Escin alleviates cerebral ischemia-induced intestinal pyroptosis via the GR-dependent p38 MAPK/NF-κB signaling and NLRP3 inflammasome activation.

Cerebral ischemia-induced systemic inflammation and inflammasome-dependent pyroptotic cell death in ileum, causing serious intestinal injury. Glucocorticoid receptor (GR) mediates the effects of glucocorticoids and participates in inflammation. Escin has corticosteroid-like, neuroprotective, and anti-intestinal dysfunction effects. This study aimed to investigate the effect of Escin on the intestinal barrier injury in rats subjected to middle cerebral artery occlusion (MCAO) and on Caco-2 cells exposed to lipopolysaccharides. The MCAO-caused brain injury was evaluated by assessing neurological function, cerebral infarct volume, and plasma corticosterone (Cort) levels. Intestinal injury was evaluated by observing the histopathological changes, assessing the intestinal barrier function, and determining blood FD4, endotoxin and IL-1ß levels. The levels of the tight-junction proteins such as claudin-1, occludin, and ZO-1, and proteins involved in the GR/p38 MAPK/NF-κB pathway and NLRP3-inflammasome activation were evaluated using western blotting or immunofluorescence. Administration of Escin suppressed the cerebral ischemia-induced increases in Garcia-test scores and infarct volume, alleviated the injury to the intestinal barrier, and decreased the levels of Cort, endotoxin, and IL-1ß. Additionally, Escin upregulated GR and downregulated phospho(p)-p65, p-p38MAPK, NLRP3, GSDMD-N, and cleaved-caspase-1 in the intestine. The effects of Escin could be suppressed by the GR antagonist RU486 or enhanced by the p38 MAPK antagonist SB203580. We revealed details how Escin improves cerebral ischemia-induced intestinal barrier injury by upregulating GR and thereby inhibiting the pyroptosis induced by NF-κB-mediated NLRP3 activation. This study will provide a experimental foundation for the features of glucocorticoid-like activity and the discovery of new clinical application for Escin.

Silica nanoparticle design for colorectal cancer treatment: Recent progress and clinical potential.

Colorectal cancer (CRC) is the third most common cancer worldwide and the second most common cause of cancer death. Nanotherapies are able to selectively target the delivery of cancer therapeutics, thus improving overall antitumor efficiency and reducing conventional chemotherapy side effects. Mesoporous silica nanoparticles (MSNs) have attracted the attention of many researchers due to their remarkable advantages and biosafety. We offer insights into the recent advances of MSNs in CRC treatment and their potential clinical application value.

Threonine Aldolase-Catalyzed Enantioselective α-Alkylation of Amino Acids through Unconventional Photoinduced Radical Initiation.

Visible light-driven pyridoxal radical biocatalysis has emerged as a promising strategy for the stereoselective synthesis of valuable noncanonical amino acids (ncAAs). Previously, the use of well-tailored photoredox catalysts represented the key to enable efficient pyridoxal phosphate (PLP) enzyme-catalyzed radical reactions. Here, we report a PLP-dependent threonine aldolase-catalyzed asymmetric α-C-H alkylation of abundant amino acids using Katritzky pyridinium salts as alkylating agents. The use of engineered threonine aldolases allowed for this redox-neutral radical alkylation to proceed efficiently, giving rise to challenging α-trisubstituted and -tetrasubstituted ncAA products in a protecting-group-free fashion with excellent enantiocontrol. Mechanistically, this enantioselective α-alkylation capitalizes on the unique reactivity of the persistent enzymatic quinonoid intermediate derived from the PLP cofactor and the amino acid substrate to allow for novel radical C-C coupling. Surprisingly, this photobiocatalytic process does not require the use of well-established photoredox catalysts and operates through an unconventional photoinduced radical generation involving a PLP-derived aldimine. The ability to develop photobiocatalytic reactions without relying on classic photocatalysts or photoenzymes opens up new avenues for advancing stereoselective intermolecular radical reactions that are not known in either organic chemistry or enzymology.

Optimization of extended Kozak elements enhances recombinant proteins expression in CHO cells.

In eukaryotes, the localization of small ribosomal subunits to mRNA transcripts requires the translation of Kozak elements at the starting site. The sequence of Kozak elements affects the translation efficiency of protein synthesis. However, whether the upstream nucleotide of Kozak sequence affects the expression of recombinant proteins in Chinese hamster ovary (CHO) cells remains unclear. In order to find the optimal sequence to enhance recombinant proteins expression in CHO cells, -10 to +4 sequences around ATG in 100 CHO genes were compared, and the extended Kozak elements with different translation intensities were constructed. Using the classic Kozak element as control, the effects of optimized extended Kozak elements on the secreted alkaline phosphatase (SEAP) and human serum albumin (HSA) gene were studied. The results showed that the optimized extended Kozak sequence can enhance the stable expression level of recombinant proteins in CHO cells. Furthermore, it was found that the increased expression level of the recombinant protein was not related with higher transcription level. In summary, optimizing extended Kozak elements can enhance the expression of recombinant proteins in CHO cells, which contributes to the construction of an efficient expression system for CHO cells.

In vivo Assessment of AMP2, a Novel Ceramic-Binding BMP-2, in Ovine Lumbar Interbody Fusion.

STUDY DESIGN: Assessment of bone formation in an ovine interbody fusion study. OBJECTIVE: To compare OsteoAdapt SP which consists of AMP-2, a modified variant of recombinant human bone morphogenetic protein (rhBMP-2) bound to a tricalcium phosphate-containing carrier, to autologous iliac crest bone graft (ICBG) in a lumbar interbody fusion model. SUMMARY OF BACKGROUND DATA: Treatment of lumbar disc degeneration often involves spinal fusion to reduce pain and motion at the affected spinal segment by insertion of a cage containing bone graft material. Three graft materials were compared in this study - ICBG and OsteoAdapt SP (low or high dose). METHODS: Sheep underwent lateral lumbar fusion surgery with PEEK or Titanium interbody cages packed with OsteoAdapt SP (low or high dose) or ICBG. Outcomes were evaluated at 8-, 16- and 26- weeks. Newly formed bone quality, bone mineralization, and fusion were assessed by manual palpation, qualitative and semi-quantitative histopathology, histomorphometry, computed tomography (CT) and microCT (mCT) analysis. RESULTS: OsteoAdapt SP was implanted into 43 animals and ICBG into 21 animals (L3-L4). No group showed evidence of systemic toxicity by multiple assessments. All levels were fused by manual palpation at 26-weeks. Serial CT scans showed increasing fusion scores over time. Both doses of OsteoAdapt SP resulted in robust new bone formation and progression of fusion in the interbody cage. Range of motion tests for treatment groups were lower compared to ICBG at 8- and 16-weeks. Similarly, histology at 8-weeks demonstrated more robust new bone formation for both OsteoAdapt SP groups compared to autograft. CONCLUSION: We have demonstrated the preclinical safety and efficacy of OsteoAdapt SP in a clinically relevant large animal model; supporting faster and more robust new bone formation within the interbody cage, comparable to or better than the gold standard, ICBG, in all measures.

Incidence and patterns of lymph node metastases in head and neck rhabdomyosarcoma: One-institution study.

INTRODUCTION: Head and neck rhabdomyosarcoma (HNRMS) is an aggressive malignant soft tissue tumor that easily develops lymph node metastasis (LNM) and distant metastasis. No literature investigates the pattern of LNM in HNRMS. METHODS: Ninety-five consecutive patients with HNRMS newly diagnosed at one institution between November 2011 and July 2023 were retrospectively reviewed. All the patients underwent head and neck contrast-enhanced MRI and/or CT, PET-CT if necessary. The associations between LNMs and clinical characteristics and histopathological parameters were discovered. RESULTS: 44.2% of patients had evidence of LNM at diagnosis, and the most common LNM occurred in the ipsilateral retropharyngeal space. The primary tumor metastasizes to the retropharyngeal space, and then next to level II is the most common LN drainage basin. In multivariate analysis, only distant metastasis determines the prognosis, other than LN status. CONCLUSIONS: LNM has a high incidence in HNRMS and rarely causes contralateral metastasis for localized lesions or skip metastasis.

Integration of High-Resolution LC-Q-TOF Mass Spectrometry and Multidimensional Chemical-Biological Analysis to Detect Nanomolar-Level Acetylcholinesterase Inhibitors from Different Parts of Zanthoxylum nitidum.

Zanthoxyli radix is a popular tea among the elderly, and it is believed to have a positive effect on Alzheimer's disease. In this study, a highly effective three-step strategy was proposed for comprehensive analysis of the active components and biological functions of Zanthoxylum nitidum (ZN), including high-resolution LC-Q-TOF mass spectrometry (HRMS), multivariate statistical analysis for heterogeneity (MSAH), and experimental and virtual screening for bioactivity analysis (EVBA). A total of 117 compounds were identified from the root, stem, and leaf of ZN through HRMS. Bioactivity assays showed that the order of acetylcholinesterase (AChE) inhibitory activity from strong to weak was root > stem > leaf. Nitidine, chelerythrine, and sanguinarine were found to be the main differential components of root, stem, and leaf by OPLS-DA. The IC50 values of the three compounds are 0.81 ± 0.02, 0.14 ± 0.01, and 0.48 ± 0.01 µM respectively, indicating that they are potent and high-quality AChE inhibitors. Molecular docking showed that pi-pi T-shaped interactions and pi-lone pairs played important roles in AChE inhibition. This study not only explains the biological function of Zanthoxyli radix in alleviating Alzheimer's disease to some extent, but also lays the foundation for the development of stem and leaf of ZN.

Aerophobic P-MoS2 on MOF-Derived Co,N-Codoped Carbon Nanosheets with Accelerated H2 Bubble Release Dynamics for Efficient Alkaline Water Splitting at 1000 mA cm-2.

Rapid bubble release at high current densities results in the detachment of catalysts and performance degradation, posing a persistent challenge in actual alkaline water electrolysis (AWE). Here, hierarchical nanosheet structures (CoNC@P-MoS2) are constructed, with P-doped MoS2 on the surface of Co,N-codoped carbon. It exhibits low hydrogen evolution reaction overpotentials of 30 and 354 mV at 10 and 1000 mA cm-2 in 1 M KOH, respectively, with a small Tafel slope of 36 mV dec-1. The constructed CoNC@P-MoS2||NiFe-DLH cell requires only 1.44 and 1.92 V to achieve overall water splitting at 10 and 1000 mA cm-2, which outperforms the traditional catalysts like Pt/C||IrO2. The introduction of P stabilizes surface hydroxyl (OH*) and increases the proton penetration depth, thereby greatly enhancing its intrinsic activity. It also makes the surface aerophobic by introducing more microfeatures, which greatly improves the geometric activity by increasing the bubble release rate (∼5.8 times). Low energy consumption of 3.92 kW h Nm-3 was achieved with an energy efficiency close to 80%. Bubble growth kinetics analysis reveals that the time and growth factors for CoNC@P-MoS2 are increased to 0.54 and 11.79 from 0.45 and 6.09 for CoNC, respectively, which highlights its fast bubble reaction dynamics. The results suggest the feasibility of CoNC@P-MoS2 as a potential high-performance catalyst in commercial AWE.

[Chemical constituents from stems and leaves of Artocarpus tonkinensis and their inhibitory effects on proliferation of synovioblasts in vitro].

The chemical constituents from the stems and leaves of Artocarpus tonkinensis in Artocarpus of Moraceae were systematically studied by means of silica gel, octadecylsilyl(ODS), and Sephadex LH-20 gel column chromatographies, as well as preparative high-performance liquid chromatography(Pre-HPLC) and a variety of chromatographic separation techniques. The spectral data and physicochemical properties of the compounds were obtained from separation and compared with those of the compounds reported in the literature. As a result, 11 compounds isolated from the 90% ethanol extract of the stems and leaves of A. tonkinensis were identified as artocatonkine(1), 5,6,7,4'-tetramethoxyflavone(2), apigenin-4'-O-ß-D-glucoside(3), rayalinol(4), psorachalcone A(5), 4-ketopinoresinol(6), ficusesquilignan B(7), pinnatifidanin AI(8), pinnatifidanin A(9), O-methylmellein(10), and trans-4-hydroxymellein(11). Among these compounds, compound 1 was a new prenylated flavone, and compounds 2-11 were isolated from the plants belonging to the genus Artocarpus for the first time. Furthermore, all compounds 1-11 were evaluated for their anti-rheumatoid arthritis activities, and the MTS method was used to measure their inhibitory effects on the proliferation of synovioblasts in vitro. The results of activity evaluation showed that flavonoid compounds 1-3, 5, and lignan compounds 8 and 9 displayed significant anti-rheumatoid arthritis activities, showing the IC_(50) values in inhibiting the proliferation of synovioblasts MH7A from(6.38±0.06) µmol·L~(-1) to(168.58±0.28)µmol·L~(-1).

[Mechanism of protective effect of n-butanol extract of Pulsatilla Decoction on vaginal epithelial cells under Candida albicans stimulation through EGFR/MAPK pathway based on transcriptomics].

This study aimed to investigate the protective effect and its underlying mechanism of n-butanol extract of Pulsatilla Decoction(BEPD) containing medicinal serum on vaginal epithelial cells under Candida glabrata stimulation via the epidermal growth factor receptor/mitogen activated protein kinase( EGFR/MAPK) pathway based on transcriptomics. A vulvovaginal candidiasis(VVC) mouse model was established first and transcriptome sequencing was performed for the vaginal mucosa tissues to analyze the gene expression differences among the control, VVC model, and BEPD intervention groups. Simultaneously, BEPD-containing serum and fluconazole-containing serum were prepared. A431 cells were divided into the control, model, blank serum, fluconazole-containing serum, BEPD-containing serum, EGFR agonist and EGFR inhibitor groups. Additionally, in vitro experiments were conducted using BEPD-containing serum, fluconazole-containing serum, and an EGFR agonist and inhibitor to investigate the intervention mechanisms of BEPD on C. glabrata-induced vaginal epithelial cell damage. Cell counting kit-8(CCK-8) assay was utilized to determine the safe concentrations of C. glabrata, drug-containing serum, and compounds on A431 cells. Enzyme-linked immunosorbent assay(ELISA)was employed to measure the expression levels of interleukin(IL)-1ß, IL-6, granulocyte-macrophage colony-stimulating factor(GMCSF), granulocyte CSF(G-CSF), chemokine(C-X-C motif) ligand 20(CCL20), and lactate dehydrogenase(LDH). Gram staining was used to evaluate the adhesion of C. glabrata to vaginal epithelial cells. Flow cytometry was utilized to assess the effect of C.glabrata on A431 cell apoptosis. Based on the transcriptomics results, immunofluorescence was performed to measure the expressions of p-EGFR and p-ERK1/2 proteins, while Western blot validated the expressions of p-EGFR, p-ERK1/2, p-C-Fos, p-P38, Bax and Bcl-2 proteins. Sequencing results showed that compared with the VVC model, BEPD treatment up-regulated 1 075 genes and downregulated 927 genes, mainly enriched in immune-inflammatory pathways, including MAPK. Mechanistically, BEPD significantly reduced the expression of p-EGFR, p-ERK1/2, p-C-Fos and p-P38, as well as the secretion of IL-1ß, IL-6, GM-CSF, G-CSF and CCL20, LDH release induced by C. glabrata, and the adhesion of C. glabrata to A431 cells, suggesting that BEPD exerts a protective effect on vaginal epithelial cells damaged by C. glabrata infection by modulating the EGFR/MAPK axis. In addition, BEPD downregulated the pro-apoptotic protein Bax expression and up-regulated the anti-apoptotic protein Bcl-2 expression, leading to a reduction in C. glabrata-induced cell apoptosis. In conclusion, this study reveals that the intervention of BEPD in C. glabrata-induced VVC may be attributed to its regulation of the EGFR/MAPK pathway, which protects vaginal epithelial cells.

Natural Affinity Driven Modification by Silicene to Construct a "Thermal Switch" for Tumorous Bone Loss.

Tumorous bone defects present significant challenges for surgical bio-reconstruction due to the dual pathological conditions of residual tumor presence and extensive bone loss following excision surgery. To address this challenge, a "thermal switch" smart bone scaffold based on the silicene nanosheet-modified decalcified bone matrix (SNS@DBM) is developed by leveraging the natural affinity between collagen and silicene, which is elucidated by molecular dynamics simulations. Benefitting from its exceptional photothermal ability, biodegradability, and bioactivity, the SNS@DBM "thermal switch" provides an integrated postoperative sequential thermotherapy for tumorous bone loss by exerting three levels of photothermal stimulation (i.e., strong, moderate, and nonstimulation). During the different phases of postoperative bioconstruction, the SNS@DBM scaffold realizes simultaneous residual tumor ablation, tumor recurrence prevention, and bone tissue regeneration. These biological effects are verified in the tumor-bearing nude mice of patient-derived tissue xenografts and critical cranium defect rats. Mechanism research prompts moderate heat stimulus generated by and coordinating with SNSs can upregulate osteogenic genes, promote macrophages M2 polarization, and intensify angiogenesis of H-type vessels. This study introduces a versatile approach to the management of tumorous bone defects.

Comparative analysis of the fatty acid profiles in goat milk during different lactation periods and their interactions with volatile compounds and metabolites.

This study aimed to compare the composition of fatty acids in goat milk during lactation with human milk, as well as analyze the differences in their interaction with odor and metabolites. Polyunsaturated fatty acids content was higher in human milk, while odd-chain, branched-chain, and monounsaturated fatty acids content were higher in goat milk with a decreasing trend during lactation. PUFAs in human milk undergo auto-oxidation to produce aldehydes (hexanal), giving it a mild aroma. Butyric acid in goat colostrum mediates the synthesis and auto-oxidation of PUFA, while taurine mediated the hydrolysis of amino acids. They produce a furanone compound (2(5H)-furanone) with a buttery flavor. The presence of butyric acid in goat transitional milk had an impact on flavor and metabolites. The medium chain fatty acid composition of the goat mature milk was affected by nucleic acid compounds, which then oxidized to produce methyl ketone (2-nonanone), giving it an unpleasant flavor.

A strategy to distinguish similar traditional Chinese medicines by liquid chromatography-mass spectrometry, electronic senses, and gas chromatography-ion mobility spectrometry: Marsdeniae tenacissimae Caulis and Paederiae scandens Caulis as examples.

INTRODUCTION: Marsdeniae tenacissimae Caulis (MTC), a popular traditional Chinese medicine, has been widely used in the treatment of tumor diseases. Paederiae scandens Caulis (PSC), which is similar in appearance to MTC, is a common counterfeit product. It is difficult for traditional methods to effectively distinguish between MTC and PSC. Therefore, there is an urgent need for a rapid and accurate method to identify MTC and PSC. OBJECTIVES: The aim is to distinguish between MTC and PSC by analyzing the differences in nonvolatile organic compounds (NVOCs), taste, odor, and volatile organic compounds (VOCs). METHODS: Liquid chromatography-mass spectrometry (LC-MS) was utilized to analyze the NVOCs of MTC and PSC. Electronic tongue (E-tongue) and electronic nose (E-nose) were used to analyze their taste and odor respectively. Gas chromatography-ion mobility spectrometry (GC-IMS) was applied to analyze VOCs. Finally, multivariate statistical analyses were conducted to further investigate the differences between MTC and PSC, including principal component analysis, orthogonal partial least squares discriminant analysis, discriminant factor analysis, and soft independent modeling of class analysis. RESULTS: The results of this study indicate that the integrated strategy of LC-MS, E-tongue, E-nose, GC-IMS, and multivariate statistical analysis can be effectively applied to distinguish between MTC and PSC. Using LC-MS, 25 NVOCs were identified in MTC, while 18 NVOCs were identified in PSC. The major compounds in MTC are steroids, while the major compounds in PSC are iridoid glycosides. Similarly, the distinct taste difference between MTC and PSC was precisely revealed by the E-tongue. Specifically, the pronounced bitterness in PSC was proven to stem from iridoid glycosides, whereas the bitterness evident in MTC was intimately tied to steroids. The E-nose detected eight odor components in MTC and six in PSC, respectively. The subsequent statistical analysis uncovered notable differences in their odor profiles. GC-IMS provided a visual representation of the differences in VOCs between MTC and PSC. The results indicated a relatively high relative content of 82 VOCs in MTC, contrasted with 32 VOCs exhibiting a similarly high relative content in PSC. CONCLUSION: In this study, for the first time, the combined use of LC-MS, E-tongue, E-nose, GC-IMS, and multivariate statistical analysis has proven to be an effective method for distinguishing between MTC and PSC from multiple perspectives. This approach provides a valuable reference for the identification of other visually similar traditional Chinese medicines.

Synthesis of two Fluorescent Complexes and Their use as Multifunctional Nanomedicine Carriers for Rhabdomyosarcoma Treatment.

This study focuses on the design and synthesis of two novel coordination polymers (CPs), named 1 and 2, with excellent fluorescent properties. Their structures were characterized by X-ray single-crystal diffraction, revealing that both materials exhibit promising fluorescence performance, indicating their potential as fluorescent detection tools. Additionally, 1 was chosen to be combined with chitosan (CS), resulting in the successful fabrication of a biodegradable and non-toxic efficient drug carrier, termed CS-1@Cisplatin. This carrier possesses a large surface area and good solubility, enabling sustained drug release to target cells. Given that CXC motif chemokine receptor type 4 (CXCR4) is a key marker gene highly expressed in Rhabdomyosarcoma (RMS) cells and tissues, RMS was chosen as the biological model for testing. The results demonstrated that CS-1@Cisplatin effectively inhibited the invasiveness of RMS cells by significantly suppressing CXCR4 expression. Therefore, the system shows great potential for applications in RMS treatment, biometrics, and drug delivery, particularly in its unique advantage of targeting RMS by inhibiting the key marker gene CXCR4.

Identification of DNase I hypersensitive sites in the human genome by multiple sequence descriptors.

DNase I hypersensitive sites (DHSs) are chromatin regions highly sensitive to DNase I enzymes. Studying DHSs is crucial for understanding complex transcriptional regulation mechanisms and localizing cis-regulatory elements (CREs). Numerous studies have indicated that disease-related loci are often enriched in DHSs regions, underscoring the importance of identifying DHSs. Although wet experiments exist for DHSs identification, they are often labor-intensive. Therefore, there is a strong need to develop computational methods for this purpose. In this study, we used experimental data to construct a benchmark dataset. Seven feature extraction methods were employed to capture information about human DHSs. The F-score was applied to filter the features. By comparing the prediction performance of various classification algorithms through five-fold cross-validation, random forest was proposed to perform the final model construction. The model could produce an overall prediction accuracy of 0.859 with an AUC value of 0.837. We hope that this model can assist scholars conducting DNase research in identifying these sites.

Engineering an enzyme-like catalytic sensor for on-site dual-mode evaluation of total antioxidant capacity.

A novel Fe-MoOx nanozyme, engineered with enhanced peroxidase (POD)-like activity through strategic doping and the creation of oxygen vacancies, is introduced to catalyze the oxidation of TMB with high efficiency. Furthermore, Fe-MoOx is responsive to single electron transfer (SET) and hydrogen atom transfer (HAT) mechanisms related to antioxidants and can serve as a desirable nanozyme for total antioxidant capacity (TAC) determination. The TAC colorimetric platform can reach a low LOD of 0.512 µM in solution and 24.316 µM in the smartphone-mediated RGB hydrogel (AA as the standard). As proof of concept, the practical application in real samples was explored. The work paves a promising avenue to design diverse nanozymes for visual on-site inspection of food quality.

Enhanced drug resistance suppression by serum-stable micelles from multi-arm amphiphilic block copolymers and tocopheryl polyethylene glycol 1000 succinate.

Aim: To develop a robust drug-delivery system using multi-arm amphiphilic block copolymers for enhanced efficacy in cancer therapy. Materials & methods: Two series of amphiphilic polymer micelles, PEG-b-PCLm and PEG-b-PCLm/TPGS, were synthesized. Doxorubicin (DOX) loading into the micelles was achieved via solvent dialysis. Results: The micelles displayed excellent biocompatibility, narrow size distribution, and uniform morphology. DOX-loaded micelles exhibited enhanced antitumor efficacy and increased drug accumulation at tumor sites compared with free DOX. Additionally, 4A-PEG47-b-PCL21/TPGS micelles effectively suppressed drug-resistant MCF-7/ADR cells. Conclusion: This study introduces a novel micelle formulation with exceptional serum stability and efficacy against drug resistance, promising for cancer therapy. It highlights innovative strategies for refining clinical translation and ensuring sustained efficacy and safety in vivo.

[Box: see text].

Mendelian randomization evidence for the causal effect of mental well-being on healthy aging.

Mental well-being relates to multitudinous lifestyle behaviours and morbidities and underpins healthy aging. Thus far, causal evidence on whether and in what pattern mental well-being impacts healthy aging and the underlying mediating pathways is unknown. Applying genetic instruments of the well-being spectrum and its four dimensions including life satisfaction, positive affect, neuroticism and depressive symptoms (n = 80,852 to 2,370,390), we performed two-sample Mendelian randomization analyses to estimate the causal effect of mental well-being on the genetically independent phenotype of aging (aging-GIP), a robust and representative aging phenotype, and its components including resilience, self-rated health, healthspan, parental lifespan and longevity (n = 36,745 to 1,012,240). Analyses were adjusted for income, education and occupation. All the data were from the largest available genome-wide association studies in populations of European descent. Better mental well-being spectrum (each one Z-score higher) was causally associated with a higher aging-GIP (ß [95% confidence interval (CI)] in different models ranging from 1.00 [0.82-1.18] to 1.07 [0.91-1.24] standard deviations (s.d.)) independent of socioeconomic indicators. Similar association patterns were seen for resilience (ß [95% CI] ranging from 0.97 [0.82-1.12] to 1.04 [0.91-1.17] s.d.), self-rated health (0.61 [0.43-0.79] to 0.76 [0.59-0.93] points), healthspan (odds ratio [95% CI] ranging from 1.23 [1.02-1.48] to 1.35 [1.11-1.65]) and parental lifespan (1.77 [0.010-3.54] to 2.95 [1.13-4.76] years). Two-step Mendelian randomization mediation analyses identified 33 out of 106 candidates as mediators between the well-being spectrum and the aging-GIP: mainly lifestyles (for example, TV watching and smoking), behaviours (for example, medication use) and diseases (for example, heart failure, attention-deficit hyperactivity disorder, stroke, coronary atherosclerosis and ischaemic heart disease), each exhibiting a mediation proportion of >5%. These findings underscore the importance of mental well-being in promoting healthy aging and inform preventive targets for bridging aging disparities attributable to suboptimal mental health.

The asymmetric expression of plasma membrane H+-ATPase family genes in response to pulvinus-driven leaf phototropism movement in Vitis vinifera.

Phototropism movement is crucial for plants to adapt to various environmental changes. Plant P-type H+-ATPase (HA) plays diverse roles in signal transduction during cell expansion, regulation of cellular osmotic potential and stomatal opening, and circadian movement. Despite numerous studies on the genome-wide analysis of Vitis vinifera, no research has been done on the P-type H+-ATPase family genes, especially concerning pulvinus-driven leaf movement. In this study, 55 VvHAs were identified and classified into nine distinct subgroups (1 to 9). Gene members within the same subgroups exhibit similar features in motif, intron/exon, and protein tertiary structures. Furthermore, four pairs of genes were derived by segmental duplication in grapes. Cis-acting element analysis identified numerous light/circadian-related elements in the promoters of VvHAs. qRT-PCR analysis showed that several genes of subgroup 7 were highly expressed in leaves and pulvinus during leaf movement, especially VvHA14, VvHA15, VvHA16, VvHA19, VvHA51, VvHA52, and VvHA54. Additionally, we also found that the VvHAs genes were asymmetrically expressed on both sides of the extensor and flexor cell of the motor organ, the pulvinus. The expression of VvHAs family genes in extensor cells was significantly higher than that in flexor cells. Overall, this study serves as a foundation for further investigations into the functions of VvHAs and contributes to the complex mechanisms underlying grapevine pulvinus growth and development.