bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metabolomics combined with network pharmacology reveals a role for astragaloside IV in inhibiting enterovirus 71 replication via PI3K-AKT signaling
Authors: Hao JinFang , Zhang Xiaoyan , Hu Ruixian , Lu Xiufeng , Wang Hui , Li Yuanhong , Cheng Kai , Li Qingshan 
Published: June 2024

Abstract
Background
Astragaloside IV (AST-IV), as an effective active ingredient of Astragalus membranaceus (Fisch.) Bunge. It has been found that AST-IV inhibits the replication of dengue virus, hepatitis B virus, adenovirus, and coxsackievirus B3. Enterovirus 71 (EV71) serves as the main pathogen in severe hand-foot-mouth disease (HFMD), but there are no specific drugs available. In this study, we focus on investigating whether AST-IV can inhibit EV71 replication and explore the potential underlying mechanisms.

Methods
The GES-1 or RD cells were infected with EV71, treated with AST-IV, or co-treated with both EV71 and AST-IV. The EV71 structural protein VP1 levels, the viral titers in the supernatant were measured using western blot and 50% tissue culture infective dose (TCID50), respectively. Network pharmacology was used to predict possible pathways and targets for AST-IV to inhibit EV71 replication. Additionally, ultra-high performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS) was used to investigate the potential targeted metabolites of AST-IV. Associations between metabolites and apparent indicators were performed via Spearman’s algorithm.

Results
This study illustrated that AST-IV effectively inhibited EV71 replication. Network pharmacology suggested that AST-IV inhibits EV71 replication by targeting PI3K-AKT. Metabolomics results showed that AST-IV achieved these effects by elevating the levels of hypoxanthine, 2-ketobutyric acid, adenine, nicotinic acid mononucleotide, prostaglandin H2, 6-hydroxy-1 H-indole-3- acetamide, oxypurinol, while reducing the levels of PC (14:0/15:0). Furthermore, AST-IV also mitigated EV71-induced oxidative stress by reducing the levels of MDA, ROS, while increasing the activity of T-AOC, CAT, GSH-Px. The inhibition of EV71 replication was also observed when using the ROS inhibitor N-Acetylcysteine (NAC). Additionally, AST-IV exhibited the ability to activate the PI3K-AKT signaling pathway and suppress EV71-induced apoptosis.

Conclusion
This study suggests that AST-IV may activate the cAMP and the antioxidant stress response by targeting eight key metabolites, including hypoxanthine, 2-ketobutyric acid, adenine, nicotinic acid mononucleotide, prostaglandin H2, 6-Hydroxy-1 H-indole-3-acetamide, oxypurinol and PC (14:0/15:0). This activation can further stimulate the PI3K-AKT signaling to inhibit EV71-induced apoptosis and EV71 replication.

Graphical Abstract
Integrating plasma protein-centric multi-omics to identify potential therapeutic targets for pancreatic cancer
Authors: Zhou Siyu , Tao Baian , Guo Yujie , Gu Jichun , Li Hengchao , Zou Caifeng , Tang Sichong , Jiang Shuheng , Fu Deliang , Li Ji 
Published: June 2024

Abstract
Background
Deciphering the role of plasma proteins in pancreatic cancer (PC) susceptibility can aid in identifying novel targets for diagnosis and treatment.

Methods
We examined the relationship between genetically determined levels of plasma proteins and PC through a systemic proteome-wide Mendelian randomization (MR) analysis utilizing cis-pQTLs from multiple centers. Rigorous sensitivity analyses, colocalization, reverse MR, replications with varying instrumental variable selections and additional datasets, as well as subsequent meta-analysis, were utilized to confirm the robustness of significant findings. The causative effect of corresponding protein-coding genes’ expression and their expression pattern in single-cell types were then investigated. Enrichment analysis, between-protein interaction and causation, knock-out mice models, and mediation analysis with established PC risk factors were applied to indicate the pathogenetic pathways. These candidate targets were ultimately prioritized upon druggability and potential side effects predicted by a phenome-wide MR.

Results
Twenty-one PC-related circulating proteins were identified in the exploratory phase with no evidence for horizontal pleiotropy or reverse causation. Of these, 11 were confirmed in a meta-analysis integrating external validations. The causality at a transcription level was repeated for neutrophil elastase, hydroxyacylglutathione hydrolase, lipase member N, protein disulfide-isomerase A5, xyloside xylosyltransferase 1. The carbohydrate sulfotransferase 11 and histo-blood group ABO system transferase exhibited high-support genetic colocalization evidence and were found to affect PC carcinogenesis partially through modulating body mass index and type 2 diabetes, respectively. Approved drugs have been established for eight candidate targets, which could potentially be repurposed for PC therapies. The phenome-wide investigation revealed 12 proteins associated with 51 non-PC traits, and interference on protein disulfide-isomerase A5 and cystatin-D would increase the risk of other malignancies.

Conclusions
By employing comprehensive methodologies, this study demonstrated a genetic predisposition linking 21 circulating proteins to PC risk. Our findings shed new light on the PC etiology and highlighted potential targets as priorities for future efforts in early diagnosis and therapeutic strategies of PC.
Association between serum uric acid levels and dietary fiber intake in adults: the Korea national health and nutrition examination survey (KNHANES VII, 2016–2018)
Authors: Kim Jinyoung , Jung Da Young , Lee Jin-Hee , Kim Mee Kyoung , Kwon Hyuk-Sang , Yim Hyeon Woo , Moon Su-Jin 
Published: June 2024

Abstract
Background
Hyperuricemia could be a risk for various chronic diseases, and it could be largely corrected by diet control. This study was a nationwide cross-sectional study to investigate the association between serum uric acid level and dietary fiber intake.

Methods
This study analyzed data based on the Korean National Health and Nutrition Examination Survey conducted from 2016 to 2018. Adults over 20 years of age with normal renal function, defined as an estimated glomerular filtration rate (eGFR) over 30mL/min/1.73m2, were included. The criteria for hyperuricemia were ≥ 7 mg/dL in men and ≥ 6 mg/dL in women. Data regarding dietary intake were obtained using the 24-hour recall method.

Results
A total of 15,278 subjects (6,455 males/8,823 females) were analyzed. The prevalence of hyperuricemia was 19.3% in men and 6.8% in women. There were significant, negative associations between serum uric acid and total fiber intake in both men and women. Consuming more than 27.9 g of dietary fiber in men and 20.7 g in women reduced the risk of hyperuricemia by approximately 30% with odds ratios of 0.72 (0.62–0.83) and 0.71 (0.56–0.88) in men and women, respectively. With regard to the risk reduction by the type of dietary fiber, cereal fiber was significantly identified in both men and women, while fruit fiber was only significant in men. In the subgroup analysis, this association remained significantly in young and metabolically healthy populations with normal weight.

Conclusions
Dietary fiber intake was inversely associated with serum uric acid levels. This relationship was particularly significant in metabolically healthy young adults.
Physical working conditions over time: a repeated cross-sectional study in German employees
Authors: Beller Johannes , Graßhoff Julia , Safieddine Batoul 
Published: June 2024

Abstract
Background
This study aimed to examine time trends in physical working conditions across and within occupational groups in Germany between 2006 and 2018.

Methods
Logistic regression analyses were conducted using data from the BIBB/BAuA Employment Surveys in 2006, 2012, and 2018, with a total sample size of 59,006 participants. The study investigated changes in various self-reported occupational exposure measures over time, along with demographic shifts in the workforce.

Results
The results showed overall improvements in most occupational exposure measures during the study period, alongside an aging and upskilling workforce. However, exposure to awkward postures, microorganisms, and, to a lesser extent, noise increased. Substantial variation was observed between occupational groups, with more favourable trends among white-collar high-skilled and blue-collar low-skilled workers, and less favourable trends among white-collar low-skilled and blue-collar high-skilled workers.

Conclusions
While trends in physical working conditions in Germany are partly promising, some exposures are worsening, and substantial inequalities between occupations persist. As occupational exposures remain common, there is still a need for targeted interventions to improve working conditions, particularly in higher-risk occupations.
B7-H3 and ICAM-1 are potentially therapeutic targets for thyroid carcinoma
Authors: Song Pengtao , Xu Yongcan , Ye Guochao 
Published: June 2024

AbstractAlthough most differentiated thyroid carcinoma has a clinically favorable prognosis, some of specific types of thyroid cancer (such as anaplastic thyroid carcinoma and advanced papillary thyroid carcinoma) show fatal outcomes and require novel treatments. Immunotherapy is a promising avenue for the treatment of advanced thyroid carcinoma. B7-H3 (B7 homolog 3 protein) and ICAM-1 (intercellular adhesion molecule 1), as two important immune checkpoints (ICPs), is becoming hopeful target spots for immunotherapy. A growing amount of evidence has suggested that B7-H3 and ICAM-1 are upregulated in papillary thyroid carcinoma. However, their expression level in specific types of thyroid cancer remains largely unclear. In the present study, we explored the expression level of B7-H3 and ICAM-1 in different types of thyroid carcinoma. In the groups of the TCGA cohort, both B7-H3 and ICAM-1 mRNA were highly expressed in thyroid carcinoma. Furthermore, the patients with Stage2, 61-80y, Follicular thyroid papillary carcinoma and N0 had lower B7-H3 and ICAM-1 mRNA expression. In the groups of our cohort, PTCs and ATCs showed frequently moderate to strong expression of B7-H3 and ICAM-1 protein expression. The significant relevance of B7-H3 staining score with ICAM-1 staining score was observed in TCGA database and our cohort, which might open avenues for the combination therapy in advanced thyroid cancer.
Retention strategies are routinely communicated to potential trial participants but often differ from what was planned in the trial protocol: an analysis of adult participant information leaflets and their corresponding protocols
Authors: Murphy Ellen , Gillies Katie , Shiely Frances 
Published: June 2024

Abstract
Background
Retaining participants in randomised controlled trials (RCTs) is challenging and trial teams are often required to use strategies to ensure retention or improve it. Other than monetary incentives, there is no requirement to disclose the use of retention strategies to the participant. Additionally, not all retention strategies are developed at the planning stage, i.e. post-funding during protocol development, but some protocols include strategies for participant retention as retention is considered and planned for early in the trial planning stage. It is yet unknown if these plans are communicated in the corresponding participant information leaflets (PILs). The purpose of our study was to determine if PILs communicate plans to promote participant retention and, if so, are these outlined in the corresponding trial protocol.

Methods
Ninety-two adult PILs and their 90 corresponding protocols from Clinical Trial Units (CTUs) in the UK were analysed. Directed (deductive) content analysis was used to analyse the participant retention text from the PILs. Data were presented using a narrative summary and frequencies where appropriate.

Results
Plans to promote participant retention were communicated in 81.5% (n = 75/92) of PILs. Fifty-seven percent (n = 43/75) of PILs communicated plans to use “combined strategies” to promote participant retention. The most common individual retention strategy was telling the participants that data collection for the trial would be scheduled during routine care visits (16%; n = 12/75 PILs). The importance of retention and the impact that missing or deleted data (deleting data collected prior to withdrawal) has on the ability to answer the research question were explained in 6.5% (n = 6/92) and 5.4% (n = 5/92) of PILs respectively. Out of the 59 PILs and 58 matching protocols that both communicated plans to use strategies to promote participant retention, 18.6% (n = 11/59) communicated the same information, the remaining 81.4% (n = 48/59) of PILs either only partially communicated (45.8%; n = 27/59) the same information or did not communicate the same information (35.6%; n = 21/59) as the protocol with regard to the retention strategy(ies).

Conclusion
Retention strategies are frequently communicated to potential trial participants in PILs; however, the information provided often differs from the content in the corresponding protocol. Participant retention considerations are best done at the planning stage of the trial and we encourage trial teams to be consistent in the communication of these strategies in both the protocol and PIL.
Differential transcriptome study on the damage of testicular tissues caused by chronic infection of T. gondii in mice
Authors: Li Haoxin , Yuan Hao , Yang Zi-Peng , Song Yining , Wang Jun-Jie , Wen Qingyuan , Zheng Yu-Xiang , Zhang Xiu-Xiang , Yu Miao , Yuan Zi-Guo 
Published: June 2024

Abstract
Background
Toxoplasma gondii is an intracellular protozoan parasite that is widely distributed in humans and warm-blooded animals. T. gondii chronic infections can cause toxoplasmic encephalopathy, adverse pregnancy, and male reproductive disorders. In male reproduction, the main function of the testis is to provide a stable place for spermatogenesis and immunological protection. The disorders affecting testis tissue encompass abnormalities in the germ cell cycle, spermatogenic retardation, or complete cessation of sperm development. However, the mechanisms of interaction between T. gondii and the reproductive system is unclear. The aims were to study the expression levels of genes related to spermatogenesis, following T. gondii infection, in mouse testicular tissue.

Methods
RNA-seq sequencing was carried out on mouse testicular tissues from mice infected or uninfected with the T. gondii type II Prugniaud (PRU) strain and validated in combination with real-time quantitative PCR and immunofluorescence assays.

Results
The results showed that there were 250 significant differentially expressed genes (DEGs) (P < 0.05, |log2fold change| ≧ 1). Bioinformatics analysis showed that 101 DEGs were annotated to the 1696 gene ontology (GO) term. While there was a higher number of DEGs in the biological process classification as a whole, the GO enrichment revealed a significant presence of DEGs in the cellular component classification. The Arhgap18 and Syne1 genes undergo regulatory changes following T. gondii infection, and both were involved in shaping the cytoskeleton of the blood–testis barrier (BTB). The number of DEGs enriched in the MAPK signaling pathway, the ERK1/2 signaling pathway, and the JNK signaling pathway were significant. The PTGDS gene is located in the Arachidonic acid metabolism pathway, which plays an important role in the formation and maintenance of BTB in the testis. The expression of PTGDS is downregulated subsequent to T. gondii infection, potentially exerting deleterious effects on the integrity of the BTB and the spermatogenic microenvironment within the testes.

Conclusions
Overall, our research provides in-depth insights into how chronic T. gondii infection might affect testicular tissue and potentially impact male fertility. These findings offer a new perspective on the impact of T. gondii infection on the male reproductive system.

Graphical Abstract
Taking it with a grain of salt: tolerance to increasing salinization in Culex pipiens (Diptera: Culicidae) across a low-lying delta
Authors: Boerlijst Sam Philip , van der Gaast Antje , Adema Lisa Maria Wilhelmina , Bouman Roderick Wiebe , Boelee Eline , van Bodegom Peter Michiel , Schrama Maarten 
Published: June 2024

Abstract
Background
Salinity, exacerbated by rising sea levels, is a critical environmental cue affecting freshwater ecosystems. Predicting ecosystem structure in response to such changes and their implications for the geographical distribution of arthropod disease vectors requires further insights into the plasticity and adaptability of lower trophic level species in freshwater systems. Our study investigated whether populations of the mosquito Culex pipiens, typically considered sensitive to salt, have adapted due to gradual exposure.

Methods
Mesocosm experiments were conducted to evaluate responses in life history traits to increasing levels of salinity in three populations along a gradient perpendicular to the North Sea coast. Salt concentrations up to the brackish–marine transition zone (8 g/l chloride) were used, upon which no survival was expected. To determine how this process affects oviposition, a colonization experiment was performed by exposing the coastal population to the same concentrations.

Results
While concentrations up to the currently described median lethal dose (LD50) (4 g/l) were surprisingly favored during egg laying, even the treatment with the highest salt concentration was incidentally colonized. Differences in development rates among populations were observed, but the influence of salinity was evident only at 4 g/l and higher, resulting in only a 1-day delay. Mortality rates were lower than expected, reaching only 20% for coastal and inland populations and 41% for the intermediate population at the highest salinity. Sex ratios remained unaffected across the tested range.

Conclusions
The high tolerance to salinity for all key life history parameters across populations suggests that Cx. pipiens is unlikely to shift its distribution in the foreseeable future, with potential implications for the disease risk of associated pathogens.

Graphical Abstract
CDK7/CDK9 mediates transcriptional activation to prime paraptosis in cancer cells
Authors: Chiang Shih-Kai , Chang Wei-Chao , Chen Shuen-Ei , Chang Ling-Chu 
Published: June 2024

Abstract
Background
Paraptosis is a programmed cell death characterized by cytoplasmic vacuolation, which has been explored as an alternative method for cancer treatment and is associated with cancer resistance. However, the mechanisms underlying the progression of paraptosis in cancer cells remain largely unknown.

Methods
Paraptosis-inducing agents, CPYPP, cyclosporin A, and curcumin, were utilized to investigate the underlying mechanism of paraptosis. Next-generation sequencing and liquid chromatography-mass spectrometry analysis revealed significant changes in gene and protein expressions. Pharmacological and genetic approaches were employed to elucidate the transcriptional events related to paraptosis. Xenograft mouse models were employed to evaluate the potential of paraptosis as an anti-cancer strategy.

Results
CPYPP, cyclosporin A, and curcumin induced cytoplasmic vacuolization and triggered paraptosis in cancer cells. The paraptotic program involved reactive oxygen species (ROS) provocation and the activation of proteostatic dynamics, leading to transcriptional activation associated with redox homeostasis and proteostasis. Both pharmacological and genetic approaches suggested that cyclin-dependent kinase (CDK) 7/9 drive paraptotic progression in a mutually-dependent manner with heat shock proteins (HSPs). Proteostatic stress, such as accumulated cysteine-thiols, HSPs, ubiquitin-proteasome system, endoplasmic reticulum stress, and unfolded protein response, as well as ROS provocation primarily within the nucleus, enforced CDK7/CDK9–Rpb1 (RNAPII subunit B1) activation by potentiating its interaction with HSPs and protein kinase R in a forward loop, amplifying transcriptional regulation and thereby exacerbating proteotoxicity leading to initiate paraptosis. The xenograft mouse models of MDA-MB-231 breast cancer and docetaxel-resistant OECM-1 head and neck cancer cells further confirmed the induction of paraptosis against tumor growth.

Conclusions
We propose a novel regulatory paradigm in which the activation of CDK7/CDK9–Rpb1 by nuclear proteostatic stress mediates transcriptional regulation to prime cancer cell paraptosis.

Graphical Abstract
New advances in the diagnosis and treatment of autism spectrum disorders
Authors: Qin Lei , Wang Haijiao , Ning Wenjing , Cui Mengmeng , Wang Qian 
Published: June 2024

AbstractAutism spectrum disorders (ASD) are a group of neurodevelopmental disorders that affect individuals' social interactions, communication skills, and behavioral patterns, with significant individual differences and complex etiology. This article reviews the definition and characteristics of ASD, epidemiological profile, early research and diagnostic history, etiological studies, advances in diagnostic methods, therapeutic approaches and intervention strategies, social and educational integration, and future research directions. The highly heritable nature of ASD, the role of environmental factors, genetic–environmental interactions, and the need for individualized, integrated, and technology-driven treatment strategies are emphasized. Also discussed is the interaction of social policy with ASD research and the outlook for future research and treatment, including the promise of precision medicine and emerging biotechnology applications. The paper points out that despite the remarkable progress that has been made, there are still many challenges to the comprehensive understanding and effective treatment of ASD, and interdisciplinary and cross-cultural research and global collaboration are needed to further deepen the understanding of ASD and improve the quality of life of patients.
Development and validation of an LC–MS/MS method for the determination of BLU-945, a fourth-generation EGFR tyrosine kinase inhibitor, in rat and mouse plasma: application to a pharmacokinetic study in rats
Authors: Oh Ji-Hoon , Nguyen Thi-Thao-Linh , Maeng Han-Joo 
Published: June 2024

AbstractBLU-945, a new-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is a potential drug candidate for the treatment of non-small-cell lung cancer (NSCLC) in patients with mutations that are resistant to previous generations of EGFR TKI. This compound has been investigated in preclinical and phase 1 dose-escalation studies that require a bioanalytical method for drug quantitation. In this study, an LC–MS/MS method was developed and validated for the quantitation of BLU-945 in rodent plasma and was applied to pharmacokinetic studies. The compound was extracted from plasma samples using a simple protein precipitation method. The method was validated in the linearity range of 1–1000 ng/mL with acceptable accuracy and precision, no matrix effects, and complete extraction recovery. BLU-945 was stable in the plasma quality control samples under various handling and storage conditions. The compound was stable after 4-h incubation in human, mouse, and rat plasma but was extensively metabolized in the microsomal fractions of these species. Furthermore, the validated analytical method was applied to a pharmacokinetic study in rats, revealing that BLU-945 had a high oral bioavailability range (55.91–105.6%) with a nonlinear pharmacokinetic profile up to an oral dose of 20 mg/kg. The validated bioanalytical method and findings of our study represent valuable assets for future investigations and clinical studies of BLU-945.