bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hypoxia‐Inducible Factor‐1α Regulates BNIP3‐Dependent Mitophagy and Mediates Metabolic Reprogramming Through Histone Lysine Lactylation Modification to Affect Glioma Proliferation and Invasion
Authors: Dong Feng , Yin Haichang , Zheng Zhixing 
Published: January 2025

ABSTRACTObjectiveGliomas are the predominant form of malignant brain tumors. We investigated the mechanism of hypoxia‐inducible factor‐1α (HIF‐1α) affecting glioma metabolic reprogramming, proliferation and invasion.MethodsHuman glioma cell U87 was cultured under hypoxia and treated with small interfering (si)HIF‐1α, si‐B cell lymphoma‐2/adenovirus E1B 19‐kDa interacting protein 3 (siBNIP3), si‐YT521‐B homology domain 2 (siYTHDF2), 3‐methyladenine and 2‐deoxyglucose, with exogenous sodium lactate‐treated normally‐cultured cells as a lactate‐positive control. Cellular hexokinase 2, lactate dehydrogenase A and pyruvate dehydrogenase kinase 1 enzyme activities, glucose uptake, and levels of lactic acid and adenosine triphosphate (ATP), and HIF‐1α, glycolysis‐related proteins, mitophagy‐related proteins, histone H3 lysine 18 lactylation (H3K18la) and YTHDF2 were determined by ELISA, 2‐NBDG, kits, and Western blot. Extracellular acidification rate (ECAR), and cell proliferation, invasion, apoptosis and mitophagy were evaluated by extracellular flux analysis, CCK‐8, Transwell, flow cytometry, and immunofluorescence staining. H3K18la‐YTHDF2 relationship and YTHDF2‐BNIP3 interaction were assessed by ChIP and Co‐IP assays.ResultsHypoxia‐induced highly‐expressed HIF‐1α in glioma cells increased glycolysis‐related protein levels, glycolytic enzyme activities, glucose uptake, lactic acid production, ATP level and ECAR, thereby promoting metabolic reprogramming, invasion and proliferation. HIF‐1α mediated metabolic reprogramming, proliferation and invasion through BNIP3‐dependent mitophagy, which were partly negated by mitophagy inhibition. HIF‐1α induced histone Kla modification to upregulate YTHDF2. YTHDF2 downregulation impeded YTHDF2‐BNIP3 interaction and inhibited HIF‐1α‐induced BNIP3‐dependent mitophagy, curbing glioma cell metabolic reprogramming, proliferation and invasion.ConclusionsHypoxia‐induced high HIF‐1α expression upregulated YTHDF2 through hH3K18la modification, enhanced YTHDF2‐BNIP3 interaction, and regulated BNIP3‐dependent mitophagy‐mediated metabolic reprogramming to affect glioma proliferation and invasion.
B4GALNT1 Regulates Hepatocellular Carcinoma Cell Proliferation and Apoptosis via the PI3K–AKT–mTOR Pathway
Authors: Bie Lihan , Chen Guangquan , Lei Xin , Xiao Feng , Xu Zheng , Xiang Zhouhong , Lu Zhicheng , Jiang Xiudi 
Published: January 2025

ABSTRACTBackgroundHepatocellular carcinoma (HCC) is a ubiquitous malignancy linked to significant mortality. The abnormal expression of β‐1,4‐N‐acetyl‐galactosaminyltransferase 1 (B4GALNT1) seemed to be implicated in tumorigenesis. Nonetheless, this enzyme's roles in HCC are unclear.MethodsBy analyzing the TCGA_LIHC, GSE77509, and GSE135631 datasets, the levels of B4GALNT1 expression in HCC and surrounding non‐cancerous tissues were compared. The prognostic implications of B4GALNT1 were assessed using the Cox regression analysis (CRA). The relationship of B4GALNT1 mutations with CpG island methylation levels and prognosis was examined by analyzing the cBioPortal and MethSurv databases. We sifted the evidence of B4GALNT1 expression correlating with 28 immune cell types' infiltration by harnessing the “GSVA” R package. To delve into the influences of genes associated with B4GALNT1 on HCC, we implemented gene set enrichment analysis (GSEA). We constructed a lentiviral vector expressing B4GALNT1 and knocked down B4GALNT1 in HepG2 cells. The resulting effects on HCC cell proliferation and apoptosis were analyzed via cell proliferation assays and flow cytometry.ResultsHCC tissues presented significant B4GALNT1 overexpression relative to surrounding non‐cancerous tissues, marking it as a standalone risk factor for HCC progression. Methylation levels of two CpG islands were high, suggesting poor prognosis. It was detectable that B4GALNT1 expression interrelated with the infiltration extent of natural killer T cells in HCC tissues. B4GALNT1‐fueled cell proliferation and enhanced resistance to apoptosis in HCC cells.ConclusionB4GALNT1 is a strong regulator of HCC progression and holds promise as a marker for prognosis and a hallmark for therapy in HCC.
Prevalence of Cachexia and Outcomes in Patients With Chronic Diseases: A National Database Analysis of 5 484 103 Hospitalisations
Authors: Lainscak Mitja , Zupanic Tina , Omersa Daniel , Erzen Ivan , Farkas Jerneja 
Published: January 2025

ABSTRACTBackgroundCachexia is a frequent companion of chronic diseases and a well‐established predictor of poor patient performance and outcome. Since cachexia as a discharge diagnosis is not much investigated, we aimed to investigate prevalence of cachexia in hospitalised patients and their outcome.MethodsWe conducted a retrospective analysis of the National Hospital Health Care Statistics Database using the 10th revision of the International Classification of Diseases codes. During period 2004–2019, patients with cachexia were identified, as well as patients with cancer, heart failure, chronic obstructive pulmonary disease and chronic kidney disease. The primary endpoint was the discharge code of cachexia; secondary endpoints were length of hospital stay, in‐hospital and post discharge all‐cause mortality.ResultsIn period 2004–2019, 5 484 103 hospitalisations were screened; cachexia was coded 19 348 times (0.35%) in 14 089 patients (67 ± 13 years, 42% women). From 2004 to 2019, prevalence of cachexia increased steadily from 1.2% to 1.9%, which was most prominent for cancer and chronic obstructive pulmonary disease. At one year post discharge, 49% patients with cachexia were dead as compared to 26% in patients without cachexia. In Cox multivariate analysis, cachexia predicted post‐discharge death in any of chronic diseases (hazard ratio of 1.28 in heart failure to 1.47 in chronic kidney disease).ConclusionsIn our report from a National Hospital Health Care Statistics Database, we found that cachexia was underreported as ICD‐10 coded discharge diagnosis in patients with chronic diseases. When diagnosed, it was associated with higher hazard of post discharge mortality.
The extinction burst: Effects of reinforcement magnitude
Authors: Shahan Timothy A. , Avellaneda Matias 
Published: January 2025

AbstractThe extinction burst is an increase in an operant behavior early in the transition to extinction. A matching‐law‐based quantitative theory suggests that it results from the elimination of competition from reinforcement‐related behavior that accompanies the transition to extinction. This experiment examined the effects of reinforcement magnitude on the extinction burst with rats. Responding produced either 1 pellet or 6 pellets prior to a within‐session transition to extinction. Baseline response rates were lower with 6 pellets than with 1 pellet but increased more in the first minute of extinction following 6 pellets. Furthermore, an order effect was observed where rats having first experienced extinction following 1 pellet showed a smaller extinction burst when subsequently trained with 6 pellets—an outcome resulting from a faster deceleration of responding during extinction. The model described the data well, including the order effect, when augmented to include the potential asymmetrical influence of learning to discriminate the continued absence of different magnitudes of reinforcement. We conclude that the approach holds promise by formally incorporating the extinction burst into the corpus of matching theory and serving as an example of the utility of better aligning basic research methods and theorizing with areas of applied concern.
A Single‐Center Retrospective Cohort Study of Biopterin Metabolism Disorders in the United Arab Emirates
Authors: Jarrah Omar , Nouri Mahmood , Al Shamsi Aisha 
Published: January 2025

ABSTRACTBackgroundTetrahydrobiopterin (BH4) deficiencies comprise a group of five neurometabolic disorders caused by five genetic defects responsible for BH4 biosynthesis and regeneration. Their global prevalence remains unknown, and variance exists among different countries.AimsTo describe clinical, biochemical, molecular genetic data and follow‐up of patients with BH4 deficiency seen in Tawam Hospital.MethodsA retrospective study of all patients with BH4 disorders who were followed up between January 2010 and December 2023 in Tawam Hospital. All data were retrieved from patients' electronic charts, including baseline characteristics, developmental milestones, family history, and clinical examination. Radiological and laboratory investigations, including phenylalanine levels, prolactin levels, CSF study, urine and plasma pterin profiles, and molecular tests, were reviewed.ResultsTen patients with BH4 deficiencies were found. The youngest patient was diagnosed at 3‐ weeks, and the oldest was nine; 70% were male, consanguineous 80%, and 40% were Emirati. Prematurity was reported in two patients. Intrauterine growth restriction was found in 70%, and microcephaly in 40%. Eighty percent had developmental delay, and 2 patients had behavioral issues. Seizure and movement disorders were reported in five and three patients, respectively. Brain MRI showed cortical atrophic changes, corpus callosum hypoplasia, hyperintensities in the parieto‐occipital region, and periventricular white matter. Abnormal Newborn screening was found in 60%, with initial high phenylalanine levels (>120 μmol/L) in 80%. Prolactin level was high in all studied patients. Four patients' cerebrospinal fluid neurotransmitter metabolites were evaluated. Blood for DHPR screening and urine pterin profile were done on eight patients. Nine patients had molecular testing. DHPR deficiency was most commonly reported among studied patients (50%), with five novel variants in the QDPR gene. The second prevalent disorder was PTPS deficiency and only one patient with SR deficiency.ConclusionThis cohort offers an in‐depth clinical and genetic understanding of BH4 deficiencies from a single center in the UAE. It describes new genetic variants and addresses diagnostic challenges to enhance the patient's diagnosis and treatment.
Ecomorphology of South American Penguins
Authors: Bloom Elliott , Torres‐Mura Juan Carlos , Bertellotti Marcelo , Hertel Fritz 
Published: January 2025

ABSTRACTA major goal of evolutionary ecology is to understand the interaction between ecological differences and the functional morphology of organisms. Studies of this type are common among flying birds but less so in penguins. Penguins (Spheniscidae) are the most derived extant underwater flying birds using their wings for swimming and beak when foraging. The Humboldt Penguin (Spheniscus humboldti) and Magellanic Penguin (S. magellanicus) occur along the coast of South America and their morphology was compared in allopatry and sympatry throughout their ranges. Measurements included: mass, tarsus length, four beak/head dimensions, bite force, wing loading, and aspect ratio. A thin‐plate spline/relative warp analysis was also used to detect subtle differences in wing shape. Both species generally overlapped in trait morphology, but Magellanic Penguins showed greater trait diversity. Wing morphology was more homogenous between species than beak morphology indicating a similar mode of locomotion but potential differences in prey procurement. Morphological character displacement in sympatry was only evident in beak length. Local adaptation was common in other traits, and Punta Norte (Argentina) was often distinct in having high variation, notably in beak depth, wing loading, and wing shape (relative warp 1). This may be attributed to the fact that penguins here dive deep and forage farther from their colony; they also have a greater colony size that may contribute to greater intraspecific competition for resources. These results support a potentially optimal wing design for aquatic movement, which likely applies to other penguin species. Differences in morphology may also be related to differences between Atlantic and Pacific ecosystems.
Human Cytomegalovirus Infection Induces Long‐Term Changes in the Cytokine Milieu of Kidney Transplant Recipients
Authors: Redondo Natalia , Valverde‐Manso Andrea , Ruiz‐Merlo Tamara , Rodríguez‐Goncer Isabel , Parra Patricia , López‐Medrano Francisco , González Esther , Polanco Natalia , San Juan Rafael , Andrés Amado , Aguado José María , Fernández‐Ruiz Mario 
Published: January 2025

ABSTRACTThe impact of human cytomegalovirus (HCMV) infection on the mid‐ and long‐term balance between pro‐inflammatory and anti‐inflammatory cytokines among kidney transplant recipients (KTRs) remains unclear. We measured plasma levels of 12 Th1/Th2‐type cytokines (granulocyte‐macrophage colony‐stimulating factor, interferon‐γ, interleukin [IL]‐1β, IL‐2, IL‐4, IL‐5, IL‐6, IL‐10, IL‐12p70, IL‐13, IL‐18 and tumor necrosis factor‐α) in a cohort of 290 KTRs at four time points through month 12 after transplantation. Cytokine levels at each point were compared according to the previous documentation of HCMV replication by two approaches: “cumulative exposure” from the time of transplantation and “recent exposure” within the 2–3 months preceding cytokine assessment. Significance levels were Bonferroni‐corrected for multiple pairwise comparisons. Plasma levels of IL‐6, IL‐10, and IL‐12p70 at month 1 were significantly increased in KTRs that had experienced HCMV infection during the first 30 days. By month 3, IL‐6 and IL‐10 remained increased in KTRs with cumulative exposure through day 90. Cumulative exposure to HCMV replication through day 180 was also associated to increased IL‐10 levels at month 6. In addition, KTRs with recent HCMV exposure had increased IL‐10 levels at months 3 and 6. After multivariable adjustment, cumulative exposure to HCMV infection and/or the area under curve of HCMV DNAemia during the corresponding period were associated to IL‐10 levels within the highest quartile at months 1, 3, and 6. Preceding HCMV infection induces sustained changes in the plasma cytokine milieu of KTRs, with elevated IL‐6 and IL‐10 levels throughout the first 6 months after transplantation.
Modulation of Lymphotoxin β Surface Expression by Kaposi's Sarcoma‐Associated Herpesvirus K3 Through Glycosylation Interference
Authors: Kang Soowon , Brulois Kevin , Choi Youn Jung , Zhang Shaoyan , Jung Jae U. 
Published: January 2025

ABSTRACTKaposi's sarcoma‐associated herpesvirus (KSHV) employs diverse mechanisms to subvert host immune responses, contributing to its infection and pathogenicity. As an immune evasion strategy, KSHV encodes the Membrane‐Associated RING‐CH (MARCH)‐family E3 ligases, K3, and K5, which target and remove several immune regulators from the cell surface. In this study, we investigate the impact of K3 and K5 on lymphotoxin receptor (LTβR) ligands, LTβ and LIGHT, which are type II transmembrane proteins and function as pivotal immune mediators during virus infection. Upon co‐expression of viral MARCH proteins with LTβR ligands, we showed that K3 and K5 selectively targeted LTβ, but not LIGHT, for the downregulation of surface expression. Specifically, K3 and K5 E3 ligases interacted with the transmembrane domain of LTβ. Intriguingly, K3 interacted with an immature form of LTβ, whereas K5 targeted the fully mature form. Subsequent biochemical analyses revealed that K3 disrupted the initial steps of N‐glycosylation maturation of LTβ. This interference resulted in the sequestration of LTβ within the endoplasmic reticulum, impeding its trafficking to the plasma membrane. Consequently, the K3‐mediated downregulation of LTβ surface expression suppressed the LTβR downstream signaling pathway. These findings uncover a novel mechanism by which KSHV K3 E3 ligase inhibits the membrane trafficking pathway of the LTβ inflammatory ligand through glycosylation interference, potentially evading LTβR‐mediated antiviral immunity.
Single‐Cell RNA Sequencing Reveals the Cellular Origin and Evolution of Small‐Cell Neuroendocrine Carcinoma of the Cervix
Authors: Chen Xinyi , Wang Kunyu , Liao Xingyu , Zheng Xingzheng , Yang Shuli , Han Chao , Lu Chang , Wang Xiaodan , Jin Lingge , Kang Haili , Han Yiding , Wei Jiacong , Fan Linyuan , Zhang Zhan , Kong Weimin 
Published: January 2025

ABSTRACTSmall‐cell neuroendocrine cancer (SCNEC) of the uterine cervix is an exceedingly rare, highly aggressive tumor with an extremely poor prognosis. The cellular heterogeneity, origin, and tumorigenesis trajectories of SCNEC of the cervix remain largely unclear. We performed single‐cell RNA sequencing and whole‐exome sequencing on tumor tissues and adjacent normal cervical tissues from two patients diagnosed with SCNEC of the cervix. Here, we provide the first comprehensive insights into the cellular composition, HPV infection‐related features, and gene expression profiles of SCNEC of the cervix at single‐cell resolution. Correlation analyses suggested that SCNEC of the cervix may originate from squamous epithelial cells, and this observation was validated with bulk RNA‐seq data from external cervical neuroendocrine cancer. Furthermore, sex‐determining region Y‐box 2 (SOX2), a key transcription factor that functions in direct neural differentiation, was located in the copy number gain region and highly expressed in neuroendocrine tumor cells from both patients. Notable, the distributions of the HPV‐infected epithelium and SOX2 highly expressed epithelium were consistent with each other. Therefore, we supposed that high‐risk HPV infection and amplification of SOX2 in the squamous epithelium may contribute to the progression of small‐cell neuroendocrine tumorigenesis in the cervix.
Women's Participation in Operational and High Managerial Positions in Family Businesses: Evidence From Saudi Context
Authors: Khan Subuhi , Aloulou Wassim J. , Shahab Sana , Aliani Khaoula 
Published: January 2025

ABSTRACTThis research explores the increasing participation of women in family businesses in Saudi Arabia, focusing on their roles in operational and high managerial positions within the context of Saudi Vision 2030. The research aims to fill the gap in understanding the profiles and drivers that encourage Saudi women to assume leadership roles in traditionally male‐dominated family businesses. Using a survey of 80 female participants, this study applies multiple correspondence analysis (MCA) and multinomial logistic regression (MLR) to explore the influence of factors such as education, sibling order, and family support on their advancement. The findings reveal that women's progression in family businesses is strongly linked to educational attainment and family backing, with significant emphasis on the growing support for women in the Kingdom in the last decade. While cultural and social barriers persist, there is a drastic shift in how women increasingly find opportunities for jobs and entrepreneurial ventures and contribute to the economy, even if in a smaller percentage than in other countries. The paper highlights that familial encouragement, higher education, and entrepreneurial spirit propel Saudi women to break through traditional limitations. Support from male family members, such as fathers or husbands, emerges as a critical driver that enables women to overcome traditional cultural barriers and assume leadership roles. The research also contributes to ongoing discussions about gender equality. It offers practical insights into creating supportive environments for women in leadership, thus fostering a more inclusive and diverse business landscape in Saudi Arabia. Additionally, the study draws attention to the importance of Saudi Vision 2030, which emphasizes women's empowerment and their economic contribution to eventually promoting gender equality and the advancement of the kingdom. This vision and various government initiatives, combined with increasing access to resources, social media, and digital platforms, open previously closed doors and present new opportunities for Saudi women to engage in business operations, particularly in fashion, healthcare, education, and retail. The findings are expected to inspire future research on women's leadership in the context of family businesses.
Extinction, Ultimate Boundedness, and Persistence in the Mean of a Stochastic Heroin Epidemic Model With Distributed Delay
Authors: Zhang Xiaofeng 
Published: January 2025

ABSTRACTIn this paper, we consider a stochastic heroin epidemic model with distributed delay. We analyze the model in detail: We prove the existence and uniqueness of the global positive solution of the system, the asymptotic behavior around the equilibrium point of the deterministic system, the stochastically ultimate boundedness, and the persistence in the mean of the disease. Finally, we verify the main conclusions of this paper through numerical simulation and explore the influence of system parameters on the persistence and extinction of diseases. According to the numerical simulation results, we can give some suggestions on controlling diseases.
Deterministic, Stochastic, and Deep Learning Approaches to Understand the Economic Fluctuations in India
Authors: Karmakar Saptaporni , Chakraborty Arkaprovo 
Published: January 2025

ABSTRACTIn the present work, a new mathematical framework is proposed for studying the interrelation among population growth rate, GDP, inflation rate, and unemployment rate within deterministic and stochastic frameworks. The values of the parameters of the proposed model are estimated using real data from India. The local and global uniqueness of solutions is established for the stochastic model. The deterministic model is solved by using the Adams‐Bashforth‐Moulton predictor‐corrector method, and Milstein's method is used for solving the stochastic model. Numerical simulations correlated quite strongly with observed data, while projections for the 2024–2030 period indicate that controlled population growth bodes well for the outlook of the economy for India, supporting economic prosperity alongside reduced inflation and better employment conditions. The findings presented in this work are correlational; therefore, to find the possible cause for this phenomenon, further research is required with detailed datasets. Comparing our model's GDP predictions with that obtained using a long short‐term memory recurrent neural network model returned very high values of predictive accuracy, thus reinforcing the strength and reliability of our framework.
Associations Between TCF7L2, PPARγ, and KCNJ11 Genotypes and Insulin Response to an Oral Glucose Tolerance Test: A Systematic Review
Authors: Blanken Carmen P. S. , Bayer Sandra , Buchner Carro Sophie , Hauner Hans , Holzapfel Christina 
Published: January 2025

ABSTRACTScope: Insulin responses to standardized meals differ between individuals. This variability may in part be explained by genotype. This systematic review evaluates associations between genotype and insulin response to an oral glucose tolerance test (OGTT) in terms of insulin area under the curve (AUC). Methods and results: Three electronic databases (Web of Science, Embase, PubMed) were searched for studies investigating associations between insulin AUC after an OGTT and single nucleotide polymorphisms (SNPs) belonging to the transcription factor 7 like 2 (TCF7L2) gene, the peroxisome proliferator‐activated receptor gamma (PPARγ) gene, or the potassium inwardly rectifying channel subfamily J member 11 (KCNJ11) gene in persons without diabetes. A total of 5199 articles were identified, of which 38 were included. Among them were family‐based studies (9), twin studies (2), and studies with unrelated participants (27). Seventeen articles investigated TCF7L2 (7 SNPs), 14 investigated PPARγ (1 SNP), and 8 investigated KCNJ11 (5 SNPs). For all investigated SNPs, at least half of the reports indicated no statistically significant association with postprandial insulin AUC. Conclusion: No evidence was found for associations between TCF7L2, PPARγ, and KCNJ11 genotypes and insulin AUC after an OGTT. Future studies should investigate the effect of genetic risk scores on postprandial insulin.