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Aging occurs heterogeneously across organs, leading to progressive tissue dysfunction. Cellular senescence is a stress response triggered by age-associated insults, yet the mechanisms regulating senescence and organ aging remain incompletely understood. Here, we defined a role for lysine-specific demethylase 1 (LSD1) in DNA damage–mediated senescence and organ aging. LSD1 was upregulated in aged organs and senescent cells. In response to natural aging or ionizing radiation–induced DNA damage, LSD1 interacted with and demethylated ATM at lysine 3,016, as confirmed using a newly generated ATM-K3016me antibody. This modification sustained ATM phosphorylation, amplified DNA damage signaling, and delayed checkpoint recovery, promoting senescence and organ aging. Inhibition of LSD1 accelerated ATM dephosphorylation via WIP1, enhanced DNA repair, reduced senescence and DNA damage, and prevented irradiation-induced hair graying. Elimination of senescent cells with senolytics reduced LSD1 protein in aged organs, indicating a feedback loop between LSD1 and senescence. Mechanistically, LSD1 underwent autophagosome-lysosome degradation through interaction with LC3 and Beclin1, and autophagy impairment during DNA damage contributed to LSD1 accumulation in senescent cells. This study revealed LSD1 as a key regulator of DNA damage–induced senescence and organ aging and suggested that targeting LSD1 may attenuate senescence, delay organ aging, and prevent hair graying.

Abstract. Introduction: Preterm birth drives adverse perinatal maternal and infant health outcomes through heterogeneous symptoms, severity, and etiologies. Delivery prior to reaching 37 weeks of gestation may result from medically indicated intervention for pregnancy complications or spontaneously in the absence of prior symptoms. Placental tissue collected following preterm birth exhibits differential DNA methylation compared to full-term placentas and may indicate pregnancy health during gestation. Placental DNA currently has limited utility for assessing health of ongoing pregnancy, as sampling placental tissue during gestation increases the risk of infection and miscarriage. Risks associated with placental sampling during pregnancy limit the use of DNA methylation in clinical preterm birth prediction. Assessing preterm birth risk during gestation requires non-invasive methods for characterizing placental DNA methylation. Results: We quantified genome-wide DNA methylation patterns of hypermethylated cell-free DNA in pregnant (n = 99) and non-pregnant (n = 93) plasma using cell-free methylated DNA immunoprecipitation sequencing (cfMeDIP-seq). In each sample, we assessed DNA methylation status in 300-bp genomic windows, examining both sequencing read counts and calculated absolute molar DNA amount. Known hypermethylated placental regions, including RASSF1, STAT5A, and ERG promoters showed significantly increased odds of detection in pregnant samples, suggesting enrichment of cell-free placental DNA. Of the 536,444 300-bp windows examined, 173,071 (32%) showed significant enrichment in pregnant plasma. Linear modeling identified 107,505 differentially methylated regions (DMRs) associated with pregnancies later diagnosed with intrauterine growth restriction (IUGR) (n = 22). Alu elements showed increased representation in these DMRs than expected, while other repetitive elements exhibited underrepresentation. Discussion: These results demonstrate cfMeDIP-seq's ability to enrich for cell-free placental DNA and characterize cell-free DNA methylation signatures of pregnancies complicated by IUGR. Enrichment of cell-free placental DNA enables non-invasive profiling of placental DNA methylation from maternal plasma. Detectable epigenetic signatures in maternal plasma may identify pregnancies at elevated risk for preterm birth before clinical symptoms appear. Our findings further highlight the potential of cell-free placental DNA for monitoring pregnancy health.

Abstract Objectives/Background Our objectives were to characterize the geographic distribution and local availability of United Council for Neurologic Subspecialties‐certified headache specialists across US counties, hospital referral regions, and states, and to examine associations with socioeconomic deprivation, social vulnerability, and urbanicity. Headache disorders are highly prevalent and disabling, yet local availability of certified headache subspecialty care in the United States remains uneven. Although prior studies have described national and state‐level distributions of United Council for Neurologic Subspecialties‐certified headache specialists, important gaps remain in understanding county‐level availability and disparities in access. Prior state‐level summaries may mask within‐state differences in access to United Council for Neurologic Subspecialties‐certified headache specialists. Methods We conducted a cross‐sectional geospatial workforce analysis of United Council for Neurologic Subspecialties‐certified headache specialists in the United States as of January 7, 2026. Practice locations were mapped to counties, hospital referral regions, and states, and compared with general neurologist supply from the National Provider Identifier registry. Estimated population need was calculated by applying a national migraine prevalence to adult population denominators. We examined associations between specialist distribution and county‐level socioeconomic vulnerability, urbanicity, and region. Results Among 3144 US counties, 2870 (91.3%) had no United Council for Neurologic Subspecialties‐certified headache specialists, and 2085 (66.3%) had no neurologists. Headache specialists were entirely absent from counties without neurologists. Median county‐level headache specialist density was 0 per 100,000 adults, reflecting the absence of local subspecialty care in most US counties. Accounting for county adult population, neurologist density, urbanicity, and region, higher Area Deprivation Index and Social Vulnerability Index scores were associated with lower headache specialist rates. Each 10‐point increase in Area Deprivation Index was associated with lower expected headache specialist rate (adjusted incidence rate ratio = 0.87, 95% confidence interval = 0.82–0.93), and each 0.1‐unit increase in Social Vulnerability Index was also associated with lower expected rate (adjusted incidence rate ratio = 0.94, 95% confidence interval = 0.90–0.98). Headache specialist availability relative to estimated population need varied markedly across counties, with substantial estimated local differences between migraine burden and certified subspecialty supply that were not apparent in state‐level summaries. Conclusion United Council for Neurologic Subspecialties‐certified headache specialists are unevenly distributed across the United States, with limited local availability of certified headache subspecialty care in socioeconomically disadvantaged and nonmetropolitan counties. County‐level analyses identified substantial local gaps in certified headache subspecialty availability that were not apparent in state‐level summaries.

PURPOSE Age ≥40 years is regarded as a high-risk feature and an indication for adjuvant chemoradiotherapy for patients with lower-grade glioma in clinical practice guidelines. It is unclear whether age remains a relevant prognostic factor for contemporary definitions of lower-grade gliomas in the molecular era. METHODS The Prospective Gliomas Research (PROGRES) database contains individual patient-level data from 11 prospective clinical trials or observational registries of histologically defined lower-grade 2-3 oligodendroglioma or astrocytoma. We determined the association of age (18-39 years v ≥40 years) with progression-free survival (PFS) stratified by isocitrate dehydrogenase 1 or 2 ( IDH1/2 ) status, using log-rank tests and Cox regression models. We validated our findings in a separate multi-institutional retrospective cohort (Retrospective Glioma Research [REGRES] database). RESULTS We identified 1,619 and 1,292 eligible patients in the PROGRES and REGRES cohorts, respectively. IDH -wildtype tumors were more common in patients 40 years and older (38% v 5%, odds ratio: 11.3 [95% CI, 6.5 to 19.7]). Age was associated with PFS in IDH -wildtype (5-year PFS for ≥40 v 18-39 years: 6% v 24%, hazard ratio [HR], 1.74 [95% CI, 1.21 to 2.50]) but not in IDH -mutant glioma (60% v 59%, HR, 0.89 [95% CI, 0.76 to 1.05], P interaction < .001). In IDH -wildtype tumors, older age predicted aggressive molecular features, including TERT promoter mutation (65% v 28%), EGFR amplification (41% v 15%), and chromosome +7/–10 alteration (57% v 25%). In a pooled analysis of four clinical trials, age was not predictive of a benefit from chemoradiotherapy versus radiotherapy alone for IDH -mutant glioma. CONCLUSION In the absence of additional clinical or molecular risk factors, age alone should not be considered an indication for administration or deferral of adjuvant treatment. Practice guidelines should be revised to reflect contemporary prognostic factors in the molecular era.

ABSTRACT Objectives To investigate pharmacological treatment patterns in individuals with bipolar disorder (BD) with and without comorbid substance use disorder (SUD) and anxiety disorder (AX), we leveraged the Global Bipolar Cohort to analyze cross‐regional practices across North America, Europe, and the Pacific. Methods Fourteen cohorts contributed aggregate data on pharmacotherapy, demographics, diagnostic subtypes, and comorbidities. Proportional meta‐analyses using generalized linear mixed models were conducted to examine prescription trends and identify clinical differences. Results The sample ( N = 11,521) was 60% female and 84% Caucasian. Participants were categorized into four mutually exclusive groups based on comorbidity status: those with comorbid AX only, comorbid SUD only, both AX and SUD, or neither. The AX+SUD subgroup showed higher rates of attention‐deficit/hyperactivity disorder (ADHD), post‐traumatic stress disorder (PTSD), rapid cycling, obesity, and unemployment, reflecting a more severe clinical profile. Regional variations were notable: North American cohorts reported higher prevalence of AX and SUD than European and Pacific cohorts. Antidepressants use for AX were more common in Europe and the Pacific, while North American prescribing patterns were more variable. Benzodiazepine use was high among individuals with SUD across all regions. Lithium and first‐generation antipsychotic prescriptions varied, with higher rates observed in Europe. Conclusions Findings underscore the heterogeneity of BD and the influence of comorbid AX and SUD on illness burden and treatment. Regional prescribing variations underscore the need for context‐specific guidelines. Gaps in data on medication‐assisted treatment for SUD point to areas for future research. These insights can support more individualized and effective care for complex BD presentations.

Abstract Colorectal cancer develops through a normal-adenoma-carcinoma sequence, yet only 5-10% of adenomas progress to malignancy, and the cellular programs governing that sequence remain poorly defined. Here we generate a spatial multi-omics atlas of human colon adenomas, combining Visium CytAssist and protein co-detection across 24 nonadvanced and advanced tubular adenomas with single-cell resolution Xenium Prime 5K profiling of 101 patient-matched normal, adenoma, and carcinoma cores from 16 patients. Integrating whole-transcriptome and 31-plex protein data identifies nine spatial clusters and two dysplastic epithelial populations that co-express stemness, proliferation, and senescence programs. These programs occupy a shared, spatially confined epithelial niche that expands from adenoma to carcinoma. Spatial analysis revealed GDF15, a senescence-associated secretory factor, mediated the coupling between senescence and stemness in advanced adenomas, and that GDF15-high epithelium locally excludes CD8+ T cells in adenoma and, more broadly, in carcinoma. These findings position senescence as a spatially instructive rather than merely tumor-suppressive program during colorectal carcinogenesis and suggest GDF15 might be a potential candidate target for cancer prevention and interception in the colon.

Urinary urea is a key biomarker for tracking protein oxidation and nitrogen balance. A persistent analytical limitation is that conventional total-nitrogen assays do not deconvolute urinary urea from urinary ammonia, and direct measurement still requires capital-intensive clinical analyzers. Here, we implement and independently validate two cost-effective methods that resolve urinary urea by pairing the presence and absence of urease: Method 1 is a urease-coupled potentiometric assay using an ammonium ion-selective electrode (ISE method); Method 2 is a microplate Berthelot–salicylate colorimetric assay employing a repurposed consumer-grade aquarium ammonia test kit (API®) (API method). Each method was validated against the Roche Cobas C311 clinical analyzer (ISE for urinary ammonia and API for urinary urea) in healthy adult volunteers (n = 10 each), and API–ISE were then compared head-to-head for urinary urea. ISE vs. Cobas yielded R2 = 0.967, slope 95% CI [0.867, 1.173], and Bland–Altman bias of −1.02 mM (95% LoA [−7.40, +5.36] mM). API vs. Cobas yielded R2 = 0.973, slope 95% CI [0.790, 1.039], and bias of −1.55 mM (95% LoA [−11.56, +8.46] mM). API–ISE urinary urea comparison confirmed mutual agreement (R2 = 0.9976, slope 95% CI [0.946, 1.024]; bias of +3.47 mM; 95% LoA [−14.60, +21.53] mM), with mean recoveries near 100% (API: 100.7 ± 2.9%; ISE: 100.6 ± 5.4%; 20–350 mM). Both methods agreed with the clinical analyzer, supporting their potential for decentralized, resource-limited testing; clinical and point-of-care validations are needed.

MOGAD is a rare autoimmune encephalomyelitis that shares similar clinical manifestations with other central nervous system demyelinating diseases. However, they must be distinguished due to their distinct pathogenesis and treatment methods. Currently, the clinical diagnosis of MOGAD primarily relies on patients’ clinical manifestations and imaging features, with biomarker application being relatively limited. Meanwhile, research on MOGAD biomarkers has advanced rapidly, with findings mainly focusing on imaging features, antibody titers, nerve cell markers, cytokines, and inflammatory cell ratios. These biomarkers can distinguish among various autoimmune with similar clinical manifestations and exhibit certain specificity. If these biomarker findings are applied to the clinical diagnosis of MOGAD, they could enhance diagnostic accuracy and support earlier and more accurate diagnosis, while providing a scientific basis for evaluating disease progression and prognosis. We discuss the biomarkers and emerging biomarkers of MOGAD, emphasizing the specific changes and aspects that may be applicable to clinical diagnosis and treatment.