bluuebunny/crossref_metadata_2025_split huggingface dataset:
The causal effect of reproductive factors on pelvic floor dysfunction: a Mendelian randomization study
Authors: Zhang Shufei , Li BingShu , Liu Jianfeng , Yang Lian , Li Hanyue , Hong Li 
Published: January 2024

Abstract
Background
Pelvic floor dysfunction (PFD) is an extremely widespread urogynecologic disorder, the prevalence of which increases with aging. PFD has severely affected women’s quality of life and has been called a social cancer. While previous studies have identified risk factors such as vaginal delivery and obesity for PFD, other reproductive factors, including age at menarche (AAMA), have been largely overlooked. Therefore, we used a Mendelian randomization (MR) study for the first time to investigate the potential causal relationship between reproductive factors and PFD.

Methods
We obtained summary statistics from genome-wide association studies (GWAS) for female genital prolapse (FGP), stress urinary incontinence (SUI), and five reproductive factors. Two-sample Mendelian randomization analysis (TSMR) was performed to explore the causal associations between these factors. The causal effects of reproductive factors on FGP and SUI were primarily estimated using the standard inverse variance weighting (IVW) method, with additional complementary and sensitivity analyses conducted using multiple approaches. A multivariate Mendelian randomization (MVMR) study was also conducted to adjust for pleiotropic effects and possible sources of selection bias and to identify independent exposure factors.

Results
Our findings revealed that advanced age at first sexual intercourse (AFS) and age at first birth (AFB) exhibited negative causal effects on both FGP and SUI. AAMA showed negative causal effects solely on FGP, while age at last live birth (ALB) and age at menopause (AAMO) did not demonstrate any causal effect on either FGP or SUI. And the MVMR results showed that AFB and AFS had independent negative causal effects on FGP and SUI, respectively.

Conclusions
This study, for the first time, investigates the causal relationship between reproductive factors and PFD. The results suggested a causal relationship between some reproductive factors, such as AFB and AFS, and PFD, but there were significant differences between FGPand SUI. Therefore, future studies should explore the underlying mechanisms and develop preventive measures for reproductive factors to reduce the disease burden of PFD.
Tanshinone IIA inhibits proliferation and migration by downregulation of the PI3K/Akt pathway in small cell lung cancer cells
Authors: Jiang Yuxin , Bi Yanli , Zhou Lingjie , Zheng Senwen , Jian Tingting , Chen Jian 
Published: January 2024

Abstract
Background
Small cell lung cancer (SCLC) is the most malignant lung cancer type. Due to the high rates of metastasis and drug resistance, effective therapeutic strategies remain lacking. Tanshinone IIA (Tan IIA) has been reported to exhibit anti-tumor activity. Therefore, this study investigated the ability and underlying mechanism of Tan IIA to inhibit the metastasis and proliferation of SCLC.

Methods
H1688 and H446 cells were treated in vitro with Tan IIA (0, 1, 2 and 4 µM) or LY294002 (10 µM) for 24, 48, 72 h. H1688 and H446 cell migration was evaluated in wound healing and transwell migration assays. RNA-sequencing helped assess gene expression. BALB/c nude mice were injected with H1688 cells and treated with the Tan IIA group (10 mg/kg/day) or a control. Expression of E-cadherin, vimentin and PI3K/Akt signaling pathway proteins in tumors and H1688 was investigated by immunohistochemical analysis and western blot.

Results
Tan IIA inhibited H1688 and H446 cell proliferation without inducing apoptosis and suppressed H1688 and H446 cell migration. E-cadherin expression was increased, while vimentin expression was reduced after administration of Tan IIA. RNA-sequencing revealed that some genes related with the PI3K/Akt signaling pathway were altered using Tan IIA treatment. Furthermore, western blot helped detect PI3K and p-Akt expression was also reduced by Tan IIA treatment. Tan IIA inhibited tumor growth in vivo. Moreover, Tan IIA increased tumoral expression of E-cadherin accompanied by PI3K and p-Akt downregulation.

Conclusion
Tan IIA suppresses SCLC proliferation and metastasis by inhibiting the PI3K/Akt signaling pathway, thereby highlighting the potential of Tan IIA as a new and relatively safe drug candidate to treat SCLC.
A study on the epidemiology of brucellosis in bovine population of peri-urban and rural areas of district Multan, southern Punjab, Pakistan
Authors: Awais Mian Muhammad , Khadim Gohar , Akhtar Masood , Anwar Muhammad Irfan , Shirwany Abdul Sammad Ali Khan , Raza Ahmad , Razzaq Abdul , Fatima Zahida , Ali Muhammad Amjad , Bhatti Muhammad Sibtain 
Published: January 2024

Abstract
Background
Brucellosis is a zoonotic disease caused by a bacterial pathogen belonging to the genus Brucella. It is one of the most frequent bacterial zoonoses globally but unfortunately, it is still considered as a neglected disease in the developing world. Keeping in view, this study was conducted to determine the prevalence and risk determinants of brucellosis in large ruminants of peri-urban and rural areas of district Multan-Pakistan. For this purpose, blood samples (n = 490) were collected from the cattle (n = 245) and buffalo (n = 245) population of the study area and subjected to preliminary screening of brucellosis using local and imported RBPT reagents. All the samples were further analyzed using commercially available multi-specie indirect ELISA kit followed by their confirmation by PCR using genus and species-specific primers. Data obtained from lab analysis and questionnaires were subjected to statistical analysis for Pearson Chi-square, Odds Ratio and Confidence intervals (95%).

Results
The results showed that the maximum seropositivity was recorded with local RBPT reagent (VRI, Pakistan; 12.45%; 95%CI = 9.72–15.65%) followed by RBPT-IDEXX (12.24%; 95%CI = 9.52–15.45%) and RBPT-ID.vet (11.84%; 95%CI = 9.18–14.95%) however statistical difference was non-significant (P = 0.956). The ELISA results showed an overall seroprevalence rate of 11.22% (95%CI = 8.59–14.33%) with comparatively higher rate in cattle (12.65%; 95%CI = 8.82–17.44%) as compared to buffaloes (9.80%; 95%CI = 6.49–14.15%). The PCR analysis confirmed the presence of genus Brucella in all seropositive samples whereas frequency of B. abortus and B. melitensis in seropositive samples was 80% and 20%, respectively. The co-existence of both species was also observed in 5.45% samples. The statistical analysis showed a significant association of bovine brucellosis with herd size, breed, reproductive disorders, mode of insemination, educational status and farmers’ awareness about brucellosis (P < 0.05). Conversely, locality, age, weight, gender, pregnancy status, parity and puberty status had no associations with brucellosis (P > 0.05).

Conclusion
In conclusion, brucellosis is prevalent in large ruminants of district Multan, Pakistan. It is suggested to devise and implement stringent policies for the effective control and prevention of brucellosis in the region. Further, the current situation also warrants the need to strengthen interdisciplinary coordination among veterinarians and physicians in one health perspective to ensure and strengthen the human and animal health care systems in the region.
Clinical features and molecular genetic investigation of infantile-onset ascending hereditary spastic paralysis (IAHSP) in two Chinese siblings caused by a novel splice site ALS2 variation
Authors: Zhang Qiang , Yang Qi , Luo Jingsi , Zhou Xunzhao , Yi Shang , Tan Shuyin , Qin Zailong 
Published: January 2024

Abstract
Objective
ALS2-related disorder involves retrograde degeneration of the upper motor neurons of the pyramidal tracts, among which autosomal recessive Infantile-onset ascending hereditary spastic paralysis (IAHSP) is a rare phenotype. In this study, we gathered clinical data from two Chinese siblings who were affected by IAHSP. Our aim was to assess the potential pathogenicity of the identified variants and analyze their clinical and genetic characteristics.

Method
Here, Whole-exome sequencing (WES) was performed on proband to identify the candidate variants. Subsequently, Sanger sequencing was used to verify identified candidate variants and to assess co-segregation among available family members. Utilizing both silico prediction and 3D protein modeling, an analysis was conducted to evaluate the potential functional implications of the variants on the encoded protein, and minigene assays were performed to unravel the effect of the variants on the cleavage of pre-mRNA.

Results
Both patients were characterized by slurred speech, astasia, inability to walk, scoliosis, lower limb hypertonia, ankle clonus, contracture of joint, foot pronation and no psychomotor retardation was found. Genetic analysis revealed a novel homozygous variant of ALS2, c.1815G > T(p.Lys605Asn) in two Chinese siblings. To our knowledge, it is the first confirmed case of a likely pathogenic variant leading to IAHSP in a Chinese patient.

Conclusion
This study broadens the range of ALS2 variants and has practical implications for prenatal and postnatal screening of IAHSR. Symptom-based diagnosis of IAHSP is frequently difficult for medical practitioners. WES can be a beneficial resource to identify a particular disorder when the diagnosis cannot be determined from the symptoms alone.
ASGR1 deficiency diverts lipids toward adipose tissue but results in liver damage during obesity
Authors: Svecla Monika , Da Dalt Lorenzo , Moregola Annalisa , Nour Jasmine , Baragetti Andrea , Uboldi Patrizia , Donetti Elena , Arnaboldi Lorenzo , Beretta Giangiacomo , Bonacina Fabrizia , Norata Giuseppe Danilo 
Published: January 2024

Abstract
Background
Asialoglycoprotein receptor 1 (ASGR1), primarily expressed on hepatocytes, promotes the clearance and the degradation of glycoproteins, including lipoproteins, from the circulation. In humans, loss-of-function variants of ASGR1 are associated with a favorable metabolic profile and reduced incidence of cardiovascular diseases. The molecular mechanisms by which ASGR1 could affect the onset of metabolic syndrome and obesity are unclear. Therefore, here we investigated the contribution of ASGR1 in the development of metabolic syndrome and obesity.

Methods
ASGR1 deficient mice (ASGR1−/−) were subjected to a high-fat diet (45% Kcal from fat) for 20 weeks. The systemic metabolic profile, hepatic and visceral adipose tissue were characterized for metabolic and structural alterations, as well as for immune cells infiltration.

Results
ASGR1−/− mice present a hypertrophic adipose tissue with 41% increase in fat accumulation in visceral adipose tissue (VAT), alongside with alteration in lipid metabolic pathways. Intriguingly, ASGR1−/− mice exhibit a comparable response to an acute glucose and insulin challenge in circulation, coupled with notably decreased in circulating cholesterol levels. Although the liver of ASGR1−/− have similar lipid accumulation to the WT mice, they present elevated levels of liver inflammation and a decrease in mitochondrial function.

Conclusion
ASGR1 deficiency impacts energetic homeostasis during obesity leading to improved plasma lipid levels but increased VAT lipid accumulation and liver damage.
Association of temporal change in body mass index with sudden cardiac arrest in diabetes mellitus
Authors: Jeong Joo Hee , Kim Yun Gi , Han Kyung-Do , Roh Seung-Young , Lee Hyoung Seok , Choi Yun Young , Shim Jaemin , Choi Jong-Il , Kim Young-Hoon 
Published: January 2024

Abstract
Background
Underweight imposes significant burden on cardiovascular outcomes in patients with diabetes mellitus. However, less is known about the impact of serial change in body weight status measured as body mass index (BMI) on the risk of sudden cardiac arrest (SCA). This study investigated the association between SCA and temporal change in BMI among patients with diabetes mellitus.

Methods
Based on Korean National Health Insurance Service database, participants with diabetes mellitus who underwent health examination between 2009 and 2012 and had prior health examination data (four years ago, 2005–2008) were retrospectively analyzed. BMI was measured at baseline (2005–2008) and 4-year follow-up health examination (2009–2012). Patients were classified in four groups according to the body weight status and its temporal change: sustained non-underweight, sustained underweight, previous underweight, and newly developed underweight. Primary outcome was defined as occurrence of SCA.

Results
A total of 1,355,746 patients with diabetes mellitus were included for analysis, and SCA occurred in 12,554 cases. SCA was most common in newly developed underweight (incidence rate = 4.45 per 1,000 person-years), followed by sustained underweight (incidence rate = 3.90), previous underweight (incidence rate = 3.03), and sustained non-underweight (incidence rate = 1.34). Adjustment of covariates resulted highest risk of SCA in sustained underweight (adjusted hazard ratio = 2.60, 95% confidence interval [2.25–3.00], sustained non-underweight as a reference), followed by newly developed underweight (2.42, [2.15–2.74]), and previous underweight (2.12, [1.77–2.53]).

Conclusions
In diabetes mellitus, sustained underweight as well as decrease in body weight during 4-year follow-up imposes substantial risk on SCA. Recovery from underweight over time had relatively lower, but yet increased risk of SCA. Both underweight and dynamic decrease in BMI can be associated with increased risk of SCA.
Joint angle estimation during shoulder abduction exercise using contactless technology
Authors: Barzegar Khanghah Ali , Fernie Geoff , Roshan Fekr Atena 
Published: January 2024

Abstract
Background
Tele-rehabilitation, also known as tele-rehab, uses communication technologies to provide rehabilitation services from a distance. The COVID-19 pandemic has highlighted the importance of tele-rehab, where the in-person visits declined and the demand for remote healthcare rises. Tele-rehab offers enhanced accessibility, convenience, cost-effectiveness, flexibility, care quality, continuity, and communication. However, the current systems are often not able to perform a comprehensive movement analysis. To address this, we propose and validate a novel approach using depth technology and skeleton tracking algorithms.

Methods
Our data involved 14 participants (8 females, 6 males) performing shoulder abduction exercises. We collected depth videos from an LiDAR camera and motion data from a Motion Capture (Mocap) system as our ground truth. The data were collected at distances of 2 m, 2.5 m, and 3.5 m from the LiDAR sensor for both arms. Our innovative approach integrates LiDAR with the Cubemos and Mediapipe skeleton tracking frameworks, enabling the assessment of 3D joint angles. We validated the system by comparing the estimated joint angles versus Mocap outputs. Personalized calibration was applied using various regression models to enhance the accuracy of the joint angle calculations.

Results
The Cubemos skeleton tracking system outperformed Mediapipe in joint angle estimation with higher accuracy and fewer errors. The proposed system showed a strong correlation with Mocap results, although some deviations were present due to noise. Precision decreased as the distance from the camera increased. Calibration significantly improved performance. Linear regression models consistently outperformed nonlinear models, especially at shorter distances.

Conclusion
This study showcases the potential of a marker-less system, to proficiently track body joints and upper-limb angles. Signals from the proposed system and the Mocap system exhibited robust correlation, with Mean Absolute Errors (MAEs) consistently below $$10^\circ$$

10
∘

. LiDAR’s depth feature enabled accurate computation of in-depth angles beyond the reach of traditional RGB cameras. Altogether, this emphasizes the depth-based system’s potential for precise joint tracking and angle calculation in tele-rehab applications.
Exosome-based delivery strategies for tumor therapy: an update on modification, loading, and clinical application
Authors: Yang Qian , Li Shisheng , Ou Haibo , Zhang Yuming , Zhu Gangcai , Li Shaohong , Lei Lanjie 
Published: January 2024

AbstractMalignancy is a major public health problem and among the leading lethal diseases worldwide. Although the current tumor treatment methods have therapeutic effect to a certain extent, they still have some shortcomings such as poor water solubility, short half-life, local and systemic toxicity. Therefore, how to deliver therapeutic agent so as to realize safe and effective anti-tumor therapy become a problem urgently to be solved in this field. As a medium of information exchange and material transport between cells, exosomes are considered to be a promising drug delivery carrier due to their nano-size, good biocompatibility, natural targeting, and easy modification. In this review, we summarize recent advances in the isolation, identification, drug loading, and modification of exosomes as drug carriers for tumor therapy alongside their application in tumor therapy. Basic knowledge of exosomes, such as their biogenesis, sources, and characterization methods, is also introduced herein. In addition, challenges related to the use of exosomes as drug delivery vehicles are discussed, along with future trends. This review provides a scientific basis for the application of exosome delivery systems in oncological therapy.
Graphical Abstract
Association of spatial proximity to fixed-site syringe services programs with HCV serostatus and injection equipment sharing practices among people who inject drugs in rural New England, United States
Authors: Romo Eric , Stopka Thomas J. , Jesdale Bill M. , Wang Bo , Mazor Kathleen M. , Friedmann Peter D. 
Published: January 2024

Abstract
Background
Hepatitis C virus (HCV) disproportionately affects rural communities, where health services are geographically dispersed. It remains unknown whether proximity to a syringe services program (SSP) is associated with HCV infection among rural people who inject drugs (PWID).

Methods
Data are from a cross-sectional sample of adults who reported injecting drugs in the past 30 days recruited from rural counties in New Hampshire, Vermont, and Massachusetts (2018–2019). We calculated the road network distance between each participant’s address and the nearest fixed-site SSP, categorized as ≤ 1 mile, 1–3 miles, 3–10 miles, and > 10 miles. Staff performed HCV antibody tests and a survey assessed past 30-day injection equipment sharing practices: borrowing used syringes, borrowing other used injection equipment, and backloading. Mixed effects modified Poisson regression estimated prevalence ratios (aPR) and 95% confidence intervals (95% CI). Analyses were also stratified by means of transportation.

Results
Among 330 PWID, 25% lived ≤ 1 mile of the nearest SSP, 17% lived 1–3 miles of an SSP, 12% lived 3–10 miles of an SSP, and 46% lived > 10 miles from an SSP. In multivariable models, compared to PWID who lived within 1 mile of an SSP, those who lived 3 to 10 miles away had a higher prevalence of HCV seropositivity (aPR: 1.25, 95% CI 1.06–1.46), borrowing other used injection equipment (aPR: 1.23, 95% CI 1.04–1.46), and backloading (aPR: 1.48, 95% CI 1.17–1.88). Similar results were observed for PWID living > 10 miles from an SSP: aPR [HCV]: 1.19, 95% CI 1.01–1.40; aPR [borrowing other used equipment]:1.45, 95% CI 1.29–1.63; and aPR [backloading]: 1.59, 95% CI 1.13–2.24. Associations between living 1 to 3 miles of an SSP and each outcome did not reach statistical significance. When stratified by means of transportation, associations between distance to SSP and each outcome (except borrowing other used injection equipment) were only observed among PWID who traveled by other means (versus traveled by automobile).

Conclusions
Among PWID in rural New England, living farther from a fixed-site SSP was associated with a higher prevalence of HCV seropositivity, borrowing other used injection equipment, and backloading, reinforcing the need to increase SSP accessibility in rural areas. Means of transportation may modify this relationship.
Preclinical translational platform of neuroinflammatory disease biology relevant to neurodegenerative disease
Authors: Larson Kelley C. , Martens Lauren H. , Marconi Michael , Dejesus Christopher , Bruhn Suzanne , Miller Thomas A. , Tate Barbara , Levenson Jonathan M. 
Published: January 2024

AbstractNeuroinflammation is a key driver of neurodegenerative disease, however the tools available to model this disease biology at the systems level are lacking. We describe a translational drug discovery platform based on organotypic culture of murine cortical brain slices that recapitulate disease-relevant neuroinflammatory biology. After an acute injury response, the brain slices assume a chronic neuroinflammatory state marked by transcriptomic profiles indicative of activation of microglia and astrocytes and loss of neuronal function. Microglia are necessary for manifestation of this neuroinflammation, as depletion of microglia prior to isolation of the brain slices prevents both activation of astrocytes and robust loss of synaptic function genes. The transcriptomic pattern of neuroinflammation in the mouse platform is present in published datasets derived from patients with amyotrophic lateral sclerosis, Huntington’s disease, and frontotemporal dementia. Pharmacological utility of the platform was validated by demonstrating reversal of microglial activation and the overall transcriptomic signature with transforming growth factor-β. Additional anti-inflammatory targets were screened and inhibitors of glucocorticoid receptors, COX-2, dihydrofolate reductase, and NLRP3 inflammasome all failed to reverse the neuroinflammatory signature. Bioinformatics analysis of the neuroinflammatory signature identified protein tyrosine phosphatase non-receptor type 11 (PTPN11/SHP2) as a potential target. Three structurally distinct inhibitors of PTPN11 (RMC-4550, TN0155, IACS-13909) reversed the neuroinflammatory disease signature. Collectively, these results highlight the utility of this novel neuroinflammatory platform for facilitating identification and validation of targets for neuroinflammatory neurodegenerative disease drug discovery.