bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epigenome-wide characterization reveals aberrant DNA methylation of host genes regulating CD4+ T cell HIV-1 reservoir size in women with HIV
Authors: Xu Ke , Zhang Xinyu , Asam Kesava , Quach Bryan C. , Page Grier P. , Konkle-Parker Deborah , Martinez Claudia , Lahiri Cecile D. , Topper Elizabeth T. , Cohen Mardge H. , Kassaye Seble G. , DeHovitz Jack , Kuniholm Mark H. , Archin Nancie M. , Valizadeh Amir , Tien Phyllis C. , Marconi Vincent C. , Hancock Dana B. , Johnson Eric Otto , Aouizerat Bradley E. 
Published: July 2024

AbstractThe underlying mechanism of the HIV-1 reservoir, a major barrier to an HIV cure, is largely unknown. The integration of HIV-1 DNA and immune defense mechanisms can disrupt the host epigenetic landscape, potentially silencing HIV-1 replication. Using bisulfite capture DNA methylation sequencing, we profiled approximately 3.2 million CpG sites in CD4+T cells isolated from the blood of 427 virally suppressed women with HIV. The average total CD4+T cell HIV-1 Reservoir (HRCD4) size was 1,409 copies per million cells. Most proviruses were defective with only a small proportion being intact. We found 245 differentially methylated positions (CpG sites) and 85 methylated regions associated with the total HRCD4size. Notably, 52% of significant methylation sites were in intronic regions. HRCD4-associated genes were involved in viral replication (e.g.,ISG15), HIV-1 latency (e.g.,MBD2), and cell growth and apoptosis (e.g.,IRF9). A subset of the identified genes with aberrant methylation was an established target of HIV-1 integration (e.g.,NFIA, SPPL3, DLEU2, ELMSAN1). Overall, HRCD4size was inversely associated with DNA methylation of interferon signaling genes and positively associated with methylation at established HIV-1 integration sites. HRCD4-associated genes were enriched in pathways including immune defense against the virus (i.e., interferon-α response and interferon-γ response), DNA binding transcription repression, and host-virus interaction such as Tau protein binding. Together, our results show that epigenomic alterations in CD4+T cells are associated with total HIV-1 reservoir size, offering new insights into HIV-1 latency and may provide potential molecular targets for future HIV-1 eradication strategies.
Proteomic Profiling Reveals Age-Related Changes in Transporter Proteins in the Human Blood-Brain Barrier
Authors: Zhou Xujia , Azimi Mina , Handin Niklas , Riselli Andrew , Vora Bianca , Chun Eden , Yee Sook Wah , Artursson Per , Giacomini Kathleen M 
Published: July 2024

AbstractThe Blood-Brain Barrier (BBB) is a crucial, selective barrier that regulates the entry of molecules including nutrients, environmental toxins, and therapeutic medications into the brain. This function relies heavily on brain endothelial cell proteins, particularly transporters and tight junction proteins. The BBB continues to develop postnatally, adapting its selective barrier function across different developmental phases, and alters with aging and disease. Here we present a global proteomics analysis focused on the ontogeny and aging of proteins in human brain microvessels (BMVs), predominantly composed of brain endothelial cells. Our proteomic profiling quantified 6,223 proteins and revealed possible age-related alteration in BBB permeability due to basement membrane component changes through the early developmental stage and age-dependent changes in transporter expression. Notable changes in expression levels were observed with development and age in nutrient transporters and transporters that play critical roles in drug disposition. This research 1) provides important information on the mechanisms that drive changes in the metabolic content of the brain with age and 2) enables the creation of physiologically based pharmacokinetic models for CNS drug distribution across different life stages.
Epithelial memory after respiratory viral infection results in long-lasting enhancement of antigen presentation
Authors: Janas Piotr P. , T’Jonck Wouter , Burgess Matthew O. , Chauché Caroline , Vermeren Matthieu , Lucas Christopher , Bain Calum , Illingworth Robert , Roberts Edward W. , McSorley Henry J. , Schwarze Jürgen 
Published: July 2024

AbstractBackgroundViral lower respiratory tract infections (LRTIs) can reduce severity of subsequent LRTIs but have also been linked to respiratory allergy development and exacerbation. Here, we show that viral LRTI can imprint lung epithelial cells (LECs), leading to long-term phenotypic and functional changes in their response to subsequent challenges.MethodsMice were infected via intranasal administration of respiratory syncytial virus (RSV). After 28 days, LECs were isolated using cold dispase digestion followed by magnetic-activated cell sorting. Epigenetic changes were assessed using CUT&RUN, while transcriptional changes were evaluated using NanoString and qPCR. Flow cytometry was employed to measure cell surface MHC levels, antigen uptake and processing rates, and OT-I proliferation.ResultsWe identified epigenetic and transcriptomic changes in murine LECs 28 days post respiratory syncytial virus (RSV) infection after recovery in genes associated with major histocompatibility complexes (MHC). Lasting upregulation of MHC-I and MHC-II was further increased followingin vivoLPS stimulation. Importantly, MHC upregulation was associated with increased antigen uptake and processing, as well as increased antigen presentation to T cells.ConclusionsOur data suggest that LRTI can induce long-term upregulation of antigen-presentation by LECs, thus facilitating local T cell responses to microbial antigens and allergens, potentially enhancing immunity or in susceptible hosts respiratory allergy.
Modelling molecular differences in the innate immune system responses of chickens and ducks to highly pathogenic avian influenza virus
Authors: Wood Tamsin , An Gary , Bryant Clare E. , Ferguson Brian J. 
Published: July 2024

AbstractHighly pathogenic avian influenza virus (HPAIV) presents a global threat to chicken livestock; chickens infected by HPAIV tend to show severe symptoms and high mortality rates. In 2022, the largest recorded outbreak of HPAIV in Europe resulted in millions of chickens being culled in the UK alone to try to prevent further spread. Unlike chickens, mallard ducks show reduced symptom severity and lower mortality rates to HPAIV infection. Research into the immune system responses of these two species shows they differ in their molecular outputs: chickens produce a pro-inflammatory response; mallards produce an anti-viral response. These differences in immune responses are thought to be in part due to chickens missing pattern recognition receptor retinoic acid-inducible gene-I (RIG-I). This project aimed to model the innate immune systems of chickens and mallard ducks to an abstracted molecular level. A literature search was conducted, and the immune systems were modelled in NetLogo as an avian innate immune response agent-based model (AIIRABM). The AIIRABM enabled examination of the relative importance of molecular differences between the chicken and mallard duck innate immune systems and produced similar differences in chicken and mallard duck molecular outputs to those observedin vitroandin vivo. Simulation experiments with the AIIRABM supported the molecular difference RIG-I as key in causing the differences in the chicken and mallard duck innate immune responses to HPAIV. The AIIRABM will be used in further research on the chicken and mallard duck immune responses to HPAIV as the baseline in an iterative modelling cycle.
Reticulon dependent ER-phagy mediates adaptation to heat stress inC. elegans
Authors: Scarcelli Vincent , Serot Claudia , Pouget Alexandre , Largeau Céline , Sagot Audrey , El-Hachimi Kenza , Dupuy Denis , Culetto Emmanuel , Lefebvre Christophe , Legouis Renaud 
Published: July 2024

SummaryThe selective degradation of ER by autophagy, named ER-phagy, promotes the recovery of ER homeostasis after a stress. Depending on the ER stress, different types of ER-phagy involve various selective autophagy receptors. In this study, we report a macroER-phagy induced by the fragmentation of tubular ER in response to acute heat stress. We identified a novel ER-phagy receptor encoded by the reticulon long isoform RET-1d. RET-1d is mainly expressed in the nervous system and the epidermis and colocalize with the ubiquitin-like autophagy protein LGG-1/GABARAP during heat stress induced autophagy. Two LIR motifs in the long intrinsically disordered region of RET-1d mediate its interaction with LGG-1 protein. The specific depletion of RET-1d isoform resulted in a delay in autophagosome biogenesis and a decrease in the capacity of animals to adapt to heat stress. Our data revealed a RET-1d dependent ER-phagy mechanism that takes place in neurons and epidermis and participates to the adaptation ofC. elegansto heat stress.
Segmentation and Feature Extraction of Fingernail Plate and Lunula Based on Deep Learning
Authors: Fan Yu , You Mengxiang , Ge Jieyu , Zhai Guangtao , Wang Sijia 
Published: July 2024

AbstractThis paper proposes a novel deep learning method for accurate segmentation of the fingernail plate and lunula. To achieve this, we designed a new network structure called Nailnet, which segments the fingernail from images of the whole hand. The results show that Nailnet achieved an Intersection over Union (IoU) score of 0.9529 and an accuracy of 0.9725 for fingernail plate segmentation. For lunula segmentation, Nailnet achieved an IoU score of 0.7784 and an accuracy of 0.8846. Additionally, Nailnet successfully recognized the fingernail index, enabling the extraction of various fingernail phenotypes, including plate color, plate shape, lunula color, and lunula proportion.
Statistical learning beyond words in human neonates
Authors: Fló Ana , Benjamin Lucas , Palu Marie , Dehaene-Lambertz Ghislaine 
Published: July 2024

ABSTRACTInterest in statistical learning in developmental studies stems from the observation that 8-month-olds were able to extract words from a monotone speech stream solely using the transition probabilities (TP) between syllables (Saffran et al., 1996). A simple mechanism was thus part of the human infant’s toolbox for discovering regularities in language. Since this seminal study, observations on statistical learning capabilities have multiplied across domains and species, challenging the hypothesis of a dedicated mechanism for language acquisition. Here, we leverage the two dimensions conveyed by speech –speaker identity and phonemes– to examine (1) whether neonates can compute TPs on one dimension despite irrelevant variation on the other and (2) whether the linguistic dimension enjoys an advantage over the voice dimension. In two experiments, we exposed neonates to artificial speech streams constructed by concatenating syllables while recording EEG. The sequence had a statistical structure based either on the phonetic content, while the voices varied randomly (Experiment 1) or on voices with random phonetic content (Experiment 2). After familiarisation, neonates heard isolated duplets adhering, or not, to the structure they were familiarised with. In both experiments, we observed neural entrainment at the frequency of the regularity and distinct Event-Related Potentials (ERP) to correct and incorrect duplets, highlighting the universality of statistical learning mechanisms and suggesting it operates on virtually any dimension the input is factorised. However, only linguistic duplets elicited a specific ERP component, potentially an N400 precursor, suggesting a lexical stage triggered by phonetic regularities already at birth. These results show that, from birth, multiple input regularities can be processed in parallel and feed different higher-order networks.HIGHLIGHTSHuman neonates are sensitive to regularities in speech, encompassing both phonetic content and voice dimension.There is no observed advantage for statistical computations of linguistic content over voice content.Both speech dimensions are processed in parallel by distinct networks.Phonetic regularities evoked a specific ERP component in the post-learning phase, suggesting activations along the pathway to the lexicon.
Cdhr1a and pcdh15b link photoreceptor outer segments with inner segment calyceal processes revealing a potential mechanism for cone-rod dystrophy
Authors: Patel Meet K. , Piedade Warlen , Famulski Jakub K. 
Published: July 2024

ABSTRACTCone rod dystrophy (CRD) is a macular degeneration disorder characterized by initial cone cell photoreceptor degeneration and subsequently of rod photoreceptors. Mutations in CDHR1, a photoreceptor specific cadherin have been found to be associated with the incidence of cone-rod dystrophy and recapitulated in mouse CDHR1 knockouts. However, the molecular function of CDHR1 remains unknown. CDHR1 has been shown to localize at the leading edge of murine rod nascent outer segment (OS) making junctions to an unknown partner in the inner segment. Using Structured Illumination Microscopy (SIM), we observed that the localization of zebrafish cdhr1a extends from basal nascent OS discs above the periciliary ridge of the inner segment to a considerable length along the OS, akin to calyceal process (CPs). When labeling the CPs using pcdh15b, a CP specific cadherin, we observed that cdhr1a at the leading edge of OS juxtaposes with pcdh15b in the CP. Similar localization patterns were detected in human, macaque, xenopus, ducks, and various rodent PRCs indicating conservation. Importantly, using immunoprecipitation and K652 cell aggregation assays we demonstrate that pcdh15b and cdhr1a can interact and potentially link the OS and CP. To analyze the consequences of OS-CP interactions in CRD, we established a zebrafishcdhr1amutant line (cdhr1afs*146) and analyzed CRD progression at high temporal resolution. Homozygouscdhr1afs*146mutants begin to exhibit minor cone OS morphology defects starting at 15 dpf (days post fertilization) and severe OS disruption and cell loss by 3 months. Rod OS defects were delayed until 3-6 months. Furthermore, we show that loss of cdhr1a function leads to disorganization and shortening of CPs coinciding with cone outer OS defects which is significantly exacerbated when combined with the loss of pcdh15b. In conclusion, we propose that cdhr1a and pcdh15b function to link cone OSs with CPs to maintain proper OS homeostasis thus revealing a potential novel mechanism for CRD.
Signatures of selective sweeps in continuous-space populations
Authors: Chotai Meera , Wei Xinzhu , Messer Philipp W. 
Published: July 2024

AbstractSelective sweeps describe the process by which an adaptive mutation arises and rapidly fixes in the population, thereby removing genetic variation in its genomic vicinity. The expected signatures of selective sweeps are relatively well understood in panmictic population models, yet natural populations often extend across larger geographic ranges where individuals are more likely to mate with those born nearby. To investigate how such spatial population structure can affect sweep dynamics and signatures, we simulated selective sweeps in populations inhabiting a two-dimensional continuous landscape. The maximum dispersal distance of offspring from their parents can be varied in our simulations from an essentially panmictic population to scenarios with increasingly limited dispersal. We find that in low-dispersal populations, adaptive mutations spread more slowly than in panmictic ones, while recombination becomes less effective at breaking up genetic linkage around the sweep locus. Together, these factors result in a trough of reduced genetic diversity around the sweep locus that looks very similar across dispersal rates. We also find that the site frequency spectrum around hard sweeps in low-dispersal populations becomes enriched for intermediate-frequency variants, making these sweeps appear softer than they are. Furthermore, haplotype heterozygosity at the sweep locus tends to be elevated in low-dispersal scenarios as compared to panmixia, contrary to what we observe in neutral scenarios without sweeps. The haplotype patterns generated by these hard sweeps in low-dispersal populations can resemble soft sweeps from standing genetic variation that arose from substantially older alleles. Our results highlight the need for better accounting for spatial population structure when making inferences about selective sweeps.
SGLT2 inhibitors activate pantothenate kinase in the human heart
Authors: Forelli Nicholas , Eaton Deborah , Patel Jiten , Bowman Caitlyn E. , Kawakami Ryo , Kuznetsov Ivan A. , Li Kristina , Brady Claire , Bedi Kenneth , Yang Yijun , Koya Kaustubh , Megill Emily , Kanter Daniel S. , Smith Louis G. , Bowman Gregory R. , Snyder Nathaniel , Edwards Jonathan , Margulies Kenneth , Arany Zoltan 
Published: July 2024

AbstractInhibitors of sodium glucose cotransporter-2 (SGLT2i) demonstrate strong symptomatic and mortality benefits in the treatment of heart failure but appear to do so independently of SGLT2. The relevant pharmacologic target of SGLT2i remains unclear. We show here that SGLT2i directly activate pantothenate kinase 1 (PANK1), the rate-limiting enzyme that initiates the conversion of pantothenate (vitamin B5) to coenzyme-A (CoA), an obligate co-factor for all major pathways of fuel use in the heart. Using stable-isotope infusion studies, we show that SGLT2i promote pantothenate consumption, activate CoA synthesis, rescue decreased levels of CoA in human failing hearts, and broadly stimulate fuel use inex vivoperfused human cardiac blocks from patients with heart failure. Furthermore, we show that SGLT2i bind to PANK1 directly at physiological concentrations and promote PANK1 enzymatic activity in assays with purified components. Novelin silicodynamic modeling identified the site of SGLT2i binding on PANK1 and indicated a mechanism of activation involving prevention of allosteric inhibition of PANK1 by acyl-CoA species. Finally, we show that inhibition of PANK1 prevents SGLT2i-mediated increased contractility of isolated adult human cardiomyocytes. In summary, we demonstrate robust and specific off-target activation of PANK1 by SGLT2i, promoting CoA synthesis and efficient fuel use in human hearts, providing a likely explanation for the remarkable clinical benefits of SGLT2i.
A Novel Computational Pre-Procedural Planning Model for Coronary Interventions Based on Coronary CT Angiography
Authors: Lyu Mengzhe , Liang Ce , Zhang Xuehuan , Wang Xiao , Li Qiaoqiao , Torii Ryo , Ventikos Yiannis , Chen Duanduan 
Published: July 2024

AbstractIn percutaneous coronary intervention (PCI), the ability to predict post-PCI fractional flow reserve (FFR) and stented vessel informs procedural planning. However, highly precise and effective methods to quantitatively simulate coronary intervention are lacking. This study developed a validated virtual coronary intervention (VCI) technique for non-invasive physiological and anatomical assessment of PCI. In this study, patients with substantial lesions (pre-PCI FFR of less than 0.80) were enrolled. VCI framework was used to predict vessel reshape and post-PCI FFR. The accuracy of predicted post-VCI FFR, luminal cross-sectional area (CSA) and centreline curvature was validated with post-PCI computed tomography (CT) angiography datasets. Overall, 21 patients were selected for the study, of which 9 patients (9 vessels) were included in the analysis. The average time for PCI simulation was 24.92 ± 1.00 s on a single processor. The calculated post-PCI FFR was 0.92 ± 0.09 and the predicted post-VCI FFR was 0.90 ± 0.08 (mean difference: -0.02 ± 0.05 FFR unit; limits of agreement: -0.08 to 0.05). Morphologically, the predicted CSA is 16.36 ± 4.41 mm2and post-CSA is 17.91 ± 4.84 mm2(mean difference: -1.55 ± 1.89 mm2; limits of agreement: -5.22 to 2.12), the predicted centreline curvature of stented region is 0.15 ± 0.04 mm□1and post-PCI centreline curvature is 0.17 ± 0.03 mm□1(mean difference: -0.02 ± 0.06 mm□1; limits of agreement: -0.12 to 0.09). The proposed VCI technique achieves non-invasive pre-procedural anatomical and physiological assessment of coronary intervention. The proposed model has the potential to optimize PCI pre-procedural planning and improve the safety and efficiency of PCI.HighlightsPresent a computational pre-procedural planning model for coronary interventions.Develop a computational framework to predict post-PCI FFR.Validation of the model with post-PCI CT angiography datasets.The proposed model has the potential to optimize PCI pre-procedural planning.
Unlocking the Potential: FKK6 as a Microbial Mimicry-Based Therapy for Chronic Inflammation-Associated Colorectal Cancer in a Murine Model
Authors: Sládeková Lucia , Li Hao , DesMarais Vera M. , Beck Amanda P. , Guzik Hillary , Vyhlídalová Barbora , Gu Haiwei , Mani Sridhar , Dvořák Zdeněk 
Published: July 2024

ABSTRACTChronic intestinal inflammation significantly contributes to the development of colorectal cancer (CRC) and remains a pertinent clinical challenge, necessitating novel therapeutic approaches. Indole-based microbial metabolite mimics FKK6, which is a ligand and agonist of the pregnane X receptor (PXR), was recently demonstrated to have PXR-dependent anti-inflammatory and protective effects in a mouse model of dextran sodium sulfate (DSS)-induced acute colitis. Here, we examined the therapeutic potential of FKK6 in a mouse model (C57BL/6 FVB humanized PXR mice) of colitis-associated colon cancer (CAC) induced by azoxymethane (AOM) and dextran sodium sulfate (DSS). FKK6 (2 mg/kg) displayed substantial anti-tumor activity, as revealed by reduced size and number of colon tumors, improved colon histopathology, and decreased expression of tumor markers (c-MYC, β-catenin, Ki-67, cyclin D) in the colon. In addition, we carried out the chronic toxicity (30 days) assessment of FKK6 (1 mg/kg and 2 mg/kg) in C57BL/6 mice. Histological examination of tissues, biochemical blood analyses, and immunohistochemical staining for Ki-67 and γ-H2AX showed no difference between FKK6-treated and control mice. Comparative metabolomic analyses in mice exposed for 5 days to DSS and administered with FKK6 (0.4 mg/kg) revealed no significant effects on several classes of metabolites in the mouse fecal metabolome. Ames and micronucleus tests showed no genotoxic and mutagenic potential of FKK6in vitro. In conclusion, anticancer effects of FKK6 in AOM/DSS-induced CAC, together with FKK6 safety data fromin vitrotests andin vivochronic toxicity study, and comparative metabolomic study, are supportive of the potential therapeutic use of FKK6 in the treatment of CAC.