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PubMed2026

DNM1L depletion leads to accelerated heteroplasmy shifting of m.10191C allele through ATG7-dependent pathways.

Nucleotide composition bias in mitochondrial DNA (mtDNA) makes the heavy strand prone to form a DNA secondary structure called a guanine quadruplex (G4). This secondary structure has been shown to inhibit polymerase processivity in vitro. We previously identified pathogenic mtDNA variants that lead to increased G4-forming propensity, including a T to C mutation at m.10191 (m.10191 T > C) that causes Leigh syndrome. Cells treated with G4 binding agent (G4BA) berberine show a reduction in m.10191C pathogenic heteroplasmy levels. To help better understand the underlying mechanism behind berberine-induced heteroplasmy shift, we examined the relationship between mitochondrial fission and berberine-mediated shift. Here we show that knockdown of the fission factor DNM1L leads to an accelerated heteroplasmy shift towards the healthy mtDNA allele, lowering m.10191C by 10% in 3 weeks, compared to the 5 weeks required for berberine alone. The specific mechanism involves ATG7, as knockdown of ATG7 is able to partially delay this accelerated heteroplasmy shift. Taken together, we show that DNM1L knockdown is able to accelerate berberine-induced m.10191C heteroplasmy shifting through an autophagy-related mechanism.

Humans↗

PubMed2026

Diffusion MRI radiomics in meningiomas: imaging correlates of tumor grade and intraoperative consistency.

OBJECTIVE: Despite advancements in imaging studies, the preoperative prediction of the biological behavior and intraoperative consistency of intracranial meningiomas remains limited. This study evaluated the association of volumetric diffusion-based and texture-derived radiomic features extracted from routine MRI with histopathological aggressiveness and intraoperative tumor consistency. METHODS: Ninety-seven intracranial meningiomas resected at two tertiary centers were retrospectively analyzed. Volumetric segmentation was performed on contrast-enhanced T1-weighted MRI and coregistered to apparent diffusion coefficient (ADC) maps. Data on first-order diffusion metrics and selected texture features were collected. The associations between World Health Organization (WHO) grade and Ki-67 index were assessed using nonparametric tests and Spearman correlation analysis. Independent factors associated with intraoperative tumor consistency (Zada grades 1-5) were evaluated via multivariate ordinal logistic regression analysis that adjusted for tumor volume, skull base location, calcification status, and WHO grade. Secondary receiver operating characteristic (ROC) curve analyses were performed to differentiate solid (Zada grades 4-5) from soft (Zada grades 1-2) tumors. ROC analyses were performed within the study cohort and were intended as exploratory assessments of discriminative performance. RESULTS: The mean ADC (ADCmean) and the 10th percentile of the ADC decreased significantly with increasing WHO grade (p < 0.001). ADCmean had a moderate inverse correlation with the Ki-67 index (r = -0.42, p < 0.001) and intraoperative tumor consistency (r = -0.45, p < 0.001). In the multivariate analysis, the ADCmean remained independently associated with increasing tumor firmness. Each 0.1 × 10-3 mm2/sec increase corresponded to a 38% reduction in the odds of belonging to a higher consistency category (OR 0.62, 95% CI 0.51-0.74, p < 0.001). The ROC analysis showed good discrimination for solid tumors (area under the curve 0.847, 95% CI 0.742-0.953) and soft tumors (area under the curve 0.824, 95% CI 0.714-0.935). Texture features had weaker associations with intraoperative tumor consistency. CONCLUSIONS: Volumetric diffusion-derived metrics, particularly ADCmean, are associated with both histopathological aggressiveness and intraoperative tumor firmness in meningiomas. Diffusion imaging may reflect a graded microstructural continuum rather than a purely dichotomous property, providing complementary preoperative insights into surgical complexity.

Humans↗

PubMed2026

From host response to genomic targets: electrochemical biosensing of tuberculosis biomarkers.

Tuberculosis (TB) remains one of the leading causes of death from a single infectious agent worldwide, with timely diagnosis continuing to be a major challenge, particularly in resource-limited settings. Conventional TB diagnostic methods are limited by low sensitivity, long turnaround times, and an inability to reliably differentiate latent from active disease. Biomarker-based diagnostic strategies have therefore gained increasing attention as they offer the potential to improve early detection, disease differentiation, and treatment monitoring. Herein, we examine electrochemical biosensing strategies for TB diagnostics using a biomarker-class-driven framework, covering host-response biomarkers (IFN-γ and TNF-α), pathogen-derived antigens (ESAT6, CFP10, CFP10-ESAT6, MPT64, Ag85, HspX and LpqH), cell-wall signatures and whole-cell markers (LAM and whole cell Mtb), and genomic markers (Mtb DNA and IS6110). Through structured comparison of recognition elements, biointerface designs, signal amplification strategies, electrochemical techniques, matrices, and validation levels, this review identifies the most promising technical approaches for different TB biomarker classes. It further highlights key translational bottlenecks, including limited clinical validation, buffer-based testing, complex multistep amplification, redox-probe dependence, matrix fouling, and insufficient evidence of manufacturability. This review therefore provides practical guidance for developing electrochemical TB biosensors that are analytically sensitive, clinically relevant, and suitable for decentralized diagnostic applications.

Biosensing Techniques↗

PubMed2026

Reinforcement learning-based dynamic ensemble for missense variant effect prediction and tiered prioritization of VUS.

BACKGROUND: Accurate classification of missense variants remains a challenging task despite major advances in genomics. Numerous computational models have been developed to assist in variant classification, but often require repeated integration and benchmarking efforts. Ensemble methods have been proposed to overcome the limitations of single predictors, but mostly rely on fixed, predefined weights that constrain their ability to capture interactions among predictive signals. METHODS: We present GenixRL, a dynamic ensemble framework that reformulates model fusion as a reinforcement learning optimization problem. GenixRL uses a Q-learning agent to learn a policy that dynamically weights the probabilistic outputs of complementary predictors, including BayesDel (addAF and noAF), ClinPred, and MetaRNN. Replacing static weighting with policy learning allows GenixRL to adaptively identify optimal weightings and substantially improve classification accuracy. RESULTS: In benchmark evaluation against 25 state-of-the-art predictors, GenixRL achieved an AUROC of 0.9644 on an independent ClinVar dataset. On saturation genome editing assays for BRCA1 and BRCA2, GenixRL achieved the best performance and ranked highest on 14 of 17 clinically significant genes in a zero-shot evaluation. Applied to uncertain and conflicting ClinVar variants, GenixRL enabled tiered, evidence-based prioritization of hundreds of thousands of variants as likely pathogenic or pathogenic with high confidence, supported by orthogonal population evidence from gnomAD. CONCLUSION: GenixRL advances pathogenicity prediction for missense variants and provides an adaptive ensemble that sorts variants of uncertain significance into tiered candidates for expert curation and functional validation.

Mutation, Missense↗

PubMed2026

Prognostic Value of Circulating Tumor DNA-Based Minimal Residual Disease for Recurrence-Free Survival in Resectable Gastric Cancer: A Systematic Review and Meta-Analysis with Serial Monitoring Analysis.

BACKGROUND: Circulating tumor DNA (ctDNA)-based minimal residual disease (MRD) is an emerging biomarker, but its utility in resectable gastric cancer remains incompletely characterized. METHODS: We conducted a systematic review and meta-analysis of eight studies (520 patients) to evaluate the prognostic value of ctDNA-based MRD for recurrence-free survival (RFS) and overall survival (OS) in resectable gastric cancer. RESULTS: In localized resectable gastric cancer (Stage I-III), the setting in which postoperative ctDNA most coherently represents true molecular residual disease after curative-intent surgery, postoperative ctDNA positivity was associated with diminished recurrence-free survival (RFS: HR 12.26, 95% CI 3.30-45.52) and overall survival (OS: HR 8.57, 95% CI 3.06-23.98). The test for subgroup differences between localized and mixed-stage cohorts was not statistically significant (P = 0.57), and the numerically higher HR in the localized subgroup should therefore not be interpreted as evidence of a quantitatively stronger prognostic effect. Postoperative ctDNA detection demonstrated substantially stronger prognostic value (overall RFS: HR 10.00, 95% CI 4.53-22.10) compared to preoperative assessment (HR 2.17, 95% CI 1.10-4.28). Both tumor-informed and tumor-agnostic strategies effectively stratified high-risk patients. However, these effect sizes should be interpreted cautiously given the small number of studies and substantial heterogeneity (I2 = 65-72%). Results from mixed-stage cohorts including Stage IV disease are supportive but should not be considered equivalent to localized-disease findings, as ctDNA in metastatic disease reflects persistent systemic burden rather than minimal residual disease in the postoperative sense. CONCLUSIONS: Postoperative ctDNA-based MRD shows a consistent adverse prognostic association in resectable gastric cancer, with localized disease (Stage I-III) representing the most biologically and clinically coherent setting for interpretation. However, the large pooled hazard ratios (HR 10.00-12.26) should be interpreted as a directionally consistent signal rather than precise quantitative estimates, given the small number of studies, wide confidence intervals, and substantial heterogeneity (I2 = 65-73%). This heterogeneity is largely driven by substantial variation in postoperative sampling timing (4 days to 16 weeks) and ctDNA assay characteristics (platform, sensitivity, coverage, variant filtering, and positivity thresholds), which require standardization in future studies. While ctDNA is prognostically valuable, its clinical utility remains unestablished. Prospective randomized trials are needed to determine whether ctDNA-guided strategies improve patient outcomes before routine clinical implementation can be recommended.

Humans↗

PubMed2026

Choice of Anesthesia in Microelectrode Recording-guided Deep Brain Stimulation Surgery for Parkinson's Disease (CHAMPION): A Noninferiority Randomized Controlled Trial.

BACKGROUND: Deep brain stimulation for Parkinson's disease is often performed under conscious sedation or general anesthesia. However, anesthetic agents may influence intraoperative microelectrode recording, and the optimal anesthesia method for microelectrode recording remains unclear. This study compared general anesthesia and conscious sedation in preserving microelectrode recording signal intensity during deep brain stimulation. METHODS: In this prospective, noninferiority randomized controlled trial, patients with Parkinson's disease (United Kingdom Brain Bank criteria) undergoing elective bilateral surgery were randomized 1:1 to the conscious sedation or the general anesthesia group. During surgery, a desflurane anesthetic titrated against the quality of the electrophysiologic signal was applied in the general anesthesia group, whereas patients in the conscious sedation group received dexmedetomidine anesthesia. The primary outcome was the proportion of patients with high-quality microelectrode recording (normalized root mean square greater than 2.0), assessed postoperatively off-line. Secondary outcomes included operation and recording duration, 6-month clinical efficacy, and complication rates. RESULTS: Of 188 randomized patients (94 general anesthesia, 93 conscious sedation), desflurane anesthesia was noninferior for high normalized root mean square proportion (89.4% vs . 90.3%; difference, -0.96%; 95% CI, -9.62 to 7.70). The general anesthesia group had shorter operative time (difference, -9.07 min; 95% CI, -13.99 to -4.14; P < 0.001). At 6 months, changes in Unified Parkinson's Disease Rating Scale score (difference, -2.50; 95% CI, -7.20 to 2.20; P = 0.297), levodopa equivalent daily dose (difference, -58.4 mg; 95% CI, -133.56 to 16.75; P = 0.128), and complication rates (general anesthesia: 10.9% vs . conscious sedation: 8.9%; P = 0.655) were comparable between the groups. CONCLUSIONS: General anesthesia is noninferior to conscious sedation for microelectrode-guided subthalamic nucleus deep brain stimulation, providing equivalent signal intensity and clinical outcomes while improving procedural efficiency, supporting its use as a valid clinical option.

Humans↗

PubMed2026

Strategy for enhanced production of A40926B0 in Nonomuraea gerenzanensis using an efficient CRISPR/AsCas12f1 system.

The global emergence of vancomycin-resistant Gram-positive pathogens underscores the urgent need for efficient production of novel lipoglycopeptide antibiotics. Dalbavancin, a last-resort therapeutic agent, relies on its key biosynthetic precursor A40926B0, whose industrial manufacture is severely limited by the low yield of wild-type Nonomuraea gerenzanensis and inefficient genetic tools for this rare actinomycete. Here, we developed a high-efficiency CRISPR/AsCas12f1 genome editing system and applied systematic metabolic engineering to boost A40926B0 biosynthesis. First, conjugation conditions were optimized to elevate the transfer efficiency in N. gerenzanensis D11. The hypercompact AsCas12f1 nuclease showed markedly lower cytotoxicity than SpCas9 and enabled 100% gene deletion efficiency with preferred PAMs (TTTG, CTTG, GTTG). Second, we strengthened the shikimate pathway via multiple genetic strategies: overexpressing feedback-resistant DAHP synthase (aroG fbr ) and chorismate mutase/prephenate dehydrogenase (tyrA fbr ), as well as knocking out pheA. This manipulation blocks the phenylalanine synthetic branch and redirects metabolic flux toward the l-tyrosine branch. Third, we engineered the branched-chain fatty acid (BCFA) pathway via promoter replacement of bkdA2B2C2, LipAB, fabF and deletion of acdH to enhance isododecanoyl side-chain supply. The combinatorial engineering yielded strain B-13, which produced 1740 mg/L A40926B0 in shake flasks. Finally, 50-L fed-batch fermentation with continuous maltodextrin feeding further increased the titer to 1817 mg/L, the highest reported titer to date. This work establishes a robust CRISPR editing tool for N. gerenzanensis and provides valuable engineering references for precursor-oriented strain improvement targeting lipoglycopeptide antibiotics, offering insights for the industrial scale production of A40926B0.

A40926B0↗

PubMed2026

Treatment of Hot Flashes in Men With Prostate Cancer Undergoing Androgen Deprivation Therapy.

BACKGROUND: Hot flashes are common and often debilitating side effects of castration therapy; a cornerstone in the treatment of metastatic prostate cancer (PCa) as well as in localized or locally advanced PCa when combined with radiotherapy. The evidence for relieving vasomotor symptoms is limited. This systematic review presents both pharmacological and non-pharmacological interventions for treating hot flashes in men with PCa undergoing castration therapy, primarily androgen deprivation therapy (ADT). METHODS: a systematic literature search was conducted in PubMed using ("hot flash*" OR "hot flush*" OR "vasomotor*") AND ("prostate") as keywords. Studies with intervention for hot flashes due to castration therapy, estimation of treatment response (e.g., reduction in frequency or impact on quality of life) and patients with PCa (any stage) were eligible. RESULTS: Of 469 papers, 35 were included in the review. The included studies evaluated cyproterone acetate, estrogen or estrogen derivatives, progesterone derivatives, selective serotonin reuptake inhibitors (SSRIs), gabapentin, oxybutynin, and clonidine, as well as non-pharmacological interventions such as acupuncture, cognitive behavioral therapy (CBT), and dietary supplements (e.g., Dong Quai/Angelica Sinensis, Serelys Homme, soy protein, and Salvia officinalis). Across all blinded pharmacological interventions, the relative reduction in hot flash frequency ranged from -21% to -84%, and the placebo effect was between -19% and -30%. CONCLUSION: Hormonal agents such as cyproterone acetate and estrogen appear to be the most effective treatments, although they are associated with side effects. Non-pharmacological options like acupuncture and CBT may offer some benefit, while dietary supplements seem to be ineffective. Future studies are needed also to evaluate newer treatments, such as fezolinetant, in this patient population.

Humans↗

PubMed2026

A Pilot Study: Developing a Lactating Dairy Goat Model to Study Staphylococcus aureus Mastitis in Women.

INTRODUCTION: Lactational mastitis is common in lactating women, with Staphylococcus aureus as the most commonly isolated agent associated with infectious lactational mastitis. Currently, there are no evidence-based guidelines for antimicrobial treatment due to barriers in obtaining pharmacokinetic data from lactating women. To overcome this barrier, a suitable large animal model is needed. Goats are an ideal translational model for human mastitis due to their anatomical and physiological similarity to humans. The objective of this pilot study was to assess if goats would develop clinical mastitis following intramammary inoculation with a clinical human isolate of S. aureus with the goal of establishing an alternative in vivo model for future research. The hypothesis was that the infected mammary gland half would show similar clinical signs to women with mastitis and demonstrate a similar local immune response when compared to the control mammary gland half. METHODS: One half of the mammary gland of two healthy lactating does was inoculated with a clinical human isolate of S. aureus. The other half of the mammary gland was sham inoculated with sterile buffered saline. Physical examinations, mammary gland assessments, and sterile milk samples were collected every 12 hours post inoculation. At 96 hours post inoculation, the goats were euthanized, and the mammary glands were examined for pathological changes. RESULTS: Goats did not develop systemic signs of disease following inoculation. Focal infected mammary gland changes included warmth, swelling, redness, discoloration, and reduced milk production; the other mammary gland half remained normal throughout the study period. S. aureus was enumerated from only the infected mammary gland half. The microscopic findings of the infected half showed neutrophilic inflammation and cell necrosis consistent with acute mastitis. DISCUSSION: This pilot study demonstrated lactating does can develop clinical signs like those observed in women. Goats have the potential to be a promising animal model to study infectious lactational mastitis.

Animals↗

PubMed2026

Efficacy and safety of JAK inhibitors in Behçet syndrome: systematic literature review.

OBJECTIVES: Given the active role of the JAK signaling pathway and the multifactorial immune mediators observed in Behçet syndrome (BS), JAK inhibitors (JAKi) may be promising agents. In this systematic literature review (SLR), we aim to evaluate the efficacy and safety of JAKi in BS. METHODS: A systematic literature search was conducted in Embase, PubMed, and the Cochrane Library to identify all reports on the efficacy and safety of JAKi in patients with BS. The SLR protocol was registered with the International Prospective Registry of Systematic Reviews (CRD420251000172). We additionally presented our patient with gastrointestinal involvement treated with upadacitinib. RESULTS: Among the 92 patients (48 men, mean (SD) age 38.5 (13.5) years), 46 used tofacitinib, 31 used baricitinib, and 15 used upadacitinib. All but 1 patient had used at least one previous conventional immunosuppressive, and 57.6% were refractory to at least one prior tumor necrosis factor inhibitor. JAKi were used in combination with conventional immunosuppressive and/or glucocorticoids in 90.6% of the patients. The primary indication for JAKi initiation was gastrointestinal involvement in 46 (50%) patients including our patient, vascular involvement in 22 (23.9%), uveitis in 19 (20.6%), and mucocutaneous and/or articular involvement in 5 (5.6%) patients. The remission rates for overall, gastrointestinal, vascular, and eye involvement were 85.9%, 82.6%, 90.9%, and 84.2%. Serious adverse events were observed in 5.4% of the patients. No thrombotic events were reported. CONCLUSION: This SLR showed that JAKi may be effective in refractory BS patients with a favorable safety profile.

Humans↗

PubMed2026

Genomic characterization of a hypervirulent Aeromonas veronii NN0115 from Nile tilapia and head kidney transcriptome of infected fish reveals B-cell-dominated immune response with specific immunoglobulin downregulation.

Aeromonas veronii is a pathogen of multiple fish species, yet systematic understanding of its infection in Nile tilapia (Oreochromis niloticus) remains limited. A dominant strain, NN0115, was isolated from a natural outbreak and identified as A. veronii by 16S rRNA and whole-genome average nucleotide identity (ANI, 96.33%). Experimental infection revealed high virulence (LD50 = 3.41 × 106 CFU/mL, equivalent to 8.53 × 104 CFU/fish). The genome is 4.58 Mb (58.57% GC) and encodes 4216 proteins. Virulence factor analysis identified 1253 genes, dominated by motility-related (264) and immune modulation (208) factors. Genomic island GI2 harbors 7 virulence genes and two dual-function resistance-virulence genes. The strain is resistant to 9 of 25 agents tested but carries three RND efflux pump genes whose predicted resistance was not phenotypically observed. The head kidney transcriptome of tilapia at 24 h post-bacterial infection identified 773 differentially expressed genes; among them, 57 were immunoglobulin (Ig) genes, and 56 were down-regulated. Integration of published single-cell transcriptomic data showed that non-Ig B-cell marker genes were down-regulated by 32%, whereas Ig genes were reduced by 63%, indicating selective transcriptional suppression of Ig genes rather than a general decrease in B-cell transcriptional activity. Together, this study provides a comprehensive characterization of a highly virulent A. veronii from Nile tilapia and reveals that selective downregulation of B-cell Ig genes is the dominant transcriptional feature of the host head kidney response.

Animals↗

PubMed2026

An oxidative stress - and immunotherapy-related six-gene signature defines immune subtypes and predicts prognosis and immunotherapy response in hepatocellular carcinoma.

BACKGROUND: Oxidative stress and the tumor immune microenvironment jointly shape hepatocellular carcinoma (HCC) progression and response to immunotherapy, yet integrated biomarkers linking these processes are lacking. METHODS: Transcriptomic and clinical data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets were used to identify oxidative stress- and immunotherapyrelated differentially expressed genes (OSIRDEGs). Functional enrichment, weighted gene co-expression network analysis (WGCNA) and LASSO-Cox regression were used to construct a prognostic signature. Consensus clustering, TIDE, CIBERSORT and ssGSEA characterized immune phenotypes. Somatic mutation, copy-number and drug-response data were integrated to assess genomic alterations and drug sensitivity. Expression of model genes was validated by qRT-PCR and western blotting in HCC cell lines. RESULTS: We identified 24 OSIRDEGs enriched in cell-cycle and mitotic pathways. WGCNA intersection yielded 18 module genes, from which a six-gene signature (BUB1B, CDKN2A, CENPE, HMMR, PTTG1, SPP1) was derived. The signature robustly stratified patients into high- and low-risk groups with significantly different progression-free and disease-free survival in both TCGA-LIHC and GSE14520. Based on signature expression, two molecular subtypes were defined, exhibiting distinct survival, immune landscapes and predicted immunotherapy responsiveness. Model genes harbored recurrent alterations and showed significant correlations with anticancer agents. All six genes were upregulated at mRNA and protein levels in metastatic HCC cell lines versus normal hepatocytes. CONCLUSIONS: We systematically explored the landscape of OSIRDEGs in HCC, and proposed a validated six-gene signature that refines prognostic stratification, delineates immunerelevant HCC subtypes and highlights candidate biomarkers for therapeutic selection and mechanistic investigation.

Humans↗

PubMed2026

Eating Experiences During Cancer Treatment in Adolescents and Young Adults: A Systematic Literature Review and Meta-Synthesis.

Adolescents and young adults (AYAs) aged 15-39 with cancer face distinct challenges during treatment, with eating consistently emerging as one of the most distressing and underrecognized concerns. At a critical life stage, AYAs must navigate illness-related consequences that profoundly affect well-being. Eating reflects these broader challenges and is identified as a key issue requiring health care attention. To address this, we synthesized evidence on AYAs' eating experiences and well-being during mealtime-related activities to inform health care practice. Qualitative and mixed-method studies were identified through searches across CINAHL, Embase, PubMed, Scopus, and Web of Science for studies published up to May 2025, supplemented by snowball searches. Of 3214 records, 74 full-text articles were reviewed, and 18 met the inclusion criteria. These represented 302 AYAs, 73 relatives, and 88 health care professionals. Studies were analyzed using Joanna Briggs Institute review methods and GRADE-CERQual to support clinical interpretability. The meta-synthesis identified one core theme: "Eating as an embodied struggle and act of agency," with three subthemes: (a) living through physical and sensory disruption, (b) carrying the weight of new emotions and shifting relations, and (c) finding ways through gaps in support. Eating emerged as a disrupted, emotionally charged, yet agentic act requiring sensitive, individualized approaches. Thirteen evidence-informed recommendations were developed to guide clinical application. These emphasize early nutritional screening, dietetic support, flexible meal options, respectful family involvement, and psychosocially attuned care. Future research should codevelop and evaluate tailored interventions that address AYAs' embodied, emotional, and social needs to improve eating-related quality of life during cancer treatment.

Humans↗

PubMed2026

Proteome-level evidence that tebuconazole, both alone and in interaction with thiacloprid, affects epigenetic events in bumblebee heads.

Tebuconazole, a widely used ergosterol biosynthesis-inhibiting fungicide, can affect nontargets, especially when combined with insecticides. We employed label-free quantitative proteomics to investigate the effects of long-term exposure to sublethal concentrations (100 μg/L) of tebuconazole, either by itself or alongside the neonicotinoid thiacloprid (100 μg/L), on the heads of Bombus terrestris workers. A Bayesian factor power analysis revealed that the experiment produced conclusive proteomic results. Tebuconazole treatment revealed eleven differentially abundant proteins, which increased elevenfold with thiacloprid. The proteins that changed in the same direction in both treatments suggest the occurrence of epigenetic events because they are involved in histone trimethylation (H3K4me3), pre-mRNA processing, and folate (vitamin B9) metabolism. Following co-exposure, the abundance of histone H2A.V and its associated proteins was affected. Two important detoxification-related proteins, CYP6BE1 and CYP6AQ1 (honey bee homologs), were identified, as well as proteins that suggest hormonal and neurotoxic effects. Overall, this study suggests that tebuconazole affects key epigenetic processes in bumblebee heads at the proteome level, though this was not confirmed at the biological level or through orthogonal methods. The tested chemicals were previously found to affect trimethylations, but not H3K4me3. We suggest analyzing the different trimethylations, their interplay, and associated hallmarks, such as folate levels. SIGNIFICANCE: The effects of pesticides and their combinations on organisms can be unexpected until they are examined using modern, complex methods. High-throughput proteomics can provide data on important biochemical processes affected by pesticides, offering a different perspective to that at the expression level. Despite their low acute toxicity, a group of fungicides that inhibit (ergo)sterol biosynthesis (EBI or SBI) are considered dangerous to pollinators, including bumblebees. This is due to the increasing toxicity of insecticides through the inhibition of cytochrome P450 detoxification enzymes. We found that tebuconazole had a similar effect on epigenetic events when used alone or in combination with the insecticide thiacloprid. Key proteins suggest that H3K4 histone trimethylation (H3K4me3) was impacted. To our knowledge, this expands the existing evidence suggesting that tebuconazole/triazole fungicides affect histone trimethylation H3K27me3. Since literature shows that thiacloprid affects H3K9me3, it is possible that thiacloprid and tebuconazole interact in these epigenetic events that affect each other. Overall, our results suggest that tebuconazole affects proteins involved in histone trimethylation, pre-mRNA processing, and folate metabolism. These are all hallmarks of epigenetic processes and were further extended by the co-exposure of tebuconazole and thiacloprid to more differently abundant proteins. Additionally, the results provide data on cytochrome P450s of the CYP6 family, which act as detoxifying proteins, as well as proteins that indicate hormonal and neurotoxic effects in bumblebee heads. Finally, the results of the Bayesian power analysis confirmed the meaningfulness of the proteomic data analyzed in this study. If the new findings obtained at the proteome level are verified by different methods, the full extent of the side effects of tebuconazole can be revealed.

Animals↗

PubMed2026

Systematic Review of Pharmacologic Treatment for Migraine Prevention in Adults: Report of the AAN Guidelines Subcommittee and the American Headache Society.

BACKGROUND AND OBJECTIVES: This systematic review (SR) provides updated evidence-based conclusions regarding the use of pharmacologic migraine prevention in adults to inform a new joint American Academy of Neurology (AAN) and American Headache Society practice guideline. METHODS: A multidisciplinary panel conducted an SR following the 2017 AAN Clinical Practice Guideline Process Manual. Randomized controlled trials evaluating pharmacologic preventive treatments for adults with episodic or chronic migraine were included. Searches encompassed MEDLINE, Embase, and ClinicalTrials.gov from database inception through June 6, 2024. Studies were screened in duplicate, with dual independent risk-of-bias assessment. Outcomes included change in monthly headache days, ≥50% responder rate, and validated patient-reported quality of life (QOL) measures. Raw mean differences, standardized mean differences, and risk ratios were calculated. A modified Grading of Recommendations Assessment, Development, and Evaluation process was used to classify certainty of evidence. RESULTS: A total of 217 studies met inclusion criteria. For episodic migraine, high-confidence evidence showed that galcanezumab and erenumab are more effective than placebo in reducing headache frequency. Moderate-confidence evidence supported benefit from atogepant, eptinezumab, fremanezumab, propranolol, topiramate, and valproate. Several additional oral agents including amitriptyline, bisoprolol, flunarizine, fluoxetine, levetiracetam, metoprolol, nifedipine, pizotifen, and telmisartan had low-confidence evidence suggesting possible benefit. For chronic migraine, high-confidence evidence supported reductions in headache frequency with fremanezumab, galcanezumab, and onabotulinumtoxinA. Moderate-confidence evidence supported benefit from atogepant, eptinezumab, erenumab, topiramate and valproate. Across both episodic and chronic migraine populations, erenumab, fremanezumab, galcanezumab, eptinezumab, rimegepant, atogepant, topiramate and onabotulinumtoxinA demonstrated improvements in patient-reported QOL outcomes on validated instruments. Evidence comparing active treatments was limited and generally of low or very low confidence, restricting conclusions about comparative effectiveness. DISCUSSION: This SR provides a comprehensive synthesis of evidence on pharmacologic migraine prevention in adults. High- and moderate-confidence findings confirm the efficacy of several established and newer preventive therapies and demonstrate improvements in patient-reported outcomes across multiple validated measures. These conclusions informed the development of evidence-based recommendations, presented in a companion publication, to guide clinicians in selecting preventive medications for adults with episodic and chronic migraine.

Humans↗

PubMed2026

Protein persulfidation emerges as a conserved component of the redox response to DNA damage.

Genotoxic stress is frequently accompanied by alterations in cellular redox homeostasis; however, the mechanisms linking redox regulation to the DNA damage response (DDR) remain incompletely understood. Here, we investigated the early redox response to DNA damage induced by methyl methanesulfonate (MMS) in Saccharomyces cerevisiae, focusing on cysteine oxidative post-translational modifications (PTM). We show that activation of the DNA damage response is accompanied by rapid redox changes that occur in the absence of a generalized oxidative stress response. MMS exposure promotes selective remodeling of cysteine oxidative modifications, characterized by decreased free thiols, robust induction of protein persulfidation, and comparatively modest changes in sulfenylation. These alterations are accompanied by increased intracellular hydrogen sulfide levels, supporting the involvement of reactive sulfur species in the cellular response to DNA damage. Proteome-wide analyses revealed that cysteine oxidative modifications preferentially target proteins involved in central metabolism, nucleotide biosynthesis, and genome maintenance. Consistent with these observations, MMS-induced genotoxic stress promotes metabolic adaptation characterized by increased mitochondrial respiration, elevated ATP production, and mitochondrial morphological remodeling, linking bioenergetic adaptation to redox regulation. Importantly, perturbation of intracellular redox balance using N-acetylcysteine compromises survival under DNA-damaging conditions, supporting a functional role for redox signaling during the DDR. Finally, MMS treatment also induces protein persulfidation in mammalian cells. Moreover, exposure to etoposide, a mechanistically distinct genotoxic agent that induces DNA double-strand breaks through topoisomerase II inhibition, showed a similar trend, suggesting that protein persulfidation may not be restricted to alkylation-induced DNA damage. Together our findings identify protein persulfidation as a prominent component of the redox response to DNA damage and provide new insight into the functional interplay between mitochondrial metabolism, cysteine-based redox regulation, and genome maintenance.

Oxidation-Reduction↗

PubMed2026

Functions of tandem-repeat galectins and domain coordination governs galectin-4 activity in grass carp (Ctenopharyngodon idella).

Galectins are β-galactoside-binding lectins that play essential roles in innate immunity. Among them, tandem-repeat galectins (TrGals), typically composed of two distinct carbohydrate-recognition domains (CRDs) connected by a linker peptide, are well established as key regulators of pathogen recognition and host defense in mammals. However, their structural diversity and immunological functions in teleost fish remain poorly understood. In this study, five TrGals (Gal-4, Gal-8a, Gal-8b, Gal-9, and Gal-9like) were identified in grass carp. Sequence and structural analysis revealed that Gal-8a/b, Gal-9, and Gal-9like possess the canonical two-CRD architecture, whereas Gal-4 uniquely contains four highly similar tandem-repeat domains. All five TrGals were broadly expressed across examined tissues, with predominant expression in the liver. Upon Aeromonas hydrophila infection, Gal-4, Gal-8a, Gal-8b, and Gal-9 were rapidly up-regulated at early time points (3-6 h). To elucidate the functional significance of CRD number, recombinant full-length CiGal-4 (CiGal4-full) and three truncated variants containing one, two, or three CRDs (CiGal4-1CRD, CiGal4-2CRD, and CiGal4-3CRD) were generated and systematically characterized. All recombinant proteins contained the conserved β-sheet structure typical of galectin CRDs. Functional assays revealed that CiGal4-full displayed the strongest growth-inhibitory activity against all tested bacteria, whereas CiGal4-1CRD showed the weakest effect. Notably, CiGal4-2CRD exhibited the most potent bactericidal activity, surpassing the full-length protein, while CiGal4-3CRD showed no further enhancement. CiGal4-full and CiGal4-2CRD showed superior carbohydrate-binding activities compared with the other variants. Collectively, these results reveal that CRD copy number alone does not linearly determine galectin function. Instead, domain organization and conformational coordination are critical for optimizing antimicrobial activity. This study provides new insights into the structure-function relationships and evolutionary diversification of galectins in teleosts and highlights their potential as novel antimicrobial and immunomodulatory agents in aquaculture.

Animals↗

PubMed2026

Antibody-drug conjugates against multidrug-resistant cancers: Biomarker-guided patient selection, payload engineering, linker chemistry, and bystander effects.

Antibody-drug conjugates (ADCs) are one of the most significant advancements in modern cancer therapeutics. Combining the target selectivity of monoclonal antibodies with the cytotoxic potential of payloads, ADCs effectively kill cancer cells and offer hope to patients with even refractory cancer types. Beyond simply increasing the number of therapeutic options available for cancer patients, ADCs have become a powerful frontline agent in overcoming multidrug resistance (MDR). As one of the most challenging obstacles to effective cancer care, MDR is mediated by ATP-binding cassette (ABC) transporter-mediated drug efflux, target-based mutations, and dysregulated apoptosis. The clinical success of ADCs specifically engineered to overcome MDR, including in heterogeneous tumors and cancer cells that exhibit bypass signaling, is well established. This is especially evident with trastuzumab deruxtecan (T-DXd) in HER2-low, HER2-positive, and HER2-mutant cancers; sacituzumab govitecan (SG) in TROP2-expressing triple-negative breast cancer (TNBC) and urothelial carcinoma; and enfortumab vedotin in Nectin-4-positive bladder cancer. By overcoming MDR, ADCs have enabled more effective treatment algorithms across multiple malignancies. Most importantly, the clinical application of ADCs has become inextricably linked to cancer genomics. HER2 testing has evolved from a two-tiered system to a continuous spectrum including HER2-ultralow, HER2-low, HER2-positive, and ERBB2-mutant categories. Each of these categories exhibits different eligibility guidelines for ADC patient selection. As cancer cells continue to evolve and develop resistance to even ADCs through mutations and variants, researchers and clinicians have used pharmacogenomics to predict ADC response and resistance. To define the genomic architecture of ADC-resistant tumor subpopulations, single-cell transcriptomic studies and liquid biopsy approaches are being used to enable real-time examination of the tumor genome during ADC therapy, thereby optimizing treatment and circumventing resistance driven by emerging mutations and variants. This review provides a comprehensive analysis of the molecular structure of ADCs, the pharmacological principles underlying their potent cytotoxic activity against MDR cancer cells, the genomic and transcriptomic biomarkers that guide ADC patient selection, and the emerging resistance mechanisms that will shape the next generation of promising ADC development.

Humans↗