Six-gene prognostic signature for non-alcoholic fatty liver disease susceptibility using machine learning.

BACKGROUND: nonalcoholic fatty liver disease (NAFLD) is a common liver disease affecting the global population and its impact on human health will continue to increase. Genetic susceptibility is an important factor influencing its onset and progression, and there is a lack of reliable methods to predict the susceptibility of normal populations to NAFLD using appropriate genes. METHODS: RNA sequencing data relating to nonalcoholic fatty liver disease was analyzed using the "limma" package within the R software. Differentially expressed genes were obtained through preliminary intersection screening. Core genes were analyzed and obtained by establishing and comparing 4 machine learning models, then a prediction model for NAFLD was constructed. The effectiveness of the model was then evaluated, and its applicability and reliability verified. Finally, we conducted further gene correlation analysis, analysis of biological function and analysis of immune infiltration. RESULTS: By comparing 4 machine learning algorithms, we identified SVM as the optimal model, with the first 6 genes (CD247, S100A9, CSF3R, DIP2C, OXCT 2 and PRAMEF16) as predictive genes. The nomogram was found to have good reliability and effectiveness. Six genes' receiver operating characteristic curves (ROC) suggest an essential role in NAFLD pathogenesis, and they exhibit a high predictive value. Further analysis of immunology demonstrated that these 6 genes were closely connected to various immune cells and pathways. CONCLUSION: This study has successfully constructed an advanced and reliable prediction model based on 6 diagnostic gene markers to predict the susceptibility of normal populations to NAFLD, while also providing insights for potential targeted therapies.

The anti-depression effect and potential mechanism of the petroleum ether fraction of CDB: Integrated network pharmacology and metabolomics.

The combination of Chaidangbo (CDB) is an antidepressant traditional Chinese medicine (TCM) prescription simplified by Xiaoyaosan (a classic antidepressant TCM prescription) through dismantling research, which has the effect of dispersing stagnated liver qi and nourishing blood in TCM theory. Although the antidepressant effect of CBD has been confirmed in animal studies, the material basis and possible molecular mechanism for antidepressant activity in CBD have not been clearly elucidated. Herein, we investigated the effects and potential mechanisms of CDB antidepressant fraction (petroleum ether fraction of CDB, PEFC) on chronic unpredictable mild stress (CUMS)-induced depression-like behavior in mice using network pharmacology and metabolomics. First, a UPLC-QE/MS was employed to identify the components of PEFC. To extract active ingredients, SwissADME screening was used to the real PEFC components that were found. Potential PEFC antidepressant targets were predicted based on a network pharmacology approach, and a pathway enrichment analysis was performed for the predicted targets. Afterward, a CUMS mouse depression model was established and LC-MS-based untargeted hippocampal metabolomics was performed to identify differential metabolites, and related metabolic pathways. Finally, the protein expressions in mouse hippocampi were determined by Western blot to validate the network pharmacology and metabolomics deduction. A total of 16 active compounds were screened in SwissADME that acted on 73 core targets of depression, including STAT3, MAPKs, and NR3C1; KEGG enrichment analysis showed that PEFC modulated signaling pathways such as PI3K-Akt signaling pathway, endocrine resistance, and MAPK to exert antidepressant effects. PEFC significantly reversed abnormalities of hippocampus metabolites in CUMS mice, mainly affecting the synthesis and metabolism of glycine, serine, and threonine, impacting catecholamine transfer and cholinergic synapses and regulating the activity of the mTOR signaling pathway. Furthermore, Western blot analysis confirmed that PEFC significantly influenced the main protein levels of the PI3K/Akt/mTOR signaling pathways in the hippocampus of mice subjected to CUMS. This study integrated metabolomics, network pharmacology and biological verification to explore the potential mechanism of PEFC in treating depression, which is related to the regulation of amino acid metabolism dysfunction and the activation of PI3K/Akt/mTOR signaling pathways in the hippocampus. The comprehensive strategy also provided a reasonable way for unveiling the pharmacodynamic mechanisms of multi-components, multi-targets, and multi-pathways in TCM with antidepressant effect.

Emission of CO2 and its related carbonate system dynamics in a hotspot area during winter and summer: The Changjiang River estuary.

The carbonate chemistry in river-dominated marginal seas is highly heterogeneous, and there is ongoing debate regarding the definition of atmospheric CO2 source or sink. On this basis, we investigated the carbonate chemistry and air-sea CO2 fluxes in a hotspot estuarine area: the Changjiang Estuary during winter and summer. The spatial characteristics of the carbonate system were influenced by water mixing of three end-members in winter, including the Changjiang freshwater with low total alkalinity (TA) concentration, the less saline Yellow Sea Surface Water with high TA, and the saline East China Sea (ECS) offshore water with moderate TA. While in summer with increased river discharge, the carbonate system was regulated by simplified two end-member mixing between the Changjiang freshwater and the ECS offshore water. By performing the end-member mixing model on DIC variations in the river plume region, significant biological addition of DIC was found in winter with an estimation of -120 ± 113 µmol kg-1 caused by wintertime organic matter remineralization from terrestrial source. While this biological addition of DIC shifted to DIC removal due to biological production in summer supported by the increased nutrient loading from Changjiang River. The pCO2 dynamics in the river plume and the ECS offshore were both subjected to physical mixing of freshwater and seawater, whether in winter and summer. In the inner estuary without horizontal mixing, the pCO2 dynamics were mainly influenced by biological uptake in winter and temperature in summer. The inner estuary, the river plume, and the ECS offshore were sources of atmospheric CO2, with their contributions varying seasonally. The Changjiang runoff enhanced the inner estuary's role as a CO2 source in summer, while intensive biological uptake reduced the river plume's contribution.

Microneedle patch with pure drug tips for delivery of liraglutide: pharmacokinetics in rats and minipigs.

Transdermal delivery of peptide drugs is almost impossible with conventional penetration enhancers because of epidermal barrier function. Microneedle (MN) patches can bypass the epidermal barrier and have been developed for trans- and intradermal delivery of peptide drugs and vaccines. However, dissolving MN patches are limited by low drug loading capacities due to their small size and admixture of drug and water-soluble excipients. Furthermore, few in vivo pharmacokinetic studies, especially in large animals such as pigs, have been performed to assess post-application systemic drug exposure. Here, we developed a dissolving MN patch with pure liraglutide at the needle tips. The MN patch could load up to 2.21 ± 0.14 mg of liraglutide in a patch size of 0.9 cm2, which was nearly two orders of magnitude higher than that obtained with conventional MN patches of the same size. Raman imaging confirmed that liraglutide was localized at the MN tips. The MN had sufficient mechanical strength to penetrate the epidermis and could deliver up to 0.93 ± 0.04 mg of liraglutide into skin with a dosing variability of less than 6.8%. The MN patch delivery enabled faster absorption of liraglutide than that provided by subcutaneous (S.C.) injection, and achieved relative bioavailability of 69.8% and 46.3% compared to S.C. injection in rats and minipigs, respectively. The MN patch also exhibited similar patterns of anti-hyperglycemic effect in diabetic rats and individual variability in pharmacokinetic parameters as S.C. injection. The liraglutide MN application was well tolerated; no skin irritation was observed in minipigs except for mild erythema occurring within 4 h after once daily administration for 7 days at the same site. Our preclinical study suggests that MN patch with pure drug needle tips might offer a safe and effective alternative to S.C. injection for administration of liraglutide.

Barriers and facilitators to using ophthalmic clinical health services following school vision screening: a mixed-methods study.

OBJECTIVE: To identify determinants of the utilisation of ophthalmic clinical health services among students who failed school vision screening. METHODS: This study employed a sequential explanatory mixed methods design, underpinned by Andersen's Behavioural Model of Health Service Utilisation. Data were initially gathered through interviews with 27 stakeholders-comprising 5 ophthalmologists, 7 community doctors, 7 public health professionals and 8 teachers. The qualitative insights informed the construction of a questionnaire, which subsequently garnered responses from 6215 participants. Qualitative data underwent thematic analysis with NVivo V.12, while quantitative data were analysed using multivariable multinomial logistic regression in SAS V.9.4. Data integration was performed using the Pillar Integration Process for a deductive, evidence-based synthesis of findings. RESULTS: The research revealed that students attending vision demonstration schools and receiving encouragement from schools or communities to access clinical ophthalmic services demonstrated higher adherence to referral (OR=1.66, 95% CI 1.30 to 2.12; OR=1.54, 95% CI 1.33 to 1.80). Conversely, older students and those from higher-income families exhibited lower adherence rates (OR=0.31, 95% CI 0.23 to 0.44; OR=0.34, 95% CI 0.25 to 0.46). Moreover, students with less urgent medical needs were more likely to adhere to referrals compared with those needing immediate referrals (OR=1.24, 95% CI 1.06 to 1.45).Four pillars emerged: (a) adherence decreased with age, (b) financial constraints did not pose an obstacle, (c) public health services played a critical role, (d) referral urgency did not linearly correlate with adherence. CONCLUSION: The utilisation of ophthalmic clinical health services following vision screening failure in students is significantly influenced by public health services provided by schools or communities, such as prompting those with abnormal screening results to access ophthalmic clinical health services.

Flexible Supercapacitor with Wide Electrochemical Stable Window Based on Hydrogel Electrolyte.

Hydrogel electrolyte can endow supercapacitors with excellent flexibility, which has developed rapidly in recent years. However, the water-rich structures of hydrogel electrolyte are easy to freeze at subfreezing and dry at high temperatures, which will affect its energy storage characteristics. The low energy density of micro supercapacitors also hinders their development. Herein, a strategy is proposed to reduce the free water activity in the hydrogel to improve the operating voltage and the energy density of the device, which is achieved through the synergistic effect of the hydrogel skeleton, N, N'-dimethylformamide (DMF), NaClO4 and water. High concentrations of DMF and NaClO4 are introduced into sodium alginate/polyacrylamide (SA/PAAM) hydrogel through solvent exchange to obtain SA/PAAM/DMF/NaClO4 hydrogel electrolyte, which exhibited a high ionic conductivity of 82.1 mS cm-1, a high breaking strength of 563.2 kPa, and a wide voltage stability window of 3.5 V. The supercapacitor devices are assembled by the process of direct adhesion of the hydrogel electrolyte and  laser induced graphene (LIG). The micro-supercapacitor exhibited an operating voltage of 2.0 V, with a specific capacitance of 2.41 mF cm-2 and a high energy density of 1.34 µWh cm-2, and it also exhibit a high cycle stability, good flexibility, and integration performance.

The role of the annexin A protein family at the maternal-fetal interface.

Successful pregnancy requires the tolerance of the maternal immune system for the semi-allogeneic embryo, as well as a synchrony between the receptive endometrium and the competent embryo. The annexin family belongs to calcium-regulated phospholipid-binding protein, which functions as a membrane skeleton to stabilize the lipid bilayer and participate in various biological processes in humans. There is an abundance of the annexin family at the maternal-fetal interface, and it exerts a crucial role in embryo implantation and the subsequent development of the placenta. Altered expression of the annexin family and dysfunction of annexin proteins or polymorphisms of the ANXA gene are involved in a range of pregnancy complications. In this review, we summarize the current knowledge of the annexin A protein family at the maternal-fetal interface and its association with female reproductive disorders, suggesting the use of ANXA as the potential therapeutic target in the clinical diagnosis and treatment of pregnancy complications.

'Environmental standard limit concentration' arsenic exposure is associated with anxiety, depression, and autism-like changes in early-life stage zebrafish.

Arsenic is a worldwide environmental pollutant that can impair human health. Previous studies have identified mental disorders induced by arsenic, but the environmental exposure concentrations in the early life stages associated with these disorders are poorly understood. In the present study, early-life stage zebrafish were used to explore the effects on mental disorders under 'environmental standard limit concentrations' arsenic exposures of 5, 10, 50, 150, and 500 µg/L. The results showed that arsenic exposure at these concentrations changed the locomotor behavior in larval zebrafish and was further associated with anxiety, depression, and autism-like behavior in both larval and juvenile zebrafish. Changes were noted at benchmark dose limit (BMDL) concentrations as low as 0.81 µg/L. Transcriptomics showed that immediate early genes (IEGs) fosab, egr1, egr2a, ier2b, egr3, and jund were decreased after arsenic exposure in larval and juvenile zebrafish. Nervous system impairment and anxiety, depression, and autism-like behaviors in early-life stage zebrafish at 'environmental standard limit concentrations' may be attributed to the downregulation of IEGs. These findings in zebrafish provided new experimental support for an arsenic toxicity threshold for mental disorders, and they suggest that low levels of environmental chemicals may be causative developmental factors for mental disorders.

Induction sintilimab and chemotherapy followed by concurrent chemoradiotherapy for locally advanced esophageal cancer: a proof-of-concept, single-arm, multicenter, phase 2 trial.

Background: Concurrent chemoradiotherapy is the standard nonoperative treatment for locally advanced esophageal squamous cell carcinoma. However, local recurrence is still the main failure pattern, accounting for more than half of all treatment failures, indicating that the sensitivity of radiotherapy still needs to be improved. This trial aimed at demonstrating whether PD-1 inhibitors followed by chemoradiotherapy could promote esophageal tumor vascular normalization, alleviate hypoxia, and thus enhance radiosensitivity and improve local control. Methods: We did a multicenter, single-arm, phase 2 trial in China. Patients with locally advanced esophageal cancer were enrolled in this study. In induction phase, patients received two cycles of sintilimab, paclitaxel and carboplatin once per 21 days. In concurrent phase, patients were treated with five cycles of carboplatin and paclitaxel once per week concurrent with radiotherapy of 50.4Gy delivered in 28 fractions. The primary endpoint was 2-year local control rate. Hypoxia and vessel normalization was assessed before and after induction phase using immunofluorescence and perfusion CT. This trial is registered with ClinicalTrials.gov (NCT03985046). Findings: Seventy-five patients with esophageal cancer were enrolled in this study between October 2019 and April 2021. The median follow-up of surviving patients was 33.6 months (IQR 29.3-35.7). The 2-year local control rate was 81.7% (95% confidence interval, 72.7%-90.7%), which was much higher than that in concurrent chemoradiation only (71.3%) in previous studies. Vascular normalization and hypoxia alleviation were observed in both biopsy specimens and perfusion CT. Interpretation: The addition of induction immunotherapy to standard concurrent chemoradiotherapy could improve radiosensitivity for locally advanced esophageal cancer as non-surgical treatment. New treatment combination led to higher local control rate through promoting vascular normalization and alleviating hypoxia. Our findings suggest that induction immunotherapy followed by concurrent chemoradiotherapy could be a potential option in future treatment. Funding: National Natural Science Foundation of China and Shanghai Rising-Star Program.

Superhydrophilic and oleophobic sponges prepared based on Mussel-Inspired chemistry for efficient oil-water separation.

Superhydrophilic/oleophobic materials are considered to be the best materials for achieving oil-water separation, but their preparation is difficult and the existing methods are not universal. In this paper, a two-step modification strategy was used to prepare superhydrophilic/oleophobic sponges by adjusting the polar and nonpolar components of the materials using mussel-inspired chemistry. While remaining superhydrophilic, the modified sponge surface has a maximum contact angle of 135° with different oils in air. The modified sponge exhibited superoleophobicity in water, and the contact angle of oil could reach more than 150°. In addition, the modified sponges were also reusable, chemically stable, and mechanically durable. Its oil-water separation flux was up to 24900 Lm-2 h-1 bar-1 , and the separation efficiency was above 97 %. We believe that this method will provide an environmentally friendly and efficient way to prepare the superhydrophilic/oleophobic materials.

The use of multicomponent reactions in the development of bis-boronic acids for the detection of ß-sialic acid.

Sialic acid (SA) is a naturally occurring monosaccharide found in glycoproteins and glycolipids. Changes in the expression of SA are associated with several diseases; thus, the detection of SA is of great significance for biological research, cancer diagnosis, and treatment. Boronic acid analogs have emerged as a promising tool for detecting sugars such as SA due to its reversible covalent bonding ability. In this study, 11 bis-boronic acid compounds and 2 mono-boronic acid compounds were synthesized via a highly efficient Ugi-4CR strategy. The synthesized compounds were subjected to affinity fluorescence binding experiments to evaluate their binding capability to SA. Compound A1 was shown to have a promising binding constant of 2602 ± 100 M-1 at pH = 6.0. Density Functional Theory (DFT) calculations examining the binding modes between A1 and SA indicated that the position of the boronic acid functional group was strongly correlated with its interaction with SA's α-hydroxy acid unit. The DFT calculations were consistent with the observations from the fluorescence experiments, demonstrating that the number and relative positions of the boronic acid functional groups are critical factors in enhancing the binding affinity to SA. DFT calculations of both S and R configuration of A1 indicated that the effect of the S/R configuration of A1 on its binding with ß-sialic acid was insignificant as the Ugi-4CR generated racemic products. A fluorine atom was incorporated into the R2 substituent of A1 as an electron-withdrawing group to produce A5, which possessed a significantly higher capability to bind to SA (Keq = 7015 ± 5 M-1 at pH = 6.0). Finally, A1 and A5 were shown to possess exceptional binding selectivity toward ß-sialic acid under pH of 6.0 and 6.5 while preferring to bind with glucose, fructose, and galactose under pH of 7.0 and 7.5.

Time-weighted blood pressure with cardiovascular risk among patients with or without diabetes.

BACKGROUND: Usual measures of blood pressure (BP) do not account for both the magnitude and duration of exposure to elevated BP over time. We aimed to demonstrate the effect of a novel time-weighted BP on cardiovascular outcomes using a post hoc analysis of two published randomized trials. HYPOTHESIS: Time-weighted blood pressure is associated with cardiovascular risk among patients with or without diabetes. METHODS: The limited-access ACCORD and SPRINT data sets were used for the current study. Time-weighted BP is obtained by dividing cumulative BP by the total follow-up time. Time-weighted BP burden above a threshold is also determined after deriving the time-weighted BP by re-zeroing the interpolated pressure values at two different hypertension thresholds (>140/90 and >130/80 mmHg). RESULTS: Eighteen thousand five hundred forty-one patients from the two clinical trials were enrolled in this study. A J-curve relation was observed between time-weighted BP and major cardiovascular events (MACE). The systolic blood pressure (SBP) burden independently predicted MACE across the two trials at different thresholds (ACCORD: SBP > 130 mmHg, HR = 1.05 [1.03-1.06]; SBP > 140 mmHg, HR = 1.06 [1.04-1.08]; SPRINT: SBP > 130 mmHg, HR = 1.04 [1.03-1.05]; SBP > 140 mmHg, HR = 1.05 [1.04-1.07]). Consistent results were found for diastolic blood pressure (DBP) burden (ACCORD: DBP > 80 mmHg, HR = 1.10 [1.06-1.15]; DBP > 90 mmHg, HR = 1.20 [1.11-1.30]. SPRINT: DBP > 80 mmHg, HR = 1.06 [1.02-1.09]; DBP > 90 mmHg, HR = 1.12 [1.06-1.18]). Significant associations were also observed for stroke, myocardial infarction, cardiovascular death, and all-cause mortality. CONCLUSION: Both time-weighted SBP and DBP independently influenced the risk of adverse cardiovascular events among patients with and without diabetes, regardless of the definition of hypertension (130/80 or <140/90 mmHg).

Myeloid cell-associated aromatic amino acid metabolism facilitates CNS myelin regeneration.

Regulation of myeloid cell activity is critical for successful myelin regeneration (remyelination) in demyelinating diseases, such as multiple sclerosis (MS). Here, we show aromatic alpha-keto acids (AKAs) generated from the amino acid oxidase, interleukin-4 induced 1 (IL4I1), promote efficient remyelination in mouse models of MS. During remyelination, myeloid cells upregulated the expression of IL4I1. Conditionally knocking out IL4I1 in myeloid cells impaired remyelination efficiency. Mice lacking IL4I1 expression exhibited a reduction in the AKAs, phenylpyruvate, indole-3-pyruvate, and 4-hydroxyphenylpyruvate, in remyelinating lesions. Decreased AKA levels were also observed in people with MS, particularly in the progressive phase when remyelination is impaired. Oral administration of AKAs modulated myeloid cell-associated inflammation, promoted oligodendrocyte maturation, and enhanced remyelination in mice with focal demyelinated lesions. Transcriptomic analysis revealed AKA treatment induced a shift in metabolic pathways in myeloid cells and upregulated aryl hydrocarbon receptor activity in lesions. Our results suggest myeloid cell-associated aromatic amino acid metabolism via IL4I1 produces AKAs in demyelinated lesions to enable efficient remyelination. Increasing AKA levels or targeting related pathways may serve as a strategy to facilitate the regeneration of myelin in inflammatory demyelinating conditions.

Rosmarinic acid alleviate CORT-induced depressive-like behavior by promoting neurogenesis and regulating BDNF/TrkB/PI3K signaling axis.

Rosmarinic acid (RA), a natural phenolic acid compound with a variety of bioactive properties. However, the antidepressant activity and mechanism of RA remain unclear. The aim of this study is to investigate the effects and potential mechanisms of RA on chronic CORT injection induced depression-like behavior in mice. Male C57BL/6 J mice were intraperitoneally injected with CORT (10 mg/kg) and were orally given RA daily (10 or 20 mg/kg) for 21 consecutive days. In vitro, the HT22 cells were exposed to CORT (200 µM) with RA (12.5, 25 or 50 µM) and LY294002 (a PI3K inhibitor) or ANA-12 (a TrkB inhibitor) treatment. The depression-like behavior and various neurobiological changes in the mice and cell injury and levels of target proteins in vitro were subsequently assessed. Here, RA treatment decreased the expression of p-GR/GR, HSP90, FKBP51, SGK-1 in mice hippocampi. Besides, RA increased the average optical density of Nissl bodies and number of dendritic spines in CA3 region, and enhanced Brdu and DCX expression and synaptic transduction in DG region, as well as up-regulated both the BDNF/TrkB/CREB and PI3K/Akt/mTOR signaling. Moreover, RA reduced structural damage and apoptosis in HT22 cells, increased the differentiation and maturation of them. More importantly, LY294002, but not ANA-12, reversed the effect of RA on GR nuclear translocation. Taken together, RA exerted antidepressant activities by modulating the hippocampal glucocorticoid signaling and hippocampal neurogenesis, which related to the BDNF/TrkB/PI3K signaling axis regulating GR nuclear translocation, provide evidence for the application of RA as a candidate for depression.

Comprehensive assessment of occurrence, temporal-spatial variations, and ecological risks of heavy metals in Jiaozhou Bay, China: A comprehensive study.

Heavy metals play a significant role in marine ecosystems, exerting notable impacts on the environment and human health. In this study, water, sediment, and aquatic organism samples from Jiaozhou Bay were investigated to comprehensively assess the distribution, temporal-spatial variations, and ecological risks of heavy metals. The results indicate that pollution from industrial wastewater discharge contributes to regional differences in the distribution of heavy metals, possibly being a major source of Zn, Cr, Cd, and Hg (r > 0.7, p < 0.05). Biological and physicochemical processes influence the distribution of Zn, Cr, and Pb in the water and sediment. Hg exhibits a polluted state in both the water and sediment, with As and Hg being the two highest-risk heavy metals in water and sediment, respectively. Among the organisms, crustaceans show significantly higher levels of heavy metal content and accumulation compared to mollusks and fish (p < 0.05), and the bioamplification of heavy metals occurs in the sediment-Rapana venosa-Portunus trituberculatus biological pathway. Portunus trituberculatus, Charybdis japonica, Oratosquilla oratoria, and Octopus ocellatus could pose risks to human health, especially for children and vulnerable populations. This study aims to enhance our understanding of the current status of heavy metal pollution in Jiaozhou Bay and to provide a scientific basis and favorable support for the ecological environmental protection and prevention of ecological risks associated with heavy metal pollution in Jiaozhou Bay and other bays in China.

Genetic insights into the association of statin and newer nonstatin drug target genes with human longevity: a Mendelian randomization analysis.

BACKGROUND: It remains controversial whether the long-term use of statins or newer nonstatin drugs has a positive effect on human longevity. Therefore, this study aimed to investigate the genetic associations between different lipid-lowering therapeutic gene targets and human longevity. METHODS: Two-sample Mendelian randomization analyses were conducted. The exposures comprised genetic variants that proxy nine drug target genes mimicking lipid-lowering effects (LDLR, HMGCR, PCKS9, NPC1L1, APOB, CETP, LPL, APOC3, and ANGPTL3). Two large-scale genome-wide association study (GWAS) summary datasets of human lifespan, including up to 500,193 European individuals, were used as outcomes. The inverse-variance weighting method was applied as the main approach. Sensitivity tests were conducted to evaluate the robustness, heterogeneity, and pleiotropy of the results. Causal effects were further validated using expression quantitative trait locus (eQTL) data. RESULTS: Genetically proxied LDLR variants, which mimic the effects of lowering low-density lipoprotein cholesterol (LDL-C), were associated with extended lifespan. This association was replicated in the validation set and was further confirmed in the eQTL summary data of blood and liver tissues. Mediation analysis revealed that the genetic mimicry of LDLR enhancement extended lifespan by reducing the risk of major coronary heart disease, accounting for 22.8% of the mediation effect. The genetically proxied CETP and APOC3 inhibitions also showed causal effects on increased life expectancy in both outcome datasets. The lipid-lowering variants of HMGCR, PCKS9, LPL, and APOB were associated with longer lifespans but did not causally increase extreme longevity. No statistical evidence was detected to support an association between NPC1L1 and lifespan. CONCLUSION: This study suggests that LDLR is a promising genetic target for human longevity. Lipid-related gene targets, such as PCSK9, CETP, and APOC3, might potentially regulate human lifespan, thus offering promising prospects for developing newer nonstatin therapies.

Comparative physiological and transcriptome analysis of leaf nitrogen fluxes in stay-green maize during the vegetative stage.

In maize, nitrogen (N) stored in leaves is an important internal source for supporting subsequent growth and development. However, the regulation of N fluxes and photosynthesis and the molecular and genotypic regulations that modify them are less clear in source leaves during the vegetative stage. This knowledge is crucial for improving N use efficiency (NUE). By using 15N labeling and transcriptome methods, an analysis of the physiological and molecular basis of leaf N import and export processes and photosynthetic N use efficiency (PNUE) was conducted in two maize hybrids (XY335 and XY696) with different stay-green characteristics during the vegetative stage. Leaf N import and export in XY696 were 45% and 33% greater than those in XY335. However, the PNUE in XY335 was 17% greater than that in XY696 due to the higher net photosynthetic rate (A) and lower SLN. Correspondingly, the chlorophyll content and photosynthesis-related enzyme (PEPc, PEPck, PPDK) activities increased by 18∼30% in XY335. Transcriptome analysis indicated that the expression levels of several N and carbon metabolism-related genes encoding Rubisco, PEPc, Nir, GS and AS were significantly increased or decreased in XY696 in parallel with enzyme activities. Moreover, there was a large difference in the expression abundance of genes encoding nitrate/nitrite transporters and transmembrane proteins. Our results suggest that two hybrids modulate leaf N fluxes and photosynthesis differently by altering gene expression and enzyme activities. Our study contributes to understanding leaf N fluxes and PNUE regulation and serves as a crucial reference for NUE improvement in maize breeding research.

ITPR1-AS1 promotes small cell lung cancer metastasis by facilitating P21HRAS splicing and stabilizing DDX3X to activate the cRaf-MEK-ERK cascade.

The mechanisms underlying the involvement of long non-coding RNAs (lncRNAs) in the metastasis of small cell lung cancer (SCLC) remain largely unknown. Here, we identified that the lncRNA ITPR1-AS1 was upregulated in SCLC and lymph node metastasis tissues and positively correlated with SCLC malignant features. The overexpression of ITPR1-AS1 in SCLC was an independent risk factor for the overall survival of patients with SCLC. Our data confirmed that ITPR1-AS1 induces SCLC cell metastasis both in vitro and in vivo. Mechanistically, ITPR1-AS1 acts as a scaffold to enhance the interaction between SRC-associated in mitosis 68 kDa and heterogeneous nuclear ribonucleoprotein A1, which facilitates the alternative splicing of the H-Ras proto-oncogene (HRAS) pre-mRNA (P21HRAS). Moreover, we observed that ITPR1-AS1 could associate in a complex with and maintain the stability of DEAD-box polypeptide 3 (DDX3X), which inhibited the latter's ubiquitination and degradation. Our data provide evidence that ITPR1-AS1 activates the cRaf-MEK-ERK cascade by upregulating P21HRAS production and stabilizing DDX3X, to promote SCLC metastasis.

Driving force of tidal pulses on denitrifiers-dominated nitrogen oxide emissions from intertidal wetland sediments.

Intertidal wetland sediments are an important source of atmospheric nitrogen oxides (NOx), but their contribution to the global NOx budget remains unclear. In this work, we conducted year-round and diurnal observations in the intertidal wetland of Jiaozhou Bay to explore their regional source-sink patterns and influence factors on NOx emissions (initially in the form of nitric oxide) and used a dynamic soil reactor to further extend the mechanisms underlying the tidal pulse of nitric oxide (NO) observed in our investigations. The annual fluxes of NOx in the vegetated wetland were significantly higher than those in the wetland without vegetation. Their annual variations could be attributed to changes in temperature and the amount of organic carbon in the sediment, which was derived from vegetated plants and promoted the carbon-nitrogen cycle. Anaerobic denitrifiers had advantages in the intertidal wetland sediment and accounted for the major NO production (63.8 %) but were still limited by nitrite and nitrate concentrations in the sediment. Moreover, the tidal pulse was likely a primary driver of NOx emissions from intertidal wetlands over short periods, which was not considered in previous investigations. The annual NO exchange flux considering the tide pulse contribution (8.93 ± 1.72 × 10-2 kg N ha-1 yr-1) was significantly higher than that of the non-pulse period (4.14 ± 1.13 × 10-2 kg N ha-1 yr-1) in our modeling result for the fluxes over the last decade. Therefore, the current measurement of NOx fluxes underestimated the actual gas emission without considering the tidal pulse.

PKC modulator bryostatin-1 therapeutically targets CNS innate immunity to attenuate neuroinflammation and promote remyelination.

In multiple sclerosis (MS), microglia and macrophages within the central nervous system (CNS) play an important role in determining the balance between myelin repair and demyelination/neurodegeneration. Phagocytic and regenerative functions of these CNS innate immune cells support remyelination, whereas chronic and maladaptive inflammatory activation promotes lesion expansion and disability, particularly in the progressive forms of MS. No currently approved drugs convincingly target microglia and macrophages within the CNS, contributing to the critical lack of therapies promoting remyelination and slowing progression in MS. Here, we found that the protein kinase C (PKC)-modulating drug bryostatin-1 (bryo-1), a CNS-penetrant compound with an established human safety profile, produces a shift in microglia and CNS macrophage transcriptional programs from pro-inflammatory to regenerative phenotypes, both in vitro and in vivo. Treatment of microglia with bryo-1 prevented the activation of neurotoxic astrocytes while stimulating scavenger pathways, phagocytosis, and secretion of factors that promote oligodendrocyte differentiation. In line with these findings, systemic treatment with bryo-1 augmented remyelination following a focal demyelinating injury in vivo. Our results demonstrate the potential of bryo-1 and functionally related PKC modulators as myelin regenerative and neuroprotective agents in MS and other neurologic diseases through therapeutic targeting of microglia and CNS-associated macrophages.