INHBA–S100A16 dysregulation enables a non-invasive molecular stratification platform for rapid detection of oral squamous cell carcinoma: results from a large diagnostic case-control study - Biomarker Research

Background Early diagnosis of oral squamous cell carcinoma (OSCC) is critical, yet most oral potentially malignant disorders (OPMDs) are benign, and patients frequently undergo unnecessary invasive scalpel biopsies, creating diagnostic delays and patient harm. A rapid, non-invasive molecular diagnostic tool could improve early detection and reduce unnecessary procedures. This study aims to determine whether a previously validated microbiopsy-based multigene assay (qMIDSV2) could be adapted into a rapid, non-invasive brush biopsy test (qMIDSV3) for accurate OSCC detection. A prespecified hypothesis was that qMIDSV3 could distinguish OSCC from low-risk OPMD and contralateral normal mucosa with high diagnostic sensitivity. Methods This prospective diagnostic case-control study validated a multigene mRNA test (qMIDSV3) for OSCC detection using 1090 oral brush biopsies from 545 patients. Each patient provided paired brush biopsies from oral lesion and contralateral non-lesion mucosa, including OSCC (n = 443), oral leukoplakia (OL; n = 63), and oral lichen planus (OLP; n = 39). qPCR quantified mRNA levels of four genes (INHBA, S100A16, YAP1, POLR2A) from each brush biopsy, and an algorithm generated a malignancy index for cancer risk stratification. Results qMIDSV3 distinguished OSCC from OL and OLP with AUC 0.975, sensitivity 95.7%, specificity 95.1%, and overall accuracy 95.5%. False-positive and false-negative rates were 4.9% and 4.3%, demonstrating high specificity for detecting malignant cells rather than premalignant or inflammatory lesions. Conclusions Our findings highlight the clinical utility of qMIDSV3 as a rapid case-finding or triage test, potentially sparing over 90% of low-risk OPMD patients from unnecessary invasive tissue biopsies while accurately identifying OSCC cases. Non-invasive brush biopsy allows safe, repeatable sampling for long-term surveillance with minimal patient harm and enhancing early oral cancer detection. By reducing unnecessary scalpel biopsies and specialty referrals, qMIDSV3 provides a molecularly guided and rapid triage pathway.

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Dissecting cancer in a non-mammalian model: genomic insights from lemon frost geckos - BMC Biology

Background Comparative oncology can uncover novel mechanisms of cancer resistance and progression across animals. Non-traditional model organisms with naturally high or low cancer prevalence may provide further insights into metastasis or cancer resistance. In this context, the “lemon frost” morph of the leopard gecko (Eublepharis macularius) shows high prevalence of iridophoromas, exceeding 80%. These tumors can recur and metastasize, presenting a unique opportunity to study pigment cell cancer and tumor progression in a non-mammalian vertebrate. Results We performed high-coverage whole-genome sequencing on matched tumor and non-tumor samples from three lemon frost individuals. A shared missense mutation in the TATA-box binding protein (TBP) suggests possible disruption to transcriptional regulation in tumor samples. Additionally, a recurrent gene fusion between IARS1 and RNF213 was identified across all tumor samples. Copy number neutral loss of heterozygosity events were observed in three mutated genes that have a role in cancer: MAP3K13, TENM4, and OR2AT4-like, while copy number gains were observed in four genomic regions. Pathway analysis revealed dysregulation in actin filament organization, a hallmark of metastatic potential. These findings suggest a multifaceted genomic basis for tumorigenesis in this model, including transcriptional misregulation, chromatin remodeling defects, and cytoskeletal disruption. Conclusions This study provides the first characterization of genomic changes associated with iridophoroma in a reptilian species and establishes the lemon frost gecko as a promising model for cancer research. Our findings identify candidate pathways of tumor progression and metastasis in a non-traditional system, highlighting both conserved and novel mechanisms relevant to human disease.

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Pressure-targeted neurocritical care at the bedside: the emerging role of transcranial doppler - Critical Care

Management of acute brain injury (ABI) focuses on maintaining cerebral perfusion pressure through systemic blood pressure optimization. However, traditional approaches relying on fixed pressure thresholds may not fully capture the complex interaction between systemic hemodynamics, cerebrovascular resistance, and cerebral autoregulation. Transcranial Doppler (TCD) ultrasonography offers a noninvasive bedside method to assess cerebral blood flow velocity patterns and their response to hemodynamic interventions. Doppler-derived parameters such as diastolic flow velocity (FVd) and pulsatility index (PI) provide physiological information that may help interpret the relationship between systemic arterial pressure and cerebral circulation. Observing how these signals change during controlled adjustments of mean arterial pressure may allow clinicians to identify pressure ranges in which cerebral perfusion appears more favorable for an individual patient. Importantly, TCD findings should not be interpreted in isolation but integrated with systemic hemodynamic assessment, including cardiac output, fluid responsiveness, and the underlying mechanism of hypotension. When used within a multimodal monitoring strategy, TCD may serve as a practical physiological tool to complement traditional neurocritical care monitoring. This viewpoint discusses the physiological rationale, potential clinical applications, and current limitations of Doppler-guided blood pressure targeting in patients with ABI.

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Functional analysis of late-onset Alzheimer’s disease risk genes in Caenorhabditis elegans identifies regulators of neuronal aging

Translational Neurodegeneration -

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Efficacy of a psychotherapeutic group intervention for patients with Post-COVID-19 condition: a randomized controlled trial (PsyLoCo study) - BMC Psychology

Background Persistent physical symptoms such as fatigue following SARS-CoV-2 infection are common and often accompanied by cognitive complaints. Alongside biological mechanisms, psychosocial processes can contribute to symptom persistence. Psychotherapeutic interventions could be beneficial in symptom reduction. However, evidence of group-based psychotherapies tailored to Post-COVID-19 condition (PCS) remains limited. Methods In this randomized waitlist-controlled crossover study in an outpatient psychosomatic setting, adults with prior SARS-CoV-2 infection and persisting functionally impairing symptoms were randomized to immediate group psychotherapeutic treatment (intervention group, IG) or treatment as usual with delayed group treatment (control/waitlist group, CG). The intervention comprised 10 bi-weekly manual-guided group sessions (50 min) covering psychoeducation, somatic symptom processing, emotional regulation, and social reintegration. Primary outcome was somatic symptom burden (SSS-8). Secondary outcomes were depressive symptoms (PHQ-9) and anxiety symptoms (GAD-7). Childhood maltreatment (CTS) was examined as a moderator. Efficacy in the randomized phase was tested using ANCOVA comparing post-treatment outcomes in the IG with post-waiting outcomes in the CG, adjusted for baseline severity. Three-month follow-up assessments were analyzed descriptively and exploratorily. Trial registration: https://bit.ly/4xa46sj on Feb 13, 2024 and German Clinical Trials Register DRKS00040598, registered on 12th June 2026. Retrospectively registered. Results Forty-eight patients were included (IG n = 21; CG n = 27; mean age 53.3 years; 68.8% females). At baseline, somatic symptom burden was high (SSS-8 M = 15.21; SD = 5.62) with clinically relevant depressive symptoms (PHQ-9 M = 10.94, SD = 4.61) and moderate anxiety (GAD-7 M = 7.22; SD = 4.38). Fatigue-related physical exhaustion and cognitive complaints were the most prominent symptoms. No significant efficacy of the psychotherapeutic group intervention over TAU was observed for SSS-8 (β = − 2.20, SE = 1.25, 95% CI [− 4.77, 0.38], t(27) = − 1.75, p = .091), PHQ-9 (β = − 1.77, SE = 1.51, 95% CI [− 4.87, 1.33], t(26) = − 1.18, p = .251), or GAD-7 (β = − 0.81, SE = 1.47, 95% CI [− 3.84, 2.22], t(26) = − 0.55, p = .588) comparing post-treatment outcomes in the IG with post-waiting outcomes in the CG. Baseline symptom severity robustly predicted post-randomization outcomes during the randomized phase (p < .001). CTS was no moderator for the intervention effect. Conclusions In this exploratory randomized controlled trial, the intervention did not show significant superiority over the control condition; findings should be interpreted cautiously given limited statistical power. Future psychotherapeutic group interventions for patients with PCS have to consider outcome measures beyond severity of persistent physical symptoms rather than evaluating global symptom scores. Group-based psychotherapeutic approaches might benefit from flexibility in adaptation for individual patients’ needs. Stratification by baseline severity and dominant symptom profiles (e.g., fatigue severity, trauma history) may improve sensitivity to clinically meaningful change. Trial registration Trial registration: DRKS German Clinical Trials Register DRKS00040598, registered on 12th June 2026. Retrospectively registered.

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Tailored FcγR blockade enhances immune checkpoint therapy and overcomes resistance - Journal of Experimental & Clinical Cancer Research

Background Fc-gamma receptors (FcγRs) regulate IgG antibody activity, and Fc-engineering is a proven method to improve the efficacy of tumor-targeting antibodies. Here, we explore tailored FcγR blockade to enhance the therapeutic efficacy and tolerability of immune checkpoint-blocking (ICB) antibodies. Methods Mechanistically matched murine surrogate and human lead FcγR-blocking and immune checkpoint-blocking antibodies were used to study whether tailored FcγR-blockade, targeting FcγRIIB selectively or all FcγRs, can enhance the efficacy and overcome resistance to immune checkpoint therapy in vivo and in vitro. Mechanistic studies were performed with clinical reagents, including ipilimumab, nivolumab, pembrolizumab, and human FcγRIIB-selective (BI-1607) and pan-FcγR-blocking (BI-1206) antibodies, using human cells and transgenic animals with clinically relevant expression of immune checkpoint receptors. Results We demonstrate that FcγRIIB-selective and pan-FcγR-blocking antibodies increase the in vivo efficacy of αCTLA-4 and αPD-1 antibodies, respectively. FcγRIIB-selective antibody enhancement of αCTLA-4 was associated with increased intratumoral Treg depletion, myeloid reprogramming, interferon-γ and CXCL10-induction, and increased activated effector CD8+ T cells, correlating with higher activating-to-inhibitory (A:I) FcγR engagement ratios. Conversely, pan-FcγR blockade protected αPD-1-coated T cells from macrophage phagocytosis, increasing intratumoral activated CD8+ T cells by decreasing activating and inhibitory FcγRs. Conclusions Our studies provide in vivo proof of concept that tailored FcγR blockade enhances immune checkpoint therapy and overcomes resistance through mechanistically distinct pathways. Clinical trials with tailored human FcγRIIB-blocking antibodies are ongoing. Graphical Abstract FcγRIIB-selective blockade enhances αCTLA-4-mediated Treg depletion, myeloid reprogramming, and effector CD8+ T cell activation by increasing the activating-to-inhibitory (A:I) FcγR engagement ratio. Conversely, pan-FcγR blockade protects αPD-1-coated T cells from macrophage phagocytosis and from αPD-1 removal via trogocytosis, thereby increasing intratumoral activated CD8+ T cells by decreasing activating and inhibitory FcγRs.

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Decoding 3D chromatin architecture reveals distinct enhancer classes underlying hierarchical gene regulation in prostate cancer - Genome Biology

Background The transcription process is controlled by non-coding regulatory elements, more than 70% of which are putative enhancers. These enhancers comprise over 600,000 regions and are marked by histone modifications. However, the mechanisms by which altered enhancers in cancer cooperate within the three-dimensional chromatin architecture to drive oncogenic programs remain poorly understood. Results By integrating 201 H3K27ac ChIP-seq datasets from prostate, we identify 3,216 high-confidence prostate cancer-specific putative enhancers. Ultra-high-resolution chromatin interaction profiling by Region Capture Micro-C at a representative chr6q24.1 locus reveals that these enhancers form cancer-specific, highly nested interactions with promoters that coalesce into a multi-connected hub absent in normal prostate cells. CRISPR/Cas9 perturbations of these enhancers, examined one by one, distinguish enhancer classes within the hub. Deletion of a central enhancer collapses hub-wide enhancer activities and architecture, leading to the downregulation of target genes, impaired proliferation, and reduced clonogenic growth. In contrast, deletion of a redundant enhancer results in minimal transcriptional changes, as neighboring enhancers rescue cancer signaling through compensatory architectural rewiring that strengthens alternative enhancer-promoter interactions. We also observe that FOXA1, a pioneer transcription factor activated in prostate cancer, directly binds to these enhancers and regulates distinct enhancer classes, leading to varying degrees of chromatin accessibility and gene expression changes. Conclusions These findings suggest that enhancers function in a coordinated manner, forming multi-connected cancer-specific chromatin interaction hubs, with distinct enhancer classes contributing differently to gene regulation. This study advances our ability to modulate gene expression in a cell type-specific manner, opening new avenues for precision therapies.

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SuperAging is not the inverse of common-variant Alzheimer’s risk: evidence across genetic ancestries - Alzheimer's Research & Therapy

Background As longevity increases and the population over age 65 expands, advancing age remains the most reliable predictor of cognitive decline, highlighting the need to identify biological mechanisms that support exceptional cognitive aging. We tested whether lower inherited risk of Alzheimer’s disease (AD) dementia predicts SuperAger status (adults ≥ 80 years with episodic memory at least as good as middle-age adults) using prospectively enrolled SuperAgers and Cognitively Average Controls (Controls) from the multisite SuperAging Research Initiative. Methods We studied 231 participants (SuperAgers n = 142; Controls n = 89). We confirmed that the genetic ancestry structure across groups was comparable. We evaluated whether APOE status (ε2, ε3, ε4) and three AD polygenic risk scores (PRS) derived from large contemporary Genome-Wide Association Studies (GWAS) (PRSLambert, PRSWightman, PRSBellenguez) predicted SuperAging status using logistic regression models adjusted for age, sex, and education, considering ancestry interactions. Results APOE allele and genotype distributions did not differ between groups, and neither APOE nor any of the three PRS predicted SuperAger status. Results were unchanged when accounting for global non-European or African ancestry or principal components. In this well-characterized cohort, neither APOE nor contemporary PRS explained SuperAger status. Conclusions These findings suggest that the exceptional late-life memory phenotype that is characteristic of SuperAging is not explained by common-variant AD genetic risk captured by APOE or contemporary AD PRS, motivating a deeper investigation of potential rare genetic variations and experiential factors contributing to exceptional cognitive aging.

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Prevalence and associated factors of subjective cognitive decline (SCD Plus): a cross-sectional analysis of three population-based European cohorts - Alzheimer's Research & Therapy

Background Subjective cognitive decline (SCD) is considered an early preclinical marker for Alzheimer’s disease (AD). However, prevalence estimates vary widely due to inconsistent definitions. SCD Plus criteria were proposed by experts to improve specificity for preclinical AD. Population-based evidence on the prevalence and correlates of SCD Plus remains limited. Methods Data from three population-based European cohorts (LIFE-Adult-Study, English Longitudinal Study of Ageing, and Cognitive Function and Ageing Study) comprising adults aged ≥ 60 years without dementia or marked cognitive impairment were harmonized to derive a common definition of SCD Plus based on available core criteria. Generalized linear models examined correlates of SCD Plus in pooled and study-specific analyses. Results Among 18,795 participants (mean age (SD): 72.1 (6.8) years; 55.5% women), prevalence of SCD Plus, based on the harmonized operationalization, was 37.9% (33.3–53.7% across cohorts). In pooled analyses, SCD Plus was associated with higher education, depression, anxiety, hypertension, diabetes, heart disease, Parkinson’s disease, and history of stroke, and inversely associated with smoking and better cognitive performance. Study-specific analyses additionally indicated associations with sleep and hearing-related problems, lower physical activity, thyroid disease, and personality traits (higher neuroticism and lower openness, agreeableness, conscientiousness). Discussion SCD Plus was highly prevalent in three large European cohorts, assessed using a harmonized operationalization approach. Associations with several established, modifiable dementia risk factors underscore the relevance of SCD Plus for clinical risk assessment. Longitudinal studies are needed to determine whether the identified correlates influence subsequent cognitive decline in individuals with SCD Plus.

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Cerebellar volume alterations are associated with cognitive dysfunction and fatigue in patients with systemic lupus erythematosus - BMC Rheumatology

Background Systemic lupus erythematosus (SLE) is a systemic autoimmune disease targeting multiple organ systems, including the nervous system. The cerebellum may be involved in prevalent neuropsychiatric manifestations, such as depression and cognitive dysfunction, alongside other prevalent SLE manifestations such as pain and fatigue. We aim to compare cerebellar volumes in SLE patients and healthy individuals (HI) and assess the correlation between cerebellar volumes and cognitive impairment, fatigue, pain, and depression in SLE. Methods 72 female SLE patients and 25 age- and sex-matched HI underwent 3 tesla magnetic resonance imaging (MRI), clinical evaluations, and cognitive testing. T1-weighted MRI scans were segmented using CEREbellum Segmentation (CERES) volBrain automatic segmentation. Extracted cerebellar lobule volumes (normalized to total cerebellar volume) were compared between SLE and HI using analyses of covariance (ANCOVA). In regions showing significant volume changes between SLE and HI, the relationship between volume and clinical scores for cognitive impairment, fatigue, pain, and depression was analyzed using either ANCOVAs or partial correlation analyses. Results Lobular analysis of the cerebellum revealed significant (p < 0.05) region-specific volume alterations in SLE compared with HI. Bilateral and left lobule IV volumes were larger, while bilateral, right, and left lobule VIIB volumes were smaller in SLE compared to HI. Smaller white matter volumes in right lobule VIIIA, and right lobule X and larger white matter volumes in lobule crus I were observed in SLE compared to HI. In SLE, smaller VIIB volumes were significantly correlated with poorer cognitive performance (both complex attention and cognitive flexibility), and with higher fatigue scores. Conclusion The findings suggest that the cerebellum, and particularly lobule VIIB, is involved in SLE and may contribute to both cognitive dysfunction and fatigue in patients with systemic lupus erythematosus. Trial registration Not applicable.

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The direct cost of amphibian metamorphosis: insights from body weight loss in facultative paedomorphs - BMC Biology

Background Metamorphosis is a key event in the life history of many organisms, including amphibians, because it can involve abrupt changes in morphology and habitat. However, metamorphosis can also be bypassed by paedomorphic processes that allow reproduction at the larval stage. The evolution of these alternative developmental processes depends on the payoffs of life in larval and adult environments, as well as the cost of transition. Previous studies on the cost of metamorphosis have focused on the larval stage, which is still subject to the achievement of a minimal size threshold as well as growth to adulthood. Therefore, facultatively paedomorphic species could be valuable models for testing the direct costs of metamorphosis. This is because facultative paedomorphs are sexually dimorphic adults that are capable of metamorphosis. Results By modelling weight loss using an experimental, longitudinal design that manipulated the ecological drivers of metamorphosis in a facultatively paedomorphic amphibian, the palmate newt (Lissotriton helveticus), we found that metamorphosis imposes costs in terms of body weight, whereas temperature has a smaller effect. In contrast, newts that do not metamorphose did not lose weight. The costs were sex-related with females at a disadvantage during metamorphosis. Furthermore, the decrease in food consumption associated with metamorphosis resulted in a loss of body weight. Conclusions Overall, these results emphasise the importance of considering direct costs when studying the evolutionary ecology of metamorphosis. They also show that polymorphic species are suitable models for investigating the drivers of metamorphosis and its loss in micro- and macroevolution.

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Impact of post-exertional malaise frequency and fatigue in Long COVID patients on health-related quality of life - Health and Quality of Life Outcomes

Purpose The aim of this study was to investigate the impact of post-exertional malaise (PEM) frequency and PEM severity on health-related quality of life (HRQoL) among individuals with Long COVID. Methods We conducted a cross-sectional online survey including adults in Germany with self-reported Long COVID and PEM. Fatigue severity was assessed with the Fatigue Assessment Scale (FAS), and HRQoL was measured using the EQ-5D-3L (descriptive index and visual analogue scale [EQ-VAS]). Associations between PEM frequency, fatigue, and HRQoL were examined using correlations and non-parametric group comparisons. Multiple linear regression models were fitted to predict HRQoL while controlling for age, sex, employment status, and subjective social status. Results Higher PEM frequency was associated with significantly lower EQ-5D index scores (ρ = − 0.32, p<.001). PEM severity was also strongly correlated with reduced HRQoL (EQ-5D index: ρ = − 0.43, p<.001). In multivariable regression models, greater fatigue and higher PEM frequency independently predicted poorer HRQoL, even after adjustment for sociodemographic factors. Conclusion Both PEM frequency and PEM severity substantially impair HRQoL in individuals with Long COVID. These findings underscore the clinical relevance of PEM as a key symptom and highlight the need for targeted management strategies to mitigate its impact on daily life. Clinical trial number German Clinical Trials Register DRKS00026007; registration date: 9 September 2021.

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Shared and niche-specific transcriptional signatures of macrophage aging revealed by a cross-tissue meta-analysis - BMC Biology

Background Aging is accompanied by widespread transcriptional remodeling across tissues, yet how aging impacts different categories of tissue-resident macrophages is not well understood. Macrophages are highly specialized innate immune cells shaped by their local microenvironments, suggesting that aging may elicit both shared and niche-specific transcriptional responses. Here, we performed a meta-analysis of publicly available bulk and single-cell RNA-seq datasets to characterize age-associated transcriptional changes in murine macrophages across tissues and sexes. We curated and uniformly processed 33 macrophage transcriptomic datasets, derived from 10 distinct tissue niches, in male and female C57BL/6 mice, examining transcriptional changes as a function of age. Results The similarity of differentially expressed aging genes was compared across niches and pathway-level analysis uncovered conserved age-associated signatures, including upregulation of gene sets related to antigen presentation, antioxidant responses, and negative regulation of ferroptosis, alongside downregulation of gene sets related to Wnt, GTPase, and extracellular matrix organization signaling. Transcription factor activity inference identified consistent age-associated activation of AP-1 (Fos, Jun), C/EBPβ, PU.1, and Egr1 across niches. Meta-analysis defined 593 consistently age-altered genes in > 3/4 of analyzed datasets, converging on dysregulation of small GTPase signaling. Focused analysis of alveolar macrophages and microglia, made possible by the larger number of available datasets, revealed sex-specific transcriptional programs altered with age in these macrophage subtypes. Conclusions These findings demonstrate that macrophage aging is shaped by both tissue niche and sex and provides a framework for understanding the transcriptomic signatures of macrophage aging across tissues.

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Association of long-COVID with major adverse cardiovascular events and mortality: a real-world data cohort study - BMC Cardiovascular Disorders

Background There is a limited body of research examining the association between long COVID and major adverse cardiovascular events (MACE) as well as all-cause mortality. This study aimed to investigate the association between long COVID and both MACE and mortality. Methods This retrospective cohort study utilized multicenter real-world data from the TriNetX research network platform, which contains electronic health records from multiple healthcare organizations. Patients aged 18 years and older who were diagnosed with COVID-19 between 2020 and 2023 were included. The exposure group comprised individuals diagnosed with long-COVID within 3 to 6 months after their initial COVID-19 diagnosis, while the comparison group included COVID-19 patients without a diagnosis of long-COVID. The primary outcomes were the risk of major adverse cardiovascular events (MACE) and all-cause mortality. Follow-up commenced 90 days after the index date and continued until the occurrence of the study outcome or the date of the last available medical record. Results The risk of MACE was markedly higher in the long-COVID cohort compared to the non-long-COVID cohort. The overall hazard ratio (HR) for MACE was 4.48 (95% CI: 3.95–5.07). Specific conditions such as coronary artery disease and stroke exhibited particularly high HRs, at 6.48 (5.29–7.95) and 3.46 (2.96–4.04) respectively. Mortality was significantly higher in the long-COVID group, with an HR of 1.53 (1.38–1.69). Conclusions Compared to patients without long COVID, patients with long COVID had a higher risk of developing MACE.

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Gastrointestinal symptoms correlate with core clinical features and systemic inflammation in myalgic encephalomyelitis/chronic fatigue syndrome - Journal of Translational Medicine

Background Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystem illness marked by fatigue, cognitive impairment, and post-exertional malaise. Gastrointestinal (GI) symptoms are frequently reported, yet their relationship to central features of the illness and biological correlates remains poorly understood. Objectives We aimed to characterize GI symptom burden in ME/CFS and evaluate its associations with core clinical features and specific immune and inflammatory markers, with attention to potential gut-related contributions to disease expression. Methods GI symptoms and 49 additional symptoms across nine domains were assessed in 116 ME/CFS patients and 80 matched controls. Plasma C-reactive protein (CRP) and antibodies against dietary and microbial antigens were measured as indicators of systemic inflammation and putative gut-derived antigen exposure. Results ME/CFS patients reported significantly elevated GI symptom frequency and severity compared with controls, with 53% of ME/CFS patients versus 8% of controls reporting a prior diagnosis of irritable bowel syndrome. GI symptom burden correlated with fatigue, cognitive difficulties, flu-like symptoms, pain, sleep disturbances, neurological complaints, and sensory sensitivities, independent of illness duration. CRP levels were higher in patients with greater GI symptoms and correlated with GI, fatigue, musculoskeletal pain, and flu-like symptom burden. Patients with greater flu-like symptom expression exhibited higher IgM responses to dietary gliadin and bacterial lipopolysaccharide. These associations were not detected in controls. Conclusions GI symptoms are a prominent, clinically relevant dimension of ME/CFS, associated with broader symptom burden and inflammatory heterogeneity. These findings highlight the relevance of gut-related and immune processes in ME/CFS and underscore the value of incorporating GI symptom assessment in translational studies to help refine mechanistic understanding and improve therapeutic stratification.

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Ketogenic diet as a therapeutic strategy for neurodegenerative diseases: from mechanisms to translational challenges - Translational Neurodegeneration

The ketogenic diet (KD) is increasingly recognized as a promising therapeutic strategy for neurodegenerative disorders because of its multifaceted impacts on key pathophysiological mechanisms. This review explores the molecular pathways through which KD may protect against neurodegeneration, including the use of ketone bodies as alternative energy substrates, reduction of oxidative stress and inflammation, modulation of autophagy and protein aggregation, and impact on the gut microbiome. The potential benefits of KD are explored across neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and multiple sclerosis, based on both preclinical and clinical evidence that supports its feasibility. However, challenges in long-term safety, patient adherence, and clinical practicality limit its widespread adoption. This review underscores the potential of KD for treating neurodegeneration on the basis of current scientific evidence while highlighting the need for further research to optimize its application and address existing gaps.

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Lack of cortistatin drives neuroimmune and vascular dysfunction in brain ischemia - Journal of Biomedical Science

Background Ischemic stroke remains a leading cause of death and disability, with limited therapies addressing its pathophysiology. Neuroinflammation, blood–brain barrier disruption, and immune dysregulation critically contribute to both acute neuronal injury and chronic functional decline. Elucidating the endogenous factors that govern these processes and understanding the intricate interplay among them is essential for developing effective therapeutic strategies. Cortistatin, a neuropeptide expressed in the nervous and immune systems, exhibits potent immunomodulatory actions, but its role in neuroinflammatory diseases remains unclear. Methods In this study, we combined human and murine transcriptomic analyses with a preclinical stroke model in cortistatin-deficient mice to investigate the endogenous and therapeutic roles of cortistatin during the acute (48 h) and subacute (7 days) phases of ischemic stroke. Results We demonstrate for the first time that cortistatin deficiency amplified ischemia-induced transcriptional programs, heightening neuroinflammation and glial/neurovascular dysfunction, and worsening neurological outcomes. Interestingly, cortistatin deficiency accelerated aging-associated pathological features, underscoring its essential role in neuroimmune and cerebrovascular homeostasis. Conversely, cortistatin administration improved neuronal survival, mitigated immune dysfunction, and preserved myelin and vascular integrity during both the acute and subacute stages. Conclusions These findings provide the first evidence identifying cortistatin as an endogenous neuroimmune regulator in ischemic stroke and a promising multimodal therapeutic agent for improving acute and long-term outcomes.

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From cognitive abstraction to adaptive behavior: neural bases of concept learning in autistic adolescents - Molecular Autism

Background Learned knowledge does not consistently generalize to new contexts in autistic individuals, limiting potential for adapting to real-world demands. This challenge is hypothesized to stem from difficulties with forming abstract representations, potentially arising from perceptual processing that favors local details over the gestalt. We tested the prediction that generalization would be primarily based on exemplar-specific representations in autistic youth using computational modelling coupled with neuroimaging. Methods Sixty-four autistic adolescents without intellectual disability (69% males; ages 14–18 years) completed a category generalization task during functional magnetic resonance imaging at two time points. Computational models estimated abstract (prototype-based) and specific (exemplar-based) representations and underlying neural correlates. We further examined associations with adaptive functioning and moderation by autistic traits. Results Contrary to predictions, we observed a consistent prototype-dominant majority, a subgroup who generalized without consistent representational reliance, and a small minority who failed to acquire category structure. Neural prototype correlates were observed in bilateral ventromedial prefrontal cortex (VMPFC), inferior parietal lobule (IPL), right frontal pole, and right lateral occipital cortex, while neural exemplar correlates were observed in bilateral cuneus. Better generalization predicted better real-world adaptive functioning. Moreover, greater prototype-related activation in left IPL predicted better adaptive functioning in participants with higher autistic traits. Limitations Generalizability is limited to autistic adolescents without intellectual disability as the design did not include typically developing youth. Conclusions These findings challenge the prevailing view that concept learning in autism relies primarily on hyper-specific perceptual processing, identify meaningful variability in representational strategies, and reveal neural pathways through which abstract representation may support real-world adaptive behavior. These findings set the foundation for exploring abstract representation as an intervention target in autism.

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Synergistic senolytic–regenerative therapy significantly extends healthspan and lifespan - Journal of Translational Medicine

Background Current barriers to achieving radical life extension include the inability to use syngeneic, youthful mesenchymal stem cells (MSCs) and the anti-regenerative effects of senescence-associated secretory phenotype (SASP) factors. We aim to overcome this by a combination approach in which senescent cell burden is reduced utilizing SenoVax™ a dendritic cell based senolytic immunotherapy combined with syngeneic pluripotent stem cell derived MSC. Methods We induced hepatic injury and accelerated aging using two established murine models: carbon tetrachloride (CCl₄) mediated liver injury and doxorubicin induced systemic senescence. Animals were treated with control, SenoVax, pMSCs or the combination. Outcomes included biochemical and histologic indices of liver injury, circulating and tissue biomarkers of senescence (IL-11, YKL-40, IL-6, IL-23 R) and regeneration (Klotho, FGF-2, neo-VEGF, GDF-11), Results Both CCl₄ and doxorubicin induced a robust senescent phenotype characterized by increased pro-inflammatory and pro-fibrotic mediators and downregulation of regenerative biomarkers. Combined senolytic and pMSC therapy outperformed mono therapies and produced clear synergistic benefits, including significant biochemical improvement of liver failure parameters, reversal of accelerated aging features, and restoration of regenerative signaling pathways. Senolytic monotherapy yielded partial improvements, while pMSCs alone showed limited activity in the presence of a high senescent-cell burden. Conclusions These findings support a mechanistic model in which senescent cells and SASP factors directly suppress MSC-mediated tissue repair. Targeted senolytic immunotherapy enhances the efficacy of regenerative interventions and represents a promising combinatorial strategy for chronic disease management and potentially for modifying biological aging itself. Clinical trial number Not applicable.

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Veterinarians’ perception of livestock infectious disease: results from a five country cross-European survey (2024) - BMC Veterinary Research

Livestock production accounts for nearly half of all agricultural output globally, but the long-term sustainability of the sector is threatened by a range

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Obesity-derived metabolites modulate anti-tumor immunity in the tumor microenvironment: from mechanisms to clinical applications - BMC Medicine

The tumor microenvironment (TME) is increasingly understood as a metabolically dynamic ecosystem in which local metabolite availability, composition, and trafficking shape immune cell fitness and therapeutic responsiveness. Against the backdrop of the global obesity epidemic, obesity-associated systemic metabolic dysregulation has been implicated in tumor initiation and progression and may also influence the immune contexture and treatment responsiveness of tumors. This Review examines how obesity-derived systemic metabolites may modulate anti-tumor immunity and influence cancer immunotherapy, with particular emphasis on pathways involved in metabolic reprogramming and TME remodeling. We further discuss intervention strategies spanning (i) upstream metabolite generation, (ii) systemic-to-local trafficking into the TME, and (iii) direct functional antagonism within the TME. However, the available evidence remains heterogeneous across metabolite classes, tumor types, and experimental contexts, and this heterogeneity is likely to contribute to divergent immunotherapeutic phenotypes, including obesity-associated heterogeneity in immune checkpoint blockade (ICB) responsiveness. By integrating these layers into a source-to-sink framework, we highlight translationally relevant directions for understanding how systemic metabolites may reshape the metabolic niche of the TME and for informing more precise, context-aware, and safety-conscious metabolite-directed strategies in cancer immunotherapy.

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Chemical and Biological Technologies in Agriculture

Chemical and Biological Technologies in Agriculture (CBTA) offers the first opportunity to stimulate discussion on the latest chemical and biochemical ...

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INHBA–S100A16 dysregulation enables a non-invasive molecular stratification platform for rapid detection of oral squamous cell carcinoma: results from a large diagnostic case-control study - Biomarker Research

Background Early diagnosis of oral squamous cell carcinoma (OSCC) is critical, yet most oral potentially malignant disorders (OPMDs) are benign, and patients frequently undergo unnecessary invasive scalpel biopsies, creating diagnostic delays and patient harm. A rapid, non-invasive molecular diagnostic tool could improve early detection and reduce unnecessary procedures. This study aims to determine whether a previously validated microbiopsy-based multigene assay (qMIDSV2) could be adapted into a rapid, non-invasive brush biopsy test (qMIDSV3) for accurate OSCC detection. A prespecified hypothesis was that qMIDSV3 could distinguish OSCC from low-risk OPMD and contralateral normal mucosa with high diagnostic sensitivity. Methods This prospective diagnostic case-control study validated a multigene mRNA test (qMIDSV3) for OSCC detection using 1090 oral brush biopsies from 545 patients. Each patient provided paired brush biopsies from oral lesion and contralateral non-lesion mucosa, including OSCC (n = 443), oral leukoplakia (OL; n = 63), and oral lichen planus (OLP; n = 39). qPCR quantified mRNA levels of four genes (INHBA, S100A16, YAP1, POLR2A) from each brush biopsy, and an algorithm generated a malignancy index for cancer risk stratification. Results qMIDSV3 distinguished OSCC from OL and OLP with AUC 0.975, sensitivity 95.7%, specificity 95.1%, and overall accuracy 95.5%. False-positive and false-negative rates were 4.9% and 4.3%, demonstrating high specificity for detecting malignant cells rather than premalignant or inflammatory lesions. Conclusions Our findings highlight the clinical utility of qMIDSV3 as a rapid case-finding or triage test, potentially sparing over 90% of low-risk OPMD patients from unnecessary invasive tissue biopsies while accurately identifying OSCC cases. Non-invasive brush biopsy allows safe, repeatable sampling for long-term surveillance with minimal patient harm and enhancing early oral cancer detection. By reducing unnecessary scalpel biopsies and specialty referrals, qMIDSV3 provides a molecularly guided and rapid triage pathway.

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JMCR: Clinical Reasoning From Case Reports

Beyond Motor Recovery: What Does Objective Gait Analysis Reveal After Childhood Ischemic Stroke?

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Beyond the arterial line: less, more, or smarter use?

Critical Care -

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The protective effect of breastfeeding on infant inflammation: a mediation analysis of the plasma lipidome and metabolome - BMC Medicine

Background Inflammation has long-term health impacts across the life course. Breastfeeding substantially reduces inflammation risk, but key pathways, including the extent that this is due to protection against early life infection, are poorly understood. We aimed to investigate the relationships between breastfeeding, inflammation, and infection burden, and to determine the extent to which metabolomic and lipidomic profiles associated with breastfeeding mediate these health outcomes. Methods We utilised data from the Barwon Infant Study (BIS), a longitudinal birth cohort in Victoria, Australia. Infants (n = 889) with available breastfeeding (categorised as yes/no) clinical, metabolomic, and Lipidomic data at 6 and/or 12 months were included (n = 793 at 6 months, n = 734 at 12 months). Inflammation, measured via glycoprotein acetyls (GlycA), at 6 and 12 months and infection burden, including parent-reported and medically attended infections assessed through standardised 3-monthly questionnaires were used as outcomes. Results Any breastfeeding, regardless of supplementary feeding, was associated with lower inflammation, fewer infections, and significant, potentially beneficial changes in metabolomic and lipidomic markers, particularly plasmalogens. There was evidence of bidirectional mediation: metabolomic biomarkers and lipids mediated breastfeeding’s effects on inflammation, while inflammation partly mediated breastfeeding’s impact on certain metabolites and lipids. Conclusions These findings highlight pathways through which breastfeeding reduces inflammation and infection burden, identifying potential targets for optimising infant feeding.

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Explainable deep learning ensemble framework for accurate classification of wild poisonous mushroom species - BMC Biotechnology

This study introduces an explainable deep learning framework for the accurate classification of wild poisonous mushroom species, contributing to food safet

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