Projections from the ventral tegmental area to zona incerta regulate fear generalization in a mouse model of PTSD.

Generalized fear is a maladaptive behavior in which non-threatening stimuli elicit a fearful response. The ventral tegmental area (VTA) has been demonstrated to play important roles in fear response and fear memory generalization, but the precious neural circuit mechanism is still unclear. Here, we demonstrated that VTA-zona incerta (ZI) glutamatergic projection is involved in regulating high-intensity threatening training induced generalization and anxiety. Combining calcium signal recording and chemogentics, our work reveals that VTA glutamatergic neurons respond to closed arm entering in the model of PTSD. Inhibition of VTA glutamatergic neurons or the glutamatergic projection to ZI could both relieve fear generalization and anxiety. Together, our study proves the VTA - ZI glutamatergic circuit is involved in mediating fear generalization and anxiety, and provides a potential target for treating post-traumatic stress disorder.

Population-based prevalence of self-reported pediatric diabetes and screening for undiagnosed type 2 diabetes in Chinese children in years 2017-2019, a cross-sectional study.

Background: The worldwide geographical and temporal variation in the prevalence of diabetes represents a challenge, but also an opportunity for gaining etiological insights. Encompassing the bulk of East Asians, a large and distinct proportion of the world population, China can be a source of valuable epidemiological insights for diabetes, especially in early life, when pathophysiology begins. We carried out a nationwide, epidemiological survey of Prevalence and Risk of Obesity and Diabetes in Youth (PRODY) in China, from 2017 to 2019, to estimate the population-based prevalence of diagnosed pediatric diabetes and screen for undiagnosed pediatric type 2 diabetes (T2D). Methods: PRODY was a nation-wide, school population-based, cross-sectional, multicenter survey by questionnaire, fasting urine glucose test and simple oral glucose tolerance test (s-OGTT), among a total number of 193,801 general-population children and adolescents (covered a pediatric population of more than 96.8 million), aged 3-18, from twelve provinces across China. The prevalence of the self-reported pediatric diabetes, the proportion of subtypes, the crude prevalence of undiagnosed T2D and prediabetes in general juvenile population and the main risk factors of type 1 (T1D) and type 2 (T2D) diabetes had been analyzed in the study. Findings: The prevalence of all self-reported pediatric diabetes was estimated at 0.62/1000 (95% CI: 0.51-0.74), with T1D at 0.44/1000 (95% CI: 0.35-0.54) and T2D at 0.18/1000 (95% CI: 0.13-0.25). For undiagnosed T2D, the crude prevalence was almost ten-fold higher, at 1.59/1000, with an estimated extra 28.45/1000 of undiagnosed impaired glucose tolerance (IGT) and 53.74/1000 of undiagnosed impaired fasting glucose (IFG) by s-OGTT screening. Maternal diabetes history is the major risk factors for all subtypes of pediatric diabetes in China. Interpretation: The PRODY study provides the first population-based estimate of the prevalence of pediatric diabetes China and reveals a magnitude of the problem of undiagnosed pediatric T2D. We propose a practical screening strategy by s-OGTT to address this serious gap. Funding: The National Key Research and Development Programme of China, Key R&D Program of Zhejiang, the National Natural Science Foundation of China and the Zhejiang Provincial Key Disciplines of Medicine, Key R&D Program Projects in Zhejiang Province.

Prognostic Value of Plasma Immunoglobulin G N-Glycome Traits in Pulmonary Arterial Hypertension.

BACKGROUND: B-type natriuretic peptide or N-terminal pro-B-type natriuretic peptide is the only blood biomarker in established risk calculators for pulmonary arterial hypertension (PAH). Profiling systemic-originated plasma immunoglobulin G (IgG) N-glycans, which reflect different components of the pathophysiology of PAH including immune dysregulation and inflammation, may improve PAH risk assessment. OBJECTIVES: This study sought to identify plasma IgG N-glycan biomarkers that predict survival in PAH to improve risk assessment. METHODS: This cohort study examined 622 PAH patients from 2 national centers (Beijing [discovery] cohort: n = 273; Shanghai [validation] cohort: n = 349). Plasma IgG N-glycomes were profiled by a robust mass spectrometry-based method. Prognostic IgG N-glycan traits were identified and validated in the 2 cohorts using Cox regression and Kaplan-Meier survival analyses. The added value of IgG N-glycan traits to previously established risk models was assessed using Harrell C-indexes and survival analysis. RESULTS: Plasma IgG fucosylation was found to predict survival independent of age and sex in the discovery cohort (HR: 0.377; 95% CI: 0.168-0.845; P = 0.018) with confirmation in the validation cohort (HR: 0.445; 95% CI: 0.264-0.751; P = 0.005). IgG fucosylation remained a robust predictor of mortality in combined cohorts after full adjustment and in subgroup analyses. Integrating IgG fucosylation into previously established risk models improved their predictive capacity, marked by an overall elevation in Harrell C-indexes. IgG fucosylation was useful in further stratifying the intermediate-risk patients classified by a previously established model. CONCLUSIONS: Plasma IgG fucosylation informs PAH prognosis independent of established factors, offering additional value for predicting PAH outcomes.

Machine Learning-Driven discovery of immunogenic cell Death-Related biomarkers and molecular classification for diabetic ulcers.

In this study, we redefine the diagnostic landscape of diabetic ulcers (DUs), a major diabetes complication. Our research uncovers new biomarkers linked to immunogenic cell death (ICD) in DUs by utilizing RNA-sequencing data of Gene Expression Omnibus (GEO) analysis combined with a comprehensive database interrogation. Employing a random forest algorithm, we have developed a diagnostic model that demonstrates improved accuracy in distinguishing DUs from normal tissue, with satisfactory results from ROC analysis. Beyond mere diagnosis, our model categorizes DUs into novel molecular classifications, which may enhance our comprehension of their underlying pathophysiology. This study bridges the gap between molecular insights and clinical practice. It sets the stage for transformative strategies in DUs management, marking a significant step forward in personalized medicine for diabetic patients.

Spatial multiomics reveals a subpopulation of fibroblasts associated with cancer stemness in human hepatocellular carcinoma.

BACKGROUND: Cancer-associated fibroblasts (CAFs) are the prominent cell type in the tumor microenvironment (TME), and CAF subsets have been identified in various tumors. However, how CAFs spatially coordinate other cell populations within the liver TME to promote cancer progression remains unclear. METHODS: We combined multi-region proteomics (6 patients, 24 samples), 10X Genomics Visium spatial transcriptomics (11 patients, 25 samples), and multiplexed imaging (92 patients, 264 samples) technologies to decipher the expression heterogeneity, functional diversity, spatial distribution, colocalization, and interaction of fibroblasts. The newly identified CAF subpopulation was validated by cells isolated from 5 liver cancer patients and in vitro functional assays. RESULTS: We identified a liver CAF subpopulation, marked by the expression of COL1A2, COL4A1, COL4A2, CTGF, and FSTL1, and named F5-CAF. F5-CAF is preferentially located within and around tumor nests and colocalizes with cancer cells with higher stemness in hepatocellular carcinoma (HCC). Multiplexed staining of 92 patients and the bulk transcriptome of 371 patients demonstrated that the abundance of F5-CAFs in HCC was associated with a worse prognosis. Further in vitro experiments showed that F5-CAFs isolated from liver cancer patients can promote the proliferation and stemness of HCC cells. CONCLUSIONS: We identified a CAF subpopulation F5-CAF in liver cancer, which is associated with cancer stemness and unfavorable prognosis. Our results provide potential mechanisms by which the CAF subset in the TME promotes the development of liver cancer by supporting the survival of cancer stem cells.

Consumption of Total and Specific Alcoholic Beverages and Long-Term Risk of Gout Among Men and Women.

Importance: Previous studies on alcohol consumption and incident gout have mostly included men or combined both sexes, and the sex-specific associations between alcohol consumption and gout are poorly understood. Objective: To evaluate the consumption of total and specific alcoholic beverages in association with incident gout in men and women. Design, Setting, and Participants: This prospective cohort study included 401 128 participants in the UK Biobank aged 37 to 73 years who were free of gout at baseline (2006-2010). Participants were followed up through December 31, 2021, and data were analyzed between August 2023 and June 2024. Exposure: Questionnaire-based consumption of total alcohol and specific alcoholic beverages. Main Outcomes and Measures: The outcome was incident gout, identified using hospital records. Multivariable Cox proportional hazards regression models were used to estimate sex-specific hazard ratios (HRs) and 95% CIs of incident gout associated with alcohol consumption, with a particular consideration of reverse causation bias. Results: The main analysis included 179 828 men (mean [SD] age, 56.0 [8.2] years) and 221 300 women (mean [SD] age, 56.0 [8.0] years). Current drinkers showed a higher risk of gout than never drinkers among men (HR, 1.69; 95% CI, 1.30-2.18) but not among women (HR, 0.83; 95% CI, 0.67-1.03). Among current drinkers, higher total alcohol consumption was associated with a higher risk of gout among both sexes and more strongly among men than women (men: HR, 2.05 [95% CI, 1.84-2.30]; women: HR, 1.34 [95% CI, 1.12-1.61]). The most evident sex difference in the consumption of specific alcoholic beverages was observed for beer or cider (men: mean [SD], 4.2 [4.8] pints per week; women: mean [SD], 0.4 [1.1] pints per week). Consumption of champagne or white wine, beer or cider, and spirits each was associated with a higher risk of gout among both sexes, with beer or cider showing the strongest association per 1 pint per day (men: HR, 1.60 [95% CI, 1.53-1.67]; women: HR, 1.62 [95% CI, 1.02-2.57]). Some inverse associations between light to moderate consumption of specific alcoholic beverages and gout were eliminated after adjusting for other alcoholic beverages and excluding individuals who had reduced alcohol consumption for health reasons, self-reported poor health, or had cardiovascular disease, cancer, or kidney failure at baseline, or developed gout within the first 2 years of follow-up. Conclusions and Relevance: In this cohort study, higher consumption of several specific alcoholic beverages was associated with a higher risk of gout among both sexes. The sex-specific associations for total alcohol consumption may be associated with differences between men and women in the types of alcohol consumed.

DHPS-Mediated Hypusination Regulates METTL3 Self-m6A-Methylation Modification to Promote Melanoma Proliferation and the Development of Novel Inhibitors.

Discovering new treatments for melanoma will benefit human health. The mechanism by which deoxyhypusine synthase (DHPS) promotes melanoma development remains elucidated. Multi-omics studies have revealed that DHPS regulates m6A modification and maintains mRNA stability in melanoma cells. Mechanistically, DHPS activates the hypusination of eukaryotic translation initiation factor 5A (eIF5A) to assist METTL3 localizing on its mRNA for m6A modification, then promoting METTL3 expression. Structure-based design, synthesis, and activity screening yielded the hit compound GL-1 as a DHPS inhibitor. Notably, GL-1 directly inhibits DHPS binding to eIF5A, whereas GC-7 cannot. Based on the clarification of the mode of action of GL-1 on DHPS, it is found that GL-1 can promote the accumulation of intracellular Cu2+ to induce apoptosis, and antibody microarray analysis shows that GL-1 inhibits the expression of several cytokines. GL-1 shows promising antitumor activity with good bioavailability in a xenograft tumor model. These findings clarify the molecular mechanisms by which DHPS regulates melanoma proliferation and demonstrate the potential of GL-1 for clinical melanoma therapy.

Female reproductive factors, exogenous hormone use, and incident chronic kidney disease and end-stage renal disease.

CONTEXT: Younger women have a slower progressive loss of kidney function than age-matched men and the sex advantage diminishes after menopause, suggesting a role for female hormones in the development of kidney diseases. OBJECTIVE: To examine the relationships of numerous reproductive factors and exogenous hormone use with long-term risk of chronic kidney disease (CKD) and end-stage renal disease (ESRD) in women. METHODS: A total of 260,108 women without prevalent CKD and ESRD were included. The relationships of various reproductive factors and exogenous hormone use with incident CKD and ESRD were assessed, with multivariable adjustment for potential confounders. RESULTS: During a median of ∼12.5 years of follow-up, 8,766 CKD and 554 ESRD cases were identified. Younger age at first live birth, hysterectomy or bilateral oophorectomy before 50 years old, menopausal before 45 years old, and menopausal hormone therapy (MHT) initiated before 50 years old was associated with a higher risk of CKD. The relationships of these factors with ESRD were generally consistent with those for CKD. Each 5-year increment in menopausal age was associated with an 11% lower risk of CKD (HR = 0.89; 95% CI: 0.87, 0.91) and a 13% lower risk of ESRD (HR = 0.87; 95% CI: 0.79, 0.95). Each 5-year delay in starting MHT was associated with a 13% lower risk of CKD (HR = 0.87; 95% CI: 0.84, 0.90) and a 15% lower risk of ESRD (HR = 0.85; 95% CI: 0.73, 0.99). CONCLUSION: Several reproductive characteristics reflecting shorter cumulative exposure to endogenous estrogen or premature exposure to exogenous hormones are associated with a greater risk of CKD and ESRD in women, supporting a potential role of female hormones in renal pathophysiology.

Identification of Angiogenesis-Related Genes and Molecular Subtypes for Psoriasis Based on Random Forest Algorithm.

Psoriasis is a chronic immune-mediated recurrent skin disease causing systemic damage. Increased angiogenesis has been reported to participate in the progression of psoriasis. However, angiogenesis-related genes (ARGs) in psoriasis have not been systematically elucidated. Therefore, we aim to identify potential biomarkers and subtypes using two algorithms. Transcriptome sequencing data of patients with psoriasis were obtained, in which differentially expressed genes were assessed by principal component analysis (PCA). A diagnostic model was developed using random forest algorithm (ntree=400) and validated by ROC curves. Subsequently, we performed consensus clustering to calculate angiogenesis-associated molecular subtypes of psoriasis. Additionally, a correlation analysis was conducted between ARGs and immune cell infiltration. Finally, validation of potential ARG genes was performed by qRT-PCR. We identified 29 differentially expressed ARGs, including 13 increased and 16 decreased. Ten ARGs, CXCL8, ANG, EGF, HTATIP2, ANGPTL4, TNFSF12, RHOB, PML, FOXO4, and EMCN were subsequently sifted by the diagnostic model based on a random forest algorithm. Analysis of the ROC curve (area under the curve [AUC] = 1.0) indicated high diagnostic performance in internal validation. The correlation analysis suggested that CXCL8 has a high positive correlation with neutrophil (R =0.8, P<0.0001) and interleukins pathway (R=0.79, P<0.0001). Furtherer, two ARG-mediated subtypes were obtained, indicating potential heterogeneity. Finally, the qRT-PCR demonstrated that the mRNA expression levels of CXCL8 and ANGPTL4 were elevated in psoriasis patients, with a reduced expression of EMCN observed. The current paper indicated potential ARG-related biomarkers of psoriasis, including CXCL8, ANGPTL4, and EMCN, with two molecular subtypes.

Up-regulating GABA transporter-3 in the zona incerta prevents surgery-induced memory impairment in mice.

Clinical surgery can lead to severe neuroinflammation and cognitive dysfunctions. It has been reported that astrocytes mediate memory formation and postoperative cognitive dysfunction (POCD), however, the thalamic mechanism of astrocytes in mediating POCD remains unknown. Here, we report that reactive astrocytes in zona incerta (ZI) mediate surgery-induced recognition memory impairment in male mice. Immunostaining results showed that astrocytes are activated with GABA transporter-3 (GAT-3) being down-expressed, and neurons were suppressed in the ZI. Besides, our work revealed that reactive astrocytes caused increased tonic current in ZI neurons. Up-regulating the expression of GAT-3 in astrocytes ameliorates surgery-induced recognition memory impairment. Together, our work demonstrates that the reactive astrocytes in the ZI play a crucial role in surgery-induced memory impairment, which provides a new target for the treatment of surgery-induced neural dysfunctions.

Sirtuin-6 knockout causes exacerbated stalled healing of diabetic ulcers in mice.

BACKGROUND: Diabetic ulcers (DUs) are characterized by chronic inflammation and delayed re-epithelialization, with a high incidence and weighty economic burden. The primary therapeutic strategies for refractory wounds include surgery, non-invasive wound therapy, and drugs, while the optimum regimen remains controversial. Sirtuin-6 (SIRT6) is a histone deacetylase and a key epigenetic factor that exerts anti-inflammatory and pro-proliferatory effects in wound healing. However, the exact function of SIRT6 in DUs remains unclear. METHODS: We generated tamoxifen-inducible SIRT6 knockout mice by crossing SIRT6flox/flox homozygous mice with UBC-creERT2+ transgenic mice. Systemic SIRT6 null mice, under either normal or diabetic conditions, were utilized to assess the effects of SIRT6 in DUs treatment. Gene and protein expressions of SIRT6 and inflammatory cytokines were measured by Western blotting and RT-qPCR. Histopathological examination confirmed the altered re-epithelialization (PCNA), inflammation (NF-κB p50 and F4/80), and angiogenesis (CD31) markers during DUs restoration. RESULTS: Knockout of SIRT6 inhibited the healing ability of DUs, presenting attenuated re-epithelialization (PCNA), exacerbated inflammation responses (NF-κB p50, F4/80, Il-1ß, Tnf-α, Il-6, Il-10, and Il-4), and hyperplasia vascular (CD31) compared with control mice. CONCLUSIONS: SIRT6 could boost impaired wound healing through improving epidermal proliferation, inflammation, and angiogenesis. Our study highlighted the therapeutic potential of the SIRT6 agonist for DUs treatment.

Reducing Door-to-Puncture Times for Mechanical Thrombectomy in a Large Tertiary Hospital.

Background and Objectives: Endovascular therapy (EVT) for stroke has emerged as an important therapy for selected stroke patients, and shorter times to clot removal improve functional outcomes. EVT requires the close coordination of multiple departments and poses unique challenges to care coordination in large hospitals. We present the results of our quality improvement project that aimed to improve our door-to-groin puncture (DTP) times for patients who undergo EVT after direct presentation to our emergency department. Methods: We conducted time-motion studies to understand the full process of an EVT activation and conducted Gemba walks in multiple hospitals. We also reviewed the literature and interviewed stakeholders to create interventions that were implemented over 4 Plan-Do-Study-Act (PDSA) cycles. We retrospectively collected data starting from baseline and during every PDSA cycle. During each cycle, we studied the impact of the interventions, adjusted the interventions, and generated further interventions. A variety of interventions were introduced targeting all aspects of the EVT process. This included parallel processing to reduce waiting time, standardization of protocols and training of staff, behavioral prompts in the form of a stroke clock, and push systems to empower staff to facilitate the forward movement of the patient. A novel role-based communication app to facilitate group communications was also used. Results: Eighty-eight patients spanning across 22 months were analyzed. After the final PDSA cycle, the median DTP time was reduced by 36.5% compared with baseline (130 minutes (interquartile range [IQR] 111-140) to 82.5 minutes (IQR 74.8-100)). There were improvements in all phases of the EVT process with the largest time savings occurring in EVT decision to patient arrival at the angiosuite. Interventions that were most impactful are described. Discussion: EVT is a complex process involving multiple processes and local factors. Analysis of the process from all angles and intervening on multiple small aspects can add up to significant improvements in DTP times.

A randomized controlled clinical trial of concentrated growth factor combined with sodium hyaluronate in the treatment of temporomandibular joint osteoarthritis.

OBJECTIVE: To investigate the effect of concentrated growth factor (CGF) combined with sodium hyaluronate (SH) on temporomandibular joint osteoarthritis (TMJOA). METHODS: Sixty patients with TMJOA who were diagnosed by cone-beam computed tomography (CBCT) between March 2020 and March 2023 at the Stomatological Hospital of Xi'an Jiaotong University were randomly divided into a control group (n = 30) and an experimental group (n = 30). The patients in the experimental group were treated with CGF + SH, and those in the control group were treated with SH only. The visual analogue scale (VAS) score indicating pain in the temporomandibular joint (TMJ) area; the Helkimo Clinical Dysfunction Index (Di); and changes in condylar CBCT at the first visit and 2 weeks, 3 months and 6 months after treatment were recorded. The CBCT data of the patients in the experimental and control groups were collected, and the three-dimensional CBCT image sequences were imported into Mimics Medical 19.0 software in DICOM format for condylar reconstruction. RESULTS: The VAS scores at 2 weeks, 3 months and 6 months after treatment were significantly lower in the experimental group than in the control group (P < 0.05), and the pain in the experimental group was significantly relieved. The Di was significantly lower in the experimental group than in the control group (P < 0.05), and the clinical function of the TMJ improved. After treatment, the CBCT score was significantly lower in the experimental group than in the control group (P < 0.05), and the condylar bone cortex was obviously repaired. Observation of the condylar bone cortex by three-dimensional reconstruction showed the same results as those obtained by CBCT. CONCLUSION: CGF combined with SH is effective in the treatment of TMJOA and can improve muscle pain, TMJ pain, Impaired TMJ function, Impaired range of movement, Pain on movement of the mandible and promote bone repair. THE REGISTRATION NUMBER (TRN): ChiCTR2400082712. THE DATE OF REGISTRATION: April 5, 2024.

A randomized, double-blind, placebo-controlled phase I clinical trial of rotavirus inactivated vaccine (Vero cell) in a healthy adult population aged 18-49 years to assess safety and preliminary observation of immunogenicity.

We conducted a phase I, randomized, double-blind, placebo-controlled trial including healthy adults in Sui County, Henan Province, China. Ninety-six adults were randomly assigned to one of three groups (high-dose, medium-dose, and low-dose) at a 3:1 ratio to receive one vaccine dose or placebo. Adverse events up to 28 days after each dose and serious adverse events up to 6 months after all doses were reported. Geometric mean titers and seroconversion rates were measured for anti-rotavirus neutralizing antibodies using microneutralization tests. The rates of total adverse events in the placebo group, low-dose group, medium-dose group, and high-dose group were 29.17 % (12.62 %-51.09 %), 12.50 % (2.66 %-32.36 %), 50.00 % (29.12 %-70.88 %), and 41.67 % (22.11 %-63.36 %), respectively, with no significant difference in the experimental groups compared with the placebo group. The results of the neutralizing antibody assay showed that in the adult group, the neutralizing antibody geometric mean titer at 28 days after full immunization in the low-dose group was 583.01 (95 % confidence interval [CI]: 447.12-760.20), that in the medium-dose group was 899.34 (95 % CI: 601.73-1344.14), and that in the high-dose group was 1055.24 (95 % CI: 876.28-1270.75). The GMT of serum-specific IgG at 28 days after full immunization in the low-dose group was 3444.26 (95 % CI: 2292.35-5175.02), that in the medium-dose group was 6888.55 (95 % CI: 4426.67-10719.6), and that in the high-dose group was 7511.99 (95 % CI: 3988.27-14149.0). The GMT of serum-specific IgA at 28 days after full immunization in the low-dose group was 2332.14 (95 % CI: 1538.82-3534.45), that in the medium-dose group was 4800.98 (95 % CI: 2986.64-7717.50), and that in the high-dose group was 3204.30 (95 % CI: 2175.66-4719.27). In terms of safety, adverse events were mainly Grades 1 and 2, indicating that the safety of the vaccine is within the acceptable range in the healthy adult population. Considering the GMT and positive transfer rate of neutralizing antibodies for the main immunogenicity endpoints in the experimental groups, it was initially observed that the high-dose group had higher levels of neutralizing antibodies than the medium- and low-dose groups in adults aged 18-49 years. This novel inactivated rotavirus vaccine was generally well-tolerated in adults, and the vaccine was immunogenic in adults (ClinicalTrials.gov number, NCT04626856).

Plant-based diets, mediating biomarkers, and mortality risk among adults with diabetes or prediabetes.

Background: A healthy eating pattern characterized by a higher intake of healthy plant foods has been associated with a lower risk of premature mortality, but whether this applies to individuals with varying glycemic status remains unclear. Methods: This study included 4621 participants with diabetes and 8061 participants with prediabetes from the US National Health and Nutrition Examination Survey (2007-2016). Using the dietary data assessed by two 24 h dietary recalls, a healthful plant-based diet index (hPDI) and an unhealthful plant-based diet index (uPDI) were created based on 15 food groups and were assessed for their relationships with mortality risk. Results: Over a median follow-up of 7.2 years, there were 1021 deaths in diabetes and 896 deaths in prediabetes. A higher hPDI (highest vs. lowest quartile) was associated with a 41% (HR = 0.59, 95% CI: 0.49-0.72; P-trend < 0.001) lower risk of all-cause mortality in diabetes and a 31% (HR = 0.69, 95% CI: 0.55-0.85; P-trend < 0.001) lower risk in prediabetes. A higher uPDI was associated with an 88% (HR = 1.88, 95% CI: 1.55-2.28; P-trend < 0.001) higher risk of mortality in diabetes and a 63% (HR = 1.63, 95% CI: 1.33-1.99; P-trend < 0.001) higher risk in prediabetes. Mediation analysis suggested that C-reactive protein and γ-glutamine transaminase explained 6.0% to 10.9% of the relationships between hPDI or uPDI and all-cause mortality among participants with diabetes. Conclusions: For adults with diabetes as well as those with prediabetes, adhering to a plant-based diet rich in healthier plant foods is associated with a lower mortality risk, whereas a diet that incorporates less healthy plant foods is associated with a higher mortality risk.

Functions and novel regulatory mechanisms of key glycolytic enzymes in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a progressive vascular disease characterized by remodeling of the pulmonary vasculature and elevated pulmonary arterial pressure, ultimately leading to right heart failure and death. Despite its clinical significance, the precise molecular mechanisms driving PAH pathogenesis warrant confirmation. Compelling evidence indicates that during the development of PAH, pulmonary vascular cells exhibit a preference for energy generation through aerobic glycolysis, known as the "Warburg effect", even in well-oxygenated conditions. This metabolic shift results in imbalanced metabolism, increased proliferation, and severe pulmonary vascular remodeling. Exploring the Warburg effect and its interplay with glycolytic enzymes in the context of PAH has yielded current insights into emerging drug candidates targeting enzymes and intermediates involved in glucose metabolism. This sheds light on both opportunities and challenges in the realm of antiglycolytic therapy for PAH.

Immune persistence after different polio sequential immunization schedules in Chinese infants.

Trivalent oral poliovirus vaccine (tOPV) has been withdrawn and instead an inactivated poliovirus vaccine (IPV) and bivalent type 1 and type 3 OPV (bOPV) sequential immunization schedule has been implemented since 2016, but no immune persistence data are available for this polio vaccination strategy. This study aimed to assess immune persistence following different polio sequential immunization schedules. Venous blood was collected at 24, 36, and 48 months of age from participants who had completed sequential schedules of combined IPV and OPV in phase III clinical trials. The serum neutralizing antibody titers against poliovirus were determined, and the poliovirus-specific antibody-positive rates were evaluated. A total of 1104 participants were enrolled in this study. The positive rates of poliovirus type 1- and type 3-specific antibodies among the sequential immunization groups showed no significant difference at 24, 36, or 48 months of age. The positive rates of poliovirus type 2-specific antibody in the IPV-IPV-tOPV group at all time points were nearly 100%, which was significantly higher than the corresponding rates in other immunization groups (IPV-bOPV-bOPV and IPV-IPV-bOPV). Immunization schedules involving one or two doses of IPV followed by bOPV failed to maintain a high positive rate for poliovirus type 2-specific antibody.

SHMT2 Mediates Small-Molecule-Induced Alleviation of Alzheimer Pathology Via the 5'UTR-dependent ADAM10 Translation Initiation.

It is long been suggested that one-carbon metabolism (OCM) is associated with Alzheimer's disease (AD), whereas the potential mechanisms remain poorly understood. Taking advantage of chemical biology, that mitochondrial serine hydroxymethyltransferase (SHMT2) directly regulated the translation of ADAM metallopeptidase domain 10 (ADAM10), a therapeutic target for AD is reported. That the small-molecule kenpaullone (KEN) promoted ADAM10 translation via the 5' untranslated region (5'UTR) and improved cognitive functions in APP/PS1 mice is found. SHMT2, which is identified as a target gene of KEN and the 5'UTR-interacting RNA binding protein (RBP), mediated KEN-induced ADAM10 translation in vitro and in vivo. SHMT2 controls AD signaling pathways through binding to a large number of RNAs and enhances the 5'UTR activity of ADAM10 by direct interaction with GAGGG motif, whereas this motif affected ribosomal scanning of eukaryotic initiation factor 2 (eIF2) in the 5'UTR. Together, KEN exhibits therapeutic potential for AD by linking OCM with RNA processing, in which the metabolic enzyme SHMT2 "moonlighted" as RBP by binding to GAGGG motif and promoting the 5'UTR-dependent ADAM10 translation initiation.