Air pollution exposure during preconception and first trimester of pregnancy and gestational diabetes mellitus in a large pregnancy cohort, Hebei Province, China.

Objective: To explore the relationship between the exposure level of particulate matter 2.5 (PM2.5) and particulate matter 10 (PM10) in the air of pregnant women during preconception and first trimester of pregnancy and the risk of gestational diabetes mellitus (GDM). Methods: The data of pregnant women delivered in 22 monitoring hospitals in Hebei Province from 2019 to 2021 were collected, and the daily air quality data of their cities were used to calculate the exposure levels of PM2.5 and PM10 in different pregnancy stages, and logistic regression model was used to analyze the impact of exposure levels of PM2.5 and PM10 on GDM during preconception and first trimester of pregnancy. Results: 108,429 singleton live deliveries were included in the study, of which 12,967 (12.0%) women had a GDM diagnosis. The prevalence of GDM increased over the course of the study from 10.2% (2019) to 14.9% (2021). From 2019 to 2021, the average exposure of PM2.5 and PM10 was relatively 56.67 and 103.08µg/m3 during the period of preconception and first trimester of pregnancy in Hebei Province. Handan, Shijiazhuang, and Xingtai regions had the most severe exposure to PM2.5 and PM10, while Zhangjiakou, Chengde, and Qinhuangdao had significantly lower exposure levels than other regions. The GDM group had statistically higher exposure concentrations of PM2.5 and PM10 during the period of preconception, first trimester, preconception and first trimester (P<0.05). Multivariate logistic regression analysis showed that the risk of GDM increases by 4.5%, 6.0%, and 10.6% for every 10ug/m3 increase in the average exposure value of PM2.5 in preconception, first trimester, preconception and first trimester, and 1.7%, 2.1%, and 3.9% for PM10. Moreover, High exposure to PM2.5 in the first, second, and third months of preconception and first trimester is associated with the risk of GDM. And high exposure to PM10 in the first, second, and third months of first trimester and the first, and third months of preconception is associated with the risk of GDM. Conclusion: Exposure to high concentrations of PM2.5 and PM10 during preconception and first trimester of pregnancy can significantly increase the risk of GDM. It is important to take precautions to prevent exposure to pollutants, reduce the risk of GDM, and improve maternal and fetal outcomes.

Turning to immunosuppressive tumors: Deciphering the immunosenescence-related microenvironment and prognostic characteristics in pancreatic cancer, in which GLUT1 contributes to gemcitabine resistance.

Increasing evidence indicates that the remodeling of immune microenvironment heterogeneity influences pancreatic cancer development, as well as sensitivity to chemotherapy and immunotherapy. However, a gap remains in the exploration of the immunosenescence microenvironment in pancreatic cancer. In this study, we identified two immunosenescence-associated isoforms (IMSP1 and IMSP2), with consequential differences in prognosis and immune cell infiltration. We constructed the MLIRS score, a hazard score system with robust prognostic performance (area under the curve, AUC = 0.91), based on multiple machine learning algorithms (101 cross-validation methods). Patients in the high MLIRS score group had worse prognosis (P < 0.0001) and lower abundance of immune cell infiltration. Conversely, the low MLIRS score group showed better sensitivity to chemotherapy and immunotherapy. Additionally, our MLIRS system outperformed 68 other published signatures. We identified the immunosenescence microenvironmental windsock GLUT1 with certain co-expression properties with immunosenescence markers. We further demonstrated its positive modulation ability of proliferation, migration, and gemcitabine resistance in pancreatic cancer cells. To conclude, our study focused on training of composite machine learning algorithms in multiple datasets to develop a robust machine learning modeling system based on immunosenescence and to identify an immunosenescence-related microenvironment windsock, providing direction and guidance for clinical prediction and application.

Platelet-Derived Growth Factor C Facilitates Malignant Behavior of Pancreatic Ductal Adenocarcinoma by Regulating SREBP1 Mediated Lipid Metabolism.

Lipid metabolism reprogramming stands as a fundamental hallmark of cancer cells. Unraveling the core regulators of lipid biosynthesis holds the potential to find promising therapeutic targets in pancreatic ductal adenocarcinoma (PDAC). Here, it is demonstrated that platelet-derived growth factor C (PDGFC) orchestrated lipid metabolism, thereby facilitated the malignant progression of PDAC. Expression of PDGFC is upregulated in PDAC cohorts and is corelated with a poor prognosis. Aberrantly high expression of PDGFC promoted proliferation and metastasis of PDAC both in vitro and in vivo. Mechanistically, PDGFC accelerated the malignant progression of PDAC by upregulating fatty acid accumulation through sterol regulatory element-binding protein 1 (SREBP1), a key transcription factor in lipid metabolism. Remarkably, Betulin, an inhibitor of SREBP1, demonstrated the capability to inhibit proliferation and metastasis of PDAC cell lines, along with attenuating the process of liver metastasis in vivo. Overall, the study underscores the pivotal role of PDGFC-mediated lipid metabolism in PDAC progression, suggesting PDGFC as a potential biomarker for PDAC metastasis. Targeting PDGFC-induced lipid metabolism emerges as a promising therapeutic strategy for metastatic PDAC, with the potential to improve clinical outcomes.

Short- and long-term cost-effectiveness of abrocitinib versus dupilumab in adults with moderate-to-severe atopic dermatitis in China.

BACKGROUNDS: Biologics and JAK inhibitors were the most effective innovative systemic treatments for moderate-to-severe atopic dermatitis (AD). However, their cost-effectiveness in China remains unclear. This study aims to compare both the short- and long-term cost-effectiveness of abrocitinib and dupilumab in adults with moderate-to-severe AD from the perspective of the Chinese healthcare system. METHODS: A hybrid decision tree and Markov model were developed to simulate the costs and health outcomes of interventions on both short-term and long-term horizons. Short- and long-term horizons were employed to reflect the 26-week induction treatment and model the extended 10-year maintenance treatment period, respectively. The cost-effectiveness of strategies was measured by incremental cost-effectiveness ratios (ICERs), which were then compared with the willingness-to-pay threshold (WTP) that was equivalent to the gross domestic product (GDP) per capita of China in 2023 ($12,681 [€11679.26]). One-way and probabilistic sensitivity analyses were conducted to validate the robustness of the model. RESULTS: Over the short-term horizon, the QALYs (quality-adjusted life years) gained were 0.43 for the abrocitinib group and 0.42 for the dupilumab group, with the costs being $2,716.01 (€2501.46) and $3,940.33 (€3629.06), respectively. Over the long-time horizon, abrocitinib therapy yields higher QALYs (6.60 versus 6.53) and incurs a lower cost ($22,765.15 [€20966.81] versus $30,683.38 [€28259.54]) compared to dupilumab. The probability of abrocitinib being cost-effective was nearly 100% under the current WTP. Both short- and long-term results showed that abrocitinib was more effective and less costly than dupilumab, making abrocitinib the dominant option. CONCLUSIONS: Abrocitinib was dominant compared to dupilumab both over the short- and long-term horizon for moderate-to-severe AD in China. Future research incorporating real-world evidence and long-term efficacy outcomes could further refine these economic evaluations.

Identification of mitochondrial ATP synthase as the cellular target of Ru-polypyridyl-ß-carboline complexes by affinity-based protein profiling.

Ruthenium polypyridyl complexes are promising anticancer candidates, while their cellular targets have rarely been identified, which limits their clinical application. Herein, we design a series of Ru(II) polypyridyl complexes containing bioactive ß-carboline derivatives as ligands for anticancer evaluation, among which Ru5 shows suitable lipophilicity, high aqueous solubility, relatively high anticancer activity and cancer cell selectivity. The subsequent utilization of a photo-clickable probe, Ru5a, serves to validate the significance of ATP synthase as a crucial target for Ru5 through photoaffinity-based protein profiling. Ru5 accumulates in mitochondria, impairs mitochondrial functions and induces mitophagy and ferroptosis. Combined analysis of mitochondrial proteomics and RNA-sequencing shows that Ru5 significantly downregulates the expression of the chloride channel protein, and influences genes related to ferroptosis and epithelial-to-mesenchymal transition. Finally, we prove that Ru5 exhibits higher anticancer efficacy than cisplatin in vivo. We firstly identify the molecular targets of ruthenium polypyridyl complexes using a photo-click proteomic method coupled with a multiomics approach, which provides an innovative strategy to elucidate the anticancer mechanisms of metallo-anticancer candidates.

[Guasha-fangsha therapy combined with electroacupuncture in treatment of greater occipital neuralgia: a randomized controlled trial].

OBJECTIVE: To observe the clinical effect of guasha-fangsha (scrapping and bleeding) therapy combined with electroacupuncture (EA) on greater occipital neuralgia. METHODS: Ninety patients with greater occipital neuralgia were randomly divided into an observation group (45 cases) and a control group (45 cases, 2 cases dropped out). In the control group, EA was delivered at Fengfu (GV 16) and bilateral Tianzhu (BL 10), Fengchi (GB 20), Wangu (GB 12), Yuzhen (BL 9) and Houxi (SI 3), with disperse-dense wave, at 2 Hz/100 Hz in frequency and 2 mA to 6 mA in intensity, for 30 min in each intervention, once every other days, 3 times a week. In the observation group, on the basis of the intervention as the control group, guasha-fangsha therapy was used along the distribution of the bladder meridian of foot-taiyang on the occipital region and that of the gallbladder meridian of foot-shaoyang on the lateral side of the head, once weekly. The duration of treatment was 3 weeks in the two groups. In the two groups, before treatment, after 1, 2 and 3 weeks of treatment and in follow-up visit after 3 weeks of treatment completion, the score of visual analogue scale (VAS) was observed; before and after treatment, as well as in follow-up visit after 3 weeks of treatment completion, the scores of self-rating anxiety scale (SAS), self-rating depression scale (SDS) and 36-item short-form health survey (SF-36) were observed; after treatment and in follow-up visit after 3 weeks of treatment completion, the clinical efficacy was evaluated. RESULTS: After one week of treatment, the VAS score in the observation group decreased when compared with that before treatment (P<0.05), while the scores in 2 and 3 weeks of treatment and in follow-up visit after 3 weeks of treatment completion were lower than those before treatment in the two groups (P<0.05) separately. At each time point after treatment, the VAS scores in the observation group were lower than those in the control group (P<0.05). After treatment and during the follow-up visit, the scores of SAS and SDS decreased when compared with those before treatment in the two groups (P<0.05), and the scores in the observation group were lower than those in the control group (P<0.05); the scores of each item in SF-36 were elevated in comparison with those before treatment in the two groups (P<0.05), and the scores in the observation group were higher than those in the control group (P<0.05). After treatment, the total effective rate of the observation group was 91.1% (41/45), higher than that (76.7%, 33/43) of the control group (P<0.05). In follow-up visit, the total effective rate of the observation group was 91.1% (41/45), which was higher than 72.1% (31/43) of the control group (P<0.05). CONCLUSION: Guasha-fangsha therapy combined with electroacupuncture can effectively relieve greater occipital neuralgia, alleviate pain severity, ameliorate anxiety and depression and improve the quality of life in the patients.

Impact of competition on reimbursement decisions for cancer drugs in China: an observational study.

Background: Annual Chinese National negotiations for including innovative drugs in the National Reimbursement Drug List (NRDL) reveal an increasing number of new drugs with overlapping action mechanisms of action and similar indications. Yet, it is unclear if competition affects reimbursement decisions. Thus, we explored the impact of competition on reimbursement decisions for cancer drugs in China. Methods: We identified the cancer drugs involved in NRDL negotiations from 2017 to 2022 and focused on the initial reimbursement decision for eligible newly negotiated drugs. Drugs were classified as within-class competitors based on their equivalent biological mechanisms of action and approved indications, including identified and potential competitors. Other variables included drug type, clinical benefit and safety, monthly drug cost, and disease incidence rate. We employed traditional univariate and multivariate Firth's penalized logistic regression to assess the association between reimbursement decisions and variables at the indication and drug levels. Findings: Between 2017 and 2022, 102 cancer drugs corresponding to 141 indications were studied, and 66 drugs (64.7%) covering 95 indications (67.4%) were added to the NRDL. The proportion of reimbursements for indications with identified competition was significantly higher than that for indications without identified competition (84.6% vs 52.6%, p < 0.0001). However, the difference in reimbursement proportions between groups with and without potential competition was not statistically significant (66.7% vs 68.3%, p = 0.84). Firth's penalized logistic regression showed that identified competition was positively correlated with successful NRDL inclusion, whereas potential competition had no significant effect on negotiation outcomes. Improved overall survival or progression-free survival were positively associated with NRDL inclusion, whereas disease incidence negatively impacted reimbursement decisions. Interpretation: Improved clinical benefit and identified competition were positively correlated with NRDL inclusion. In China's value-based negotiation model, clinical benefits served as a crucial foundation of price negotiation for cancer drugs, and market competition helped these drugs enter the NRDL at more reasonable prices. This has important implications for reimbursement decisions and accessibility and affordability improvement for innovative drugs worldwide. Funding: National Natural Science Foundation of China (No. 72104151).

Immune response and protection efficacy of formalin-killed vaccines against Streptococcus iniae in four-finger threadfin Eleutheronema tetradactylum.

Four-finger threadfin, Eleutheronema tetradactylum farming in southern Taiwan has been facing disease problems caused by Streptococcus iniae since 2018. The development of a vaccine against infectious S. iniae in the cultured threadfin industry is necessary. Thus, this study aimed to examine the efficacy of threadfin immunized formalin-killed cells (FKC) from S. iniae GSI-111 for 42 days post-vaccination (dpv) using two doses of FKC alone (a booster at 14 dpv) as group A, and FKC mixed with ISA763A adjuvant using a single dose as group B or double doses as group C. Immunoglobulin (Ig)-M was purified from threadfin, and rabbit anti-threadfin IgM polyclonal antibodies were used to detect antibody level in immunized fish; the vaccinated group A displayed higher levels at 3 dpv and all vaccinated treatments demonstrated high antibody levels between 14 and 42 dpv. All vaccine groups showed significantly higher values of lysozyme activity at 42 dpv compared with the control group; the vaccinated A group peaked at 14 dpv. The expression profiles of pro-inflammatory and immune-related genes, TNF-α, IL-12A, and C2 were upregulated at 3 dpv, while CD8A and chemokine receptor CXCR4 were upregulated at 42 dpv. Finally, the threadfins were challenged with S. iniae at 42 dpv. The average relative percent survival was 96% for vaccination A and B treatments, and 100% for vaccination C treatment. In summary, this study demonstrated that FKC vaccines whether formulated with an adjuvant could stimulate immune response and effective protect threadfins against S. iniae infection.

Cost-effectiveness analysis of osimertinib plus chemotherapy for patients with EGFR-mutated advanced non-small cell lung cancer.

INTRODUCTION: First-line osimertinib plus chemotherapy significantly prolonged progression-free survival of patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC) compared to osimertinib, according to the FLAURA2 trial. METHODS: We established a Markov model to compare the cost-effectiveness of osimertinib plus chemotherapy with that of osimertinib alone. Clinical data were obtained from the FLAURA and FLAURA2 trials, and additional data were extracted from online resources and publications. Sensitivity analyses were conducted to evaluate the robustness of the findings. We used A willingness-to-pay threshold of $150,000 per quality-adjusted life-years (QALYs) gained. The main outcomes were QALYs, overall costs, incremental cost-effectiveness ratio (ICER), incremental net monetary benefit, and incremental net health benefit. Subgroup analyses were conducted according to patients' mutation type and central nervous system (CNS) metastatic status. RESULTS: In a 20-year time horizon, the ICER of osimertinib plus chemotherapy versus osimertinib alone was $223,727.1 per QALY gained. The sensitivity analyses identified the cost of osimertinib and the hazard ratio for overall survival as the top 2 influential factors and a 1.9% probability of osimertinib plus chemotherapy to be cost-effective. The subgroup analyses revealed ICERs of $132,614.1, $224,449.8, $201,464.1, and $130,159.7 per QALY gained for L858R mutations, exon 19 deletions, CNS metastases, and no CNS metastases subgroups, respectively. CONCLUSIONS: From the perspective of the United States health care system, osimertinib plus chemotherapy is not cost-effective compared to osimertinib alone for treatment-naïve patients with EGFR-mutated advanced NSCLC, but more favorable cost-effectiveness occurs in patients with L858R mutations and patients without baseline CNS metastases.

Individualized regimen of Posaconazole oral suspension in Chinese HSCT patients based on population pharmacokinetic model.

To establish a population pharmacokinetic (PopPK) model of posaconazole suspension in Chinese hematopoietic stem cell transplantation (HSCT) patients and to recommend an optimal dosing regimen. A single-center, retrospective, model-based study was conducted in 62 Chinese patients, including 103 with posaconazole plasma concentrations. PopPK analysis using NONMEM software. A one-compartment model of first-order elimination and absorption was in good agreement with the experimental data. Analysis of covariance showed that body weight (WT), creatinine clearance (CCR), and proton pump inhibitor (PPI) had a significant effect on the pharmacokinetics of posaconazole. The dose simulation results show that patients with CCR ≥ 90 mL/min require at least 3 mg/kg TID and 7 mg/kg BID dosing regimens for prevention and treatment, respectively. However, when combined with PPI, at least 5 mg/kg BID and 5 mg/kg TID dosing regimens are required for prevention and treatment, respectively. Regardless of whether it is used in combination with PPI or not, patients with a CCR of 60-90 mL/min can achieve PTA goals by using a 4 mg/kg BID and 4 mg/kg TID regimen for prevention and treatment, respectively. A dosing regimen of 3 mg/kg BID in patients with a CCR of 30-60 mL/min is sufficient to meet the PTA goal of prophylaxis, and the dose needs to be elevated to 4 mg/kg BID for the treatment of fungal infections, and there is no need to change the dose according to the coadministration of PPI. When the patient's CCR is less than 30 mL/min, whether or not combined with PPI, the administration regimen of 2 mg/kg BID and 3 mg/kg BID can meet the PTA goals for prevention and treatment, respectively.

PRL1 and PRL3 promote macropinocytosis via its lipid phosphatase activity.

PRL1 and PRL3, members of the protein tyrosine phosphatase family, have been associated with cancer metastasis and poor prognosis. Despite extensive research on their protein phosphatase activity, their potential role as lipid phosphatases remains elusive. Methods: We conducted comprehensive investigations to elucidate the lipid phosphatase activity of PRL1 and PRL3 using a combination of cellular assays, biochemical analyses, and protein interactome profiling. Functional studies were performed to delineate the impact of PRL1/3 on macropinocytosis and its implications in cancer biology. Results: Our study has identified PRL1 and PRL3 as lipid phosphatases that interact with phosphoinositide (PIP) lipids, converting PI(3,4)P2 and PI(3,5)P2 into PI(3)P on the cellular membranes. These enzymatic activities of PRLs promote the formation of membrane ruffles, membrane blebbing and subsequent macropinocytosis, facilitating nutrient extraction, cell migration, and invasion, thereby contributing to tumor development. These enzymatic activities of PRLs promote the formation of membrane ruffles, membrane blebbing and subsequent macropinocytosis. Additionally, we found a correlation between PRL1/3 expression and glioma development, suggesting their involvement in glioma progression. Conclusions: Combining with the knowledge that PRLs have been identified to be involved in mTOR, EGFR and autophagy, here we concluded the physiological role of PRL1/3 in orchestrating the nutrient sensing, absorbing and recycling via regulating macropinocytosis through its lipid phosphatase activity. This mechanism could be exploited by tumor cells facing a nutrient-depleted microenvironment, highlighting the potential therapeutic significance of targeting PRL1/3-mediated macropinocytosis in cancer treatment.

Genetic evidence for the causal impact of insomnia on gastrointestinal diseases and the mediating effects of adiposity traits.

BACKGROUND AND AIM: Insomnia has been implicated in gastrointestinal diseases (GIs), but the causal effect between insomnia and GIs and underlying mechanisms remain unknown. METHODS: By using the released summary-level data, we conducted a two-step Mendelian randomization (MR) analysis to examine the relationship between insomnia and four GIs and estimate the mediating role of candidate mediators. The first step was to investigate the causal association between insomnia and GIs using univariable MR analysis. The second step was to estimate the mediation proportion of selected mediators in these associations using multivariable MR analysis. Subsequently, results from different datasets were combined using the fixed-effect meta-analysis. RESULTS: Univariable MR analysis provided strong evidence for the causal effects of insomnia on four GIs after Bonferroni correction for multiple comparisons, including peptic ulcer disease (PUD) (odds ratio [OR] = 1.15, 95% interval confidence [CI] = 1.10-1.20, P = 1.83 × 10-9), gastroesophageal reflux (GORD) (OR = 1.19, 95% CI = 1.16-1.22, P = 5.95 × 10-42), irritable bowel syndrome (IBS) (OR = 1.18, 95% CI = 1.15-1.22, P = 8.69 × 10-25), and inflammatory bowel disease (IBD) (OR = 1.09, 95% CI = 1.03-1.05, P = 3.46 × 10-3). In the mediation analysis, body mass index (BMI) and waist-to-hip ratio (WHR) were selected as mediators in the association between insomnia and PUD (BMI: mediation proportion [95% CI]: 13.61% [7.64%-20.70%]; WHR: 8.74% [5.50%-12.44%]) and GORD (BMI: 11.82% [5.94%-18.74%]; WHR: 7.68% [4.73%-11.12%]). CONCLUSIONS: Our findings suggest that genetically instrumented insomnia has causal effects on PUD, GORD, IBS, and IBD, respectively. Adiposity traits partially mediated the associations between insomnia and GIs. Further clinical studies are warranted to evaluate the protective effect of insomnia treatment on GIs.

Phase-Field Model of Electronic Antidoping.

Charge carrier doping usually reduces the resistance of a semiconductor or insulator, but was recently found to dramatically enhance the resistance in certain series of materials. This remarkable antidoping effect has been leveraged to realize synaptic memory trees in nanoscale hydrogenated perovskite nickelates, opening a new direction for neuromorphic computing. To understand these phenomena, we formulate a physical phase-field model of the antidoping effect based on its microscopic mechanism and simulate the voltage-driven resistance change in the prototypical system of hydrogenated perovskite nickelates. Remarkably, the simulations using this model, containing only one adjustable parameter whose magnitude is justified by first-principles calculations, quantitatively reproduce the experimentally observed treelike resistance states, which are shown unambiguously to arise from proton redistribution-induced local band gap enhancement and carrier blockage. Our work lays the foundation for modeling the antidoping phenomenon in strongly correlated materials at the mesoscale, which can provide guidance to the design of novel antidoping-physics-based devices.

First-line treatments for advanced non-squamous non-small cell lung cancer with immune checkpoint inhibitors plus chemotherapy: a systematic review, network meta-analysis, and cost-effectiveness analysis.

Introduction: The combination of immune checkpoint inhibitors (ICIs) and chemotherapy is a promising first-line therapy for patients with advanced non-squamous non-small cell lung cancer (NSCLC). The cost-effectiveness of combinations with different ICIs is yet to be compared. Methods: We utilized Bayesian network meta-analyses for the comparisons of overall survival, progression-free survival, and incidence of adverse events of the included treatments in the total population and subgroups with different programmed death-ligand 1 tumor proportional scores (TPS). The cost-effectiveness of the treatments from the perspectives of the US and Chinese healthcare systems was assessed using Markov models. Results: Three combinations, including pembrolizumab + chemotherapy (PembroC), nivolumab + ipilimumab + chemotherapy (NivoIpiC), and atezolizumab + chemotherapy (AteC), were included in our study. In terms of efficacy, PembroC was most likely to be ranked first for extending progression-free survival (PFS) (93.16%) and overall survival (OS) (90.73%). Nevertheless, from the US perspective, NivoIpiC and PembroC showed incremental cost-effectiveness ratios (ICERs) of $68,963.1/quality-adjusted life-years (QALY) and $179,355.6/QALY, respectively, compared with AteC. The one-way sensitivity analysis revealed that the results were primarily sensitive to the hazard ratios for OS or the cost of immunotherapy agents. At a willingness-to-pay (WTP) threshold of $150,000/QALY, NivoIpiC had the highest probability of being cost-effective (63%). As for the Chinese perspective, NivoIpiC and PembroC had ICERs of $145,983.4/QALY and $195,863.3/QALY versus AteC, respectively. The results were primarily sensitive to the HRs for OS. At a WTP threshold of $38,017/QALY, AteC had the highest probability of cost-effectiveness (94%). Conclusion: Although PembroC has the optimal efficacy, NivoIpiC and AteC were the most favorable treatments in terms of cost-effectiveness for patients with advanced non-squamous NSCLC from the US and Chinese perspectives, respectively.

Staphylococcal enterotoxin B exposed to pregnant rats inhibits the hedgehog signaling pathway in thymic T lymphocytes of the offspring.

The Hedgehog (Hh) signaling pathway is involved in T cell differentiation and development and plays a major regulatory part in different stages of T cell development. A previous study by us suggested that prenatal exposure to staphylococcal enterotoxin B (SEB) changed the percentages of T cell subpopulation in the offspring thymus. However, it is unclear whether prenatal SEB exposure impacts the Hh signaling pathway in thymic T cells. In the present study, pregnant rats at gestational day 16 were intravenously injected once with 15 µg SEB, and the thymi of both neonatal and adult offspring rats were aseptically acquired to scrutinize the effects of SEB on the Hh signaling pathway. It firstly found that prenatal SEB exposure clearly caused the increased expression of Shh and Dhh ligands of the Hh signaling pathway in thymus tissue of both neonatal and adult offspring rats, but significantly decreased the expression levels of membrane receptors of Ptch1 and Smo, transcription factor Gli1, as well as target genes of CyclinD1, C-myc, and N-myc in Hh signaling pathway of thymic T cells. These data suggest that prenatal SEB exposure inhibits the Hh signaling pathway in thymic T lymphocytes of the neonatal offspring, and this effect can be maintained in adult offspring via the imprinting effect.

Regioselective 1,4-/1,3-Difunctionalization of 1,3-Enynes with Selenosulfonates in Water.

1,4-/1,3-Regioselective bifunctionalization of 1,3-enynes with selenosulfonates in water under catalyst-free conditions for the construction of sulfonyl allene and 1,3-disulfonyl-conjugated dienes respectively have been developed. The reactions feature mild reaction conditions in aqueous solution and remarkable regioselectivity controlled by substrates.

N6-methyladenosine modified TGFB2 triggers lipid metabolism reprogramming to confer pancreatic ductal adenocarcinoma gemcitabine resistance.

Gemcitabine resistance is a major obstacle to the effectiveness of chemotherapy in pancreatic ductal adenocarcinoma (PDAC). Therefore, new strategies are needed to sensitize cancer cells to gemcitabine. Here, we constructed gemcitabine-resistant PDAC cells and analyzed them with RNA-sequence. Employing an integrated approach involving bioinformatic analyses from multiple databases, TGFB2 is identified as a crucial gene in gemcitabine-resistant PDAC and is significantly associated with poor gemcitabine therapeutic response. The patient-derived xenograft (PDX) model further substantiates the gradual upregulation of TGFB2 expression during gemcitabine-induced resistance. Silencing TGFB2 expression can enhance the chemosensitivity of gemcitabine against PDAC. Mechanistically, TGFB2, post-transcriptionally stabilized by METTL14-mediated m6A modification, can promote lipid accumulation and the enhanced triglyceride accumulation drives gemcitabine resistance by lipidomic profiling. TGFB2 upregulates the lipogenesis regulator sterol regulatory element binding factor 1 (SREBF1) and its downstream lipogenic enzymes via PI3K-AKT signaling. Moreover, SREBF1 is responsible for TGFB2-mediated lipogenesis to promote gemcitabine resistance in PDAC. Importantly, TGFB2 inhibitor imperatorin combined with gemcitabine shows synergistic effects in gemcitabine-resistant PDAC PDX model. This study sheds new light on an avenue to mitigate PDAC gemcitabine resistance by targeting TGFB2 and lipid metabolism and develops the potential of imperatorin as a promising chemosensitizer in clinical translation.

First detection of Tetraparvovirus ungulate 1 in diseased cattle (Chinese Simmental) from Hunan province, China.

Tetraparvovirus is an emerging parvovirus infecting a variety of mammals and humans, and associated with human diseases including severe acute respiratory infection and acute encephalitis syndrome. In the present study, a Tetraparvovirus ungulate 1 (formerly known as bovine hokovirus) strain HNU-CBY-2023 was identified and characterized from diseased Chinese Simmental from Hunan province, China. The nearly complete genome of HNU-CBY-2023 is 5346 nt in size and showed genomic identities of 85-95.5% to the known Tetraparvovirus ungulate 1 strains from GenBank, indicating a rather genetic variation. Phylogenetic and genetic divergence analyses indicated that Tetraparvovirus ungulate 1 could be divided into two genotypes (I and II), and HNU-CBY-2023 was clustered into genotype II. This study, for the first time, identified Tetraparvovirus ungulate 1 from domestic cattle from mainland China, which will be helpful to understand the prevalence and genetic diversity of Tetraparvovirus ungulate 1.

Integrated analysis of the DNA methylome and RNA transcriptome during the development of skeletal muscle in Duroc pigs.

BACKGROUND: Skeletal muscle development plays a crucial role in yield and quality of pork; however, this process is influenced by various factors. In this study, we employed whole-genome bisulfite sequencing (WGBS) and transcriptome sequencing to comprehensively investigate the longissimus dorsi muscle (LDM), aiming to identify key genes that impact the growth and development of Duroc pigs with different average daily gains (ADGs). RESULTS: Eight pigs were selected and divided into two groups based on ADGs: H (774.89 g) group and L (658.77 g) group. Each pair of the H and L groups were half-siblings. The results of methylation sequencing revealed 2631 differentially methylated genes (DMGs) involved in metabolic processes, signalling, insulin secretion, and other biological activities. Furthermore, a joint analysis was conducted on these DMGs and the differentially expressed genes (DEGs) obtained from transcriptome sequencing of the same individual. This analysis identified 316 differentially methylated and differentially expressed genes (DMEGs), including 18 DMEGs in promoter regions and 294 DMEGs in gene body regions. Finally, LPAR1 and MEF2C were selected as candidate genes associated with muscle development. Bisulfite sequencing PCR (BSP) and quantitative real-time PCR (qRT-PCR) revealed that the promoter region of LPAR1 exhibited significantly lower methylation levels (P < 0.05) and greater expression levels (P < 0.05) in the H group than in the L group. Additionally, hypermethylation was observed in the gene body region of MEF2C, as was a low expression level, in the H group (P < 0.05). CONCLUSIONS: These results suggest that the differences in the ADGs of Duroc pigs fed the same diet may be influenced by the methylation levels and expression levels of genes related to skeletal muscle development.

Construction of 5-Fluorouracil and Gallium Corrole Conjugates for Enhanced Photodynamic Therapy.

Molecular hybridization is a well-established strategy for developing new drugs. In the pursuit of promising photosensitizers (PSs) with enhanced photodynamic therapy (PDT) efficiency, a series of novel 5-fluorouracil (5FU) gallium corrole conjugates (1-Ga-4-Ga) were designed and synthesized by hybridizing a chemotherapeutic drug and PSs. Their photodynamic antitumor activity was also evaluated. The most active complex (2-Ga) possesses a low IC50 value of 0.185 µM and a phototoxic index of 541 against HepG2 cells. Additionally, the 5FU-gallium corrole conjugate (2-Ga) exhibited a synergistic increase in cytotoxicity under irradiation. Excitedly, treatment of HepG2 tumor-bearing mice with 2-Ga under irradiation could completely ablate tumors without harming normal tissues. 2-Ga-mediated PDT could disrupt mitochondrial function, cause cell cycle arrest in the sub-G1 phase, and activate the cell apoptosis pathway by upregulating the cleaved PARP expression and the Bax/Bcl-2 ratios. This work provides a useful strategy for the design of new corrole-based chemo-photodynamic therapy drugs.