bluuebunny/crossref_metadata_2025_split huggingface dataset:
The combination of pimavanserin and atomoxetine reduces obstructive sleep apnea severity: a randomized crossover trial
Authors: Messineo Ludovico , Preuss Madison , Azarbarzin Ali , Vena Daniel , Gell Laura , Aishah Atqiya , Esmaeili Neda , Kim Molly , Burdick Isabel , Chen Tom , White David , Sands Scott A , Wellman Andrew 
Published: January 2025

ABSTRACTBackgroundObstructive sleep apnea (OSA) pharmacological interventions like the noradrenergic muscle stimulant atomoxetine have wake-promoting properties. Pimavanserin, a promising serotonin 2Areceptor antagonist, may help counteract atomoxetine’s noradrenergic effects by increasing arousal threshold and possibly reduce OSA severity.Research questionIn a randomized, crossover, two-period, double-blind clinical trial, we tested the effect of this drug combination on apnea-hypopnea index (AHI; primary outcome), arousal index and nadir oxygen saturation (SpO2; secondary outcomes).Study design and methodsFollowing baselinepolysomnography, 18 OSA participants (AHI>15events/h) took pimavanserin-plus-atomoxetine (34/80mg; 34/40mg for the first 3 days) or placebo for one-week; follow-up polysomnography was performed to provide study outcomes. Safety outcomes, subjective sleep quality, and flow-estimated endotypes (using oronasal pneumotachograph flow) were also explored.ResultsEleven and seven participants were randomized to atomoxetine-plus-pimavanserin and placebo first, respectively. The combination reduced AHI by 42 [95%CI: 18, 60] % vs. placebo, meeting the primary outcome (P<0.001). Absolute AHI reduction was 16.9 [8.1, 23.6] events/h greater than placebo. Nadir SpO2and arousal index were also improved, by 5.0 [1, 8] %and10.9 [2.4, 18.1] events/h vs. placebo. Overnight heart rate was increased (+4.8 [1.5, 8.1]), but no other change in subjective sleep quality or next-morning vital signs was evident. There was no increased risk for side effects on the combination vs. placebo. Treatment vs. placebo improved pharyngeal collapsibility (+7.9 [1.6, 14.1]%VEUPNEA), reduced loop gain by 20% (0.15 [-0.23, -0.07]), and did not reduce the arousal threshold.InterpretationPimavanserin with atomoxetine is a strong pharmacological therapy candidate for OSA.
Identifying clinical skill gaps of healthcare workers using a digital clinical decision support algorithm during outpatient pediatric consultations in primary health centers in Rwanda
Authors: Karoui Haykel , Rwandarwacu Victor P. , Niyonzima Jonathan , Makuza Antoinette , Nkuranga John B. , D’Acremont Valérie , Kulinkina Alexandra V. 
Published: January 2025

AbstractDigital clinical decision support algorithms (CDSAs) that guide healthcare workers during consultations can enhance adherence to guidelines and the resulting quality of care. However, this improvement depends on the accuracy of inputs (symptoms and signs) entered by healthcare workers into the digital tool, which relies mainly on their clinical skills, that are often limited, especially in resource-constrained primary care settings. This study aimed to identify and characterize potential clinical skill gaps based on CDSA data patterns and clinical observations. We retrospectively analyzed data from 20,204 pediatric consultations conducted using an IMCI-based CDSA in 16 primary health centers in Rwanda. We focused on clinical signs with numerical values: temperature, mid-upper arm circumference (MUAC), weight, height, z-scores (MUAC for age, weight for age, and weight for height), heart rate, respiratory rate and blood oxygen saturation. Statistical summary measures (frequency of skipped measurements, frequent plausible and implausible values) and their variation in individual health centers compared to the overall average were used to identify 10 health centers with irregular data patterns signaling potential clinical skill gaps. We subsequently observed 188 consultations in these health centers and interviewed healthcare workers to understand potential error causes. Observations indicated basic measurements not being assessed correctly in most children; weight (70%), MUAC (69%), temperature (67%), height (54%). These measures were predominantly conducted by minimally trained non-clinical staff in the registration area. More complex measures, done mostly by healthcare workers in the consultation room, were often skipped: respiratory rate (43%), heart rate (37%), blood oxygen saturation (33%). This was linked to underestimating the importance of these signs in child management, especially in the context of high patient loads typical at primary care level. Addressing clinical skill gaps through in-person training, eLearning and regular personalized mentoring tailored to specific health center needs is imperative to improve quality of care and enhance the benefits of CDSAs.
Comprehensive Analysis of Metabolic Reprogramming-Associated Key Genes and Immune Microenvironment in Heart Failure with Preserved Ejection Fraction
Authors: Yan Na , Yang Jiangyong 
Published: January 2025

AbstractBackgroundHeart failure with preserved ejection fraction (HFpEF) represents a profoundly heterogeneous cardiovascular condition; characterized by intricate molecular pathways that have not yet been fully elucidated. This study seeks to uncover metabolic reprogramming-associated key genes (Key Genes) linked to HFpEF, investigate their functional significance and influence on the immune microenvironment, and establish a robust early diagnostic framework.MethodsWe obtained datasets GSE194151 and GSE180065 from the GEO database. In order to counteract batch effects, metabolic reprogramming-related differentially expressed genes (MRRDEGs) were identified by differential expression analysis using the sva R package. Enrichment analysis using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomics (KEGG) elucidated the associated biological functions and pathways. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were used to examine biological differences within subgroups using risk assessment. Single sample gene set enrichment analysis (ssGSEA) was used to measure immune cell infiltration. Protein-protein interaction networks (PPI Networks), mRNA-TF, mRNA-RBP, and mRNA-miRNA interaction networks were used to investigate multilevel regulatory mechanisms. A diagnostic model for HFpEF, constructed using logistic regression, SVM, and LASSO, was validated through ROC analysis and external datasets.ResultsIn total, 34 MRRDEGs were identified, significantly enriched in processes like fatty acid metabolism and circadian rhythm regulation. A diagnostic model comprising five Key Genes(Hnrnpd,Hpcal1,Hadha,Hspd1, andNaa10) showed strong performance, withHspd1achieving an Area Under Curve (AUC) > 0.9. The validation using GSE180065 and HFpEF_2020 confirmed the reliability of the model. Immune analysis revealed significant enrichment of Activated CD4 T cells, type 2 T helper cells, and macrophages in the high-risk groups, correlating with specific Key Genes (p < 0.05). GSEA and GSVA linked high-risk groups to TGF-β signaling and fatty acid oxidation. PPI and regulatory network analyses further underscored the functional importance of Key Genes.ConclusionOur study systematically identified metabolic reprogramming-related Key Genes and their associations with immune microenvironment changes in HFpEF. These findings reveal the potential mechanisms underlying HFpEF and offer a high-performance diagnostic model, providing novel insights and therapeutic targets for molecular studies and immunotherapy in HFpEF.
Shoulder injuries in elite female cricket players: Insights from 8 seasons
Authors: Pritchard Gordon , Deshmukh Pallavi , Saw Anna E. , Beerworth Kate , Sims Kevin 
Published: January 2025

AbstractObjectivesTo describe the incidence, prevalence, characteristics, and management of shoulder injuries requiring medical attention in elite female cricket players.DesignRetrospective cohort.SettingAustralian state, territory, and national cricket teams between July 2015 and June 2023.ParticipantsElite female cricket players.Independent variablesMedical attention and general time-loss shoulder injuries.Main outcome measuresIncidence, prevalence, characteristics, recovery time-frames, activity modifications.Results409 shoulder injuries were recorded, with an average incidence of 12.9 per 100 players per season. Gradual onset injuries were most commonly experienced by pace bowlers (51%). Sudden onset injuries were most commonly sustained whilst fielding (69%). Four in five injuries did not require the player to be unavailable to play or train. Modified activities (e.g., throwing, diving, bowling) were typically required for between 2 weeks and 6 months. Players typically returned to full unrestricted match play between 1-8.5 months, longer for recurrent injuries (p=0.007).ConclusionsShoulder injuries are a considerable burden in elite female cricket players. Despite only one in five injuries resulting in a player being unavailable to play or train, impaired shoulder function may reduce the overall performance of the player and the team. Risk reduction strategies may be targeted to at risk players (pace bowlers) and activities (throwing and diving) to reduce the burden of shoulder injuries in this cohort. Further consideration may also be given to management strategies to reduce the risk of exacerbations and recurrent injuries which may prolong recovery.
Harnessing glucocorticoid receptor antagonization to enhance the efficacy of cardiac regenerative growth factors and cytokines
Authors: Da Pra Silvia , Boriati Stefano , Miano Carmen , Del Bono Irene , Sacchi Francesca , Bongiovanni Chiara , Aharonov Alla , Pianca Nicola , Tassinari Riccardo , Ventura Carlo , Lauriola Mattia , Tzahor Eldad , D’Uva Gabriele 
Published: January 2025

AbstractSevere myocardial injuries in mammals lead to cardiomyocyte loss and heart failure. Activation of Glucocorticoid Receptor (GR) by endogenous glucocorticoids limit cardiomyocyte proliferation and cardiac regeneration. Here, we reveal that glucocorticoids suppress the proliferative response of cardiomyocytes to a diverse range of regenerative factors, including Neuregulin 1 (NRG1), FGF1, IGF2, IGF1, BMP7, Oncostatin M (OSM), LIF, RANKL, IL6, IL13, IL4, and IL1-beta.Transcriptomic analyses revealed that glucocorticoids-GR axis induces the expression of MAPK/ERK pathway inhibitors ERRFI1/MIG6 and DUSP1. Using NRG1 as a model system for cardiac regenerative factors, we demonstrate that glucocorticoids suppress growth factor-induced ERK activation, nuclear translocation, and transcriptional output. Knockdown experiments confirmed that ERRFI1 and DUSP1 are key mediators of glucocorticoid-mediated suppression of cardiomyocyte proliferation induced by growth factors. The cardiac expression of GR target genes, includingDusp1andErrfi1,increases during early postnatal development, coinciding with the transition to post-mitotic cardiomyocytes. In juvenile and adult stage, regenerative growth factors failed to activate MAPK/ERK pathway and induce proliferation effectively; however, DUSP1 inhibition rescues these responses. Consistently, GR antagonization during early postnatal development preserved MAPK/ERK pathway activity. Importantly, GR antagonization or deletion reinstated growth-factor-induced proliferation of postmitotic cardiomyocytes. Finally, GR antagonization enhanced thein vivoeffectiveness of growth factor-based regenerative therapy in an adult mouse model of myocardial injury, enhancing cardiomyocyte proliferation and cardiac function. These findings reveal a previously unrecognized mechanism by which systemic hormones, specifically glucocorticoids, regulate the regenerative potential of cardiac paracrine factors. This study highlights transient glucocorticoid inhibition as a promising strategy to enhance the therapeutic efficacy of growth factor-based cardiac regenerative approaches.HighlightsPhysiological glucocorticoids suppress the proliferative response of cardiomyocytes to regenerative growth factors and cytokines.Glucocorticoids inhibit growth factor-induced MAPK/ERK activation in cardiomyocytes by upregulating the expression of negative regulators DUSP1 and ERRFI1.Increased glucocorticoid-induced expression of DUSP1 and ERRFI1 during early postnatal development impairs the mitogenic activity of cardiac regenerative factors.GR antagonization restores growth factor-induced MAPK signaling and mitogenic activity in postmitotic cardiomyocytes and enhances the efficacy of growth factor-based regenerative therapies following myocardial injury.
Ontogeny drives stage-specific effects of a Gata1 mutation
Authors: Sommer Alina , Fischer Stephan , Freyer Laina , Lallemand Yvan , Dardenne Pascal , Gomez Perdiguero Elisa 
Published: January 2025

SummaryThe biography of an organism, including, for instance, its genetic background and exposure to environmental influences, determines the penetrance and expressivity of monogenic diseases between individuals. This also applies at the single-cell level. Interestingly, mature blood and immune cells originate from anatomically and temporally distinct stem and progenitor populations at different stages of development. Here we show that the ontogeny or progenitor origin of megakaryocytes determines their developmental trajectory at the cellular and transcriptional level. As a result, a mutation in the key transcription factor Gata1 dysregulates megakaryopoiesis in an ontogeny-specific manner causing a stage-specific disorder. Particularly, only early extraembryonic hematopoietic progenitors drive blast-like cell development leading to a transient accumulation of megakaryocytes in the fetus but not in the adult. Therefore, pediatric blood disorders may differ functionally from adult diseases due to changing progenitor sources of mature blood and immune cells throughout development.HighlightsFetal and adult megakaryopoiesis pass through distinct immunophenotypic stagesOntogeny of megakaryocytes dictates their unique transcriptional trajectoryProgenitor origin rather than the differentiation pathway determines the effect of mutant Gata1Block in maturation at the progenitor level causes the accumulation of yolk sac-derived megakaryocytes in the presence of mutant Gata1Mutant Gata1 drives blast cell formation exclusively in yolk sac-derived lineages
ThePaulinellachromatophore transit peptide part2 adopts a structural fold similar to the γ-glutamyl-cyclotransferase fold
Authors: Klimenko Victoria , Reiners Jens , Applegate Violetta , Reimann Katharina , Hoeppner Astrid , Smits Sander H. J. , Nowack Eva C. M. 
Published: January 2025

AbstractThe chromatophores of the cercozoan amoebaPaulinellaare photosynthetic organelles that evolved from a cyanobacterial endosymbiont. Many nucleus-encoded chromatophore-targeted proteins carry unusual N-terminal targeting signals termed crTPs. The crTPs are bipartite. Whereas crTPpart1that likely mediates trafficking through the secretory pathway is cleaved off during import, crTPpart2remains attached to its cargo protein. The function of crTPpart2is unknown. To contribute to unravel the functional role of crTPpart2, here we elucidated the structures of crTPpart2from two different chromatophore-targeted proteins by X-ray crystallography at ∼2.3 Å resolution. Interestingly, the crTPpart2of both proteins adopts a structural fold. Both structures share a conserved structured core and a flexible N-terminal arm. The structured core resembles proteins of the γ-glutamyl cyclotransferase superfamily within which crTPpart2structures form a novel protein (sub)-family. The proposed catalytic center typical for proteins with cyclotransferase activity is not conserved in crTPpart2. A Cys pair that is conserved in crTPpart2of many chromatophore-targeted proteins has been captured as disulfide bridge. Together, our data suggests that chromatophore-targeted proteins are imported in their folded state and that the fold adopted by crTPpart2plays a functional role during import. The characterization of its structure and flexibility provides important steps towards elucidating this novel protein translocation mechanism.
Melbournevirus encodes a shorter H2B-H2A doublet histone variant that forms structurally distinct nucleosome structures
Authors: Villalta Alejandro , Bisio Hugo , Toner Chelsea M. , Abergel Chantal , Luger Karolin 
Published: January 2025

AbstractUnique among viruses, some giant viruses utilize histones to organize their genomes into nucleosomes. Melbournevirus encodes a distinct H2B-H2A histone doublet variant in addition to the canonical H4-H3 and H2B-H2A doublets. This viral histone variant has a truncated H2B portion and its amino acid sequence deviates from that of the main viral H2B-H2A throughout the entire coding region. It is less abundant than the main H2B-H2A doublet, is essential for melbournevirus fitness, and is conserved in allMarseilleviridae. The cryo-EM structure of a nucleosome-like particle reconstituted with this H2B-H2A variant and viral H4-H3 reveals that only 90 base pairs of DNA are stably bound, significantly less than in eukaryotic nucleosomes and viral nucleosomes made with the main fused viral histone doublets. The reduced ability to bind DNA can be attributed to structural differences between variant and main H2B-H2A. Variant melbournevirus nucleosomes are less stable, possibly aiding rapid genome unpacking to initiate gene expression. Our results highlight the remarkable propensity of giant viruses to appropriate the utility of histones for their specialized purposes.
Experience directs the instability of neuronal tuning for critical period plasticity in mouse visual cortex
Authors: Brown Thomas C. , McGee Aaron W. 
Published: January 2025

AbstractBrief monocular deprivation during a developmental critical period, but not thereafter, alters the receptive field properties (tuning) of neurons in visual cortex, but the characteristics of neural circuitry that permit this experience-dependent plasticity are largely unknown. We performed repeated calcium imaging at neuronal resolution to track the tuning properties of populations of excitatory layer 2/3 neurons in mouse visual cortex during or after the critical period, as well as innogo-66 receptor (ngr1)mutant mice that sustain critical-period plasticity as adults. The instability of tuning for populations of neurons was greater in juvenile mice and adultngr1mutant mice. We propose instability of neuronal tuning gates plasticity and is directed by experience to alter the tuning of neurons during the critical period.
Formation and Gelation of Elastin-like Polypeptide Complex Coacervates
Authors: Fisher Rachel S. , Cheng Yihan , Goessling Lavinia , Obermeyer Allie C. 
Published: January 2025

AbstractProtein liquid-liquid phase separation underlies the formation of membraneless organelles in cells and performs a key role in the assembly process of natural materials such as the assembly of tropoelastin into elastic fibers. Here, we engineered a series of charged elastin-like polypeptides (ELPs) that form complex coacervates, providing a rapid method to concentrate proteins into a fluid state. Compared to coacervates formed from simple coacervation, complex coacervates exhibited greater fluidity, likely due to differences between electrostatic interactions and hydrophobic forces. We designed these ELP’s to further contain crosslinking domains compatible with tyrosinase or transglutaminase and found that crosslinking was enhanced when proteins were in a complex coacervate compared to free in solution. Crosslinking the ELP complex coacervates led to the formation of gels with distinct properties dependent on the nature of the crosslinking. This work expands the design space of ELP hydrogels, offering a novel strategy for forming crosslinked networks from complex coacervates and providing opportunity for future use in tissue engineering and biocompatible biomaterials applications.
Multi-System Dysregulation in Placental Malaria Contributes to Adverse Perinatal Outcomes in Mice
Authors: Ekregbesi Phebe , Seibert Brittany , Parish Maclaine A. , Flores-Garcia Yevel , Creisher Patrick S. , Hoffmann Joseph P. , Liu Jennifer , Brayton Cory , Zavala Fidel , Klein Sabra L. 
Published: January 2025

ABSTRACTSequestration ofPlasmodiumparasites in the placental vasculature causes increased morbidity and mortality in pregnant compared to non-pregnant patients in malaria- endemic regions. In this study, outbred pregnant CD1 mice with semi allogeneic fetuses were infected with transgenicPlasmodium bergheior mock-inoculated by mosquito bite at either embryonic day (E) 6 (first trimester-equivalent) or 10 (second trimester- equivalent) and compared with non-pregnant females.P. berghei-infected mosquitoes had greater biting avidity for E10 dams than uninfected mosquitoes, which was not apparent for E6 dams nor non-pregnant females. Infected E10 dams had greater numbers of parasites than E6 dams in the uterus and spleen, but not in the blood or liver. While parasites were found in placentas, no parasites were present in fetuses. Maternal infection at E6 caused greater maternal morbidity, with greater rates of fetal reabsorption and stillbirths than at E10. Infection at E10 caused adverse offspring outcomes, including growth restriction. To identify possible mechanisms of adverse offspring outcomes, E10 dams were euthanized during peak parasitemia (8 days post infection), and outcomes were compared with mock-infected dams.P. bergheicaused significant systemic maternal immune activation with elevated circulating lymphocytes, eosinophils, and neutrophils and splenic cytokine concentrations.P. bergheiinfection at E10 increased corticosterone and decreased progesterone concentrations, which could contribute to adverse perinatal outcomes through immunomodulation. There were limited changes in the maternal fecal microbiome afterP. bergheiinfection. Mosquito bite infection of outbred dams withP. bergheicauses placental malaria and provides a novel, tractable model to investigate therapeutic treatments.
Nuclear level density and
γ
-ray strength function of
Ni67
and the impact on the
i
process
Authors: Ingeberg V. W. , Siem S. , Wiedeking M. , Choplin A. , Goriely S. , Siess L. , Abrahams K. J. , Arnswald K. , Bello Garrote F. , Bleuel D. L. , Cederkäll J. , Christoffersen T. L. , Cox D. M. , De Witte H. , Gaffney L. P. , Görgen A. , Henrich C. , Illana A. , Jones P. , Kheswa B. V. , Kröll T. , Majola S. N. T. , Malatji K. L. , Ojala J. , Pakarinen J. , Rainovski G. , Reiter P. , von Schmid M. , Seidlitz M. , Tveten G. M. , Warr N. , Zeiser F. ,   The ISOLDE Collaboration
Published: January 2025

Proton-γ coincidences from (d,p) reactions between a Ni66 beam and a deuterated polyethylene target have been analyzed with the inverse-Oslo method to find the nuclear level density (NLD) and γ-ray strength function (γSF) of Ni67. The Ni66(n,γ) capture cross section has been calculated using the Hauser-Feshbach model in using the measured NLD and γSF as constraints. The results confirm that the Ni66(n,γ) reaction acts as a bottleneck when relying on one-zone nucleosynthesis calculations. However, the impact of this reaction is strongly dampened in multizone models of low-metallicity AGB stars experiencing i-process nucleosynthesis.

Published by the American Physical Society
2025