Lacto-ovo-vegetarian diet is inversely associated with the osteosarcopenia in older adults.

OBJECTIVE: Osteosarcopenia adversely affects the quality of life and physical health of older adults. We sought to explore the association between dietary patterns and osteosarcopenia in community-dwelling older adults. METHODS: This is a cross-sectional study from Northeast China, in which, we included older community adults aged 60 and above. Through face-to-face interviews, we collected dietary information from participants using a food frequency questionnaire. Subsequently, principal component analysis (PCA) was used to obtain the dietary patterns of the participants. Through physical examination, we obtained the participants' information on osteosarcopenia, which was defined by the coexist of osteopenia and sarcopenia. We analysed the association between dietary patterns and dietary compositions with ostesarcopenia. RESULTS: In this study, a total of 9429 participants were included, and the prevalence of osteosarcopenia in community-dwelling older adults was 6.2%. PCA identified three main dietary patterns, and the lacto-ovo-vegetarian dietary pattern was inversely associated with osteosarcopenia. Compared to the lowest lacto-ovo-vegetarian quartile (Q1), the Q4 group (OR = 0.64, 95% CI:0.49-0.83) was inversely associated with osteosarcopenia. Through the weighted quantile sum regression model, we also found that the overall effect of the lacto-ovo-vegetarian dietary components was inversely associated with osteosarcopenia (OR = 0.58, 95% CI: 0.37-0.92); the largest contributors were vegetables, fresh milk, eggs, and dairy products. CONCLUSION: Overall, we found that a lacto-ovo-vegetarian dietary pattern, particularly the consumption of vegetables, fresh milk, eggs, and dairy products, was inversely associated with osteosarcopenia in older adults. And this might provide new insights for the prevention and treatment of osteosarcopenia.

Adverse childhood experiences, sarcopenia, and social participation in older adults: a cohort study.

OBJECTIVES: To examine the relationships between adverse childhood experiences (ACEs) and developing sarcopenia in older adults and the modifying effects of active social participation. METHODS: This prospective cohort study used survey data from the China Health and Retirement Longitudinal Study, including baseline surveys from 2011, follow-up data from 2013, follow-up data from 2015, and information on ACEs from the 2014 Life History Survey. Information concerning 10 ACEs, including five threat-related ACEs and five deprivation-related ACEs before 17 years of age was obtained by questionnaires through face-to-face interviews. Sarcopenia status was assessed according to the Asian Working Group for Sarcopenia 2019 algorithm, consisted of low muscle mass, and low muscle strength, or poor physical performance. The relationship between ACEs, social participation, and sarcopenia was evaluated using Cox proportional hazard regression models. RESULTS: The study population comprised 6859 older adults in main analyses. Having experienced ≥ 3 ACEs led to an increased 31% risk of developing sarcopenia (hazard ratio [HR]:1.31, 95% confidence interval [CI]:1.10-1.56). Participants having experienced ≥ 2 threat-related ACEs (HR:1.22, 95%CI:1.04-1.43) or deprivation-related ACEs (HR:1.22, 95%CI:1.02-1.46) had a 22% higher risk of developing sarcopenia. Active social participation significantly modified the association between ACEs (p < 0.05), especially threat-related ACEs (p < 0.05), and sarcopenia. CONCLUSIONS: ACEs were associated with the development of sarcopenia; however, social participation had a modifying effect. These findings provide insights for early identification of vulnerable groups, advance intervention timing, and highlight the benefits of promoting active social participation among individuals with sarcopenia who have experienced ACEs.

Monocytes Release Pro-Cathepsin D to Drive Blood-to-Brain Transcytosis in Diabetes.

BACKGROUND: Microvascular complications are the major outcome of type 2 diabetes progression, and the underlying mechanism remains to be determined. METHODS: High-throughput RNA sequencing was performed using human monocyte samples from controls and diabetes. The transgenic mice expressing human CTSD (cathepsin D) in the monocytes was constructed using CD68 promoter. In vivo 2-photon imaging, behavioral tests, immunofluorescence, transmission electron microscopy, Western blot analysis, vascular leakage assay, and single-cell RNA sequencing were performed to clarify the phenotype and elucidate the molecular mechanism. RESULTS: Monocytes expressed high-level CTSD in patients with type 2 diabetes. The transgenic mice expressing human CTSD in the monocytes showed increased brain microvascular permeability resembling the diabetic microvascular phenotype, accompanied by cognitive deficit. Mechanistically, the monocytes release nonenzymatic pro-CTSD to upregulate caveolin expression in brain endothelium triggering caveolae-mediated transcytosis, without affecting the paracellular route of brain microvasculature. The circulating pro-CTSD activated the caveolae-mediated transcytosis in brain endothelial cells via its binding with low-density LRP1 (lipoprotein receptor-related protein 1). Importantly, genetic ablation of CTSD in the monocytes exhibited a protective effect against the diabetes-enhanced brain microvascular transcytosis and the diabetes-induced cognitive impairment. CONCLUSIONS: These findings uncover the novel role of circulatory pro-CTSD from monocytes in the pathogenesis of cerebral microvascular lesions in diabetes. The circulatory pro-CTSD is a potential target for the intervention of microvascular complications in diabetes.

Postoperative interictal epileptiform discharges predict seizure recurrence after antiepileptic drug withdrawal regardless of concordance with surgical site.

Objective: The study aimed to explore the association between the site of interictal epileptic discharges (IEDs) on postoperative electroencephalogram (EEG) and seizure recurrence after antiepileptic drug (AED) withdrawal. The study hypothesizes that the concordance of IED sites with surgical sites indicates incomplete resection of epileptic focus, while non-concordance of IED sites with surgical sites indicates postoperative changes or cortical stimulation. The former has a higher risk of seizure recurrence. Methods: We retrospectively analyzed the postoperative EEG pattern of 182 consecutive children who underwent resection surgery. To identify the risk factors for seizure recurrence, we compared the attributes of seizure recurred and seizure-free groups by univariate and multivariate analyses. AED tapering was standardized, involving a 25% reduction in the dose of a single type of AED every 2 weeks, independent of the presurgical AED load. Results: We attempted AED withdrawal in 116 (63.7%) children. Twenty-eight (24.1%) children experienced seizure recurrence during or after AED withdrawal. A greater number of AEDs used at the time of surgery (p=0.005), incomplete resection (p=0.001), and presence of IED on postoperative EEG (p=0.011) are predictors of seizure recurrence. The completeness of resection and seizure recurrence after AED withdrawal were related to the presence of IED on the EEG, but not to the concordance of IED with surgical sites. Conclusion: For children with abnormal EEG, the decision to discontinue AED should be made more cautiously, regardless of the relative location of the discharge site and the surgical site.

Dynamic changes of endothelial and stromal cilia are required for the maintenance of corneal homeostasis.

Primary cilia are distributed extensively within the corneal epithelium and endothelium. However, the presence of cilia in the corneal stroma and the dynamic changes and roles of endothelial and stromal cilia in corneal homeostasis remain largely unknown. Here, we present compelling evidence for the presence of primary cilia in the corneal stroma, both in vivo and in vitro. We also demonstrate dynamic changes of both endothelial and stromal cilia during corneal development. In addition, our data show that cryoinjury triggers dramatic cilium formation in the corneal endothelium and stroma. Furthermore, depletion of cilia in mutant mice lacking intraflagellar transport protein 88 compromises the corneal endothelial capacity to establish the effective tissue barrier, leading to an upregulation of α-smooth muscle actin within the corneal stroma in response to cryoinjury. These observations underscore the essential involvement of corneal endothelial and stromal cilia in maintaining corneal homeostasis and provide an innovative strategy for the treatment of corneal injuries and diseases.

Strategy for Comprehensive Detection and Annotation of Gut Microbiota-Related Metabolites Based on Liquid Chromatography-High-Resolution Mass Spectrometry.

Gut microbiota, widely populating the mammalian gastrointestinal tract, plays an important role in regulating diverse pathophysiological processes by producing bioactive molecules. Extensive detection of these molecules contributes to probing microbiota function but is limited by insufficient identification of existing analytical methods. In this study, a systematic strategy was proposed to detect and annotate gut microbiota-related metabolites on a large scale. A pentafluorophenyl (PFP) column-based liquid chromatography-high-resolution mass spectrometry (LC-HRMS) method was first developed for high-coverage analysis of gut microbiota-related metabolites, which was verified to be stable and robust with a wide linearity range, high sensitivity, satisfactory recovery, and repeatability. Then, an informative database integrating 968 knowledge-based microbiota-related metabolites and 282 sample-sourced ones defined by germ-free (GF)/antibiotic-treated (ABX) models was constructed and subsequently used for targeted extraction and annotation in biological samples. Using pooled feces, plasma, and urine of mice for demonstration application, 672 microbiota-related metabolites were annotated, including 21% neglected by routine nontargeted peak detection. This strategy serves as a useful tool for the comprehensive capture of the intestinal flora metabolome, contributing to our deeper understanding of microbe-host interactions.

Evaluating the performance of the language model ChatGPT in responding to common questions of people with epilepsy.

OBJECTIVE: People with epilepsy desire to acquire accurate information about epilepsy and actively engage in its management throughout the long journey of living with seizures. ChatGPT is a large language model and we aimed to assess the accuracy and consistency of ChatGPT in responding to the common concerns of people with epilepsy and to evaluate its ability to provide emotional support. METHODS: Questions were collected from the International League against Epilepsy and the China Association against Epilepsy. The responses were independently assessed by two board-certified epileptologists from the China Association against Epilepsy, and a third reviewer resolved disagreements. The reviewers assessed its ability to provide emotional support subjectively. RESULTS: A total of 378 questions related to epilepsy and 5 questions related to emotional support were included. ChatGPT provided "correct and comprehensive" answers to 68.4% of the questions. The model provided reproducible answers for 82.3% questions. The model performed poorly in answering prognostic questions, with only 46.8% of the answers rated as comprehensive. When faced with questions requiring emotional support, the model can generate natural and understandable responses. SIGNIFICANCE: ChatGPT provides accurate and reliable answers to patients with epilepsy and is a valuable source of information. It also provides partial emotional support, potentially assisting those experiencing emotional distress. However, ChatGPT may provide incorrect responses, leading users to inadvertently accept incorrect and potentially dangerous advice. Therefore, the direct use of ChatGPT for medical guidance is not recommended and its primary use at present is in patients education.

Pan-cancer mutational signature analysis of 111,711 targeted sequenced tumors using SATS.

Tumor mutational signatures have the potential to inform cancer diagnosis and treatment. However, their detection in targeted sequenced tumors is hampered by sparse mutations and variability in targeted gene panels. Here we present SATS, a scalable mutational signature analyzer addressing these challenges by leveraging tumor mutational burdens from targeted gene panels. Through analyzing simulated data, pseudo-targeted sequencing data generated by down-sampling whole exome and genome data, and samples with matched whole genome sequencing and targeted sequencing, we showed that SATS can accurately detect common mutational signatures and estimate signature burdens. Applying SATS to 111,711 targeted sequenced tumors from the AACR Project GENIE, we generated a pan-cancer catalogue of mutational signatures tailored to targeted sequencing, enabling estimation of signature burdens within individual tumors. Integrating signatures with clinical data, we demonstrated SATS's clinical utility, including identifying signatures enriched in early-onset hypermutated colorectal cancers and signatures associated with cancer prognosis and immunotherapy response.

Early antiseizure medication withdrawal and risk of seizure recurrence in children after epilepsy surgery: A retrospective study.

OBJECTIVE: The timing of antiseizure medication (ASM) withdrawal in children after epilepsy surgery remains controversial and lacks recognized standards. Given the various negative effects of ASM on development in children, this study aimed to evaluate the safety and feasibility of early ASM withdrawal after epileptic resection surgery. METHODS: We retrospectively assessed the seizure outcomes and ASM profiles of children who had undergone epileptic resection surgery between August 2015 and August 2020 and attempted ASM reduction in the early postoperative phase. Tapering the dose of ASM was attempted when children were seizure-free with no interictal epileptiform discharges (IEDs) on electroencephalogram (EEG) for at least 6 months postoperatively. RESULTS: This study included 145 children with a median follow-up duration of 40 months. Early ASM tapering was attempted postoperatively in 99 (68.3 %) children. Postoperative ASM discontinuation was attempted in 87 (60.0 %) children. Nine (9.1 %) children experienced seizure recurrence during the ASM reduction stage, and 10 (11.5 %) experienced recurrence after ASM discontinuation. Incomplete resection (P = 0.003) and postoperative seizures before ASM tapering (P = 0.003) were independent predictors of seizure recurrence during and after early ASM withdrawal. SIGNIFICANCE: ASM withdrawal is viable and safe to be initiated in children who are seizure-free postoperatively and have no IEDs on the scalp EEG for at least 6 months. Children with incomplete resection and postoperative seizures before ASM withdrawal are at a higher risk of seizure recurrence and may need to continue ASM for a longer period.

The roles of nuclear receptors in cholesterol metabolism and reverse cholesterol transport in nonalcoholic fatty liver disease.

As the most prevalent chronic liver disease globally, NAFLD encompasses a pathological process that ranges from simple steatosis to NASH, fibrosis, cirrhosis, and HCC, closely associated with numerous extrahepatic diseases. While the initial etiology was believed to be hepatocyte injury caused by lipid toxicity from accumulated triglycerides, recent studies suggest that an imbalance of cholesterol homeostasis is of greater significance. The role of nuclear receptors in regulating liver cholesterol homeostasis has been demonstrated to be crucial. This review summarizes the roles and regulatory mechanisms of nuclear receptors in the 3 main aspects of cholesterol production, excretion, and storage in the liver, as well as their cross talk in reverse cholesterol transport. It is hoped that this review will offer new insights and theoretical foundations for the study of the pathogenesis and progression of NAFLD and provide new research directions for extrahepatic diseases associated with NAFLD.

Nur77 alleviates cardiac fibrosis by upregulating GSK-3ß transcription during aging.

Cardiac fibrosis is associated with aging, for which no targeted therapies are available. With aging, the levels of nerve growth factor-induced gene B (Nur77) are reduced during cardiac remodelling; however, its role in cardiac fibrosis in aging remains unclear. Here, we found that Nur77 knockout increased cardiac structure abnormalities, systolic and diastolic dysfunction, cardiac hypertrophy, and fibrotic marker expression in 15-month-old mice. Furthermore, Nur77 deficiency induced collagen type I (Col-1) and α-smooth muscle actin overproduction in transforming growth factor beta (TGF-ß) treated H9c2 cells, whereas Nur77 overexpression attenuated this effect. Nur77 deficiency in vivo and in vitro downregulated glycogen synthase kinase (GSK)-3ß expression and increased ß-catenin activity, while its overexpression increased GSK-3ß expression. GSK-3ß knockdown counteracted the anti-fibrotic effect of Nur77 on TGF-ß-treated H9c2 cells. Chromatin immunoprecipitation and luciferase reporter assay results suggested GSK-3ß as the direct target of Nur77. Our findings suggest that Nur77 directly initiates GSK-3ß transcription and age-related cardiac fibrosis partly through the GSK-3ß/ß-catenin pathway. This study proposes a novel mechanism for Nur77 regulating cardiac fibrosis and suggests Nur77 as a target for the prevention and treatment of aging-associated cardiac fibrosis and heart failure.

The Helicobacter pylori Genome Project: insights into H. pylori population structure from analysis of a worldwide collection of complete genomes.

Helicobacter pylori, a dominant member of the gastric microbiota, shares co-evolutionary history with humans. This has led to the development of genetically distinct H. pylori subpopulations associated with the geographic origin of the host and with differential gastric disease risk. Here, we provide insights into H. pylori population structure as a part of the Helicobacter pylori Genome Project (HpGP), a multi-disciplinary initiative aimed at elucidating H. pylori pathogenesis and identifying new therapeutic targets. We collected 1011 well-characterized clinical strains from 50 countries and generated high-quality genome sequences. We analysed core genome diversity and population structure of the HpGP dataset and 255 worldwide reference genomes to outline the ancestral contribution to Eurasian, African, and American populations. We found evidence of substantial contribution of population hpNorthAsia and subpopulation hspUral in Northern European H. pylori. The genomes of H. pylori isolated from northern and southern Indigenous Americans differed in that bacteria isolated in northern Indigenous communities were more similar to North Asian H. pylori while the southern had higher relatedness to hpEastAsia. Notably, we also found a highly clonal yet geographically dispersed North American subpopulation, which is negative for the cag pathogenicity island, and present in 7% of sequenced US genomes. We expect the HpGP dataset and the corresponding strains to become a major asset for H. pylori genomics.

Cooperative effects of SIRT1 and SIRT2 on APP acetylation.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by amyloid-ß (Aß) deposition and neurofibrillary tangles. Although the NAD+ -dependent deacetylases SIRT1 and SIRT2 play pivotal roles in age-related diseases, their cooperative effects in AD have not yet been elucidated. Here, we report that the SIRT2:SIRT1 ratio is elevated in the brains of aging mice and in the AD mouse models. In HT22 mouse hippocampal neuronal cells, Aß challenge correlates with decreased SIRT1 expression, while SIRT2 expression is increased. Overexpression of SIRT1 prevents Aß-induced neurotoxicity. We find that SIRT1 impedes SIRT2-mediated APP deacetylation by inhibiting the binding of SIRT2 to APP. Deletion of SIRT1 reduces APP recycling back to the cell surface and promotes APP transiting toward the endosome, thus contributing to the amyloidogenic processing of APP. Our findings define a mechanism for neuroprotection by SIRT1 through suppression of SIRT2 deacetylation, and provide a promising avenue for therapeutic intervention of AD.

Nur77 is involved in the regulation of obesity-related lower muscle mass by promoting Pten degradation.

Obesity may impair muscle function and is sometimes associated with lower muscle mass. However, the internal regulatory mechanism is still unclear. Nur77 has been reported to improve obesity phenotype by regulating glucose and lipid metabolism and inhibiting the production of inflammatory factors and reactive oxygen species. Concurrently, Nur77 also plays an important role in muscle differentiation and development. We aimed to investigate the role of Nur77 in obesity-related lower muscle mass. Our in vivo and in vitro experiments illustrated that the reduction of obesity-related Nur77 accelerated the occurrence of lower muscle mass by interfering with the signaling pathways involved in the regulation of myoprotein synthesis and degradation. We further demonstrated that Nur77 activates the PI3K/Akt pathway by promoting Pten degradation, which enhances the phosphorylation of the Akt/mTOR/p70S6K pathway and inhibits the expression of skeletal muscle-specific E3 ligases (MAFbx/MuRF1). Nur77 induces Pten degradation by increasing the transcription of its specific E3 ligase Syvn1. Our study confirms that Nur77 is a key factor in ameliorating obesity-related lower muscle mass, providing a new therapeutic target and theoretical basis for the treatment of obesity-related lower muscle mass.

SIRT2 regulates extracellular vesicle-mediated liver-bone communication.

The interplay between liver and bone metabolism remains largely uncharacterized. Here, we uncover a mechanism of liver-bone crosstalk regulated by hepatocyte SIRT2. We demonstrate that hepatocyte SIRT2 expression is increased in aged mice and elderly humans. Liver-specific SIRT2 deficiency inhibits osteoclastogenesis and alleviates bone loss in mouse models of osteoporosis. We identify leucine-rich α-2-glycoprotein 1 (LRG1) as a functional cargo in hepatocyte-derived small extracellular vesicles (sEVs). In SIRT2-deficient hepatocytes, LRG1 levels in sEVs are upregulated, leading to increased transfer of LRG1 to bone-marrow-derived monocytes (BMDMs), and in turn, to inhibition of osteoclast differentiation via reduced nuclear translocation of NF-κB p65. Treatment with sEVs carrying high levels of LRG1 inhibits osteoclast differentiation in human BMDMs and in mice with osteoporosis, resulting in attenuated bone loss in mice. Furthermore, the plasma level of sEVs carrying LRG1 is positively correlated with bone mineral density in humans. Thus, drugs targeting hepatocyte-osteoclast communication may constitute a promising therapeutic strategy for primary osteoporosis.

Implications from proteomic studies investigating circadian rhythm disorder-regulated neurodegenerative disease pathology.

Neurodegenerative diseases (NDs) affect 15% of the world's population and are becoming an increasingly common cause of morbidity and mortality worldwide. Circadian rhythm disorders (CRDs) have been reported to be involved in the pathogenic regulation of various neurologic diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis and amyotrophic lateral sclerosis. Proteomic technology is helpful to explore treatment targets for CRDs in patients with NDs. Here, we review the key differentially expressed (DE) proteins identified in previous proteomic studies investigating NDs, CRDs and associated models and the related pathways identified by enrichment analysis. Furthermore, we summarize the advantages and disadvantages of the above studies and propose new proteomic technologies for the precise study of circadian disorder-mediated regulation of ND pathology. This review provides a theoretical and technical reference for the precise study of circadian disorder-mediated regulation of ND pathology.

Does Adjustment of Antiseizure Medication Regimen after Failed Epilepsy Surgery Improve Outcomes?

Background and Objectives: After failed epilepsy surgery, patients often revert to an antiseizure medication (ASM) ASM regimen, which can be adjusted or optimized in three ways: increasing the dose, alternative therapy, and combination therapy. It is unclear which type of antiseizure medication adjustment method can improve outcomes. Materials and Methods: Children who underwent failed epileptic resection surgery at the Department of Neurosurgery, Children's Hospital of Chongqing Medical University between January 2015 and December 2021 were included in this cohort, who were reviewed for whether they underwent adjustment of ASM with increased dose, alternative therapy, or combination therapy. The seizure outcome and quality of life (QoL) were assessed. Two-tailed Fisher exact test and Mann-Whitney U test were used for statistical analysis. Results: Sixty-three children with failed surgery were included for further analysis, with a median follow-up time of 53 months. The median seizure recurrence time was 4 months. At the last follow-up, 36.5% (n = 23) of patients achieved seizure freedom, 41.3% (n = 26) achieved seizure remission, and 61.9% (n = 39) had a good QoL. None of the three types of ASM adjustment improved children's outcomes, whether considered in terms of seizure-free rate, seizure remission rate, or QoL. Early recurrences were significantly associated with decreased probability of seizure freedom (p = 0.02), seizure remission (p = 0.02), and a good QoL (p = 0.01). Conclusions: Children who underwent failed epilepsy surgery remains some potential for late seizure remission from ASM. Yet adjusting ASM regimen does not increase the probability of seizure remission nor does it improve the QoL. Clinicians should complete evaluations and consider the need for other antiepileptic treatment as soon as possible after surgery failed, especially when dealing with children with an early recurrence.

Neurodevelopmental outcomes of neonatal posthemorrhagic hydrocephalus and psychological effects on the parents.

BACKGROUND: Neonatal posthemorrhagic hydrocephalus remains a common complication in preterm infants, with high rates of mortality and morbidity, placing parents at high risk of anxiety and depression. We sought to investigate the neurodevelopmental outcomes of infants with posthemorrhagic hydrocephalus who underwent surgery and the psychological effect on their parents. METHODS: We retrospectively analysed all infants with posthemorrhagic hydrocephalus born between 2014 and 2020 in the Children's Hospital of Chongqing Medical University, China. The neurodevelopmental outcomes of 28 patients were evaluated by the Pediatric Stroke Outcome Measure score, and the psychological states of the parents of survivors were assessed by the Hospital Anxiety and Depression Scale. RESULTS: The families of the 28 patients were followed up for a median duration of 3 years; 6 (21.4%) patients died within 6 months after discharge, 12 (42.9%) patients had moderate to severe dysfunction, and only 10 (35.7%) patients had good outcomes. Regarding the 22 parents of the survivors, 5 (22.7%) and 4 (18.2%) had borderline anxiety and depression symptoms, respectively. Two (9.1%) caregivers had exact anxiety and depression symptoms. Leukomalacia after intraventricular haemorrhage was associated with adverse neurological outcomes. The infants' histories of epileptic seizures during the neonatal period were associated with the anxiety of their parents. CONCLUSION: The overall outcome of posthemorrhagic hydrocephalus patients is unsatisfactory, and children with leukomalacia after haemorrhage tend to have poor outcomes. A history of epileptic seizures during the course of the disease may exacerbate the anxiety of the caregivers.