Search Results (2,253)

Nerve injuries are frequent complications of complex oral and maxillofacial surgical procedures, particularly following extensive tumor resections. Secretome-based, cell-free therapies derived from mesenchymal stromal cells have emerged as promising regenerative approaches; however, robust manufacturing requires the identification of critical quality attributes (CQAs) that ensure product potency and consistency. The influence of replicative senescence during in vitro expansion on the quality of jaw periosteum-derived mesenchymal stromal cell (JPC) secretomes has not yet been established. This study investigated whether the expansion state of JPCs affects the composition and neuro-supportive potency of their secretomes. Secretomes from four independent JPC donors were collected separately at early and late passages, pooled within each passage-specific preparation, and applied to human induced pluripotent stem cell-derived neurons. Neuronal survival, neurite outgrowth, and neuronal marker expression were assessed as functional readouts. Secretome composition was characterized by quantitative proteomics and enzyme-linked immunosorbent assay (ELISA) of selected senescence-associated secretory phenotype (SASP) factors. Secretomes derived from early-passage JPCs significantly enhanced neuronal survival and neurite outgrowth, whereas late-passage secretomes displayed reduced neuro-supportive activity. Proteomic profiling identified a pronounced shift toward inflammatory and stress-associated signaling, whereas performed ELISAs confirmed senescence-associated remodeling of the secretome, including increased abundance of SASP-associated factors in late-passage preparations. These findings demonstrate that prolonged in vitro expansion profoundly influences both the composition and biological potency of JPC-derived secretomes. Collectively, this study identifies the passage-associated senescence-like phenotype of JPCs as a key determinant of secretome quality and supports its consideration as a critical quality attribute for the manufacturing and standardization of JPC-derived secretome products. Monitoring and controlling the expansion state of JPCs may therefore be essential to ensure the consistency, potency, and clinical translation of secretome-based regenerative therapies. Full article

Trehalose-6-phosphate (T6P) is a key signalling metabolite that integrates carbon availability with development and stress responses in plants. T6P levels are controlled by trehalose phosphate synthase (TPS) and trehalose-6-phosphate phosphatase (TPP) enzymes; however, while TPS enzymes have been studied extensively, the physiological functions of individual TPPs remain incompletely understood. Here, we investigated the role of TPPI in Arabidopsis using loss-of-function tppi mutants, a complemented line (tppi+35S::TPPI), and TPPI-overexpressing (TPPI-OEX) plants. The tppi mutant exhibited delayed flowering accompanied by reduced expression of CO, FT, and SPL3, while complementation restored wild-type (WT) flowering time. TPPI-OEX plants displayed an intermediate flowering phenotype with moderate reductions in CO and FT expression. Under nitrogen starvation, tppi plants showed enhanced anthocyanin accumulation, altered nitrate reductase regulation, characterised by lower total enzyme activity but a higher activation state, and enhanced expression of nitrate assimilation and uptake genes (NIA1, NIA2, NRT1.1, and NRT2.1). TPPI deficiency also altered photosynthetic performance, with enhanced photosystem I (PSI) acceptor-side limitation, increased non-photochemical quenching (NPQ), and a tendency toward reduced photosystem II (PSII) electron transport, indicating altered photosynthetic electron transport and energy dissipation. Taken together, these results indicate that TPPI contributes to the regulation of flowering time, nitrogen responses, and photosynthetic performance, suggesting broader effects of TPPI on plant developmental and physiological processes. Full article

Macrophages are highly plastic innate immune cells that integrate diverse microenvironmental cues to adopt pro-inflammatory (M1) or anti-inflammatory (M2) functional states, which critically influence the pathogenesis of infectious, autoimmune, inflammatory, and malignant diseases. This review provides an overview of current concepts of macrophage ontogeny, functional heterogeneity, and disease-associated phenotypes, with a specific focus on experimental approaches used as M1/M2 test systems for macrophage phenotyping. The scope of the review encompasses commonly used experimental models, induction protocols for M1- and M2-like polarization, and key readouts, including gene-expression signatures and metabolic parameters. Particular emphasis is placed on reporter-based platforms (luciferase, BRET, fluorescent nanoparticle probes), label-free biophysical methods such as electrical impedance monitoring and metabolic profiling, and their application to dynamic, real-time assessment of macrophage phenotype in the context of tumor microenvironments and chemotherapeutic exposure. The potential of integrating reporter systems with single-cell omics, spatial transcriptomics, and patient-derived ex vivo platforms is considered, with a view to transforming M1/M2 test systems into clinically oriented assays capable of tracking macrophage programs during therapy and supporting the development of macrophage-targeted diagnostics and treatments. Full article

Age-associated mitochondrial decline reduces NAD⁺ availability, impairs oxidative phosphorylation (OXPHOS), and leads to accumulation of reactive oxygen species (ROS) thereby reshaping cellular metabolism. However, the regulatory logic coupling mitochondrial aging to metabolic dysregulation resulting in tumorigenic cell-fate transitions has not been modeled systematically. In this work, we propose a Boolean biomolecular network model of mitochondrial aging and integrate it with metabolic, cell-cycle, and apoptotic biomolecular networks comprising 94 nodes and 370 edges. We then examined how NAD⁺ decline, hypoxia and extracellular ROS shifts the balance between OXPHOS and glycolysis. To this end, the consolidated network model underwent dynamical analysis to elucidate the system-level outcomes as well as its molecular triggers. In particular, we investigated whether the metabolic phenotypes are reversible and how cancer-driver perturbations act in the absence of extracellular pyruvate. The model recapitulates a quiescent, OXPHOS-leaning baseline and predicts that progressive NAD⁺ decline lowers OXPHOS propensity (0.686 to 0.186) while raising glycolysis (0.256 to 0.426). Hypoxia and extracellular ROS synergize glycolytic and hybrid oxidative–glycolytic (W/O) states. Furthermore, these two triggers, together with elevated mitogenic signaling, give rise to a hyperproliferative, glycolytic, and apoptosis-resistant cellular state. Interesting, this state is conditionally reversible wherein receptor tyrosine kinase (RTK) inhibition redirects this cell fate toward apoptosis and collapses the W/O state. Cancer-driver analysis further indicates that, without extracellular pyruvate, VHL loss and RAS, PI3K, or AKT activation preferentially stabilizes glycolytic and hybrid states. Age-resolved TCGA-BRCA analysis provided expression-level support for the predicted remodeling, with declining OXPHOS-associated expression and concurrent OXPHOS/glycolysis activity in older Basal-like tumors. Together, our results show that mitochondrial aging is a priming condition whose tumor-permissive metabolic output is gated by microenvironmental and nutrient inputs. The model provides a novel framework for evaluating age-associated metabolic reprogramming and predicting early tumorigenic cell fates. Full article

Type 1 diabetes (T1D) is characterized by autoimmune β-cell destruction, metabolic instability, and long-term susceptibility to vascular and renal complications. Oxidative stress has been widely implicated in these processes, but it is often described as a generalized consequence of hyperglycemia, not as a measurable and heterogeneous biological state. In this review, we propose exploratory redox phenotyping as a framework for characterizing oxidative stress in pediatric and early-stage T1D. This approach integrates biomarkers of antioxidant defense, lipid peroxidation, protein oxidation, DNA oxidation, and inflammation-associated redox activity to explore potentially distinct patterns of redox dysregulation. Key biomarker domains include enzymatic antioxidant systems, lipid-peroxidation products, protein- and DNA-oxidation markers, and inflammatory mediators, which may collectively characterize the intensity, molecular compartment, and possible clinical relevance of redox dysregulation. Across pediatric presymptomatic T1D, newly diagnosed disease, partial remission, and short-duration established T1D, longitudinal redox profiling may help distinguish stage-specific or transient metabolic responses from persistent oxidative dysregulation. These clinical phases are considered separately as they differ in immune activity, residual C-peptide secretion, glycemic exposure, and biological susceptibility. Redox phenotyping may also improve the design of antioxidant, mitochondrial, anti-inflammatory, and NRF2-targeted interventions by enabling biomarker-based patient selection. By defining oxidative stress as a stratifiable biological domain, this framework may advance precision risk assessment and guide more rational, targeted redox-directed therapies for children and individuals with early-stage T1D. At present, these proposed profiles remain hypothetical and require validation in prospective cohorts using standardized assays, reproducible thresholds, and clinically meaningful outcomes. Full article

Neurologic manifestations of long COVID, also called neurologic post-acute sequelae of SARS-CoV-2 infection (Neuro-PASC: NP) include persistent alteration of cognitive functions. We investigated whether these could be driven by immune perturbations. We combined flow cytometry (FC), sleep profiling, and single-cell RNA sequencing of peripheral blood immune cells from older adult (>55 years) individuals with and without NP to evaluate relationships with objective cognitive performance. NP participants showed reduced numbers of blood monocytes with increased mitochondrial superoxide, indicating an altered monocyte mitochondrial redox state. Higher peripheral capillary oxygen saturation (SpO₂) was associated with better processing speed in NP participants. Monocyte transcriptional analyses identified mitochondrial adenosine triphosphate (ATP) synthase/Complex V (Complex V) pathway associated with cognitive performance in people without NP; this coupling was abrogated in NP patients, in whom cognitive performance instead showed an opposite relationship with Complex V. Shared leading-edge genes defined a 13-gene monocyte anchor representing this cognition-associated NP phenotype. Higher anchor scores were associated with coordinated oxidative phosphorylation and cytotoxic programs across CD3⁺ T-cell subsets in individuals without NP, but not in NP participants. T-cell receptor stratified analyses showed that this altered relationship occurred in both expanded and unexpanded T-cell populations. FC correlations also supported reduced monocyte-to-lymphocyte mitochondrial coordination in NP. These exploratory findings identify a sleep and cognition-linked monocyte mitochondrial phenotype characterized by altered myeloid–lymphoid immune coordination in NP. Full article

This study evaluated how culture system and culture medium composition influence the phenotype and functional quality of Talaromyces sayulitensis HC1 conidia. Conidia were produced by solid-state fermentation (SSF) and submerged fermentation (SmF) using two culture medium compositions differing in sucrose and ammonium phosphate concentrations and, consequently, in C:N ratio. Morphological, ultrastructural, physicochemical and functional attributes were analyzed together with the expression of four selected conidiation-related genes (brlA, abaA, fluG and rodA). Conidia produced under SSF were significantly smaller and displayed a more cylindrical morphology and accumulated significantly more melanin than those produced under SmF, whereas SmF-derived conidia exhibited significantly higher relative ergosterol content. Outer cell wall thickness was significantly influenced by both culture system and culture medium composition. Across both culture systems, the medium containing a lower sucrose concentration and a higher ammonium phosphate concentration (C:N ratio 10:1) resulted in significantly higher germination but significantly lower thermotolerance than the medium containing a higher sucrose concentration and a lower ammonium phosphate concentration (C:N ratio 50:1). The medium was also associated with significantly greater melanization. Expression of brlA, abaA, fluG and rodA was generally higher under SSF, although the magnitude of the response varied among genes and culture medium compositions. The integrated analysis revealed that germination and thermotolerance were not necessarily coupled and that culture system and culture medium composition influenced different dimensions of conidial quality. The main innovation of this study is the integration of structural, physicochemical, functional and selected molecular indicators to identify distinct conidial quality profiles relevant to application-oriented production of fungal inoculants. Full article

MCT1 (encoded by SLC16A1) is a key regulator of cellular metabolism, mediating proton-coupled transport of lactate, pyruvate, ketone bodies, and other monocarboxylates across biological membranes. Long recognised for its canonical role in metabolic homeostasis and the lactate shuttle, MCT1 is now implicated in tumour-promoting processes, including metabolic symbiosis, angiogenesis, immune evasion, and therapy resistance. Aberrant plasma membrane MCT1 (PM MCT1) expression is observed in diverse malignancies, where it may carry prognostic or predictive value, making it an attractive therapeutic target. This review integrates established metabolic functions of MCT1 with emerging evidence showing its unexpected nuclear localisation (nMCT1) and potential to modulate chromatin state through metabolite-driven epigenetic regulation. In particular, we discuss how PM MCT1 substrates such as lactate, pyruvate, and ketone bodies may influence histone modifications and gene regulation through direct or indirect metabolic mechanisms. We also examine reports of nuclear or nuclear-associated MCT1 (nMCT1) staining in immune and cancer contexts, while emphasising that functions of nMCT1 remain insufficiently validated. By distinguishing established transport biology from substrate-mediated epigenetic effects, this review highlights both the therapeutic promise of MCT1 targeting and the experimental gaps that must be addressed. We conclude by outlining priorities for future research, including orthogonal validation of putative nMCT1, improved patient stratification based on MCT1 expression and metabolic phenotype, and rational combination strategies for MCT1-directed therapies. Full article

Postoperative atrial fibrillation (POAF) after cardiac surgery is often managed as a transient inpatient arrhythmia, yet recurrent or silent atrial fibrillation (AF) after discharge may identify persistent atrial vulnerability. This issue is particularly relevant in cancer survivors, whose thrombotic and bleeding risks vary according to cancer activity, treatment exposure, thrombocytopenia, frailty and planned procedures. For this narrative review, PubMed/MEDLINE and Scopus were searched from inception to 16 June 2026, with Google Scholar used for supplementary citation tracking. A total of 50 publications were included in the final narrative synthesis. Direct evidence at the intersection of cancer, cardiac surgery, POAF and digital monitoring remains limited. Accordingly, the proposed “Digital Cancer-POAF Survivorship Pathway” is presented as a conceptual, hypothesis-generating framework, rather than a validated clinical algorithm. Its distinctive contribution is to connect cancer-state phenotyping and treatment-specific arrhythmic risk with post-discharge rhythm surveillance, electrocardiogram (ECG) confirmation, multidisciplinary interpretation, data governance and outcomes for prospective validation. Digital monitoring may increase AF detection; however, whether it reduces stroke, bleeding, readmission, or healthcare utilisation in this population is unknown. Neither a low detected AF burden nor the absence of AF during finite monitoring has been validated as an independent basis for anticoagulation decisions. Full article

Plant diseases lead to substantial yield losses and pose a persistent threat to global food security, creating an urgent demand for high-throughput, accurate, scalable, and non-destructive disease-monitoring approaches. Remote sensing has emerged as a powerful tool, yet progress in plant disease detection remains fragmented across various disciplines, tasks, sensing methods, and data modalities. This review introduces a hex-view perspective to synthesise remote-sensing-based plant disease detection within a cohesive conceptual framework. Instead of treating sensing technologies, algorithms, and datasets independently, the hex-view incorporates six interconnected dimensions that jointly capture how biological processes, the measurement scale, and data characteristics constrain disease detectability, including when detection is possible and how reliably it can be achieved. The hex-view framework comprises six interconnected dimensions and forms an integrated framework called BTSCAD: (1) Biology (B): plant–pathogen interactions constituting the biological foundation of disease development and expression. (2) Task (T): the diverse disease-detection tasks and their corresponding research objectives. (3) Sensor (S): the sensing modalities that define the data acquisition type and richness of captured information. (4) Condition (C): the environmental conditions, sensing platforms, and spatial scales that shape disease observations and bridge controlled experiments and real-world deployment across leaf, canopy, plot, and regional scales. (5) Algorithm (A): the classical and state-of-the-art data-analysis algorithms used to extract disease-related information from sensor data. (6) Dataset (D): the data sources that underpin model development, evaluation, and generalisability. The hex-view perspective provides a clear framework for interpreting previous research and identifying future research directions. This review lays a structured foundation for developing robust, interpretable, and transferable disease-detection systems, supporting advancements in precision agriculture, high-throughput phenotyping, and sustainable crop production. Full article

Background: Aggression and violence are complex behavioral phenomena with substantial biological underpinnings involving immune activation and lipid metabolism. Previous evidence has linked inflammatory signaling and altered cholesterol homeostasis to impulsive and antisocial behaviors. The present exploratory study investigated differential gene expression patterns associated with severe violent offending and their relationship with aggression-related phenotypes. Methods: Whole-blood samples from 19 male severe violent offenders and 11 healthy controls were analyzed using Clariom S gene expression arrays followed by qPCR validation. Participants additionally completed psychometric assessments including the State Trait Anger Expression Inventory-II (STAXI-II), the Psychopathic Personality Inventory-Revised (PPI-R), and the Appetitive and Facilitative Aggression Scale (AFAS). Results: Differential expression analysis identified 833 significantly dysregulated genes (FDR < 0.1; fold change ≥ 1.5) in violent offenders relative to controls. Among the most strongly altered genes were IL1B, TLR4, PTGS2 (COX-2), ABCA1, IL6R, PRF1, and MMP9. qPCR validation confirmed significant upregulation of MMP9, PTGS2, IL6R, and PRF1. Gene x behavior analyses demonstrated significant associations between PTGS2 expression and reactive as well as outwardly directed aggression, while MMP9 expression correlated with psychopathy-related traits. Furthermore, several lipid metabolism-related genes, including ABCA1, ABCG1, NPC1, DGAT2, and TLR4, showed expression patterns suggestive of altered intracellular lipid trafficking and lysosomal lipid accumulation. ABCA1 expression correlated positively with outward anger expression (STAXI-II), whereas ABCG1 and TLR4 were negatively associated with inwardly expressed anger (STAXI-II). Conclusions: These findings support a model in which innate immune activation and dysregulated lipid metabolism contribute to aggression-related phenotypes and severe violent behavior. Although exploratory and limited by sample size, the results highlight potential molecular pathways underlying pathological aggression and warrant further investigation in larger cohorts. Full article

Objective: Depressive symptoms exist on a continuum in the general population, yet the underlying neurobiological mechanisms, particularly the interplay between resting-state networks and task-evoked social cognitive responses, remain elusive. Methods: Leveraging the Human Connectome Project (HCP) dataset, we included 867 participants. With depression scores as the independent variable and age/sex as covariates, we systematically examined associations with sleep quality, negative emotions, sensory scores, gray matter volume (GMV), fractional amplitude of low-frequency fluctuations (fALFF), multi-seed resting-state functional connectivity (rsFC), as well as brain activation and behavioral performance during working memory, emotion recognition, social cognition, relational reasoning, language comprehension, and gambling tasks. The statistical threshold was set at voxel-level p < 0.001 (uncorrected) combined with cluster-level FWE correction at p < 0.05. Results: (1) Depression scores were positively correlated with sleep disturbances, negative emotions (anger/fear), and pain. (2) In resting-state, depression scores negatively correlated with ventral striatum (VS)–cerebellum/parahippocampal gyrus/fusiform rsFC, yet positively correlated with pregenual anterior cingulate cortex (preACC)–supplementary motor area (SMA) rsFC. (3) In task-fMRI, only the social task showed a positive association with task accuracy and regional activation in bilateral pre/postcentral gyri, superior temporal gyri, left middle frontal gyrus, and SMA/paracentral lobule. Conclusions: Elevated depression scores are linked to a pattern that may reflect relative decoupling between reward and perceptual systems, along with enhanced connectivity in cognitive control circuits. Socially, high scorers exhibit a pattern suggestive of compensatory hypervigilance, accompanied by enhanced behavioral performance. This study provides multidimensional evidence for the dimensional neural representation of depressive symptoms. Full article

Considered a global public health priority, sepsis is characterized by life-threatening organ dysfunction caused by a dysregulated host response to infection. Its heterogeneous clinical presentation arises, in part, from pre-existing chronic conditions such as hypertension, metabolic syndrome, diabetes, alcohol exposure, psychosocial stress, and periodontitis, which induce persistent systemic changes even before the infectious event. This narrative review synthesizes evidence from experimental models and clinical studies to clarify the molecular and immunological mechanisms by which chronic conditions influence the septic state. We discuss how these conditions converge on common pathophysiological mechanisms, including low-grade chronic inflammation, oxidative stress, endothelial and mitochondrial dysfunction, and changes in the microbiota and neuroimmune regulation. Pathways such as TLR-NF-κB signaling and the NLRP3 inflammasome are maintained in a basal state of activation, lowering the threshold for hyperinflammatory responses and increasing the risk of multiple organ dysfunction syndrome. In conclusion, understanding these phenotypes can guide the identification of biomarkers and the development of personalized therapeutic strategies, thereby moving beyond one-size-fits-all approaches to the management of sepsis and septic shock. Full article

Postbiotic preparations contain inanimate microbial cells and a diverse mixture of cell-wall structures, proteins, polysaccharides, lipids, metabolites, and vesicle-associated materials. Although many of these components have been proposed as key bioactives, most are identified through compositional profiling, enrichment in active fractions, or testing of purified molecules. Such findings demonstrate biological activity but do not necessarily show that a candidate contributes to the effect of the original preparation. This review examines the experimental approaches used to narrow candidate lists and evaluate functional contribution, including phenotype-guided comparison, activity-guided fractionation, selective depletion, multi-omics profiling, structural characterization, dose–response testing, mechanistic intervention, and reconstitution. A structured narrative search of Web of Science Core Collection, PubMed, and Scopus through 30 March 2026, supplemented by citation tracking, identified the relevant literature; 15 representative primary studies that examined defined candidates and provided evidence beyond compositional detection were selected and appraised across seven preparation-level attribution domains. An appraisal of representative studies shows that current evidence largely supports the activity of individual candidates, whereas preparation-level attribution remains uncommon. Stronger evidence requires quantification of the candidate in the source material, selective removal with appropriate controls, and restoration at a preparation-relevant dose. Structural heterogeneity, processing history, molecular state, dose, and experimental context must also be considered. This evidence-based approach can support bioactive-component validation, batch consistency, and the design of future preclinical and human studies. Full article

Background: Thromboembolic events (TEEs) are recognized complications in thalassaemia, arising from a hypercoagulable state driven by multiple proposed mechanisms. These concerns have prompted numerous investigations to better understand the underlying prothrombotic pathways. This study aimed to compare and correlate the levels of fragmented red blood cells (FRCs), hypercoagulable protein markers, and erythrocyte phosphatidylserine (PS) exposure in thalassaemia patients. This 12-month prospective case-control study at HPUSM recruited 34 thalassaemia patients (21 with thalassaemia major and 13 with thalassaemia intermedia) and 10 healthy controls. Methods: FRCs, erythrocyte PS, protein C, free protein S, and antithrombin III levels were measured. Results: A total of 44 subjects were included, with a mean age of 22.43 ± 10.45 years; most were male (61.4%) and Malay (86.4%). Median FRCs and PS exposure were significantly elevated in both thalassaemia groups compared to controls (p < 0.001 for FRCs; p = 0.048 for PS). Mean protein C and free protein S levels were significantly reduced in thalassaemia major (55.00 ± 10.20% and 65.77 ± 8.66%) and thalassaemia intermedia (61.23 ± 16.99% and 61.11 ± 14.65%) compared to controls (101.60 ± 18.97% and 95.12 ± 23.57%) (p < 0.001 for both), while antithrombin III levels were not significantly different. A significant negative correlation was observed between PS exposure and protein C (p = 0.014). Protein C was positively correlated with free protein S (p = 0.021) and antithrombin III (p < 0.001). Conclusions: Elevated PS exposure and reduced protein C and free protein S levels in thalassaemia patients indicate a potential procoagulant phenotype. Full article