bluuebunny/crossref_metadata_2025_split huggingface dataset:
Supramolecular complexes of GCAP1: towards the development of effective biologics for inherited retinal dystrophies
Authors: Biasi A. , Marino V. , Dal Cortivo G. , Dell’Orco D. 
Published: March 2024

AbstractGuanylate Cyclase Activating Protein 1 (GCAP1) is a neuronal Ca2+-sensor protein expressed in photoreceptors where it regulates the enzymatic activity of retinal Guanylate Cyclase 1 (GC1) in a Ca2+-dependent manner. Recently, over 20 missense mutations inGUCA1A(encoding for GCAP1) have been associated with inherited autosomal dominant retinal diseases, namely cone dystrophy (COD) and cone-rod dystrophy (CORD). Since GCAP1 is known to be a functional dimer, COD/CORD patients present a heterogeneous pool of GCAP1 assemblies constituted by wild-type and mutated homodimers and heterodimers. Here, we present an integratedin silicoand biochemical investigation on the effects of the E111V substitution, associated with a severe form of CORD, on GCAP1 homo- and hetero-dimerization. Despite inducing a constitutive activation of GC1 due to impaired Ca2+-binding in the high-affinity EF-hand 3 motif, the E111V substitution did not affect either the homo- or the hetero dimerization process as clearly highlighted by aSEC and molecular docking experiments. Indeed, both variants exhibited micromolar monomer-dimer equilibrium constants in the presence of both Mg2+and Ca2++, indicating that at physiological cellular concentrations both variants are predominantly monomers under Ca2+-loaded and, to a lesser extent, Mg2+-loaded conditions. Molecular docking and dynamics simulations confirmed chromatographic results highlighting slight alterations in free energy of binding involving the pathogenic E111V variant in the Ca2+-bound state and increased mobility over time affecting the Ca2+-coordinating EF3 motif. In addition, to evaluate possible therapeutic approaches, the regulation of the catalytic activity of GC1 by WT and E111V-GCAP1 was studied in the presence of retinal degeneration protein 3 (RD3), an α-helical protein that strongly inhibits GC1, and a RD3-derived peptide (RD3ppt) which encompasses a region of RD3 that is essential for its inhibitory activity. GC1 activity assays in the presence of RD3ppt suggest that the enzymatic activity is partially inhibited by the peptide at low micromolar concentrations when GCAP1 variants are present. The incomplete shut down of GC1 by RD3 could be explained by the interaction occurring between RD3 and GCAP1, known to form a complex with GC1 in the endoplasmic reticulum. This fundamental interaction was here investigated spectroscopically andin silico, unveiling major structural rearrangements upon complex formation. Interestingly, the full RD3 protein was able to better modulate GC1 activity and restore the abnormal cGMP production induced by the pathogenic E111V-GCAP1 variant to a physiological level.
Leveraging multiple data types for improved compound-kinase bioactivity prediction
Authors: Theisen Ryan , Wang Tianduanyi , Ravikumar Balaguru , Rahman Rayees , Cichońska Anna 
Published: March 2024

AbstractMachine learning methods offer time- and cost-effective means for identifying novel chemical matter as well as guiding experimental efforts to map enormous compound-kinase interaction spaces. However, considerable challenges for compound-kinase interaction modeling arise from the heterogeneity of available bioactivity readouts, including single-dose compound profiling results, such as percentage inhibition, and multi-dose-response results, such as IC50. Standard activity prediction approaches utilize only dose-response data in the model training, disregarding a substantial portion of available information contained in single-dose measurements. Here, we propose a novel machine learning methodology for compound-kinase activity prediction that leverages both single-dose and dose-response data. Our two-stage model first learns a mapping between single-dose and dose-response bioactivity readouts, and then generates proxy dose-response activity labels for compounds that have only been tested in single-dose assays. The predictions from the first-stage model are then integrated with experimentally measured dose-response activities to model compound-kinase binding based on chemical structures and kinase features. We demonstrate that our two-stage approach yields accurate activity predictions and significantly improves model performance compared to training solely on dose-response labels, particularly in the most practical and challenging scenarios of predicting activities for new compounds and new compound scaffolds. This superior performance is consistent across five evaluated machine learning methods, including traditional models such as random forest and kernel learning, as well as deep learning-based approaches. Using the best performing model, we carried out extensive experimental profiling on a total of 347 selected compound-kinase pairs, achieving a high hit rate of 40% and a negative predictive value of 78%. We show that these rates can be improved further by incorporating model uncertainty estimates into the compound selection process. By integrating multiple activity data types, we demonstrate that our approach holds promise for facilitating the development of training activity datasets in a more efficient and cost-effective way.
Variation and interaction of distinct subgenomes contribute to growth diversity in intergeneric hybrid fish
Authors: Ren Li , Luo Mengxue , Cui Jialin , Gao Xin , Zhang Hong , Wu Ping , Wei Zehong , Tai Yakui , Li Mengdan , Luo Kaikun , Liu Shaojun 
Published: March 2024

AbstractIntergeneric hybridization greatly reshapes regulatory interactions among allelic and non-allelic genes. However, their effects on growth diversity remain poorly understood in animals. In this study, we conducted whole-genome sequencing and mRNA-seq analyses in diverse hybrid varieties resulting from the intergeneric hybridization of goldfish (Carassius auratusred var.) and common carp (Cyprinus carpio). These hybrid individuals were characterized by distinct mitochondrial genomes and copy number variations. Through a weighted gene correlation network analysis, we identified 3693 genes as candidate growth-regulated genes. Among them, the expression of 3672 genes in subgenome R (originating from goldfish) displayed negative correlations with growth rate, whereas 20 genes in subgenome C (originating from common carp) exhibited positive correlations. Notably, we observed intriguing patterns in the expression ofslc2a12in subgenome C, showing opposite correlations with body weight that changed with water temperatures, suggesting differential interactions between feeding activity and weight gain in response to seasonal changes for hybrid animals. In 40.31% of alleles, we observed dominanttrans-regulatory effects in the regulatory interaction between distinct alleles from subgenomes R and C. Integrating analyses of allelic-specific expression and DNA methylation data revealed that the influence of DNA methylation on both subgenomes shapes the relative contribution of allelic expression to the growth rate. These findings provide novel insights into the interaction of distinct subgenomes that underlie heterosis in growth traits and contribute to a better understanding of multiple-allele traits in animals.
Hyperinsulinemia counteracts inflammation by suppressing IFNγ and inducing senescence in CD4+T cells of patients with rheumatoid arthritis
Authors: Erlandsson Malin C , Weman Lauri , Malmhäll-Bah Eric , Chandrasekaran Venkataragavan , Tuameh Mahomud , Andersson Karin ME , Silfverswärd Sofia Töyrä , Nilsson Lisa M , Sandström Tatiana Zverkova , Pullerits Rille , Dehlin Mats , Sokka-Isler Tuulikki , Bokarewa Maria I 
Published: March 2024

AbstractBackgroundClinical evidence connects hyperinsulinemia with obesity, and development of type 2 diabetes (T2D). However, its role in autoimmune conditions was questioned. We investigated consequences of hyperinsulinemia for development of T2D and CD4 T cell function in rheumatoid arthritis (RA).MethodsIncident T2D was prospectively studied in two independent RA cohorts and in gout patients matched to RA by age and gender, for 10 years. Effect of hyperinsulinemia and JAK-STAT signaling inhibition (JAKi) in CD4 T cells was studied by integrating transcriptional sequencing with direct effect of insulin, and JAKi on cell proliferation, DNA enrichment, and cytokine production.ResultsT2D was 3.2-2.5 times less prevalent in RA compared to gout, particularly in females. Hyperinsulinemia predicted the development of T2D, regardless of metabolic parameters and insulin resistance. Additionally, hyperinsulinemia correlated with the senescence-associated high serum levels of IL6, IL8, and VEGF.Hyperinsulinemia, along with ex-vivo exposure of CD4 cells to insulin, inhibited cell cycle progression and induced DNA enrichment through the suppression of the PI3K-Src kinases and cell cycle promoting genes. It also reduced IFNγ production. JAKi-treated CD4+cells regained insulin sensitivity, which activated glucose metabolism and facilitated senescence. This insulin-dependent mechanism promoted the accumulation of naïve CD4 cells in JAKi-treated patients.ConclusionsThis study shows that insulin has important immunosuppressive ability controlling the adaptive immunity by suppressing IFNγ production and inducing senescence in the effector CD4 T cells. Inhibition of JAK-STAT signaling enhances insulin sensitivity and rejuvenates CD4 cell population in RA patients.
Cardioprotective effects of antiretroviral treatment in adolescents with perinatal HIV infection are heterogeneous depending on age at treatment initiation
Authors: Magodoro Itai M , Guerrero-Chalela Carlos E , Claggett Brian , Jermy Stephen , Samuels Petronella , Myer Landon , Zar Heather , Jao Jennifer , Ntsekhe Mpiko , Siedner Mark J , Ntusi Ntobeko AB 
Published: March 2024

SummaryThe cardioprotective effects of antiretroviral treatment (ART) in adolescents with perinatal HIV infection (APHIV) may depend on age at ART initiation. We used cardiovascular magnetic resonance (CMR) to characterize and compare residual cardiac changes in apparently healthy APHIV with early and delayed ART initiation compared to sex- and age-similar HIV uninfected peers. We defined early and delayed ART as, respectively, treatment initiated at <5 years and ≥5 years of age. Cardiac function, mechanical deformation, geometry and tissue composition were assessed. APHIV had distinct albeit subclinical cardiac phenotypes depending on timing of ART initiation. For example, changes in early ART suggested comparatively worse diastology with preserved systolic function while delayed ART was associated with comparatively increased diffuse fibrosis and LV dilatation with reduced systolic function. The long-term clinical significance of these changes remains to be determined.
Multicenter Randomized Controlled Trial of Exercise in Aortic Dissection Survivors: Rationale, Design, and Initial Hemodynamic Data
Authors: Toy Yasmin A. , House Kayla N. , Boyer Leslie M. , McNamara Jennifer L. , Hofmann-Bowman Marion A. , Eagle Kim A. , Lim Michelle S. , Braverman Alan C. , Prakash Siddharth K. 
Published: March 2024

AbstractThere are currently no evidence-based guidelines for exercise after thoracic aortic dissection (TAD), leading to highly variable recommendations that frequently lead patients to restrict their physical activities. This multicenter randomized controlled trial was intended to evaluate the safety and efficacy of a moderate intensity guided exercise program for TAD survivors. Participants were eligible for the trial if they had a Type A or Type B dissection at least 90 days before enrollment and could attend two in-person study visits. The guided exercise circuit consisted of six aerobic, isotonic, or isometric exercises that participants continued at home with virtual follow up sessions. The primary endpoint is the change in the composite anxiety and depression PROMIS-29 T-score at 12 months. Secondary endpoints include changes in grip strength, weight, 24-hr ambulatory blood pressure, and arterial biomechanical properties measured by central arterial waveform analysis. Preliminary analysis of the first 81 enrolled participants demonstrated that the guided exercise circuit was completed safely and was not associated with severe exertional hypertension, injury, or adverse cardiovascular events. At enrollment, most participants had adverse central waveform or ABPM characteristics that are associated with increased cardiovascular mortality, such as increased arterial stiffness, nocturnal hypertension, elevated pulse pressure, or blunted nocturnal dipping. Follow up of enrolled participants with longitudinal hemodynamic data to evaluate the impact of the exercise program will conclude in October 2024.
A Reassessment of Sodium Correction Rates and Hospital Length of Stay Accounting for Admission Diagnosis
Authors: Gottlieb Eric Raphael , Celi Leo Anthony 
Published: March 2024

AbstractBackgroundSlow correction of severe hyponatremia has been historically recommended due to the risk of rare but catastrophic neurologic events with rapid correction. A recent study challenging this paradigm reported that rapid correction is associated with shorter hospital length of stay, but that study did not control for admission diagnosis. The objective of this study was to determine whether rapid correction is associated with shorter length of stay when controlling for admission diagnosis.MethodsThis retrospective cohort study is based on the fourth edition of the Medical Information Mart for Intensive Care, MIMIC-IV, a deidentified, publicly available clinical research database which includes admissions from 2008-2019. Patients were identified who presented to the hospital with initial sodium <120 mEq/L and were categorized according to total sodium correction achieved in the first day (<6 mEq/L; 6-10 mEq/L; >10 mEq/L). Linear regression was used to assess for an association between correction rate and hospital length of stay, and to determine if this association was significant when controlling for admission diagnosis classifications based on diagnosis related groups (DRGs).ResultsThere were 419 patients with severe hyponatremia (<120 mEq/L) included in this study, of whom 374 survived to discharge. Median [IQR] hospital length of stay was 6 [4, 11] days. In a univariable linear regression, there was a trend towards a significant association between the highest rate of correction (>10 mEq/L) and shorter length of stay, as compared with a moderate rate of correction (coef. -2.764, 95% CI [-5.791, 0.263], p=0.073), but the association was not significant when controlling for admission diagnosis group (coef. -1.561, 95% CI [-4.398, 1.276], p=0.280). There was a significant association in the survivor subset (coef. -3.455, 95% CI [-6.668, -0.242], p=0.035), but it was also not significant when controlling for admission diagnosis group (coef. -2.200, 95% CI [-5.144, 0.743], p=0.142).ConclusionsRapid correction is not associated with shorter length of stay when controlling for admission diagnosis, suggesting that the disease state confounds this association. Findings from prior and future studies reporting this association should not drive clinical decision making if the confounding effect of hospital admission diagnosis and competing risk of death are not fully accounted for.
Automated Detection of Keratorefractive Laser Surgeries on Optical Coherence Tomography using Deep Learning
Authors: Assaf Jad F. , Yazbeck Hady , Reinstein Dan Z. , Archer Timothy , Assaf Roland , de Ortueta Diego , Arbelaez Juan , Arbelaez Maria Clara , Awwad Shady T. 
Published: March 2024

ABSTRACTPURPOSETo report a deep learning neural network on anterior segment optical coherence tomography (AS-OCT) for automated detection of different keratorefractive laser surgeries— including Laser In-Situ Keratomileusis with femtosecond microkeratome (Femto-LASIK), LASIK with mechanical microkeratome, photorefractive keratectomy (PRK), keratorefractive lenticule extraction (KLEx), and non-operated eyes—while also distinguishing the targeted ametropias, such as myopic and hyperopic treatments, within these procedures.DESIGNCross-sectional retrospective study.METHODSA total of 14,948 eye scans from 2,278 eyes of 1,166 subjects were used to develop a deep learning neural network algorithm with an 80/10/10 patient distribution for training, validation, and testing phases, respectively. The algorithm was evaluated for its accuracy, F1-scores, area under precision-recall curve (AUPRC), and area under receiver operating characteristic curve (AUROC).RESULTSOn the test dataset, the neural network was able to detect the different surgical classes with an accuracy of 96%, a weighted-average F1-score of 96% and a macro-average F1-score of 96%. The neural network was further able to detect hyperopic and myopic subclasses within each surgical class, with an accuracy of 90%, weighted-average F1 score of 90%, and macro-average F1-score of 83%.CONCLUSIONSDetermining a patient’s keratorefractive laser history is vital for customizing treatments, performing precise intraocular lens (IOL) calculations, and enhancing ectasia risk assessments, especially when electronic health records are incomplete or unavailable. Neural networks can be used to accurately classify keratorefractive laser history from AS-OCT scans, a step in transforming the AS-OCT from a diagnostic to a screening tool in the refractive clinic.
Dynamics of T cell responses to COVID-19 vaccines and breakthrough infection in people living with HIV receiving antiretroviral therapy
Authors: Datwani Sneha , Kalikawe Rebecca , Waterworth Rachel , Mwimanzi Francis M. , Liang Richard , Sang Yurou , Lapointe Hope R. , Cheung Peter K. , Omondi F. Harrison , Duncan Maggie C. , Barad Evan , Speckmaier Sarah , Moran-Garcia Nadia , DeMarco Mari L. , Hedgcock Malcolm , Costiniuk Cecilia T. , Hull Mark , Harris Marianne , Romney Marc G. , Montaner Julio S.G. , Brumme Zabrina L. , Brockman Mark A. 
Published: March 2024

ABSTRACTIntroductionPeople living with HIV (PLWH) can exhibit impaired immune responses to vaccines. Accumulating evidence indicates that PLWH, particularly those receiving antiretroviral therapy, mount strong antibody responses to COVID-19 vaccination, but fewer studies have examined cellular immune responses to vaccination. We measured SARS-CoV-2 spike-specific CD4+ and CD8+ T cell responses generated by two and three doses of COVID-19 vaccine in PLWH receiving antiretroviral therapy, compared to control participants without HIV. We also quantified T cell responses after post-vaccine breakthrough infection, and receipt of fourth vaccine doses, in a subset of PLWH.MethodsWe quantified CD4+ and CD8+ T cells reactive to overlapping peptides spanning the ancestral SARS-CoV-2 spike protein in 50 PLWH and 87 controls without HIV, using an activation induced marker (AIM) assay. All participants remained SARS-CoV-2 naïve until at least one month after their third vaccine dose. SARS-CoV-2 infection was determined by seroconversion to nucleocapsid (N) antigen, which occurred in 21 PLWH and 38 controls post-third dose. Multivariable regression analyses were used to investigate relationships between sociodemographic, health and vaccine-related variables and vaccine-induced T cell responses, as well as breakthrough infection risk.ResultsA third vaccine dose boosted spike-specific CD4+ and CD8+ T cell frequencies significantly above those measured after the second dose (all p<0.0001). Median T cell frequencies did not differ between PLWH and controls after the second dose (p>0.1), but CD8+ T cell responses were modestly lower in PLWH after the third dose (p=0.02), an observation that remained significant after adjustment for sociodemographic, health and vaccine-related variables (p=0.045). In PLWH who experienced breakthrough infection, median T cell frequencies increased even higher than those observed after three vaccine doses (p<0.03), and CD8+ T cell responses in this group remained higher even after a fourth vaccine dose (p=0.03). In multivariable analysis, the only factor associated with increased breakthrough infection risk was younger age, consistent with the rapid increases in SARS-CoV-2 seropositivity among younger adults in Canada after the initial appearance of the Omicron variant.ConclusionPLWH receiving antiretroviral therapy mount strong T cell responses to COVID-19 vaccines that can be enhanced by booster doses or breakthrough infection.
Strain heterogeneity in a non-pathogenic fungus highlights factors contributing to virulence
Authors: Rinker David C. , Sauters Thomas J. C. , Steffen Karin , Gumilang Adiyantara , Raja Huzefa A. , Rangel-Grimaldo Manuel , Pinzan Camila Figueiredo , de Castro Patrícia Alves , dos Reis Thaila Fernanda , Delbaje Endrews , Houbraken Jos , Goldman Gustavo H. , Oberlies Nicholas H. , Rokas Antonis 
Published: March 2024

ABSTRACTFungal pathogens exhibit extensive strain heterogeneity, including variation in virulence. Whether closely related non-pathogenic species also exhibit strain heterogeneity remains unknown. Here, we comprehensively characterized the pathogenic potentials (i.e., the ability to cause morbidity and mortality) of 16 diverse strains ofAspergillus fischeri, a non-pathogenic close relative of the major pathogenAspergillus fumigatus.In vitroimmune response assays andin vivovirulence assays using a mouse model of pulmonary aspergillosis showed thatA. fischeristrains varied widely in their pathogenic potential. Furthermore, pangenome analyses suggest thatA. fischerigenomic and phenotypic diversity is even greater. Genomic, transcriptomic, and metabolomic profiling identified several pathways and secondary metabolites associated with variation in virulence. Notably, strain virulence was associated with the simultaneous presence of the secondary metabolites hexadehydroastechrome and gliotoxin. We submit that examining the pathogenic potentials of non-pathogenic close relatives is key for understanding the origins of fungal pathogenicity.
A reference database of reptile images
Authors: Uetz Peter , Patel Maya , Gbadamosi Zainab , Nguyen Jeremy , Shoope Stacey 
Published: March 2024

AbstractWhile there are millions of reptile images available online, they are not well organized and not easily findable, accessible, interoperable, or reproducible (FAIR). More importantly, they are not standardized and thus hardly comparable. Here we present a reference database of more than 14,000 standardized images of 1,045 reptile species (969 lizard and 76 snake species), that are based on preserved specimens in 20 different collections, including 533 type species of genera and type specimens of 72 species. All images were taken with standardized views, including dorsal and ventral body shots as well as dorsal, ventral, and lateral views of the heads and other body parts. Although only 11 out of the 20 collections are cross-referenced in Vertnet, some others are indexed in GBIF, and this fraction will certainly grow in the near future. The utility of this and similar image collections will further grow with additional material and further cross-referencing, e.g., to DNA sequence databases or citizen science projects. The images are searchable and freely available onMorphobank.org(Project 5121) and on Figshare.com.