bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integration of functional genomics and statistical fine-mapping systematically characterizes adult-onset and childhood-onset asthma genetic associations
Authors: Zhong Xiaoyuan , Mitchell Robert , Billstrand Christine , Thompson Emma , Sakabe Noboru J. , Aneas Ivy , Salamone Isabella M. , Gu Jing , Sperling Anne I. , Schoettler Nathan , Nóbrega Marcelo A. , He Xin , Ober Carole 
Published: February 2025

AbstractBackgroundGenome-wide association studies (GWAS) have identified hundreds of loci underlying adult-onset asthma (AOA) and childhood-onset asthma (COA). However, the causal variants, regulatory elements, and effector genes at these loci are largely unknown.MethodsWe performed heritability enrichment analysis to determine relevant cell types for AOA and COA, respectively. Next, we fine-mapped putative causal variants at AOA and COA loci. To improve the resolution of fine-mapping, we integrated ATAC-seq data in blood and lung cell types to annotate variants in candidatecis-regulatory elements (CREs).We then computationally prioritized candidate CREs underlying asthma risk, experimentally assessed their enhancer activity by massively parallel reporter assay (MPRA) in bronchial epithelial cells (BECs) and further validated a subset by luciferase assays. Combining chromatin interaction data and expression quantitative trait loci, we nominated genes targeted by candidate CREs and prioritized effector genes for AOA and COA.ResultsHeritability enrichment analysis suggested a shared role of immune cells in the development of both AOA and COA while highlighting the distinct contribution of lung structural cells in COA. Functional fine-mapping uncovered 21 and 67 credible sets for AOA and COA, respectively, with only 16% shared between the two. Notably, one-third of the loci contained multiple credible sets. Our CRE prioritization strategy nominated 62 and 169 candidate CREs for AOA and COA, respectively. Over 60% of these candidate CREs showed open chromatin in multiple cell lineages, suggesting their potential pleiotropic effects in different cell types. Furthermore, COA candidate CREs were enriched for enhancers experimentally validated by MPRA in BECs. The prioritized effector genes included many genes involved in immune and inflammatory responses. Notably, multiple genes, includingTNFSF4, a drug target undergoing clinical trials, were supported by two independent GWAS signals, indicating widespread allelic heterogeneity. Four out of six selected candidate CREs demonstrated allele-specific regulatory properties in luciferase assays in BECs.ConclusionsWe present a comprehensive characterization of causal variants, regulatory elements, and effector genes underlying AOA and COA genetics. Our results supported a distinct genetic basis between AOA and COA and highlighted regulatory complexity at many GWAS loci marked by both extensive pleiotropy and allelic heterogeneity.
Serum IL-6, IL-10, TNF-α and IFN-γ bio-signature for neonatal sepsis diagnosis and treatment outcome
Authors: T Suraj , Ahmed Riya , Debata Pradeep , Gaind Rajni , Kaushal GP , Gur Renu , Nirmal Kirti , Kaur Ravinder , Nangia Sushma , Kumar Vivek , Ghosh Dipankar , Chandele Anmol , Atmakuri Krishnamohan , Sankar M Jeeva , Nanda Ranjan Kumar 
Published: February 2025

AbstractBackgroundDiagnosing sepsis in preterm neonates is a significant challenge, underscoring the urgent need for timely and accurate methods. Serum inflammatory protein signatures show promising potential for early and precise disease diagnosis.MethodsIn this study, a cohort of preterm neonates (n=50, 25-35 weeks gestation, female 40%) at the time of suspicion and follow-up were enrolled along with healthy neonates. Based on clinical presentation and blood culture or MALDI results, the sepsis suspicion cases were categorized into culture-positive (CP)/culture-negative (CN) sepsis (n=13 each) or no-sepsis (NS, n=12) and compared with healthy controls (HC, n=12) from similar settings. These sub-groups (CP, CN, and NS) were followed up till completion of antibiotic therapy. Serum inflammatory proteins and trace elementals (57Fe,66Zn,63Cu,77Se,44Ca,24Mg) were profiled using the Olink® Target 96 inflammation panel and inductively coupled plasma mass spectrometry (ICP-MS), respectively. Serum proteins with log2fold changes>±1.3 and p<0.05 were identified as differentially expressed proteins (DEPs) and monitored in the follow-up samples receiving treatment. Elements showing significant differences (p<0.05) between the study groups were also identified for correlation analysis.ResultsSerum inflammatory protein levels showed group-specific trends. Significantly higher serum IL-6, IL-10, TNF-α and LIF levels with low IFN-γ and CCL28 were observed in the CP sepsis group compared to HC. CN group also showed reduced serum IFN-γ along with CXCL10 and CCL11 levels when compared to HC. Also, the serum IL-6 level in CP cases was positively correlated with IFN-γ and IL-10 levels (r<0.77, p<0.05), and an increased IL6:IFN-γ was observed in the CP, CN and NS groups compared to the HC. Serum of NS patients showed higher FGF-23 levels with lower IFN-γ and CCL11 than HC. Upon recovery, the serum IL-6 levels reached normal levels in CP, whereas the CN group showed IFN-γ, CXCL10, and CCL11 levels returned to normal. Serum iron levels were significantly reduced in both the CP and CN groups, while serum selenium was low in the CP group and serum copper was lower in the CN group, with all levels returning to normal upon recovery.ConclusionsAbsolute levels of IL-6, IL-10, IFN-γ, and TNF-α in serum can be used as biosignatures for neonatal sepsis, offering the potential for early disease diagnosis and monitoring therapeutic response. Additionally, these markers implicated in disease resolution mechanisms might serve as therapeutic targets in sepsis treatment.
Systematic Bias in Clinical Decision Instrument Development: A Quantitative Meta-Analysis
Authors: Obra Jed Keenan , Singh Chandan , Watkins Kenshata , Feng Jean , Obermeyer Ziad , Kornblith Aaron 
Published: February 2025

AbstractClinical decision instruments (CDIs) face an equity dilemma. On the one hand, they often reduce disparities in patient care through data-driven standardization of best practices. On the other hand, this standardization may itself inadvertently perpetuate bias and inequality within healthcare systems. Here, we quantify different measures of potential for implicit bias present in CDI development that can inform future CDI development. We find evidence for systematic bias in the development of 690 CDIs that underwent validation through various analyses: self-reported participant demographics are skewed—e.g. 73% of participants are White, 55% are male; investigator teams are geographically skewed—e.g. 52% in North America, 31% in Europe; CDIs use predictor variables that may be prone to bias—e.g. 13 CDIs explicitly useRace and Ethnicity; outcome definitions may further introduce bias—e.g. 28% of CDIs involve follow-up, which may disproportionately skew outcome representation based on socioeconomic status. As CDIs become increasingly prominent in medicine, we recommend that these factors are considered during development and clearly conveyed to clinicians using CDIs.
Tumor suppressor collateral damage screens reveal mRNA homeostasis protein HBS1L as a novel vulnerability in ch9p21 driven FOCAD deleted cancer
Authors: Zhang Hongxiang , Tonini Matthew R. , Martires Lauren Catherine M. , Pratt Charlotte B. , Jenkins Helena N. , Gordon Eden N. , Zhao Shanchuan , Choi Ashley H. , Meier Samuel R. , Khendu Tenzing , Liu Shangtao , Shen Binzhang , Stowe Hannah , Pashiardis Katerina , Pan Xuewen , Bandi Madhavi , Zhang Minjie , Yu Yi , Min Chengyin , Huang Alan , Andersen Jannik N. , Nicholson Hilary E. , Teng Teng 
Published: February 2025

ABSTRACTChromosomal deletion of tumor suppressor genes often occurs in an imprecise manner, leading to co-deletion of neighboring genes. This collateral damage can create novel dependencies specific to the co-deleted context. One notable example is the dependency on PRMT5 activity in tumors withMTAPdeletion, which co-occurs withCDKN2A/Bloss, leading to the development of MTA-cooperative PRMT5 inhibitors. To identify additional collateral damage context/target pairs for chromosome 9p and other common loci of chromosomal deletions, we conducted a combinatorial CRISPR screen knocking out frequently co-deleted genes in combination with a focused target library. We identified the gene encoding the ribosome rescue factor PELO as synthetic lethal with the SKI complex interacting exonuclease FOCAD, which is frequently co-deleted alongsideMTAPandCDKN2A/Bon chromosome 9p. A genome-wide screen inFOCADisogenic cells further identified the ribosome rescue GTPase and PELO binding partner HBS1L as the top synthetic lethal target forFOCADloss. Analysis of publicly available data and genetic manipulation ofHBS1Lusing orthogonal modalities validated this interaction. HBS1L dependency inFOCAD-deleted cells was rescued byFOCADre-expression, andFOCADintact cells could be rendered HBS1L-dependent byFOCADknockout, demonstrating the context specificity of this interaction. Mechanistically,HBS1Lloss led to translational arrest and activated the unfolded protein response inFOCAD-deleted cells.In vivo,HBS1Ldeletion eliminated growth ofFOCAD-deleted tumors. Here we propose a model where the FOCAD/SKI complex and HBS1L/PELO work together to resolve aberrant mRNA-induced ribosomal stalling, making the HBS1L/PELO complex an intriguing novel target for treatingFOCAD-deleted tumors.
A positive feedback loop of ‘MPK3-PIN1A trafficking-auxin flux’ trio governs dual gravitropic and wounding response in rice
Authors: Manna Mrinalini , Rengasamy Balakrishnan , Jonwal Sarvesh , Pal Uttam , Banerjee Gopal , Sinha Alok Krishna 
Published: February 2025

AbstractThe auxin flow in plants plays a pivotal role in gravitropic organ movement and tissue regeneration following injury. However, the regulatory aspects of these phenomena are not entirely understood. In this study, we found that hyperactivity of MAP Kinase 3 (MPK3) led to downregulation ofPINsand reduction in tissue auxin content, impairing gravitropic response of rice and accelerating tissue senescence following mechanical wounding. The MPK3 was found to phosphorylate PIN1A majorly at its Ser351residue, mutation of which into its phospho-mimic variant enhanced latter’s endosomal trafficking and consequently improved auxin flux. Further, overexpression of the phospho-null variant ofPIN1Alowered gravitropic response of rice, thus causing wider tiller angle similar to thepin1aknockout lines. Additionally, upon wounding, their tissue senescence was faster in comparison to the overexpression lines of wild-type and phospho-mimic variants ofPIN1A, which also displayed improved resistance to wounding byBipolaris oryzae. The PIN1A trafficking-mediated auxin flux also regulated MPK3 activity via a positive feedback loop. Together, these results uncover a novel feedback loop encompassing “MPK3-PIN1A trafficking-auxin flux” trio that regulates dual gravitropic and wounding response in rice.
Application of a human lectin array to rapidin vitroscreening of sugars used as targeting tags for therapeutics
Authors: Benjamin Stefi V. , Taylor Maureen E. , Drickamer Kurt 
Published: February 2025

AbstractAn increasing number of clinical applications employ oligosaccharides as tags to direct therapeutic proteins and RNA molecules to specific target cells. Current applications are focused on endocytic receptors that result in cellular uptake, but additional applications of sugar-based targeting in signaling and protein degradation are emerging. These approaches all require development of ligands that bind selectively to specific sugar-binding receptors, known as lectins. In the work reported here, a human lectin array has been employed as a predictor of targeting specificity of different oligosaccharide ligands and as a rapidin vitroscreen to identify candidate targeting ligands. The approach has been validated with existing targeting ligands, such as a GalNAc cluster ligand that targets siRNA molecules to hepatocytes through the asialoglycoprotein receptor. Additional small oligosaccharides that can selectively target other classes of cells have also been identified and the potential of larger glycans derived from glycoproteins has been investigated. In initial screens, ligands for targeting either vascular or sinusoidal endothelial cells and plasmacytoid dendritic cells have been identified. Lectin array screening has also been used to characterize the specificity of glycolipid-containing liposomes that are used as carriers for targeted delivery. The availability of a rapidin vitroscreening approach to characterizing natural oligosaccharides and glycomimetic compounds has the potential to facilitate selection of appropriate targeting tags before undertaking more complexin vivostudies.
Inhibiting fibronectin assembly in the breast tumor microenvironment increases cell death and improves response to doxorubicin
Authors: Gari Metti K. , Lee Hye Jin , Inman David R. , Burkel Brian M. , Highland Margaret A. , Kwon Glen S. , Gupta Nikesh , Ponik Suzanne M. 
Published: February 2025

AbstractPurposeEffective therapies for solid tumors, including breast cancers, are hindered by several roadblocks that can be largely attributed to the fibrotic extracellular matrix (ECM). Fibronectin (FN) is a highly upregulated ECM component in the fibrotic tumor stroma and is associated with poor patient prognosis. This study aimed to investigate the therapeutic potential of an anti-fibrotic peptide that specifically targets FN and blocks the fibrillar assembly of FN.MethodsTo target FN, we used PEGylated Functional Upstream Domain (PEG-FUD), which binds to the 70 kDa N-terminal region of FN with high affinity, localizes to mammary tumors, and potently inhibits FN assembly in vitro and in vivo. Here, we used the 4T1 tumor model to investigate the efficacy and mechanisms of PEG-FUD to inhibit tumor growth.ResultsOur data demonstrates that PEG-FUD monotherapy reduces tumor growth without systemic toxicity. Analysis of the tumor microenvironment revealed that PEG-FUD effectively inhibited FN matrix assembly within tumors and reduced adhesion-mediated signaling through α5 integrin and FAK leading to enhanced tumor cell death. Notably, signaling through FAK has been associated with resistance mechanisms to doxorubicin (DOX). Therefore, we tested the combination of PEG-FUD and Dox, which significantly reduced tumor growth by 60% compared to vehicle control and 30% compared to Dox monotherapy.ConclusionsOur findings demonstrate that PEG-FUD significantly modifies the peritumoral ECM of breast cancer, leading to increased tumor cell death, and potentiates the efficacy of conventional breast cancer therapy.
Breast Cancer Risk Factors in the Abu Dhabi Population: A Retrospective Cohort Study
Authors: AlKetbi Latifa Baynouna , AlAzeezi Maha , Ashoor Rawan , Nagelkerke Nico , AlAlawi Noura , AlKetbi Rudina , Aleissaee Hamda , AlShamsi Noura , Humaid Ahmed , Abdulbaqi Hanan , Fahmawee Toqa , AlHashaikeh Basil , AlDobaee Muna , AlAhbabi Nayla , AlAzeezi AlYazia , Shuaib Fatima , Alnuaimi Jawaher , Mahmoud Esraa , AlMansoori Mohammed , AlKalbani Sanaa , AlDerie Wesayef , Saeed Ekram , AlAhmadi Amira , Sahyouni Mohammad , AlShamsi Reem 
Published: February 2025

AbstractBackgroundBreast cancer is the most common cancer in the United Arab Emirates (UAE), with the majority of cases characteristically occurring in women younger than 50 years. Studies on breast cancer risk factors in the UAE are few.MethodsThis retrospective study, from 2011 to 2013 until 2023, aimed to estimate the prevalence of a history of cancer and lifetime risk. A nested case-control study was designed from the cohort to study breast cancer risk with four controls for each case matched by the date of diagnosis.ResultsBreast cancer incidence was 0.85 %, 37 cases out of the 4338 females in the cohort. No males were diagnosed with the condition. Out of the 129 females with cancer, breast cancer was the most common type, 28% of all kinds of cancers.Three risk factors for breast cancer were identified using conditional Cox regression analysis of the matched nested case-control study. The strongest was being a patient with diabetes Mellitus, HR=13.1 (3.2-52.8) P<0.001. Another metabolic abnormality that is associated with the occurrence of breast cancer in this population was a higher level of total cholesterol, HR=1.59 (1.03-2.44), P-value=0.035. Vitamin D showed a protective association with 58% reduced risk with levels above 75, HR=0.042 (0.002-0.73) P=0.042. The area under the ROC Curve for predicting breast cancer using this model was 0.753 (0.666-0.839). The area under the ROC Curve for predicting breast cancer using this model was 0.753 (0.666-0.839).ConclusionThis study highlights the importance of understanding the various risk factors associated with breast cancer development and stresses the pivotal role of advancing diagnostic methods to improve early detection. By synthesizing current knowledge, this study aims to enhance our understanding of breast cancer’s complex nature and guide future research directions, screening practices, and preventive measurements.
T cell responses in repeated controlled human schistosome infection compared to natural exposure
Authors: Driciru Emmanuella , Koopman Jan Pieter R. , Steenbergen Sanne , Sonnet Friederike , Stam Koen A. , de Bes-Roeleveld Helena , Iliopoulou Eva , Janse Jacqueline J. , Sijtsma Jeroen , Nambuya Irene , Hilt Stan T. , König Marion , Kruize Yvonne , Casacuberta-Partal Miriam , Egesa Moses , van Dam Govert J. , Corstjens Paul L.A.M. , van Lieshout Lisette , Mpairwe Harriet , MacDonald Andrew S. , Yazdanbakhsh Maria , Elliott Alison M. , Roestenberg Meta , Houlder Emma L. 
Published: February 2025

AbstractSchistosomiasis affects over 250 million people, predominantly in Sub-Saharan Africa. InSchistosoma-endemic regions a lack of natural sterilizing immunity means individuals are repeatedly infected, treated and reinfected. Due to difficulties in tracking infection in endemic areas, the kinetics of the host immune response during these reinfections have not been elucidated. Here, we use repeated (3x) controlled humanSchistosoma mansoni(Sm) infection (repeated CHI) to directly study how antigen-specific T cells develop during reinfection. We compared these responses to naturalSm-infected endemic Ugandan individuals. We report that a mixed Th1/Th2/regulatory CD4+T cell response develops in repeated CHI, primarily against adult worm antigens. Adult worm-specific responses after repeated CHI were similar to those observed in naturally infected endemic participants. However, endemic participants showed differential responses to antigens from the egg and cercariae life-cycle stages. Repeated CHI (3x) with sequential exposure toSmcercariae of different sexes (male-female-male) revealed an elevated CD4+T cell cytokine response to adult worm and egg antigens. Our findings demonstrate that reinfection with single-sex schistosomes elicits adult worm-specific T cell cytokine responses that reflect endemic-natural infection, highlighting the translatability of the CHI model to natural infection in endemic settings. Overall, this study advances our understanding of how schistosome immune responses develop over reinfection cycles in the human host, thereby increasing our understanding of the immunology of natural schistosome (re)infection.
Serum Troponin T levels as a therapy response marker in SOD1-mediated ALS
Authors: Bernsen Sarah , Fabian Rachel , Koc Yasemin , Schumann Peggy , Körtvélyessy Peter , Castro-Gomez Sergio , Meyer Thomas , Weydt Patrick 
Published: February 2025

AbstractIntroductionSerum cardiac troponin T (cTnT) levels are elevated in the majority of amyotrophic lateral sclerosis (ALS) patients and increase over time. Neurofilament light chain (NfL) is an established therapy response biomarker in ALS as superoxide dismutase 1 (SOD1)-ALS patients treated with the antisense oligonucleotide tofersen show a decrease in NfL. In this study we assess the course of cTnT levels in SOD1-ALS at baseline and during tofersen treatment.MethodsSerum cTnT was analyzed at baseline and during tofersen treatment in 23 SOD1-ALS patients at two specialized ALS centers in Germany and compared to a control cohort of 74 ALS patients without SOD1-mutations and not treated with tofersen.ResultscTnT levels increased in the control ALS-cohort over time (p<0.0001) but not in the tofersen group (p=0.36). CK, and CK-MB levels did not show relevant changes over time. The median monthly increase of cTnT was 0.045 points (IQR 0.02-0.08) in the control ALS cohort and 0.01 points (IQR −0.01-0.03) in the tofersen group (p=0.0013). The fold change in cTnT levels of the tofersen-treated cohort (median 1.2; IQR 0.77-1.59) was significantly less and even showed a reduction in some patients compared to the control group (median 1.89; IQR 1.35-2.75) (p=0.0003).DiscussionIn this study, we find a response signal of cTnT to tofersen treatment, which supports the value of cTnT as an independent biomarker in ALS. These results contribute to the notion that cTnT may provide additional value as a progression and treatment response biomarker in ALS complementary to NfL and warrant further investigations.Graphical Abstract
Association of Cut-point Free Metrics and Common Clinical Tests among Older Adults after Proximal Femoral Fracture
Authors: Younesian Hananeh , Singleton David , Vereijken Beatrix , Garcia-Aymerich Judith , Rochester Lynn , Berge Martin Aursand , Engdal Monika , Buekers Joren , Koch Sarah , Helbostad Jorunn L. , Alvarez Paula , Jansen Carl-Philipp , Aminian Kamiar , Ionescu Anisoara , Becker Clemens , Caulfield Brian 
Published: February 2025

AbstractWearable and lightweight devices facilitate real-world physical activity (PA) assessments. MX metrics, as a cut-point-free parameter, evaluate acceleration above which the most active X minutes are accumulated. It provides insights into the intensity of PA over specific durations. This study evaluated the association of MX metrics and clinical tests in older adults recovering from proximal femoral fracture (PFF). Analyses were conducted on the PFF cohort from the baseline assessment of the Mobilise-D project using an accelerometer-based device. Participants (N=396) were categorized into four recovery groups: acute, post-acute, extended recovery, and long-term recovery. Mobility capacity was assessed through the 6-min walking test (6MinWT), Short Physical Performance Battery (SPPB), 4-meter walking test (4MWT), and hand grip (HG) strength. Mobility perception was evaluated using the Late-Life Function and Disability Instrument (LLFDI). Eight MX metrics (M1-M90) were calculated using the GGIR package in R. Results showed moderate to strong positive correlation between M1-M30 and lower limb mobility capacity tests, and mobility perception (Lower Extremity domains) particularly in the extended and long-term recovery groups. MX metrics can be used for measuring PA intensity among older adults recovering from PFF. Shorter duration of MX metrics had higher association with lower limb mobility capacity and perception outcomes.HighlightsWhat are the main findings?Clinical lower limb assessments (both subjective and objective) were more discriminative in differentiating between the four PFF recovery groups in older adults.Older adults in the acute proximal femoral fracture recovery group demonstrated lower physical activity intensity compared to those in later recovery groups, with the differences being more pronounced for shorter-duration MX metrics (M1-M5)What is the implication of the main finding?The cut-point free method (e.g., MX metrics) is useful for measuring physical activity magnitude of older adult recovering from proximal femoral fracture.Higher lower limb capacity and perception outcomes were strongly correlated with greater daily activity intensity, particularly in older adults at later stages of proximal femoral fracture recovery.