bluuebunny/crossref_metadata_2025_split huggingface dataset:
Promotion of endoplasmic reticulum retrotranslocation by overexpression of E3 ubiquitin‐protein ligase synoviolin 1 reduces endoplasmic reticulum stress and preserves cone photoreceptors in cyclic nucleotide‐gated channel deficiency
Authors: Yang Fan , Ma Hongwei , Boye Sanford L. , Boye Shannon E. , Ding Xi‐Qin 
Published: August 2024

AbstractCone photoreceptor cyclic nucleotide‐gated (CNG) channels play an essential role in phototransduction and cellular Ca2+ homeostasis. Mutations in genes encoding the channel subunits CNGA3 and CNGB3 are associated with achromatopsia, progressive cone dystrophy, and early‐onset macular degeneration. Cone loss in patients with achromatopsia and cone dystrophy associated with CNG channel mutations has been documented by optical coherence tomography and in mouse models of CNG channel deficiency. Cone death in CNG channel‐deficient retinas involves endoplasmic reticulum (ER) stress‐associated apoptosis, dysregulation of cellular/ER Ca2+ homeostasis, impaired protein folding/processing, and impaired ER‐associated degradation (ERAD). The E3 ubiquitin‐protein ligase synoviolin 1 (SYVN1) is the primary component of the SYVN1/SEL1L ER retrotranslocon responsible for ERAD. Previous studies have shown that manipulations that protect cones and reduce ER stress/cone death in CNG channel deficiency, such as increasing ER Ca2+ preservation or treatment with an ER chaperone, increase the expression of SYVN1 and other components of the ER retrotranslocon. The present work investigated the effects of SYVN1 overexpression. Intraocular injection of AAV5‐IRBP/GNAT2‐Syvn1 resulted in overexpression of SYVN1 in cones of CNG channel‐deficient mice. Following treatment, cone density in Cnga3−/− mice was significantly increased, compared with untreated controls, outer segment localization of cone opsin was improved, and ER stress/apoptotic cell death was reduced. Overexpression of SYVN1 also led to increased expression levels of the retrotranslocon components, degradation in ER protein 1 (DERL1), ERAD E3 ligase adaptor subunit (SEL1L), and homocysteine inducible ER protein with ubiquitin‐like domain 1 (HERPUD1). Moreover, overexpression of SYVN1 likely enhanced protein ubiquitination/proteasome degradation in CNG channel‐deficient retinas. This study demonstrates the role of SYVN1/ERAD in cone preservation in CNG channel deficiency and supports the strategy of promoting ERAD for cone protection.
Fc immunoreceptors promote autophagy to regulate monocyte functions
Authors: Nugue Mathilde , D’Allemagne Marie , Koumantou Despoina , Vetillard Mathias , Cragg Mark S , Bourdely Pierre , Lotersztajn Sophie , Saveanu Loredana 
Published: August 2024

AbstractReceptors for the Fc fragment of immunoglobulin G (FcyRs) are critical in the defense against pathogens and in monoclonal antibody-based therapies. When activated by immune complexes or opsonized particles, FcyRs are endocytosed. Components of the endocytosis machinery are used during autophagy, a process which is triggered by starvation or by activation of specific receptors. In this work, we demonstrate that activation of FcyRs initiates autophagy, characterized by formation of p62 protein puncta and activation of ULK1, a major component of the autophagy initiation complex. Autophagy induction downstream of FcyRs activation involves the protein phosphatase Pp2a and its enzymatic activity, as demonstrated byin situprotein labeling. In animal models in which autophagy was inactivated or enhanced in myeloid cells, autophagy negatively regulates pro-inflammatory cytokine production downstream of FcyRs receptors, while being required for FcyRs -mediated antibody-induced cell phagocytosis and myeloid cell survival. Our results suggest that, for antibody-based therapeutic strategies that target the activation of FcyRs, an additional level of control can be obtained by manipulation of autophagy.
Learning to Move and Plan like the Knight: Sequential Decision Making with a Novel Motor Mapping
Authors: Velázquez-Vargas Carlos A. , Taylor Jordan A. 
Published: August 2024

AbstractMany skills that humans acquire throughout their lives, such as playing video games or sports, require substantial motor learning and multi-step planning. While both processes are typically studied separately, they are likely to interact during the acquisition of complex motor skills. In this work, we studied this interaction by assessing human performance in a sequential decision-making task that requires the learning of a non-trivial motor mapping. Participants were tasked to move a cursor from start to target locations in a grid world, using a standard keyboard. Notably, the specific keys were arbitrarily mapped to a movement rule resembling the Knight chess piece. In Experiment 1, we showed the learning of this mapping in the absence of planning, led to significant improvements in the task when presented with sequential decisions at a later stage. Computational modeling analysis revealed that such improvements resulted from an increased learning rate about the state transitions of the motor mapping, which also resulted in more flexible planning from trial to trial (less perseveration or habitual responses). In Experiment 2, we showed that incorporating mapping learning into the planning process, allows us to capture (1) differential task improvements for distinct planning horizons and (2) overall lower performance for longer horizons. Additionally, model analysis suggested that participants may limit their search to three steps ahead. We hypothesize that this limitation in planning horizon arises from capacity constraints in working memory, and may be the reason complex skills are often broken down into individual subroutines or components during learning.
Atlas-scale Single-cell DNA Methylation Profiling with sciMETv3
Authors: Nichols Ruth V. , Rylaarsdam Lauren E. , O’Connell Brendan L. , Shipony Zohar , Iremadze Nika , Acharya Sonia N. , Adey Andrew C. 
Published: August 2024

SummarySingle-cell methods to assess DNA methylation have not yet achieved the same level of cell throughput compared to other modalities. Here, we describe sciMETv3, a combinatorial indexing-based technique that builds on our prior technology, sciMETv2. SciMETv3 achieves nearly a 100-fold improvement in cell throughput by increasing the index space while simultaneously reducing hands-on time and total costs per experiment. To reduce the sequencing burden of the assay, we demonstrate compatibility of sciMETv3 with capture techniques that enrich for regulatory regions, as well as the ability to leverage enzymatic conversion which can yield higher library diversity. We showcase the throughput of sciMETv3 by producing a >140k cell library from human middle frontal gyrus split across four multiplexed individuals using both Illumina and Ultima sequencing instrumentation. This library was prepared over two days by one individual and required no expensive equipment (e.g. a flow sorter, as required by sciMETv2). The same experiment produced an estimated 650k additional cells that were not sequenced, representing the power of sciMETv3 to meet the throughput needs of the most demanding atlas-scale projects. Finally, we demonstrate the compatibility of sciMETv3 with multimodal assays by introducing sciMET+ATAC, which will enable high- throughput exploration of the interplay between two layers of epigenetic regulation within the same cell, as well as the ability to directly integrate single-cell methylation datasets with existing single-cell ATAC-seq.HighlightsAtlas-scale production of single-cell DNA methylation libraries in a single experimentProtocols and evaluation using both Illumina and Ultima Genomics sequencing platformsCompatibility of sciMETv3 with capture techniques to reduce sequencing burdenCompatibility of sciMETv3 with enzymatic conversion methodsGeneration of an integrated >140,000 cell dataset from human middle frontal gyrus across four individualsAbility to profile both ATAC and genome-wide DNA methylation from the same cells and integration with datasets from each modalityA novel implementation of the s3-ATAC technology that leverages a nanowell chip for increased throughputMotivationDNA methylation forms a basal layer of epigenomic regulatory control, shaping the genomic permissiveness of mammalian cells during lineage specification and development. Aberrant DNA methylation has been associated with myriad health conditions ranging from developmental disorders to cancer. The high cell type specificity necessitates analysis at the single-cell level, much like transcription or other epigenomic properties. However, robust and cost-effective techniques to produce atlas-scale datasets have not been realized for DNA methylation. Here, we directly meet this need by introducing sciMETv3, a high-throughput protocol capable of producing hundreds of thousands of single-cell DNA methylation profiles in a single experiment.
Epigenomic anomalies in induced pluripotent stem cells from Alzheimer’s disease cases
Authors: Flamier Anthony , Katbe Alisar , Serhani Dounya , Hamam Rimi , Hogan Ryan , Tavares Erika , Héon Élise , Hanna Roy , Bernier Gilbert 
Published: August 2024

SUMMARYReprogramming of adult somatic cells into induced pluripotent stem cells (iPSCs) resets the aging clock. However, primed iPSCs can retain cell-of-origin epigenomic marks, especially those linked to heterochromatin and lamina-associated regions. Here we show that iPSCs produced from dermal fibroblasts of late-onset sporadic Alzheimer’s disease (AD) cases retain epigenomic anomalies that supersede developmental defects and neurodegeneration. When compared to iPSCs from elderly controls, AD iPSCs show reducedBMI1expression, lower H3K9me3 levels, and an altered DNA methylome. Gene Ontology analysis of differentially methylated DNA regions (DMRs) reveals terms linked to cell-cell adhesion and synapse, with the cognitive resilience-associated MEF2 family of transcription factors being the most enriched at DMRs. Upon noggin exposure, AD iPSCs show lesser efficient neural induction and forebrain specification, together with increased ZIC2, ZIC5 and WNT-related gene expression. Long-term AD neuronal cultures present a dedifferentiation and loss-of-cell identity phenotype. Despite these epigenomic anomalies, AD iPSCs generate cortical neurons in normal proportion and readily form cerebral organoids developing amyloid and Tau pathology. BMI1 overexpression in AD neurons mitigates amyloid and tau accumulation, heterochromatin fragmentation, and G4 DNA induction. These findings implicate reprogramming resistant epigenomic anomalies or uncharacterized genetic alterations working in trans on the epigenome in AD pathophysiology.
Determining the off-target activity of antibiotics and novel translation initiation sites in mitochondria
Authors: Marks James , Young Emma , Hafner Markus 
Published: August 2024

AbstractMitochondria translate the 13 mitochondrially encoded proteins using a dedicated translation system that closely resembles the one found in prokaryotes. Consequently, many bacterial protein synthesis inhibitors, used as antibiotics, exhibit mitochondrial toxicity as off-target effects. However, whether these antibiotics act through the same mechanisms in mitochondria as in bacteria remains unclear. To address this, we characterized the impact of a panel of bacterial translation and elongation inhibitors on mitochondrial translation through mitoribosome profiling. We found that the mechanism of action for every antibiotic, except telithromycin, is the same in both bacteria and mitochondria. Additionally, mitoribosome profiling data showed thatMT-ND1andMT-ND5have incorrectly annotated translation initiation sites and suggested several novel mitochondrial translation events. Careful study of the mechanisms of mitochondrial translation inhibition can guide development of antibiotics with increased target specificity and reduced mitochondrial toxicity.
DEVELOPMENT OF AN IDENTIFICATION METHOD FORLeishmaniaspp BASED ON REAL-TIME PCR WITH HIGH-RESOLUTION MELTING
Authors: Villareal Julio Rafael , Ordoñez Brayan E. , Pérez Gabriel A. , Manjarrez Valeria , Julio Katia Villarreal , Muskuz Carlos 
Published: August 2024

SummaryIntroductionLeishmaniasisis a disease caused by parasites of the genusLeishmania. In Colombia, 6 pathogenic species have been reported. Traditional parasitological diagnosis based on the observation of parasites does not allow the species to be identified, which is why biochemical or molecular methods must be used, including conventional PCR, but this has some limitations and requires long periods of time to obtain results., which are sometimes inconclusive.General ObjectiveImplement a methodology based on PCR-HRM, which allows the simultaneous detection and identification of parasites of theLeishmaniagenus in clinical samples from patients or parasites in cultures.Materials and methodsA PCR-HRM was standardized, through which 237 clinical samples were evaluated, 98 classified as positive and 139 as parasitologically negative by direct and/or culture. The typings were compared with a previously standardized PCR-RFLP.ResultsIt was possible to implement a PCR-HRM for the diagnosis and identification ofLeishmaniaspecies, obtaining 100% agreement with the typings obtained by PCR-RFLP. It was even possible to detect and identify the parasite in samples diagnosed as negative by conventional methods. It was found that, with a reliability percentage greater than 95%, 91 samples out of 98 were typed, of which 81.63% of the cases were L. panamensis, 11.22% were L. braziliensis and 7.14 were indeterminate.% of cases.ConclusionsPCR-HRM is a good method that allows the identification of the most prevalent species in Colombia, comparing specific mean denaturation temperatures according to theLeishmaniaspecies involved.
Exome sequencing identifiesABCA7as an important gene for familial AD cases from Eastern India
Authors: Sadhukhan Dipanwita , Mukherjee Adreesh , Bhattacharyya Bidisha , Mishra Smriti , Banerjee Tapas Kumar , Das Gautam , Sinharoy Uma , Hui Subhra Prakash , Gupta Soma , Biswas Atanu , Biswas Arindam 
Published: August 2024

ABSTRACTIntroductionAD is the most complex disorder leading to dementia worldwide. Despite the disease burden among Indians the mutation spectrum in our subcontinent is not well examined.MethodsTo identify probable causal variants for AD, in a total of 29 clinically diagnosed, majorly familial and young onset AD cases from Eastern India, whole exome analysis in Illumina NovoSeq. 6000 sequencing platform was performed as per standard methodology. Next, the coding variants were prioritised based on the literature and our bioinformatic analyses for genotype-to-phenotype correlation.ResultsA total of 25 missense variants and 4 nonsense variants in 17 genes among 23 AD cases were identified as probable damaging ones in our study cohort. Amongst all,ABCA7account for the maximum number of pathogenic variants (5/29). A lowering in the age of onset was observed for mutation carriers and cases belonging to the posterior cortical atrophy (PCA) subgroup. Our further comparative analyses suggested that variants in APP metabolism pathway genes are more common in PCA, frontal AD, and young-onset multi-domain amnestic phenotypes than dysexecutive and typical AD.ConclusionOur study suggests that whole exome sequencing among Indian AD patients holds the potential to identify the most common gene as well as clinically relevant new causal variants which may highlight new insight into disease mechanism through future research.
The social determinants of maternal and congenital syphilis at the Colombia-Venezuela border: A qualitative study of twenty mothers of newborns with congenital syphilis
Authors: Parada Doris , Wirtz Andrea , Olarte Rafael , Pedraza Magaly , Hoffmann Bert , Blofield Merike 
Published: August 2024

AbstractHumanitarian crises and resulting out-migration have created contexts in which treatable diseases such as syphilis have expanded in prevalence. Untreated syphilis can have potentially irreversible and devastating consequences, especially for infants born with congenital syphilis. Our study aimed to understand the experiences of postpartum mothers whose newborns have been diagnosed with congenital syphilis and explore the social determinants of maternal and congenital syphilis. The setting of our study is the main public hospital in Cúcuta, Colombia, at the border with Venezuela, which provides emergency care to everyone regardless of documentation and thus receives a high share of Venezuelan migrants. We conducted twenty in-depth interviews with women who had their newborns hospitalized with a diagnosis of congenital syphilis. Sampling was conducted purposively at the hospital, between March and June 2023. Study participants were mostly Venezuelan migrants and Colombian returnees, from their teens to their forties. We used a grounded theory technique to conduct thematic analysis. Four major themes emerged: 1) experiencing a pregnancy in the context of a lack of resources, violence and ignorance; 2) guilt with and reinfection of syphilis; 3) challenges and limitations in accessing health care; and 4) limited support networks and machismo. Reported challenges were intertwined with the high costs of health care in the country of origin, the lack of knowledge of sexually transmitted infections, the limited public health education targeting this population group, and the absence of Colombian public policies that promote care for the non-regularized migrant population.
Predictors of successful weaning from Veno-Arterial Extracorporeal Membrane Oxygenation (V-A ECMO): A Systematic Review and Meta-analysis
Authors: Hsu Henry R. , Sekhar Praba , Grover Jahnavi , Tian David H. , Downey Ciaran , Maudlin Ben , Dissanayake Chathuri , Dennis Mark 
Published: August 2024

ABSTRACTBackgroundVenoarterial extracorporeal membrane oxygenation (V-A ECMO) use to support patients in cardiac failure is increasing. Despite this increased use, predicting successful weaning from ECMO can be challenging, no uniform guidelines on weaning exist. Therefore, we completed a systematic review to evaluate prognostic factors that predict successful weaning from V-A ECMO.MethodsFollowing the PRIMSA guidelines, a systematic literature search of Medline, Embase, SCOPUS and CENTRAL identified original research studies of patients requiring V-A ECMO where weaning was attempted. Data was collected on demographic factors and weaning protocol, biomarkers, haemodynamic, echocardiographic factors for the successfully weaned (SW) and not successfully weaned (NSW) groups. Two investigators reviewed studies for relevance, extracted data, and assessed risk of bias using the ROBINS-I tool. The study was registered on the international prospective register of systematic reviews (PROSPERO ID# CRD42022366153).Results1219 records were screened, of which 20 studies were deemed sufficient to be included in the statistical analysis based on pre-specified criteria. Factors associated with successful weaning were higher left ventricular ejection fraction (LVEF) (MD 9.0, 95% CI 4.1 – 13.8; p<0.001) and left ventricular outflow tract velocity time integral (LVOT VTI) at time of weaning, (MD 1.35, 95% CI 0.28 – 2.40 lactate at admission (MD -2.5, 95%CI -3.8 – -1.1, p<0.001;), and CK-MB at admission (MD -4.11, 95%CI -6.6 to -1.6, p=0.001). Critical appraisal demonstrated moderate-high risk of bias owing to confounding and low sample sizes.ConclusionIn patients on V-A ECMO support being assessed for weaning multi-parametric assessment is required. Moderate-high heterogeneity and low sample sizes warrant higher-quality studies to help guide decisions to wean patients from V-A ECMO.
Coupled stack-up volume RF coils for low-field open MR imaging
Authors: Zhao Yunkun , Bhosale Aditya A , Zhang Xiaoliang 
Published: August 2024

AbstractBackgroundLow-field open magnetic resonance imaging (MRI) systems, typically operating at magnetic field strengths below 1 Tesla, has greatly expanded the accessibility of MRI technology to meet a wide range of patient needs. However, the inherent challenges of low-field MRI, such as limited signal-to-noise ratios and limited availability of dedicated radiofrequency (RF) coils, have prompted the need for innovative coil designs that can improve imaging quality and diagnostic capabilities.PurposeIn response to these challenges, we introduce the coupled stack-up volume coil, a novel RF coil design that addresses the shortcomings of conventional birdcage in the context of low-field open MRI.MethodsThe proposed coupled stack-up volume coil design utilizes a unique architecture that optimizes both transmit/receive efficiency and RF field homogeneity and offers the advantage of a simple design and construction, making it a practical and feasible solution for low-field MRI applications. This paper presents a comprehensive exploration of the theoretical framework, design considerations, and experimental validation of this innovative coil design.ResultsWe demonstrate the superior performance of the coupled stack-up volume coil in achieving 47.7% higher transmit/receive efficiency and 68% more uniform magnetic field distribution compared to traditional birdcage coils in electromagnetic simulations. Bench tests results show that the B1 field efficiency of coupled stack-up volume coil is 57.3% higher compared with that of conventional birdcage coil.ConclusionsThe proposed coupled stack-up volume coil outperforms the conventional birdcage coil in terms of B1 efficiency, imaging coverage, and low-frequency operation capability. This design provides a robust and simple solution to low-field MR RF coil design.
Studying Veteran food insecurity longitudinally using electronic health record data and natural language processing
Authors: Chapman Alec B. , Panadero Talia , Dalrymple Rachel , Cohen Alicia , Kamdar Nipa , Pethani Farhana , Kalvesmaki Andrea , Nelson Richard E. , Butler Jorie 
Published: August 2024

AbstractFood insecurity is an important social risk factor that is directly linked to patient health and well-being. The Department of Veterans Affairs (VA) aims to identify and resolve food insecurity through social and clinical interventions. However, evaluating the impact of such interventions is made challenging by the lack of follow-up data on Veteran food insecurity status. One potential solution is to leverage documentation of food insecurity in electronic health records (EHRs). In this paper, we developed and validated a natural language processing system to identify food insecurity status from clinical notes and applied it to study longitudinal trajectories of food insecurity among a large cohort of food insecure Veterans. Our analyses provide insight into the timing and persistence of Veteran food insecurity; in the future, our methods will be used to evaluate food insecurity interventions and evaluate VA policy.