bluuebunny/crossref_metadata_2025_split huggingface dataset:
FTO inhibition mitigates high-fat diet-induced metabolic disturbances and cognitive decline in SAMP8 mice
Authors: Irisarri Alba , Corral Ana , Perez-Salvador Núria , Bellver-Sanchis Aina , Ribalta-Vilella Marta , Bentanachs Roger , Alegret Marta , Laguna Juan Carlos , Barroso Emma , Palomer Xavier , Ortuño-Sahagún Daniel , Vázquez-Carrera Manuel , Pallàs Mercè , Herrero Laura , Griñán-Ferré Christian 
Published: February 2025

Abstract
This study investigated the effects of fat mass and obesity-associated (FTO) inhibition on cognitive function and metabolic parameters of senescence-accelerated mouse prone 8 (SAMP8) mice fed a high-fat diet (HFD). SAMP8 mice fed an HFD exhibited increased body weight, impaired glucose tolerance, and elevated serum leptin levels. In epididymal white adipose tissue (eWAT), pharmacological treatment with FB23, a well-established FTO inhibitor, increased leptin production and modulated genes involved in lipid metabolism (Cpt1a, Atgl
,
Hsl
,
Fas), oxidative stress (OS) (Bip
,
Edem), and inflammation (Mcp1, Tnfα). Expression of hepatic genes related to lipid metabolism (Cpt1a, Atgl
,
Mgl, Dgat2, Srebp
,
Plin2) and OS (catalase, Edem) were modulated by FB23, although hepatic steatosis remained unchanged. Remarkably, FB23 treatment increased m6A RNA methylation in the brain, accompanied by changes in N6-methyladenosine (m6A)-regulatory enzymes and modulation of neuroinflammatory markers (Il6, Mcp1, iNOS). FTO inhibition reduced the activity of matrix metalloproteases (Mmp2, Mmp9) and altered IGF1 signaling (Igf1, Pten). Notably, enhanced leptin signaling was observed through increased expression of immediate early genes (Arc, Fos) and the transcription factor Stat3. Improved synaptic plasticity was evident, as shown by increased levels of neurotrophic factors (Bdnf
,
Ngf) and restored neurite length and spine density. Consistent with these findings, behavioral tests demonstrated that FB23 treatment effectively rescued cognitive impairments in SAMP8 HFD mice. The novel object recognition test (NORT) and object location test (OLT) revealed that treated mice exhibited enhanced short- and long-term memory and spatial memory compared to the HFD control group. Additionally, the open field test showed a reduction in anxiety-like behavior after treatment with FB23. In conclusion, pharmacological FTO inhibition ameliorated HFD-induced metabolic disturbances and cognitive decline in SAMP8 mice. These results suggest that targeting FTO may be a promising therapeutic approach to counteract obesity-induced cognitive impairment and age-related neurodegeneration.
Validation of loci and genes associated with fertility in Holstein cows using gene-set enrichment analysis-SNP and genotype-by-sequencing
Authors: Kiser Jennifer N. , Seabury Christopher M. , Neupane Mahesh , Moraes Joao G. N. , Herrick Allison L. , Dalton Joseph , Burns Gregory W. , Spencer Thomas E. , Neibergs Holly L. 
Published: February 2025

Abstract

Background
The financial strain fertility issues cause the dairy cattle industry is substantial, with over $7 billion in lost revenue accrued annually due to a relatively low cow conception rate (CCR; 30–43%) for US dairy cows. While CCR has been improving through genomic selection, identification of causal mutations would help improve the rate of genetic progress with genomic selection and provide a better understanding of infertility. The objectives of this study were to: (1) identify genes and gene-sets associated with CCR to the first breeding (CCR1) and the number of breedings required to conceive (TBRD) in Holstein cows and (2) identify putative functional variants associated with CCR1 and TBRD through a custom genotype-by-sequencing array. The study consisted of 1,032 cows (494 pregnant to first breeding, 472 pregnant to subsequent [2–20] services, and 66 that never conceived). Cows were artificially inseminated, and pregnancy was determined 35d later by rectal palpation of uterine contents. Gene-set enrichment analyses with SNP data (GSEA-SNP) were conducted for CCR1 and TBRD with a normalized enrichment score (NES) ≥ 3.0 required for significance. Leading edge genes (LEG) and positional candidate genes from this and 26 additional studies were used to validate 100 loci associated (P < 1 × 10− 5) with cow fertility using a custom sequencing genotyping array of putative functional variants (exons, promoters, splice sites, and conserved regions).

Results
GSEA-SNP identified 95 gene-sets (1,473 LEG) enriched for CCR1 and 67 gene sets enriched (1,438 LEG) for TBRD (NES ≥ 3). Thirty-four gene-sets were shared between CCR1 and TBRD along with 788 LEG. The association analysis for TBRD identified three loci: BTA1 at 83 Mb, BTA1 at 145 Mb, and BTA 20 at 46 Mb (P < 1 × 10− 5). The loci associated with TBRD contained candidate genes with functions relating to implantation and uterine receptivity. No loci were associated with CCR1, however a single locus on BTA1 at 146 Mb trended toward significance with an FDR of 0.04.

Conclusions
The validation of three loci associated with CCR and TBRD in Holsteins can be used to improve fertility through genomic selection and provide insight into understanding infertility.
Comprehensive implementations of multiple imputation using retrieved dropouts for continuous endpoints
Authors: Wang Shuai , Schwartz Pamela F. , Mancuso James P. 
Published: February 2025

Abstract

Background
In the metabolic disease area, there has been a long-time debate against using mixed models for repeated measures (MMRM) as the primary analysis of longitudinal continuous endpoints. As missing data arising from missing not at random assumptions are not addressed in MMRM, multiple imputation based on specific assumptions has been brought into play. Among many missing not at random assumptions with varying degrees of conservativeness, multiple imputation based on retrieved dropouts (MIRD) has been accepted by regulatory agencies in several type 2 diabetes and chronic weight management products in recent years, marking the beginning of a new standard for analysis of longitudinal data in this disease area.

Methods
On top of the established MIRD approach of which the imputation is based on last on-treatment data of retrieved dropout (RD)s, we propose a new class of MIRD approaches utilizing all available data from RDs. The imputation implementation can be one-step Markov Chain Monte Carlo (MCMC) or two-step (creating monotone missingness, followed by regression approach). ANCOVA can be applied to the complete dataset post imputation and Rubin’s rule can be used to combine all estimates into a single estimate. Simulation studies in a wide range of scenarios are conducted to understand the type-I error and power rates of the new class versus the established MIRD approach and other reference statistical methods such as MMRM.

Results
Overall, the new class has very similar performance compared to the established MIRD approach based on last on-treatment data. What’s more interesting is the one-step MCMC approach has better controlled type-I error and is more powerful than the established MIRD approach in certain scenarios with the difference gradually diminishing with larger sample size. The data analyses based on two real phase 3 datasets further manifest the power conclusions, with the results based on the new class applied to the larger of the two datasets almost identical to that of on-study MMRM.

Conclusions
We have presented comprehensive implementations of the MIRD approach for continuous endpoints in a longitudinal setting that fully fit within the strategy of treatment policy. The proposed new class based on all observed data of RDs is proved to be as powerful as the established MIRD approach based on last on-treatment visit in most scenarios. The one-step MCMC approach is more powerful than the established MIRD approach in certain scenarios. Since the new class involves less programming derivation of additional flags, it’s anticipated to be more easily implemented in clinical trial reporting.
Treating neuromuscular diseases: unveiling gene therapy breakthroughs and pioneering future applications
Authors: Wu Yu-Fu , Chen Jun-An , Jong Yuh-Jyh 
Published: February 2025

Abstract
In this review, we highlight recent advancements in adeno-associated virus (AAV)-based gene therapy for genetic neuromuscular diseases (NMDs), focusing on spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD). We discuss the current FDA-approved gene therapies for NMDs and provide updates on preclinical studies that demonstrate the potential of various AAV-based gene therapies to reduce SMA severity and serve as effective treatments for DMD. Additionally, we explore the transformative impact of CRISPR/Cas9 technology on the future of gene therapy for NMDs. Despite these encouraging developments, further research is required to identify robust biomarkers that can guide treatment decisions and predict outcomes. Overall, these pioneering advancements in AAV-based gene therapy lay the groundwork for future efforts aimed at curing genetic NMDs and offer a roadmap for developing gene therapies for other neurodegenerative diseases.
Deficiency in nucleoside diphosphate kinase B leads to endothelial activation of the hexosamine biosynthesis pathway and cardiac dysfunction
Authors: Shao Feng , Wieland Johanna , Wang Yixin , Keles Merve , Meng Zenghui , Lomada Santosh , Qin Miao , Leiss Veronika , Martin-Garrido Abel , Fuhrmann Manuela , Qiu Yi , Felix Trogisch , Vettel Christiane , Heineke Joerg , Feng Yuxi 
Published: February 2025

Abstract

Background
Nucleoside diphosphate kinase B (NDPKB) deficiency in endothelial cells (ECs) promotes the activation of the hexosamine biosynthesis pathway (HBP), leading to vascular damage in the retina. The aim of this study was to investigate the consequences of NDPKB deficiency in the mouse heart.

Methods
NDPKB deficient mice were used in the study. Echocardiography was employed to assess cardiac function in vivo. Characterization of contractility in hiPSC-derived cardiomyocytes (hiPSC-CMs) was measured with the IonOptix contractility system. Immunoblotting and immunofluorescence were carried out to analyze the expression and localization of proteins in cultured cells and left ventricles (LVs).

Results
NDPKB deficient mice displayed impaired glucose tolerance and increased heart weight compared to controls. Echocardiographic analysis revealed an increase in the diastolic diameter of the left ventricular posterior wall (LVPW), a decrease in the early diastolic mitral valve E and E′ wave, and in the ratios of E/A and E′/A′ in NDPKB deficient hearts, suggesting cardiac hypertrophy and diastolic dysfunction. In line with cardiac dysfunction, the phosphorylation of myocardial phospholamban (PLN) and the expression of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2 (SERCA2) in the NDPKB deficient LVs were significantly reduced. Moreover, the accumulation of collagen, fibronectin as well as the upregulation of transforming growth factor β (TGF-β), were detected in NDPKB deficient LVs. In addition, activation of the HBP and its downstream O-GlcNAc cycle was observed in the LVs and cardiac ECs (CECs) isolated from the NDPKB−/− mice. Furthermore, a bipolar O-GlcNAc regulation was identified in CMs. O-GlcNAc was decreased in NDPKB-depleted CMs, while conditioned medium from NDPKB-depleted ECs significantly increased O-GlcNAc levels, along with contractile and relaxation dysfunction of the hiPSC-CMs, which was attenuated by inhibiting endothelial HBP activation.

Conclusions
Deficiency in NDPKB leads to endothelial activation of the HBP and cardiac dysfunction. Our findings may highlight the crucial role of proper endothelial HBP in maintaining cardiovascular homeostasis.
Post-traumatic growth and influencing factors of parents with children with Duchenne muscular dystrophy: a cross-sectional survey study
Authors: Xu Li , Liu Meili , Chen Yuewei , Wu Liwen , Gan Siyi , Xie Jianhui , Latour Jos M. 
Published: February 2025

Abstract

Background
The aim of the study was to identify the post-traumatic growth status and influencing factors of parents with children with Duchenne muscular dystrophy (DMD).

Methods
We adopted a cross-section survey study. Between February and December 2022, 181 parents responded to the survey including a participants’ characteristics section, post-traumatic growth assessment scale, caregiver burden scale, and social support assessment scale. Multiple linear regression analysis was used to investigate influencing factors of post-traumatic growth.

Results
The mean score of post-traumatic growth of parents was 56.66 (SD ± 18.67). Post-traumatic growth was positively correlated with social support (r = 0.452, P < 0.01) and negatively correlated with care burden (r = -0.207, P < 0.01). Multiple linear regression showed that the child’s age, course of disease, self-care ability, parent’s working condition, residence, education, number of children, and health status were the main influencing factors for the post-traumatic growth of parents (P < 0.001).

Conclusion
The post-traumatic growth of parents with children with DMD was at a moderate level. Healthcare professionals should pay attention to the psychological state of parents with children with this rare disease and promote post-traumatic growth through psychological mindfulness interventions, strengthening family and social support, and providing care knowledge and skills.
De novo familial adenomatous polyposis with germline double heterozygosity of APC/BRCA2: a case report and literature review
Authors: Zhang Tian-Qi , Cai Ji-Dong , Li Cong , Xu Yun , Xu Ye 
Published: February 2025

Abstract

Background
The widespread application of colonoscopy screening and genetic testing in colorectal cancer (CRC) treatment has led to the identification of a subset of familial adenomatous polyposis (FAP) patients who lack a family history of the disease but harbor germline gene mutations. Moreover, distinct genotypes may be associated with varied clinical presentations and therapeutic options. This case report describes a male patient with de novo FAP who harbored germline double heterozygosity (GDH) for APC and BRCA2 mutations. The patient underwent total colectomy, and genetic testing enabled personalized surveillance and management strategies for his family members.

Case presentation
A 43-year-old male with no family history of cancer presented to the outpatient clinic of the Colorectal Surgery Department with complaints of constipation and hematochezia. Colonoscopy revealed hundreds of polyps throughout the colon and a rectal adenocarcinoma located 5 cm from the anal verge. Gastroduodenal endoscopy did not detect any upper gastrointestinal adenomas. The patient underwent laparoscopic total colectomy with abdominoperineal resection of the rectum and end ileostomy. With the consent of the patient and his family, genetic testing was performed. The index patient was found to carry an APC splicing site mutation (exon 15: c.1744-1G > A) and a BRCA2 missense mutation (exon 17: c.7976G > A: p.R2659K). His daughter was found to have inherited the same germline BRCA2 variant. Additionally, the rectal cancer exhibited proficient DNA mismatch repair (pMMR) status, ERBB2 copy number amplification, and a missense mutation, while the KRAS, NRAS, and BRAF genes were wild-type. Based on the genetic testing results and clinical manifestations, the index patient was diagnosed with familial adenomatous polyposis (FAP) and rectal cancer. Personalized surveillance and management strategies were implemented for the patient and his family, focusing on the risks of extra-colonic diseases and potential malignancies in the prostate, pancreas, breast, and ovaries.

Conclusion
De novo FAP with double germline mutations in APC and BRCA2, along with somatic ERBB2 mutations, is exceptionally rare among hereditary cancer cases. With the rapid advancements in genomics, the detection of multiple gene variants in individuals or families has become increasingly common. Additionally, the application of artificial intelligence (AI) in medical research may provide powerful tools for genetic analysis and clinical decision-making. Consequently, a comprehensive evaluation of family history, a deep understanding of hereditary cancer syndromes, and precise interpretation of genetic mutations are essential for personalized clinical management in the era of precision medicine. However, these tasks pose significant challenges for clinicians and genetic counselors alike.
Awareness and perception of antimicrobial stewardship program among healthcare professionals in the hospitals of ministry of health and population, Egypt: antimicrobial stewardship toolkit survey
Authors: Abd El Azeem Khalaf Yara Mohsen , Gad Zahira Metwally , Arafa Mostafa Ahmed , Abdou Marwa Shawky 
Published: February 2025

Abstract

Background
Antimicrobial resistance (AMR) has been recognized by international policymakers as a serious threat due to its current and projected influence on global population health, healthcare expenditures and gross domestic product (GDP). The present work aimed to assess the awareness, perceptions, and practices of healthcare professionals regarding the implementation of the Antimicrobial Stewardship program (ASP).

Methods
A cross-sectional study was conducted among 310 health care professionals. A self-administered questionnaire based on Antimicrobial Stewardship Toolkit for Acute and Long-Term Care Facilities; Greater New York Hospital Association (GNYAHA) was used to assess perceptions and knowledge about AMR and automatic selective perception.

Results
A total of 310 healthcare professionals participated in the study, of which 60.6% were females, with a mean age of 37.32 ± 8.71, mean years of working of 6.0 ± 5.95 and mean years of experience of 7.97 ± 7.14. The mean scores for AMR awareness, antibiotic (AB) prescribing practices, ASP perception, and intervention beliefs were 73.05 ± 11.21, 32.97 ± 8.22, 52.85 ± 13.99, and 18.24 ± 2.71, respectively. Bivariate analysis showed that profession, primary work unit, staff position significantly affect the AMR awareness and ASP perception, while only staff position affect intervention beliefs. The Multivariate linear regression showed that working in pharmacy, ABs prescribing practice and ASP perception were independent predictors of AMR awareness. Years of work in hospital, AMR awareness and ASP perception were the independent predictors of ABs prescribing practice. AMR awareness, ABs prescribing practice and intervention beliefs were independent predictors of ASP perception while ASP perception was the only independent predictors of intervention beliefs.

Conclusions
The study found a high level of awareness and practice regarding AMR and ASP among healthcare professionals. Pharmacists had higher levels of AMR awareness and ASP perception than physician in different specialities. Levels of AMR awareness, ABs prescribing practice, ASP perception and intervention beliefs affect each other in different ways. Linear regression supported our findings that pharmacists had a higher level of AMR awareness, while years of work in hospital had a significant effect on ABs prescribing practice.
Snail control as a crucial approach to schistosomiasis elimination: evidence from the People’s Republic of China
Authors: Lv Shan , Xu Jing , Li Yin-Long , Bao Zi-Ping , Zhang Li-Juan , Yang Kun , Lin Dan-Dan , Liu Jian-Bing , Wang Tian-Ping , Ren Guang-Hui , Zhong Bo , Dong Yi , Cai Li , Wen Li-Yong , Jiang Zhi-Hua , Deng Zhuo-Hui , Xie Han-Guo , Li Shi-Zhu , Bergquist Robert , Utzinger Jürg , Zhou Xiao-Nong 
Published: February 2025

Abstract

Background
Asian schistosomiasis is projected to be eliminated by 2030 according to World Health Organization road map for neglected tropical diseases 2021–2030. Snail control is an important measure but has not yet been systematically evaluated at a country scale. Here, we report the findings from a nationwide survey to demonstrate the dynamics of Oncomelania and its potential role in transmission interruption of schistisomiasis in the People’s Republic of China (P.R. China).

Methods
Between March 2016 and December 2017, we conducted a nationwide census on Oncomelania snail habitats in P.R. China. All historically recorded snail habitats were identified and reviewed. Information on habitat attributes, including the infestation of snails, was collected. The shape of habitats was determined using global positioning system and geographical information system technologies. The relationship between snail control and schistosomiasis elimination was established in 378 endemic counties. The comparison of accumulated snail-infested range (ASR) and the median ratio of eliminated ASR between the transmission-interrupted and endemic counties was tested by a non-parametric test (Mann–Whitney) with a significance level of 0.05.

Results
Overall, 15,377.7 million m2 of potential snail habitats with a total of 356,550 snail habitats were identified in P.R. China. The ASR amounted to 86.0% of the total area. Most of the ASR (94.9%) and habitats (68.5%) were distributed in the middle and lower reaches of the Yangtze River. Snail habitats were found up to an altitude of 2859 m above the mean sea level. By 2017, 85.1% of habitats (73.0% of the ASR) had been eliminated with almost half of them eliminated between 1965 and 1982. The elimination of snail habitats promoted transmission interruption of schistosomiasis, but showed variable patterns in different landscapes. The ratio of eliminated ASR was 99.6 and 91.4% in water network and hilly areas, respectively, while it was only 64.8% in marshland areas, particularly in Hunan and Jiangxi where the two largest freshwater lakes of P.R. China are located. Marshland habitats were seen as the most difficult for transmission interruption, which calls for additional control measures in these settings.

Conclusions
Our results support recent recommendations by the World Health Organization to implement snail control and demonstrate that schistosomiasis elimination can be achieved. The nationwide, high-resolution map of Oncomelania snail habitats in P.R. China will support further efforts to eliminate schistosomiasis.

Graphical Abstract