Diabetes

Obesity affects one in three adults and is complicated by adipose inflammation, lipotoxicity and cell death. We previously identified RIPK1 as a genetic determinant of human obesity risk and adipose inflammation. Because RIPK1 is the apical kinase in the necroptosis pathway upstream of RIPK3 and the executioner protein MLKL, and emerging evidence links MLKL to lipid metabolism, MLKL has surfaced as a potential metabolic regulator. However, conflicting findings in Mlkl knockout mice fed a high fat diet have left its therapeutic relevance unresolved. MLKL has not been previously targeted through therapeutic knockdown in vivo in the context of diet-induced obesity. Here, we evaluated two independent MLKL antisense oligonucleotides (ASOs) in high fat diet (HFD)-fed C57BL/6J mice. In a 24-week progression model, MLKL ASO markedly reduced body weight, fat mass and hepatic steatosis compared with controls, while preserving lean mass. MLKL knockdown also lowered the respiratory exchange ratio, indicating a shift toward increased fat oxidation. In the intervention model, once obesity was established after 12 weeks of HFD feeding, both MLKL ASOs, and similarly, two independent RIPK1 ASOs, reversed weight gain and improved systemic glucose control. In vitro, MLKL-CRISPR/Cas9 knockout blocked 3T3-L1 adipogenesis, indicating a requirement for MLKL during adipocyte differentiation. However, in mature adipocytes, MLKL siRNA reduced palmitic acid-induced lipid accumulation, increased isoprenaline-stimulated lipolysis, and prevented TNF-mediated suppression of insulin-mediated AKT signalling and glucose uptake. Collectively, these findings demonstrate that partial MLKL suppression reprograms whole-body energy metabolism, enhances insulin sensitivity and limits diet-induced adiposity. MLKL, therefore, represents a promising and mechanistically novel therapeutic target for obesity and insulin resistance.

Microglia, the resident macrophages of the central nervous system, are recognized for their heterogeneity and integral role in brain function and diseases. In the context of high fat diet (HFD) feeding and obesity, microglia become overactive, acquiring a prevailing lipid associated microglial phenotype (also known as LAM). Yet, how microgliosis is induced and regulated remains unclear. Here we report a key role for the Complement 3a Receptor (C3aR), on HFD-induced hypothalamic gliosis and weight gain in mice. HFD consumption leads to elevated microglial expression of C3aR, which parallels widespread accumulation of reactive microglia, selectively in the hypothalamus. Conditional microglial C3aR deletion protects mice from HFD-induced hypothalamic reactive microgliosis. C3aR deletion or pharmacological antagonism opposes HFD-induced weight gain in male but not female mice. Mechanistically, we demonstrated that C3aR is essential for lipid-induced lipid droplet formation, and acquisition of a LAM molecular signature. In summary, we uncovered a previously unknown role for C3aR in the acquisition of a LAM signature driving diet-induced gliosis, identifying this receptor as a new viable therapeutic candidate for conditions associated with hypothalamic neuroinflammation.

Type 2 diabetes (T2D) is a heterogeneous disease shaped by genetic pathways related to insulin resistance and beta cell dysfunction, but how this heterogeneity is reflected molecularly remains unclear. We integrated partitioned polygenic scores (pPS) with proteomic and metabolomic profiling to define molecular signatures of T2D and their clinical relevance. We analyzed UK Biobank participants with genomic, proteomic, and metabolomic data. In a disease-free training subset, we used LASSO regression to identify multi-omic signatures associated with each pPS by jointly modeling proteins and metabolites. In an independent testing set, we constructed multi-omic scores and examined their associations with clinical traits and diabetes-related outcomes. Mediation analyses were used to investigate putative causal pathways. Key findings were evaluated in the Multi-Ethnic Study of Atherosclerosis (MESA). We identified distinct multi-omic signatures that capture the molecular architecture of T2D genetic risk across physiological subtypes. Compared with genetic scores alone, multi-omic pPS showed larger effect sizes and better disease discrimination. These scores recapitulated subtype-specific physiology and were associated with T2D risk. The Beta-Cell 2 multi-omic score showed marked stratification for insulin use, which was replicated in MESA, where it also predicted future insulin use. Mediation analyses implicated lipoprotein remodeling and fatty acid metabolism in the Lipodystrophy 1 cluster, accounting for up to 45% of the total effect of pPS on T2D risk. Integrating process-specific genetic risk with circulating multi-omic profiles reveals biologically distinct endotypes of T2D and supports a framework for improved patient stratification and risk assessment.

Diabetes mellitus is characterized by chronic hyperglycemia and loss of pancreatic {beta}-cell function and mass. Current therapies focus on {beta}-cell protection and regeneration, led by GLP-1 receptor agonists. The G protein -subunit (Gs) acts as a key signaling node downstream of numerous GPCRs, integrating diverse signals that impact {beta}-cell mass and function. Elucidating the integrative role of pancreatic Gs signaling is thus crucial for understanding {beta}-cell biology. Our map of the pancreatic Gs-coupled GPCR landscape reveals sophisticated, cell-type-specific networks, positioning Gs as a central hub for intra-pancreatic communication. Previous studies in mice with {beta}-cell-specific or whole-pancreatic Gs deletion demonstrated reduced {beta}-cell mass, impaired insulin secretion, and glucose intolerance. The stronger phenotype in the whole-pancreas model--marked by -cell expansion and abnormal distribution--points to a crucial role for Gs in differential control of postnatal - and {beta}-cell proliferation. Here, we analyze the organ-wide consequences of Gs deletion using pancreas-specific Gs knockout mice (PGsKO). Consistent with prior findings, PGsKO mice exhibit reduced weight gain from four weeks and severe diabetes due to decreased {beta}-cell mass and concomitant -cell expansion. Furthermore, Gs loss induces profound architectural and functional defects in the exocrine pancreas, linked to YAP reactivation in acinar cells. Importantly, we observed attempted {beta}-cell regeneration in PGsKO mice. Although insufficient to reverse diabetes, our results delineate the full pancreatic phenotype that may facilitate these regenerative efforts and suggest that strategically biasing GPCR signaling network away from Gs could be a viable strategy to promote {beta}-cell regeneration from other pancreatic cell types. ARTICLE HIGHLIGHTSO_LIGs is a central signaling hub that integrates diverse GPCR inputs across pancreatic cell types, yet its organ-wide role remained poorly defined. C_LIO_LIWe addressed how pancreas-wide Gs deletion disrupts both endocrine and exocrine compartments, and whether regenerative programs are engaged. C_LIO_LIGs loss caused severe diabetes through {beta}-cell loss and -cell expansion, induced profound exocrine defects with YAP reactivation, and triggered attempted {beta}-cell regeneration from ducts and potentially other cell types. C_LIO_LIOur findings suggest that strategically biasing GPCR signaling away from Gs could promote regeneration from non-{beta}-cell sources, offering new therapeutic avenues for diabetes. C_LI

Type 2 diabetes mellitus (T2DM) is a progressive metabolic disorder characterized by persistent hyperglycemia, insulin resistance, and chronic low-grade inflammation. Despite the widespread use of established therapies such as metformin, long-term glycemic control remains suboptimal, and disease progression is often not adequately prevented. This highlights the need for novel therapeutic strategies that address both metabolic dysfunction and the underlying immunometabolic components of the disease. In this study, GLX10 (GLXM100) was evaluated as a novel immune modulator in a high-fat diet (HFD) and low-dose streptozotocin (STZ)-induced rat model of T2DM over a 91-day period. Glycemic outcomes were assessed using terminal random blood glucose and oral glucose tolerance testing (OGTT), with glucose exposure quantified by area under the curve (AUC 0-120). Complementary in vitro investigations were performed in hepatic and macrophage cell models to assess cytocompatibility, nitric oxide production, and modulation of pro-inflammatory cytokines, including IL-6 and TNF-. GLX10 treatment resulted in a significant reduction in random blood glucose levels and a marked improvement in glucose tolerance compared to diabetic control animals. Importantly, GLX10 demonstrated greater improvement in OGTT AUC compared to metformin under the same experimental conditions, indicating enhanced dynamic glucose regulation. In vitro, GLX10 maintained viability in normal hepatic cells while significantly suppressing nitric oxide production and inflammatory cytokine outputs in macrophages, supporting a favorable safety and immune profile. Collectively, these findings demonstrate that GLX10 exerts robust antidiabetic activity through a dual mechanism involving metabolic regulation and suppression of inflammatory signaling. The integration of in vivo efficacy with supportive in vitro safety and mechanistic data provides a strong preclinical foundation and supports the further development of GLX10 as a promising therapeutic candidate for T2DM.

Abstract Background: Cardiometabolic diseases arise from metabolic dysfunction that develops decades before clinical onset. Conventional genetic risk models are typically derived in middle-aged or older populations, where genetic effects are confounded by cumulative environmental exposures, chronic comorbidities, and clinical interventions. Whether the life stage at which genetic liability is modelled influences the biological signal captured by polygenic scores remains unclear, particularly in underrepresented populations. We therefore tested whether genetic liability modelled in early adulthood, a period of relative physiological stability, is associated with cardiometabolic risk across the life course in Asian populations. Methods: We developed a polygenic score for metabolic syndrome, GenMetS, using data from 1,368 Singaporean women aged 18-45 years. The model integrates 15 established polygenic scores for metabolic traits and applies elastic-net penalized regression to optimize variant weights. GenMetS was evaluated in five cohorts comprising 670,952 individuals aged 0-94 years across population-based and disease-enriched settings, including Asian and European ancestry groups. Associations with metabolic traits, cardiometabolic diseases, multimorbidity, and early-life growth patterns were assessed. Results: In Asian populations, GenMetS explained 5.0-12.4% of the variance in metabolic syndrome in adults and 10.3% in children, with negligible performance in European populations (R squared < 0.001). Higher GenMetS was associated with increased odds of cardiometabolic diseases, including type 2 diabetes, heart failure, and stroke (odds ratios 1.32-1.52 per standard deviation). In UK Biobank participants of Asian ancestry, GenMetS improved discrimination of cardiometabolic multimorbidity beyond age alone. Associations were consistent across sexes. In children, higher GenMetS was associated with obesogenic growth trajectories and increased abdominal adiposity. Conclusions: Genetic liability to metabolic dysfunction modelled in early adulthood captures a stable biological signal associated with metabolic traits, disease risk, and multimorbidity from childhood to adulthood in Asian populations. These findings indicate that the life stage of model derivation shapes the biological signal captured by polygenic scores and support the development of life-stage and ancestry-informed approaches for cardiometabolic risk assessment and prevention.

Daily hepatic mitochondrial rhythms are strengthened by time-restricted feeding in diet-induced obesity in male mice, as shown by metabolomics, including an early enhancement of oscillations within the de novo pyrimidine pathway. We tested whether timed inhibition of dihydroorotate dehydrogenase (DHODH, which links pyrimidine synthesis to respiratory-chain flux), can reproduce selected TRF-associated mitochondrial and metabolic effects. Administering the short-half-life inhibitor BAY2402234 at dawn transiently decreased DHODH activity, restored daily mitochondrial oxidative dynamics (ubiquinone/ubiquinol ratio), and amplified rhythms of respiratory exchange ratio and mitochondrial dynamics-related markers upon high-fat diet. Under ZT0 dosing, mice showed reduced weight gain, reduced adiposity and hepatic triglycerides, and improved glucose tolerance without changes in food intake; while ZT12 dosing was ineffective. Hepatic Dhodh knockdown did not reproduce the anti-obesity phenotype, and uridine supplementation blunted BAY2402234 benefits, implicating de novo pyrimidine flux. Our findings reveal rhythm-aware DHODH inhibition as a chronopharmacological preclinical candidate approach against overnutrition.

GLP-1 receptor agonists have reshaped obesity therapeutics, but their impact on neuropsychiatric outcomes remains poorly characterized. From 29 million patients in a large federated data platform across the USA, including 489,785 semaglutide treated patients, we conducted an observational study integrating longitudinal neuropsychiatric outcomes. From this population, we assembled a cohort of 63,215 patients with baseline neuropsychiatric conditions before treatment initiation and evaluated 24 incident neuropsychiatric outcomes. In propensity-matched comparator analyses, during the 2 year time-period from treatment initiation, semaglutide was associated with broadly lower neuropsychiatric event risk than metformin, SGLT2 inhibitors, and DPP-4 inhibitors. Within the semaglutide-treated cohort, higher attained dose during the first two years after the first prescription ("pre-landmark period") was associated with significantly lower incidence during the following two years ("post-landmark period") of diagnostic codes associated with substance-related disorders (P<0.001), mood disorders (P<0.001), anxiety- and stress-related disorders (P<0.001), CNS atrophies (P<0.001), neuromuscular disorders (P=0.013), eating/sleep/behavioral disorders (P=0.022), and personality/impulse-control disorders (P=0.028). Consistent with previous clinical trials, the post-landmark incidence of dementia or CNS degenerative diseases was similar between the high-dose and low-dose semaglutide cohorts (P=0.15). For most neuropsychiatric diagnoses, post-landmark incidence was strongly associated with the maximum attained semaglutide dose during the pre-landmark period, but incident cognitive symptoms and speech/language symptoms were more closely linked to the pre-landmark weight-loss magnitude (p<0.001 and p<0.003, respectively). Bulk and single-cell transcriptomic analyses demonstrated GLP1R expression in CNS tissues (hypothalamus, caudate, putamen, nucleus accumbens, cerebellum) and peripheral nerves. Age-associated heterogeneity in GLP1R expression was evident in several of these compartments including the caudate nucleus, suggesting dynamic changes in the availability of the neurobiological substrate for semaglutide response. Together, these data support a model in which semaglutide confers a sustained, dose-dependent, weight loss-independent benefit across multiple neuropsychiatric conditions via direct CNS target engagement. This observational study motivates prospective clinical studies and mechanistic analyses to clarify the impact of GLP-1 receptor agonists on human neuropsychiatric pathways and disease processes.

ImportanceEmerging data show that B-cell depleting chemotherapies, which are increasingly used to treat autoimmune disorders and multiple sclerosis, can be associated with mucosal side effects such as inflammatory vaginitis. ObjectiveEvaluate the impact of rituximab treatment on vaginal mucosal immune markers, endocervical immune cell populations and vaginal microbiome. DesignCross-sectional observational study conducted between 2022 - 2024. SettingAcademic medical center, Boston Massachusetts. ParticipantsWe enrolled women aged >18 years who were either 1) receiving rituximab for autoimmune renal disease or were 2) healthy controls ExposureTreatment with rituximab, an anti CD20 monoclonal antibody. Main outcome and measureWe compared endocervical immune cell populations, vaginal fluid immune markers, vaginal fluid immunoglobulins and vaginal microbiome composition between individuals being treated with rituximab and healthy controls. ResultsWe enrolled 26 women treated with rituximab for autoimmune renal disease and 26 healthy controls. Median circulating and endocervical B-cell and plasma cell proportions were significantly lower in treated participants compared to controls. Median vaginal fluid IgA concentrations were significantly lower in participants treated with rituximab, while ILE, IgM, IgG1, IgG2, IgG3 and IgG4 were not different between groups. Total T cell frequencies were similar between groups, but the proportion of activated T cells (CD4+CD38+HLADR+) was significantly lower in people treated with rituximab. Concentrations of IL10, IL13, IL17, IL21, IL23, IL4, ITAC and TNFa were elevated in vaginal fluid from the rituximab group, while IL-8 was lower. A CST-IV-C, low-Lactobacillus pattern of vaginal microbiota was more common in the rituximab group. Conclusions and RelevanceSystemic B-cell depletion is associated with reduced vaginal fluid IgA, a more diverse microbiome composition, and increases in many vaginal fluid immune markers compared to healthy controls. The reduction in vaginal fluid IgA may provide opportunities for vaginal bacteria to induce inflammation. Key pointsO_ST_ABSQuestionC_ST_ABSHow does circulating B-cell depletion impact the vaginal microenvironment? FindingsIn this cross-sectional study of 52 women, B cell and plasma cell proportions were significantly lower in both blood and vaginal mucosa among rituximab-treated participants compared to healthy controls. Vaginal IgA concentrations, but not other immunoglobulins, were significantly lower in rituximab treated participants. In treated participants, vaginal cytokine concentrations were elevated, and microbiome composition shifted toward non-Lactobacillus-dominant communities. In six people with inflammatory vaginitis, both circulating and endocervical B cells were lowest in people with the most severe symptoms. MeaningSystemic B cell depletion is associated with alterations in vaginal mucosal immune markers and microbiome composition which increase local inflammation.

Aims The oral glucose tolerance test (OGTT) is effective for detecting post-load dysglycemia, but it is burdensome and therefore not routinely used. Continuous glucose monitoring (CGM) offers a convenient way to capture real-world glucose patterns, yet it remains unclear whether CGM-derived metrics reflect OGTT-defined dysglycemia. We therefore aimed to evaluate CGM-derived and clinical metrics for predicting OGTT 2-hour glucose, classifying OGTT-defined dysglycemia, and assessing day-to-day repeatability. Methods We analyzed a cohort with paired free-living CGM and OGTT. Multiple CGM-derived metrics and clinical measures were compared for prediction of OGTT 2-hour glucose, classification of OGTT-defined dysglycemia, and day-to-day stability. Predictive performance was assessed primarily by leave-one-out (LOO) R^2, and day-to-day repeatability by intraclass correlation coefficients (ICC). Results The glycemic persistence index (GPI), a metric integrating the magnitude and duration of glycemic elevation, was the strongest single predictor of OGTT 2-hour glucose (LOO R^2 = 0.439). GPI also showed strong day-to-day repeatability (ICC = 0.665) and ranked first on a combined prediction-stability score. For classification of OGTT-defined dysglycemia, HbA1c had a slightly higher AUC than GPI, but GPI plus HbA1c performed best overall, indicating complementary information. Conclusions GPI was a strong predictor of OGTT 2-hour glucose and showed a favorable balance between predictive performance and day-to-day stability, supporting its potential utility as a CGM-derived marker of dysglycemia.

Childhood obesity remains a pressing global health challenge, yet the impact of dynamic adiposity changes during active developmental window retains poorly understood. Leveraging longitudinal data from the Adolescent Brain Cognitive Development (ABCD) Study (N=8519 at baseline; N=1873 at 4-year follow-up), our study reveals distinct neurodevelopmental implications of central fat dynamics during adolescence. At baseline, central fat indices (body roundness index, BRI / waist-to-height ratio, WHtR) outperformed BMI in predicting cognitive deficits, showing robust associations with impaired inhibitory control and episodic memory. The prediction effect was partially mediated by cortical changes in prefrontal and temporal regions. Longitudinally, the rate of fat accumulation ({Delta}) emerged as a critical predictor: faster adiposity accrual predicted attenuated cortical thinning (i.e., slower development) in parietal lobes and poorer executive function at follow-up, while baseline adiposity showed no significant effects on the follow-up brain morphology or cognitive development. Notably, subgroup analyses uncovered that obese adolescents with central fat reduction exhibited accelerated cortical thinning in posterior cingulate (change difference p=0.006-0.029) alongside rapid improvement in inhibitory control (Flanker slope difference p<0.05), whereas those with persistent adiposity showed delayed thinning in the postcentral gyrus. The study reveals that central fat (BRI/WHtR) is closely linked to neurocognitive risks, and longitudinal fat accumulation?rather than baseline adiposity?drives cortical alteration. Notably, fat reduction activated adaptive neural change in obese adolescents, underscoring the importance of weigh regulation during neurodevelopment.

BackgroundHeterozygous c.283+1G>A and c.283G>A variants in the THRB gene, encoding for thyroid hormone receptor (TR){beta}1 and {beta}2, lead to autosomal dominant macular dystrophy (ADMD). We report the detailed clinical characterization of two first-degree relatives with ADMD, heterozygous for THRB c.283+1G>A, and an unrelated ADMD patient with a novel variant, c.283G>C. The genomic and molecular consequences of both variants were studied. MethodsgDNA and mRNA were obtained from leukocytes. Clinical characterization included biochemistry, bone density and body composition, ECG, echocardiography, ultrasound, audiometry and color-vision. In vitro assays investigated TR function and DNA binding. ResultsThe patients manifested no resistance to thyroid hormone beta (RTH{beta}) and had normal FT4 and TSH. Detailed studies in two patients showed no goiter, tachycardia, hypercholesterinemia or hepatic steatosis. Hearing was not impaired. Both had impaired color vision and reduced bone density. RT-PCR from all three patients revealed skipping of exon 4 exclusive to TR{beta}1, producing a deletion of 87 amino acids in the N-terminal domain (TR{beta}1{Delta}NTD). In vitro, DNA-binding affinity of TR{beta}1{Delta}NTD to DR4-TRE with or without RXR was comparable to TR{beta}1WT. Surprisingly, TR{beta}1{Delta}NTD was transcriptionally twice more active than TR{beta}1WT with a similar EC50 for T3, demonstrating gain-of-function of TR{beta}1{Delta}NTD. THRA expression in leukocytes was increased by 3-fold compared to unrelated controls and different from RTH{beta} patients. ConclusionThese THRB splice site variants produce TR{beta}1 exon 4 skipping, resulting in a gain-of-function mutant, TR{beta}1{Delta}NTD. This explains the dominant ADMD phenotype devoid of RTH{beta} and suggests a TR{beta}1 gain-of-function syndrome.

Porcine organotypic retinal explant cultures are widely used to study retinal neurodegeneration under controlled conditions, but the biological process that occurs in the retinal explant over time due to preparation-induced injury and culture are not well understood. Here, we generated a time-resolved transcriptomic reference for porcine neural retinal explants-maintained ex vivo for 10 days. Global expression profiles are strongly separated by culture time, with Day 0 clearly distinct from cultured samples and at Day 7 and Day 10 showing the highest similarity, indicating a transition toward a later stabilized state. Across the time course, 3,187 genes were differentially expressed relative to Day 0, with the largest shifts occurring at an early stage of culture (Day 1-Day 3). Pathway-level analyses revealed coordinated remodeling involving inflammatory signaling, and metabolic/bioenergetic changes, including reduced mitochondrial and oxidative phosphorylation-related programs at later time points. Here, we provide a time-resolved transcriptomics reference dataset for cultured porcine retinal explants. These data can build a foundation to interpret data generated in this model, differentiate changes inherent to the explant culture from treatment-specific effects and to select appropriate experimental windows for mechanistic studies of retinal degeneration.

Glycosylation is a key structural modification of immunoglobulin G (IgG) that modulates its effector functions and has multiple roles in balancing inflammation. Altered IgG glycosylation has been reported in many diseases, often years before clinical manifestation, suggesting its causal role and biomarker potential. Here, we analyzed IgG glycome composition in 20,405 individuals from 42 different studies processed at the Genos Glycoscience Research Laboratory between 2008 and 2025. Across nearly all diseases, specific IgG glycome profiles reflected accelerated biological aging. Accelerated glycan aging was strongly associated with increased risk of all-cause mortality, independent of established clinical risk factors and potential confounders. Moreover, interventions known to reduce mortality risk, including hormone replacement therapy, therapeutic plasma exchange and caloric restriction, were associated with reversal of glycan aging. Given their role in modulating low-grade systemic inflammation, IgG glycans may represent a functional link between chronic inflammation, aging, disease susceptibility and all-cause mortality.

Type 2 diabetes and prediabetes affect hundreds of millions of people globally, yet the metabolic networks underlying disease development remain poorly understood. Using untargeted liquid chromatography-mass spectrometry (LC-MS/MS), we profiled a total of 15,470 (900 known) serum metabolite features across the human diabetes spectrum (the most comprehensive coverage reported to date). Weighted coexpression network analysis of samples from people with normal glucose tolerance, prediabetes, and type 2 diabetes, collected at baseline and 2 hours after an oral glucose tolerance test, revealed tightly coregulated modules strongly associated with glycemic dysregulation, insulin resistance, and islet dysfunction. Notably, short-chain organic acids, particularly crotonic acid, emerged as hubs of the diabetes-associated networks, accumulating progressively with disease severity. Reanalysis of extracellular vesicle proteomics from the same cohort showed that 16.5% of circulating proteins were crotonylated, with 47.6% correlated with crotonic acid and other hub metabolites, establishing a metabolome-crotonylome axis as a novel mechanism in diabetes development.

Metabolic dysfunction and proteinopathy are hallmarks of many neurodegenerative diseases, yet their mechanistic interplay remains poorly understood. Here, we demonstrate that amyloid precursor protein (APP) processing in cortical neurons is disrupted upon loss of Nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2), the NAD-synthesizing enzyme in neurons, resulting in accumulation of APP C-terminal fragments (APP-CTFs). Knockdown (KD) of the NAD hydrolase sterile alpha and TIR motif-containing protein 1 (SARM1) restores APP-CTF levels in NMNAT2 knockout (KO) neurons to wild-type levels, whereas NAD supplementation yields modest rescue. Redox profiling indicates that NMNAT2 loss reduces NAD/NADH redox potential when APP-CTF starts accumulating. Seahorse metabolic flux analysis shows that NMNAT2 deficiency induces early glycolytic impairment, followed by deficits in mitochondrial respiration. Notably, SARM1 KD, but not NAD supplementation, rescues mitochondrial function in NMNAT2 KO neurons. Temporal profiling of NMNAT2 KO neurons revealed a biphasic pattern in APP-CTF accumulation, with an initial gradual increase followed by a marked acceleration, paralleling the transition from an initially small number to a substantially greater number of differentially expressed proteins. Pathway enrichment analysis of proteomic changes suggests JNK/MAPK signaling is upregulated in the early phase, with late-phase downregulation of mitochondrial function and upregulation of endoplasmic reticulum stress and unfolded protein response pathways. Collectively, these findings demonstrate that neuronal NAD depletion drives a progressive, SARM1-dependent disruption of redox homeostasis and proteostasis, resulting in impaired APP processing. The NMNAT2-SARM1 axis emerges as a critical pathway linking metabolic stress to proteinopathy, positioning SARM1 as a key mediator of neurodegenerative dysfunction.

This updated systematic review and network meta-analysis evaluated the efficacy and safety of obesity management medications (OMMs) in terms of reducing body weight and obesity related complications. Medline and Embase were searched up to 21 November 2025 for randomized controlled trials comparing OMMs versus placebo or active comparators in adults. The primary endpoint was percentage total body weight loss (TBWL%) at the end of the study. Secondary endpoints were TBWL% at 1, 2 and 3 years, anthropometric, metabolic, mental health and quality of life outcomes, cardiovascular morbidity and mortality, remission of obesity related complications, serious adverse events and all cause mortality. Sixty six RCTs (66 comparisons) were identified: orlistat (22), semaglutide (18), liraglutide (11), tirzepatide (8), naltrexone/bupropion (5) and phentermine/topiramate (2), enrolling 63,909 patients (34,861 and 29,048 with active compound and placebo, respectively). All OMMs showed significantly greater TBWL% versus placebo; tirzepatide and semaglutide exceeded 10% TBWL and showed the most favourable glycaemic effects. Semaglutide reduced major adverse cardiovascular events and all cause mortality. In dedicated complication specific trials, semaglutide and tirzepatide showed benefit on heart failure related outcomes; tirzepatide was associated with improved obstructive sleep apnoea syndrome and semaglutide with knee osteoarthritis pain remission. Tirzepatide and semaglutide were associated with improvements in metabolic dysfunction-associated steatohepatitis remission, and semaglutide with improvement in liver fibrosis. No OMMs were associated with an increased risk of serious adverse events. These updated results reinforce the need to individualize OMMs selection according to weight loss efficacy, complication profile and safety.

Vaccination programs worldwide have effectively reduced the burden of childhood diseases, yet immune responses remain highly heterogeneous among individuals. While host characteristics such as age and sex are established determinants of vaccine immunogenicity, the timing of vaccination, specifically the calendar season of vaccination, remains largely underexplored. Although circadian rhythms are known to regulate daily immune function, evidence for long-term circannual patterns has been limited by the difficulty of collecting year-round vaccination data across diverse populations. Here, we show that the season of vaccination systematically shapes the immune response across a broad range of pediatric vaccines. By leveraging data from 96 randomized control trials worldwide, including over 48,000 children vaccinated against 14 pathogens, we demonstrate that immunogenicity after vaccination follows a pronounced latitudinal gradient, typically peaking during colder months in temperate regions and exhibiting distinct variability in the tropics. These findings suggest that the circadian human immune response might extend to a circannual scale, potentially synchronized by environmental cues. Incorporating the season of vaccination into the design of clinical trials and public health campaigns may optimize vaccine performance and enhance seroprotection.

Non-invasive glucose monitoring (NIGM) has been pursued for decades, yet no device has achieved regulatory approval despite numerous studies reporting high accuracy. This systematic review and meta-analysis of 32 studies (38 cohorts: 20 NIGM, 18 iCGM; N = 1,693) investigated methodological factors underlying this accuracy-regulatory gap. The pooled Mean Absolute Relative Difference (MARD) for NIGM (10.21%; 95% CI: 8.73-11.69%) showed no significant difference from iCGM (11.82%; 95% CI: 10.36-13.29%; p = 0.13), with extreme heterogeneity (I^2 = 95.2%). Meta-regression revealed that study duration was the strongest predictor of NIGM accuracy ({beta} = 3.94, p < 0.001), with MARD degrading from 8.7% in short-term to 15.2% in long-term studies, while iCGM accuracy remained stable. Only 15% of NIGM cohorts validated in the hypoglycemia range, compared to 89% of iCGM studies (p < 0.001). These findings suggest that reported NIGM accuracy is substantially influenced by methodological asymmetries.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract that encompasses ulcerative colitis and Crohns disease. Here we identify the cystine/glutamate antiporter xCT as being markedly upregulated in the inflamed intestinal epithelium of patients with IBD. To clarify its functional contribution to disease pathogenesis, we performed genetic loss-of-function study and found that inhibition of xCT confers robust protection against dextran sulfate sodium (DSS)-induced colitis in mice. Intestinal epithelial cell (IEC)-specific deletion of xCT markedly attenuated colitis severity, demonstrating that epithelial xCT upregulation acts as a disease-exacerbating factor in IBD. Mechanistically, xCT deficiency preserved intracellular glutamate levels and protein polyglutamylation, thereby maintaining epithelial barrier integrity and protecting IECs from inflammatory injury. Consistently, pharmacological inhibition of glutamine synthetase, which increases intracellular glutamate, exerted a potent anti-inflammatory effect on the DSS-induced colitis. These findings identify intracellular glutamate retention in IECs as a previously unrecognized mechanism of epithelial protection and highlight both inhibition of xCT-dependent glutamate efflux and suppression of glutamine synthetase as potential therapeutic strategies for IBD.