bluuebunny/crossref_metadata_2025_split huggingface dataset:
Racial and Ethnic Disparities in the Utilization and Outcomes with WATCHMAN FLX: A SURPASS analysis of the NCDR LAAO Registry
Authors: Alli Oluseun O , Garg Jalaj , Boursiquot Brian C. , Kapadia Samir R , Yeh Robert W , Price Matthew J , Piccini Jonathan P , Nair Devi G , Hsu Jonathan C , Gibson Douglas N , Alloco TDominic , Christen Thomas , Sutton Brad , Freeman James V 
Published: May 2024

AbstractBackgroundLeft atrial appendage occlusion (LAAO) is increasingly used as an alternative to oral anticoagulation for stroke prevention in select patients with atrial fibrillation. Data on outcomes in racial and ethnic minority individuals are limited. This analysis assessed differences in the utilization and outcomes of LAAO by race and ethnicity in a large national registry.MethodsThis analysis acquired data on WATCHMAN FLX patients from the National Cardiovascular Data Registry (NCDR) LAAO Registry through September 2022. All patients with an attempted WATCHMAN FLX implantation and known race and ethnicity were included. Baseline characteristics and 1 year event rates were compared.ResultsA total of 97,185 patients were analyzed; 87,339 were White (90%), 3,750 Black (Black/African American 3.9%), and 2,866 Hispanic ([Hispanic/Latinx] 2.9%). Black and Hispanic patients were younger with a higher incidence of prior stroke and significant bleeding compared to White patients. Black and Hispanic patients were treated with LAAO in smaller numbers relative to their proportion of the US population. Rates of procedural success were similar between groups. Though direct oral anticoagulants were prescribed in most patients across the groups, dual and single antiplatelet therapy were prescribed more often in Black patients. Black patients had significantly higher rates of 1-year death and bleeding compared to White and Hispanic patients.ConclusionsPatients from racial and ethnic minority groups comprise a disproportionately small fraction of all patients who undergo LAAO. Black and Hispanic patients were younger but had significantly higher comorbidities compared to White patients. Procedural success was similar amongst the groups but Black patients experienced higher rates of death and bleeding at 1 year.Graphic AbstractWhat is knownThere is underutilization of LAAO among racial and ethnic minority patients with AF and there are racial and ethnic differences in periprocedural outcomes.What this study addsIn this study from a large US national registry of patients undergoing LAAO, Black patients were younger but had higher baseline comorbidities and experienced higher rates of bleeding at 45 days and 1-year and higher 1-year mortality. Further work is needed to enroll diverse patients into research trials and to provide equitable AF-related access to advanced care and intra- procedural and post-procedural care in US real-world practice.
KAS-ATAC reveals the genome-wide single-stranded accessible chromatin landscape of the human genome
Authors: Kim Samuel H. , Marinov Georgi K. , Greenleaf William J. 
Published: May 2024

AbstractGene regulation in most eukaryotes involves two fundamental physical processes – alterations in the packaging of the genome by nucleosomes, with activecis-regulatory elements (CREs) generally characterized by an open-chromatin configuration, and the activation of transcription. Mapping these physical properties and biochemical activities genome-wide – through profiling chromatin accessibility and active transcription – are key tools used to understand the logic and mechanisms of transcription and its regulation. However, the relationship between these two states has until now not been accessible to simultaneous measurement. To address this, we developed KAS-ATAC, a combination of the KAS-seq (Kethoxal-Assisted SsDNA sequencing and ATAC-seq (Assay for Transposase-Accessible Chromatin using sequencing) methods for mapping single-stranded DNA (and thus active transcription) and chromatin accessibility, respectively, enabling the genome-wide identification of DNA fragments that are simultaneously accessible and contain ssDNA. We use KAS-ATAC to evaluate levels of active transcription over different classes of regulatory elements in the human genome, to estimate the absolute levels of transcribed accessible DNA over CREs, to map the nucleosomal configurations associated with RNA polymerase activities, and to assess transcription factor association with transcribed DNA through transcription factor binding site (TFBS) footprinting. We observe lower levels of transcription over distal enhancers compared to promoters, surprisingly high abundance of ssDNA immediately around/within CTCF occupancy footprints, and distinct nucleosomal configurations around transcription initiation sites associated with active transcription. Remarkably, most TFs associate equally with transcribed and non-transcribed DNA but a few factors specifically do not exhibit footprints over ssDNA-containing fragments. We anticipate KAS-ATAC to continue to derive useful insights into chromatin organization and transcriptional regulation in other contexts in the future.
State- and circuit-dependent opponent-processing of fear
Authors: Yau Joanna Oi-Yue , Li Amy , Abdallah Lauren , Lisowksi Leszek , McNally Gavan P. 
Published: May 2024

AbstractThe presence of valence coding neurons in the basolateral amygdala (BLA) that form distinct projections to other brain regions implies functional opposition between aversion and reward during learning. However, evidence for opponent interactions in fear learning is sparse and may only be apparent under certain conditions. Here we test this possibility by studying the roles of the BLA➔central amygdala (CeA) and BLA➔nucleus accumbens (Acb) pathways in fear learning in male rats. First, we assessed the organisation of these pathways in the rat brain. BLA➔CeA and BLA➔Acb pathways were largely segregated in the BLA but shared overlapping molecular profiles. Then we assessed activity of the BLA➔CeA and BLA➔Acb pathways during two different forms of fear learning - fear learning in a neutral context and fear learning in a reward context. BLA ➔ CeA neurons were robustly recruited by footshock regardless of where fear learning occurred whereas recruitment of BLA➔Acb neurons was state-dependent because footshock only recruited this pathway in a reward context. Finally, we assessed the causal roles of activity in these pathways in fear learning. Photoinhibition of the BLA➔CeA pathway during the footshock US impaired fear learning, regardless of where fear learning occurred. In contrast, photoinhibition of the BLA➔Acb pathway augmented fear learning, but only in the reward context. Taken together, our findings show circuit- and state-dependent opponent processing of fear. Footshock-driven activity in the BLA➔Acb pathway can functionally oppose the BLA➔CeA pathway to limit how much fear is learned.Significance StatementHere we identify a fear opponent process in the brain. We show that an aversive event can recruit distinct populations of neurons in the rat basolateral amygdala. One population projects to the central amygdala to promote fear learning. A second population projects to the nucleus accumbens to oppose fear learning. These nucleus accumbens projecting neurons limit how much fear is learned and are candidates for therapeutic targeting to minimize the amount of fear learned after a traumatic experience.
Engineered Oxalate decarboxylase boosts activity and stability for biological applications
Authors: Dindo Mirco , Conter Carolina , Uechi Gen-ichiro , Pampalone Gioena , Ruta Luana , Pey Angel L. , Rossi Luigia , Laurino Paola , Magnani Mauro , Cellini Barbara 
Published: May 2024

AbstractOxalate decarboxylase (OxDC) fromBacillus subtilisis a Mn-dependent hexameric enzyme which converts oxalate to carbon dioxide and formate. Recently, OxDC has attracted the interest of the scientific community, due to its biotechnological and medical applications for the treatment of hyperoxalurias, a group of pathologic conditions associated with excessive oxalate urinary excretion due to either increased endogenous production or increased exogenous absorption. The fact that OxDC displays optimum pH in the acidic range, represents a big limitation for most biotechnological applications involving processes occurring at neutral pH, where the activity and stability of the enzyme are remarkably reduced. Here, through bioinformatics-guided protein engineering, followed by combinatorial mutagenesis and analyses of activity and thermodynamic stability, we identified a double mutant of OxDC endowed with enhanced catalytic efficiency and stability under physiological conditions. The obtained engineered form of OxDC offers a potential tool for improved intestinal oxalate degradation in hyperoxaluria patients.
Pore formation in complex biological membranes: torn between evolutionary needs
Authors: Starke Leonhard J. , Allolio Christoph , Hub Jochen S. 
Published: May 2024

AbstractThe primary function of biological membranes is to enable compartmentalization among cells and organelles. Loss of integrity by the formation of membrane pores would trigger uncontrolled depolarization or influx of toxic compounds, posing a fatal thread to living cells. How the lipid complexity of biological membranes enables mechanical stability against pore formation while simultaneously allowing ongoing membrane remodeling is largely enigmatic. We performed molecular dynamics simulations of eight complex lipid membranes including the plasma membrane and membranes of the organelles ER, Golgi, lysosome, and mitochondrion. To quantify the mechanical stability of these membranes, we computed the free energies for nucleating a transmembrane pore as well as the line tension along the rim of open pores. Our simulations reveal that complex biological membranes are overall remarkably stable, however with the plasma membrane standing out as exceptionally stable, which aligns with its crucial role as a protective layer. We observe that sterol content is the main regulator for biomembrane stability, and that lateral sorting among lipid mixtures influences the energetics of membrane pores. A comparison of 25 model membranes with varying sterol content, tail length, tail saturation, and head group type shows that the pore nucleation free energy is mostly associated with the lipid tilt modulus, whereas the line tension along the pore rim is determined by the lipid intrinsic curvature. Together, our study provides an atomistic and energetic view on the role of lipid complexity on biomembrane stability.Significance statementBiomembranes have evolved to fulfill seemingly conflicting requirements. Membranes form a protective layer against bacterial or viral infection and against external mechanical and toxic stress, thus requiring mechanical stability. However, membranes are furthermore involved in ongoing remodeling for homeostasis, signaling, trafficking, and morphogenesis, necessitating a high degree of plasticity. How the chemical diversity of membranes, comprising hundreds of lipid species, contributes to enable both stability and plasticity is not well understood. We used molecular simulations and free energy calculations of pore formation in complex biomembranes to reveal how mechanical and geometric properties of lipids as well as lateral lipid sorting control the integrity of complex membranes.
Evidence of optimal control theory over active inference in corticospinal excitability modulations
Authors: Brandt I.M. , Grünbaum T. , Christensen M.S. 
Published: May 2024

AbstractTwo theories, optimal control theory and active inference, dominate the motor control field. We use transcranial magnetic stimulation (TMS) in force and angle tasks to examine whether corticospinal excitability represents a motor command, as proposed by the optimal control theory, or a proprioceptive prediction, as proposed by active inference. Our results strongly support optimal control theory. We encourage comparisons of the theories against each other based on empirically testable predictions.
Peripheral B Lymphocyte Serves as A Reservoir for The Persistently Covert Infection of MandarinfishSiniperca chuatsiRanavirus
Authors: Zhang Wenfeng , Gong Hui , Sun Qianqian , Fu Yuting , Wu Xiaosi , Deng Hengwei , Weng Shaoping , He Jianguo , Dong Chuanfu 
Published: May 2024

ABSTRACTGenusRanavirusin familyIridoviridaeis composed of large members with various genomic sizes and viral gene contents, infecting a variety of ectothermic vertebrates including reptile, amphibians and bony fish worldwide. Mandarinfish ranavirus (MRV) is a very distinctive member among genusRanavirus. Persistently convert infection of MRV were previously observed in natural outbreak of MRV, but the underlying mechanism remains unclear. We here evidenced that mandarinfish peripheral B lymphocytes are implemented as viral reservoirs to maintain persistent and covert infection. When mandarinfish were infected with sublethal dosage of MRV under nonpermissive temperature (19 ºC) and permissive temperature (26 ºC), respectively, all fish in 19 ºC group survived and entered persistent phase of infection characterized with very low viral load in white blood cell, whereas partial fish died of MRV infection in 26 ºC group, and the survivals then initiated persistent status. Gradually raising temperature, vaccination and dexamethasone treatment can reactivate the quiescent MRV to replicate and result in partial mortality. The viral reservoir investigates showed that IgM+-labelled B lymphocytes but not CD3Δ+-labelled T lymphocytes and MRC-1+-labelled macrophages are target cells for the persistent infection of MRV. Moreover, the quiescent MRV could not be reactivated by heat-killedEscherichia coli, indicating a very different reactivation mechanism from that of other known rannaviral member. Collectively, we are the first to confirm the presence of B cell-dependent persistent and covert infection of ranavirus, and provide a new clue for better understanding the complex infection mechanism of vertebrate iridovirus, especially regarding ranavirus.IMPORTANCEViruses known as HIV, HBV and EBV etc. evade host immune clearance by establishing long-term even lifelong persistent or latent infection. In vertebrate iridovirus, FV3, the type species of genusRanaviruswas evidenced to establish persistent infection by usingXenopusperitoneal macrophages as reservoirs. MRV is a very distinctive ranavirus from FV3 with very different genomic content and host species. We here uncovered MRV establishes persistent and covert infection by using peripheral B lymphocytes as virus reservoirs. During persistent infection, very low copies of quiescent MRV were harbored in peripheral B lymphocytes. Water temperature stress, vaccination stimulation, and dexamethasone treatment can reactivate quiescent MRV to replicate in abundance via a non-TLR5-mediated manner, and results in recurrence of MRV disease. Our finding suggests the diversity and complexity of the pathogenic mechanisms among ranaviruses, and also has important scientific significance for in-depth understanding of the infection and immunity interaction of vertebrate iridoviruses.
Validation and identification of new QTLs for plant and fruit developmental and composition traits in eggplant under low N conditions
Authors: Villanueva Gloria , Vilanova Santiago , Plazas Mariola , Gramazio Pietro , Prohens Jaime 
Published: May 2024

AbstractEnhancing plant adaptation to low input conditions is a fundamental goal for implementing sustainable agriculture. In the present study, two eggplant (Solanum melongena) accessions (MEL1 and MEL5), two introgression lines (ILs) derived from eggplant wild relativesS. dasyphyllum(IL-M1-D1) andS. insanum(IL-M5-I9), and a heterozygous version of this last IL (ILHet-M5-I9), along with hybrids among them were evaluated under low N (LN) conditions. IL-M1-D1 carries an introgressed fragment of 4.9 Mb in homozygosis fromS. dasyphyllumon chromosome 2, while IL-M5-I9 and ILHet-M5-I9 carry an introgression of 21.5 Mb on chromosome 9 in homozygosis and heterozygosis, respectively, fromS. insanum. Multiple quantitative trait loci (QTLs) for several traits of interest were associated with both introgressions under LN conditions in a previous study with segregating advanced backcrosses. Here we evaluated the performance of these materials for 22 agronomic and developmental traits under low N fertilization (LN) conditions. Hybrids with the ILs enabled the study of genetic background effects on QTLs expression. The materials evaluated showed a significant phenotypic variation, particularly within hybrids segregating for the introgression fromS. insanumin chromosome 9. Statistical analysis revealed no significant differences among hybrids carrying or not the introgression on chromosome 2 ofS. dasyphyllum, and only slight differences were observed between the IL-M1-D1 and its recurrent parentS. melongenaMEL1, suggesting a limited impact of this introgression on chromosome 2 on the phenotype variation. However, the differences observed between IL-M5-I9 and its recurrent parentS. melongenaMEL5, together with the association between genotypic and phenotypic variation in hybrids segregating for this introgression, allowed the identification of 13 QTLs on chromosome 9. These results successfully validated the previously identified QTLs for flavonol content in leaves, nitrogen balanced index, fruit mean weight, and nitrogen content in leaves and, also revealed nine new QTLs associated with the introgressed genomic region in chromosome 9. This study emphasizes the influence of environmental conditions, genotypes, and genetic backgrounds on the phenotypic expression of eggplant QTLs introgressed from wild relatives and highlights the importance of QTL validation. These findings contribute valuable insights for developing new eggplant cultivars for a more sustainable agriculture, particularly with adaptation to LN conditions.
Prognostic importance of splicing-triggered aberrations of protein complex interfaces in cancer
Authors: Newaz Khalique , Schaefers Christoph , Weisel Katja , Baumbach Jan , Frishman Dmitrij 
Published: May 2024

AbstractAberrant alternative splicing (AS) is a prominent hallmark of cancer. AS can perturb protein-protein interactions (PPIs) by adding or removing interface regions encoded by individual exons. Identifying prognostic exon-exon interactions (EEIs) from PPI interfaces can help discover AS-affected cancer-driving PPIs that can serve as potential drug targets. Here, we assessed the prognostic significance of EEIs across 15 cancer types by integrating RNA-seq data with three-dimensional (3D) structures of protein complexes. By analyzing the resulting EEI network we identified patient-specific perturbed EEIs (i.e., EEIs present in healthy samples but absent from the paired cancer samples or vice versa) that were significantly associated with survival. We provide the first evidence that EEIs can be used as prognostic biomarkers for cancer patient survival. Our findings provide mechanistic insights into AS-affected PPI interfaces. Given the ongoing expansion of available RNA-seq data and the number of 3D structurally-resolved (or confidently predicted) protein complexes, our computational framework will help accelerate the discovery of clinically important cancer-promoting AS events.
Design of a new model yeast consortium for ecological studies of enological fermentation
Authors: Pourcelot Eléonore , Vigna Audrey , Marlin Thérèse , Galeote Virginie , Nidelet Thibault 
Published: May 2024

AbstractWine fermentation involves complex microbial communities of non-Saccharomycesyeast species besides the well-knownSaccharomyces cerevisiae. While extensive research has enhanced our understanding ofS. cerevisiae, the development of multi-species fermentation starters has led to increased interest in yeast interactions and the role of microbial diversity in winemaking. Consequently, molecular methods have emerged to identify the different species at different stages of the winemaking process. Model microbial communities or consortia, which provide simplified systems resembling natural microbial diversity, offer opportunities to investigate population dynamics and understand the role of community diversity in ecosystem performance.Here, this work aims to design a yeast consortium reflecting the diversity of wine yeasts and to develop a method for accurately tracking their population dynamics during fermentation. We developed and characterized a six-species consortium, withS. cerevisiae,Hanseniaspora uvarum,Starmerella bacillaris,Metschnikowia pulcherrima,Lachancea thermotoleransandTorulaspora delbrueckii. By tagging each yeast species with distinct fluorescent markers, the study enables real-time monitoring of individual species within the consortium using flow cytometry. We have carried out a complete analysis of this consortium, studying the evolution of populations over time and examining factors such as metabolite production and fermentation kinetics.In addition, the yeast consortium was used to test the diversity-function relationship as a proof of concept. We sought to determine the impact of the initial evenness on communities’ performances subjected to osmotic stress. To this end, ten randomly designed consortia with varying initial species proportions were followed in enological fermentation with 200 and 280 g/L of initial sugars. The initial proportion of certain species affected the population dynamics and metabolite production however no demonstrable effect of the initial evenness on the response to osmotic stress was shown.These results demonstrated the usefulness of the presented consortium, which is now available to the scientific community and can contribute to future work trying to decipher multispecies dynamics and the role of yeast diversity in wine fermentation.
Jchain-DTRMice Allow for Diphtheria Toxin-Mediated Depletion of Antibody-Secreting Cells and Evaluation of Their Differentiation Kinetics
Authors: Pioli KimAnh T. , Ritchie Matthew , Haq Hira , Pioli Peter D. 
Published: May 2024

SummaryAntibody-secreting cells (ASCs) are generated following B cell activation and constitutively secrete antibodies. As such, ASCs are key mediators of humoral immunity whether it be in the context of pathogen exposure, vaccination or even homeostatic clearance of cellular debris. Therefore, understanding basic tenants of ASC biology such as their differentiation kinetics following B cell stimulation is of importance. Towards that aim, we developed a mouse model which expresses simianHBEGF(a.k.a., diphtheria toxin receptor (DTR)) under the control of the endogenousJchainlocus (or J-DTR). ASCs from these mice expressed high levels of cell surface DTR and were acutely depleted following diphtheria toxin treatment. Furthermore, proof-of-principle experiments demonstrated the ability to use these mice to track ASC reconstitution following depletion in 3 distinct organs. Overall, J-DTR mice provide a new and highly effective genetic tool allowing for the study of ASC biology in a wide range of potential applications.