eli , Corander Jukka , Oren Yaara , Pupko Tal 
Published: March 2023

AbstractSelective sweeps occur when a beneficial mutation spreads rapidly throughout the population due to natural selection. Searching for selective sweeps has proved to be one of the most fruitful ways to detect the footprints selection leaves on the genome. With a plethora of detection tools, the study of selective sweeps in eukaryotic systems is a well-established field of research. However, the search for fragment-specific selective sweeps among bacterial strains received little to no attention so far. In our work, we demonstrate that inter-strains locus-specific selective sweeps can be detected in bacteria. We introduce theSINCOPAalgorithm, the first phylogeny-based method for soft and incomplete selective sweeps detection. We useSINCOPAto explore inter-strains locus-specific selective sweeps in a dataset containing more than 500 microbial genomes. We observe strong evidence in several loci for locus-specific selective sweeps including genes involved in biofilm formation and others that are related to coping with various unfavorable environmental conditions.SINCOPAis freely accessible as a user-friendly web server application athttps://sincopa.tau.ac.il/.
NVX-CoV2373 Vaccine Efficacy Against Hospitalization: Apost hocanalysis of the PREVENT-19 phase 3, randomized, placebo-controlled trial
Authors: Marchese Anthony M. , Zhou Xiang , Kinol John , Underwood Eddie , Woo Wayne , McGarry Alice , Beyhaghi Hadi , Áñez Germán , Toback Seth , Dunkle Lisa M. 
Published: March 2023

ABSTRACTPREVENT-19, the pivotal phase 3 trial of the Novavax adjuvanted, recombinant spike protein COVID-19 vaccine (NVX-CoV2373) demonstrated that the vaccine was safe and efficacious (vaccine efficacy, VE= 90%) for the prevention of symptomatic COVID-19. In the trial, participants were randomly assigned in a 2:1 ratio to receive 2 doses of NVX-CoV2373 or placebo 21 days apart. Throughout the study, SARS-CoV-2 circulating variant was predominantly alpha, but other variants circulated (i.e., beta, gamma, epsilon, and iota). VE among the per-protocol efficacy analysis population was calculated according to pre-specified disease severity (mild, moderate, or severe) criteria, but the impact on the risk of COVID-19– associated hospitalization was not specifically investigated. During the placebo-controlled portion of the trial (January 25, 2021, to April 30, 2021), 4 hospitalizations occurred among the 77 events analyzed for the primary endpoint using the per-protocol population, 0 among vaccine recipients and 4 among placebo recipients, yielding a VE against hospitalization of 100% (95% CI: 28.8, 100). Among an expanded efficacy population, which included COVID-19–associated hospitalizations without a requirement for diagnostic polymerase chain reaction testing performed at the study central laboratory, 12 total hospitalizations were identified, 0 among vaccine recipients and 12 among placebo recipients, yielding apost hocVE against hospitalization of 100% (95% CI: 83.1, 100). These additional data from the PREVENT-19 trial provide relevant public health information concerning the attributes of NVX-CoV2373.