bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD8 T-cell dysfunction is linked with CAR T-cell failure and can be mitigated by a non-alpha IL-2 agonist, pegenzileukin
Authors: Reville Patrick K , Sheikh Irtiza N , Choi Ahyun , Dai Enyu , Henderson Jared , Li Xubin , Rojas Estela , Le Cuong , Okwuchi Chizitara , Devonish Mikielia , Carrio Roberto , Pate Nathan , Malley Katie , Bangari Dinesh , Givigan Julie-Ann , Shi Chaomei , Liu Bing , Byers Tony , Westin Jason , Ahmed Sairah , Fowler Nathan , Fayad Luis , Lee Hun Ju , Nastoupil Loretta , Sassoon Ingrid , Cucchetti Margot , Wang Rui , Agarwal Maria , Abbadessa Giovanni , Meng Robin , Meibalan Elamaran , Powers Laura , Cao James , Ying Xiaoyou , Balko Kelly , Yu Qunyan , Jiao Jing , Cortez-Retamozo Virna , Sidhu Sukhvinder , Shaffer Donald , Neelapu Sattva , Wang Linghua , Li Xiangming , Green Michael 
Published: August 2023

SUMMARYChimeric antigen receptor (CAR) T-cell therapy has been a breakthrough for relapsed or refractory large B-cell lymphoma (rrLBCL). However, suboptimal CAR T-cell activity can lead to therapeutic failure and dismal outcome. Using single cell RNA-sequencing of rrLBCL tumors, we identify a prominent population of clonally expanded dysfunctional CAR+ CD8 T-cells indicative of ongoing tumor cell engagement, proliferation, and dysfunction at the time of progression from CAR T-cell therapy. Furthermore, we show that rrLBCL patient-derived CAR T-cells are more prone to dysfunction and loss of cytotoxicity compared to healthy donor-derived CAR T-cells. Using both antigen-driven and CAR-driven models of T-cell dysfunction, we show that pegenzileukin, a non-alpha IL2 agonist, can prevent T-cell dysfunction. In bothin vitroandin vivoCAR T-cell models, pegenzileukin improved T-cell expansion and tumor control. This provides pre-clinical rational for use of pegenzileukin in combatting T-cell dysfunction, a central mechanism of CAR T-cell failure.HIGHLIGHTSTumor-infiltrating CD8 CAR T-cells show clonal expansion and dysfunction at the time of progression.rrLBCL patient-derived CAR T-cells are more prone to dysfunction compared to healthy-donor-derived CAR T-cells.Pegenzileukin, a non-alpha IL2 agonist, rescues antigen– and CAR-driven CD8 T-cell dysfunction and improves CAR T-cell responses in vivo.
Cis-regulatory polymorphism atfizecdysone oxidase contributes to polygenic adaptation to malnutrition inDrosophila
Authors: Cavigliasso Fanny , Savitskiy Mikhail , Koval Alexey , Erkosar Berra , Savary Loriane , Gallart-Ayala Hector , Ivanisevic Julijana , Katanaev Vladimir L. , Kawecki Tadeusz J. 
Published: August 2023

AbstractWe investigate the contribution of a candidate gene,fiz(fezzik), to complex polygenic adaptation to juvenile malnutrition inDrosophila melanogaster. We show that experimental populations adapted during >250 generations of experimental evolution to a nutritionally poor larval diet (Selected populations) evolved several-fold lowerfizexpression compared to unselected Control populations. This divergence infizexpression is mediated by a cis-regulatory polymorphism. This polymorphism, which was originally present in a sample from a natural population in Switzerland, is distinct from a second cis-regulatory SNP previously identified in non-AfricanD. melanogasterpopulations, implying that two independent cis-regulatory variants promoting highfizexpression segregate in non-African populations. Enzymatic analyses of Fiz protein expressed inE. colidemonstrate that it has ecdysone oxidase activity acting on both ecdysone and 20-hydroxyecdysone. Four of fivefizparalogs annotated to ecdysteroid metabolism also show reduced expression in Selected larvae, suggesting that malnutrition-driven selection favored general downregulation of ecdysone oxidases. Finally, as an independent test of the role offizin poor diet adaptation, we show thatfizknockdown by RNAi results in faster larval growth on the poor diet, but at the cost of greatly reduced survival. These results imply that downregulation offizin Selected populations was favored because of its role in suppressing growth in response to nutrient shortage. However,fizdownregulation is only adaptive in combination with other changes evolved by Selected populations, such as in nutrient acquisition and metabolism, which ensure that the organism can actually sustain the faster growth promoted byfizdownregulation.
Machine learning-based investigation of regulated cell death for predicting prognosis and immunotherapy response in glioma patients
Authors: Zhang Wei , Liu Hongyi , Dang Ruiyue , Dai Luohuan , Liu Hongwei , Adegboro Abraham Ayodeji , Zhang Yihao , jiang Nian , Li Xuejun 
Published: August 2023

AbstractBackgroundGlioblastoma is a highly aggressive and malignant type of brain cancer that originates from glial cells in the brain, with a median survival time of 15 months and a 5-year survival rate of less than 5%. Regulated cell death (RCD) is the autonomous and orderly cell death under genetic control, controlled by precise signaling pathways and molecularly defined effector mechanisms, modulated by pharmacological or genetic interventions, and plays a key role in maintaining homeostasis of the internal environment. The comprehensive and systemic landscape of the RCD in glioma is not fully investigated and explored.MethodAfter collecting 18 RCD-related signatures from the opening literatures, we comprehensively explored the RCD landscape, integrating the multi-omics data, including large-scale bulk data, single-cell level data, glioma cell lines, and proteome level data. We also provided a machine learning framework for screening the potentially therapeutic candidates.ResultHere, we explored RCD-related phenotypes, investigated the profile of the RCD, and developed a RCD gene pair scoring system, named RCD.GP signature. Using the machine learning framework consisting of Lasso, RSF, XgBoost, Enet, CoxBoost and Boruta, we identified seven RCD genes as potential therapeutic targets in glioma and verified the SLC43A3 by q-PCR in glioma grades and glioma cell lines.ConclusionOur study provided comprehensive insights into the RCD roles in glioma, developed a robust RCD gene pair signature for predicting the prognosis of glioma patients, constructed a machine learning framework for screening the core candidates and identified the SLC43A3 as an oncogenic role and a prediction biomarker in glioblastoma.
Preliminary cross-sectional investigations into the human glymphatic system using multiple novel non-contrast MRI methods
Authors: Levendovszky Swati Rane , Flores Jaqueline , Peskind Elaine R. , Václavů Lena , van Osch Matthias J.P. , Iliff Jeffrey 
Published: August 2023

ABSTRACTWe discuss two potential non-invasive MRI methods to cross-sectionally study two distinct facets of the glymphatic system and its association with sleep and aging.We apply diffusion-based intravoxel incoherent motion (IVIM) imaging to evaluate pseudodiffusion coefficient,D*, or cerebrospinal fluid (CSF) movement across large spaces like the subarachnoid space (SAS). We also performed perfusion-based multi-echo, Hadamard encoded multi-delay arterial spin labeling (ASL) to evaluate whole brain cortical cerebral blood flow (CBF) and transendothelial exchange (Tex) of water from the vasculature into the perivascular space and parenchyma. Both methods were used in young adults (N=9, 6F, 23±3 years old) in the setting of sleep and sleep deprivation. To study aging, 10 older adults, (6F, 67±3 years old) were imaged after a night of normal sleep only and compared with the young adults.D*in SAS was significantly (p<0.05) lesser after sleep deprivation (0.014±0.001 mm2/s) than after normal sleep (0.016±0.001 mm2/s), but was unchanged with aging. Cortical CBF and Texon the other hand, were unchanged after sleep deprivation but were significantly lower in older adults (37±3 ml/100g/min, 476±66 ms) than young adults (42±2 ml/100g/min, 624±66 ms). IVIM was thus, sensitive to sleep physiology and multi-echo, multi-delay ASL was sensitive to aging.
Neuronal APOE4-induced Early Hippocampal Network Hyperexcitability in Alzheimer’s Disease Pathogenesis
Authors: Tabuena Dennis R. , Jang Sung-Soo , Grone Brian , Yip Oscar , Aery Jones Emily A. , Blumenfeld Jessica , Liang Zherui , Koutsodendris Nicole , Rao Antara , Ding Leonardo , Zhang Alex R. , Hao Yanxia , Xu Qin , Yoon Seo Yeon , Leon Samuel De , Huang Yadong , Zilberter Misha 
Published: August 2023

ABSTRACTThe full impact of apolipoprotein E4 (APOE4), the strongest genetic risk factor for Alzheimer’s disease (AD), on neuronal and network function remains unclear. We found hippocampal region-specific network hyperexcitability in young APOE4 knock-in (E4-KI) mice which predicted cognitive deficits at old age. Network hyperexcitability in young E4-KI mice was mediated by hippocampal region-specific subpopulations of smaller and hyperexcitable neurons that were eliminated by selective removal of neuronal APOE4. Aged E4-KI mice exhibited hyperexcitable granule cells, a progressive inhibitory deficit, and E/I imbalance in the dentate gyrus, exacerbating hippocampal hyperexcitability. Single-nucleus RNA-sequencing revealed neuronal cell type-specific and age-dependent transcriptomic changes, including Nell2 overexpression in E4-KI mice. Reducing Nell2 expression in specific neuronal types of E4-KI mice with CRISPRi rescued their abnormal excitability phenotypes, implicating Nell2 overexpression as a cause of APOE4-induced hyperexcitability. These findings highlight the early transcriptomic and electrophysiological alterations underlying APOE4-induced hippocampal network dysfunction and its contribution to AD pathogenesis with aging.
The adaptive immune response toTrichurisin wild versus laboratory mice: An established model system in context
Authors: Mair Iris , Fenn Jonathan , Wolfenden Andrew , Lowe Ann E. , Bennett Alex , Muir Andrew , Thompson Jacob , Dieumerci Olive , Logunova Larisa , Shultz Susanne , Bradley Janette E. , Else Kathryn J. 
Published: August 2023

AbstractLaboratory model organisms have provided a window into how the immune system functions. An increasing body of evidence, however, suggests that the immune responses of naive laboratory animals may differ substantially to those of their wild counterparts. Past exposure, environmental challenges and physiological condition may all impact on immune responsiveness. Chronic infections of soil-transmitted helminths impose significant health burdens on humans, livestock and wildlife, with limited treatment success. In laboratory mice, Th1 versus Th2 immune polarisation is the major determinant of helminth infection outcome. Here we compared antigen-specific immune responses to the soil-transmitted whipwormTrichuris murisbetween controlled laboratory and wild free-ranging populations of house mice (Mus musculus domesticus). Wild mice harbouring chronic, low-level infections produced lower levels of cytokines in response to Trichuris antigen than laboratory-housed C57BL/6 mice. Wild mouse effector/memory CD4+ T cell phenotype reflected the antigen-specific cytokine response across the Th1/Th2 spectrum. Increasing worm burden was associated with body condition loss. However, local Trichuris-specific Th1/Th2 balance was positively associated with worm burden only in older wild mice. Thus, although the fundamental relationships between the CD4+ T helper cell response and resistance to T. muris infection are similar in both laboratory and wildM.m.domesticus,there are quantitative differences and age-specific effects that are analogous to human immune responses. These context-dependent immune responses demonstrate the fundamental importance of understanding the differences between model and natural systems for translating mechanistic models to ‘real world’ immune function.
ClipperQTL: ultrafast and powerful eGene identification method
Authors: Zhou Heather J. , Ge Xinzhou , Li Jingyi Jessica 
Published: August 2023

AbstractA central task in expression quantitative trait locus (eQTL) analysis is to identify cis-eGenes (henceforth “eGenes”), i.e., genes whose expression levels are regulated by at least one local genetic variant. Among the existing eGene identification methods, FastQTL is considered the gold standard but is computationally expensive as it requires thousands of permutations for each gene. Alternative methods such as eigenMT and TreeQTL have lower power than FastQTL. In this work, we propose ClipperQTL, which reduces the number of permutations needed from thousands to 20 for data sets with large sample sizes (>450) by using the contrastive strategy developed in Clipper; for data sets with smaller sample sizes, it uses the same permutation-based approach as FastQTL. We show that ClipperQTL performs as well as FastQTL and runs about 500 times faster if the contrastive strategy is used and 50 times faster if the conventional permutation-based approach is used. The R package ClipperQTL is available athttps://github.com/heatherjzhou/ClipperQTL.
Does sex influence element accumulation in honey bees: workers vs drones
Authors: Zarić Nenad M. , Brodschneider Robert , Goessler Walter 
Published: August 2023

AbstractHoney bees are social insects that have divided their work. Bees have two sexes, male and female. Female honey bees are queens and worker bees, while males are called drones. Worker bees have different tasks in the hive including gathering of food, its processing, caring for brood, protecting the hive, produce wax, nourish workers, drones and queen. Drones are male bees whose only role is to mate with a virgin queen. Many studies have dealt with physiology, behavior, morphology of workers and drones. This is the first study that compared differences in element accumulation and composition between workers and drones honey bees. It was observed that worker honey bees have higher concentration, from 116 % to 517 %, of most elements analyzed. Drones had higher concentration of essential elements to bees, Na, Mg, P, S, K, Zn, Cu and especially Se which was 2.2-fold higher. These differences can be attributed to environmental exposure; reproductive role of drones, high Se in sperm; but mostly to the food workers and drones eat. Worker bees feed on unprocessed food, mostly pollen, which is rich in minerals. Drones are fed by worker bees pre-processed food. Here we show that worker honey bees have a filtering mechanism that enables them to accumulate non-essential elements and not pass them on through the processed food to drones or larva.
RichPathR: a gene set enrichment analysis and visualization tool
Authors: Regmi Binod , Brooks Stephen R. , Uhlman Andrew J. , Sun Hong-Wei 
Published: August 2023

AbstractGene set enrichment analysis (GSEA) is an important step for disease and drug discovery. Genomic, transcriptomics, proteomics and epigenetic analysis of tissue or cells generates gene lists that need to be further investigated in the known biological context. The advent of high-throughput technologies generates the vast number of gene lists that are up or down regulated together. One way of getting meaningful insights of the relationship of these genes is utilizing existing knowledge bases linking them with biological functions or phenotypes. Multiple public databases with annotated gene sets are available for GSEA, andenrichRis the most popular web application still requiring custom tools for large-scale mining.richPathRpackage is a collection of R functions that helps researchers carry out exploratory analysis and visualization of gene set enrichment usingEnrichR.AvailabilityThe package, test data and additional figures can be downloaded fromhttps://github.com/niams-bdmds/richPathR.git.Contactsunh1@nih.gov
Dysregulated actin dynamics and cofilin correlate with TDP-43 pathology in sporadic amyotrophic lateral sclerosis
Authors: Jagaraj Cyril Jones , Mehta Prachi , Parakh Sonam , Shadfar Sina , Jamali Shafi , Suchowerska Alexandra K , Sultana Jessica , Fath Thomas , Atkin Julie D 
Published: August 2023

AbstractAmyotrophic lateral sclerosis (ALS) is a fatal, rapidly progressive neurodegenerative disorder affecting motor neurons, that overlaps significantly with frontotemporal dementia (FTD). Most cases are sporadic (90%) with undefined aetiology, but pathological forms of TAR-binding protein 43 (TDP-43), involving its misfolding, aggregation and mislocalisation from the nucleus to the cytoplasm, are present in motor neurons in almost all cases (97%) and ∼45% FTD cases. Actin is the most abundant protein in eukaryotic cells, with structural roles in the cytoskeleton and diverse signalling functions. This includes neuronal-specific roles in dendritic spines, synapses, axonal growth cones, and plasticity. Actin is in constant dynamic equilibrium between two forms: free monomeric, globular actin (G-actin) and polymeric, filamentous actin (F-actin). Actin dynamics is regulated by several key actin-binding proteins, including tropomyosin 4.2 (Tpm4.2) and cofilin, which depolymerises actin filaments. Cofilin is activated by phosphorylation at Ser3 via LIM domain kinase1/2 (LIMK1/2), which is also regulated by phosphorylation via Rac1/cdc42. Here we demonstrate that actin dynamics is closely associated with pathological TDP-43 in ALS. More F-actin relative to G-actin was detected in lumbar spinal cords from both sporadic ALS patients and a mouse model displaying TDP-43 pathology (rNLS), and in neuronal cells expressing cytoplasmic TDP-43. Hence actin dynamics is dysregulated in sporadic ALS, resulting in more actin polymerization. We also detected increased levels of Tpm 4.2, Rac1/cdc42, and increased phosphorylation of both LIMK1/2 and cofilin, in sporadic ALS patients. TDP-43 also physically interacted with actinin vitroand in cell lysates, providing additional insights into actin dysregulation in ALS. rNLS mice display motor neuron loss and key ALS/MND behavioural phenotypes, and increased cofilin phosphorylation was also detected in these animals at symptom onset, implying that actin dynamics actively contributes to neurodegeneration. Moreover, pharmacological induction of actin polymerization produced features typical of pathological TDP-43 (cytoplasmic mis-localisation and formation of inclusions and stress granules) implying that actin dysregulation contributes to TDP-43 pathology in ALS. Importantly, we also detected more cofilin phosphorylation in spinal motor neurons from sporadic patients compared to healthy controls, revealing that our observations are clinically relevant and present in the relevant cell type. This study therefore identifies dysregulated actin dynamics as a novel disease mechanism associated with TDP-43 pathology and hence most ALS cases. It also implies that regulating cofilin or LIMK1/2 phosphorylation may be a novel therapeutic strategy in ALS, FTD and other diseases involving TDP-43 pathology.
Madariaga and Venezuelan equine encephalitis virus seroprevalence in rodent enzootic hosts in Eastern and Western Panama
Authors: Carrera Jean-Paul , Galué Josefrancisco , de Souza William M. , Torres-Cosme Rolando , Lezcano-Coba Carlos , Cumbrera Alberto , Vasilakis Nikos , Tesh Robert B. , Guzman Hilda , Weaver Scott C. , Vittor Amy Y. , Samudio Rafael , Pascale Juan Miguel , Valderrama Anayansi , Carrera Lorenzo Cáceres , Donnelly Christl A. , Faria Nuno R. 
Published: August 2023

AbstractWhile rodents are primary reservoirs of Venezuelan equine encephalitis virus (VEEV), their role in Madariaga virus (MADV) transmission remains uncertain, particularly given their overlapping geographic distribution. This study explores the interplay of alphavirus prevalence, rodent diversity, and land use within Darien and Western Panama provinces. A total of three locations were selected for rodent sampling in Darien province: Los Pavitos, El Real de Santa Maria and Santa Librada. Two sites were selected in Western Panama province: El Cacao and Cirí Grande. We used plaque reduction neutralization tests to assess MADV and VEEV seroprevalences in 599 rodents of 16 species across five study sites. MADV seroprevalence was observed at higher rates in Los Pavitos (Darien province), 9.0%, 95% CI: 3.6-17.6, while VEEV seroprevalence was elevated in El Cacao (Western Panama province), 27.3%, 95% CI: 16.1-40.9, and El Real de Santa María (Darien province), 20.4%, 95% CI: 12.6-29.7. Species likeOryzomys coesi, 23.1%, 95% CI: 5.0-53.8, andTransandinomys bolivaris, 20.0%, 95% CI: 0.5-71.6 displayed higher MADV seroprevalences than other species, whereasTransandinomys bolivaris, 80.0%, 95% CI: 28.3-99.4, andProechimys semispinosus, 27.3%, 95% CI: 17.0-39.6, exhibited higher VEEV seroprevalences. Our findings provide support to the notion that rodents are vertebrate reservoirs of MADV and reveal spatial variations in alphavirus seropositivity among rodent species, with different provinces exhibiting distinct rates for MADV and VEEV. Moreover, specific rodent species are linked to unique seroprevalence patterns for these viruses, suggesting that rodent diversity and environmental conditions might play a significant role in shaping alphavirus distribution.
Estimating seroprevalence of SARS-CoV-2 infection after a highly contagious Omicron outbreak: A cross sectional study in a university setting
Authors: Hou Ching-Wen , Williams Stacy , Trivino-Soto Guillermo , Boyle Veronica , Rainford David , Vicino Selina , Magee Mitch , Chung Yunro , LaBaer Joshua , Murugan Vel 
Published: August 2023

AbstractObjectiveThis study aimed to investigate the seroprevalence of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) antibodies among individuals aged 18 years and olderDesignProspective cohort study.SettingsPopulation-based study was conducted within the Arizona State University (ASU) community.ParticipantsThe study recruited 1,397 adult participants that volunteered over a period of three days (March 1-March 3 of 2022).Primary outcome measuresSeroprevalence was conducted in the community to assess the presence of SARS-CoV-2-specific antibodies resulting from previous exposure to SARS-CoV-2 and/or vaccination.ResultsThe seroprevalence of anti-receptor binding domain (RBD) antibodies was found to be 96.3% using a semi-quantitative chemiluminescent immunoassay and 98% using an electrochemiluminescent immunoassay. For anti-nucleocapsid (NC) antibodies, the seroprevalence was 39.1% by an ELISA assay and 41.4% by an electrochemiluminescent immunoassay. Individuals that experienced breakthrough infections exhibited the highest levels of anti-RBD antibodies. Additionally, saliva samples showed promise as a potential diagnostic biofluid for measuring antibody levels, as they exhibited a strong correlation with the data obtained from serum samples.ConclusionAccurate estimation of population-based serosurveillance for SARS-CoV- 2 will monitor the trend of infection in the community and delineate the geographical spread of the infection. Cumulative incidence of SARS-CoV-2 infection during and after outbreaks is crucial for informing the development of effective risk mitigation protocols within the community. Protocols may include measures such as encouraging booster shots, extending mask mandates, or transitioning to online classes. Serosurveys repeated at regular intervals can also guide containment measures in communities and prompt response to future outbreaks.Strengths and limitations of this studyWe simultaneously investigated active infection and seroprevalence for the university population.Our study was strengthened by having the participants’ self-report data independently validated with diagnostic tests.Saliva samples could be a potential diagnostic biofluid for measuring antibody levels.Our study was performed within the university setting therefore it only reflects the COVID-19 situation within that community.The number of breakthrough infections and the longitudinal samples were small, thus requiring confirmation.