bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhancing endometrial receptivity: the roles of human chorionic gonadotropin in autophagy and apoptosis regulation in endometrial stromal cells
Authors: Wang Bin , Gao Mingxia , Yao Ying , Shen Haofei , Li Hongwei , Sun Jingjing , Wang Liyan , Zhang Xuehong 
Published: April 2024

AbstractInadequate endometrial receptivity often results in embryo implantation failure and miscarriage. Human chorionic gonadotropin (hCG) is a key signaling molecule secreted during early embryonic development, which regulates embryonic maternal interface signaling and promotes embryo implantation. This study aimed to examine the impact of hCG on endometrial receptivity and its underlying mechanisms. An exploratory study was designed, and endometrial samples were obtained from women diagnosed with simple tubal infertility or male factor infertile (n = 12) and recurrent implantation failure (RIF, n = 10). Using reverse transcription-quantitative PCR and western blotting, luteinizing hormone (LH)/hCG receptor (LHCGR) levels and autophagy were detected in the endometrial tissues. Subsequently, primary endometrial stromal cells (ESCs) were isolated from these control groups and treated with hCG to examine the presence of LHCGR and markers of endometrial receptivity (HOXA10, ITGB3, FOXO1, LIF, and L-selectin ligand) and autophagy-related factors (Beclin1, LC3, and P62). The findings revealed that the expressions of receptivity factors, LHCGR, and LC3 were reduced in the endometrial tissues of women with RIF compared with the control group, whereas the expression of P62 was elevated. The administration of hCG to ESCs specifically activated LHCGR, stimulating an increase in the endometrial production of HOXA10, ITGB3, FOXO1, LIF and L-selectin ligands. Furthermore, when ESCs were exposed to 0.1 IU/mL hCG for 72 h, the autophagy factors Beclin1 and LC3 increased within the cells and P62 decreased. Moreover, the apoptotic factor Bax increased and Bcl-2 declined. However, when small interfering RNA was used to knock down LHCGR, hCG was less capable of controlling endometrial receptivity and autophagy molecules in ESCs. In addition, hCG stimulation enhanced the phosphorylation of ERK1/2 and mTOR proteins. These results suggest that women with RIF exhibit lower levels of LHCGR and compromised autophagy function in their endometrial tissues. Thus, hCG/LHCGR could potentially improve endometrial receptivity by modulating autophagy and apoptosis.
Systematic proteome-wide Mendelian randomization using the human plasma proteome to identify therapeutic targets for lung adenocarcinoma
Authors: Zhang Long , Xiong Yajun , Zhang Jie , Feng Yuying , Xu Aiguo 
Published: April 2024

Abstract
Background
Lung adenocarcinoma (LUAD) is the predominant histological subtype of lung cancer and the leading cause of cancer-related mortality. Identifying effective drug targets is crucial for advancing LUAD treatment strategies.

Methods
This study employed proteome-wide Mendelian randomization (MR) and colocalization analyses. We collected data on 1394 plasma proteins from a protein quantitative trait loci (pQTL) study involving 4907 individuals. Genetic associations with LUAD were derived from the Transdisciplinary Research in Cancer of the Lung (TRICL) study, including 11,245 cases and 54,619 controls. We integrated pQTL and LUAD genome-wide association studies (GWASs) data to identify candidate proteins. MR utilizes single nucleotide polymorphisms (SNPs) as genetic instruments to estimate the causal effect of exposure on outcome, while Bayesian colocalization analysis determines the probability of shared causal genetic variants between traits. Our study applied these methods to assess causality between plasma proteins and LUAD. Furthermore, we employed a two-step MR to quantify the proportion of risk factors mediated by proteins on LUAD. Finally, protein–protein interaction (PPI) analysis elucidated potential links between proteins and current LUAD medications.

Results
We identified nine plasma proteins significantly associated with LUAD. Increased levels of ALAD, FLT1, ICAM5, and VWC2 exhibited protective effects, with odds ratios of 0.79 (95% CI 0.72–0.87), 0.39 (95% CI 0.28–0.55), 0.91 (95% CI 0.72–0.87), and 0.85 (95% CI 0.79–0.92), respectively. Conversely, MDGA2 (OR, 1.13; 95% CI 1.08–1.19), NTM (OR, 1.12; 95% CI 1.09–1.16), PMM2 (OR, 1.35; 95% CI 1.18–1.53), RNASET2 (OR, 1.15; 95% CI 1.08–1.21), and TFPI (OR, 4.58; 95% CI 3.02–6.94) increased LUAD risk. Notably, none of the nine proteins showed evidence of reverse causality. Bayesian colocalization indicated that RNASET2, TFPI, and VWC2 shared the same variant with LUAD. Furthermore, NTM and FLT1 demonstrated interactions with targets of current LUAD medications. Additionally, FLT1 and TFPI are currently under evaluation as therapeutic targets, while NTM, RNASET2, and VWC2 are potentially druggable. These findings shed light on LUAD pathogenesis, highlighting the tumor-promoting effects of RNASET2, TFPI, and NTM, along with the protective effects of VWC2 and FLT1, providing a significant biological foundation for future LUAD therapeutic targets.

Conclusions
Our proteome-wide MR analysis highlighted RNASET2, TFPI, VWC2, NTM, and FLT1 as potential drug targets for further clinical investigation in LUAD. However, the specific mechanisms by which these proteins influence LUAD remain elusive. Targeting these proteins in drug development holds the potential for successful clinical trials, providing a pathway to prioritize and reduce costs in LUAD therapeutics.
Exploring the effects of the dietary fiber compound mediated by a longevity dietary pattern on antioxidation, characteristic bacterial genera, and metabolites based on fecal metabolomics
Authors: Shi Fengcui , Liu Qingli , Yue Dayong , Zhang Yanan , Wei Xueying , Wang Ying , Ma WenJian 
Published: April 2024

Abstract
Background
Age-related dysbiosis of the microbiota has been linked to various negative health outcomes. This study aims to investigate the effects of a newly discovered dietary fiber compound (DFC) on aging, intestinal microbiota, and related metabolic processes. The DFC was identified through in vitro fermentation screening experiments, and its dosage and composition were determined based on a longevity dietary pattern.

Methods
Aged SPF C57BL/6 J mice (65 weeks old) and young mice (8 weeks old) were divided into three groups: a subgroup without dietary fiber (NDF), a low DFC dose subgroup (LDF, 10% DFC), and a high DFC dose subgroup (HDF, 20% DFC). The total antioxidant capacity (T-AOC), total superoxide dismutase (T-SOD) activity, malondialdehyde (MDA) content, and glutathione peroxidase (GSH-Px) activity in liver and serum samples of the mice were measured according to the manufacturer’s protocol. The expression levels of characteristic bacterial genera and fecal metabolite concentrations in mice were determined using quantitative real-time PCR (qPCR) and nuclear magnetic resonance hydrogen spectroscopy (1H NMR). Metabolomics analysis was further conducted to identify biological functions and potential pathways related to aging.

Results
After an 8-weeks dietary intervention, DFC supplementation significantly attenuated age-related weight loss, organ degeneration, and oxidative stress. And promoted the growth of Lactobacillus and Bifidobacterium and inhibited the growth of Escherichia coli (E. coli) and Bacteroides (p < 0.05) in the intestinal tracts of aged mice. Metabolomic analysis identified glycolipid and amino acid metabolic pathway biomarkers associated with aging that were differentially regulated by DFC consumption. Correlation analysis between the identified microbial flora and the biomarkers revealed potential mechanistic links between altered microbial composition and metabolic activity with aging markers.

Conclusions
In conclusion, this study revealed an important mechanism by which DFC consumption impacts healthspan and longevity, shedding light on optimizing dietary fiber or developing fiber-based interventions to improve human health.
Single-cell analysis of mesenchymal cells in permeable neural vasculature reveals novel diverse subpopulations of fibroblasts
Authors: Bastedo William E. , Scott R. Wilder , Arostegui Martin , Underhill T. Michael 
Published: April 2024

Abstract
Background
In the choroid plexus and pituitary gland, vasculature is known to have a permeable, fenestrated phenotype which allows for the free passage of molecules in contrast to the blood brain barrier observed in the rest of the CNS. The endothelium of these compartments, along with secretory, neural-lineage cells (choroid epithelium and pituitary endocrine cells) have been studied in detail, but less attention has been given to the perivascular mesenchymal cells of these compartments.

Methods
The Hic1CreERT2 Rosa26LSL−TdTomato mouse model was used in conjunction with a PdgfraH2B−EGFP mouse model to examine mesenchymal cells, which can be subdivided into Pdgfra+ fibroblasts and Pdgfra− pericytes within the choroid plexus (CP) and pituitary gland (PG), by histological, immunofluorescence staining and single-cell RNA-sequencing analyses.

Results
We found that both CP and PG possess substantial populations of distinct Hic1+ mesenchymal cells, including an abundance of Pdgfra+ fibroblasts. Within the pituitary, we identified distinct subpopulations of Hic1+ fibroblasts in the glandular anterior pituitary and the neurosecretory posterior pituitary. We also identified multiple distinct markers of CP, PG, and the meningeal mesenchymal compartment, including alkaline phosphatase, indole-n-methyltransferase and CD34.

Conclusions
Novel, distinct subpopulations of mesenchymal cells can be found in permeable vascular interfaces, including the CP, PG, and meninges, and make distinct contributions to both organs through the production of structural proteins, enzymes, transporters, and trophic molecules.
Revisiting echocardiographic features of prosthetic heart valves: the necessity of correct differentiation of mono-leaflet vs. bileaflet mechanical heart valves in a case report
Authors: Larti Farnoosh , Geraiely Babak , Asli Samaneh Hasanpour , Moghadam Arman Soltani 
Published: April 2024

AbstractBackgroundMechanical heart valve replacement is a standard treatment for severe valvular disorders. The use of mono-leaflet valves has decreased recently. Recognizing the echocardiographic features of mono-leaflet and bileaflet valves is crucial for accurate complication diagnosis and proper management.Case PresentationA 65-year-old female with mono-leaflet mitral and bileaflet tricuspid valves underwent an echocardiographic assessment. This simple educational case provides a unique opportunity to compare the echocardiographic features of these valves within a single patient.ConclusionThere is a crucial need for clinicians, particularly those in training, to differentiate between mono-leaflet and bileaflet mechanical heart valves adeptly. With mono-leaflet valves decreasing in prevalence, proficiency in recognizing the echocardiographic nuances of each type is imperative. Failure to do so may result in misdiagnoses and inappropriate management. This underscores the significance of continuous education and vigilance in echocardiographic assessments to ensure optimal patient care.
GPR65 sensing tumor-derived lactate induces HMGB1 release from TAM via the cAMP/PKA/CREB pathway to promote glioma progression
Authors: Yan Chaolong , Yang Zijiang , Chen Pin , Yeh Yuyang , Sun Chongjing , Xie Tao , Huang Wei , Zhang Xiaobiao 
Published: April 2024

Abstract
Background
Lactate has emerged as a critical regulator within the tumor microenvironment, including glioma. However, the precise mechanisms underlying how lactate influences the communication between tumor cells and tumor-associated macrophages (TAMs), the most abundant immune cells in glioma, remain poorly understood. This study aims to elucidate the impact of tumor-derived lactate on TAMs and investigate the regulatory pathways governing TAM-mediated tumor-promotion in glioma.

Methods
Bioinformatic analysis was conducted using datasets from TCGA and CGGA. Single-cell RNA-seq datasets were analyzed by using UCSC Cell Browser and Single Cell Portal. Cell proliferation and mobility were evaluated through CCK8, colony formation, wound healing, and transwell assays. Western blot and immunofluorescence staining were applied to assess protein expression and cell distribution. RT-PCR and ELISA were employed to identify the potential secretory factors. Mechanistic pathways were explored by western blotting, ELISA, shRNA knockdown, and specific inhibitors and activators. The effects of pathway blockades were further assessed using subcutaneous and intracranial xenograft tumor models in vivo.

Results
Elevated expressions of LDHA and MCT1 were observed in glioma and exhibited a positive correlation with M2-type TAM infiltration. Lactate derived from glioma cells induced TAMs towards M2-subtype polarization, subsequently promoting glioma cells proliferation, migration, invasion, and mesenchymal transition. GPR65, highly expressed on TAMs, sensed lactate-stimulation in the TME, fueling glioma cells malignant progression through the secretion of HMGB1. GPR65 on TAMs triggered HMGB1 release in response to lactate stimulation via the cAMP/PKA/CREB signaling pathway. Disrupting this feedback loop by GPR65-knockdown or HMGB1 inhibition mitigated glioma progression in vivo.

Conclusion
These findings unveil the intricate interplay between TAMs and tumor cells mediated by lactate and HMGB1, driving tumor progression in glioma. GPR65, selectively highly expressed on TAMs in glioma, sensed lactate stimulation and fostered HMGB1 secretion via the cAMP/PKA/CREB signaling pathway. Blocking this feedback loop presents a promising therapeutic strategy for GBM.
The mechanisms of MicroRNA 21 in premature ovarian insufficiency mice with mesenchymal stem cells transplantation
Authors: Yin Na , Luo Chao , Wei Lun , Yang Guangzhao , Bo Le , Mao Caiping 
Published: April 2024

AbstractUmbilical cord-derived mesenchymal stem cell (UCMSC) transplantation has been deeply explored for premature ovarian insufficiency (POI) disease. However, the associated mechanism remains to be researched. To explore whether and how the microRNA 21 (miR-21) functions in POI mice with UCMSCs transplantation, the autoimmune-induced POI mice model was built up, transplanted with or without UCMSCs transfect with the LV-hsa-miR-21-5p/LV-hsa-miR-21-5p-inhibition, with the transfection efficiency analyzed by QRT-PCR. Mice hormone secretion and the anti-Zona pellucida antibody (AZPAb) levels were analyzed, the ovarian morphological changes and folliculogenesis were observed, and the ovarian apoptosis cells were detected to evaluate ovarian function. The expression and localization of the PTEN/Akt/FOXO3a signal pathway-related cytokines were analyzed in mice ovaries.Additionally, the spleen levels of CD8 + CD28-T cells were tested and qualified with its significant secretory factor, interleukin 10 (IL-10). We found that with the LV-hsa-miR-21-5p-inhibition-UCMSCs transplantation, the mice ovarian function can be hardly recovered than mice with LV-NC-UCMSCs transplantation, and the PTEN/Akt/FOXO3a signal pathway was activated. The expression levels of the CD8 + CD28-T cells were decreased, with the decreased levels of the IL-10 expression. In contrast, in mice with the LV-hsa-miR-21-5p-UCMSCs transplantation, the injured ovarian function can be reversed, and the PTEN/AKT/FOXO3a signal pathway was detected activated, with the increased levels of the CD8 + CD28-T cells, and the increased serum levels of IL-10. In conclusion, miR-21 improves the ovarian function recovery of POI mice with UCMSCs transplantation, and the mechanisms may be through suppressing the PTEN/AKT/FOXO3a signal pathway and up-regulating the circulating of the CD8 + CD28-T cells.
Alternative consent methods used in the multinational, pragmatic, randomised clinical trial SafeBoosC-III
Authors: Vestager Maria Linander , Hansen Mathias Lühr , Greisen Gorm ,   the SafeBoosC-III trial group, Pellicer Adelina , Chathasaigh Caitriona Ni , Lecart Chantal , Knoepfli Claudia , Hagmann Cornelia , Gallo Dario , Ergenekon Ebru , Hatzidaki Eleftheria , Dempsey Eugene , Papathoma Evangelina , Dimitrou Gabriel , Pichler Gerhard , Hahn Gitte Holst , Naulaers Gunnar , Fuchs Hans , Ozkan Hilal , de las Cuevas Isabel , Serrano-Viñuales Itziar , Sirc Jan , de Buyst Julie , Sarafidis Kosmos , Arrusa Luis , Baserga Mariana , Stocker Martin , Cetinkaya Merih , Alsina Miguel , Fumagalli Monica , Vaccarello Olalla Otero , Baud Olivier , Zafra-Rodríguez Pamela , Maton Pierre , Cheng Quoqiang , del Rio Florentino Ruth , Lauterbach Ryszard , Piris-Borregas Salvador , Nesargi Saudamini , Fredly Siv , Marciniak Sylwia , Szczapa Tomasz , Gao Xiaoyang , Xu Xin 
Published: April 2024

Abstract
Background
The process of obtaining prior informed consent for experimental treatment does not fit well into the clinical reality of acute and intensive care. The therapeutic window of interventions is often short, which may reduce the validity of the consent and the rate of enrolled participants, to delay trial completion and reduce the external validity of the results. Deferred consent and ‘opt-out’ are alternative consent methods. The SafeBoosC-III trial was a randomised clinical trial investigating the benefits and harms of cerebral oximetry monitoring in extremely preterm infants during the first 3 days after birth, starting within the first 6 h after birth. Prior, deferred and opt-out consent were all allowed by protocol.
This study aimed to evaluate the use of different consent methods in the SafeBoosC-III trial, Furthermore, we aimed to describe and analyse concerns or complaints that arose during the first 6 months of trial conduct.

Methods
All 70 principal investigators were invited to join this descriptive ancillary study. Each principal investigator received a questionnaire on the use of consent methods in their centre during the SafeBoosC-III trial, including the possibility to describe any concerns related to the consent methods used during the first 6 months of the trial, as raised by the parents or the clinical staff.

Results
Data from 61 centres were available. In 43 centres, only prior informed consent was used: in seven, only deferred consent. No centres used the opt-out method only, but five centres used prior and deferred, five used prior, deferred and opt-out (all possibilities) and one used both deferred and opt-out. Six centres applied to use the opt-out method by their local research ethics committee but were denied using it. One centre applied to use deferred consent but was denied. There were only 23 registered concerns during the execution of the trial.

Conclusions
Consent by opt-out was allowed by the protocol in this multinational trial but only a few investigators opted for it and some research ethics boards did not accept its use. It is likely to need promotion by the clinical research community to unfold its potential.
Trx4, a novel thioredoxin protein, is important for Toxoplasma gondii fitness
Authors: Zhang Zhi-Wei , Wang Meng , Sun Li-Xiu , Elsheikha Hany M. , Lei Cheng-Lin , Wang Jin-Lei , Fu Bao-Quan , Luo Jian-Xun , Zhu Xing-Quan , Li Ting-Ting 
Published: April 2024

Abstract
Background
To successfully replicate within the host cell, Toxoplasma gondii employs several mechanisms to overcome the host cell defenses and mitigate the harmful effects of the free radicals resulting from its own metabolic processes using effectors such as thioredoxin proteins. In this study, we characterize the location and functions of a newly identified thioredoxin in T. gondii, which was named Trx4.

Methods
We characterized the functional role of Trx4 in T. gondii Type I RH and Type II Pru strains by gene knockout and studied its subcellular localization by endogenous protein HA tagging using CRISPR-Cas9 gene editing. The enzyme-catalyzed proximity labeling technique, the TurboID system, was employed to identify the proteins in proximity to Trx4.

Results
Trx4 was identified as a dense granule protein of T. gondii predominantly expressed in the parasitophorous vacuole (PV) and was partially co-localized with GRA1 and GRA5. Functional analysis showed that deletion of trx4 markedly influenced the parasite lytic cycle, resulting in impaired host cell invasion capacity in both RH and Pru strains. Mutation of Trx domains in Trx4 in RH strain revealed that two Trx domains were important for the parasite invasion. By utilizing the TurboID system to biotinylate proteins in proximity to Trx4, we identified a substantial number of proteins, some of which are novel, and others are previously characterized, predominantly distributed in the dense granules. In addition, we uncovered three novel proteins co-localized with Trx4. Intriguingly, deletion of trx4 did not affect the localization of these three proteins. Finally, a virulence assay demonstrated that knockout of trx4 resulted in a significant attenuation of virulence and a significant reduction in brain cyst loads in mice.

Conclusions
Trx4 plays an important role in T. gondii invasion and virulence in Type I RH strain and Type II Pru strain. Combining the TurboID system with CRISPR-Cas9 technique revealed many PV-localized proximity proteins associated with Trx4. These findings suggest a versatile role of Trx4 in mediating the processes that occur in this distinctive intracellular membrane-bound vacuolar compartment.

Graphical Abstract
Low-level physical activity predictors among adults living with HIV in Ethiopia’s southern region, focusing on work, transportation, and recreation domains: unmatched case-control study
Authors: Bune Girma Tenkolu 
Published: April 2024

Abstract
Background
Low-level physical activity (LLPA) is crucial for the well-being of adults living with HIV (PLWHs). However, many do not engage in enough physical activity, leading to adverse health outcomes. Identifying the determinants of LLPA can aid in developing effective interventions. Despite this, Ethiopia lacks evidence on this topic. This study aimed to identify predictors of LLPA among PLWHs in the Gedeo zone, located in southern Ethiopia.

Methods
An unmatched case-control study was conducted on PLWHs in the Gedeo zone who visited two hospitals and healthcare institutions between December 29th, 2017 and January 22nd, 2019. Respondents were classified into three categories based on their total physical activity levels: high, moderate, and low. Cases were defined as those meeting the criteria for LLPA, while controls were those who did not fall under the cases category. Data was collected using the WHO Stepwise surveillance tool and analyzed using Epidata v3.1 templates and SPSS v22. Predictor variables with a P-value < 0.25 in bivariable analysis and < 0.05 with a 95% confidence interval in multivariable analysis were selected.

Results
The study involved 633 HIV-positive adults, with a response rate of 92.41%. Most participants were under 34 years old, with an average age of 36.47±(9.055) for cases and 36.38±(8.389) for controls. The multivariable analysis revealed that educational status (AOR = 4.85, P = 0.02, 95%CI (1.28–18.44)), sex (AOR = 0.24, P = 0.04, 95%CI (0.07–0.90)), duration on ART being exposed for 1–4 Years (AOR = 0.12, P < 0.001, 95%CI (0.03–0.44)) and being exposed for 5–9 Years (AOR = 0.03, P < 0.001, 95%CI (0.01–0.16)), and former alcohol use (AOR = 0.11, P < 0.01, 95%CI (0.02–0.56) were significant predictors of LLPA performance.

Conclusions
The study concluded that educational status, sex, ART duration, and past alcohol use are key determinants of LLPA performance among PLWHs in southern Ethiopia. This suggests that policymakers should implement public health campaigns to promote healthy habits, particularly low-level physical activity, among PLWHs.