Adverse event profile of memantine and donepezil combination therapy: a real-world pharmacovigilance analysis based on FDA adverse event reporting system (FAERS) data from 2004 to 2023.

Background: Donepezil in combination with memantine is a widely used clinical therapy for moderate to severe dementia. However, real-world population data on the long-term safety of donepezil in combination with memantine are incomplete and variable. Therefore, the aim of this study was to analyze the adverse events (AEs) of donepezil in combination with memantine according to US Food and Drug Administration Adverse Event Reporting System (FAERS) data to provide evidence for the safety monitoring of this therapy. Methods: We retrospectively analyzed reports of AEs associated with the combination of donepezil and memantine from 2004 to 2023 extracted from the FAERS database. Whether there was a significant association between donepezil and memantine combination therapy and AEs was assessed using four disproportionality analysis methods, namely, the reporting odds ratio, proportional reporting ratio, Bayesian confidence propagation neural network, and multi-item gamma Poisson shrinker methods. To further investigate potential safety issues, we also analyzed differences and similarities in the time of onset and incidence of AEs stratified by sex and differences and similarities in the incidence of AEs stratified by age. Results: Of the 2,400 adverse drug reaction (ADR) reports in which the combination of donepezil and memantine was the primary suspected drug, most of the affected patients were female (54.96%) and older than 65 years of age (79.08%). We identified 22 different system organ classes covering 100 AEs, including some common AEs such as dizziness and electrocardiogram PR prolongation; fall, pleurothotonus and myoclonus were AEs that were not listed on the drug label. Moreover, we obtained 88 reports of AEs in men and 100 reports of AEs in women; somnolence was a common AE in both men and women and was more common in women, whereas pleurothotonus was a more common AE in men. In addition, we analyzed 12 AEs in patients younger than 18 years, 16 in patients between 18 and 65 years, and 113 in patients older than 65 years. The three age groups had distinctive AEs, but lethargy was the common AE among all age groups. Finally, the median time to AE onset was 19 days in all cases. In both men and women, most AEs occurred within a month of starting donepezil plus memantine, but some continued after a year of treatment. Conclusion: Our study identified potential and new AEs of donepezil in combination with memantine; some of these AEs were the same as in the specification, and some of the AE signals were not shown in the specification. In addition, there were sex and age differences in some of the AEs. Therefore, our findings may provide valuable insights for further studies on the safety of donepezil and memantine combination therapy, which are expected to contribute to the safe use of this therapy in clinical practice.

AGAMOUS-LIKE 24 senses continuous inductive photoperiod in the inflorescence meristem to promote anthesis in chrysanthemum.

During the floral transition, many plant species including chrysanthemum (Chrysanthemum morifolium) require continuous photoperiodic stimulation for successful anthesis. Insufficient photoperiodic stimulation results in flower bud arrest or even failure. The molecular mechanisms underlying how continuous photoperiodic stimulation promotes anthesis are not well understood. Here, we reveal that in wild chrysanthemum (C. indicum), an obligate short-day (SD) plant, floral evocation is not limited to SD conditions. However, SD signals generated locally in the inflorescence meristem (IM) play a vital role in ensuring anthesis after floral commitment. Genetic analyses indicate that the florigen FLOWERING LOCUS T-LIKE3 (CiFTL3) plays an important role in floral evocation, but a lesser role in anthesis. Importantly, our data demonstrate that AGAMOUS-LIKE 24 (CiAGL24) is a critical component of SD signal perception in the IM to promote successful anthesis, and that floral evocation and anthesis are two separate developmental events in chrysanthemum. We further reveal that the central circadian clock component PSEUDO-RESPONSE REGULATOR 7 (CiPRR7) in the IM activates CiAGL24 expression in response to SD conditions. Moreover, our findings elucidate a negative feedback loop in which CiAGL24 and SUPPRESSOR OF OVEREXPRESSION OF CO 1 (CiSOC1) modulate LEAFY (CiLFY) expression. Together, our results demonstrate that the CiPRR7-CiAGL24 module is vital for sustained SD signal perception in the IM to ensure successful anthesis in chrysanthemum.

Landscape of transcriptome-wide m6A modification in diabetic liver reveals rewiring of PI3K-Akt signaling after physical exercise.

AIM: Type 2 diabetes mellitus (T2DM) is one of the most common diseases, and epigenetic modification N6-methyladenosine (m6A) is essential for transcriptional modulation involved in its development. However, the precise role and landscape of transcriptome-wide m6A alterations in molecular adaptations after physical exercise have yet to be fully elucidated. METHODS: Four-week-old male C57BL/6J mice received a high-fat diet (HFD) for 12 weeks to establish a diabetic state, and HFD mice were simultaneously subjected to physical exercise (HFD + EX). The hepatic RNA m6A methylome was examined, the conjoint MeRIP-seq and RNA-seq was performed, and the exercise-modulated genes were confirmed. RESULTS: Physical exercise significantly ameliorates liver metabolic disorder and triggers a dynamic change in hepatic RNA m6A. By analyzing the distribution of m6A in transcriptomes, an abundance of m6A throughout mRNA transcripts and a pattern of conserved m6A after physical exercise was identified. It is noteworthy that conjoint MeRIP-seq and RNA-seq data revealed that both differentially methylated genes and differentially expressed genes were enriched in all stages of the PI3K-Akt signaling pathway, in particular the upstream nodes of this pathway, which are considered a valuable therapeutic target for T2DM. Moreover, in vivo and in vitro analyses showed that exercise-mediated methyltransferase Rbm15 positively regulated the expression of two upstream genes (Itga3 and Fgf21) in an m6A-dependent manner. CONCLUSION: These findings highlight the pivotal role of the exercise-induced m6A epigenetic network and contribute insights into the intricate epigenetic mechanism underlying insulin signaling.

Effects of different curing concentrations and drying times on the microbial community structure and metabolites of dried Spanish mackerel.

Cured Spanish mackerel has a promising market owing to its nutritious nature as well as ease of transportation and preservation. However, the nutritional and flavor formation mechanism of Spanish mackerel after curing and drying is unclear. To overcome this problem, the effects of different processing conditions on the free amino acid, microbial community, and flavor of Spanish mackerel were explored. Staphylococcus and Cobetia are the main microorganisms in cured mackerel and are closely associated with the formation of their quality. Compared with fresh mackerel, cured mackerel contains increased levels of protein, fat, and chloride, contributing to its distinctive flavor. The contents of free amino acids in the BA64 group were substantially higher than those in other groups, particularly the contents of threonine, glycine, and tyrosine. These findings will contribute to the development of high-quality cured Spanish mackerel products and cured aquatic products.

Global scientific trends in research of epigenetic response to exercise: A bibliometric analysis.

The purpose of this work is to comprehensively understand the adaptive response of multiple epigenetic modifications on gene expression changes driven by exercise. Here, we retrieved literatures from publications in the PubMed and Web of Science Core Collection databases up to and including October 15, 2023. After screening with the exclusion criteria, 1910 publications were selected in total, comprising 1399 articles and 511 reviews. Specifically, a total of 512, 224, and 772 publications is involved in DNA methylation, histone modification, and noncoding RNAs, respectively. The correlations between publication number, authors, institutions, countries, references, and the characteristics of hotspots were explored by CiteSpace. Here, the USA (621 publications) ranked the world's most-influential countries, the University of California System (68 publications) was the most productive, and Tiago Fernandes (14 publications) had the most-published publications. A comprehensive keyword analysis revealed that cardiovascular disease, cancer, skeletal muscle development, and metabolic syndrome, and are the research hotspots. The detailed impact of exercise was further discussed in different aspects of these three categories of epigenetic modifications. Detailed analysis of epigenetic modifications in response to exercise, including DNA methylation, histone modification, and changes in noncoding RNAs, will offer valuable information to help researchers understand hotspots and emerging trends.

Identification and verification on prognostic index of glioblastoma immune-related lncRNAs.

BACKGROUND: Glioblastoma (GBM) is the most common cause of primary brain malignancy. Recently, many immune-related long noncoding ribonucleic acids (ir-lncRNAs) are indicated to be closely related to the regulation of the immune microenvironment and immune cell infiltration of GBM. OBJECTIVES: Through the joint analysis of multiple public databases, key ir-lncRNAs in GBM were screened. The ir-lncRNAs were used to construct risk-scoring models and promote the development of novel GBM biomarkers. MATERIAL AND METHODS: In this study, we performed a three-way Venn analysis combined with a least absolute shrinkage and selection operator (LASSO) regression analysis on all lncRNAs in The Cancer Genome Atlas (TCGA), the Chinese Glioma Genome Atlas (CGGA) and Imm-Lnc datasets, and identified 10 ir-lncRNAs. Multivariate Cox analysis was used to calculate the coefficient and construct a risk-scoring model. RESULTS: By plotting calibration curves and receiver operating characteristic (ROC) curves, the model showed excellent prediction results. Based on the Tumor Immune Estimation Resource (TIMER) database, the correlation analysis showed that 10 ir-lncRNAs risk scores were related to immune cell infiltration. The enrichment analysis was subsequently performed, which showed that these ir-lncRNAs played an important role in the progression of GBM. Among the 10 lncRNAs, we found that AL354993.1 was highly expressed in GBM, had not been reported, and was shown to be closely related to GBM progression. CONCLUSIONS: In conclusion, the 10 ir-lncRNAs have the potential to predict the prognosis of GBM patients and may play a vital role in the progression of the disease.

The F-box protein RhSAF destabilizes the gibberellic acid receptor RhGID1 to mediate ethylene-induced petal senescence in rose.

Roses are among the most popular ornamental plants cultivated worldwide for their great economic, symbolic, and cultural importance. Nevertheless, rapid petal senescence markedly reduces rose (Rosa hybrida) flower quality and value. Petal senescence is a developmental process tightly regulated by various phytohormones. Ethylene accelerates petal senescence, while gibberellic acid (GA) delays this process. However, the molecular mechanisms underlying the crosstalk between these phytohormones in the regulation of petal senescence remain largely unclear. Here, we identified SENESCENCE-ASSOCIATED F-BOX (RhSAF), an ethylene-induced F-box protein gene encoding a recognition subunit of the SCF-type E3 ligase. We demonstrated that RhSAF promotes degradation of the GA receptor GIBBERELLIN INSENSITIVE DWARF1 (RhGID1) to accelerate petal senescence. Silencing RhSAF expression delays petal senescence, while suppressing RhGID1 expression accelerates petal senescence. RhSAF physically interacts with RhGID1s and targets them for ubiquitin/26S proteasome-mediated degradation. Accordingly, ethylene-induced RhGID1C degradation and RhDELLA3 accumulation are compromised in RhSAF-RNAi lines. Our results demonstrate that ethylene antagonizes GA activity through RhGID1 degradation mediated by the E3 ligase RhSAF. These findings enhance our understanding of the phytohormone crosstalk regulating petal senescence and provide insights for improving flower longevity.

SlBEL11 regulates flavonoid biosynthesis, thus fine-tuning auxin efflux to prevent premature fruit drop in tomato.

Auxin regulates flower and fruit abscission, but how developmental signals mediate auxin transport in abscission remains unclear. Here, we reveal the role of the transcription factor BEL1-LIKE HOMEODOMAIN11 (SlBEL11) in regulating auxin transport during abscission in tomato (Solanum lycopersicum). SlBEL11 is highly expressed in the fruit abscission zone, and its expression increases during fruit development. Knockdown of SlBEL11 expression by RNA interference (RNAi) caused premature fruit drop at the breaker (Br) and 3 d post-breaker (Br+3) stages of fruit development. Transcriptome and metabolome analysis of SlBEL11-RNAi lines revealed impaired flavonoid biosynthesis and decreased levels of most flavonoids, especially quercetin, which functions as an auxin transport inhibitor. This suggested that SlBEL11 prevents premature fruit abscission by modulating auxin efflux from fruits, which is crucial for the formation of an auxin response gradient. Indeed, quercetin treatment suppressed premature fruit drop in SlBEL11-RNAi plants. DNA affinity purification sequencing (DAP-seq) analysis indicated that SlBEL11 induced expression of the transcription factor gene SlMYB111 by directly binding to its promoter. Chromatin immunoprecipitation-quantitative polymerase chain reaction and electrophoretic mobility shift assay showed that S. lycopersicum MYELOBLASTOSIS VIRAL ONCOGENE HOMOLOG111 (SlMYB111) induces the expression of the core flavonoid biosynthesis genes SlCHS1, SlCHI, SlF3H, and SlFLS by directly binding to their promoters. Our findings suggest that the SlBEL11-SlMYB111 module modulates flavonoid biosynthesis to fine-tune auxin efflux from fruits and thus maintain an auxin response gradient in the pedicel, thereby preventing premature fruit drop.

Abscisic acid-induced transcription factor PsMYB306 negatively regulates tree peony bud dormancy release.

Bud dormancy is a crucial strategy for perennial plants to withstand adverse winter conditions. However, the regulatory mechanism of bud dormancy in tree peony (Paeonia suffruticosa) remains largely unknown. Here, we observed dramatically reduced and increased accumulation of abscisic acid (ABA) and bioactive gibberellins (GAs) GA1 and GA3, respectively, during bud endodormancy release of tree peony under prolonged chilling treatment. An Illumina RNA sequencing study was performed to identify potential genes involved in the bud endodormancy regulation in tree peony. Correlation matrix, principal component, and interaction network analyses identified a downregulated MYB transcription factor gene, PsMYB306, the expression of which positively correlated with 9-CIS-EPOXYCAROTENOID DIOXYGENASE 3 (PsNCED3) expression. Protein modeling analysis revealed 4 residues within the R2R3 domain of PsMYB306 to possess DNA binding capability. Transcription of PsMYB306 was increased by ABA treatment. Overexpression of PsMYB306 in petunia (Petunia hybrida) inhibited seed germination and plant growth, concomitant with elevated ABA and decreased GA contents. Silencing of PsMYB306 accelerated cold-triggered tree peony bud burst and influenced the production of ABA and GAs and the expression of their biosynthetic genes. ABA application reduced bud dormancy release and transcription of ENT-KAURENOIC ACID OXIDASE 1 (PsKAO1), GA20-OXIDASE 1 (PsGA20ox1), and GA3-OXIDASE 1 (PsGA3ox1) associated with GA biosynthesis in PsMYB306-silenced buds. In vivo and in vitro binding assays confirmed that PsMYB306 specifically transactivated the promoter of PsNCED3. Silencing of PsNCED3 also promoted bud break and growth. Altogether, our findings suggest that PsMYB306 negatively modulates cold-induced bud endodormancy release by regulating ABA production.

Effects of Temperature, Duration, and Heating Height of Foot Thermal Therapy on Sleep Quality of Older Adults: A Systematic Review and Meta-Analysis.

Background: Sleep disturbances, which are common problems in older adults, often lead to cognitive decline and depression and may even increase mortality risk. Foot thermal therapy is a simple and safe approach for improving sleep and is associated with relatively few side effects. However, the effect of different operations of foot thermal therapy on sleep quality in older adults is inconclusive. This study aimed to access the effects of temperature, duration, and heating height of foot thermal therapy (administered through a footbath) on the subjective and objective sleep quality of older adults. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline, eight databases were searched for all relevant articles published up to July 2023, and a rigorous systematic review and meta-analysis was conducted. This study was registered in the PROSPERO database (CRD42022383460). Inclusion criteria were: (1) participants with a mean age ≥60 years; (2) interventions that included foot thermal therapy; (3) a control group that received routine care but no thermal therapy; (4) outcome measurements that assessed sleep quality; and (5) the studies that utilized randomized controlled trials or quasi-experimental studies. Methodological quality was assessed using the Joanna Briggs Institute critical appraisal tools. The meta-analysis was performed using RevMan version 5.4. Results: A total of 11 studies were included. Foot thermal therapy before bedtime improved subjective sleep quality in older adults, with optimal parameters of 40°C temperature (standardized mean difference [SMD] = 0.66, 95% confidence interval [CI]: 0.33 to 0.99), ≤20-min duration (SMD = 0.66, 95% CI: 0.39 to 0.93), and 10 cm heating height (SMD = 0.78, 95% CI: 0.45 to 1.11). Subgroup analyses revealed that a temperature of 41°C-42°C can improve objective sleep latency (SMD = 0.54, 95% CI: 0.09 to 0.99). Conclusions: It is recommended to administer foot thermal therapy (40°C; ≤20 min; 10 cm above the ankle) to older adults 1 h before their bedtime. If they have trouble falling asleep, the temperature can be increased to 41°C-42°C.

Malignant peripheral nerve sheath tumor with hemophilic syndrome and bone marrow fibrosis: A rare case report.

BACKGROUND: Malignant schwannoma is a rare tumor in the peripheral nervous system, accounting for approximately 5% to 10% of systemic soft tissue sarcomas. Especially, malignant schwannoma occurring in the broad ligament of the uterus with hemophilic syndrome and bone marrow fibrosis is extremely rare in clinical practice. Here, we report the first case of an patient diagnosed with malignant peripheral nerve sheath tumor (MPNST) of the broad ligament of the uterus with hemophilic syndrome and bone marrow fibrosis, and share our reference clinical diagnosis and treatment experience. CASE SUMMARY: A patient was diagnosed with MPNST of the uterus harboring hemophilic syndrome and bone marrow fibrosis. She received combination, and repeated imaging revealed further encountered rare complications (hemophilia syndrome and bone marrow fibrosis) after two cycles of chemotherapy. Thereafter, combined treatment with pazopanib, gemcitabine, and dacarbazine was initiated. Unfortunately, the patient succumbed to death at hospital after two weeks. CONCLUSION: This report firstly provided reference clinical practice for a patient with MPNST of the uterus harboring hemophilic syndrome and bone marrow fibrosis. Our case raises a reminder about the tolerance and safety of combination therapy, especially in young women.

A petunia transcription factor, PhOBF1, regulates flower senescence by modulating gibberellin biosynthesis.

Flower senescence is commonly enhanced by the endogenous hormone ethylene and suppressed by the gibberellins (GAs) in plants. However, the detailed mechanisms for the antagonism of these hormones during flower senescence remain elusive. In this study, we characterized one up-regulated gene PhOBF1, belonging to the basic leucine zipper transcription factor family, in senescing petals of petunia (Petunia hybrida). Exogenous treatments with ethylene and GA3 provoked a dramatic increase in PhOBF1 transcripts. Compared with wild-type plants, PhOBF1-RNAi transgenic petunia plants exhibited shortened flower longevity, while overexpression of PhOBF1 resulted in delayed flower senescence. Transcript abundances of two senescence-related genes PhSAG12 and PhSAG29 were higher in PhOBF1-silenced plants but lower in PhOBF1-overexpressing plants. Silencing and overexpression of PhOBF1 affected expression levels of a few genes involved in the GA biosynthesis and signaling pathways, as well as accumulation levels of bioactive GAs GA1 and GA3. Application of GA3 restored the accelerated petal senescence to normal levels in PhOBF1-RNAi transgenic petunia lines, and reduced ethylene release and transcription of three ethylene biosynthetic genes PhACO1, PhACS1, and PhACS2. Moreover, PhOBF1 was observed to specifically bind to the PhGA20ox3 promoter containing a G-box motif. Transient silencing of PhGA20ox3 in petunia plants through tobacco rattle virus-based virus-induced gene silencing method led to accelerated corolla senescence. Our results suggest that PhOBF1 functions as a negative regulator of ethylene-mediated flower senescence by modulating the GA production.

A pear S1-bZIP transcription factor PpbZIP44 modulates carbohydrate metabolism, amino acid, and flavonoid accumulation in fruits.

Fruit quality is defined by attributes that give value to a commodity. Flavor, texture, nutrition, and shelf life are key quality traits that ensure market value and consumer acceptance. In pear fruit, soluble sugars, organic acids, amino acids, and total flavonoids contribute to flavor and overall quality. Transcription factors (TFs) regulate the accumulation of these metabolites during development or in response to the environment. Here, we report a novel TF, PpbZIP44, as a positive regulator of primary and secondary metabolism in pear fruit. Analysis of the transient overexpression or RNAi-transformed pear fruits and stable transgenic tomato fruits under the control of the fruit-specific E8 promoter demonstrated that PpZIP44 substantially affected the contents of soluble sugar, organic acids, amino acids, and flavonoids. In E8::PpbZIP44 tomato fruit, genes involved in carbohydrate metabolism, amino acid, and flavonoids biosynthesis were significantly induced. Furthermore, in PpbZIP44 overexpression or antisense pear fruits, the expression of genes in the related pathways was significantly impacted. PpbZIP44 directly interacted with the promoter of PpSDH9 and PpProDH1 to induce their expression, thereby depleting sorbitol and proline, decreasing citrate and malate, and enhancing fructose contents. PpbZIP44 also directly bound to the PpADT and PpF3H promoters, which led to the carbon flux toward phenylalanine metabolites and enhanced phenylalanine and flavonoid contents. These findings demonstrate that PpbZIP44 mediates multimetabolism reprogramming by regulating the gene expression related to fruit quality compounds.

Untargeted metabonomic analysis of a cerebral stroke model in rats: a study based on UPLC-MS/MS.

Introduction: Brain tissue damage caused by ischemic stroke can trigger changes in the body's metabolic response, and understanding the changes in the metabolic response of the gut after stroke can contribute to research on poststroke brain function recovery. Despite the increase in international research on poststroke metabolic mechanisms and the availability of powerful research tools in recent years, there is still an urgent need for poststroke metabolic studies. Metabolomic examination of feces from a cerebral ischemia-reperfusion rat model can provide new insights into poststroke metabolism and identify key metabolic pathways, which will help reveal diagnostic and therapeutic targets as well as inspire pathophysiological studies after stroke. Methods: We randomly divided 16 healthy adult pathogen-free male Sprague-Dawley (SD) rats into the normal group and the study group, which received middle cerebral artery occlusion/reperfusion (MCAO/R). Ultra-performance liquid chromatography-tandem mass spectrometry (UPLCMS/MS) was used to determine the identities and concentrations of metabolites across all groups, and filtered high-quality data were analyzed for differential screening and differential metabolite functional analysis. Results: After 1 and 14 days of modeling, compared to the normal group, rats in the study group showed significant neurological deficits (p < 0.001) and significantly increased infarct volume (day 1: p < 0.001; day 14: p = 0.001). Mass spectra identified 1,044 and 635 differential metabolites in rat feces in positive and negative ion modes, respectively, which differed significantly between the normal and study groups. The metabolites with increased levels identified in the study group were involved in tryptophan metabolism (p = 0.036678, p < 0.05), arachidonic acid metabolism (p = 0.15695), cysteine and methionine metabolism (p = 0.24705), and pyrimidine metabolism (p = 0.3413), whereas the metabolites with decreased levels were involved in arginine and proline metabolism (p = 0.15695) and starch and sucrose metabolism (p = 0.52256). Discussion: We determined that UPLC-MS/MS could be employed for untargeted metabolomics research. Moreover, tryptophan metabolic pathways may have been disordered in the study group. Alterations in the tryptophan metabolome may provide additional theoretical and data support for elucidating stroke pathogenesis and selecting pathways for intervention.

Prognostic model and treatment choices for patients with primary intracranial central nervous system lymphoma: A population-based study.

BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a non-Hodgkin lymphoma that occurs in the CNS. With the advancement of medical care, its prognosis and treatment have also undergone tremendous changes. This study aimed to construct a prognostic model and compare the effects of different treatments for intracranial PCNSL. METHODS: Cases diagnosed as PCNSL between 2004 and 2015 were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. Data were analyzed using Kaplan-Meier method and Cox regression analysis. Nomogram was built and validated using the R program. RESULTS: A total of 2861 PCNSL patients were included in the analysis. Age, year of diagnosis, surgery and chemotherapy were independent predictors for both overall survival (OS) and cancer-specific survival (CSS). A nomogram was established to predict 3-, 5- and 10-year OS and CSS for patients. Receiver operating characteristic (ROC) curves and decision curve analysis (DCA) showed the nomogram had good predictive performance and clinical application value. We also revealed that gross total resection had significantly better OS and CSS than biopsy alone (P < 0.001). Patients who received only chemotherapy had the best prognosis and did not benefit from additional radiotherapy. CONCLUSION: We developed a nomogram to predict patient survival rates based on independent predictors. It is an effective tool to help clinicians make survival predictions. Our results showed that patients can benefit from gross total resection of tumor, if it is feasible, and chemotherapy. The role of radiotherapy remained to be further assessed.

Insight into the relationship between metabolite dynamic changes and microorganisms of sea urchin (S. intermedius) gonads during storage.

Sea urchin gonads have high nutritional value and degenerate rapidly during storage. Previous assessment of the freshness of sea urchin gonads was based on experience without valid biochemical indicators. Thus, the current study is to find biochemical indicators representing the freshness of sea urchin gonads. Results showed that the dominant genera of sea urchin gonads were changed from Psychromonas, Ralstonia, and Roseimarinus to Aliivibrio, Psychrilyobacter, and Photobacterium. The differential metabolites of sea urchin gonads were mainly produced through amino acids metabolism. Among them, GC-TOF-MS based differential metabolites had the greatest enrichment in the valine, leucine and isoleucine biosynthesis pathway, while LC-MS based differential metabolites had the greatest enrichment in the alanine, aspartate and glutamate metabolism pathway. The growth of dominant genus (Aliivibrio) had a great influence on the production of differential metabolites. These results will provide valuable information for accurately judging the freshness and shelf life of sea urchin gonads.

Ethylene controls cambium stem cell activity via promoting local auxin biosynthesis.

The vascular cambium is the main secondary meristem in plants that produces secondary phloem (outside) and xylem (inside) on opposing sides of the cambium. The phytohormone ethylene has been implicated in vascular cambium activity, but the regulatory network underlying ethylene-mediated cambial activity remains to be elucidated. Here, we found that PETAL MOVEMENT-RELATED PROTEIN1 (RhPMP1), an ethylene-inducible HOMEODOMAIN-LEUCINE ZIPPER I transcription factor in woody plant rose (Rosa hybrida), regulates local auxin biosynthesis and auxin transport to maintain cambial activity. Knockdown of RhPMP1 resulted in smaller midveins and reduced auxin content, while RhPMP1 overexpression resulted in larger midveins and increased auxin levels compared with the wild-type plants. Furthermore, we revealed that Indole-3-pyruvate monooxygenase YUCCA 10 (RhYUC10) and Auxin transporter-like protein 2 (RhAUX2), encoding an auxin biosynthetic enzyme and an auxin influx carrier, respectively, are direct downstream targets of RhPMP1. In summary, our results suggest that ethylene promotes an auxin maximum in the cambium adjacent to the xylem to maintain cambial activity.

Emerging trends in DNA and RNA methylation modifications in type 2 diabetes mellitus: a bibliometric and visual analysis from 1992 to 2022.

Background: Type 2 diabetes mellitus (T2DM) is a pathological metabolic disorder induced by the interaction of genetic and environmental factors. Epigenetic modifications, especially DNA and RNA methylation, might be the bridge between hereditary and environmental factors. This study aimed to comprehensively analyze the status and prospective trends of the association between T2DM and DNA/RNA methylation modifications by using bibliometric software. Methods: All the publications in the Web of Science database for the research of T2DM with DNA and RNA methylation modifications were obtained from the earliest mention to December 2022. CiteSpace software was used to analyze countries, institutions, journals/cited-references, authors/cited-authors, and keywords. Results of the comprehensive visualization and bibliometric analysis were displayed relative to the research hotspots and knowledge structure. Results: A total of 1,233 publications related to DNA and RNA methylation modifications and T2DM were collected. The number of publications per year and the overall trend consistently and significantly increased during the investigation period. Based on the highest publication counts, the most influential country was the USA, while Lund University was the most productive institution. DIABETES was considered the most popular journal. The most frequent keywords identified in the field of methylation and T2DM were mainly involved in developmental origin, insulin resistance, and metabolism. The study suggested that the study of methylation modifications had an increasingly significant role in understanding the progression of T2DM. Conclusion: CiteSpace visualization software was utilized to investigate the status and trends of DNA and RNA methylation modifications in the pathology of T2DM over the past 30 years. Findings from the study provide a guiding perspective for researchers regarding future research directions in this field.

Effects of 12 weeks of Tai Chi on neuromuscular responses and postural control in elderly patients with sarcopenia: a randomized controlled trial.

Objective: To explore the effect of 12 weeks of Tai Chi on neuromuscular responses and postural control in elderly patients with sarcopenia. Methods: One hundred and twenty-four elderly patients with sarcopenia from ZheJiang Hospital and surrounding communities were selected, however, 64 were later disqualified. Sixty elderly patients with sarcopenia were randomly assigned to the Tai Chi group (n = 30) and the control group (n = 30). Both groups received 45-min health education sessions once every 2 weeks for 12 weeks, and the Tai Chi group engaged in 40-min simplified eight-style Tai Chi exercise sessions 3 times per week for 12 weeks. Two assessors who had received professional training and were unaware of the intervention allocation assessed the subjects within 3 days prior to the intervention and within 3 days after completion of the intervention. They chose the unstable platform provided by the dynamic stability test module in ProKin 254 to evaluate the patient's postural control ability. Meanwhile, surface EMG was utilized to assess the neuromuscular response during this period. Results: After 12 weeks of intervention, the Tai Chi group showed a significant decrease in neuromuscular response times of the rectus femoris, semitendinosus, anterior tibialis, and gastrocnemius and overall stability index (OSI) compared to before the intervention (p < 0.05), while there was no significant difference in the control group for these indicators before and after intervention (p > 0.05). In addition, these indicators in the Tai Chi group were significantly lower than those in the control group (p < 0.05). The changes in neuromuscular response times of the rectus femoris, semitendinosus, anterior tibialis, and gastrocnemius were positively correlated with the changes in OSI (p < 0.05) in the Tai Chi group, but there were no significant correlations between changes in neuromuscular response times of the aforementioned muscles and changes in OSI in the control group (p < 0.05). Conclusion: Twelve-weeks of Tai Chi exercise can improve the neuromuscular response of the lower extremities in elderly patients with sarcopenia, shorten their neuromuscular response time when balance is endangered, enhance their dynamic posture control ability, and ultimately reduce the risk of falls.

Discovery of novel sulfonamide chromone-oxime derivatives as potent indoleamine 2,3-dioxygenase 1 inhibitors.

A series of chromone-oxime derivatives containing piperazine sulfonamide moieties were designed, synthesized and evaluated for their inhibitory activities against IDO1. These compounds displayed moderate to good inhibitory activity against IDO1 with IC50 values in low micromolar range. Among them, compound 10m bound effectively to IDO1 with good inhibitory activities (hIDO1 IC50 = 0.64 µM, HeLa IDO1 IC50 = 1.04 µM) and were selected for further investigation. Surface plasmon resonance analysis confirmed the direct interaction between compound 10m and IDO1 protein. Molecular docking study of the most active compound 10m revealed key interactions between 10m and IDO1 in which the chromone-oxime moiety coordinated to the heme iron and formed several hydrogen bonds with the porphyrin ring of heme and ALA264, consistent with the observation by UV-visible spectra that 10m induced a Soret peak shift from 403 to 421 nm. Moreover, compound 10m exhibited no cytotoxicity at its effective concentration in MTT assay. Consistently, in vivo assays results demonstrated that 10m displayed potent antitumor activity with low toxicity in CT26 tumor-bearing Balb/c mice, in comparison with 1-methyl-l-tryptophan (1-MT) and 4-amino-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1,2,5-oxadiazole-3-carboximidamide (IDO5L). In brief, the results suggested that chromone-oxime derivatives containing sulfonamide moieties might serve as IDO1 inhibitors for the development of new antitumor agents.