bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety, tolerability, pharmacokinetics and effects of diet on AD16, a novel neuroinflammatory inhibitor for Alzheimer’s disease: a randomized phase 1 study
Authors: Peng Daizhuang , Xu Sumei , Zou Ting , Wang Yahui , Ouyang Wenjuan , Zhang Yalan , Dong Chengmei , Li Dai , Guo Jie , Shen Qiuying , Hu Xiaolei , Zhou Wenzhi , Li Xiaomin , Qin Qun 
Published: November 2023

Abstract
Background
AD16 is a Class 1.1 new drug candidate for Alzheimer’s disease (AD), which has demonstrated potential benefits in AD by reducing neuroinflammation in preclinical studies. Herein, the pharmacokinetics (PK), safety, and tolerability of single and multiple-dose AD16 and the effect of food were assessed in healthy Chinese adults.

Methods
Single-center, randomized, placebo-controlled, double-blind studies were conducted for single and multiple ascending doses. A total of 62 subjects were enrolled in single-dose groups; 10 each in 5, 10, 20, 30, and 40 mg groups, and 6 each in 60 and 80 mg dose groups. Twenty subjects were divided equally into 30 and 40 mg groups for the multiple-dose study. To determine the effect of a high-fat diet on AD16, 16 subjects were administered a single 20 mg dose of AD16 under the fasted and fed condition in a single-center, randomized, open-label, two-cycle, two-crossover study. Moreover, safety and PK parameters were also assessed.

Results
Plasma exposure to a single oral dose of AD16 increased at an approximate dose-increasing rate. The pharmacodynamic dose of the AD16 can be maintained through the accumulation effect of the drug within the safety window. Compared to fasting, ingesting a high-fat meal decelerated the rate of AD16 absorption, albeit without effect on its overall absorption. No dose-related toxicities were seen in any of the studies, all treatment-emergent adverse events were grade I/II, and no serious adverse event occurred.

Conclusions
The present study exhibited favorable safety, tolerability, and PK profile of AD16, supporting its further research as a potential drug treatment for AD.

Trial registration
ClinicalTrials.gov; NCT05787028, NCT05787041, NCT05806177. The SAD and FE studies were retrospectively registered on 28 March 2023. The MAD study was retrospectively registered on 10 April 2023.
Metabolic dynamics and prediction of sFGR and adverse fetal outcomes: a prospective longitudinal cohort study
Authors: Huang Nana , Chen Wei , Jiang Hai , Yang Jing , Zhang Youzhen , Shi Huifeng , Wang Ying , Yuan Pengbo , Qiao Jie , Wei Yuan , Zhao Yangyu 
Published: November 2023

Abstract
Background
Selective fetal growth restriction (sFGR) is an extreme complication that significantly increases the risk of perinatal mortality and long-term adverse neurological outcomes in offspring, affecting approximately 15% of monochorionic diamniotic (MCDA) twin pregnancies. The lack of longitudinal cohort studies hinders the early prediction and intervention of sFGR.

Methods
We constructed a prospective longitudinal cohort study of sFGR, and quantified 25 key metabolites in 337 samples from maternal plasma in the first, second, and third trimester and from cord plasma. In particular, our study examined fetal growth and brain injury data from ultrasonography and used the Ages and Stages Questionnaire-third edition subscale (ASQ-3) to evaluate the long-term neurocognitive behavioral development of infants aged 2–3 years. Furthermore, we correlated metabolite levels with ultrasound data, including physical development and brain injury indicators, and ASQ-3 data using Spearman’s-based correlation tests. In addition, special combinations of differential metabolites were used to construct predictive models for the occurrence of sFGR and fetal brain injury.

Results
Our findings revealed various dynamic patterns for these metabolites during pregnancy and a maximum of differential metabolites between sFGR and MCDA in the second trimester (n = 8). The combination of l-phenylalanine, l-leucine, and l-isoleucine in the second trimester, which were closely related to fetal growth indicators, was highly predictive of sFGR occurrence (area under the curve [AUC]: 0.878). The combination of l-serine, l-histidine, and l-arginine in the first trimester and creatinine in the second trimester was correlated with long-term neurocognitive behavioral development and showed the capacity to identify fetal brain injury with high accuracy (AUC: 0.94).

Conclusions
The performance of maternal plasma metabolites from the first and second trimester is superior to those from the third trimester and cord plasma in discerning sFGR and fetal brain injury. These metabolites may serve as useful biomarkers for early prediction and promising targets for early intervention in clinical settings.
Male- and female-specific reproductive risk factors across the lifespan for dementia or cognitive decline: a systematic review and meta-analysis
Authors: Han Shuang-Ling , Liu De-Chun , Tan Chen-Chen , Tan Lan , Xu Wei 
Published: November 2023

Abstract
Background
Sex difference exists in the prevalence of dementia and cognitive decline. The impacts of sex-specific reproductive risk factors across the lifespan on the risk of dementia or cognitive decline are still unclear. Herein, we conducted this systemic review and meta-analysis to finely depict the longitudinal associations between sex-specific reproductive factors and dementia or cognitive decline.

Methods
PubMed, EMBASE, and Cochrane Library were searched up to January 2023. Studies focused on the associations of female- and male-specific reproductive factors with dementia or cognitive decline were included. Multivariable-adjusted effects were pooled via the random effect models. Evidence credibility was scored by the GRADE system. The study protocol was pre-registered in PROSPERO and the registration number is CRD42021278732.

Results
A total of 94 studies were identified for evidence synthesis, comprising 9,839,964 females and 3,436,520 males. Among the identified studies, 63 of them were included in the meta-analysis. According to the results, seven female-specific reproductive factors including late menarche (risk increase by 15%), nulliparous (11%), grand parity (32%), bilateral oophorectomy (8%), short reproductive period (14%), early menopause (22%), increased estradiol level (46%), and two male-specific reproductive factors, androgen deprivation therapy (18%), and serum sex hormone–binding globulin (22%) were associated with an elevated risk of dementia or cognitive decline.

Conclusions
These findings potentially reflect sex hormone-driven discrepancy in the occurrence of dementia and could help build sex-based precise strategies for preventing dementia.
S100A alarmins and thymic stromal lymphopoietin (TSLP) regulation in severe asthma following bronchial thermoplasty
Authors: Gagnon Pierre-Alexandre , Klein Martin , De Vos John , Biardel Sabrina , Côté Andréanne , Godbout Krystelle , Laviolette Michel , Laprise Catherine , Assou Said , Chakir Jamila 
Published: November 2023

Abstract
Rationale
Severe asthma affects a small proportion of asthmatics but represents a significant healthcare challenge. Bronchial thermoplasty (BT) is an interventional treatment approach preconized for uncontrolled severe asthma after considering biologics therapy. It was showed that BT long-lastingly improves asthma control. These improvements seem to be related to the ability of BT to reduce airway smooth muscle remodeling, reduce the number of nerve fibers and to modulate bronchial epithelium integrity and behavior. Current evidence suggest that BT downregulates epithelial mucins expression, cytokine production and metabolic profile. Despite these observations, biological mechanisms explaining asthma control improvement post-BT are still not well understood.

Objectives
To assess whether BT affects gene signatures in bronchial epithelial cells (BECs).

Methods
In this study we evaluated the transcriptome of cultured bronchial epithelial cells (BECs) of severe asthmatics obtained pre- and post-BT treatment using microarrays. We further validated gene and protein expressions in BECs and in bronchial biopsies with immunohistochemistry pre- and post-BT treatment.

Measurements and main results
Transcriptomics analysis revealed that a large portion of differentially expressed genes (DEG) was involved in anti-viral response, anti-microbial response and pathogen induced cytokine storm signaling pathway. S100A gene family stood out as five members of this family where consistently downregulated post-BT. Further validation revealed that S100A7, S100A8, S100A9 and their receptor (RAGE, TLR4, CD36) expressions were highly enriched in severe asthmatic BECs. Further, these S100A family members were downregulated at the gene and protein levels in BECs and in bronchial biopsies of severe asthmatics post-BT. TLR4 and CD36 protein expression were also reduced in BECs post-BT. Thymic stromal lymphopoietin (TSLP) and human β-defensin 2 (hBD2) were significantly decreased while no significant change was observed in IL-25 and IL-33.

Conclusions
These data suggest that BT might improve asthma control by downregulating epithelial derived S100A family expression and related downstream signaling pathways.
Relationship between the colours of the rivers in the Amazon and the incidence of malaria
Authors: Fonseca Fernanda , Martinez Jean-Michel , Balieiro Antônio , Orellana Jesem , Santos James D. , Filizola Naziano 
Published: November 2023

Abstract
Background
Malaria is transmitted by different Anopheles species. In Brazil, the disease is concentrated in the Amazon region. Rivers play an important role in the life cycle of malaria since the vector reproduces in aquatic environments. The waters of the rivers in the Amazon have distinct chemical characteristics, which affect the colour of the water and therefore, the study analysed whether the colour of the waters of the rivers have an on influence the distribution of malaria. The goal of the study was to correlate the different colourations of the water (black, white and mixed water) and the malaria incidence in 50 municipalities of the Amazonas state, Brazil, and then test hypotheses about the characteristics of the colour of the rivers and disease incidence.

Methods
This study was conducted for a period of seventeen years (2003–2019) in 50 municipalities in the state of Amazonas, Brazil. A conditionally Gaussian dynamic linear model was developed to analyse the association of malaria incidence and three types of river colour: white, black and mixed.

Results
The analyses indicate that the distribution of malaria is related to the colouration of the rivers. The results showed that places located near black-water rivers have a higher malaria incidence when compared to places on the banks of white-water rivers.

Conclusions
Historically, the hydrological regime has played an important role in the dynamics of malaria in the Amazon, but little is known about the relationship between river colours and the incidence of the disease. This research was carried out in a region with hydrographic characteristics that were heterogeneous enough to allow an analysis that contrasted different colours of the rivers and covered almost the whole of the state of Amazonas. The results help to identify the places with the highest risk of malaria transmission and it is believed that they will be able to contribute to more precise planning of actions aimed at controlling the disease in the region.
The impact of urban–rural medical insurance integration on medical impoverishment: evidence from China
Authors: Huo Jinkang , Hu Mingzheng , Li Shaojie 
Published: November 2023

AbstractBackgroundFinancial protection is a key dimension of Universal Health Coverage (UHC), and social medical insurance is an effective measure to provide financial protection. The aim of this study is to examine the impact of urban–rural medical insurance integration on medical impoverishment in China.MethodsWe collected the time of integration policy in 337 prefecture-level cities across China, combined with the longitudinal database of China Labor-force Dynamics Survey (CLDS) from 2012–2016, and used a difference-in-differences (DID) method with multiple time periods at the city level to study the effect of urban–rural medical insurance integration on the medical impoverishment. Besides, to explore the heterogeneity of policy effects across populations, we conducted subgroup analyses based on respondents' age, household registration, and whether they were rural–urban migrants.FindingsA total of 8,397 samples were included in the study. The integration policy has significantly reduced the incidence of medical impoverishment (average treatment effect on the treated (ATT) =  − 0.055,p < 0.05). Subgroup analysis showed that the impacts on medical impoverishment varied by age group, and the integration policy has more effect on older people than on younger people (ATT for age 15–34 =  − 0.018,p > 0.05; ATT for age 35–54 =  − 0.042,p < 0.05; ATT for age 55–64 =  − 0.163,p < 0.01). Moreover, the impacts also varied by household registration. The integration policy has a more significant impact on rural residents (ATT for rural =  − 0.067,p < 0.05) compared to urban residents (ATT for urban =  − 0.007,p > 0.05). Additionally, the policy has a bigger influence on rural–urban migrants (ATT for rural–urban migrated =  − 0.086,p < 0.05) than on those who have not migrated (ATT for rural–urban unmigrated =  − 0.071,p < 0.05).ConclusionChina's policy of integrating urban–rural medical insurance has been successful in reducing medical impoverishment, especially for older age, rural, and rural–urban migrated people. It can be speculated that the integrating policy may be adapted to other similar settings in developing countries to reduce medical impoverishment.
A review of nitric oxide and oxidative stress in typical ovulatory women and in the pathogenesis of ovulatory dysfunction in PCOS
Authors: Awonuga Awoniyi O. , Camp Olivia G , Abu-Soud Husam M 
Published: November 2023

AbstractPolycystic ovary syndrome (PCOS) is a heterogeneous functional endocrine disorder associated with a low-grade, chronic inflammatory state. Patients with PCOS present an increased risk of metabolic comorbidities and often menstrual dysregulation and infertility due to anovulation and/or poor oocyte quality. Multiple mechanisms including oxidative stress and low-grade inflammation are believed to be responsible for oocyte deterioration; however, the influence of nitric oxide (NO) insufficiency in oocyte quality and ovulatory dysfunction in PCOS is still a matter for debate. Higher production of superoxide (O2•−) mediated DNA damage and impaired antioxidant defense have been implicated as contributory factors for the development of PCOS, with reported alteration in superoxide dismutase (SOD) function, an imbalanced zinc/copper ratio, and increased catalase activity. These events may result in decreased hydrogen peroxide (H2O2) accumulation with increased lipid peroxidation events. A decrease in NO, potentially due to increased activity of NO synthase (NOS) inhibitors such as asymmetric dimethylarginine (ADMA), and imbalance in the distribution of reactive oxygen species (ROS), such as decreased H2O2 and increased O2•−, may offset the physiological processes surrounding follicular development, oocyte maturation, and ovulation contributing to the reproductive dysfunction in patients with PCOS. Thus, this proposal aims to evaluate the specific roles of NO, oxidative stress, ROS, and enzymatic and nonenzymatic elements in the pathogenesis of PCOS ovarian dysfunction, including oligo- anovulation and oocyte quality, with the intent to inspire better application of therapeutic options. The authors believe more consideration into the specific roles of oxidative stress, ROS, and enzymatic and nonenzymatic elements may allow for a more thorough understanding of PCOS. Future efforts elaborating on the role of NO in the preoptic nucleus to determine its influence on GnRH firing and follicle-stimulating hormone/Luteinizing hormone (FSH/LH) production with ovulation would be of benefit in PCOS. Consequently, treatment with an ADMA inhibitor or NO donor may prove beneficial to PCOS patients experiencing reproductive dysfunction and infertility.
New insights into the regulation of METTL3 and its role in tumors
Authors: Jin Qiu , Qu Huinan , Quan Chengshi 
Published: November 2023

AbstractAs one of the most abundant epigenetic modifications in RNA, N6-methyladenosine (m6A) affects RNA transcription, splicing, stability, and posttranscriptional translation. Methyltransferase-like 3 (METTL3), a key component of the m6A methyltransferase complex, dynamically regulates target genes expression through m6A modification. METTL3 has been found to play a critical role in tumorigenesis, tumor growth, metastasis, metabolic reprogramming, immune cell infiltration, and tumor drug resistance. As a result, the development of targeted drugs against METTL3 is becoming increasingly popular. This review systematically summarizes the factors that regulate METTL3 expression and explores the specific mechanisms by which METTL3 affects multiple tumor biological behaviors. We aim to provide fundamental support for tumor diagnosis and treatment, at the same time, to offer new ideas for the development of tumor-targeting drugs.
Association of diet and lifestyle factors with semen quality in male partners of Chinese couples preparing for pregnancy
Authors: Mai Hanran , Ke Junyi , Zheng Zilin , Luo Jieyi , Li Miaomiao , Qu Yanxia , Jiang Fan , Cai Simian , Zuo Liandong 
Published: November 2023

Abstract
Background
Semen quality significantly influences conception, and its preservation is crucial for couples seeking pregnancy. We investigated dietary and lifestyle risk factors impacting semen quality.

Methods
A total of 466 males from the Guangzhou Women and Children’s Medical Center’s pre-pregnancy consultation clinic were recruited between January 2021 and March 2023 for inclusion. Semen analysis was performed, and diet and lifestyle data were gathered via questionnaire. Logistic regression was utilized to examine the link between diet, lifestyle variables, and semen quality.

Results
Smoking worsened progressive sperm motility (38.0% vs. 36.0%, t = 2.262; P = 0.049). Alcohol consumption impaired progressive motility (40.5 ± 17.8% vs. 34.7 ± 16.1%, t = 3.396; P < 0.001) and total motility (56.0% vs. 64.0%; P = 0.001). Using plastic beverage bottles for oil or seasonings lowered sperm concentrations (40.4% vs. 59.0% vs. 65.5%; P = 0.032). A sweet diet correlated with higher total sperm motility (55.0% vs. 60.0%, 62.0% vs. 63.2%; P = 0.017). Higher milk product intake improved sperm concentration (41.6106vs. 63.7106 vs. 66.1*106; P = 0.021) and motility (54.5% vs. 56.0% vs. 63.0%; P = 0.033). More frequent egg consumption increased semen volume (3.1 mL vs. 3.8 mL vs. 4.0 mL; P = 0.038). Roughage intake enhanced sperm concentration (160.8106 vs. 224.6106; P = 0.027), and adequate sleep improved progressive sperm motility rate (35.4% ± 18.2% vs. 40.2 ± 16.3%, F = 3.747; P = 0.024) and total motility (52.7% vs. 61.5%; P = 0.013). The regression model showed that using plastic containers for condiments was a protective factor for semen volume (OR: 0.12; CI 0.03–0.55; P = 0.006), sperm concentration (OR: 0.001, CI 0.00–0.30; P = 0.012), and count (OR: 0.12, CI 0.03–0.48; P = 0.003). Milk and egg consumption were also protective for semen volume (OR: 0.18, CI 0.06–0.51; P = 0.001 and OR: 0.11, CI 0.03–0.55; P = 0.006, respectively), while sufficient sleep benefitted total sperm motility (OR: 0.47, CI 0.24–0.95; P = 0.034).

Conclusions
Smoking and drinking, type of condiment container, diet preference, sleep duration, and milk, roughage, and egg consumption may reduce semen quality.
Evaluation of ARK5 and SIRT3 expression in renal cell carcinoma and their clinical significance
Authors: Elkady Noha , Aldesoky Amira I. , Dawoud Marwa Mohammed 
Published: November 2023

Abstract
Background
Globally Renal Cell Carcinoma (RCC) represents 3% of malignant tumours in adults and 1.78% in Egypt. AMPK-related protein kinase 5 (ARK5) is mainly associated with a hypoxic microenvironment which is a feature of the major RCC subtypes. Additionally, it displays decreased mitochondrial respiration. SIRT3 is a mitochondrial deacetylase that modifies multiple mitochondrial proteins.

Material and methods
Fifty eight cases of RCC, and 30 non-neoplastic cases (of End-Stage Kidney Disease (ESKD) were subjected to immunohistochemistry by ARK5 and SIRT3. The results of IHC were correlated together and correlated with the available clinicopathologic and survival data.

Results
Although no significant difference was detected between RCC and ESKD groups regarding ARK5 expression, there was a significant association with RCC regarding H-score and nucleocytoplasmic expression (both P = 0.001). Also, SIRT3 was highly expressed in RCC in comparison to the ESKD group (H-score: P = 0.001). There were significant associations between nucleocytoplasmic ARK5 expression and higher tumour grade, low apoptotic and high mitotic indices, tumour extent, advanced tumour stage, and impaired response of tumours to chemotherapeutic drugs (P = 0.039, P = 0.001, P = 0.027, P = 0.011, P = 0.009, and P = 0.014 respectively). Moreover, the H score of ARK5 expression showed significant associations with tumour grade, apoptotic and mitotic indices, tumour extension, tumour stage, and response to therapy (P = 0.01, 0.035, 0.001, 0.004. 0.003 and 0.013). Regarding SIRT3 expression, it showed significant associations with apoptotic and mitotic indices, tumour extent, tumour stage and response to therapy (P = 0.022, 0.02, 0.042, 0.039 and 0.027). Interestingly, there was a highly significant correlation between the expression of ARK5 and SIRT3 (P = 0.009). Univariate survival analysis revealed a significant association between short survival duration and both nucleocytoplasmic expression of ARK5 and positive SIRT3 expression (P = 0.014 and 0.035).

Conclusion
ARK5 and SIRT3 are overexpressed in RCC and associated with parameters of poor prognosis as well as short survival. Both seem to influence response to therapy in RCC. So, they could be new targets for therapy that may improve tumour response and patients’ survival. There is a postulated relationship that needs more extensive investigation.