Disturbed intracellular folate homeostasis impairs autophagic flux and increases hepatocytic lipid accumulation.

BACKGROUND: Metabolic associated fatty liver disease (MAFLD), a prevalent liver disorder affecting one-third of the global population, encompasses a spectrum ranging from fatty liver to severe hepatic steatosis. Both genetic and lifestyle factors, particularly diet and nutrition, contribute to its etiology. Folate deficiency, a frequently encountered type of malnutrition, has been associated with the pathogenesis of MAFLD and shown to impact lipid deposition. However, the underlying mechanisms of this relationship remain incompletely understood. We investigated the impact of disturbed folate-mediated one-carbon metabolism (OCM) on hepatic lipid metabolism both in vitro using human hepatoma cells and in vivo using transgenic fluorescent zebrafish displaying extent-, stage-, and duration-controllable folate deficiency upon induction. RESULTS: Disturbed folate-mediated one-carbon metabolism, either by inducing folate deficiency or adding anti-folate drug, compromises autophagy and causes lipid accumulation in liver cells. Disturbed folate status down-regulates cathepsin L, a key enzyme involved in autophagy, through inhibiting mTOR signaling. Interfered mitochondrial biology, including mitochondria relocation and increased fusion-fission dynamics, also occurs in folate-deficient hepatocytes. Folate supplementation effectively mitigated the impaired autophagy and lipid accumulation caused by the inhibition of cathepsin L activity, even when the inhibition was not directly related to folate deficiency. CONCLUSIONS: Disruption of folate-mediated OCM diminishes cathepsin L expression and impedes autophagy via mTOR signaling, leading to lipid accumulation within hepatocytes. These findings underscore the crucial role of folate in modulating autophagic processes and regulating lipid metabolism in the liver.

Effectiveness of artificial reefs in enhancing phytoplankton community dynamics: A meta-analysis.

Artificial reefs (ARs) are widespread globally and play a positive role in enhancing fish communities and restoring habitat. However, the effect of ARs on phytoplankton, which are fundamental to the marine food chain, remains inconclusive. Conducting a literature review and meta-analysis, this study investigates how ARs influence phytoplankton community dynamics by comparing the biomass, density, and diversity of phytoplankton between ARs and natural water bodies across varying deployment durations, constituent materials, and climatic zones. The study findings suggest that, overall, ARs enhance the biomass, density, and diversity of phytoplankton communities, with no significant differences observed compared to natural water bodies. The enhancement effect of ARs on phytoplankton communities becomes progressively more pronounced with increasing deployment time, with the overall status of phytoplankton communities being optimal when artificial reefs are deployed for 5 years or longer. Concrete and stone ARs can significantly enhance the biomass and diversity of phytoplankton, respectively. The effect of ARs on phytoplankton diversity is unrelated to climatic zones. However, deploying ARs in temperate waters significantly enhances phytoplankton biomass, while in tropical waters, it significantly reduces phytoplankton density. The research findings provide practical implications for the formulation of artificial reef construction strategies tailored to the characteristics of different aquatic ecosystems, emphasizing the need for long-term deployment and appropriate material selection. This study offers a theoretical basis for optimizing AR design and deployment to achieve maximum ecological benefits.

Perceived discrimination and psychological distress among Mainland Chinese immigrant women in Hong Kong: The indirect effects of tolerance of uncertainty and common dyadic coping.

OBJECTIVES: By studying Mainland Chinese immigrant women who married Hong Kong men, this study examined the association between their perceived discrimination and psychological distress after the 2019-2020 social movement in Hong Kong. Additionally, this study examined the indirect effects of individual coping strategies (tolerance of uncertainty) and couples' coping strategies (common dyadic coping), guided by the cultural and developmental psychopathology framework. METHOD: Ninety-nine Mainland Chinese immigrant women who married Hong Kong men participated in this cross-sectional survey. RESULTS: We found a positive association between perceived discrimination and psychological distress (r = .50, p < .01). Reduced uncertainty tolerance and low levels of common dyadic coping both showed indirect effects on the discrimination-psychological distress association. Tolerance of uncertainty had a larger indirect effect than common dyadic coping. CONCLUSIONS: Focusing on the psychological adjustment of immigrant women facing discrimination, our findings underscore the importance of preserving individual- and couple-level resources. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Liquid-Based Cytology of Small Cell Carcinoma of the Cervix: A Multicenter Retrospective Study.

Background/Aims: There are currently few reports describing the liquid-based cytological characteristics of small cell neuroendocrine carcinoma of the cervix. This study aimed to retrospectively analyze these features to reduce missed or misdiagnosis. Methods: A total of 11 patients with histologically diagnosed small cell carcinoma of the cervix from three hospitals between 2017 and 2023 were included in this study. The cytological morphology of small cell carcinoma of the cervix and causes of missed or misdiagnosis were analyzed and summarized through a review of clinical data, liquid-based cytology, histology, immunohistochemistry, and human papillomaviruses (HPV) test results. Results: In this study, the positivity rate of preliminary cytological screening was 63.6% (7/11); however, no cases were accurately diagnosed as small cell carcinoma of the cervix. A total of 36.4% (4/11) of small cell carcinoma of the cervix cases were cytologically negative; retrospective cytology found that two of these were false negatives. The main cytological features of small cell carcinoma of the cervix were summarized. Most of the liquid-based cytology smear cells were dense, and almost all cases showed clustered and scattered cytoplasm-scanty tumor cells. The tumor cells were all deeply stained and relatively consistent small cells. Most cases showed typical nuclear molding, chromatin stippling, and no obvious nucleoli. Mild nuclear smears, nuclear fragments, and mitotic figures were seen in most cases. Conclusion: Liquid-based cytology has a high rate of missed diagnosis and misdiagnosis in small cell carcinoma of the cervix. This study confirms that reviewing cytology results can effectively reduce this proportion and that increasing understanding of small cell carcinoma of the cervix morphology is conducive to improving the cytology-based diagnosis rate.

Sodium Octahydridotriborate as a Solid Electrolyte with Excellent Stability Against Sodium-Metal Anode.

Solid-state sodium metal batteries have been extensively investigated because of their potential to improve safety, cost-effectiveness, and energy density. The development of such batteries urgently required a solid-state electrolyte with fast Na-ion conduction and favorable interfacial compatibility. Herein, the progress on developing the NaB3H8 solid-state electrolytes is reported, which show a liquid-like ionic conductivity of 0.05 S cm-1 at 56 °C with an activation energy of 0.35 eV after an order-disorder phase transformation, matching or surpassing the best single-anion hydridoborate conductors investigated up to now. The steady polarization voltage and significantly decreased resistance are achieved in the symmetric Na/NaB3H8/Na cell, indicating the great electrochemical stability and favorable interfacial contact with the Na metal of NaB3H8. Furthermore, a Na/NaB3H8/TiS2 battery, the first high-rate (up to 1 C) solid-state sodium metal battery using the single-anion hydridoborate electrolyte, is demonstrated, which exhibits superior rate capability (168.2 mAh g-1 at 0.1 C and 141.2 mAh g-1 at 1 C) and long-term cycling stability (70.9% capacity retention at 1 C after 300 cycles) at 30 °C. This work may present a new possibility to solve the interfacial limitations and find a new group of solid-state electrolytes for high-performance sodium metal batteries.

Predictive models for functional cure in patients with CHB receiving PEG-IFN therapy based on HBsAg quantification through meta-analysis.

BACKGROUND AND AIMS: The efficacy of achieving HBsAg clearance through pegylated interferon (PEG-IFNα) therapy in patients with chronic hepatitis B (CHB) remains uncertain, especially regarding the probability of achieving functional cure among patients with varying baseline HBsAg levels. We aimed to investigate the predictive value of HBsAg quantification for HBsAg seroclearance in CHB patients undergoing PEG-IFNα treatment. METHODS: A systematic search was conducted in PubMed, Embase, and the Cochrane Library up to January 11, 2022. Subgroup analyses were performed for HBeAg-positive and HBeAg-negative patients, PEG-IFNα monotherapy and PEG-IFNα combination therapy, treatment-naive and treatment-experienced patients, and patients with or without liver cirrhosis. RESULTS: This predictive model incorporated 102 studies. The overall HBsAg clearance rates at the end of treatment (EOT) and the end of follow-up (EOF) were 10.6% (95% CI 7.8-13.7%) and 11.1% (95% CI 8.4-14.1%), respectively. Baseline HBsAg quantification was the most significant factor. According to the model, it is projected that when baseline HBsAg levels are 100, 500, 1500, and 10,000 IU/ml, the HBsAg clearance rates at EOF could reach 53.9% (95% CI 40.4-66.8%), 32.1% (95% CI 24.8-38.7%), 14.2% (95% CI 9.8-18.8%), and 7.9% (95% CI 4.2-11.8%), respectively. Additionally, treatment-experienced patients with HBeAg-negative status, and without liver cirrhosis exhibited higher HBsAg clearance rates after PEG-IFNα treatment. CONCLUSION: A successful predictive model has been established to predict the achievement of functional cure in CHB patients receiving PEG-IFNα therapy.

Detecting gene-environment interactions from multiple continuous traits.

MOTIVATION: Genetic variants present differential effects on humans according to various environmental exposures, the so-called "gene-environment interactions" (GxE). Many diseases can be diagnosed with multiple traits, such as obesity, diabetes, and dyslipidemia. I developed a multivariate scale test (MST) for detecting the GxE of a disease with several continuous traits. Given a significant MST result, I continued to search for which trait and which E enriched the GxE signals. Simulation studies were performed to compare MST with the univariate scale test (UST). RESULTS: MST can gain more power than UST because of (1) integrating more traits with GxE information and (2) the less harsh penalty on multiple testing. However, if only few traits account for GxE, MST may lose power due to aggregating non-informative traits into the test statistic. As an example, MST was applied to a discovery set of 93,708 Taiwan Biobank (TWB) individuals and a replication set of 25,200 TWB individuals. From among 2,570,487 SNPs with minor allele frequencies ≥ 5%, MST identified 18 independent variance quantitative trait loci (p < 2.4E-9 in the discovery cohort and p < 2.8E-5 in the replication cohort) and 41 GxE signals (p < 0.00027) based on eight trait domains (including 29 traits). AVAILABILITY: https://github.com/WanYuLin/Multivariate-scale-test-MST. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Characterization of unique pattern of immune cell profile in patients with nasopharyngeal carcinoma through flow cytometry and machine learning.

In patients with nasopharyngeal carcinoma (NPC), the alteration of immune responses in peripheral blood remains unclear. In this study, we established an immune cell profile for patients with NPC and used flow cytometry and machine learning (ML) to identify the characteristics of this profile. After isolation of circulating leukocytes, the proportions of 104 immune cell subsets were compared between NPC group and the healthy control group (HC). Data obtained from the immune cell profile were subjected to ML training to differentiate between the immune cell profiles of the NPC and HC groups. We observed that subjects in the NPC group presented higher proportions of T cells, memory B cells, short-lived plasma cells, IgG-positive B cells, regulatory T cells, MHC II+ T cells, CTLA4+ T cells and PD-1+ T cells than subjects in the HC group, indicating weaker and compromised cellular and humoral immune responses. ML revealed that monocytes, PD-1+ CD4 T cells, memory B cells, CTLA4+ CD4 Treg cells and PD-1+ CD8 T cells were strongly contributed to the difference in immune cell profiles between the NPC and HC groups. This alteration can be fundamental in developing novel immunotherapies for NPC.

Treatment Patterns and Clinical Outcomes Among Patients with Metastatic Non-small Cell Lung Cancer Without Actionable Genomic Alterations Previously Treated with Platinum-Based Chemotherapy and Immunotherapy.

BACKGROUND: For patients with metastatic non-small cell lung cancer, timely molecular testing is essential to determine the appropriate course of therapy. Initial treatment with platinum chemotherapy and/or an immune checkpoint inhibitor (ICI) is the standard of care for patients without actionable genomic alterations. OBJECTIVE: We aimed to assess treatment patterns and clinical outcomes among patients with metastatic non-small cell lung cancer, no actionable genomic alterations, and with prior ICI and platinum-based chemotherapy in a community oncology setting. METHODS: This retrospective observational study examined electronic health records from adult patients with an initial metastatic non-small cell lung cancer diagnosis without actionable genomic alterations from 2017 to 2019. Patients had received a subsequent line of therapy (LOT) [index] after discontinuing platinum-based chemotherapy plus an ICI in the previous one or two LOTs. Patient demographics and clinical characteristics were analyzed descriptively. Clinical outcomes were evaluated using Kaplan-Meier analyses. RESULTS: Among the study population (n = 961), the most common index LOT regimens were non-platinum-based chemotherapies (57.3%), platinum-based chemotherapies (12.9%), ICI-based chemotherapies (12.7%), platinum + ICI-based chemotherapies (9.4%), and other (7.7%). The most common post-index LOT regimens were non-platinum based (61.2%), ICI based (15.3%), platinum based (10.7%), platinum + ICI based (3.2%), and other (2.5%). Median time to treatment discontinuation, time to next treatment, and overall survival were numerically longest with index LOT ICI-based regimens (6.5, 9.9, and 18.9 months, respectively) and shortest with platinum-based regimens (2.8, 5.3, and 8.0 months, respectively) and non-platinum-based regimens (2.6, 5.0, and 7.8 months, respectively). CONCLUSIONS: Among patients with metastatic non-small cell lung cancer without actionable genomic alterations previously treated with platinum + ICIs, non-platinum chemotherapy agents were most commonly prescribed in the index LOT. Clinical outcomes including time to treatment discontinuation, time to next treatment, and overall survival were short, highlighting the unmet need for more effective later-line treatments.

Urinary stone analysis and clinical characteristics of 496 patients in Taiwan.

Evaluate urinary stone components' epidemiological features in urolithiasis individuals and explore potential correlations between stone components and patients' clinical characteristics. A retrospective analysis of urinary stone compositions in 496 patients from a northern Taiwan medical center (February 2006 to October 2021) was conducted. We investigated associations between sex, age, body mass index (BMI), hypertension, diabetes mellitus (DM), hyperlipidemia (HLP), gout, coronary artery disease (CAD), cerebral vascular accident (CVA), chronic kidney disease (CKD), habits, urine pH, and three main stone groups: calcium oxalate (CaOx), calcium phosphate (CaP), and uric acid (UA). Males accounted for 66.5% of cases, with a male-to-female ratio of 1.99:1. Males were negatively associated with CaP stones (OR 0.313, p < 0.001) and positively with UA stones (OR 2.456, p = 0.009). Age showed a negative correlation with CaOx stones (OR 0.987, p = 0.040) and a positive correlation with UA stones (OR 1.023, p < 0.001). DM had a protective effect against CaP stones (OR 0.316, p = 0.004). Gout had a positive association with UA stones (OR 2.085, p = 0.035). Smoking was adversely associated with UA stones (OR 0.350, p = 0.018). Higher urine pH was a risk factor for CaP stones (OR 1.641, p = 0.001) and a protective factor against UA stones (OR 0.296, p < 0.001). These results may provide insights into the pathogenesis of urinary stones and the development of preventative strategies for high-risk populations. Further research is required to confirm and expand upon these findings.

The epigenetically regulated PP1α expression by KDM1A may contribute to oxycodone conditioned place preference in mice.

The lysine-specific demethylase 1 (KDM1A) is reported to be a regulator in learning and memory. However, the effect of KDM1A in oxycodone rewarding memory has yet to be studied. In our study, rewarding memory was assessed by using conditioned place preference (CPP) in male mice. Next generation sequencing and chromatin immunoprecipitation-PCR were used to explore the molecular mechanisms. Oxycodone significantly decreased PP1α mRNA and protein levels in hippocampal neurons. Oxycodone significantly increased KDM1A and H3K4me1 levels, while significantly decreased H3K4me2 levels in a time- and dose-dependent manner. Behavioral data demonstrated that intraperitoneal injection of ORY-1001 (KDM1A inhibitor) or intra-hippocampal injection of KDM1A siRNA/shRNA blocked the acquisition and expression of oxycodone CPP and facilitated the extinction of oxycodone CPP. The decrease of PP1α was markedly blocked by the injection of ORY-1001 or KDM1A siRNA/shRNA. Oxycodone-induced enhanced binding of CoRest with KDM1A and binding of CoRest with the PP1α promoter was blocked by ORY-1001. The level of H3K4me2 demethylation was also decreased by the treatment. The results suggest that oxycodone-induced upregulation of KDM1A via demethylation of H3K4me2 promotes the binding of CoRest with the PP1α promoter, and the subsequent decrease in PP1α expression in hippocampal neurons may contribute to oxycodone reward.

Electroacupuncture facilitates vascular normalization by inhibiting Glyoxalase1 in endothelial cells to attenuate glycolysis and angiogenesis in triple-negative breast cancer.

Recent therapeutic strategies for the treatment of triple-negative breast cancer (TNBC) have shifted the focus from vascular growth factors to endothelial cell metabolism. This study highlights the underexplored therapeutic potential of peri-tumoral electroacupuncture, a globally accepted non-pharmacological intervention for TNBC, and molecular mechanisms. Our study showed that peri-tumoral electroacupuncture effectively reduced the density of microvasculature and enhanced vascular functionality in 4T1 breast cancer xenografts, with optimal effects on day 3 post-acupuncture. The timely integration of peri-tumoral electroacupuncture amplified the anti-tumor efficacy of paclitaxel. Multi-omics analysis revealed Glyoxalase 1 (Glo1) and the associated methylglyoxal-glycolytic pathway as key mediators of electroacupuncture-induced vascular normalization. Peri-tumoral electroacupuncture notably reduced Glo1 expression in the endothelial cells of 4T1 xenografts. Using an in vivo matrigel plug angiogenesis assay, we demonstrated that either Glo1 knockdown or electroacupuncture inhibited angiogenesis. In contrast, Glo1 overexpression increased blood vessel formation. In vitro pharmacological inhibition and genetic knockdown of Glo1 in human umbilical vein endothelial cells inhibited proliferation and promoted apoptosis via downregulating the methylglyoxal-glycolytic pathway. The study using the Glo1-silenced zebrafish model further supported the role of Glo1 in vascular development. This study underscores the pivotal role of Glo1 in peri-tumoral electroacupuncture, spotlighting a promising avenue for enhancing vascular normalization and improving TNBC treatment outcomes.

Real-ambient bedroom light at night increases systemic inflammation and disrupts circadian rhythm of inflammatory markers.

BACKGROUND: Exposure to light at night (LAN) has been associated with multiple adverse health outcomes. However, evidence is limited regarding the impacts of LAN exposure on human inflammation. OBJECTIVES: To examine the association between real-ambient bedroom LAN exposure with systemic inflammation and circadian rhythm of inflammatory markers. METHODS: Using data from a prospective cohort study of Chinese young adults. At baseline, bedroom LAN exposure was measured with a portable illuminance meter; fasting blood sample for high-sensitivity C-reactive protein (hs-CRP) assay was collected. At 3-year follow-up, 20 healthy young adults (10 LANavg < 5 lx, 10 LANavg ≥ 5 lx) were recruited from the same cohort; time-series venous blood samples were sampled every 4 h over a 24 h-cycle for the detection of 8 inflammatory markers. Circadian rhythm of inflammatory markers was assessed using cosinor analysis. RESULTS: At baseline, the average age of the 276 participants was 18.7 years, and 33.3 % were male. Higher levels of bedroom LAN exposure were significantly associated with increased hs-CRP levels. The association between bedroom LAN exposure and systemic inflammation was only significant in the inactive group (MVPA < 2 h/d) but not in the physically active group (MVPA ≥ 2 h/d). In addition, exposure to higher levels of nighttime light (LANavg ≥ 5 lx) disrupted circadian rhythms (including rhythmic expression, circadian amplitude and circadian phase) of some inflammatory cytokines and inflammatory balance indicators. CONCLUSION: Exposure to bedroom nighttime light increases systemic inflammation and disrupts circadian rhythm of inflammatory markers. Keep bedroom darkness at night may represent important strategies for the prevention of chronic inflammation. Additionally, for people living a community with higher nighttime light pollution, regular physical activity may be a viable option to counteract the negative impacts of LAN exposure on chronic inflammation.

Construction of the pulmonary bio-adhesive delivery system of nintedanib nanocrystalline for effective treatment of pulmonary fibrosis.

Pulmonary fibrosis (PF) is a chronic, progressive, and fatal lung disease with a high mortality rate. Nintedanib, as a multi-tyrosine kinase inhibitor, is widely used as the first line drug for PF patients. However, only nintedanib oral formulations are used currently in clinic and show a low drug selectivity, significant first-pass effect and low bioavailability with 4.7%, thus limiting the clinical outcome of nintedanib. In this study, nintedanib was prepared in the form of nintedanib nanocrystalline (Nib-NC) and then encapsulated with hyaluronic acid (HA) to construct a nanocrystalline-in-adhesive delivery system Nib-NC@HA with high drug loading efficacy and pulmonary bio-adhesive properties, which could avoid the first-pass effects, increase the bioavailability and reduce the systemic side effects of nintedanib. After inhalation administration of Nib-NC@HA, due to the bio-adhesive properties of HA, Nib-NC@HA could prolong the retention time of drug in the lungs and inhibit the expression of inflammation associated factors such as IL-6, IL-1ß and TNF-α in lung tissue, reduce the release of pro-fibrotic growth factor, and improve the lung function, thus showing enhanced anti-fibrotic effect than Nib-NC. The results suggested that Nib-NC@HA is an efficient and optimal targeted bio-adhesive delivery system for the lungs to treat pulmonary fibrosis.

Traditional Chinese medicine for acute myelocytic leukemia therapy: exploiting epigenetic targets.

Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy with historically high mortality rates. The treatment strategies for AML is still internationally based on anthracyclines and cytarabine, which remained unchanged for decades. With the rapid advance on sequencing technology, molecular targets of leukemogenesis and disease progression related to epigenetics are constantly being discovered, which are important for the prognosis and treatment of AML. Traditional Chinese medicine (TCM) is characterized by novel pharmacological mechanisms, low toxicity and limited side effects. Several biologically active ingredients of TCM are effective against AML. This review focuses on bioactive compounds in TCM targeting epigenetic mechanisms to address the complexities and heterogeneity of AML.

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In the context of rapid urbanization, metropolitan areas are facing the risk of supply-demand mismatches among ecosystem services. Investigating the patterns, relationships, and driving factors of multiple supply-demand risks is of great significance to support the efficient management of regional ecological risks. We quantified the single/comprehensive supply-demand risk rates of six ecosystem services in Wuhan Metropolitan Area at the township scale in 2000, 2010, and 2020. By applying the self-organizing feature map network and optimal parameter geo-detector, we identified supply-demand risks bundles of ecosystem services and influencing factors of comprehensive risks. The results showed significant spatial variations in the supply-demand risks of typical ecosystem services from 2000 to 2020. The supply-demand risk associated with grain production, water yield, carbon sequestration, and green space recreation increased, while soil conservation and water purification risks decreased. The comprehensive ecosystem services supply-demand risk increased from 0.41 to 0.45, indicating a 'core area increase and periphery decrease' trend. Throughout the study period, the area exhibited bundles of comprehensive extremely high-risk bundles (B1), comprehensive high-risk bundles (B2), water purification high-risk bundles (B3), and grain production-soil conservation risk bundles (B4). The transition of risk types from B3 to B2 and from B2 to B1 suggested an increase in the combination and intensity of supply-demand risk. Vegetation cover, nighttime light index, and population density were the main driving factors for spatial variations in comprehensive supply-demand risk. Ecologi-cal risk assessment based on ecosystem services supply-demand bundles could provide an effective and reliable way to regulate multiple regional risk issues.