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PubMed2026

Multi-omics panorama of glaucoma: Pathogenesis, biomarkers, and novel therapeutic strategies.

Glaucoma is a group of irreversible, blinding eye diseases characterized by progressive loss of retinal ganglion cells, leading to gradual visual field defects that severely impact patients' quality of life. Its complex pathophysiological mechanisms remain incompletely understood, limiting the development of early diagnostic and effective therapeutic strategies. Advances in omics technologies have provided new insights into elucidating the pathophysiology of glaucoma. We summarize specific alterations in genomics, transcriptomics, proteomics, metabolomics, epigenomics, and microbiomics associated with glaucoma. We emphasize the systematic analysis of disease mechanisms, identification of clinically applicable biomarkers, and discovery of novel therapeutic targets through the integration of these data. This approach paves new pathways for glaucoma subtype diagnosis and personalized treatment, while also outlining future research directions and challenges.

Humans↗

PubMed2026

Multi-omics integrative analysis provides insight into potential molecular responses to sustained high water flow in common carp (Cyprinus carpio) cultured in recirculating aquaculture.

To investigate the potential molecular responses by which water flow intensity affects the growth of common carp (Cyprinus carpio) in a recirculating aquaculture system (RAS), a control group (CG, actual water velocity 0.3 cm/s) and three sustained flow treatment groups were established, including a low-flow group (LF, 1 body length per second, bl/s), a medium-flow group (MF, 2 bl/s), and a high-flow group (HF, 3 bl/s). After 12 weeks of culture in the RAS, growth performance was compared among groups under different flow intensities. The best-performing group and the control group were then selected for the determination of intestinal digestive enzyme activities, as well as transcriptomic and whole-genome bisulfite sequencing analyses of muscle tissue. The results showed that the specific growth rate and feed intake of the HF group were significantly higher than those of the other groups (P < 0.05), whereas no significant difference in feed conversion ratio was observed among groups. Compared with the CG group, lipase activity was significantly higher in the HF group (P < 0.05), while α-amylase and trypsin activities showed increasing trends without significant differences. RNA-seq identified a total of 273 differentially expressed genes, including 72 upregulated genes and 201 downregulated genes in the HF group relative to the CG group. These genes were mainly enriched in glycolysis, pyruvate metabolism, ATP metabolism, the pentose phosphate pathway, the insulin signaling pathway, the PPAR signaling pathway, and the adipocytokine signaling pathway, indicating that sustained high water flow induced a muscle transcriptional response characterized by remodeling of energy metabolism and substrate utilization. Whole-genome bisulfite sequencing analysis showed that DNA methylation in common carp muscle occurred predominantly in the CpG context. Differentially methylated regions between the HF and CG groups were mainly distributed in transcription-related regulatory regions, including promoters, CpG islands, and CpG island shores. In promoter regions, the number of hypermethylated regions in the HF group relative to the CG group was markedly higher than that of hypomethylated regions. Integrated analysis further identified two candidate genes showing both promoter differential methylation and differential expression, namely LOC109094644 and bcorl1, suggesting that adaptation to high water flow may involve IGF-related growth regulation and remodeling of upstream transcriptional programs. The qPCR results were consistent with the transcriptomic data. Taken together, within the tested range, a sustained water flow of 3 bl/s was more conducive to the growth of common carp in the RAS, which may be associated with enhanced lipid digestion and utilization, remodeling of the muscle energy metabolic network, changes in promoter methylation, and the coordinated regulation of key candidate genes. This study provides a theoretical basis for clarifying the exercise adaptation mechanism of common carp in recirculating aquaculture and for optimizing flow velocity parameters.

Animals↗

PubMed2026

Redox Rewiring in Nicotine-Driven Gastric Carcinogenesis: Uncovering ROS-Dependent Oncogenic Circuits.

SIGNIFICANCE: Nicotine from tobacco products, secondhand smoke, and emerging delivery systems remains a major but underappreciated driver of gastric carcinogenesis (GC). Although reactive oxygen species (ROS) have long been implicated in tumor biology, current models incompletely explain how chronic nicotine selectively reprograms gastric epithelial signaling. This review advances the concept of redox rewiring, whereby nicotine establishes a persistent oxidative state that orchestrates multiple oncogenic programs via spatially compartmentalized NOX signaling. RECENT ADVANCES: We synthesize evidence for a unified model wherein nicotine activates nAChR/β-AR signaling, Ca2+ influx, PKC, and compartmentalized NOX-derived ROS to generate distinct oncogenic outputs. Beyond the established NOX/ROS/NF-κB/MAPK-driven IL-8 and MMP-9 axes, we integrate emerging evidence into three interconnected modules governing EMT/metastasis (ABL1/STAT3/COX-2/periostin), survival/chemoresistance (ERK/GLI1/Bcl-2), and invasion/immune evasion (miR-21/PDCD4). Collectively, these circuits suggest that ROS function not merely as damaging byproducts but as spatially organized signaling mediators dictating tumor behavior. CRITICAL ISSUES: A major challenge is distinguishing established mechanisms from incompletely validated models. The three proposed axes are testable hypotheses requiring experimental validation. Most data derive from in vitro studies with nonphysiologic nicotine concentrations, and artifacts from nonspecific ROS probes are common. Compensatory pathway activation and multi-target effects of natural products remain underexplored. FUTURE DIRECTIONS: We outline a precision-redox oncology roadmap linking pathway-specific biomarkers, mechanistically matched natural products, and biomarker-enriched trials. Priorities include genetic validation of the three axes, time-resolved ROS imaging, and pulsed natural product regimens. By reframing nicotine-driven GC as adaptive redox network remodeling, this review provides a framework for prevention, stratification, and next-generation therapy. Antioxid. Redox Signal. 00, 000-000.

gastric cancer↗

PubMed2026

Pathogenic properties of myasthenia gravis AChR autoantibodies associate with clinical response to efgartigimod.

BACKGROUND: Efgartigimod, a neonatal Fc receptor (FcRn) blocker, effectively reduces total IgG, including pathogenic acetylcholine receptor (AChR) autoantibodies in myasthenia gravis (MG); however, clinical responses vary. To investigate this variability, we studied how efgartigimod impacts AChR-specific autoantibody profiles and associated pathogenic mechanisms, including complement activation, AChR internalisation and ACh-binding site blockade. METHODS: Serum samples (N=150) were sourced from 50 AChR autoantibody-positive generalised MG patients participating in the phase 3 ADAPT study, randomised to receive efgartigimod (N=40) or placebo (N=10) in cycles of 4-weekly infusions. Samples were collected at baseline, day 29 and day 57 during the first cycle. Live cell-based assays quantified AChR-specific IgG subclasses and isotypes and assessed their capacity to mediate pathomechanisms. RESULTS: Efgartigimod decreased all detectable AChR-specific IgG subclasses. At baseline, AChR autoantibody-mediated C3b deposition, AChR internalisation and ACh-binding site blockade were detected in 42 (84%), 41 (82%) and 10 (20%) patients, respectively. After 4-weekly infusions of efgartigimod, the magnitude of all three pathomechanisms was significantly decreased. However, the extent of this reduction varied across individuals. Double responders on both MG-activities of daily living and quantitative MG scores demonstrated a greater reduction in complement activity and AChR internalisation compared with patients who responded on only one score or were double non-responders. In addition, efgartigimod reduced IgG-dependent IgM binding to AChR. CONCLUSIONS: These findings suggest that clinical efficacy may be more closely associated with functional modulation of the AChR-specific autoantibodies than with their absolute quantity alone. These results support the evaluation of mechanistic pathway monitoring as a potential strategy to predict or guide efgartigimod treatment response.

Humans↗

PubMed2026

Bypassing the emergency department for testicular torsion.

BACKGROUND: Testicular torsion is a time-sensitive urologic emergency that can result in testicular ischemia, atrophy, and loss if detorsion is delayed. Patients transferred from outside hospitals oftentimes experience prolonged ischemia due to repetitive assessments in the receiving emergency department (ED) and lengthy interhospital transfers. To address these delays, our institution created a pathway allowing patients with a confirmed diagnosis of testicular torsion to bypass the ED and proceed directly to the OR. OBJECTIVE: To evaluate the efficacy of an emergency department bypass pathway on time to surgical intervention and testicular salvage rates for patients transferred from outside hospitals with confirmed testicular torsion. STUDY DESIGN: Following one year of pathway implementation and institutional review board approval, a retrospective chart review was performed. Patients aged 12-18 years that were transferred from outside hospitals for confirmed testicular torsion were included in the pathway. A pre-pathway cohort (January 2022-December 2022) of patients with ED management was compared to a post-pathway cohort (August 2023-September 2024) of patients managed via direct OR transfer. Comparisons included patient age, mean time from ED registration to surgery start, orchiectomy rates, testicular atrophy rates at follow-up, and overall length of follow-up. T-tests and Fisher's exact tests were used for statistical analysis. RESULTS: 71 patients were included. Mean time from registration to OR start was significantly shortened in the post-pathway cohort compared to the pre-pathway cohort (70 min vs. 23 min, p < 0.0001). This represents a 67% decrease in time to surgery. Post-pathway patients were significantly older than pre-pathway patients (15 years vs. 13 years, p = 0.0025). Orchiectomy rates did not significantly differ between the two groups (14% post-pathway and 28% pre-pathway, p = 0.2454). Similarly, no significant difference was observed for testicular atrophy at follow-up (17% post-pathway and 15% pre-pathway, p = 1.0). Mean length of follow-up was insignificant (90 days for post-pathway and 76 days for pre-pathway, p = 0.6605). DISCUSSION: Direct transfer to the OR with ED bypass significantly reduced time to surgical detorsion. Other variables such as orchiectomy and testicular atrophy rates were not significantly impacted. Patient-limited factors may have influenced outcomes, such as delays in symptom recognition and time to initial care. CONCLUSION: An ED bypass pathway for transferred patients with testicular torsion was highly effective at reducing time to surgical intervention. Although testicular salvage rates were not significantly affected, reducing ischemia time is clinically important and encourages pathway refinement and broader use.

Humans↗

PubMed2026

Trio-based whole-exome sequencing identifies convergent epithelial junction-related pathways in syndromic hidradenitis suppurativa.

INTRODUCTION: Hidradenitis suppurativa (HS)-related autoinflammatory syndromes, simply termed as syndromic HS (sHS), represent a group of rare immune-mediated inflammatory disorders in which HS coexists with systemic or cutaneous autoinflammatory features like PASH (pyoderma gangrenosum-PG-, acne and HS), PAPASH (PASH, pyogenic arthritis), PASS (PG, acne, HS, and ankylosing spondylitis), and SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, and osteitis). In recent years, genetic studies identified several novel pathogenic variants underlying sHS; however, most investigations rely exclusively on affected individuals sequencing and the absence of parental genomic information limits the possibility to determine inheritance patterns. METHODS: To address these gaps, we performed trio-based whole-exome sequencing (WES) on five individuals diagnosed with sHS and their unaffected parents. RESULTS: The pathway related to epidermal adhesion and desmosome organization was the most represented across our cohort, encompassing seven genes: DSC3, DSG1, FAT1, LAMA3, MICALL2, PLEC and TJP2. Integrin-extracellular matrix (ECM) adhesion signaling pathway, represented by ten genes (CSPG4, FERMT3, ITGA3, LAMA3, LAMA5, LIMS2, LTBP3, PLEC, TGM2, TNC) was also retrieved. Also, variants affecting innate immune pathways, including cytokine signalling and antigen presentation, have been observed. CONCLUSION: Our exploratory findings suggest that genetically heterogeneous variants in syndromic HS converge on biological processes involving epithelial junction organisation, extracellular matrix interactions and innate immune regulation. Although not establishing a unique pathogenic mechanism, these observations identify epithelial barrier biology as a candidate pathway warranting validation in larger cohorts and functional studies.

Journal Article↗

PubMed2026

Accelerated Diagnostic Pathways for Suspected Acute Coronary Syndrome in Practice: A Randomized Trial of 0/1-Hour vs 0/3-Hour Troponin Testing.

BACKGROUND: For suspected acute coronary syndrome (ACS), guidelines recommend using high-sensitivity troponins (hs-cTn) in accelerated diagnostic pathways (ADPs) with 0/1-hour recommended over 0/3-hour ADP. However, implementation of these ADPs, with universal use of hs-cTns, has not been directly compared in randomized trials OBJECTIVES: This study sought to compare the efficiency and safety of the European Society of Cardiology (ESC) 0/1-hour and a 0/3-hour ADP when implemented in real-world clinical practice. METHODS: This pragmatic, randomized, noninferiority implementation trial compared the safety and efficiency of clinician decision making using these 2 pathways. To prevent incorporation bias, an independent hs-cTnI was used for formal adjudication using the fourth universal definition of myocardial infarction (MI). Efficiency was judged by the proportion of patients discharged within 4 hours. The safety endpoint was major adverse cardiac events (MACE) within 30 days (adjudicated index or representation type 1 MI, cardiovascular death, and urgent coronary revascularization) for those who were considered not to have ACS and discharged. The noninferiority margin, for absolute difference in sensitivity, between the ESC 0/1-hour and the 0/3-hour ADP was set at 3%, assessed with a 1-sided 97.5% CI. RESULTS: From December 2021 to July 2024, of 13,983 screened 3,543 individual patients with suspected ACS were recruited and consented from 2 major emergency departments in North-West England, with 100% follow-up achieved for all representations to any national hospital. The median age was 60 years (IQR: 49.5-70.5 years), 53% were men, 6.7%, and 7.6% had adjudicated index type 1 MI and MACE within 30 days, respectively. The turnaround time from sample to result for central laboratory hs-cTnT was 81 minutes (IQR: 69-101 minutes). The proportion of patients discharged within 4 hours was relatively low and did not differ substantially (21.8% vs 19.2%, P = 0.07). In addition, the 0/1-hour pathway was noninferior for safety, in patients discharged, compared with the 0/3-hour pathway, absolute difference in sensitivity was +4.2% (1-sided 97.5% CI: -2.5) in favor of the 0/1-hour pathway. The calculated sensitivities were 93.7% (95% CI: 88.4%-97.1%) vs 89.5% (95% CI: 82.7%-94.3%), respectively. CONCLUSIONS: Implementation of the ESC 0/1-hour pathway failed to discharge significantly more patients within 4 hours of presentation compared with the 0/3-hour ADP. In addition, The ESC 0/1-hour was noninferior to the 0/3-hour hs-cTn pathway for safety of discharge, although safety for both pathways was less than that imputed by observational studies. This trial demonstrates that perceived benefits to emergency department efficiency of a reduced sampling interval are mitigated by central laboratory turnaround times as well as system constraints. (Pragmatic Randomised Trial of the ESC 0/1 Versus 0/3 Hour Troponin Pathway [MACROS2]; NCT05322395).

Acute Coronary Syndrome↗

PubMed2026

Translational reprogramming of TGF-β signaling via TRMT61A-mediated tRNA m1A drives prostatic fibrosis and hyperplasia.

Dysregulation of the epitranscriptomic landscape is closely linked to pathological proliferation, but its specific role in benign prostatic hyperplasia (BPH) remains unclear. Here, we identify the tRNA methyltransferase TRMT61A as a critical driver of BPH progression. We found that TRMT61A and global N1-methyladenosine (m1A) levels are aberrantly upregulated in human BPH tissues. Functionally, TRMT61A knockdown potently suppresses prostate cell proliferation and reduces stromal fibrosis, inducing G1 cell cycle arrest and reversing pathological remodeling both in vitro and in vivo. By integrating ribosome profiling (Ribo-seq) and tRNA-seq, we observed that TRMT61A drives translational reprogramming. TRMT61A preserves the stability of specific tRNA isoacceptors (e.g., tRNA-Leu-CAA), which is required for the efficient decoding of mRNAs containing m1A-dependent codons. Consequently, TRMT61A selectively promotes the translational elongation of the key receptor TGFβR1. This amplifies downstream TGF-β/SMAD signaling and drives epithelial-mesenchymal transition (EMT) without affecting mRNA transcription. In summary, our study reveals how TRMT61A drives BPH progression through TGFβR1 translation, highlighting the therapeutic potential of targeting epitranscriptomic pathways to reverse prostatic hyperplasia and fibrosis.

Male↗

PubMed2026

Pathway incompatibility between NF-κB and RAS signaling constrains oncogenicity in B-cell leukemia.

Oncogenic pathways do not always cooperate; in some contexts, their co-activation is antagonistic and suppresses tumorigenesis, a phenomenon we termed pathway incompatibility. However, the mechanisms underlying this antagonism and the role of receptor context in shaping these interactions remain unclear. During normal B-cell development, precursor B-cell receptor (pre-BCR) signaling supports survival and proliferation of early B-cell precursors before transition to expression of the mature B-cell receptor (BCR). B-cell acute lymphoblastic leukemia (B-ALL), the most common childhood cancer, is characterized by developmental arrest prior to BCR expression, and approximately 35% of cases harbor activating RAS-ERK mutations that mimic pre-BCR-dependent survival signaling. NF-κB plays context-dependent roles in B-cell malignancies, but whether it influences the compatibility between oncogenic RAS signaling and BCR expression remains poorly understood. Activation of canonical NF-κB induced apoptotic depletion of RAS-driven B-ALL cells. Mechanistically, NF-κB suppressed pre-BCR-dependent survival signaling while promoting expression of BCR components. Consistent with this shift, oncogenic RAS signaling was poorly tolerated in BCR-positive cells unless BCR expression was disrupted. Pharmacologic activation of NF-κB reduced ERK signaling and selectively impaired viability of RAS-driven B-ALL cells, with enhanced effects in combination with ERK inhibition. Together, these findings show that canonical NF-κB signaling promotes BCR expression, which constrains oncogenic RAS activity, and establish pathway incompatibility as a mechanism through which receptor context can limit oncogenic potential.

Cancer biology↗

PubMed2026

ScRNA-seq analysis reveals the effects of nitrite stress on the endocrine system of the eyestalk in Litopenaeus vannamei.

Nitrite is a harmful substance generated in Litopenaeus vannamei farming systems, largely originating from the inadequate breakdown of surplus feed and shrimp feces. Its accumulation in the water can affect the growth and physiological functions of shrimp, damage the immune system, and even cause mass mortality, thus becoming a key environmental factor restricting the green development of the industry. Under nitrite stress, the eyestalk, as an important neuroendocrine regulatory center in crustaceans, participates in the stress adaptation of the organism and exerts a protective effect by regulating energy metabolism and immune function. However, the molecular regulatory mechanism of the eyestalk in response to nitrite stress remains unclear. In this study, single-cell RNA sequencing (scRNA-seq) technology was used to analyze the heterogeneity of eyestalk cells in L. vannamei under nitrite stress. A total of 18, 394 high-quality cells were obtained, and six major cell subpopulations, including Neurosecretory cell, Motor neuron, Sensory neuron, Interneuron, Neurogliocyte, and Support cell, were identified. Differential expression analysis identified 839 differentially expressed genes, and different cell types showed distinct specific responses to nitrite stress. Functional enrichment analysis indicated that pathways such as glycolysis, oxidative phosphorylation, ribosome function, and endoplasmic reticulum protein processing were significantly activated, while signal transduction and DNA repair-related pathways were inhibited. Further analysis revealed that nitrite stress could induce mitochondrial function changes and trigger oxidative stress, thereby affecting the neuroendocrine system function of the eyestalk. This study provided insights into transcriptomic responses of the eyestalk to nitrite stress at the single-cell level, laying a theoretical foundation for the management of aquaculture environments.

Animals↗

PubMed2026

Long-term outcomes after a randomized phase II trial of nerve growth factor eye drops for optic pathway gliomas: four-year follow-up findings in children.

PURPOSE: A previous double-blind, randomized, placebo-controlled, phase II clinical trial reported beneficial effects of a short-term treatment (10 days) with murine nerve growth factor (mNGF) eye drops on visual function in children with optic pathway gliomas (OPG). The present study aimed to evaluate long-term changes in clinical and neuroradiological parameters in the cohort of OPG patients who had previously participated in the phase II mNGF trial. METHODS: Fifteen of the 18 patients originally enrolled in the phase II mNGF trial agreed to undergo clinical and neuroradiological monitoring over a 48-month follow-up period. Of these, 9 had originally been randomized to mNGF and 6 to placebo; no additional treatment (mNGF, chemotherapy, or radiotherapy) was administered during the extended follow-up. Every 6 months, patients underwent general clinical and neuro-ophthalmological examination, visual evoked potentials (VEP), and photopic negative response of the electroretinogram (PhNR). Brain MRI was performed every 12 months. RESULTS: Comparison of initial and final follow-up median values revealed no statistically significant changes in visual acuity, VEP amplitude, PhNR amplitude, or visual field radius. No significant differences were observed in any parameter relative to baseline values of the mNGF trial. Brain MRI demonstrated stable disease in all patients throughout the observation period. CONCLUSION: These findings, obtained in an observational extension of the original randomized cohort, indicate favorable long-term safety and tolerability of a short-term course of topical mNGF in children with OPG, with sustained visual and neuroradiological stability over four years, rather than evidence of persistent treatment efficacy. Further prospective, adequately powered and randomized clinical studies are needed to confirm both the short- and long-term clinical efficacy of NGF treatment in preventing OPG-induced visual loss.

Humans↗

PubMed2026

Engineering bubble structures as Cas12a activators for highly sensitive monitoring of WRN helicase function.

The Werner syndrome helicase (WRN) is a critical synthetic lethal target in microsatellite instability cancers, essential for resolving complex genomic structures like replication bubbles and R-loops. However, strategies to simultaneously discriminate WRN activity on DNA versus DNA-RNA substrates in living cells are lacking. Here, we developed a structure-specific CRISPR/Cas12a biosensing strategy to visualize WRN functional activity by engineering bubble-structure probes. These probes were rationally designed to structurally mimic DNA replication bubbles and R-loop associated DNA-RNA hybrids. Upon specific unwinding by WRN, the probes release a sequestered activator strand that triggers Cas12a trans-cleavage, effectively converting the unwinding event into an amplified fluorescent signal. This assay achieves low picomolar sensitivity (LODs: 5.6-6.0 pM) and exceptional selectivity against homologous RecQ helicases. Uniquely, this strategy enables the parallel quantification of WRN activity on both substrate types, providing insights into distinct WRN-mediated pathways for resolving genomic stress. We further demonstrated the strategy's utility by visualizing endogenous WRN dynamics in living cells and profiling the efficacy of small-molecule inhibitors. This work offers a powerful molecular toolkit for dissecting WRN biology and facilitating high-throughput drug screening in targeted cancer therapy.

Werner Syndrome Helicase↗

PubMed2026

TNFα-dependent modulation of WT1-MMP9 regulatory axis links developmental and inflammatory pathways in glaucoma.

Glaucomas are heterogeneous optic neuropathies associated with extracellular matrix dysregulation, abnormal ocular morphogenesis, and inflammatory signaling. Targeted deep sequencing of 586 primary congenital glaucoma (PCG) cases and 1,757 controls identified rare pathogenic variants in multiple genes, including WT1 and MMP9. Notably, WT1 variants clustered within the nuclear export sequence. Further, functional analyses showed that combined wt1-pax6 suppression in zebrafish disrupted ocular morphogenesis, highlighting developmental interdependence. In human trabecular meshwork cells, WT1 acted as a transcriptional repressor of MMP9, while TNF-α signaling triggered nitric oxide-dependent nuclear export of WT1, resulting in delayed MMP9 upregulation. This effect was reversible by inhibiting nuclear export or nitric oxide synthase. A patient-derived mutation in the nuclear-export region of WT1, disrupted this regulatory switch, causing abnormal MMP9 expression. These findings position WT1 as an important regulator linking developmental and inflammatory mechanisms in glaucoma pathogenesis.

anterior segment dysgenesis↗

PubMed2026

Watershed-scale risk assessment of cadmium contamination in Chinese cropland soils: Dual pathways of irrigation input and flood-driven transport.

Irrigation and flood events serve as critical pathways for the transport of cadmium (Cd) from industrial sources into cropland soils at the watershed scale, constituting a major driver of widespread Cd contamination in China's cropland soil. This study evaluated the risk of Cd contamination in cropland soils across China's nine major river basins at the watershed scale, focusing on the contributions of irrigation and flood events, and conducted a sensitivity analysis of key risk factors. The assessment was conducted within a framework that considered factors including hazard, exposure, and vulnerability. The results revealed that numerous watersheds in southeastern China are exposed to dual pressures of Cd contamination risks in cropland soils, driven by both irrigation practices and flood events. Watersheds categorized as High-High, High-Moderate, or Moderate-High risk, reflecting combined Cd contamination risks from irrigation and flood, are vital to China's grain production, contributing 67.1 % of the national cropland area and 66.4 % of the grain yield. The study suggests localized strategies for managing cropland soils Cd contamination risks from irrigation and flood at the watershed scale in China, alongside strengthened cross-regional collaboration in southeastern China.

Cadmium↗

PubMed2026

Metabolomic Responses to Oral Glucose Tolerance Test and Hyperinsulinemic-euglycemic Clamp in CKD.

BACKGROUND: The oral glucose tolerance test (OGTT) captures integrated physiological responses involving intestinal glucose absorption, incretin signaling, and endogenous insulin secretion, whereas the hyperinsulinemic-euglycemic clamp (clamp) isolates insulin-mediated glucose uptake. Comparing plasma metabolomic responses to these two challenges may identify processes specific to intestinal nutrient delivery and how they vary in CKD. METHODS: Targeted plasma metabolomics was performed in 59 adults without diabetes (39 with CKD [eGFR <60 mL/min/1.73 m2] and 20 controls) from the Study of Glucose and Insulin in Renal Disease (SUGAR). Each participant underwent a 75-g OGTT and clamp approximately one week apart. Eighty-eight plasma metabolites were quantified at fasting and during each challenge. Metabolite levels were log-transformed and normalized using Systematic Error Removal Using Random Forest (SERRF). Metabolites were classified using adjusted regression slopes relating OGTT and clamp responses. RESULTS: The mean (SD) age and eGFR were 64 (13) years and 54 (26) mL/min/1.73 m2, respectively, and 41% were female. In the overall cohort, OGTT and clamp induced broad plasma metabolic changes, with 63 (72%) and 76 (86%) metabolites significantly altered from fasting, respectively. Seventy-three metabolites (83%) demonstrated a significant relationship between OGTT and clamp responses. Of these, 22 (25%) exhibited true concordance and 51 (58%) demonstrated similar directional changes but differed in magnitude. A total of 15 (17%) metabolites were discordant or non-corresponding, of which only three were discordant. The non-corresponding metabolites were enriched in amino acid metabolism. Eleven metabolites (13%) demonstrated differential responses between OGTT and clamp by CKD status, involving amino acid and glucose metabolism pathways. CONCLUSIONS: Metabolomic responses to OGTT and clamp were largely directionally concordant but differed in magnitude, with attenuation during OGTT. Discordant metabolites were rare, while non-corresponding metabolites were confined to amino acid pathways. CKD modified OGTT-clamp correspondence for metabolites involved in amino acid and glycolytic metabolism.

Journal Article↗

PubMed2026

Studies on functional differentiation of xpr1a and xpr1b genes in zebrafish.

Xenotropic and polytropic retrovirus receptor 1 (XPR1) is known to be involved in various biological processes, including phosphate homeostasis, cellular signaling, brain and vascular mineralization, whereas its specific contribution to bone development remains incompletely characterized. Due to genome duplication in teleosts, zebrafish Danio rerio possess two paralogous genes of XPR1 namely xpr1a and xpr1b, whose functional divergence remains unclear. The amino acid sequence similarity between zebrafish xpr1a and xpr1b was 83.26%. In situ hybridization demonstrated overlapping localization in the head and spinal cord at 24-48 hpf, while diverged by 72 hpf, with xpr1a becoming restricted to the head while xpr1b persisted in both regions. CRISPR/Cas9 was used to generate xpr1a and xpr1b mutants. The xpr1a mutants are comparatively healthy, viable but with mild growth reduction, whereas the xpr1b mutants display high mortality, reduced body length and severe vertebral deformities. Interestingly, all the double mutants died at the embryonic stage. Moreover, to further investigate the molecular and regulatory mechanisms, we conducted comparative transcriptome analysis on bone and brain tissues from xpr1b+/+ and xpr1b-/- zebrafish. In bone tissue, 6749 DEGs were identified, comprising 3846 upregulated and 2903 downregulated genes. These DEGs were mainly enriched in the MAPK signaling pathway, Wnt signaling pathway, cysteine and methionine metabolism, and ECM-receptor interaction. RT-qPCR validated results showed that seven osteogenesis-related genes (col1a1a, sp7, runx2b, col1a2, col1a1b, alp1 and entpd5), and two phosphate homeostasis related genes (slc20a2 and pdgfba), which are essential for skeletal mineralization and phosphate homeostasis, exhibited significantly downregulated expression in bone tissue of xpr1b mutant zebrafish. These results highlight the pivotal role of xpr1b in regulating skeletal mineralization and phosphate metabolism, thereby elucidating the functional specialization of XPR1 paralogs while providing a theoretical basis for understanding bone developmental mechanism in teleost vertebrates.

Animals↗

PubMed2026

Policy pathways and historical insights: Canada's evolving approach to psychedelic access for end-of-life distress.

Canada's evolving attitudes toward psychedelic interventions in palliative and end-of-life care reflect a departure from historically prohibitionist policies and an emerging recognition of their therapeutic potential for individuals facing end-of-life distress. This shift parallels international regulatory developments in jurisdictions such as the United States, Australia and parts of Europe, where cautious policy liberalization has signaled growing acceptance of psychedelics within clinical contexts. Canada is also a relevant case because of its formative role in the development of modern palliative care, its contemporary frameworks emphasizing holistic approaches to suffering at the end of life, and its experience with medical assistance in dying, all of which have shaped national conversations about suffering, autonomy, and end-of-life care. Additionally, Canada's distinctive historical approach to drug regulation-marked by federal flexibility, mechanisms for compassionate access, and responsiveness to patient advocacy-combined with rising public demand and incremental provincial changes, may uniquely position the country along a transitional pathway toward clinical integration of psychedelics in palliative care. At the same time, Canadian drug policy remains heterogeneous across substances and provinces, underscoring the political contingency of reform. Within this dynamic landscape, Canada's psychedelic drug policy trajectory aligns with broader international trends toward cautious medicalization and regulated access to psychedelic therapies, while also offering an instructive case for how end-of-life frameworks and federal-provincial governance shape policy development.

Humans↗

PubMed2026

Multi-omics reveal microbial functional traits and antifungal metabolites associated with lower Pseudogymnoascus destructans loads in bat cave soils.

White-nose syndrome, caused by Pseudogymnoascus destructans (Pd), is a major fungal disease threatening hibernating bats. Cave soils can serve as environmental reservoirs for Pd, yet the microbial and biochemical mechanisms underlying naturally low Pd burdens in some cave environments remain poorly understood. Here, we integrated soil microbiome profiling, metagenomics, metabolomics, multi-omics network analysis, and in vitro validation to investigate the ecological and functional basis of differential Pd loads in hibernating bat caves in Northeast China. The three caves shared cold, humid, and weakly acidic microenvironments, but differed significantly in electrical conductivity, soil water content, nutrient availability, and extracellular enzyme activities. Soil microbial communities showed significant inter-cave variation in composition, diversity, and niche breadth, with stochastic processes contributing substantially to community assembly. Environmental variables, particularly pH and Pd load, were important predictors of microbial community structure. Functional analyses revealed that the low-Pd Gezi Cave was enriched in genes associated with organic carbon degradation, nitrogen input and retention, and secondary metabolism. Metabolomic profiling further identified cave-specific metabolite signatures, among which Biochanin A, 4-Hydroxybenzaldehyde, Vanillin, and Arachidonic acid were negatively correlated with Pd loads. Integrated pathway and network analyses showed that differential genes and metabolites jointly mapped to secondary metabolite biosynthesis, aminobenzoate degradation, and flavonoid degradation pathways, forming a microbe-metabolite-functional gene coupling network involving key taxa such as Rhodococcus, Pseudorhodoplanes, and Rhodoplanes. In vitro assays confirmed that 4-Hydroxybenzaldehyde, Coumarin, and Vanillin inhibited Pd growth. Structural equation modelling further indicated that environmental heterogeneity was associated with variation in Pd loads through microbial functional attributes and metabolite profiles. These findings suggest that naturally low-Pd cave soils are associated with coordinated environmental filtering, microbial functional specialization, and antifungal metabolite production, providing mechanistic insight into microbial and biochemical constraints on Pd persistence in cave reservoirs.

Animals↗