bluuebunny/crossref_metadata_2025 huggingface dataset:
A system biology-oriented investigation of Arabidopsis proteomes altered in chloroplast biogenesis and retrograde signaling reveals adaptive responses at whole cell level
Authors: Di Silvestre Dario , Jeran Nicolaj , Domingo Guido , Vannini Candida , Marsoni Milena , Fortunato Stefania , de Pinto Maria Concetta , Tamborrino Alberto , Negroni Yuri Luca , Zottini Michela , Hong Lien Tran , Lomagno Andrea , Mauri Pierluigi , Pesaresi Paolo , Tadini Luca
Published: June 2024

Communication across different plant cell compartments relies on an intricate network of molecular interactions, required for the orchestration of organelle development and adaptation to the environment. In this scenario, the Pentatricopeptide Repeat (PPR) Protein GENOMES UNCOUPLED1 (GUN1) plays a key role in transferring information from both developing and mature chloroplasts to the nucleus with the aim to coordinate gene expression between the two genomes. However, its role and the related signaling molecules are still under debate. To help shed light on this matter, we attempted the holistic description ofArabidopsis thalianaproteome upon perturbation of chloroplast biogenesis by lincomycin (Lin), in a genetic context devoid of GUN1-dependent plastid-to-nucleus signaling pathway. Furthermore, the topological analysis of protein-protein interaction (PPI) and protein co-expression networks allowed the identification of protein hubs/bottlenecks characterizing genotypes and conditions, such as proteases, HSPs/Chaperones and redox proteins. Taken together, our findings indicate that GUN1 is required to orchestrate a plastid-located response to plastid protein synthesis inhibition while, in its absence, the reorganization of the activities associated with extra-plastid compartments, such as cytosol, vacuole and mitochondria, prevails. From this landscape, we documented a new role of the Oxygen Evolving Complex subunit PsbO, which appears to be an unconventional photosynthetic protein, as it accumulates in non-photosynthetic plastids and plays a central role in promoting chloroplast breakdown when plastid functions are altered.
A preliminary assessment of the genome sequence of the Annual Mercury,Mercurialis annua
Authors: Dwivedi Mratunjay , Vijay Nagarjun
Published: June 2024

Review of Christenhusz et al., Wellcome Open Research. A high-quality genome sequence of the Annual Mercury,Mercurialis annuais generated as part of the Darwin Tree of Life Project. The Annual Mercury plant is a good study system for evolutionary transitions between sexual systems, mechanisms of sex determination in plants and changes in ploidy level. The XX female sequenced in this study provides a chromosome-level assembly with reasonable contiguity and high gene completeness. We compare the gene completeness of the assembly presented with those of closely related species, including another published assembly of the Annual Mercury generated using a polyploid individual. Annotation and comparative analysis of the organelle genomes suggest complete circular assemblies. However, we note that the NCBI submissions are tagged as linear. The repeat content identified on the autosomes and X chromosome appears comparable, suggesting the sex chromosomes are relatively recent. An alternative possibility is that our preliminary analysis failed to identify repeats unique to the X chromosome or that these repeat regions have not been assembled in the genome. The harder-to-assemble centromere and telomere regions are not annotated in the genome and are potentially incomplete or missing. We identify putative centromere regions with elevated GC content, but they must be validated. The demographic histories reconstructed for the autosomes and X suggest distinct trajectories irrespective of the scaling parameters. Compared to the autosomes, the older histories recorded on the X are a promising avenue for further work to study the origin of the sex chromosome. Our preliminary assessment of the genome sequence suggests the genome is of sufficiently good quality for use as a reference for diverse analysis aimed at answering important eco-evolutionary questions of interest that can be answered using this system.
Mitochondrial Dynamics and Bioenergetics in iPSC-Derived Neurons with Familial Alzheimer’s Disease Mutations
Authors: MacMullen Courtney , Sharma Neelam , Davis Ronald L.
Published: June 2024

Mitochondrial (MT) dysfunction is a hallmark of Alzheimer’s Disease (AD), but the specific defects across forms of AD are unknown. We measured multiple parameters of MT dynamics and function, and neurite degeneration, in iPSC-derived human neurons possessing natural and engineered mutations in PS1, PS2, and APP genes. Mutations in all three genes altered MT function measured by basal, ATP-linked, and maximal oxygen consumption rate; and spare respiratory capacity, with PS1/PS2 alleles being more severe than APP mutations. Electron flow through Complexes I-IV was decreased in PS1/PS2 mutations but; in contrast, APP alleles had only modest impairments of CI and CII. We measured aspects of MT dynamics including fragmentation, and neurite degeneration, both of which were dramatic in PS1/PS2 alleles, but essentially absent in APP alleles. The marked differences in MT pathology may occur from the distinct ways APP is processed into Aβ and may correlate with the disease severity.
PIP-Seq identifies novel heterogeneous lung innate lymphocyte population activation after combustion product exposure
Authors: Huang Yung-An , Wang Xinyu , Kim Jong-Chan , Yao Xiang , Sethi Anshika , Strohm Allyssa , Doherty Taylor A.
Published: June 2024

Innate lymphoid cells (ILCs) are a heterogeneous population that play diverse roles in airway inflammation after exposure to allergens and infections. However, how ILCs respond after exposure to environmental toxins is not well understood. Here we show a novel method for studying the heterogeneity of rare lung ILC populations by magnetic enrichment for lung ILCs followed by particle-templated instant partition sequencing (PIP-seq). Using this method, we were able to identify novel group 1 and group 2 ILC subsets that exist after exposure to both fungal allergen and burn pit-related constituents (BPC) that include dioxin, aromatic hydrocarbon, and particulate matter. Toxin exposure in combination with fungal allergen induced activation of specific ILC1/NK and ILC2 populations as well as promoted neutrophilic lung inflammation. Oxidative stress pathways and downregulation of specific ribosomal protein genes (Rpl41andRps19) implicated in anti-inflammatory responses were present after BPC exposure. Increased IFNγ expression and other pro-neutrophilic mediator transcripts were increased in BPC-stimulated lung innate lymphoid cells. Further, the addition of BPC inducedHspa8(encodes HSC70) and aryl hydrocarbon transcription factor activity across multiple lung ILC subsets. Overall, using an airway disease model that develops after occupational and environmental exposures, we demonstrate an effective method to better understand heterogenous ILC subset activation.
In a nutshell: pistachio genome and kernel development
Authors: Adaskaveg Jaclyn , Lee Chaehee , Wei Yiduo , Wang Fangyi , Grilo Filipa S. , Mesquida-Pesci Saskia D. , Davis Matthew , Wang Selina C. , Marino Giulia , Ferguson Louise , Brown Patrick J. , Drakakaki Georgia , Mena-Morales Adela , Marchese Annalisa , Giovino Antonio , Martinez Esau , Marra Francesco Paolo , Cuevas Lourdes Marchante , Cattivelli Luigi , Bagnaresi Paolo , Carbonell-Bejerano Pablo , Monroe J. Grey , Blanco-Ulate Barbara
Published: June 2024

Pistachio is a sustainable nut crop with exceptional climate resilience and nutritional value. To advance pistachios as a future food source and a model system for hard-shelled fruits, we generated a chromosome-scale reference genome of the most widely grown pistachio cultivar (Pistacia vera 'Kerman') and a spatiotemporal developmental study of the hull, shell, and kernel. Our study defined four distinct stages of pistachio growth and maturation by integrating tissue-level physiological and molecular data from thousands of nuts across twenty-four time points over three growing seasons. Transcriptional and metabolic changes in the kernel elucidate molecular pathways governing nutritional quality, such as the accumulation of unsaturated fatty acids, which are vital for shelf-life and dietary value. This work yields new knowledge and resources that will inform other woody crops and facilitate further improvement of pistachio as a globally significant, sustainable, and nutritious crop.
Comparative analysis of muscle thickness, muscle percentage of subcutaneous tissue, and muscle luminance in skeletal muscles of limbs of normal children and children with limb disabilities due to cerebral palsy using ultrasound imaging
Authors: Ishikura Hideki
Published: June 2024

Background

Ultrasound imaging is increasingly utilized for musculoskeletal evaluation because it is cost-effective and non-invasive. This study aims to analyze the differences in muscle thickness, muscle percentage of subcutaneous tissue, and muscle luminance in children with limb disabilities due to cerebral palsy compared with typically developing children.

Methods

This cross-sectional study included 12 children aged 6–15 years, divided equally into two groups: children with physical disabilities due to cerebral palsy and healthy controls. Ultrasound imaging was used to measure muscle thickness, percentage of muscle in subcutaneous tissue, and muscle luminance in various muscle groups of the limbs. Statistical analyses were conducted using t-tests to compare the two groups.

Results

Significant differences were observed in muscle thickness and percentage of muscle in subcutaneous tissue between the groups, particularly in the lower limbs. Muscle luminance did not exhibit consistent differences. These findings suggest a decreased muscle mass and altered composition in children with cerebral palsy, which may influence their physical function and mobility.

Conclusions

Our results underscore the value of ultrasound in clinically assessing muscle properties in children with cerebral palsy. This modality offers a promising tool for evaluating muscle alterations and potentially guiding targeted interventions to improve mobility and quality of life in affected children.
Deep Learning-Based High-Throughput Phenotyping Of Maize (Zea maysL.) Tasseling From Uas Imagery Across Environments
Authors: Shepard Nicholas R. , DeSalvio Aaron J. , Arik Mustafa , Adak Alper , Murray Seth C. , Varela Jose Ignacio , de Leon Natalia
Published: June 2024

Abstract

Flowering time is a critical phenological trait in maize (Zea maysL.) breeding programs. Traditional measurements for assessing flowering time involve semi-subjective and labor-intensive manual observation, limiting the scale and efficiency of genetics and breeding improvement. Leveraging unoccupied aerial system (UAS, also known as UAVs or drones) technology coupled with convolutional neural networks (CNNs) presents a promising approach for high-throughput phenotyping of tasseling in maize. Most CNN image analysis is overly complicated for simple tasks relevant to plant scientists. Here a methodology for extracting tasseling from RGB imagery using a CNN-based approach was applied to 220 hybrids and 30 test lines grown in eight diverse environments (Wisconsin and Texas, U.S.A.) then validated through an unrelated set of hybrids. Overall accuracies of .946, .911, .985, and .988 were obtained for classifying maize images with or without tassels from College Station, TX in 2020; College Station, TX in 2021; Arlington, WI in 2021; and Madison, WI in 2021 respectively. By employing deep learning techniques, larger volumes of phenotypic data can be processed enabling high-throughput phenotyping in breeding programs. Although large datasets are required to train CNN models, the proposed methodology prioritizes simplicity in computational architecture while maintaining effectiveness in identifying flowered maize across diverse genotypes and environments.
PlantRNA-FM: An Interpretable RNA Foundation Model for Exploration Functional RNA Motifs in Plants
Authors: Yu Haopeng , Yang Heng , Sun Wenqing , Yan Zongyun , Yang Xiaofei , Zhang Huakun , Ding Yiliang , Li Ke
Published: June 2024

The complex ‘language’ of plant RNA encodes a vast array of biological regulatory elements that orchestrate crucial aspects of plant growth, development, and adaptation to environmental stresses. Recent advancements in foundation models (FMs) have demonstrated their unprecedented potential to decipher complex ‘language’ in biology. In this study, we introduced PlantRNA-FM, a novel high-performance and interpretable RNA FM specifically designed based on RNA features including both sequence and structure. PlantRNA-FM was pre-trained on an extensive dataset, integrating RNA sequences and RNA structure information from 1,124 distinct plant species. PlantRNA-FM exhibits superior performance in plant-specific downstream tasks, such as plant RNA annotation prediction and RNA translation efficiency (TE) prediction. Compared to the second-best FMs, PlantRNA-FM achieved anF1 score improvement of up to 52.45% in RNA genic region annotation prediction and up to 15.30% in translation efficiency prediction, respectively. Our PlantRNA-FM is empowered by our interpretable framework that facilitates the identification of biologically functional RNA sequence and structure motifs, including both RNA secondary and tertiary structure motifs across transcriptomes. Through experimental validations, we revealed novel translation-associated RNA motifs in plants. Our PlantRNA-FM also highlighted the importance of the position information of these functional RNA motifs in genic regions. Taken together, our PlantRNA-FM facilitates the exploration of functional RNA motifs across the complexity of transcriptomes, empowering plant scientists with novel capabilities for programming RNA codes in plants.
Comprehensive mapping and modelling of the rice regulome landscape unveils the regulatory architecture underlying complex traits
Authors: Zhu Tao , Xia Chunjiao , Yu Ranran , Zhou Xinkai , Xu Xingbing , Wang Lin , Zong Zhanxiang , Yang Junjiao , Liu Yinmeng , Ming Luchang , You Yuxin , Chen Dijun , Xie Weibo
Published: June 2024

Unraveling the regulatory mechanisms that govern complex traits is pivotal for advancing crop improvement. Here we present a comprehensive regulome atlas for rice (Oryza sativa), charting the chromatin accessibility across 23 distinct tissues from three representative varieties. Our study uncovers 117,176 unique open chromatin regions (OCRs), accounting for ∼15% of the rice genome, a notably higher proportion compared to previous reports in plants. Integrating RNA-seq data from matched tissues, we confidently predict 59,075 OCR-to-gene links, with enhancers constituting 69.54% of these associations, including many known enhancer-to-gene links. Leveraging this resource, we re-evaluate genome-wide association study results and discover a previously unknown function ofOsbZIP06in seed germination, which we subsequently confirm through experimental validation. We optimize deep learning models to decode regulatory grammar, achieving robust modeling of tissue-specific chromatin accessibility. This approach allows to predict cross-variety regulatory dynamics from genomic sequences, shedding light on the genetic underpinnings of cis-regulatory divergence and morphological disparities between varieties. Overall, our study establishes a foundational resource for rice functional genomics and precision molecular breeding, providing valuable insights into regulatory mechanisms governing complex traits.
Hypothalamic prostaglandins facilitate recovery from hypoglycemia but exacerbate recurrent hypoglycemia in mice
Authors: Abe Takashi , Xu Shucheng , Sugiura Yuki , Arima Yuichiro , Hayasaka Takahiro , Lee Ming-Liang , Ishimoto Taiga , Araki Yudai , Ngurari Samson , Niu Ziwei , Iijima Norifumi , Diano Sabrina , Toda Chitoku
Published: June 2024

The hypothalamus monitors blood glucose levels and regulates glucose production in the liver. In response to hypoglycemia, glucose-inhibited (GI) neurons trigger counter-regulatory responses (CRRs), which stimulate the release of glucagon, epinephrine, and cortisol to elevate blood glucose. Recurrent hypoglycemia (RH), however, reduces the effectiveness of these CRRs. This study examined the role of hypothalamic prostaglandins in glucose recovery during acute hypoglycemia and RH. Using imaging mass spectrometry and liquid chromatography/mass spectrometry, phospholipid and prostaglandin levels in the hypothalamus of C57BL mice were increased following insulin or 2-deoxy-glucose administration. Ibuprofen, a nonsteroidal anti-inflammatory drug (NSAID), was infused into the ventromedial hypothalamus (VMH) to analyze its effect on glucose production during hypoglycemia, revealing that prostaglandin inhibition decreased glucagon secretion. Additionally, RH-treated mice decreased glucagon release and glucose production during hypoglycemia. Inhibiting prostaglandin production via short-hairpin RNA against cytosolic phospholipase A2 (cPLA2) in the hypothalamus restored CRRs diminished by RH via increasing glucagon sensitivity. These findings suggest that hypothalamic prostaglandins play a critical role in glucose recovery from acute hypoglycemia by activating VMH neurons and are also crucial for the attenuation of CRRs during RH.

Graphical Abstract

Article Highlights

Insulin decreases arachidonic acid-containing phospholipids and increases prostaglandin production in the hypothalamus.

Prostaglandin in the hypothalamus increases glucagon secretion and glucose production during hypoglycemia.

Recurrent hypoglycemia decreases glucagon secretion and glucose production during hypoglycemia.

Prostaglandin in the hypothalamus during recurrent hypoglycemia decreases glucagon sensitivity and glucose production.
Exact switching time distributions for autoregulated gene expression models with mRNA and protein descriptions
Authors: Liu Shan , Wu Bingjie , Jia Chen
Published: June 2024

In this study, we obtain the exact switching time distributions between the free and bound gene states for a detailed stochastic model of an autoregulatory genetic feedback loop with transcription, translation, mRNA and protein decay, as well as protein-gene interactions. The analytical solution generalizes and corrects the previous ones obtained in [Phys. Rev. Lett. 101, 118104 (2008)] and [Nat. Commun. 9, 3305 (2018)] for a reduced model of an autoregulatory loop that ignores the mRNA dynamics. We find that when the mRNA dynamics is modelled explicitly, the holding time in the free gene state can produce three shapes of steady-state distributions (decaying, bell-shaped, and bimodal). In particular, the detailed model with both mRNA and protein descriptions can produce a distribution shape that the reduced model fails to capture — the detailed model of a negative (positive) feedback loop can display a bimodal (bell-shaped) holding time distribution, while the reduced model cannot. Interestingly, we also find that an autoregulatory loop can produce a heavy-tailed holding time distribution and the origin of this heavy-tailed phenomenon is clarified using our analytical solution. Finally, we investigate how the distribution shape is affected by the type of feedback, the binding and unbinding rates, and the transcription rates.
Variant Impact Predictor database (VIPdb), version 2: Trends from 25 years of genetic variant impact predictors
Authors: Lin Yu-Jen , Menon Arul S , Hu Zhiqiang , Brenner Steven E
Published: June 2024

Background: Variant interpretation is essential for identifying patients' disease-causing genetic variants amongst the millions detected in their genomes. Hundreds of Variant Impact Predictors (VIPs), also known as Variant Effect Predictors (VEPs), have been developed for this purpose, with a variety of methodologies and goals. To facilitate the exploration of available VIP options, we have created the Variant Impact Predictor database (VIPdb). Results: The Variant Impact Predictor database (VIPdb) version 2 presents a collection of VIPs developed over the past 25 years, summarizing their characteristics, ClinGen calibrated scores, CAGI assessment results, publication details, access information, and citation patterns. We previously summarized 217 VIPs and their features in VIPdb in 2019. Building upon this foundation, we identified and categorized an additional 186 VIPs, resulting in a total of 403 VIPs in VIPdb version 2. The majority of the VIPs have the capacity to predict the impacts of single nucleotide variants and nonsynonymous variants. More VIPs tailored to predict the impacts of insertions and deletions have been developed since the 2010s. In contrast, relatively few VIPs are dedicated to the prediction of splicing, structural, synonymous, and regulatory variants. The increasing rate of citations to VIPs reflects the ongoing growth in their use, and the evolving trends in citations reveal development in the field and individual methods. Conclusions: VIPdb version 2 summarizes 403 VIPs and their features, potentially facilitating VIP exploration for various variant interpretation applications. Availability: VIPdb version 2 is available at https://genomeinterpretation.org/vipdb/
Insect metamorphosis is regulated differently between sexes by members of a microRNA cluster
Authors: Li Chade , Chan Ki Kei , Nong Wenyan , Chen ShanShan , So Wai Lok , Qu Zhe , Wu Heidi Y.C. , Yip Ho Yin , Chan Chi Bun , Tobe Stephen S. , Bendena William G. , Kai Zhen Peng , Hui Jerome H.L.
Published: June 2024

Insects comprise the majority of all described animal species and dominate the terrestrial habitats. The evolution of insect metamorphosis played a profound role in their successful adaptation and radiation. Insect metamorphosis is dependent on hormones ecdysteroids and sesquiterpenoids such as juvenile hormone. Despite the fact there are genuine differences between sexes during insect metamorphosis which facilitate their successful mating, how such sexual dimorphism in metamorphosis is being controlled is poorly known. We first generated transcriptomic profiles of male and female flies in late larvae and early pupae stages. Using a combination of genome-wide prediction andin vitrodual-luciferase validations, members of a microRNA cluster miR-277/34 were found to potentially regulate the neuropeptide receptor (AstC-R1) that when activated inhibits the sesquiterpenoid pathway and a juvenile hormone-dependent transcription factor (Kr-h1) in flyDrosophila melanogaster.Loss-of-function mutants were created deleting either miR-277 or miR-34, and expression levels of bothAstC-R1andKr-h1as well as ecdysteroid and sesquiterpenoid hormone titres were altered. Further comparison of transcriptomes of the late larvae and early pupae of both sexes revealed differential gene pathways being regulated by members of miR-277/34 between sexes during metamorphosis. This study highlights how members of a microRNA cluster control hormonal and developmental gene pathways in different sexes of insects during metamorphosis.
Structural and mechanistic insights intoPlasmodiumeIF2alpha dephosphorylation by UIS2 during the erythrocytic stage
Authors: Wu Su , Wagner Gerhard
Published: June 2024

UIS2 is a promising therapeutic target for malaria due to its essential role in the transmission and infectivity ofPlasmodiumto the host hepatocytes. InPlasmodium, UIS2 acts as a phosphatase toward phosphorylated eIF2alpha at Ser59, regulating translation initiation. However, its role during the erythrocytic stage, which causes clinical symptoms, remains unclear, and its protein structure for elucidating the dephosphorylation mechanism is unavailable. In this study, we analyzed thePlasmodiumphenotype screening database and found thatUIS2-deficientPlasmodiumfails to proliferate during the erythrocytic stages. Single-cell transcriptomic data from the Malaria Cell Atlas revealedUIS2expression during both hepatic and erythrocytic stages, with significant upregulation in trophozoites and late schizonts, suggesting UIS2’s essential role in erythrocytic stage development. Structural analyses using AlphaFold modeling demonstrated that the UIS2 phosphatase domain (UIS2-PD) shares homology with human purple acid phosphatase, featuring conserved catalytic site residues. We observed that the N-terminal domain of UIS2 interacts with the S1 domain loop of a phospho-mimic mutant (Ser59Asp) eIF2alpha via electrostatic interactions. This protein interaction is distal to the phosphatase domain, indicating a unique substrate recruitment mechanism distinct from mammalian serine/threonine phosphatase PP1. Additionally, we identified a negatively charged cavity in UIS2-PD capable of binding the Ser59-containing loop in eIF2alpha for substrate recognition. Molecular docking studies showed that the phosphatase inhibitor salubrinal binds to this negatively charged cavity, potentially obstructing enzyme-substrate interactions. These structural insights into UIS2 and its interaction with eIF2alpha provide promising avenues for developing novel antimalarial drugs.

Significance Statement

Malaria poses a significant global health challenge, particularly with rising resistance to artemisinin therapies. This study reveals the critical role of UIS2 inPlasmodiumproliferation during the symptomatic blood stage through phenotype screening and single-cell transcriptomics. We characterized the catalytic site within UIS2-PD and discovered a surface cavity for recognizing phosphorylated eIF2alpha by UIS2-PD, which can be inhibited by small molecules. Our findings identify UIS2 as a promising target for new antimalarial drugs, addressing both blood-stage parasites to alleviate clinical symptoms and liver-stage parasites for prophylactic treatment. This dual targeting strategy could prevent malaria onset post-exposure and reduce the overall parasite burden. The protein interaction between UIS2 and eIF2alpha is chemically targetable, facilitating the development of effective UIS2 inhibitors.
A multimorphic variant in ThPOK causes a novel human disease characterized by T cell abnormalities, immunodysregulation, allergy, and fibrosis
Authors: Vaseghi-Shanjani Maryam , Sharma Mehul , Yousefi Pariya , Samra Simran , Laverty Kaitlin U. , Jolma Arttu , Razavi Rozita , Yang Ally H. W. , Albu Mihai , Golding Liam , Lee Anna F. , Tan Ryan , Richmond Phillip A. , Bosticardo Marita , Rayment Jonathan H. , Yang Connie L. , Hildebrand Kyla J. , Brager Rae , Demos Michelle K. , Lau Yu Lung , Notarangelo Luigi D. , Hughes Timothy R. , Biggs Catherine M. , Turvey Stuart E.
Published: June 2024

ThPOK is best known as a regulator of CD4+ T cell lineage commitment, although it was initially cloned as a suppressor of collagen expression in the skin. The role of ThPOK has not been formally established in humans since individuals with damaging variants in ThPOK have not yet been identified. Here, we report the first case of a human with a damaging heterozygous de novo variant in ThPOK causing a syndrome encompassing CD4+ T cell deficiency, allergy, fibroinflammatory interstitial lung disease, developmental delay, and growth failure. The patient variant, ThPOK K360N, exhibited abnormal multimorphic activity, including interfering with ThPOK WT in regulating gene regulation (antimorph). Protein-DNA interaction assays showed inability of ThPOK K360N to bind to wild-type consensus sequences (amorph) and revealed a novel DNA-binding specificity (neomorph). Single-cell RNA sequencing of peripheral blood revealed potential developmental defects in maturation and activation of CD4+ and CD8+ T cells (hypomorph). To establish causality, we recapitulated the observed cellular defects in lentivirally transduced healthy control T cells and pulmonary fibroblasts. Transcriptomic analysis showed that T cells transduced with ThPOK K360N lacked the upregulation of activation, proliferation, and functional pathways observed in ThPOKWT-transduced cells. When overexpressed in healthy control fibroblasts, ThPOK K360N significantly increased the expression of pro-fibrotic genes implicated in pulmonary fibrosis, indicating a defect in regulating collagen expression. This novel human disease caused by a multimorphic variant in ThPOK confirms its role in CD4+ T cell development in an intact human context, while also revealing an unanticipated role for ThPOK in T cell function and the regulation of fibrotic pathways in fibroblasts.
In silicoscreening identifies SHPRH as a novel nucleosome acidic patch interactor
Authors: James Allison M. , Schmid Ernst W. , Walter Johannes C. , Farnung Lucas
Published: June 2024

Nucleosomes are the fundamental unit of eukaryotic chromatin. Diverse factors interact with nucleosomes to modulate chromatin architecture and facilitate DNA repair, replication, transcription, and other cellular processes. An important platform for chromatin binding is the H2A–H2B acidic patch. Here, we used AlphaFold-Multimer to screen over 7000 human proteins for nucleosomal acidic patch binding and identify 41 potential acidic patch binders. We determined the cryo-EM structure of one hit, SHPRH, with the nucleosome at 2.8 Å. The structure confirms the predicted acidic patch interaction, reveals that the SHPRH ATPase engages a different nucleosomal DNA location than other SF2-type ATPases, and clarifies the roles of SHPRH’s domains in nucleosome recognition. Our results illustrate the use ofin silicoscreening as a high throughput method to identify specific interaction types and expands the set of potential acidic patch binding factors.

All the screening data is freely available at

https://predictomes.org/view/acidicpatch
Fitbit-measured physical activity is inversely associated with incident atrial fibrillation among All of Us participants
Authors: Barua Souptik , Upadhyay Dhairya , Surapaneni Aditya , Grams Morgan , Jankelson Lior , Heffron Sean
Published: June 2024

Background and Aims

Individuals who report meeting weekly moderate to vigorous physical activity (MVPA) guidelines have lower risk of atrial fibrillation (AF). However existing studies have relied on subjective questionnaires or short-duration (<1 week) objective assessments using accelerometry. The objective of this research was to investigate an association between moderate to vigorous physical activity (MVPA) levels and the incidence of atrial fibrillation (AF), utilizing long-term, free-living accelerometry data.

Methods

1-year Fitbit data, in addition to survey and electronic health record (EHR) data, were extracted from the NIHAll of Us(AoU) research database. Cox proportional hazards regression was used to model the association of average MVPA (both continuous and categorized as <30, 30-150,151-300, and >300 minutes/week) and incident AF over a five-year follow-up period.

Results

6086 AoU participants were included (51±16 years, 70% female, 83% White, BMI 28.5±4.9 kg/m2, 41±12 complete weeks of Fitbit wear). 55 individuals (0.9%) experienced incident AF in the five-year follow-up period. More time spent in MVPA was associated with lower AF risk (HR = 0.89 [0.81,0.98], p=0.02), with a step-wise reduction for 151-300 mins (p=0.07) and >300 mins (p=0.04) of weekly MVPA, respectively. In a subset of 3847 participants with genomic data, this association persisted after adjustment for AF genetic risk score.

Conclusions

Higher amounts of objectively measured MVPA, measured using free-living, long-term accelerometry data, were inversely associated with risk of incident AF, independent of clinical and genetic risk factors.
Cholangiocyte glycocalyx degradation boosts primary sclerosing cholangitis
Authors: Klein Friederike , Wellhöner Freya , Freise Anika , Niculovic Kristina M. , Junca Howard , Vicente Manuel , Kats Elina , Luiz Gustavo dos Anjos Borges , Knegendorf Leonard , Cirksena Karsten , Triefenbach Antonia Marie , Woelfl Franziska , Abdullah Helin Fatma , Schulz Meike , Plumeier Iris , Kahl Silke , Albers Iris , Zoodsma Martijn , Vital Marius , Voigtländer Torsten , Lenzen Henrike , Schmitz Jessica , Saborowski Anna , Manns Michael P. , Solbach Philipp , Bräsen Jan Hinrich , Gerold Gisa , Xu Cheng-Jian , Wedemeyer Heiner , Münster-Kühnel Anja K. , Pieper Dietmar H. , Heidrich Benjamin
Published: June 2024

Summary

Primary sclerosing cholangitis (PSC) is an inflammatory disease of the biliary tract eventually leading to bile duct destruction, liver failure, cholangiocellular adenocarcinoma and/or death. No disease modifying treatments are available1. Especially cytotoxicity of bile acids, are discussed as potential driver of disease progression2. Cholangiocytes are protected by a bicarbonate umbrella formed by the glycocalyx, a dense layer of membrane bound polyglycans extending into the extracellular space3,4. Bile of PSC patients harbors a unique microbiome5. Here we identified a new factor in the pathogenesis of PSC. The bacterial degradation of sialic acid and galactose are associated with a poor event free survival of PSC patients and could identify bacterial liberation of sialic acid as crucial element in cholangiocyte damage using cell culture experiments, individualized organoid models and liver biopsies. With this study the view on bacteria-host interactions in bile duct associated diseases is widened. Functional patterns of the bacterial community are crucial for bile duct destruction in PSC patients. This opens a new field of diagnostic tools, disease modifying treatment options and identification of patients at risk.
Predictive Models for Secondary Epilepsy in Patients with Acute Ischemic Stroke Within One Year
Authors: Jinxin Liu , Haoyue He , Yanglingxi Wang , Jun Du , Kaixin Liang , Jun Xue , Yidan Liang , Peng Chen , Shanshan Tian , Yongbing Deng
Published: June 2024

Objective

Post-stroke epilepsy (PSE) is a major complication that worsens both prognosis and quality of life in patients with ischemic stroke. This study aims to develop an interpretable machine learning model to predict PSE using medical records from four hospitals in Chongqing.

Methods

We collected and analyzed medical records, imaging reports, and laboratory test results from 21,459 patients diagnosed with ischemic stroke. Traditional univariable and multivariable statistical analyses were performed to identify key predictive factors. The dataset was divided into a 70% training set and a 30% testing set. To address class imbalance, the Synthetic Minority Oversampling Technique combined with Edited Nearest Neighbors was used. Nine widely applied machine learning algorithms were evaluated and compared using relevant prediction metrics. SHAP (SHapley Additive exPlanations) was used to interpret the model, assessing the contributions of different features.

Results

Regression analyses showed that complications such as hydrocephalus, cerebral hernia, and deep vein thrombosis, as well as brain regions (frontal, parietal, and temporal lobes), significantly contributed to PSE. Factors like age, gender, NIH Stroke Scale (NIHSS) scores, and laboratory results such as WBC count and D-dimer levels were associated with a higher risk of PSE. Among the machine learning models, tree-based methods such as Random Forest, XGBoost, and LightGBM demonstrated strong predictive performance, achieving an AUC of 0.99.

Conclusion

Our model successfully predicts PSE risk, with tree-based models showing superior performance. The NIHSS score, WBC count, and D-dimer were identified as the most important predictors.
HighMycobacterium bovisexposure but low IGRA positivity in UK farm workers
Authors: Thomas Amy , Halliday Alice , Clapp Genevieve , Symonds Ross , Hopewell-Kelley Noreen , McGrath Carmel , Wheeler Lucy , Dacey Anna , Noel Nigel , Turner Andrea , Oliver Isabel , Wood James , Moran Ed , Virgo Paul , Goenka Anu , Brooks-Pollock Ellen
Published: June 2024

Background

Between 1999 and 2021, 505 culture-confirmed cases ofM. bovisdisease in humans (zoonotic tuberculosis, TB) were identified in England. We aimed to estimate the prevalence ofM. bovisinfection in persons exposed to TB-infected cattle in England and identify any risk factors associated with latent TB infection (LTBI) in this population.

Methods

We co-developed a retrospective cohort study in southwest England, a bovine TB high risk area, with members of the UK farming community. A questionnaire captured participant characteristics, behaviours and farming practices. Linkage with historical herd testing data was used to categorise participants as low, medium or high risk for TB exposure. Interferon gamma release assay (IGRA) positivity with Quantiferon was used to determine LTBI status and linked to questionnaire data.

Results

We recruited 90 participants at agricultural shows and a standalone event. Participants were farmers/farm workers (79/90) and veterinary professionals (11/90). Median age was 45.5 years (IQR: 19–77); 58% were male; 66% reported BCG vaccination.M. bovisexposure was via direct contact with infected cattle and consumption of raw milk. One participant in the high-risk group was IGRA positive, all other participants were IGRA negative. Estimated IGRA positivity rate was 1.1% (95% CI 0.058%–7.0%) in all participants and 4.0% (95%CI 0.21%–22%) in participants with high exposure levels.

Conclusions

We found limited LTBI in individuals in contact with TB-infected cattle in England, despite high and prolonged exposure. We identified a high-risk group of farmers who should be prioritised for future engagement.
Cost comparison of unplanned hospital admissions from care home and community settings: A retrospective cohort study using routinely collected linked data
Authors: Geue C , Ciminata G , Reddy Mukka G , Mackay D , Lewsey J , Friday JM , Dundas R , Tran QB , Brown D , Ho F , Hastie C , Fleming M , Stevenson A , du Toit C , Padmanabhan S , Pell JP
Published: June 2024

People living in care homes often have multiple morbidities and complex healthcare needs, potentially leading to more frequent healthcare utilisation (planned and unplanned) and increased costs. Unscheduled hospital attendance from a care home setting is often regarded as system failure, futile and inefficient in terms of resource use. However, there is a lack of evidence on the costs associated with these attendances. This retrospective cohort study aims to estimate these costs and provides a comparison by usual place of residence. Data were obtained from NHS Greater Glasgow and Clyde Safe Haven reference datasets. Individual-level record linkage between Trak ED, recording emergency admissions, and other routine healthcare datasets was carried out. Healthcare costs were estimated using a two-part model. The first part used a probit model to estimate the probability of positive healthcare resource utilisation, and the second part used a GLM to estimate costs, conditional on costs being positive. Annual mean costs were higher for care home residents than community-dwellers overall and in both men and women and all deprivation quintiles. No significant difference in costs was observed for care home residents who were younger than 65 years and those with no comorbidity. Our results indicate a notable increase in healthcare expenditure for individuals residing in care homes compared to those living in the community following unplanned acute care incidents, emphasising the importance of developing interventions that are specifically designed to meet the unique requirements of this demographic.
A unified genome constraint, pathogenicity, and pLoF model identifies new genes associated with epilepsy
Authors: Aguilar Oscar , Rivas Mijail , Rivas Manuel A.
Published: June 2024

Background

Epilepsy is a highly heterogeneous disorder thought to have strong genetic components. However, identifying these risk factors using whole-exome sequencing studies requires very large sample sizes and good signal-to-noise ratio in order to assess the association between rare variants in any given gene and disease.

Methods

We present a novel approach for predicting constraint in the human genome – sections of the genome where any mutation can cause a severe disorder. Through application of a Hidden Markov Model (HMM) to the Regeneron Genetics Center Million Exome dataset and the AllofUs whole genome sequencing data, we predict the probability of observing no variants across the population for each position in the genome. Next, we aggregate the constraint predictions by gene and assess its association to epilepsy. Finally, we extend our analysis model to incorporate pathogenicity predictions from AlphaMissense (AM) and pLoFs, and compare against published results.

Results

We identified a set of (p < 1×10−4) genes with stronger signals than previously published studies including KDM5B, KCNQ2, CACNA1A, CACNA1B, RYR2, and ATP2B2. Our models allow us to evaluate the contribution of constraint, protein structure based pathogenicity prediction from AM, and pLoFs jointly.

Conclusion

We showed that relatively simple sequence-dependent constraint prediction models can complement structure-based missense variant pathogenicity predictions and pLoFs for population cohort studies which require additional statistical power in the identification of gene-based signals for neurogenetic and psychiatric disorders.
High-Throughput Genotyping ofPlasmodium vivaxin the Peruvian Amazon via Molecular Inversion Probes
Authors: Popkin-Hall Zachary R. , Niaré Karamoko , Crudale Rebecca , Simkin Alfred , Fola Abebe A. , Sanchez Juan F. , Pannebaker Danielle L. , Giesbrecht David J. , Kim Isaac E. , Aydemir Özkan , Bailey Jeffrey A. , Valdivia Hugo O. , Juliano Jonathan J.
Published: June 2024

Plasmodium vivaxtransmission occurs throughout the tropics and is an emerging threat in areas ofPlasmodium falciparumdecline, causing relapse infections that complicate treatment and control. Targeted sequencing forP. falciparumhas been widely deployed to detect population structure and the geographic spread of antimalarial and diagnostic resistance. However, there are fewer such tools forP. vivax. Leveraging global variation data, we designed four molecular inversion probe (MIP) genotyping panels targeting geographically differentiating SNPs, neutral SNPs, putative antimalarial resistance genes, and vaccine candidate genes. We deployed these MIP panels on 866 infections from the Peruvian Amazon and identified transmission networks with clonality (IBD>0.99), copy number variation inPvdbpand multiplePvrbps, fixation of putative antimalarial resistance, and balancing selection in 13 vaccine candidate genes. Our MIP panels are the broadest genotyping panel currently available and are poised for successful deployment in other regions ofP. vivaxtransmission.
Diverging Patterns of Cognitive Decline by Sex and Race-Ethnicity in Seriously Ill Older Americans
Authors: Mejía-Guevara Iván , Periyakoil V.S.
Published: June 2024

Objectives

Differences in Cognitive decline are common in older adults in the last years of life, but differences across sex and race-ethnicity are poorly understood. This study investigated if sex and/or race-ethnicity moderated changes in cognitive function in older adults in the last years of life.

Methods

Data from the Health and Retirement Study (HRS) from 1993 to 2016 were used to analyze imputed cognition summary scores for total word recall and mental status of older adults aged 60-99. Loss of cognitive function was estimated using a multilevel mixed-effects model and accelerated cognitive decline was approximated by incorporating a change-point model using a restricted sample of decedent respondents who died aged 65-99.

Results

Notable disparities were seen in the rates of cognitive decline across sex and race-ethnic groups in the last years of life. Women consistently scored lower than men in word recall but higher in mental status, regardless of race-ethnicity. Non-Hispanic White respondents, men and women, consistently outperformed Hispanic and Black respondents in word recall tasks and mental status.

Conclusions

Our study shows that sex and race-ethnicity moderate cognitive decline in older adults during the last years of life. Older adults from underserved communities are at higher risk of cognitive decline. Our study could inform clinical practice and policy focused on mitigating the adverse impact of cognitive decline experienced by marginalized populations of older adults in the last years of life.
Clinical characteristics and prognosis in patients with acute myocarditis or unexplained acute chest pain: a nationwide longitudinal cohort study
Authors: Björkenstam Marie , Bobbio Emanuele , Polte Christian L. , Hjalmarsson Clara , Bergh Niklas , Omerovic Elmir , Bollano Entela
Published: June 2024

Background

Acute myocarditis is a disease with variable prognosis, ranging from complete recovery to end-stage heart failure (HF) and death. The aim of this study was to examine the risk of mortality and HF in patients with suspected acute myocarditis (AM) in comparison to patients hospitalized for unexplained acute chest pain (ACP).

Methods

We used the SWEDEHEART-registry to identify patients >16 years admitted to hospital between 1 January 1998 and 31 December 2018 with either AM or ACP. Risks of all-cause mortality and development of HF were calculated and compared by use of adjusted Cox regression analyses.

Results

A total of 3,792 patients with AM and 109,934 patients with ACP were included. Median follow-up time was 7.8 years (Q1, Q3; 3.4, 12.3). AM patients were younger compared to ACP patients, median age 37 years (Q1, Q3; 26, 52) vs 59 years (Q1, Q3; 49, 69), and more likely to be men (79.9% vs 51.4%, p <0.001). Comorbidity burden was lower within the AM cohort. Chest pain was the most common presenting symptom in both groups. Mortality rate at 30 days (OR 3.75, 95% CI 1.9-7.3, p<0,001) as well as long term (OR 2.0, 95% CI 1.69-2.39, p <0.001) were significantly higher among AM patients and AM patients were more likely to develop HF during follow-up (OR 2.3, 95% CI 1.81-2.93, p<0,001).

Conclusions

AM patients had a worse short -and long-term outcome compared with ACP. The risk for development of HF was higher for AM patients even after the first year.
Relative Improvement in Language vs Motor Functions with Reperfusion Therapies for Acute Stroke due to Large Vessel Occlusion
Authors: Ahmad Zaka , Yedavalli Vivek , Sarmiento Gonzalez Wladimir , Hillis Argye E.
Published: June 2024

Background

When weighing potential risks versus benefits of reperfusion therapy, the functions likely to recover if blood flow can be restored should be considered. Because deep and motor areas of the brain often infarct relatively early in acute stroke, we hypothesized that reperfusion therapies are more likely to improve language function and neglect (cortical functions) more than motor function.

Methods

In this retrospective review of a prospectively collected database, patients with acute stroke due to large vessel occlusion), we evaluated percent improvement (mean change in score/maximum score) for different items of the National Institutes of Health Score Scale with and without endovascular thrombectomy, and/or intravenous thrombolysis.

Results

In total, 290 patients (mean age 61.8; SD 14.0; 47.9% female) met the inclusion criteria. For all outcome measures (percent change in language, total language, motor, and neglect) there were significant effects of treatment group (p<0.0001 for all), with the greatest change in the EVT +tPA group, then EVT only group, followed by tPA only, followed by no intervention. Differences between EVT + tPA and EVT only were not significant (p=.30 to 0.79 across outcomes). For patients with aphasia and/or right sided weakness before treatment, the percent change in language was significantly greater than the percent change in weakness (29.8% vs. 12.7%; t(93)=5.3;p<0.0001). Greater percent improvement in language was observed in all treatment groups (p=0.0003 to 0.03 across treatment groups).

Conclusions

In patients with acute ischemic stroke due to LVO, improvements in all neurological functions occur with tPA, and even more with EVT (with and without IV tPA). However, gains in language are even greater than gains in motor function with both interventions. Few patients had neglect before treatment, but of those who did, the majority improved, and most (92.8%) improved with EVT.