Dynamic influence of maternal education on height among Chinese children aged 0-18 years.

Background: Maternal education is one of key factors affecting nurturing environment which significantly impacts children's height levels throughout their developmental stages. However, the influence of maternal education on children's height is less studied. This study aims to investigate the dynamic influence of maternal education on children's height among Chinese children aged 0-18 years. Methods: Children undergoing health examinations from January 2021 to September 2023 were included in this study. Clinical information including height, weight, maternal pregnancy history, blood specimens for bone metabolism-related indicators and maternal education level was collected. Children's height was categorized into 14 groups based on age and gender percentiles, following WHO 2006 growth standards. One-way analysis of variance (ANOVA), linear regression, chi-square test and Fisher's exact test were applied for data analysis. Results: A total of 6269 samples were collected, including 3654 males and 2615 females, with an average age of 8.38 (3.97) for males and 7.89 (3.55) for females. Significant correlations between maternal education level, birth weight, birth order, weight percentile, vitamin D, serum phosphorus, alkaline phosphatase levels, and children's height were identified. Birth weight's influence on height varied across age groups. Compared with normal birth weight children, low birth weight children exhibited catch-up growth within the first 6 years and a subsequent gradual widening of the height gap from 6 to 18 years old. Remarkably, the impact of maternal education on height became more pronounced among children above 3-6 years old, which can mitigate the effect of low birth weight on height. Conclusion: We found that weight percentile, birth weight, birth order, bone marker levels, and maternal education level have significant effect on height. Maternal education attenuates the impact of low birth weight on height. The findings indicated that maternal education plays a consistent and critical role in promoting robust and healthy growth.

Combination of retagliptin and henagliflozin as add-on therapy to metformin in patients with type 2 diabetes inadequately controlled with metformin: A multicentre, randomized, double-blind, active-controlled, phase 3 trial.

AIM: This study assessed the efficacy and safety of co-administering retagliptin and henagliflozin versus individual agents at corresponding doses in patients with type 2 diabetes mellitus who were inadequately controlled with metformin. METHODS: This multicentre, phase 3 trial consisted of a 24-week, randomized, double-blind, active-controlled period. Patients with glycated haemoglobin (HbA1c) levels between 7.5% and 10.5% were randomized to receive once-daily retagliptin 100 mg (R100; n = 155), henagliflozin 5 mg (H5; n = 156), henagliflozin 10 mg (H10; n = 156), co-administered R100/H5 (n = 155), or R100/H10 (n = 156). The primary endpoint was the change in HbA1c from baseline to week 24. RESULTS: Based on the primary estimand, the least squares mean reductions in HbA1c at week 24 were significantly greater in the R100/H5 (-1.51%) and R100/H10 (-1.54%) groups compared with those receiving the corresponding doses of individual agents (-0.98% for R100, -0.86% for H5 and -0.95% for H10, respectively; p < .0001 for all pairwise comparisons). Achievement of HbA1c <7.0% at week 24 was observed in 27.1% of patients in the R100 group, 21.2% in the H5 group, 24.4% in the H10 group, 57.4% in the R100/H5 group and 56.4% in the R100/H10 group. Reductions in fasting plasma glucose and 2-h postprandial glucose were also more pronounced in the co-administration groups compared with the individual agents at corresponding doses. Decreases in body weight and systolic blood pressure were greater in the groups containing henagliflozin than in the R100 group. The incidence rates of adverse events were similar across all treatment groups, with no reported episodes of severe hypoglycaemia. CONCLUSIONS: For patients with type 2 diabetes mellitus inadequately controlled by metformin monotherapy, the co-administration of retagliptin and henagliflozin yielded more effective glycaemic control through 24 weeks compared with the individual agents at their corresponding doses.

Diphthamide deficiency promotes association of eEF2 with p53 to induce p21 expression and neural crest defects.

Diphthamide is a modified histidine residue unique for eukaryotic translation elongation factor 2 (eEF2), a key ribosomal protein. Loss of this evolutionarily conserved modification causes developmental defects through unknown mechanisms. In a patient with compound heterozygous mutations in Diphthamide Biosynthesis 1 (DPH1) and impaired eEF2 diphthamide modification, we observe multiple defects in neural crest (NC)-derived tissues. Knockin mice harboring the patient's mutations and Xenopus embryos with Dph1 depleted also display NC defects, which can be attributed to reduced proliferation in the neuroepithelium. DPH1 depletion facilitates dissociation of eEF2 from ribosomes and association with p53 to promote transcription of the cell cycle inhibitor p21, resulting in inhibited proliferation. Knockout of one p21 allele rescues the NC phenotypes in the knockin mice carrying the patient's mutations. These findings uncover an unexpected role for eEF2 as a transcriptional coactivator for p53 to induce p21 expression and NC defects, which is regulated by diphthamide modification.

Contactin-associated protein-like 2 (CNTNAP2) mutations impair the essential α-secretase cleavages, leading to autism-like phenotypes.

Mutations in the Contactin-associated protein-like 2 (CNTNAP2) gene are associated with autism spectrum disorder (ASD), and ectodomain shedding of the CNTNAP2 protein plays a role in its function. However, key enzymes involved in the C-terminal cleavage of CNTNAP2 remain largely unknown, and the effect of ASD-associated mutations on this process and its role in ASD pathogenesis remain elusive. In this report we showed that CNTNAP2 undergoes sequential cleavages by furin, ADAM10/17-dependent α-secretase and presenilin-dependent γ-secretase. We identified that the cleavage sites of ADAM10 and ADAM17 in CNTNAP2 locate at its C-terminal residue I79 and L96, and the main α-cleavage product C79 by ADAM10 is required for the subsequent γ-secretase cleavage to generate CNTNAP2 intracellular domain (CICD). ASD-associated CNTNAP2 mutations impair the α-cleavage to generate C79, and the inhibition leads to ASD-like repetitive and social behavior abnormalities in the Cntnap2-I1254T knock-in mice. Finally, exogenous expression of C79 improves autism-like phenotypes in the Cntnap2-I1254T knock-in and Cntnap2-/- knockout mice. This data demonstrates that the α-secretase is essential for CNTNAP2 processing and its function. Our study indicates that inhibition of the cleavage by pathogenic mutations underlies ASD pathogenesis, and upregulation of its C-terminal fragments could have therapeutical potentials for ASD treatment.

The moderated-mediation role of risk perception and intolerance of uncertainty in the association between residual symptoms and psychological distress: a cross-sectional study after COVID-19 policy lifted in China.

BACKGROUND: A considerable number of individuals infected with COVID-19 experience residual symptoms after the acute phase. However, the correlation between residual symptoms and psychological distress and underlying mechanisms are scarcely studied. We aim to explore the association between residual symptoms of COVID-19 and psychological distress, specifically depression, anxiety, and fear of COVID-19, and examine the role of risk perception and intolerance of uncertainty in the association. METHODS: A cross-sectional survey was conducted by online questionnaire-based approach in mid-January 2023. Self-reported demographic characteristics, COVID-19-related information, and residual symptoms were collected. Depression, anxiety, fear, risk perception and intolerance of uncertainty were evaluated using the Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), Fear of COVID-19 Scale (FCV-19S), COVID-19 Risk Perception Scale and Intolerance of Uncertainty Scale-12 (IUS-12), respectively. Linear regression analyses were conducted to explore the associations. A moderated mediation model was then constructed to examine the role of risk perception of COVID-19 and intolerance of uncertainty in the association between residual symptoms and psychological distress. RESULTS: 1735 participants effectively completed the survey. 34.9% of the patients experienced residual symptoms after acute phase of COVID-19. Psychological distress was markedly increased by COVID-19 infection, while residual symptoms had a significant impact on psychological distress (Ps < 0.001), including depression (ß = 0.23), anxiety (ß = 0.21), and fear of COVID-19 (ß = 0.14). Risk perception served as a mediator between residual symptoms and all forms of psychological distress, while intolerance of uncertainty moderated the effect of risk perception on depression and anxiety. CONCLUSION: A considerable proportion of patients experience residual symptoms after acute phase of COVID-19, which have a significant impact on psychological distress. Risk perception and intolerance of uncertainty play a moderated-mediation role in the association between residual symptoms and depression/anxiety. It highly suggests that effective treatment for residual symptoms, maintaining appropriate risk perception and improving intolerance of uncertainty are critical strategies to alleviate COVID-19 infection-associated psychological distress.

miR-429-3p mediates memory decline by targeting MKP-1 to reduce surface GluA1-containing AMPA receptors in a mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is a leading cause of dementia in the elderly. Mitogen-activated protein kinase phosphatase 1 (MKP-1) plays a neuroprotective role in AD. However, the molecular mechanisms underlying the effects of MKP-1 on AD have not been extensively studied. MicroRNAs (miRNAs) regulate gene expression at the post-transcriptional level, thereby repressing mRNA translation. Here, we reported that the microRNA-429-3p (miR-429-3p) was significantly increased in the brain of APP23/PS45 AD model mice and N2AAPP AD model cells. We further found that miR-429-3p could downregulate MKP-1 expression by directly binding to its 3'-untranslated region (3' UTR). Inhibition of miR-429-3p by its antagomir (A-miR-429) restored the expression of MKP-1 to a control level and consequently reduced the amyloidogenic processing of APP and Aß accumulation. More importantly, intranasal administration of A-miR-429 successfully ameliorated the deficits of hippocampal CA1 long-term potentiation and spatial learning and memory in AD model mice by suppressing extracellular signal-regulated kinase (ERK1/2)-mediated GluA1 hyperphosphorylation at Ser831 site, thereby increasing the surface expression of GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). Together, these results demonstrate that inhibiting miR-429-3p to upregulate MKP-1 effectively improves cognitive and synaptic functions in AD model mice, suggesting that miR-429/MKP-1 pathway may be a novel therapeutic target for AD treatment.

A multi-cohort study of the hippocampal radiomics model and its associated biological changes in Alzheimer's Disease.

There have been no previous reports of hippocampal radiomics features associated with biological functions in Alzheimer's Disease (AD). This study aims to develop and validate a hippocampal radiomics model from structural magnetic resonance imaging (MRI) data for identifying patients with AD, and to explore the mechanism underlying the developed radiomics model using peripheral blood gene expression. In this retrospective multi-study, a radiomics model was developed based on the radiomics discovery group (n = 420) and validated in other cohorts. The biological functions underlying the model were identified in the radiogenomic analysis group using paired MRI and peripheral blood transcriptome analyses (n = 266). Mediation analysis and external validation were applied to further validate the key module and hub genes. A 12 radiomics features-based prediction model was constructed and this model showed highly robust predictive power for identifying AD patients in the validation and other three cohorts. Using radiogenomics mapping, myeloid leukocyte and neutrophil activation were enriched, and six hub genes were identified from the key module, which showed the highest correlation with the radiomics model. The correlation between hub genes and cognitive ability was confirmed using the external validation set of the AddneuroMed dataset. Mediation analysis revealed that the hippocampal radiomics model mediated the association between blood gene expression and cognitive ability. The hippocampal radiomics model can accurately identify patients with AD, while the predictive radiomics model may be driven by neutrophil-related biological pathways.

CSTB accelerates the progression of hepatocellular carcinoma via the ERK/AKT/mTOR signaling pathway.

Hepatocellular carcinoma (HCC) is a significant contributor to global cancer-related deaths, leading to high mortality rates. However, the pathogenesis of HCC remains unclear. In this research, by the bioinformatics data analysis, we found that elevated CSTB expression correlated with advanced disease and predicted diminished overall survival (OS) in HCC patients. We subsequently verified the oncogenic role of CSTB as well as the potential underlying mechanisms in HCC through a series of in vitro experiments, such as CCK-8 assays, cloning assays, flow cytometry, Transwell assays, and western blotting. Our findings illustrated that the silencing of CSTB effectively suppressed cellular proliferation by inducing cell cycle arrest in the G2 phase and impaired HCC cell invasion and migration by stimulating epithelial-mesenchymal transition (EMT). Additionally, we analyzed the pathways enriched in HCC using RNA sequencing and found that the ERK/AKT/mTOR signaling pathway was related to increased CSTB expression in HCC. Finally, we confirmed the tumorigenic role of CSTB via in vivo experiments. Thus, our findings revealed that silencing CSTB inhibited the HCC progression via the ERK/AKT/mTOR signaling pathway, highlighting new perspectives for investigating the mechanisms of HCC.

PCSK6 exacerbates Alzheimer's disease pathogenesis by promoting MT5-MMP maturation.

Proprotein convertase subtilisin/kexin type 6 (PCSK6) is a calcium-dependent serine proteinase that regulates the proteolytic activity of various precursor proteins and facilitates protein maturation. Dysregulation of PCSK6 expression or function has been implicated in several pathological processes including nervous system diseases. However, whether and how PCSK6 is involved in the pathogenesis of Alzheimer's disease (AD) remains unclear. In this study, we reported that the expression of PCSK6 was significantly increased in the brain tissues of postmortem AD patients and APP23/PS45 transgenic AD model mice, as well as N2AAPP cells. Genetic knockdown of PCSK6 reduced amyloidogenic processing of APP in N2AAPP cells by suppressing the activation of membrane-type 5-matrix metalloproteinase (MT5-MMP), referred to as η-secretase. We further found that PCSK6 cleaved and activated MT5-MMP by recognizing the RRRNKR sequence in its N-terminal propeptide domain in N2A cells. The mutation or knockout of this cleavage motif prevented PCSK6 from interacting with MT5-MMP and performing cleavage. Importantly, genetic knockdown of PCSK6 with adeno-associated virus (AAV) reduced Aß production and ameliorated hippocampal long-term potentiation (LTP) and long-term spatial learning and memory in APP23/PS45 transgenic mice. Taken together, these results demonstrate that genetic knockdown of PCSK6 effectively alleviate AD-related pathology and cognitive impairments by inactivating MT5-MMP, highlighting its potential as a novel therapeutic target for AD treatment.

The role of inflammasomes in human diseases and their potential as therapeutic targets.

Inflammasomes are large protein complexes that play a major role in sensing inflammatory signals and triggering the innate immune response. Each inflammasome complex has three major components: an upstream sensor molecule that is connected to a downstream effector protein such as caspase-1 through the adapter protein ASC. Inflammasome formation typically occurs in response to infectious agents or cellular damage. The active inflammasome then triggers caspase-1 activation, followed by the secretion of pro-inflammatory cytokines and pyroptotic cell death. Aberrant inflammasome activation and activity contribute to the development of diabetes, cancer, and several cardiovascular and neurodegenerative disorders. As a result, recent research has increasingly focused on investigating the mechanisms that regulate inflammasome assembly and activation, as well as the potential of targeting inflammasomes to treat various diseases. Multiple clinical trials are currently underway to evaluate the therapeutic potential of several distinct inflammasome-targeting therapies. Therefore, understanding how different inflammasomes contribute to disease pathology may have significant implications for developing novel therapeutic strategies. In this article, we provide a summary of the biological and pathological roles of inflammasomes in health and disease. We also highlight key evidence that suggests targeting inflammasomes could be a novel strategy for developing new disease-modifying therapies that may be effective in several conditions.

Enhanced Gasdermin-E-mediated Pyroptosis in Alzheimer's Disease.

Amyloid ß protein (Aß) is a critical factor in the pathogenesis of Alzheimer's disease (AD). Aß induces apoptosis, and gasdermin-E (GSDME) expression can switch apoptosis to pyroptosis. In this study, we demonstrated that GSDME was highly expressed in the hippocampus of APP23/PS45 mouse models compared to that in age-matched wild-type mice. Aß treatment induced pyroptosis by active caspase-3/GSDME in SH-SY5Y cells. Furthermore, the knockdown of GSDME improved the cognitive impairments of APP23/PS45 mice by alleviating inflammatory response. Our findings reveal that GSDME, as a modulator of Aß and pyroptosis, plays a potential role in Alzheimer's disease pathogenesis and shows that GSDME is a therapeutic target for AD.

Clarity on the blazing trail: clearing the way for amyloid-removing therapies for Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with a complex pathogenesis. Senile plaques composed of the amyloid-ß (Aß) peptide in the brain are the core hallmarks of AD and a promising target for the development of disease-modifying therapies. However, over the past 20 years, the failures of clinical trials directed at Aß clearance have fueled a debate as to whether Aß is the principal pathogenic factor in AD and a valid therapeutic target. The success of the recent phase 3 trials of lecanemab (Clarity AD) and donanemab (Trailblazer Alz2), and lessons from previous Aß clearance trials provide critical evidence to support the role of Aß in AD pathogenesis and suggest that targeting Aß clearance is heading in the right direction for AD treatment. Here, we analyze key questions relating to the efficacy of Aß targeting therapies, and provide perspectives on early intervention, adequate Aß removal, sufficient treatment period, and combinatory therapeutics, which may be required to achieve the best cognitive benefits in future trials in the real world.

Landscape of enhancer disruption and functional screen in melanoma cells.

BACKGROUND: The high mutation rate throughout the entire melanoma genome presents a major challenge in stratifying true driver events from the background mutations. Numerous recurrent non-coding alterations, such as those in enhancers, can shape tumor evolution, thereby emphasizing the importance in systematically deciphering enhancer disruptions in melanoma. RESULTS: Here, we leveraged 297 melanoma whole-genome sequencing samples to prioritize highly recurrent regions. By performing a genome-scale CRISPR interference (CRISPRi) screen on highly recurrent region-associated enhancers in melanoma cells, we identified 66 significant hits which could have tumor-suppressive roles. These functional enhancers show unique mutational patterns independent of classical significantly mutated genes in melanoma. Target gene analysis for the essential enhancers reveal many known and hidden mechanisms underlying melanoma growth. Utilizing extensive functional validation experiments, we demonstrate that a super enhancer element could modulate melanoma cell proliferation by targeting MEF2A, and another distal enhancer is able to sustain PTEN tumor-suppressive potential via long-range interactions. CONCLUSIONS: Our study establishes a catalogue of crucial enhancers and their target genes in melanoma growth and progression, and illuminates the identification of novel mechanisms of dysregulation for melanoma driver genes and new therapeutic targeting strategies.

B(C6F5)3-catalyzed hydrogermylation of enones: a facile route to germacycles.

Organogermacycles are important skeletons for medicinal chemistry and materials. Herein, we reported a B(C6F5)3 mediated domino hydrogermylation reaction of enones with dihydrogermanes, affording 21 variants of organogermacycle compounds. These germacyclic compounds were obtained in good to excellent yields (up to 99% yield) under mild reaction conditions.

Fotagliptin monotherapy with alogliptin as an active comparator in patients with uncontrolled type 2 diabetes mellitus: a randomized, multicenter, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Dipeptidyl peptidase-4 inhibitors (DPP-4i) have become firmly established in treatment algorithms and national guidelines for improving glycemic control in type 2 diabetes mellitus (T2DM).To report the findings from a multicenter, randomized, double-blind, placebo-controlled phase 3 clinical trial, which was designed to assess the efficacy and safety of a novel DPP-4 inhibitor fotagliptin in treatment-naive patients with T2DM. METHODS: Patients with T2DM were randomized to receive fotagliptin (n = 230), alogliptin (n = 113) or placebo (n = 115) at a 2:1:1 ratio for 24 weeks of double-blind treatment period, followed by an open-label treatment period, making up a total of 52 weeks. The primary efficacy endpoint was to determine the superiority of fotagliptin over placebo in the change of HbA1c from baseline to Week 24. All serious or significant adverse events were recorded. RESULTS: After 24 weeks, mean decreases in HbA1c from baseline were -0.70% for fotagliptin, -0.72% for alogliptin and -0.26% for placebo. Estimated mean treatment differences in HbA1c were -0.44% (95% confidence interval [CI]: -0.62% to -0.27%) for fotagliptin versus placebo, and -0.46% (95% CI: -0.67% to -0.26%) for alogliptin versus placebo, and 0.02% (95%CI: -0.16% to 0.19%; upper limit of 95%CI < margin of 0.4%) for fotagliptin versus alogliptin. So fotagliptin was non-inferior to alogliptin. Compared with subjects with placebo (15.5%), significantly more patients with fotagliptin (37.0%) and alogliptin (35.5%) achieved HbA1c < 7.0% after 24 weeks of treatment. During the whole 52 weeks of treatment, the overall incidence of hypoglycemia was low for both of the fotagliptin and alogliptin groups (1.0% each). No drug-related serious adverse events were observed in any treatment group. CONCLUSIONS: In summary, the study demonstrated improvement in glycemic control and a favorable safety profile for fotagliptin in treatment-naive patients with T2DM. TRIAL REGISTRATION: ClinicalTrail.gov NCT05782192.

Targeting NLRP3 inflammasome for neurodegenerative disorders.

Neuroinflammation is a key pathological feature in neurological diseases, including Alzheimer's disease (AD). The nucleotide-binding domain leucine-rich repeat-containing proteins (NLRs) belong to the pattern recognition receptors (PRRs) family that sense stress signals, which play an important role in inflammation. As a member of NLRs, the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) is predominantly expressed in microglia, the principal innate immune cells in the central nervous system (CNS). Microglia release proinflammatory cytokines to cause pyroptosis through activating NLRP3 inflammasome. The active NLRP3 inflammasome is involved in a variety of neurodegenerative diseases (NDs). Recent studies also indicate the key role of neuronal NLRP3 in the pathogenesis of neurological disorders. In this article, we reviewed the mechanisms of NLRP3 expression and activation and discussed the role of active NLRP3 inflammasome in the pathogenesis of NDs, particularly focusing on AD. The studies suggest that targeting NLRP3 inflammasome could be a novel approach for the disease modification.

USP25 ameliorates diabetic nephropathy by inhibiting TRAF6-mediated inflammatory responses.

Diabetic kidney disease (DKD) is a common diabetic vascular complication affecting nearly 40% of patients with diabetes. The lack of efficacious therapy for DKD necessitates the in-depth investigation of the molecular mechanisms underlying the pathogenesis and progression of DKD, which remain incompletely understood. Here, we discovered that the expression of USP25, a deubiquitinating enzyme, was significantly upregulated in the kidney of diabetic mice. Ablation of USP25 had no influence on glycemic control in type 1 diabetes but significantly aggravated diabetes-induced renal dysfunction and fibrosis by exacerbating inflammation in the kidney. In DKD, USP25 was mainly expressed in glomerular mesangial cells and kidney-infiltrating macrophages. Upon stimulation with advanced glycation end-products (AGEs), USP25 markedly inhibited the production of proinflammatory cytokines in these two cell populations by downregulating AGEs-induced activation of NF-κB and MAPK pathways. Mechanistically, USP25 interacted with TRAF6 and inhibited its K63 polyubiquitination induced by AGEs. Collectively, these findings identify USP25 as a novel regulator of DKD.

USP25 Inhibits Neuroinflammatory Responses After Cerebral Ischemic Stroke by Deubiquitinating TAB2.

Cerebral ischemic stroke is a leading cause of morbidity and mortality globally. However, the mechanisms underlying ischemic stroke injury remain poorly understood. Here, it is found that deficiency of the ubiquitin-specific protease USP25 significantly aggravate ischemic stroke injury in mice. USP25 has no impact on neuronal death under hypoxic conditions, but reduced ischemic stroke-induced neuronal loss and neurological deficits by inhibiting microglia-mediated neuroinflammation. Mechanistically, USP25 restricts the activation of NF-κB and MAPK signaling by regulating TAB2. As a deubiquitinating enzyme, USP25 removeds K63-specific polyubiquitin chains from TAB2. AAV9-mediated TAB2 knockdown ameliorates ischemic stroke injury and abolishes the effect of USP25 deletion. In both mouse and human brains, USP25 is markedly upregulated in microglia in the ischemic penumbra, implying a clinical relevance of USP25 in ischemic stroke. Collectively, USP25 is identified as a critical inhibitor of ischemic stroke injury and this data suggest USP25 may serve as a therapeutic target for ischemic stroke.