bluuebunny/crossref_metadata_2025_split huggingface dataset:
Performance and usability evaluation of three LDH-based malaria rapid diagnostic tests in Kédougou, Senegal
Authors: Souleymane Sambe Babacar , Zobrist Stephanie , Sheahan William , Soni Divya , Diagne Aissatou , Sarr Ibrahima , Sabene Diatta Arona , Mbacke Diaw Serigne Ousmane , Golden Allison , Slater Hannah , Jang Ihn Kyung , Roa Nerie , Pal Sampa , Diene Sarr Fatoumata , Faye Joseph , Vigan-Womas Inès , Dieye Yakou , Cisse Moustapha , Domingo Gonzalo J , Niang Makhtar 
Published: December 2024

AbstractBackgroundThe emergence ofpfhrp2/3-deleted parasites threatens histidine-rich protein 2 (HRP2)-based malaria rapid diagnostic test (RDT) performance. RDTs targetingPlasmodium falciparum(Pf) lactate dehydrogenase (LDH) may address current product limitations and improve case management.ObjectivesTo evaluate the performance and usability of three LDH-based RDTs in febrile patients.MethodsA cross-sectional diagnostic accuracy study was conducted in Kédougou, Senegal. Capillary blood was tested using the SD Bioline Ag Pf (#05FK50) and three LDH-based RDTs: BIOCREDIT Malaria Ag Pf (pLDH), BIOCREDIT Pf (pLDH/HRPII), and BIOCREDIT Pf/Pv (pLDH/pLDH) (Rapigen Inc., Republic of Korea). Venous blood was collected to repeat the BIOCREDIT RDTs and conduct microscopy. Frozen venous specimens were tested using a reference PCR assay. A quantitative multiplex malaria antigen assay measured antigen concentration. RDT performance was determined and analyzed as a function of antigen concentration distribution. Usability of thePf-only BIOCREDIT tests was evaluated using a questionnaire.Results154/220 participants (70%) werePf-positive by PCR. The Pf (pLDH/HRPII) test demonstrated the highest sensitivity at 78% (70.9%–84.5%); specificity was 89% (79.4%–95.6%). All RDTs performed better than microscopy (53% sensitivity). RDTs performed better when compared to antigen concentration over PCR results. Improved sensitivity of the Pf (pLDH/HRPII) test was driven by the HRP2 line. Line intensity correlated with antigen concentration. Predicted sensitivity using the analytical limit of detection (LOD) was comparable to observed sensitivity. RDTs demonstrated acceptable usability.ConclusionsBoth HRP2 and LDH contributed to the sensitivity of the best-performingPf-RDT. RDT analytical LODs can be used to predict performance in populations with known antigen concentrations.
A multi-level gene-diet interaction analysis of fish oil supplementation and 14 circulating polyunsaturated fatty acids-related traits identifies theFADSandGRP12loci
Authors: Ihejirika Susan Adanna , Chiang Alexandra Huong , Singh Aryaman , Stephen Eunice , Chen Han , Ye Kaixiong 
Published: December 2024

AbstractFish oil supplements (FOS) are known to alter circulating levels of polyunsaturated fatty acids (PUFAs) among individuals but in a heterogeneous manner. These varied responses may result from unidentified gene-FOS interactions. To identify genetic factors that interact with FOS to alter the circulating levels of PUFAs, we performed a multi-level genome-wide interaction study (GWIS) of FOS on 14 plasma measurements in 200,060 unrelated European-ancestry individuals from the UK Biobank. From our single-variant tests, we identified genome-wide significant interacting SNPs (P< 5 × 10−8) in theFADS1-FADS2gene cluster for total omega-3, omega-3%, docosapentaenoic acid (DHA), DHA% and the omega-6 to omega-3 ratio. Among the interaction signals for omega-3%, the lead SNP, rs35473591 (C>CT, CT allele frequency = 0.34), had a lower association effect size in the FOS-taking group (β = 0.35 for allele C) than that in the group without FOS (β = 0.42). Likewise, the effect sizes of associations between FOS and omega-3% varied across the three genotype groups (β = 0.45, 0.50, and 0.59, respectively, in C/C, C/CT, and CT/CT). Our gene-level aggregate and transcriptome-wide interaction analyses identified significant signals at two loci, aroundFADS1-FADS2andGRP12. The contribution of genome-wide gene-FOS interactions to phenotypic variance was statistically significant in omega-3-related traits. This systemic gene-FOS GWIS contributes to our understanding of the genetic architecture of circulating PUFAs underlying FOS response and informs personalized dietary recommendations.
Predictors of Response to Cardiac Resynchronization Therapy in Pediatric and Congenital Heart Disease Patients
Authors: Chubb Henry , Mah Douglas , Shah Maully , Lin Kimberly Y , Peng David , Hale Benjamin W , May Lindsay , Etheridge Susan , Goodyer William , Ceresnak Scott R , Motonaga Kara S , Rosenthal David N , Almond Christopher S , McElhinney Doff B , Dubin Anne M 
Published: December 2024

AbstractBackgroundCardiac resynchronization therapy (CRT) is an important therapeutic option in selected pediatric and congenital heart disease (CHD) patients with reduced systemic ventricular (SV) ejection fraction (EF). However, the identification of optimal responders is challenging.ObjectiveTo identify predictors of response to CRT in children and CHD patients at 5 large quaternary referral centers.MethodsPatients were <21 years or had CHD; had SVEF <45%; symptomatic heart failure; and significant electrical dyssynchrony prior to CRT. Primary outcome was defined as an ordinal response at 6/12months: (1) Improved EF [≥5%], (2) Unchanged SVEF, (3) Worse SVEF. Secondary outcome utilized a propensity score-matched control cohort. Response to CRT was defined using longitudinal trajectory of SVEF up to latest follow-up.ResultsIn total, 167 eligible CRT recipients were identified across the 5 centers. 150 had comprehensive data at 6/12months: 96(64%) with improved SVEF, 26(17%) unchanged, 28(19%) worsened. Mean increase in SVEF was 11% [IQR 3-21%]. On univariable ordinal regression, lower SVEF (p=0.013), biventricular circulation (p=0.022), systemic LV (p=0.021), and conduction delay to lateral wall of SV (p=0.01) were associated with positive response.For assessment of secondary outcome, 324 controls were identified. Mean follow-up 4.2(±3.7) yrs. Almost all subgroups demonstrated improved SVEF trend with CRT, except those with systemic RV (p=0.69) or without prior single site pacemaker (p=0.20).ConclusionCRT in children and CHD patients frequently results in an improvement in SVEF. Those with lower SVEF, conduction delay to lateral wall of the SV and those with systemic LV are most likely to respond.Condensed AbstractCardiac resynchronization therapy (CRT) is an important therapeutic option in selected pediatric and congenital heart disease (CHD) patients with reduced systemic ventricular (SV) ejection fraction (EF). However, the identification of optimal responders is challenging.In this multicenter study, pediatric and CHD CRT recipients with heart failure and EF<45% were identified. The primary outcome was change in EF at 6/12months. Those with lower baseline SVEF, conduction delay to lateral wall of the SV and/or systemic LV were most likely to respond to CRT. When compared to propensity score-matched controls, the CRT groups also demonstrated a significantly better long-term EF trajectory.
Current etiology of hypertension in European children – role of serum uric acid
Authors: Obrycki Łukasz , Skoczyński Krzysztof , Sikorski Maksymilian , Koziej Jan , Mitoraj Kacper , Pilip Jakub , Pac Michał , Feber Janusz , Litwin Mieczysław 
Published: December 2024

2.AbstractBackgroundWhile hypertension (HT) in pediatric patients is often secondary (SH), recent trends show a rise in primary hypertension (PH), which is associated with an increasing global prevalence of obesity. Our study aimed to assess the etiology of HT and predictors of PH in a large European cohort of children referred for HT based on office blood pressure (BP) measurements.MethodsWe performed retrospective analysis of 2008 children aged 0–18 years (12.3 ± 4.9 years) diagnosed with HT. Patients were classified into white coat hypertension (WCH), PH, or SH groups based on office BP and 24-hour ambulatory BP monitoring (ABPM). Clinical, anthropometric, and biochemical data were collected to differentiate PH and SH and to identify predictors of PH.ResultsOut of 2008 patients included in the analysis, HT was confirmed in 1452 patients (556 were classified as WCH). Of 1452 patients with HT: 42.8% had PH, while 57.2% had SH, mainly secondary to renal parenchymal disease (33.2% of SH patients), post-kidney transplant HT (23.1%), aortic coarctation (15.9%) and renovascular HT (13.8%). However, PH started to be the dominant cause of HT after 13 years of age and was diagnosed in 59.1% of 13–18-year-old patients with confirmed HT. Age ≥ 13 years, obesity (BMI-SDS ≥1.65), and serum uric acid ≥ 5.5 mg/dL were identified as significant PH predictors.ConclusionsOur study provides valuable insights into the current etiology of pediatric HT and highlights the role of uric acid level assessment in the diagnosis of PH in children.
Small Extracellular Vesicles by Nucleus Pulposus Cells Maintain Niche and Cell Homeostasis via Receptor Shuffling and Metabolic Enzyme Supplements
Authors: Samanta Ankita , Yoo Mi-Jeong , Koh Jin , Lufkin Thomas , Kraus Petra 
Published: December 2024

ABSTRACTBackgroundSmall extracellular vesicles (sEV) are a conserved mean of communication across the domains of life and lately gained more interest in mammalian non-cancerous work as non-cellular, biological therapeutic with encouraging results in recent studies of chronic degenerative diseases. The nucleus pulposus (NP) is the avascular and aneural center of an intervertebral disc (IVD), home to unique niche conditions and affected in IVD degeneration. We investigated the proteome of autologous and mesenchymal stem cell (MSC) sEVs for their potential to contribute to cell and tissue homeostasis in this niche.MethodsWe aimed to identify characteristics of NP sEVs via mass spectrometric proteome and functional enrichment analysis. We explored the proteome profile of sEVs generated by autologous parent cell lines from bovine coccygeal IVD and adipose tissue, with a focus on NP cells, using adult and fetal donors. We compared these findings to published sEV databases and MSC sEV data.FindingsWe propose several mechanisms associated with NP sEVs: 1. Membrane receptor trafficking to modify signal responses promoting niche homeostasis. 2. Cell homeostasis via proteasome delivery; 3. Redox and energy homeostasis via metabolic enzymes delivery. 4. Immunomodulation beyond an association with a serum protein corona.ConclusionThe proteome signature of sEVs generated by NP parent cells is similar to previously published sEV data, yet with a focus on supplementing anaerobic metabolism and redox balance while contributing to the maintenance of an aneural and avascular microniche.
Disruption of the epigenetic regulator BAP1 drives chromatin remodeling leading to the emergence of cells with breast cancer stem cell properties and aberrant glycosylation
Authors: da Silva Araujo Mariana Gomes , Sallé Aurélie , Cahais Vincent , Renard Claire , Cuenin Cyrille , Poubel Caroline Pires , Keita Stéphane , Mosler Thorsten , Carreira Christine , Levy Gabrielle Goldman , Parres Lya , Bourova-Flin Ekaterina , Rousseaux Sophie , Khochbin Saadi , Ghantous Akram , Habazin Siniša , Pučić-Baković Maja , Cosset Erika , Lauc Gordan , Herceg Zdenko , Khoueiry Rita 
Published: December 2024

ABSTRACTBackgroundEpigenetic regulator genes play critical roles in controlling cell identity and are frequently disrupted in breast cancers, suggesting a key driver role in this disease and its associated phenotypes. However, specific epigenetic drivers (epidrivers) of mammary cell plasticity and their mechanistic contributions to this phenotype are poorly characterized.MethodsTo identify potential epidrivers of the emergence of mesenchymal breast cancer stem cell-like phenotypes in non-tumorigenic mammary cells, we employed a CRISPR/Cas9 loss-of-function screening strategy targeting epigenetic regulator genes. This approach was followed by an in-depth validation and characterization of epigenomic, transcriptomic, proteomic and phenotypic changes resulting from the disruption of the putative epidriver geneBAP1.ResultsOur investigation revealed that loss of the histone deubiquitinase BAP1 impacts cellular processes associated with breast cancer cell plasticity such as epithelial-to-mesenchymal transition (EMT) and actin cytoskeleton organization. In addition, we unveiled that BAP1 loss resulted in an overall less permissive chromatin and downregulated gene expression, impacting programs that control cellular glycosylation and leading to decreased glycan abundance and complexity. BAP1 rescue restored the expression of several deregulated genes in a catalytic activity-dependent manner, suggesting that BAP1-mediated cell identity and glycosylation regulation are largely dependent on its histone deubiquitinase activity.ConclusionsOverall, our results point to BAP1 disruption as a driver of mammary cell plasticity and reveal a novel role of BAP1 as an epigenetic regulator of cellular glycosylation.
LMX1Bmissense-perturbation of regulatory element footprints disrupts serotonergic forebrain axon arborization
Authors: Eastman Brent , Tabuchi Nobuko , Zhang Xinrui , Spencer William C. , Deneris Evan S. 
Published: December 2024

AbstractPathogenic coding mutations are prevalent in human neuronal transcription factors (TFs) but how they disrupt development is poorly understood. Lmx1b is a master transcriptional regulator of postmitoticPet1neurons that give rise to mature serotonin (5-HT) neurons; over two hundred pathogenic heterozygous mutations have been discovered in humanLMX1B,yet their impact on brain development has not been investigated. Here, we developed mouse models with differentLMX1BDNA-binding missense mutations. Missense heterozygosity broadly alteredPet1neuron transcriptomes, but expression changes converged on axon and synapse genes. Missense heterozygosity effected highly specific deficits in the postnatal maturation of forebrain serotonin axon arbors, primarily in the hippocampus and motor cortex, which was associated with spatial memory defects. Digital genomic footprinting (DGF) revealed that missense heterozygosity caused complete loss of Lmx1b motif protection and chromatin accessibility at sites enriched for a distal active enhancer/active promoter histone signature and homeodomain binding motifs; at other bound Lmx1b motifs, varying levels of losses, gains or no change in motif binding and accessibility were found. The spectrum of footprint changes was strongly associated with synapse and axon genes. Further, Lmx1b missense heterozygosity caused wide disruption of Lmx1b-dependent GRNs comprising diverse TFs expressed inPet1neurons. These findings reveal an unanticipated continuum of Lmx1b missense-forced perturbations onPet1neuron regulatory element TF binding and accessibility. Our work illustrates the power of DGF for gaining unique insight into how TF missense mutations interfere with developing neuronal GRNs.Significance StatementWe modeled human LMX1B missense mutations in mice to explore how they disrupt brain serotonin neuron development. Missense heterozygosity selectively impaired postnatal formation of serotonin axon arbors throughout the forebrain, notably in the hippocampus and motor cortex. DGF revealed that Lmx1b missense heterozygosity exerted a continuum of footprint changes associated with synapse and axon gene expression. Footprint changes ranged from total eliminations to partial losses and gains within thePet1neuronal epigenome. LMX1B missense mutations may cause human brain pathogenesis by selectively disrupting cis regulatory elements controlling 5-HT axon arbor formation thus impairing 5-HT delivery to presynaptic release sites.
Protein Language Model Identifies Disordered, Conserved Motifs Driving Phase Separation
Authors: Zhang Yumeng , Zheng Jared , Zhang Bin 
Published: December 2024

AbstractIntrinsically disordered regions (IDRs) play a critical role in phase separation and are essential for the formation of membraneless organelles (MLOs). Mutations within IDRs can disrupt their multivalent interaction networks, altering phase behavior and contributing to various diseases. Therefore, examining the evolutionary fitness of IDRs provides valuable insights into the relationship between protein sequences and phase separation. In this study, we utilized the ESM2 protein language model to map the fitness landscape of IDRs. Our findings reveal that IDRs, particularly those actively participating in phase separation, contain conserved amino acids. This conservation is evident through mutational constraints predicted by ESM2 and supported by direct analyses of multiple sequence alignments. These conserved, disordered amino acids include residues traditionally identified as “stickers” as well as “spacers” and frequently form continuous sequence motifs. The strong conservation, combined with their critical role in phase separation, suggests that these motifs act as functional units under evolutionary selection to support stable MLO formation. Our findings underscore the insights into phase separation’s molecular grammar made possible through evolutionary analysis enabled by protein language models.
Within-Family GWAS does not Ameliorate the Decline in Prediction Accuracy across Populations
Authors: Zhang Luyin , Conley Dalton 
Published: December 2024

AbstractAs polygenic prediction extends beyond the research domain to involve clinical applications, the urgency of solving the “portability problem” becomes amplified—that is, the fact that polygenic indices (PGI) constructed based on discovery analysis in one population (typically of exclusively continental European descent) predict poorly in other populations. In the present paper we test whether population differences in genetic nurture, assortative mating, or population stratification contribute to the fact that polygenic indices constructed based on GWAS results from European-descent samples predict more poorly in admixed populations with Native American and African ancestry. We do this by comparing the rates of decline in prediction accuracy of classical-GWAS-based PGIs versus within-family-based PGIs, each estimated in a population of European descent, as they are deployed in two samples of Latino Americans and African Americans. Within-family GWAS putatively eliminates the effects of parental genetic nurture, assortative mating, and population stratification; thus, we can determine whether without those confounding factors in the PGI construction, the relative prediction accuracy in the out-groups is ameliorated. Results show that relative prediction accuracy is not improved, suggesting that the differences across groups can be almost entirely explained by variation in genetic architecture (i.e. allele frequencies and short-range LD) rather than the aforementioned factors. Additional analysis of the impact of genetic architecture on the decline in prediction accuracy supports this conclusion. Future researchers should test within-family analysis at the prediction rather than the discovery stage.
A novel Mannan-specific chimeric antigen receptor M-CAR redirects T cells to interact withCandidaspp. hyphae andRhizopus oryzaespores
Authors: Guimarães Júlia Garcia , de Campos Gabriela Yamazaki , Machado Michele Procópio , Oliveira Brito Patrícia Kellen Martins , dos Reis Thaila Fernanda , Goldman Gustavo Henrique , Palma Patricia Vianna Bonini , de Campos Fraga-Silva Thais Fernanda , Cavallini Daniela Cardoso Umbelino , Venturini James , da Silva Thiago Aparecido 
Published: December 2024

ABSTRACTInvasive fungal infections (IFIs) are responsible for elevated rates of morbidity and mortality, causing around of 1.5 million deaths annually worldwide. One of the main causative agents of IFIs isCandida albicans, and non-albicansCandidaspecies have emerged as a spreading global public health concernment. Furthermore, COVID-19 has contributed to a boost in the incidence of IFIs, such as mucormycosis, in whichRhizopus oryzaeis the most prevalent causative agent. The effector host immune response against IFIs depends on the activity of T cells, which are susceptible to the regulatory effects triggered by fungal virulence factors. The fungal cell wall plays a crucial role as a virulence factor, and its remodeling compromises the development of a specific T-cell response. The redirection of Jurkat T cells to targetCandidaspp. by recognizing targets expressed on the fungal cell wall can be facilitated using chimeric antigen receptor (CAR) technology. This study generated an M-CAR that contains an scFv with specificity to α-1,6 mannose backbone of fungal mannan, and the expression of M-CAR on the surface of modified Jurkat cells triggered a strong activation againstCandida albicans(hyphae form),Candida tropicalis(hyphae form),Candida parapsilosis(pseudohyphal form), andCandida glabrata(yeast form). Moreover, M-CAR Jurkat cells recognizedRhizopus oryzaespores, which induced high expression of cell activation markers. Thus, a novel Mannan-specific CAR enabled strong signal transduction in modified Jurkat cells in the presence ofCandidaspp. orR. oryzae.
Midfacial retrusion and loss of facial appendages caused by mutation of Pax9 in zebrafish
Authors: Paudel Sandhya , McLeod Sarah , Gjorcheska Stefani , Barske Lindsey 
Published: December 2024

ABSTRACTLoss of dentition has occurred repeatedly throughout vertebrate evolution. Cyprinid fish, including zebrafish, form teeth only deep within the pharynx, not on their oral jaws. However, zebrafish still robustly express transcription factors associated with mammalian tooth development in the neural crest-derived mesenchyme surrounding the mouth. We investigated whether this expression is vestigial or whether these factors contribute to the formation of non-tooth mesenchymal structures in the oral region, using Pax9 as a test case. Zebrafish homozygous for two differentpax9mutant alleles develop the normal complement of pharyngeal teeth but fail to form the premaxilla bone, most of the maxilla, and nasal and maxillary barbels. Lack of most of the upper jaw complex does not preclude effective feeding in the laboratory environment. We observed a significant deficit ofsp7:EGFP+osteoblasts and adjacentalx4a:DsRed+condensing mesenchyme where the maxilla forms, and no accumulation of either in the premaxillary domain. These phenotypes are not presaged by major disruptions in early facial patterning, Wnt signaling, proliferation, or cell death; however, loss of a small population of Wnt-responsive cells around the maxilla correlates with its stalled growth in mutants. We conclude that Pax9 is not unequivocally required for all vertebrate tooth development, but instead may be broadly involved in the development of a variety of organs forming through mesenchymal condensation around the mouth.