Reviews of physiology, biochemistry and pharmacologyUndurti N Das
AA is a crucial fatty acid in pregnancy, especially for the growth and development of the fetus and its central nervous system (CNS). As already discussed in the previous chapters, AA regulates inflammation, immune response, and cell signaling. AA has a modulatory action on gene expression, serves as a mechanotransducer, and regulates cell membrane fluidity. By regulating cell membrane fluidity, AA modulates the expression and binding of several receptors located on the cell membrane. Eicosanoids derived from AA have both beneficial and harmful effects on pregnancy. For instance, (i) AA metabolites such as 14,15-EET and 15-HETE are associated with gestational hypertension and preeclampsia, (ii) AA in association with DHA is crucial for the fetal nervous system and neurocognitive development of the newborn, and (iii) for the growth and development of the fetus, especially during the third trimester. LA and AA are involved in human fertility and in the pathobiology of gestational diabetes.
Reviews of physiology, biochemistry and pharmacologyUndurti N Das
Human essential hypertension is driven by a network of interacting nutritional, metabolic, inflammatory, and endothelial mechanisms in which AA and other PUFAs play a critical role. Beyond excess sodium intake, population data supports the role of inadequate calcium, potassium, and magnesium intake and low antioxidant vitamin status in shaping blood pressure regulation. These nutrients influence vascular smooth muscle tone and act as cofactors that support Δ6 and Δ5 desaturase activities, thereby governing tissue availability of AA, EPA, and DHA and downstream formation of vasodilator and antiplatelet mediators (e.g., PGE1, prostacyclin), as well as inflammation-resolving lipid mediators (lipoxins, resolvins, protectins, maresins, and nitrolipids).Endothelial dysfunction characterized by reduced endothelial nitric oxide (eNO) bioavailability and increased oxidative stress seems to play an important role in the pathobiology of HTN. High salt intake, asymmetric dimethylarginine (ADMA), and activation of NAD(P)H oxidase and angiotensin II signaling promote superoxide generation that quenches NO and shifts the vascular balance toward vasoconstriction. Clinical and experimental observations indicate that antihypertensive therapies can partly restore NO and antioxidant defenses, while dietary patterns rich in n-3 fatty acids (particularly DHA) and balanced n-6/n-3 intake may lower blood pressure by suppressing thromboxane formation and enhancing vasoprotective, pro-resolving pathways.Preeclampsia can be considered as a model of reversible hypertension linked to oxidative stress and angiogenic imbalance (sFlt1, soluble endoglin), highlighting mechanistic overlap with essential hypertension. Hypertension is a low-grade systemic inflammatory condition whose origins may be present in the perinatal period through long-term programming of PUFA metabolism and endothelial function.
The ProstateMarissa Sarna-McCarthy, Claweens Quetant, Quentin D'Arcy, Richard Caesar, Kourosh Zarringhalam, Jill A Macoska
BACKGROUND: Expansion of the stromal compartment of the prostate concurrent with fibroblast activation and increased collagenization is now recognized as a pathobiology likely contributing to Lower Urinary Tract Symptoms (LUTS). However, approaches to quantitatively and, ideally, non-invasively, assess prostatic collagenization in vivo are not currently available. This study sought to determine whether human urine could provide a suitable substrate for the identification of pro-fibrotic collagen proteins associated with moderate/severe LUTS. METHODS: Whole urine from two separate age-matched cohorts of men with or without severe LUTS was subjected to Sircol soluble collagen protein, specific gravity, and total protein assays. Samples were assayed fresh or after frozen storage at -20°C or -80°C. RESULTS: Both cohorts demonstrated statistically significantly (p = 0.001) higher urinary soluble collagen levels in samples from men reporting moderate/severe LUTS (cases) compared to no/mild LUTS (controls). Urinary soluble collagen levels did not differ significantly different between the cases of the 2 cohorts or the controls of the 2 cohorts. In both cohorts, urinary specific gravity and whole protein content were modestly higher in cases than controls concurrent with higher collagen content. Responses to medical treatment varied in the LURN cohort, though responses to surgical treatment were overall beneficial. Assays performed using samples stored short- or long-term at -80°C were highly reproducible. CONCLUSIONS: Urinary soluble collagen levels increase concurrently with moderate/severe LUTS, and are stable in urine after long-term storage at -80°C. These findings suggest that urinary soluble collagen levels may serve as suitable diagnostic biomarkers for prostatic collagenization consistent with fibrosis in association with LUTS. Potentially, urinary soluble collagen levels may be used as surrogate endpoint biomarkers to assess the efficacy of anti-fibrotic medical or surgical therapies to decrease prostatic urethral obstruction or resistance, and alleviate LUTS.
Cancer researchAdarsha P Malla, Matthew Flick, Jennifer R Fang, Xiaoxuan Fan, Chixiang Chen, Angad Beniwal, Chris Sereduk, Richard Drexler, Alexandros Poulopoulos, Michelle M…
Glioblastoma (GBM) is a lethal, treatment-resistant brain cancer characterized by diffuse brain invasion, complex neuron-glioma signaling, and cellular, molecular, and spatial heterogeneity. Surgery is the current mainstay of treatment, aimed at maximizing tumor cytoreduction, decompressing the brain to improve neurological function, and providing material for analyses to inform prognostication and adjuvant treatment selection. To accurately model GBM surgical resection and tissue sampling in preclinical animal models, we developed the Maximal Safe Intracranial Surgery (MSIS) system. MSIS integrated a miniaturized neurosurgical resection device and enabled a safe, tunable, and reproducible approach for intracranial tumor resection, multi-regional biopsy, and longitudinal tissue sampling in murine models, with stereotactic, sterile, and high-viability tissue collection. MSIS was applied across five distinct orthotopic brain tumor models to reproducibly generate histologically and radiologically representative models of post-surgical GBM. Similar to humans, increasing the extent of resection correlated with improved animal survival, and recurrent growth patterns varied significantly by model type. Transcriptional profiles of matched primary vs. post-surgical recurrent tumors revealed enrichment of margin-associated transcriptional states consistent with neuron-glioma signaling. Overall, the MSIS system offers opportunities to model the standard-of-care, dissect the spatial and temporal dynamics of GBM, and pair therapeutic discovery with contextual tumor pathobiology.
Chronic oxidative stress (OS) is strongly implicated in the pathobiology of adult-onset schizophrenia, while contributions to childhood- and adolescent-onset schizophrenia (CAOS) have not been extensively investigated. Here we examined abnormalities in peripheral OS markers and associations with symptoms in a large CAOS cohort. Total superoxide dismutase (T-SOD), Mn-SOD, CuZn-SOD, glutathione peroxidase (GSH-Px), thioredoxin peroxidase (TPx), and catalase (CAT) activities as well as the Mn-SOD/T-SOD ratio were measured in plasma samples from 120 CAOS cases and 40 healthy controls (HCs). Psychopathological symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) and cognitive function using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Marker diagnostic performance was assessed by receiver operating characteristic analysis. Patients exhibited significantly lower T-SOD (Cohen's d = 0.56, P = 0.002), Mn-SOD (Cohen's d = 0.67, P < 0.001), and GSH-Px (Cohen's d = 0.55, P = 0.003), reduced Mn-SOD/T-SOD (Cohen's d = 0.36, P = 0.005), and elevated TPx (Cohen's d = 1.00, P < 0.001) versus HCs. Elevated TPx activity was associated with higher PANSS negative symptom score (β=0.220, P = 0.016) and total PANSS score (β=0.220, P = 0.010); a five-factor PANSS analysis further linked TPx to the thought disturbance/disorganization dimension. Unexpectedly, higher TPx was also associated with improved RBANS attention index (β=0.218, P = 0.013) and total score (β=0.192, P = 0.011). Plasma TPx was the strongest diagnostic marker (AUC=0.711), while a combined antioxidant enzyme index (CAEI) improved diagnostic performance (AUC=0.756, sensitivity 83.3%, specificity 60.0%). CAOS patients demonstrated multiple antioxidant enzyme activity abnormalities; TPx correlated with greater negative symptoms but better attention performance. Future studies are warranted to confirm the diagnostic utility of our CAEI.
The Journal of urologyGlenn T Werneburg, Nathan P Goodrich, Victor P Andreev, Aruna Sarma, John T Stoffel, J Quentin Clemens, Anne Cameron
PURPOSE: To evaluate whether OAB subtypes urgency urinary incontinence (UUI) and urgency without incontinence (URG) are associated with vascular comorbidity, erectile dysfunction (ED), and cardiometabolic proteomic profiles. SUBJECTS: and Methods: A secondary analysis of LURN I and II cohorts (controls, URG, UUI) was performed. Vascular comorbidity comprised self-reported angina, congestive heart failure, myocardial infarction, stroke, or peripheral vascular disease. Multivariable regression adjusted for age, sex, and non-vascular comorbidity burden. Serum samples underwent cardiometabolic proteomic profiling. Vascular and non-vascular predictors of 12-month improvement (PGI-I) were evaluated in LURN II (n=581). RESULTS: Among 2,118 participants (268 controls; 1,241 UUI; 609 URG), urgency syndromes had higher odds of vascular comorbidity than controls (OR 3.2, 95% CI 1.7-6.2; p<0.001), similar for UUI and URG. Among 762 men, ED was more prevalent in urgency cases than controls (53% vs. 29%) and highest in UUI (64% vs. 41% in URG). IIEF reduction versus controls was larger in UUI than URG (-5.59, p<0.001 vs. -2.00, p=0.08). Proteomic profiling identified 22 cardiometabolic proteins more abundant in UUI than URG (FDR-adjusted p <0.05), including those involving lipid metabolism (ANGPTL3, APOM) and inflammation (CCL18). None remained significant after FDR correction following adjusting for age, sex, and non-vascular comorbidity burden. Vascular comorbidity was not associated with 12-month improvement; surgery/invasive therapy was. CONCLUSIONS: Urgency syndromes, particularly UUI, are associated with increased vascular comorbidity and erectile dysfunction relative to controls. Cardiometabolic proteomic differences between phenotypes were attenuated after adjusting for demographic and comorbidity factors. These findings support biologic heterogeneity across urinary urgency syndromes and a vascular/cardiometabolic contribution to urgency pathobiology.
Expert opinion on emerging drugsMassimo Imazio, Valentino Collini, Francesco Venturelli, Maria Cristina Tomat, Giulio Savonitto, Davide Stolfo
INTRODUCTION: Although often self-limited, acute pericarditis recurs in up to 30% of patients. Recurrent pericarditis (RP) causes substantial morbidity (pain, fatigue, and impaired quality of life) and can lead to constriction. Traditional treatments have important limitations, including corticosteroid dependence, recurrent flares, and treatment-related adverse effects. Emerging targeted immunomodulators are therefore under active investigation. AREAS COVERED: This review summarizes the burden of pericarditis across etiologies, current therapies, and the global market for pericarditis treatment. We then focus on novel agents in development with an emphasis on phase II/III studies. The pathobiology of pericardial inflammation (notably interleukin (IL)-1 and inflammasome pathways) is discussed as the rationale for targeted drugs. We review key trials of IL-1 inhibitors, NLRP3 inhibitors (VTX2735), and other innovations (e.g. cannabidiol-based CardiolRx). Potential obstacles to development are examined. EXPERT OPINION: Randomized-withdrawal trials support a marked reduction in recurrences with IL-1 blockade in selected patients with inflammatory, colchicine-resistant and corticosteroid-dependent RP. However, open-label enrichment, small samples, short follow-up, uncertain durability after withdrawal, cost, and limited evidence outside idiopathic or post-cardiac injury disease restrict generalizability. New pipeline agents hold promise for broader use, however, remain investigational until controlled trials establish their efficacy and long-term safety.
Biomarker researchYi Chye Law, Jason Yongsheng Chan
Primary central nervous system lymphoma (PCNSL) is a rare aggressive extranodal non-Hodgkin's lymphoma which outcomes remain poor despite therapeutic advances. Recent improvements in our understanding of the molecular diversity of aggressive diffuse large B cell lymphomas suggest that the biological refinement of PCNSL diagnostics may be enabled by an integrated multi-modal approach, augmenting clinical data with modern minimally-invasive liquid biopsy-based assays and multi-omic molecular profiling. Single cell sequencing and spatial imaging technologies dissecting the immune microenvironmental architecture of PCNSL are anticipated to further refine future diagnostics. Concurrently, several innovative strategies featuring immunomodulatory agents, oncogenic kinase inhibitors and immunotherapies including chimeric antigen receptor (CAR) T-cell therapy have emerged. In this review, we provide an update of recent advances in the understanding of the pathobiology of PCNSL focusing on clinically relevant molecular subclassifications, highlight emerging therapeutics, and discuss the translational roadmap to clinical implementation of next-generation diagnostic platforms based on novel technologies.
The Journal of clinical endocrinology and metabolismPeace Asuzu, Frankie Stentz, Chi-Yang Chiu, Jim Wan, Nawajes Mandal, Samuel Dagogo-Jack
CONTEXT: Plasma metabolites have been associated with the development of type 2 diabetes (T2D) and prediabetes. OBJECTIVE: To test the hypothesis that baseline metabolites predict response to lifestyle intervention (LI) in people with prediabetes. DESIGN: Longitudinal cohort study. SETTING: Academic health center. PARTICIPANTS: Adults with prediabetes enrolled in the 5-year Pathobiology and Reversibility of Prediabetes in a Biracial Cohort (PROP-ABC) study. INTERVENTIONS: PROP-ABC participants received LI for 5 years. Assessments included anthropometry, fasting and 2-hr plasma glucose (FPG, 2hrPG), insulin sensitivity and secretion, and plasma metabolites (18 amino acids, 45 acylcarnitines, 54 sphingolipids) measured with liquid chromatography tandem mass spectrometry. MAIN OUTCOME MEASURE: The primary outcome was glycemic response during 5 years of LI. The present report assessed baseline metabolites as predictors of persistent prediabetes versus reversion to normal glucose regulation (NGR) (10 subjects with T2D were excluded). RESULTS: Participants with persistent prediabetes or NGR post-LI showed significant baseline differences in specific metabolites. In logistic regression models, the odds ratio per 1-SD [95% confidence intervals] for persistent prediabetes were 2.405 [1.341-4.312], P = 0.0032 for 2hrPG and 1.850 [1.047- 3.271], P = 0.034 for ceramide C18:0/C18:1 ratio, adjusted for age, sex, race, adiposity, insulin sensitivity and secretion, and percentage changes in weight and waist circumference. CONCLUSIONS: Out of 117 metabolites examined in adults with prediabetes, higher baseline levels of 2hrPG and the saturated/monounsaturated ratio of stearic acid ceramide (C18:0/C18:1) emerged as potential candidate biomarkers for the outcome of persistent prediabetes versus reversion to normoglycemia in response to lifestyle intervention.
Journal of extracellular vesiclesStefanie Kurth, Edveena Hanser, Simone Häner-Massimi, Stavros Giaglis, Florian Geier, Dominik Burri, Katarzyna Buczak, Ute Heider, Stefan Wild, Yves P Acklin, …
Extracellular vesicles (EVs) are emerging as key mediators of disease-associated intercellular communication and as promising biomarker sources across many disease conditions, including joint disorders such as rheumatoid arthritis (RA) and osteoarthritis (OA). Molecular profiling of synovial tissue has uncovered disease-driving cellular states, but tissue biopsies are invasive and not routinely available. EVs in synovial fluid may offer a minimally invasive and complementary window into joint pathobiology. However, the molecular complexity of synovial fluid and the heterogeneity of EV populations have hindered the analysis of defined disease-relevant EV subsets. To address this challenge, we developed a refined size-exclusion chromatography-ultrafiltration (SEC-UF) workflow coupled to magnetic bead-based immunocapture for targeted enrichment of cell type-associated EV subpopulations from arthritic synovial fluid. As proof-of-concept, we targeted a stromal-associated EV population using CD90/THY1, a surface marker expressed by discrete synovial fibroblasts subsets implicated in arthritis pathobiology. In vitro validation using synovial fibroblast-derived EVs confirmed surface-accessible CD90 and demonstrated selective immunocapture of defined EV subpopulations. Application to patient-derived synovial fluid showed that SEC-UF pre-enrichment improves the robustness of CD90+ EV recovery from this complex biofluid. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) profiling established broad EV-associated proteome coverage in synovial fluid (SF)-EV preparations and identified multiple proteins reflecting the inflamed arthritic synovial environment. Fraction-resolved proteomics enabled comparison of the CD90-immunocaptured SF-EV subset with the non-captured CD90-/CD90low SF-EV pool. Differential proteomics and surfaceome-informed cell-of-origin analysis supported enrichment of stromal-associated surface markers in the CD90+ fraction, whereas the non-captured SF-EV pool retained broader immune-associated and residual stromal EV inputs. Together, this fit-for-purpose workflow provides a strategy to resolve EV heterogeneity patient synovial fluid and supports future biomarker-oriented studies of defined subpopulations in arthritic diseases.
Annual review of pathologySaba Tufail, Anindya Dutta
With advances in sequencing technologies and molecular tools, extrachromosomal circular DNA (eccDNA), once considered a mere by-product of genomic instability, is now recognized as playing important roles in genome plasticity, gene regulation, and cancer. In this review, we provide a comprehensive overview of eccDNA from its historical origins to the current state of the field. We distinguish between small eccDNAs and large eccDNAs. Small eccDNAs are usually too small to encode full genes and arise through DNA repair and replication-associated processes, while large eccDNAs carry full genes that drive oncogene amplification and tumor evolution. We summarize the current understanding of their mechanisms of biogenesis, functions, and emerging diagnostic and therapeutic applications. In addition, we discuss the broad spectrum of diseases associated with eccDNA, including cancer and aging-related diseases, as well as recent advances in engineering platforms and computational tools that are transforming our ability to study eccDNA structure and biology.
Antimicrobial resistance (AMR) constrains effective treatment and carries implications for infection control, surveillance, and public health. The World Health Organization (WHO) priority bacterial pathogen framework has intensified the need for diagnostic innovation by redefining research priorities around organisms combining high disease burden with complex resistance profiles. Molecular diagnostics have accordingly moved beyond culture-based workflows, integrating rapid pathogen identification, resistance-marker detection, genomic surveillance, and clinical decision support. The present study conducted a bibliometric mapping of the literature on WHO priority pathogens. Rather than addressing resistance at a general level or a single pathogen or technology, it integrates priority pathogens, molecular platforms, and resistance markers within a single framework, tracing their joint thematic and temporal evolution along an explicit pathogen-platform-marker axis. Scopus-indexed articles and reviews (2000-2025) were retrieved, yielding 1746 publications after screening adapted from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Analyses used Bibliometrix/Biblioshiny, R, and VOSviewer. The literature expanded markedly after 2018, led by China and the United States. Methicillin-resistant Staphylococcus aureus (MRSA), Mycobacterium tuberculosis, Enterococcus faecium, and the Enterobacterales-carbapenemase axis constituted the principal thematic cores, whereas conventional polymerase chain reaction (PCR)/nucleic acid amplification testing (NAAT) and whole-genome sequencing were the dominant platforms. Overall, the field has evolved from pathogen detection into an AMR-centered translational domain encompassing resistance prediction, genomic epidemiology, surveillance, and clinical decision support. Diagnostic development, stewardship, and surveillance depend on hybrid workflows coupling rapid marker-targeted assays with genome-based characterization, delivering actionable resistance within clinically meaningful timeframes, and extending coverage to underrepresented pathogens and platforms.
DrugsMoein Amin, Kaitlyn N Palmer, Amjad Samara, Jeffrey A Cohen
Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disorder of the central nervous system for which more than 20 disease-modifying therapies (DMTs) are currently available. Recent advances in diagnostic criteria, biomarker development, and understanding of disease biology have challenged traditional phenotype-based treatment paradigms and created new opportunities for individualized therapeutic strategies. The 2024 McDonald diagnostic criteria expand the biological definition of MS through incorporation of advanced MRI biomarkers, thereby supporting earlier diagnosis and potentially earlier treatment initiation. Aging influences both disease pathobiology and treatment risk-benefit balance, contributing to reduced focal inflammatory activity, increased progression, diminished regenerative capacity, and greater susceptibility to infections and comorbidities. These observations have important implications for treatment initiation, sequencing, escalation, de-escalation, and discontinuation. Current monitoring strategies remain centered on relapses, disability measures, and MRI lesion activity, but each has important limitations. Emerging imaging and fluid biomarkers, including brain and spinal cord atrophy metrics, neurofilament light chain, glial fibrillary acidic protein, and paramagnetic rim lesions, may improve biological stratification and therapeutic decision making, although further validation is needed. Safety considerations vary substantially across DMT classes. Real-world data have advanced our understanding of long-term risks, particularly with B-cell-depleting therapies. Novel therapeutic approaches in development are intended to more effectively target compartmentalized central nervous system inflammation and progression biology while potentially reducing systemic immunosuppression. As a result of these factors, MS management is evolving.
International journal of nanomedicineMengnan Yuan, Ping Chen, Zibo Zhan, Junqing Ruan, Xuewei Ye, Fangping Lin, Xiaoling Xu
Pulmonary hypertension (PH) is a progressive vasculopathy characterized by pulmonary vascular remodeling, right ventricular maladaptation, and premature death. Exosomes, an endosome-derived subset of small extracellular vesicles, mediate intercellular communication through the transfer of selected RNAs, proteins, and lipids. In PH, they can modulate endothelial dysfunction, pulmonary artery smooth muscle cell proliferation and phenotypic switching, immune dysregulation, and right ventricular remodeling, implicating them in key aspects of disease pathobiology. These properties have prompted interest in exosomes as minimally invasive biomarkers and as candidates for cell-free therapeutic delivery. However, clinical translation remains at an early stage. Most evidence supporting exosome-based therapeutic strategies in PH is preclinical, whereas current clinical data are largely limited to exploratory biomarker studies. Important gaps also remain in distinguishing exosomes from other extracellular vesicle populations and in addressing methodological standardization, heterogeneity, cargo attribution, biodistribution, dosing, and clinical validation. This review summarizes current evidence on exosome biology in PH and discusses both translational opportunities and the major barriers to clinical implementation.
EMBO reportsTao Zhang, Alejandro Herron-Bedoya, María Eugenia Goya, Jorien C van der Weerd, Dikaia Tsagkari, Suzanne Couzijn, Lale Güngördü, Anna P Ainslie, Renée I Seinst…
α-Synuclein (αSyn) inclusions characterize multiple age-related neurodegenerative diseases, including Parkinson's disease (PD). While interactions between αSyn and lipids are known to contribute to αSyn pathobiology, the precise cellular mechanisms linking lipids to αSyn toxicity have yet to be elucidated. Through lipidomic profiling of Caenorhabditis elegans, we find that αSyn progressively alters lipid metabolism in aging worms. αSyn reduces the overall content of triacylglycerols (TAG) and disrupts the structure of lipid droplets (LD) and mitochondria. These pathological changes depend on αSyn's properties to bind lipid and to condensate into inclusions. Apart from lowering TAG levels, αSyn proportionally increases long-chain unsaturated fatty acids (LCUFAs). Consequently, genetic inhibition of LCUFA biosynthesis alleviates αSyn-induced loss of C. elegans motility. Supplementing Medium-Chain Triglyceride (MCT) on the other hand also improves αSyn-associated toxicity phenotypes. These results link αSyn lipid binding and condensation to impaired TAG metabolism, which drives cellular toxicity. Combined with observed lower plasma TAGs in Parkinson cohorts, our findings reveal contributions of TAG remodelling to αSyn toxicity and point at MCT-supplementation as a mechanism-based therapeutic opportunity in age-related synucleinopathies.
Lactate is frequently measured in patients with acute kidney injury (AKI), but its interpretation remains challenging because circulating lactate reflects systemic metabolic stress rather than kidney injury. Although elevated lactate levels are associated with adverse outcomes in critically ill patients with AKI, its biological and clinical significance varies according to disease context, timing, and the clinical question being addressed. This structured expert narrative review integrates mechanistic insights and clinical evidence to establish a context-dependent framework for interpreting lactate in AKI. We summarize the role of the kidney in lactate metabolism and discuss how impaired renal function, altered perfusion, mitochondrial dysfunction, and immune-metabolic remodeling contribute to lactate accumulation. We further evaluate clinical evidence regarding lactate in AKI risk assessment, severity evaluation, organ-support requirement, and mortality prediction, while emphasizing limitations related to confounding factors and clinical heterogeneity. Emerging clinical contexts, including extracorporeal membrane oxygenation-supported patients, are also considered. Overall, this framework supports a more precise interpretation of lactate as a context-dependent risk marker and metabolic signal rather than a kidney-specific biomarker.
Medical science monitor : international medical journal of experimental and clinical researchQian Luo, Donggan Jin, Zhenying Zhan
Central nervous system demyelinating disorders differ substantially in pathobiology, reversibility, and capacity for tissue repair. Disease-modifying therapies can suppress inflammatory activity in multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD), but they do not replace lost oligodendrocytes or reliably reverse established neuroaxonal injury. Stem cell-based strategies therefore pursue distinct therapeutic goals, including immune reconstitution, paracrine immunomodulation and neuroprotection, direct cell replacement, remyelination, and correction of defined genetic defects. Autologous hematopoietic stem cell transplantation (AHSCT) currently has the most mature clinical evidence, particularly for carefully selected patients with highly active relapsing MS despite high-efficacy therapy, but its benefit is mediated primarily through immune ablation and reconstitution rather than direct remyelination. Mesenchymal stromal cell (MSC) approaches remain investigational because controlled trials have not established consistent efficacy and intrathecal delivery has raised route-specific safety concerns. MSC-derived extracellular vesicles and induced pluripotent stem cell (iPSC)-derived oligodendrocyte or neural progenitor products remain preclinical or early translational approaches for acquired demyelinating disease, whereas gene-modified hematopoietic stem cells have a distinct role in selected inherited leukodystrophies. Translation across these platforms is additionally constrained by product heterogeneity, potency assessment, manufacturing reproducibility, long-term safety, regulation, scalability, access, and the need for mechanism-matched clinical endpoints. This article aims to critically review the clinical evidence, therapeutic niches, safety considerations, and translational boundaries of stem cell-based therapies for central nervous system demyelinating diseases, with particular emphasis on MS and NMOSD.
Lab on a chipTwinkle Jina Minette Manoharan, Kalpana Ravi, Shwetal Mehta, Mehdi Nikkhah
Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor in adults, characterized by rapid progression and poor prognosis. Central to GBM pathobiology are glioma stem cells (GSCs), which preferentially localize within the perivascular niche (PVN) and sustain tumor growth, invasion, and therapeutic resistance through dynamic interactions with the surrounding PVN microenvironment. Notably, microglia (MG), the brain-resident immune cells, represent a substantial fraction of the GBM PVN and play a pivotal role in establishing an immunosuppressive tumor microenvironment (TME). However, the mechanisms by which MG interacts with the brain PVN and how this, in turn, regulates GSC behavior remain poorly understood. To systematically investigate these complex cellular interactions, herein we engineered a compartmentalized human GBM PVN-on-a-Chip (GPoC) model featuring a perfusable brain microvascular network surrounding a tumor core composed of patient-derived GSCs and a stromal region containing brain-resident MG. The presented biomimetic 3D model recapitulates the structural and functional features of the native PVN, enabling well-controlled experimental interrogation and spatial visualization of tumor-immune-vascular crosstalk. Through invasion assay, real-time live imaging, immunofluorescent staining, and secretome profiling, it was evident that the GSC cells exhibited enhanced invasion in the presence of both MG and vasculature. Furthermore, pharmacological intervention studies revealed attenuated GB3 migration under tri-culture conditions, highlighting that the migratory phenotype of the tumor cells is, in part, driven by MG. Overall, the engineered GPoC platform serves as a physiologically relevant human brain tumor model for dissecting MG-mediated mechanisms and advancing therapeutic targeting of the GBM microenvironment.
Journal of forensic and legal medicinePriyanshi Gangwal, Siva Sai Kumar Pulagura, Vikas Meshram, Rohit Singh Jaggi, Sudeep Khera
Hypertrophic obstructive cardiomyopathy (HOCM) is one of the common causes of sudden cardiac death which can be associated with pulmonary vascular remodelling changes also known as Pulmonary Arteriopathy (PA). Pulmonary Arteriopathy (PA) is a condition affecting the pulmonary arteries, characterised by a range of proliferative and obstructive vascular lesions that ultimately result in lumen obstruction. It may manifest under diverse settings, encompassing both acquired and congenital disorders. We present a case of a 52-year male with no previous known history of illness or disease, who was brought to the Emergency department and was pronounced dead upon arrival. During the autopsy, the heart exhibited left ventricular thickness (3 cm thick) and the interventricular septum thickness (2.5 cm thick). Histopathological examination revealed localised myocardial disarray, muscle fibre hypertrophy, and nuclear enlargement, indicative of left heart disease characterised by left ventricular hypertrophy. The histopathological examination of the both lungs revealed that the blood vessels exhibited thickened walls, characterised by medial wall hypertrophy, manifesting as muscularization suggestive of Grade 2 Pulmonary Arteriopathy (PA). This case examines the pathophysiological mechanisms connecting the characteristics of cardiomyopathy, pulmonary arterial hypertension, and pulmonary arteriopathy, thereby emphasising the significance of pulmonary vascular alterations as a consequence of HOCM but also as a sign of disease progression. Other causes of pulmonary arteriopathy along with advanced ageing should be ruled out in such cases.
Journal of the American Heart AssociationMia Y Buck, Caroline G Pass, Jaewon Choi, Divyansha Moparthy, Nathan H Law, Terence E Ryan
BACKGROUND: Peripheral artery disease is a major manifestation of atherosclerotic cardiovascular disease (ASCVD) that affects both men and women. In women, menopause increases the ASCVD risk. However, preclinical ASCVD research has historically been conducted predominantly in men, with relatively few studies focused on women and even fewer incorporating menopause models that more closely reflect human ASCVD pathobiology. Herein, we tested whether the chemical 4-vinylcyclohexene diepoxide (4-VCD)-induced ovarian failure or ovariectomy would drive atherosclerotic development and worsen ischemic limb pathophysiology. METHODS: Female C57BL/6J mice were injected with adeno-associated virus-mediated encoding a gain-of-function mutant PCSK9 (proprotein convertase subtilisin/kexin type 9) and fed an atherogenic diet for 23 weeks. Based on the baseline body weight, mice were randomly assigned to normally cycling controls, 4-VCD, or ovariectomy groups. Three weeks after the conformation of ovarian failure (4-VCD) or surgical ovarian removal (ovariectomy), hindlimb ischemia was induced via femoral artery ligation, and limb perfusion recovery and limb muscle performance were assessed. RESULTS: Both 4-VCD treatment and ovariectomy reduced uterus mass, without affecting body weight or composition, or circulating cholesterol levels compared with control mice. Despite the similar metabolic and cholesterol profiles, atherosclerotic lesion areas were 1.5 to 1.7-fold greater in 4-VCD and ovariectomy mice than control mice. Perfusion recovery following hindlimb ischemia and plantar flexor muscle function in the ischemic limb were similar across groups, though muscle oxygenation was reduced in 4-VCD and ovariectomy groups. CONCLUSIONS: Ovarian failure and removal exacerbated atherosclerotic development but had minimal impacts on perfusion recovery and limb function following hindlimb ischemia. These findings confirm the inclusion of menopausal models, whether through ovarian failure or ovariectomy, should be carefully considered to improve translatability of preclinical ASCVD studies, especially for women's health.
bioRxiv : the preprint server for biologyAline C Oliveira, Filipe da Silva, Yutao Zhang, Matthew D Alves, Ann T Pham, Charlotte Harris, Sultan Khanfar, Rafael Abdelnor, Jimena Alvarez-Castanon, Caroli…
BACKGROUND: Pulmonary hypertension (PH) is a progressive and fatal disease characterized by pulmonary vascular remodeling, inflammation, and immune dysregulation. Myeloid-derived suppressor cells (MDSCs) and macrophages contribute to PAH pathobiology; however, the molecular regulators of their pathological activation remain poorly defined. The triggering receptor expressed on myeloid cells 2 (TREM2) is an immunomodulatory receptor that shapes myeloid cell metabolism, survival, and immunosuppressive function, yet its role in PAH has not been investigated. METHODS: Single-cell RNA sequencing (scRNA-seq) data from human pulmonary artery tissue (GSE210248; n=3 PAH, n=3 donors) were analyzed to characterize TREM2 expression across cell populations. Wild-type (WT) and global TREM2 knockout (TREM2 KO) mice were exposed to chronic hypoxia (10% FiO2, 28 days). Hemodynamic, histological, flow cytometric, and ex vivo functional assessments were performed. TREM2 protein expression was measured by flow cytometry in circulating MDSCs from PAH patients (n=22) and healthy controls (n=13). RESULTS: TREM2 was markedly enriched in monocyte/macrophage (mono/macs) populations in PAH pulmonary arteries, with co-upregulation of APOE, GPNMB, and CSF1R. TREM2-high immune cells exhibited transcriptional downregulation of chemotaxis programs and upregulation of antigen processing and MHC II presentation pathways. TREM2 deficiency significantly attenuated hypoxia-induced RVSP increase, right ventricular dysfunction, pulmonary inflammation, and vascular remodeling. TREM2 KO mice showed blunted mTOR/p-S6 activation in bone marrow myeloid populations and MDSCs from TREM2 KO mice exerted significantly less suppression of CD4+ and CD8+ T cell proliferation. TREM2 KO mice tended to preserve bone marrow CD4+ T cell proportions and significant upregulation of CD62L on T cells under hypoxia. TREM2 was significantly elevated in circulating MDSCs from PAH patients and showed a directional association with hemodynamic severity. CONCLUSIONS: TREM2 is a novel regulator of myeloid-driven immunosuppression and vascular remodeling in PAH and warrants investigation as a therapeutic target and biomarker.
BACKGROUND: Whole slide imaging (WSI) has emerged as a key component of digital pathology, enabling remote diagnostics and standardized evaluation. However, its diagnostic concordance in thyroid cytopathology, particularly under real-world conditions, remains insufficiently validated. METHODS: In this retrospective pilot study, thirteen thyroid cases were evaluated using both conventional light microscopy and WSI. One pathologist performed glass slide evaluation, while two independent pathologists assessed the corresponding digital slides remotely. All evaluations were conducted in a blinded manner. Diagnostic agreement was analyzed using percentage concordance and Cohen's kappa coefficient. RESULTS: The overall concordance rate between conventional microscopy and WSI was 69.2%. Cohen's kappa values ranged from 0.58 to 0.63, indicating moderate to substantial agreement. Full concordance was observed in 7 cases, predominantly among malignant diagnoses. Partial concordance occurred in 5 cases, mainly involving borderline categories. Complete discordance was identified in 1 case, exclusively within an indeterminate cytological category. No clinically significant misclassification between benign and malignant diagnoses was observed. CONCLUSION: WSI demonstrated moderate diagnostic agreement with conventional microscopy in well-defined thyroid cytopathology categories. However, variability remains more pronounced in indeterminate cases, reflecting inherent diagnostic challenges. These findings support the preliminary feasibility of WSI in real-world and remote diagnostic workflows, although larger, multicenter studies are required to confirm these results.
Proceedings of the National Academy of Sciences of the United States of AmericaMichael Cheng, Claire M Storey, Mohamed Altai, Julie E Park, Julie Tran, Smiths S Lueong, Daniel Thorek, Liqun Mao, Wahed Zedan, Constance Yuen, Alexander Ridl…
Transforming growth factor-beta (TGFβ) has dual roles in cancer, initially suppressing tumors but later promoting metastasis and immune evasion. Efforts to inhibit TGFβ have been largely unsuccessful due to significant toxicity and indiscriminate immunosuppression. Leucine-rich repeat-containing protein 15 (LRRC15) is a TGFβ-regulated antigen expressed by cancer cells of mesenchymal origin and cancer-associated fibroblasts (CAFs). In preclinical studies, ablation of TGFβ-driven LRRC15+ CAFs enhances effector functions of CD8+ T cells. However, the pathobiological mechanisms associated with TGFβ's upregulation of LRRC15 expression in cancer cells remain unclear. Using an integrated approach combining functional compound screening with scRNA-seq, we reveal key genomic features regulating TGFβ's ability to increase LRRC15 expression on cancer cells. Construction of gene regulatory networks converged our analyses on four key genes (MMP2, SPARC, TGFβR2, and WNT5B) central to TGFβ-induced LRRC15 pathobiology in cancer cells. Validation of these genes in cell models and their use in predicting immunotherapy responses highlight their potential in refining immunotherapy strategies and personalizing cotreatment options.
Frontiers in veterinary scienceGyu-Seo Bae, Eunsu Jeon, Joonwon Mo, Ju-Yeon Lee, Ja Rang Lee, Jung Joo Hong, Dong-Ho Lee, Bon-Sang Koo
Recent outbreaks of emerging infectious diseases, along with advances in neurological and other biomedical research, have increased the use of non-human primates (NHPs) as preclinical models. Their close phylogenetic and physiological similarities to humans make them valuable for translational research, especially during public health emergencies. However, NHPs can harbor a wide range of viral pathogens, some of which pose zoonotic risks and may compromise animal health and experimental reproducibility. Therefore, quarantine procedures, pathogen surveillance, and biosecurity programs are essential for the safe and reliable use of NHPs in research. Despite this need, comprehensive reviews linking national quarantine policies with the biological and epidemiological characteristics of major viral pathogens and their relevance to disease surveillance and control remain limited. This review compares national quarantine frameworks for NHPs, examines pathogen-specific features, and discusses their implications for quarantine and surveillance. We emphasize the need for an integrated, risk-based approach incorporating longitudinal microbiological monitoring, multimodal diagnostic assessment, facility-level response procedures, occupational health preparedness, and internationally harmonized quarantine standards.
European radiology experimentalDominic Gascho, Marco Palmesino, Michael Josef Thali, Edda Emanuela Guareschi
Postmortem imaging has become an integral component of modern forensic pathology, with postmortem computed tomography (PMCT) and magnetic resonance (PMMR) imaging now routinely supplementing or, in selected cases, partially replacing conventional autopsy. Despite these advances, postmortem imaging remains predominantly static, capturing anatomy and injuries at a single point in time after death. In contrast, clinical radiology has increasingly embraced four-dimensional (4D) imaging approaches that incorporate time as a diagnostic dimension, enabling the assessment of motion, functional change, and dynamic processes. This narrative review with a conceptual perspective explores whether and how 4D concepts can be meaningfully translated into postmortem forensic imaging. By reviewing simulated motion models, multiphase PMCT angiography, ventilated PMCT, serial documentation of postmortem biological and physical processes, fracture mechanics research, and PMMR spectroscopy, it can be argued that time is already an implicit diagnostic dimension in forensic radiology. Although true real-time 4D imaging of the deceased remains technically limited, existing studies demonstrate that temporal reconstruction through controlled simulation and serial acquisition is feasible and forensically relevant. Embracing 4D thinking may allow postmortem imaging to evolve from static documentation toward a more process-oriented tool for reconstructing events and mechanisms leading to death. KEY POINTS: Question Can postmortem imaging provide time-related information that is already present after death? Findings 4D PMMCT and PMMR introduce time as an explicit element, allowing postmortem imaging to capture dynamic and evolving processes. Relevance statement This review highlights the emerging role of time-resolved ("4D") approaches in postmortem imaging, demonstrating how integrating temporal information can enhance reconstruction of injury mechanisms, postmortem processes, and medicolegal interpretation, thereby expanding forensic radiology beyond static documentation toward process-oriented forensic investigation.
Circulation. Heart failureMinkwan Kim, Vinayak Subramanian, Hamed Tavolinejad, Mateo Sarmiento Bustamante, Bianca Pourmussa, Douglas L Mann, Ali Javaheri, A Mark Richards, Robert N Doug…
BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP) is common in heart failure with preserved ejection fraction (HFpEF). However, the proteomic signatures linked to CHIP driver mutations and their prognostic implications in HFpEF remain poorly defined. We aimed to identify plasma protein signatures associated with CHIP driver mutations and to develop and externally validate a CHIP-proteomic risk score (CHIP-ProtRS) for predicting clinical outcomes in HFpEF. METHODS: The derivation cohort consisted of 118 TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) participants with available CHIP sequencing and proteomic profiling using the SomaScan platform. Associations between CHIP mutations and circulating proteins were assessed using gene-specific linear regression adjusted for age, with correction for multiple comparisons. Significant proteins were used to derive gene-specific proteomic classifiers using nested cross-validated least absolute shrinkage and selection operator logistic regression. A composite CHIP-ProtRS was generated using least absolute shrinkage and selection operator Cox regression and validated in a composite of 3 independent HFpEF cohorts (n=654). The primary end point was a composite of death and HF hospitalization. RESULTS: In TOPCAT, 30.5% of tested participants carried ≥1 CHIP mutation. Significant protein associations were identified for TET2 (7 proteins), DNMT3A (10), and PPM1D (5), all of which were enriched in immune and inflammatory pathways. Gene-specific least absolute shrinkage and selection operator models showed good discrimination for CHIP mutation (area under the curves, 0.752-0.898). The primary end point occurred in 28.0% of the derivation cohort and 34.7% of the validation cohorts. In the Cox-least absolute shrinkage and selection operator combination, only the TET2-derived proteomic signature retained a nonzero coefficient in the CHIP-ProtRS. The CHIP-ProtRS was independently associated with the primary end point after adjustment for age, sex, Meta-Analysis Global Group in Chronic Heart Failure score, NT-proBNP (N-terminal pro-B-type natriuretic peptide), and atrial fibrillation in the derivation (adjusted hazard ratio, 1.42 [95% CI, 1.01-2.00]) and validation cohorts (adjusted hazard ratio, 1.16 [95% CI, 1.01-1.32]). CONCLUSIONS: CHIP is associated with alterations in plasma concentrations of immune/inflammatory proteins. A CHIP-ProtRS is independently associated with adverse outcomes in HFpEF, supporting its potential role as a biomarker of risk and underlying pathobiology.
Peripheral venous disease represents one of the most prevalent and most persistently undertreated chronic conditions in adult populations, with venous leg ulceration standing at the severe end of a spectrum that also includes symptomatic chronic venous insufficiency and superficial venous thrombosis. The venous wound microenvironment is shaped by mechanisms that are largely specific to this etiology, including ambulatory venous hypertension, erythrocyte extravasation with cutaneous iron deposition, sustained oxidative stress, proteolytic imbalance and fibroblast senescence. Hydrogels, as three-dimensional hydrophilic polymer networks with high water content, tunable mechanics and versatile payload capacity, offer an appealing platform for addressing several of these mechanisms simultaneously. The preclinical literature is correspondingly abundant. The clinical evidence base, however, remains thin and inconclusive, and the most rigorous synthesis available has been unable to establish whether hydrogel dressings outperform simpler alternatives in venous ulcer healing. This review examines that discrepancy rather than setting it aside. We summarize the physicochemical properties that determine hydrogel performance specifically under compression and in a heavily exudating wound, map hydrogel mechanisms of action onto venous pathobiology, survey therapeutic applications across the venous spectrum, including topical formulations for superficial venous thrombosis, and appraise the preclinical and clinical evidence with attention to why translation has stalled. We conclude by proposing design criteria for venous-specific hydrogel systems and methodological priorities for the trials needed to test them.
Experimental neurologyKabiru Shehu, Onyinoyi B Onimisi, Habibu A Bunza, Sirajo M Umar, John C Oyem, Timileyin A Adewumi
Recent evidence suggests that prenatal environmental factors, particularly maternal infection or maternal immune activation (MIA), may influence the progression of brain aging and lifetime risk for neurodegenerative disorders. The hypothesis is that even a short-lived inflammatory event during pregnancy may leave a lasting imprint on the developing brain and immune system of the fetus, such that aging or subsequent insults may later unmask neurodegenerative disorders. Support for this hypothesis comes largely from animal studies, where gestational inflammation has been shown to potentiate the onset of Alzheimer's and Parkinson's diseases (AD/PD), by increasing amyloid/tau pathology, reducing synaptic connections, and damaging nigrostriatal dopaminergic neurons. We review convergent mechanisms, including microglial priming, chronic cytokine excess, oxidative stress, epigenetic marks and proteostatic deficits, through which maternal immune activation may embed a latent "hit" that synergizes with aging to precipitate AD or PD. Furthermore, we appraise experimental models and available human data linking MIA to AD versus PD, noting shared and distinct pathways. Despite growing preclinical evidence, translation to human cohorts remains limited by heterogeneity in MIA exposure timing and outcome measures. An understanding of MIA's impact on neurodegeneration could suggest preventive strategies and interventions for early diagnosis and treatment.
The revised ALS Functional Rating Scale (ALSFRS-R) and the blood plasma accumulation of neurofilament light chain (NfL) are key markers for tracking amyotrophic lateral sclerosis (ALS) progression. Based on recent studies indicating that dietary supplementation with conjugated linoleic acid (CLA) may boost antioxidant enzyme activity in ALS patients, in this study, ALSFRS-R scores (and subscores), NfL and thiol-bound protein (P-SH) levels, and intracellular activity of antioxidant enzymes (G6PD and GSR) were measured in ALS patients after 6 months (T6) of treatment with riluzole (R) or riluzole + CLA (R + CLA); we also investigated the correlations between these markers. At baseline (T0), G6PD activity in the R group was positively correlated with ALSFRS-R score (p < 0.001), whereas plasma P-SH levels in the R + CLA group were inversely correlated with ALSFRS-R score (p = 0.033). No significant baseline association was found between NfL levels and total ALSFRS-R score in the R group. At six months (T6), GSR and G6PD activities in the R + CLA group were significantly higher than in the R group (p < 0.05). Furthermore, a significant inverse correlation between plasma NfL levels and ALSFRS-R total score emerged at T6 exclusively in the R group (p = 0.002). Subscore analysis at T6 showed that plasma NfL levels negatively correlated with bulbar function in both groups (R: p = 0.010; R + CLA: p = 0.020) and with fine motor function in the R group (p = 0.031); whereas no significant correlation was observed for the respiratory subscore in either treatment group. These findings are consistent with an enhanced antioxidant activity associated with CLA supplementation. Overall, these preliminary exploratory results suggest that systemic redox biomarkers and plasma NfL may provide complementary, non-redundant information on distinct aspects of ALS pathobiology, though their precise temporal and mechanistic interactions require confirmation by dedicated longitudinal studies. The need for the combined use of neurodegeneration and oxidative-stress biomarkers for monitoring the progression of ALS is highlighted.
International journal of molecular sciencesChung-Lin Lee, Chih-Kuang Chuang, Ya-Hui Chang, Huei-Ching Chiu, Yuan-Rong Tu, Yun-Ting Lo, Jun-Yi Wu, Huang-Ying Huang, Hsiang-Yu Lin, Shuan-Pei Lin
Inherited mitochondrial cardiomyopathies arise from pathogenic variants affecting oxidative phosphorylation, mitochondrial DNA maintenance, cardiolipin remodeling, protein import, cofactor metabolism, and mitochondrial dynamics or proteostasis. These disorders may be cardiac-predominant or part of multisystem disease. Their overlapping cardiac phenotypes suggest convergence on interacting pathways of energetic stress, cristae disruption, calcium imbalance, and redox injury, but do not establish a universal requirement for defective mitophagy. Mitochondrial quality control encompasses protein surveillance, membrane remodeling, dynamics, biogenesis, and organelle disposal; mitophagy is one component. We critically examine the hypothesis that inadequate clearance of damaged mitochondria contributes to progression in a subset of genotypes and disease stages. Disease-specific studies provide support in selected Barth syndrome models, whereas findings in frataxin deficiency vary with model and assay. We distinguish mitochondrial delivery to lysosomes, dynamic turnover measurements, and changes in pathway markers, and identify indirect evidence from acquired heart disease and fatty acid oxidation deficiency. Therapeutic evidence is separated into cellular, animal, and human studies and approved indications. Elamipretide has accelerated approval for muscle-strength improvement in patients with Barth syndrome weighing at least 30 kg; cardiac disease modification remains unconfirmed. Gene replacement has reached early clinical testing, including adeno-associated virus-mediated frataxin gene delivery (AAV-FXN), whereas mitochondrial genome editing and selective mitophagy modulation remain investigational. We propose testable predictions addressing progression, selective rescue, and treatment timing, together with outcomes that would challenge the hypothesis. This framework supports genotype- and stage-specific investigation without assuming that enhanced mitophagy will benefit every mitochondrial cardiomyopathy.
Metabolic brain diseaseS T Gopukumar, Madhumita Saha, Tanveen Kaur Soni, Eid Semer Alatwi, Gazala Afreen Khan, Mohammad Rehan Asad, Samer Shamshad, Sunil Tadakod, Alok Sharma, Uddala…
Autism Spectrum Disorder (ASD) is a genetically heterogeneous neurodevelopmental condition in which hundreds of individually rare risk variants converge on a small number of shared biological pathways, including synaptic scaffolding, chromatin remodeling, excitation-inhibition balance, and cellular energy metabolism. Translating this genetic heterogeneity into mechanistic insight requires experimental systems capable of interrogating individual gene functions in human-relevant neural contexts at scale. CRISPR-enabled functional genomics in human pluripotent stem cell (hPSC)-derived neural models, spanning neural progenitors, cortical and inhibitory neurons, astrocytes, microglia, and brain organoids, provides precisely this capability. By integrating pooled perturbation screens with multimodal readouts including single-cell and spatial transcriptomics, chromatin accessibility profiling, proximity labeling proteomics, multi-electrode array electrophysiology, and metabolic flux analysis, these platforms enable systematic, causal mapping of ASD gene function at system resolution. Early applications have already revealed convergent mechanisms: BAF complex disruption expands the ventral progenitor pool and biases its fate toward oligodendrocyte and interneuron lineages; ADNP loss impairs microglial synaptic pruning through altered endocytic trafficking; and mTOR pathway dysregulation in PTEN- and TSC2-perturbed models links genetic risk directly to metabolic and mitochondrial dysfunction. Computational frameworks including MIMOSCA and SCEPTRE enable causal network reconstruction and pseudotime inference from these datasets, moving the field from gene lists toward pathway-level models of ASD pathobiology. Translational applications leverage isogenic iPSC panels and variant-level base and prime editing to stratify ASD variants by functional impact, informing gene therapy design for haploinsufficient targets such as CHD8 and SCN2A via AAV or antisense oligonucleotide delivery. Remaining challenges, including model developmental immaturity, batch variability, and the difficulty of modeling polygenic risk, are addressed by a roadmap integrating spatial perturbomics, AI-driven causal inference, and population-scale standardized biobanks. This review synthesizes the current state of CRISPR-based functional genomics in human stem cell neural models as a coherent experimental framework for converting ASD genetic associations into mechanistic understanding and therapeutic opportunity.
Reproductive medicine and biologyJan Gruszczyński, Kacper Trębacz, Beata Kubiaczyk-Paluch, Grzegorz Dworacki, Michał J Dopierała, Agata Kolecka-Bednarczyk, Andrzej Frankowski, Miłosz Kadziński…
PURPOSE: Histopathological assessment of plasma cells (PCs) via CD138 immunohistochemistry, the diagnostic gold standard for chronic endometritis (CE), is methodologically heterogeneous. Does reported variation in CE prevalence reflect underlying pathobiology, or is it primarily an artifact of counting methodology? We quantified how HPF selection strategy, field count, and magnification influence observed prevalence. METHODS: We retrospectively studied 886 treatment-naïve patients suspected of CE. CD138-stained biopsies were digitized; a three-pathologist consensus reference validated an AI pipeline for PC detection. Four counting methods were applied across two magnifications (200× vs. 400×) and multiple thresholds. RESULTS: Inter-observer reliability was higher for digital (ICC = 0.99) than microscopy-based assessment (ICC = 0.73). The AI pipeline (F1: 0.89-0.97) outperformed manual microscopy (F1: 0.67-0.89) and matched digital assessment (F1: 0.81-1.00). At a fixed threshold and field count (≥ 5 PCs, ×400, 10 HPFs), field-selection strategy alone shifted prevalence from 3.1% (Random Sampling) to 69.5% (Independent Hotspot), p < 0.001. Magnification also significantly altered CE classification (p < 0.001). CONCLUSIONS: Diagnostic threshold alone does not fully specify a CE criterion; field-selection strategy, field count, and magnification must also be reported for prevalence estimates to be comparable. Hotspot-based and AI-assisted counting are recommended over random field selection for reproducibility and sensitivity.
Acta neuropathologicaCeleste Laureyssen, Dietmar Rudolf Thal, Kristel Sleegers
Alzheimer's disease (AD) and overlapping pathologies represent a growing worldwide health concern. With the first disease-modifying treatments on the rise, it becomes increasingly important to move research in this area forward. Genetic research is excellent at discovering novel contributors to disease mechanisms, which has been demonstrated by the discovery of over 75 disease loci associated with AD. However, classical large-scale genome-wide association studies (GWAS) use cohorts of individuals that have been assigned a case or a control status based on a clinical diagnosis. For AD, this can result in bias due to the complex nature of the disease profile. More specifically, on the neuropathological level, AD is multifaceted with co-morbid pathological lesions being the norm rather than the exception. Together with the substantial preclinical phase, this can lead to the introduction of type I and type II errors. An alternative to using large-scale clinical cohorts is to shift toward studying individuals where the disease diagnosis has been neuropathologically confirmed, or cohorts where an endophenotype is used which can directly reflect ongoing pathological processes in vivo. Such endophenotypes could entail biofluid or imaging-based biomarkers, but the most undiluted signal is obtained when employing neuropathological data. These data typically represent the presence or absence of a lesion or reflects the semi-quantitative burden of pathological features. Here, we review what this shift toward more detailed phenotypes has already contributed to the field by investigating the genetic background of AD hallmark lesions as well as commonly observed co-pathologies.
Post-tuberculosis lung disease (PTLD) encompasses a spectrum of chronic pulmonary abnormalities arising from tuberculosis (TB)-associated tissue injury and maladaptive repair, and is emerging as a major contributor to long-term respiratory disability among TB survivors. In this review, we position PTLD within the broader continuum of TB pathobiology, from initial host-pathogen interactions to chronic structural and functional lung sequelae. We examine current definitions, epidemiology, and clinical burden, and present mechanistic insights into the inflammatory, proteolytic, fibrotic, immunometabolic, and vascular pathways that drive persistent lung damage. We further discuss the heterogeneous clinical phenotypes of PTLD, including airflow obstruction, bronchiectasis, restrictive lung disease, pleural complications, chronic pulmonary aspergillosis, and nontuberculous mycobacterial disease, highlighting practical approaches to diagnosis, risk stratification, and management across diverse healthcare settings. We discuss PTLD in children and adolescents, prevention opportunities throughout the TB care cascade, and health-system strategies for integrating post-TB care. Finally, we identify key knowledge gaps in PTLD nosology, biomarkers, therapeutic development, clinical trial design, and implementation science. Recognition of PTLD as a continuation rather than an endpoint of TB is essential for advancing survivorship-focused care and reducing the global burden of chronic respiratory disease after TB.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapieYing Huang, Yingping Deng, Jing Tang, Juan Wang
Pterygium is a common ophthalmic disease characterized by proliferative tissue extending from the bulbar conjunctiva to the cornea, which may gradually affect vision. Contemporary reconstructive surgery-particularly conjunctival limbal autograft (CLAU), which restores the limbal stem cell niche-has achieved excellent outcomes, with recurrence rates below 2% in specialized practice. Nevertheless, surgical excision remains inherently invasive, requires substantial operator expertise and autologous grafting, and cannot reverse the underlying ultraviolet-induced limbal progenitor cell damage or prevent de novo lesion formation. These limitations have driven growing interest in pharmacological strategies that intervene before irreversible structural damage occurs. This article reviews the pathogenesis of pterygium and current therapeutic practice. We critically analyze the benefits and limitations of surgical intervention, examine the mechanistic rationale for pharmacological targets, and evaluate drug repurposing and drug delivery systems as complementary avenues. Pharmacotherapy may offer advantages beyond surgery, including non-invasive early intervention before pterygium reaches surgical threshold, reduced dependence on operator expertise and facility resources, adjuvant suppression of residual disease activity after excision, and a safe therapeutic alternative for patients who are unsuitable for or decline invasive surgery. We believe these efforts will pave the way for safer, more effective, and precision-based treatment options for pterygium.
VirusesQingli Yang, Lijing Ye, Liting Wang, Yi Zhang, Yi Zhu, Jun Shen
Background: Fulminant myocarditis (FM) is a life-threatening inflammatory cardiac disease in children, frequently triggered by viral infections. Although mechanical circulatory support has improved short-term survival, data on viral etiology and long-term outcomes remain limited, particularly in Asian populations. Methods: We conducted a mixed retrospective-prospective analysis of pediatric FM patients at the Children's Hospital of Fudan University from 2015 to 2025. Clinical data from 2015 to 2023 were collected retrospectively, while data from 2024 onward were collected prospectively. Clinical data, microbiological findings (PCR and metagenomic next-generation sequencing), treatment strategies, and outcomes were extracted from electronic medical records. Follow-up data for survivors were collected through December 2025. Results: A total of 53 children with FM were included. Median age was 91.5 months; 43.4% were male, and 56.6% were female. Common presenting symptoms included fever (64.2%) and vomiting (56.6%). Microbiological evidence was identified in 11 patients (20.8%), with rhinovirus (5.7%) and influenza virus (5.7%) being the most frequent, followed by enterovirus (3.8%) in peripheral specimens. During hospitalization, 79.2% required mechanical ventilation, 64.2% received extracorporeal membrane oxygenation (ECMO), and 45.3% underwent continuous renal replacement therapy (CRRT). Intravenous immunoglobulin (IVIG) was administered to 84.9%. In-hospital mortality was 13.2% (7/53), and 17.0% (9/53) of patients were discharged against medical advice (DAMA). Among 35 followed patients (median 12.4 months), most achieved favorable cardiac recovery; however, persistent conduction abnormalities, structural cardiac changes, and neurological sequelae were observed in a minority. Conclusions: Pediatric FM carries substantial in-hospital morbidity and resource utilization, despite favorable recovery rates in most survivors. The low pathogen detection rate in peripheral blood and the lack of endomyocardial tissue sampling preclude definitive conclusions regarding the underlying etiology, whether active viral replication or immune-mediated injury predominates. Endomyocardial biopsy-based investigations are urgently needed to clarify the underlying pathobiology.
Journal of inflammation researchWenjun Wu, Xue Li, Rui Yu, Bin Li, Xinlu Wang, Jingjing Wei, Mingjun Zhu
Viral myocarditis (VMC) is a heterogeneous inflammatory myocardial disease initiated by viral infection and sustained by dysregulated innate and adaptive immunity. Its progression can be viewed as a stage-dependent continuum: virus-triggered macrophage and T-cell dysregulation initiates immune-inflammatory amplification; oxidative stress and autophagy-lysosomal dysfunction further intensify myocardial injury; and these processes ultimately converge on cardiomyocyte death and fibrotic remodeling. We conducted a structured narrative review of relevant clinical and preclinical studies identified through major English- and Chinese-language databases and reference-list screening. Distinct from previous reviews that mainly catalogued individual pathways or interventions, this review integrates disease-stage-specific pathobiology, evidence hierarchy, and translational readiness within a unified framework. Among clinically evaluated interventions, Huangqi-based preparations and Qidong Yixin Oral Liquid have comparatively broader-although still low-certainty-human evidence for adjunctive improvements in symptoms, myocardial injury markers, inflammatory indices, and selected functional outcomes. By contrast, oxymatrine and berberine are supported mainly by repeated preclinical studies. Across these interventions, the most consistently implicated targets include NF-κB, NLRP3, JAK/STAT, PI3K/Akt, and TGF-β/Smad signaling. Major knowledge gaps include small and heterogeneous clinical studies, variable formulations and quality control, incomplete pharmacokinetic characterization, limited disease-stage and biomarker stratification, and scarce long-term efficacy and safety data. Future translation should prioritize standardized products, exposure-response evaluation, biomarker-guided patient selection, and rigorous multicenter randomized trials. Overall, natural products and herbal medicines should currently be regarded as promising adjunctive candidates whose clinical value depends on stronger, stage-specific, and methodologically robust evidence.
Redox biologyMahmoud H Elbatreek, Vinayak Khodade, Darshan Amin, Miguel Huerta, Timothy D Allerton, David J Polhemus, Sanjiv J Shah, Thomas M Vondriska, Traci T Goodchild, …
Heart failure with preserved ejection fraction (HFpEF) is a complex, multi-organ cardiometabolic syndrome lacking universally effective therapies. We developed and validated a robust murine model leveraging complete, constitutive genetic endothelial nitric oxide synthase deficiency (eNOS KO) coupled with metabolic stress via a high-fat diet (HFD) in both male and female cohorts. eNOS KO mice subjected to HFD (10 weeks for males; 15 weeks for females) developed a severe and highly reproducible cardiometabolic HFpEF phenotype. Despite preserved left ventricular ejection fraction, both sexes exhibited profound diastolic dysfunction, characterized by elevated E/e' ratios and left ventricular end-diastolic pressures (LVEDP), alongside severe exercise intolerance. Consistent with the systemic clinical syndrome, pathological remodeling extended to multi-organ damage, featuring prominent cardiac fibrosis, severe hepatic steatosis, and renal tubulointerstitial fibrosis. Finally, chronic administration of the dual GIP/GLP-1 receptor agonist tirzepatide largely reversed the hemodynamic, functional, and systemic fibrotic derangements. In conclusion, this novel eNOS KO mouse + HFD model provides a rapidly developing, highly penetrant, and chemically unconfounded platform that ensures robust HFpEF induction across both sexes. This model can be readily adopted for the investigation of mechanistic insights into HFpEF pathobiology and for the study of novel HFpEF therapeutics.
Clinical and molecular hepatologyXuan Wang, Yunfang Wang, Shuyong Wang
Hepatocytes are highly specialized epithelial cells that maintain liver metabolic homeostasis, yet they also display remarkable plasticity in response to physiological demands, injury, disease, and oncogenic stress. In this review, we propose hepatocyte plasticity as an integrative framework that links homeostatic metabolic zonation, injury‑ and disease‑induced zonal remodeling and regeneration, hepatobiliary lineage conversion, and zonally biased malignant transformation. We first delineate homeostatic liver zonation as the baseline spatial architecture that constrains, rather than itself constitutes, hepatocyte plasticity, whereas dynamic re-zonation and state conversion represent plastic responses to perturbation. We further propose a conceptual framework that categorizes these plastic responses into four distinct yet interconnected modalities: transient adaptive state transitions, partial lineage conversion, transdifferentiation, and malignant lineage switching. We delineate the multiscale regulatory mechanisms underpinning each category, and critically assess the translational gaps between murine models and human disease. We further explore the therapeutic duality of this plasticity, evaluating emerging approaches that seek either to exploit its regenerative potential for liver repair and disease regression, or to counteract its pathological roles in cancer progression. By integrating these insights, this review establishes a comprehensive framework for understanding hepatocyte plasticity as a central determinant of liver pathobiology and highlights its translational potential for precision therapeutics in liver disease and cancer.