bluuebunny/crossref_metadata_2025 huggingface dataset:
Prenatal diagnosis of a severe form of frontonasal dysplasia with severe limb anomalies, hydrocephaly, a hypoplastic corpus callosum, and a ventricular septal defect using 3D ultrasound: a case report and literature review
Authors: Guo Cuixia , Zhang Tiejuan , Ma Ying , Yue Song , Sun Lijuan
Published: June 2024

Background

Frontonasal dysplasia (FND) is a rare congenital anomaly resulting from the underdevelopment of the frontonasal process, and it can be syndromic or nonsyndromic. The typical features of FND include a deformed nose and ocular hypertelorism, which are sometimes associated with cleft lip and/or palate. Only approximately 10 cases of prenatally diagnosed nonsyndromic FND have been reported in the past 30 years.

Case presentation

A 33-year-old woman (G2P1) was referred to our center at 20 gestational weeks for bilateral hydrocephaly. We detected typical features of FND, including severe hypertelorism, median nasal bifidity, a minor cleft lip, and multiple limb anomalies using three-dimensional (3D) ultrasound. A hypoplastic corpus callosum, unilateral microtia, and a ventricular septal defect were also detected. Genetic testing, including karyotype analysis, copy number variation (CNV) analysis, trio-whole exome sequencing (trio-WES), and trio-whole-gene sequencing (trio-WGS), was performed; however, we did not find any de novo gene variants in the fetus as compared to the parents. Postmortem examination confirmed the prenatal diagnosis of FND.

Conclusion

The present case expands the wide phenotypic spectrum of prenatal FND patients. 3D ultrasound is a useful tool for detecting facial and limb deformities.
Pathomics and single-cell analysis of papillary thyroid carcinoma reveal the pro-metastatic influence of cancer-associated fibroblasts
Authors: Wang Yixian , Li Xin , Gang Qingwei , Huang Yinde , Liu Mingyu , Zhang Han , Shen Shikai , Qi Yao , Zhang Jian
Published: June 2024

Background

Papillary thyroid carcinoma (PTC) is globally prevalent and associated with an increased risk of lymph node metastasis (LNM). The role of cancer-associated fibroblasts (CAFs) in PTC remains unclear.

Methods

We collected postoperative pathological hematoxylin–eosin (HE) slides from 984 included patients with PTC to analyze the density of CAF infiltration at the invasive front of the tumor using QuPath software. The relationship between CAF density and LNM was assessed. Single-cell RNA sequencing (scRNA-seq) data from GSE193581 and GSE184362 datasets were integrated to analyze CAF infiltration in PTC. A comprehensive suite of in vitro experiments, encompassing EdU labeling, wound scratch assays, Transwell assays, and flow cytometry, were conducted to elucidate the regulatory role of CD36+CAF in two PTC cell lines, TPC1 and K1.

Results

A significant correlation was observed between high fibrosis density at the invasive front of the tumor and LNM. Analysis of scRNA-seq data revealed metastasis-associated myoCAFs with robust intercellular interactions. A diagnostic model based on metastasis-associated myoCAF genes was established and refined through deep learning methods. CD36 positive expression in CAFs can significantly promote the proliferation, migration, and invasion abilities of PTC cells, while inhibiting the apoptosis of PTC cells.

Conclusion

This study addresses the significant issue of LNM risk in PTC. Analysis of postoperative HE pathological slides from a substantial patient cohort reveals a notable association between high fibrosis density at the invasive front of the tumor and LNM. Integration of scRNA-seq data comprehensively analyzes CAF infiltration in PTC, identifying metastasis-associated myoCAFs with strong intercellular interactions. In vitro experimental results indicate that CD36 positive expression in CAFs plays a promoting role in the progression of PTC. Overall, these findings provide crucial insights into the function of CAF subset in PTC metastasis.
Prevalence and associated factors of depression in postmenopausal women: a systematic review and meta-analysis
Authors: Li Jiaxin , Liu Fangli , Liu Ziwei , Li Mengjie , Wang Yingying , Shang Yameng , Li Yuege
Published: June 2024

Background

Depression is a prevalent mental health problem in postmenopausal women. Given its significant impact on the quality of life and overall well-being of postmenopausal women, there is need for a comprehensive review and meta-analysis of the existing research globally. This systematic review and meta-analysis evaluated the global prevalence of depression and potential associated factors in postmenopausal women.

Methods

The Cochrane Library, PubMed, EMBASE, Web of Science, MEDLINE, and PsycINFO databases were systematically searched from inception to March 22, 2023. The meta-analysis used the random-effects model to calculate the prevalence of depression rates and associated factors. In addition, subgroup analysis and sensitivity analysis were performed. Publication bias was assessed using funnel plots, Egger’s test, and nonparametric trim-and-fill tests.

Results

The meta-analysis included 50 studies that involved 385,092 postmenopausal women. The prevalence of depression in postmenopausal women was 28.00% (95% CI, 25.80–30.10). Among the factors relevant to depression among postmenopausal women, marital status (OR: 2.03, 95%CI: 1.33–3.11), history of mental illness (OR: 2.31, 95%CI: 1.50–3.57), chronic disease (OR: 3.13, 95%CI: 2.20–4.44), menstrual cycle (OR: 1.42, 95%CI: 1.17–1.72), abortion numbers (OR: 1.59, 95%CI: 1.40–1.80), menopausal symptoms (OR: 2.10, 95%CI: 1.52–2.90), and hormone replacement therapy (OR: 1.76, 95%CI: 1.31–2.35) were risk factors, while physical activity (OR: 0.56, 95%CI: 0.53–0.59), number of breastfed infants (OR: 0.43, 95%CI: 0.19–0.97), menopause age (OR: 0.44, 95%CI: 0.37–0.51) were preventive factors.

Conclusions

This study demonstrated that the prevalence of postmenopausal depression is high, and some risk factors and protective factors associated with it have been identified. It is necessary to improve screening and management and optimize prevention and intervention strategies to reduce the harmful effects of postmenopausal depression.
Do sociodemographic risk profiles for adolescents engaging in weekly e-cigarette, cigarette, and dual product use differ?
Authors: Battista Katelyn , Patte Karen A , Wade Terrance J , Cole Adam G. , Elton-Marshall Tara , Lucibello Kristen M , Pickett William , Leatherdale Scott T
Published: June 2024

Background

E-cigarette use represents a contemporary mode of nicotine product use that may be changing the risk profile of participating adolescents. Understanding differences in sociodemographic characteristics of adolescents engaging in contemporary e-cigarette use and traditional cigarette use is important for effectively developing and targeting public health intervention programs. The objective of this study was to identify and compare sociodemographic risk profiles for exclusive e-cigarette use and dual-product use among a large sample of Canadian youth.

Methods

A survey of 46,666 secondary school students in the 2021-22 wave of the COMPASS study measured frequency of past month e-cigarette and cigarette use as well as age, sex, gender, racial or ethnic background, spending money, relative family affluence, and having one’s own bedroom. Rates of cigarette-only, e-cigarette-only, and dual product use were calculated, and separate classification trees were run using the CART algorithm to identify sociodemographic risk profiles for weekly dual-product use and weekly e-cigarette-only use.

Results

Over 13% of adolescents used only e-cigarettes at least weekly, 3% engaged in weekly dual e-cigarette and cigarette use, and less than 0.5% used only cigarettes. Available spending money was a common predictor of dual-product and e-cigarette-only use. Gender diverse youth and youth with lower perceived family affluence were at higher risk for dual-product use, while white and multiethnic adolescents were at greater risk of e-cigarette-only use. Two high-risk profiles were identified for e-cigarette-only use and four high-risk profiles were identified for dual product use.

Conclusions

This study used a novel modelling approach (CART) to identify combinations of sociodemographic characteristics that profile high-risk groups for exclusive e-cigarette and dual-product use. Unique risk profiles were identified, suggesting that e-cigarettes are attracting new demographics of adolescents who have not previously been considered as high-risk for traditional cigarette use.
The perception of genetic diseases and premarital screening tests in the central region of Saudi Arabia
Authors: Al Eissa Mariam M. , Almsned Fahad , Alkharji Reem R. , Aldossary Yousif M. , AlQurashi Raghad , Hawsa Esraa A. , AlDosari Sahar M. , Alqahtani Amerh S. , Alotibi Raniah S. , Farzan Raed , Alduaiji Reema , Sulimani Suha M. , Alomary Shaker A. , Assiri Abdullah M.
Published: June 2024

The prevalence of consanguineous marriages (CMs) varies worldwide from one country to another. However, the Middle East stands out as a region with a notably high rate of CMs. CM is particularly widespread in Saudi Arabia, where the prevalence of autosomal recessive genetic diseases has increased. This study aims to identify the Saudi population’s awareness of genetic diseases and premarital screening tests (PMSTs). It also seeks to understand couples’ perceptions of genetic diseases before and after marriage and their attitudes towards PMSTs and genetic counselling (GC) in reducing the risk of CM. Through the administration of online questionnaires, this cross-sectional study surveyed 2,057 participants to assess their awareness of genetic diseases and their understanding of testing and preventive measures for inherited diseases. Descriptive analysis, nonparametric chi-square tests and logistic regressions were performed to assess the association of categorical responses. This study included 2,035 Saudi Arabian respondents. A significant correlation was found between positive family history and partner selection (p = 0.001), as well as between partnering within the same tribe (p = 0.000139), with a different tribe (p = 0.000138) and from another family (p = 0.000489). About 91.3% of participants expressed agreement regarding the need to enhance public awareness and knowledge concerning genetic disorders, while 87% agreed that increased government regulations are required to prevent the spread of genetic diseases in affected families. Despite increased awareness of genetic diseases and PMSTs, there appears to be a lack of understanding regarding the limitations of PMSTs. The persistently high rate of CM underscores the challenge of altering marriage customs. Further governmental efforts are required to promote awareness of alternative reproductive options, establish new regulations and expand screening programmes.
Association between short-term exposure to ambient air pollutants and the risk of hospital visits for acute upper respiratory tract infections among adults: a time-series study in Ningbo, China
Authors: Huang Jin-Ying , Feng Wei , Sang Guo-Xin , McDonald Stuart , He Tian-Feng , Lin Yi
Published: June 2024

Objectives

Acute upper respiratory tract infections (AURTIs) are prevalent in the general population. However, studies on the association of short-term exposure to air pollution with the risk of hospital visits for AURTIs in adults are limited. This study aimed to explore the short-term exposure to air pollutants among Chinese adults living in Ningbo.

Methods

Quasi-Poisson time serious regressions with distributed lag non-linear models (DLNM) were applied to explore the association between ambient air pollution and AURTIs cases. Patients ≥ 18 years who visit three hospitals, being representative for urban, urban–rural junction and rural were included in this retrospective study.

Results

In total, 104,441 cases with AURTIs were enrolled in hospital during 2015–2019. The main results showed that particulate matter with an aerodynamic diameter less than 2.5 μm (PM2.5), nitrogen dioxide (NO2) and nitrogen dioxide (SO2), were positively associated to hospital visits for AURTIs, except for nitrogen dioxide (O3), which was not statistically significant. The largest single-lag effect for PM2.5 at lag 8 days (RR = 1.02, 95%CI: 1.08–1.40), for NO2 at lag 13 days (RR = 1.03, 95%CI: 1.00–1.06) and for SO2 at lag 5 days (RR = 1.27, 95%CI: 1.08–1.48), respectively. In the stratified analysis, females, and young adults (18–60 years) were more vulnerable to PM2.5 and SO2 and the effect was greater in rural areas and urban–rural junction.

Conclusions

Exposure to ambient air pollution was significantly associated with hospital visits for AURTIs. This study provides epidemiological evidence for policymakers to control better air quality and establish an enhanced system of air pollution alerts.
Ge-Gen-Qin-Lian decoction alleviates the symptoms of type 2 diabetes mellitus with inflammatory bowel disease via regulating the AGE-RAGE pathway
Authors: Li Zhipeng , Zhao Ziwei , Chen Shujuan , Wang Xiaojuan , Wang Dongsheng , Nie Xiaoli , Yao Ye
Published: June 2024

Background

This study aimed to explore the mechanism of Ge-Gen-Qin-Lian decoction (GGQLD) in the alleviation of symptoms of type 2 diabetes mellitus (T2DM) with inflammatory bowel disease (IBD) by network pharmacology and experimental validation.

Methods

The active components and targets of GGQLD were identified from the TCMSP database. The potential therapeutic targets of T2DM and IBD were identified from the GEO database and 4 online disease target databases. The PPI network and KEGG/GO analyses were performed with the common targets among GGQLD, T2DM and IBD. Molecular docking was carried out between the core compounds and hub targets. To verify the above results, UHPLC-MS technology was used to identify the chemical compounds in GGQLD, and a T2DM with IBD rat model was used to explore the mechanism by which GGQLD treats T2DM with IBD.

Results

Totally, 70 potential therapeutic targets were identified among GGQLD, T2DM and IBD. Ten hub genes were selected from the PPI network. KEGG analysis revealed that GGQLD is tightly involved in the AGE-RAGE signaling pathway. Berberine, baicalein, wogonin, and quercitrin are the main active compounds of GGQLD. Animal experiments showed that GGQLD could decrease blood glucose and alleviate intestinal inflammation. Notably, the concentrations of AGEs, the expression of RAGE, c-JUN and NF-κB and the expression of inflammatory cytokines were decreased by GGQLD.

Conclusions

Our study initially demonstrated that GGQLD has favorable anti-hyperglycemic and anti-intestinal inflammation effects in a T2DM with IBD rat model, and the AGE-RAGE pathway plays a vital role in this process.
Microbially induced calcium carbonate precipitation through CO2 sequestration via an engineered Bacillus subtilis
Authors: Gilmour Katie A. , Ghimire Prakriti Sharma , Wright Jennifer , Haystead Jamie , Dade-Robertson Martyn , Zhang Meng , James Paul
Published: June 2024

Background

Microbially induced calcium carbonate precipitation has been extensively researched for geoengineering applications as well as diverse uses within the built environment. Bacteria play a crucial role in producing calcium carbonate minerals, via enzymes including carbonic anhydrase—an enzyme with the capability to hydrolyse CO2, commonly employed in carbon capture systems. This study describes previously uncharacterised carbonic anhydrase enzyme sequences capable of sequestering CO2 and subsequentially generating CaCO3 biominerals and suggests a route to produce carbon negative cementitious materials for the construction industry.

Results

Here, Bacillus subtilis was engineered to recombinantly express previously uncharacterised carbonic anhydrase enzymes from Bacillus megaterium and used as a whole cell catalyst allowing this novel bacterium to sequester CO2 and convert it to calcium carbonate. A significant decrease in CO2 was observed from 3800 PPM to 820 PPM upon induction of carbonic anhydrase and minerals recovered from these experiments were identified as calcite and vaterite using X-ray diffraction. Further experiments mixed the use of this enzyme (as a cell free extract) with Sporosarcina pasteurii to increase mineral production whilst maintaining a comparable level of CO2 sequestration.

Conclusion

Recombinantly produced carbonic anhydrase successfully sequestered CO2 and converted it into calcium carbonate minerals using an engineered microbial system. Through this approach, a process to manufacture cementitious materials with carbon sequestration ability could be developed.
Thermostable in vitro transcription-translation compatible with microfluidic droplets
Authors: Ribeiro Ana L. J. L. , Pérez-Arnaiz Patricia , Sánchez-Costa Mercedes , Pérez Lara , Almendros Marcos , van Vliet Liisa , Gielen Fabrice , Lim Jesmine , Charnock Simon , Hollfelder Florian , González-Pastor J. Eduardo , Berenguer José , Hidalgo Aurelio
Published: June 2024

Background

In vitro expression involves the utilization of the cellular transcription and translation machinery in an acellular context to produce one or more proteins of interest and has found widespread application in synthetic biology and in pharmaceutical biomanufacturing. Most in vitro expression systems available are active at moderate temperatures, but to screen large libraries of natural or artificial genetic diversity for highly thermostable enzymes or enzyme variants, it is instrumental to enable protein synthesis at high temperatures.

Objectives

Develop an in vitro expression system operating at high temperatures compatible with enzymatic assays and with technologies that enable ultrahigh-throughput protein expression in reduced volumes, such as microfluidic water-in-oil (w/o) droplets.

Results

We produced cell-free extracts from Thermus thermophilus for in vitro translation including thermostable enzymatic cascades for energy regeneration and a moderately thermostable RNA polymerase for transcription, which ultimately limited the temperature of protein synthesis. The yield was comparable or superior to other thermostable in vitro expression systems, while the preparation procedure is much simpler and can be suited to different Thermus thermophilus strains. Furthermore, these extracts have enabled in vitro expression in microfluidic droplets at high temperatures for the first time.

Conclusions

Cell-free extracts from Thermus thermophilus represent a simpler alternative to heavily optimized or pure component thermostable in vitro expression systems. Moreover, due to their compatibility with droplet microfluidics and enzyme assays at high temperatures, the reported system represents a convenient gateway for enzyme screening at higher temperatures with ultrahigh-throughput.
Folic acid-mediated hollow $$\text {Mn}_{3}\text {O}_{4}$$ nanocomposites for in vivo MRI/FLI monitoring the metastasis of gastric cancer
Authors: Yang Zhihua , Wang Chenying , Du Shangting , Ma Qin , Wang Wei , liu Changhu , Zhan Yonghua , Zhan Wenhua
Published: June 2024

Background

Metastasis is one of the main factors leading to the high mortality rate of gastric cancer. The current monitoring methods are not able to accurately monitor gastric cancer metastasis.

Methods

In this paper, we constructed a new type of hollow $$\text {Mn}_{3}\text {O}_{4}$$

Mn
3

O
4

nanocomposites, $$\text {Mn}_{3}\text {O}_{4}$$

Mn
3

O
4

@HMSN-Cy7.5-FA, which had a size distribution of approximately 100 nm and showed good stability in different liquid environments. The in vitro magnetic resonance imaging (MRI) results show that the nanocomposite has good response effects to the acidic microenvironment of tumors. The acidic environment can significantly enhance the contrast of $${\text {T}_{1}}$$

T
1

-weighted MRI. The cellular uptake and endocytosis results show that the nanocomposite has good targeting capabilities and exhibits good biosafety, both in vivo and in vitro. In a gastric cancer nude mouse orthotopic metastatic tumor model, with bioluminescence imaging’s tumor location information, we realized in vivo MRI/fluorescence imaging (FLI) guided precise monitoring of the gastric cancer orthotopic and metastatic tumors with this nanocomposite.

Results

This report demonstrates that $$\text {Mn}_{3}\text {O}_{4}$$

Mn
3

O
4

@HMSN-Cy7.5-FA nanocomposites is a promising nano-diagnostic platform for the precision diagnosis and therapy of gastric cancer metastasis in the future.

Conclusions

In vivo MRI/FLI imaging results show that the nanocomposites can achieve accurate monitoring of gastric cancer tumors in situ and metastases. BLI’s tumor location information further supports the good accuracy of MRI/FLI dual-modality imaging. The above results show that the MHCF NPs can serve as a good nano-diagnostic platform for precise in vivo monitoring of tumor metastasis. This nanocomposite provides more possibilities for the diagnosis and therapy of gastric cancer metastases.
Long-term exposure to PM2.5 air pollution and mental health: a retrospective cohort study in Ireland
Authors: Lyons Seán , Nolan Anne , Carthy Philip , Griffin Míde , O’Connell Brian
Published: June 2024

Background

Mental illness is the leading cause of years lived with disability, and the global disease burden of mental ill-health has increased substantially in the last number of decades. There is now increasing evidence that environmental conditions, and in particular poor air quality, may be associated with mental health and wellbeing.

Methods

This cross-sectional analysis uses data on mental health and wellbeing from The Irish Longitudinal Study on Ageing (TILDA), a nationally representative survey of the population aged 50+ in Ireland. Annual average PM2.5 concentrations at respondents’ residential addresses over the period 1998–2014 are used to measure long-term exposure to ambient PM2.5.

Results

We find evidence of associations between long-term exposure to ambient PM2.5 and depression and anxiety. The measured associations are strong, and are comparable with effect sizes for variables such as sex. Effects are also evident at relatively low concentrations by international standards. However, we find no evidence of associations between long-term ambient particulate pollution and other indicators of mental health and well-being such as stress, worry and quality of life.

Conclusions

The measured associations are strong, particularly considering the relatively low PM2.5 concentrations prevailing in Ireland compared to many other countries. While it is estimated that over 90 per cent of the world’s population lives in areas with annual mean PM2.5 concentrations greater than 10 μg/m3, these results contribute to the increasing evidence that suggests that harmful effects can be detected at even low levels of air pollution.
Genome wide-scale CRISPR-Cas9 knockout screens identify a fitness score for optimized risk stratification in colorectal cancer
Authors: Yang Xiangchou , Liu Jieyu , Wang Shuaibin , Al-Ameer Wail Hussein Ahmed , Ji Jingting , Cao Jiaqi , Dhaen Hassan Mansour S , Lin Ying , Zhou Yangyang , Zheng Chenguo
Published: June 2024

Background

The molecular complexity of colorectal cancer poses a significant challenge to the clinical implementation of accurate risk stratification. There is still an urgent need to find better biomarkers to enhance established risk stratification and guide risk-adapted treatment decisions.

Methods

we systematically analyzed cancer dependencies of 17 colorectal cancer cells and 513 other cancer cells based on genome-scale CRISPR-Cas9 knockout screens to identify colorectal cancer-specific fitness genes. A regression model was built using colorectal cancer-specific fitness genes, which was validated in other three independent cohorts. 30 published gene expression signatures were also retrieved.

Findings

We defined a total of 1828 genes that were colorectal cancer-specific fitness genes and identified a 22 colorectal cancer-specific fitness gene (CFG22) score. A high CFG22 score represented unfavorable recurrence and mortality rates, which was validated in three independent cohorts. Combined with age, and TNM stage, the CFG22 model can provide guidance for the prognosis of colorectal cancer patients. Analysis of genomic abnormalities and infiltrating immune cells in the CFG22 risk stratification revealed molecular pathological difference between the subgroups. Besides, drug analysis found that CFG22 high patients were more sensitive to clofibrate.

Interpretation

The CFG22 model provided a powerful auxiliary prediction tool for identifying colorectal cancer patients with high recurrence risk and poor prognosis, optimizing precise treatment and improving clinical efficacy.
γδ T cells and the PD-1/PD-L1 axis: a love–hate relationship in the tumor microenvironment
Authors: Liu Jian , Wu Min , Yang Yifan , Wang Zixuan , He Shan , Tian Xun , Wang Hui
Published: June 2024

Gamma delta (γδ) T cells demonstrate strong cytotoxicity against diverse cancer cell types in an MHC-independent manner, rendering them promising contenders for cancer therapy. Although amplification and adoptive transfer of γδ T cells are being evaluated in the clinic, their therapeutic efficacy remains unsatisfactory, primarily due to the influence of the immunosuppressive tumor microenvironment (TME). Currently, the utilization of targeted therapeutic antibodies against inhibitory immune checkpoint (ICP) molecules is a viable approach to counteract the immunosuppressive consequences of the TME. Notably, PD-1/PD-L1 checkpoint inhibitors are considered primary treatment options for diverse malignancies, with the objective of preserving the response of αβ T cells. However, γδ T cells also infiltrate various human cancers and are important participants in cancer immunity, thereby influencing patient prognosis. Hence, it is imperative to comprehend the reciprocal impact of the PD-1/PD-L1 axis on γδ T cells. This understanding can serve as a therapeutic foundation for improving γδ T cells adoptive transfer therapy and may offer a novel avenue for future combined immunotherapeutic approaches.
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

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

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

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

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

Although 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

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

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

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

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

Autism 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.