Search Results (19,088)

A muscle biopsy (MB) is an important tool to help differentiate idiopathic inflammatory myopathies (IIMs) from hereditary muscular diseases (HMDs). The usefulness of immunohistochemical stains of the major histocompatibility complex class I and the membrane attack complex are controversial, as both may be identified in some HMDs. More sensitive markers of IIMs have recently been used, such as myxovirus resistance A (MxA), a type I interferon-inducible protein. We selected skeletal MB samples from 81 patients diagnosed with IIM and HMD harbouring overt inflammatory infiltrates on their MBs in the period between March 2022 and September 2024. Two groups were identified: the IIM group (46 cases) and the HMD group (35 cases). We characterized and compared the patterns of MxA protein expression among the two groups. In the IIM group, positive sarcoplasmic MxA expression was detected on the myofibres of 10 patients (24%), among whom were eight dermatomyositis patients. In the HMD group, we did not identify any sarcoplasmic positivity. However, five patients (14%) showed positive labelling restricted to the sarcolemmal membrane, including non-necrotic or regenerating fibres. Our study demonstrates the value of MxA for increasing dermatomyositis diagnostic accuracy and suggests the potential role of interferon type I in the pathophysiology of HMD. Full article

Alzheimer’s (AD) and Parkinson’s disease (PD) are prominent neurodegenerative disorders characterized by early synaptic loss, which correlates more closely with clinical symptoms than neuronal death. This synaptic impairment is primarily driven by disruptions in synaptic vesicle (SV) trafficking, a critical process for maintaining synaptic integrity through a tightly regulated cycle involving clustering, docking-priming, Ca²⁺-triggered fusion, and endocytosis. In AD, amyloid-β (Aβ) oligomers interfere with SNARE-mediated fusion and endocytosis, while hyperphosphorylated tau obstructs vesicle mobility and docking, resulting in cumulative toxicity that aggravates SV defects. Conversely, in PD, α-synuclein (α-syn) aggregation alters vesicle clustering, membrane fusion, and recycling, and these effects are further influenced by Leucine-rich repeat kinase 2 (LRRK2)-Rab-related trafficking defects and the selective vulnerability of dopaminergic terminals. Different from previous reviews that address synaptic dysfunction in a broader manner, the present review is specifically organized around the SV trafficking cycle and compares both shared presynaptic endpoints and disease-specific upstream mechanisms in AD and PD. In addition, recent mechanism-oriented therapeutic strategies are summarized. This vesicle-cycle-centered perspective may provide a clearer framework for understanding presynaptic pathology and for guiding the development of earlier and more targeted interventions. Full article

The common carp (Cyprinus carpio) kidney uniquely integrates excretory nephrons, renal hematopoietic tissue, and hormonally active thyroid follicles, positioning it as a candidate “multipurpose biomarker organ” for pollutants like perfluorooctanoic acid (PFOA), a prototype long-chain PFAS and persistent organic pollutant exhibiting nephrotoxic, immunotoxic, and thyroid-disrupting effects. Building on prior histological, ultrastructural, and morphometric analyses from carp exposed to waterborne PFOA (0, 200 ng L⁻¹, 2 mg L⁻¹ for 56 days), a hierarchical multipurpose index comprising nephrotoxic, immunotoxic, and thyrotoxic subindices was developed from z-scored light-, electron-microscopy, and morphometric features, enabling cross-scale integration; proximal tubule vesiculations and effete rodlet cells (RCs) were newly quantified from archival electron micrographs. The subindices captured PFOA-induced glomerular hyperfiltration with proximal protein reabsorption and collecting duct RCs recruitment (nephrotoxic); hematopoietic tissue RCs recruitment, clustering, and exocytosis (immunotoxic); and increased thyroid follicle abundance/vesiculation, cross-sectional area, and perimeter (thyrotoxic). Quantification of previously only qualitatively assessed features provided statistical validation, while radar plot integration rendered results more intuitively evident—particularly highlighting the non-monotonic thyroid response—condensing organ-level complexity into a coherent framework supporting carp kidney as a translational One Health model for multi-endpoint waterborne pollutant assessment. Full article

Background/Objectives: T-cell lymphomas are relatively common in veterinary species, yet current diagnostic tools such as PCR-based clonality assays often lack sensitivity and specificity. In humans, we recently developed two related tissue-based diagnostic approaches based on the differential detection of the mutually exclusively expressed TCRbeta1 and 2 (TCRβ1 and 2) constant region proteins, or the corresponding TRBC1 and TRBC2 transcripts. Analogous to the detection of kappa/lambda light chains for the diagnosis of B-cell/plasma cell neoplasms in human clinical practice, our TCRβ1/2 diagnostic assay has the potential to transform veterinary diagnostic workflows. Methods: We identified and confirmed the sequences of the relevant TRBC1 and TRBC2 sequences in both cats and dogs, focusing on the 3′ untranslated region (UTR), where there is the least sequence homology between TRBC1 and TRBC2. To allow us to design appropriate probe sequences, we confirmed a lack of 3′UTR in either species, and we observed limited 3′ untranslated region UTR sequence polymorphism in the cat but not in the dog 3′UTR. We designed BaseScope™ RNA in situ hybridization probes targeting the 3′ UTR to distinguish between TRBC1 and TRBC2 transcripts in formalin-fixed paraffin-embedded tissues. Results: In normal tissues, we found the TRBC2:TRBC1 expression ratio to be similar to the 1.2:1 ratio in humans, between 1:1 and 3:1, skewing towards TRBC2, in both dogs and cats. These findings were corroborated using quantitative reverse transcription PCR. Applying our in situ hybridization probes to cases of T-cell lymphoma in dogs and cats, we demonstrated that an assay for differential expression of TRBC1 and TRBC2 in T-cell populations could identify clonal T-cell populations, as in human diagnostics. If further studies corroborate this proof-of-concept study, TRBC1/2 detection could obviate the need for slow, complex and expensive multiplexed PCR-based (PCR for antigen receptor rearrangements (PARR)) clonality assays. Conclusions: This study provides proof-of-concept data for a novel diagnostic approach that could simplify and substantially improve the accuracy of lymphoma diagnostics in veterinary medicine, by detecting TRBC1/2 transcripts. Full article

Background: Heart failure (HF) is a leading cause of morbidity and mortality worldwide. AMP-activated protein kinase (AMPK) is a central regulator of energy homeostasis, and its dysregulation is implicated in HF pathophysiology. Traditional Chinese Medicine (TCM) has been investigated in HF management, but a systematic synthesis of preclinical evidence on TCM-mediated AMPK modulation is lacking. Methods: PubMed and Web of Science were searched from January 2020 to December 2025 using a comprehensive strategy combining terms for AMPK, HF, and TCM. Studies were included if they were original research investigating TCM-derived compounds or formulas in HF models and reporting AMPK modulation. Study quality and evidence levels were assessed using predefined criteria. The review was conducted in accordance with PRISMA 2020 guidelines. Results: Of 243 records identified, 56 studies met the inclusion criteria (7 from database search and 49 from manual screening). Direct evidence for AMPK-dependent cardioprotection was limited. Cinnamaldehyde and paeoniflorin showed the most rigorous validation with confirmed target engagement and loss-of-function rescue. Berberine, crocin, ginsenoside Rb1, and honokiol demonstrated pathway-specific effects validated by pharmacological or genetic approaches. Most complex herbal formulas provided correlative evidence only, with Fuyu Decoction being a notable exception where AMPK agonist EX229 confirmed pathway involvement. Conclusions: Current evidence for TCM-mediated AMPK modulation in HF remains predominantly preliminary and correlative. Future research should prioritize causality validation using genetic models and human-relevant systems. Full article

Alzheimer’s disease (AD) remains a significant global health challenge, highlighting the need for novel dual inhibitors targeting acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). This study investigated the trunk bark of Terminalia triptera Stapf. as a potential source of bioactive secondary metabolites for AD management. Bioassay-guided isolation led to the identification of two flavan-3-ol derivatives, epicatechin-(4β→8)-ent-catechin (1) and (−)-catechin (2), reported here for the first time from this species. In vitro assays demonstrated that the dimeric compound 1 exhibited stronger dual inhibitory activity against AChE and BChE, with IC₅₀ values of 4.41 × 10⁻⁴ and 4.75 × 10⁻⁴ mol/L, respectively, surpassing the reference compound berberine chloride. Molecular docking analysis revealed that compound 1 formed extensive interactions within both catalytic and peripheral anionic sites of the enzymes. Density Functional Theory (DFT) calculations indicated high kinetic stability, reflected by large HOMO–LUMO energy gaps (6.66–6.97 eV), while global reactivity descriptors suggested lower electrophilicity (ω = 2.19–2.34 eV), supporting a potentially favorable safety profile. Furthermore, 100 ns molecular dynamics simulations confirmed stable ligand–protein complexes stabilized by hydrogen-bond networks and deep binding within catalytic pockets. Overall, these findings highlight T. triptera and its dimeric proanthocyanidins as promising multi-target candidates for anti-Alzheimer drug development. Full article

Diabetic retinopathy (DR) is a leading cause of vision loss worldwide and represents a complex neurovascular complication of diabetes mellitus driven by chronic hyperglycemia. Increasing evidence identifies oxidative stress—defined as an imbalance between reactive oxygen species (ROS) production and antioxidant defenses—as a central pathogenic mechanism linking metabolic dysregulation to retinal injury. The retina is particularly vulnerable to oxidative damage due to its high metabolic demand, elevated oxygen consumption, and abundance of polyunsaturated fatty acids. Hyperglycemia activates multiple interconnected biochemical pathways, including the polyol and hexosamine pathways, protein kinase C signaling, advanced glycation end-product formation, and lipid peroxidation, all of which converge on excessive ROS production and mitochondrial dysfunction. Growing attention has focused on oxidative stress biomarkers as tools to characterize DR severity and progression. Elevated systemic markers of lipid, protein, and DNA oxidation, together with impaired antioxidant capacity, correlate with disease stage, while oxidative biomarkers detected in aqueous and vitreous humor reflect localized retinal injury. Importantly, oxidative stress biomarkers are also associated with functional outcomes, including best-corrected visual acuity and diabetic macular edema. Integration of systemic and ocular oxidative biomarkers with clinical staging may improve risk stratification and support personalized therapeutic strategies in DR. Full article

Excessive macrophage activation is thought to be the primary cause of the cytokine storm that results in severe coronavirus disease 2019 (COVID-19) complications. The underlying mechanisms remain elusive, and more research is needed to find disease-critical genes and develop effective therapies. In this study, we used publicly accessible microarray datasets of cytokine storm in cultured human monocyte-derived macrophages challenged with cytokines, and employed bioinformatics, such as weighted gene co-expression network analysis (WGCNA) and differential expression analysis, to dissect gene expression profiles and identify putative disease-related molecules. Initially, three co-expression modules and related key genes were discovered, which highly correlated to macrophages challenged with cytokines. Then, a preliminary gene expression signature consisting of 203 upregulated and 24 downregulated genes was identified. Next, protein–protein interaction analysis and hub gene identification were used to identify 11 crucial hub genes, namely tripartite motif-containing 21 (TRIM21), interferon regulatory factor 1 (IRF1), guanylate binding protein 1 (GBP1), transporter associated with antigen processing 1 (TAP1), nuclear myosin I (NMI), interleukin 15 receptor subunit alpha (IL15RA), apolipoprotein L1 (APOL1), intercellular adhesion molecule 1 (ICAM-1), protein tyrosine phosphatase non-receptor type 1 (PTPN1), E74-like ETS transcription factor 4 (ELF4) and guanylate binding protein 2 (GBP2). Then, the LINCS L1000 characteristic direction signatures search engine (L1000CDS2) was employed for drug repurposing studies. Dasatinib was predicted to be the leading therapeutic compound to perturb the gene signature of cytokine storm in human macrophages. Connectivity Map results suggested that dasatinib may normalize ICAM-1 expression. In addition, the results of molecular docking studies and molecular dynamics simulation revealed that dasatinib may spontaneously interact with ICAM-1 via several key residues and form a relatively stable protein–ligand complex. Overall, this work, based on an analysis of co-expression correlation networks, gene expression signatures and pivotal genes in human macrophages challenged with cytokines, combined with drug repurposing studies, demonstrated that dasatinib may interact with ICAM-1 and could be a potential candidate for cytokine storm. However, due to the limitations of computational approaches, further experimental validation is necessary. Full article

Introduction: Ubiquinol–cytochrome c reductase core protein II (UQCRC2) encodes a core subunit of the mitochondrial electron transport chain (ETC) complex III (CIII). Biallelic pathogenic variants in UQCRC2 have been associated with mitochondrial disease characterized by lactic acidosis, developmental delay, hepatopathy, and episodic metabolic decompensation. Methods: We reviewed the biochemical phenotypes of 14 individuals possessing UQCRC2 variants, including two novel cases. We performed biochemical studies of mitochondrial respiration and oxidative phosphorylation (OXPHOS) complex measurements in patient-derived fibroblasts. Results: We report reduced CIII activity in a majority of individuals possessing variants in UQCRC2, as well as biochemical findings consistent with impaired mitochondrial energy metabolism, though impairments in mitochondrial respiration were variable. The two previously unreported, unrelated patients possessing the likely pathogenic missense variant c.361T>C, p.Tyr121His in UQCRC2 in trans with a 16p12.2 microdeletion encompassing UQCRC2 showed milder phenotypes, less severe metabolic decompensations, and no long-term neurological impairments. Both individuals display reduced CIII activity and mitochondrial respiratory dysfunction. Discussion: These data expand the current understanding of genotypes associated with UQCRC2-associated mitochondrial disease to include the novel 16p12.2 microdeletion. These data also highlight the consistent biochemical phenotype associated with UQCRC2-associated mitochondrial disease, and the need for consistent biochemical and respiratory assessment of individuals possessing UQCRC2 variants to further our understanding of this phenotype. Full article

Cancer immunotherapy has transformed the clinical management of several malignancies; however, its efficacy remains limited in tumors with low mutational burden and restricted availability of classical mutation-derived neoantigens. In this context, increasing evidence indicates that the tumor immunopeptidome extends far beyond canonical protein-coding regions, incorporating peptides derived from non-coding transcripts through non-canonical translation mechanisms. Long non-coding RNAs (lncRNAs), traditionally regarded as transcriptional or post-transcriptional regulators, have recently emerged as an unexpected source of small open reading frame-encoded peptides (lncPEPs). A subset of these peptides is processed and presented by major histocompatibility complex class I molecules, generating tumor-specific neoantigens capable of eliciting CD8⁺ T cell responses. Owing to the high tissue and context specificity of lncRNA expression, lncRNA-derived neoantigens offer unique advantages over mutation-based targets, including increased tumor selectivity and potential recurrence across patient subsets. In this review, we synthesize current knowledge on the biogenesis, detection, and immunogenic potential of lncRNA-derived peptides, highlighting experimental and computational strategies for their identification within the cancer immunopeptidome. We discuss the challenges associated with their validation and clinical translation, as well as their relevance for the development of vaccines and adoptive T cell–based therapies. Finally, we illustrate these concepts using epithelial ovarian cancer as a representative model of low-mutational-burden tumors, where lncRNA-derived neoantigens may help overcome current limitations of immunotherapy and enable patient stratification for personalized treatment approaches. Full article

Parainfluenza virus 5 (PIV5) can establish persistent infections in host cells despite encountering innate immune defenses, including the complement (C′) system. The host determinants that enable persistently infected cells (PI) to evade C’-mediated clearance remain largely undefined. Here, we identify the mitochondrial antiviral signaling (MAVS) protein, a central adaptor in double-stranded RNA-triggered antiviral and pro-survival signaling pathways, as a critical mediator of both PIV5 persistence and acquired resistance to C’ lysis. Wild-type (WT) PIV5-infected A549 cells were initially sensitive to C’-directed killing, but these cells rapidly establish a PI in culture with ~25% of the cell population becoming resistant to C’ lysis by day 2 and ~75% by day 4. In contrast, PIV5-infected A549 MAVS-deficient (MAVS KO) cells exhibited elevated viral gene expression, increased deposition of C3 and the membrane attack complex, and were more susceptible than WT cells to C′ killing. PIV5-infected MAVS KO cells showed rapid cytopathic effects and never established a stable PI. While pharmacological suppression of viral gene expression with ribavirin (RBV) restored the survival of PIV5-infected MAVS KO cells into a long-term PI-like state, these RBV-induced PI cells remained sensitive to C’ lysis. Collectively, these findings demonstrate a role of MAVS in modulating a PIV5 infection in culture, to facilitate both the conversion of a PIV5 acute infection to a PI and development of resistance to C’ killing. Full article

Premium coffee depends on high-quality beans, influenced by a combination of genetic, environmental, and postharvest factors. This review summarizes the mechanisms underlying coffee bean quality, with an emphasis on the genetic differences between Coffea arabica and Coffea canephora, as well as the integrated roles of environmental conditions, agronomic practices, including nutrient and shade management, and postharvest processing technologies. The allotetraploid genome of C. arabica is influenced by homoeologous exchanges and subgenome-biased expression (such as decreased DXMT activity that reduces caffeine), which contribute to its complex flavor profile. Key lipid metabolism genes, particularly FADS2, play a critical role in regulating lipid metabolism. The effects of altitude (1600–2000 m) and shade influence various metabolic pathways. Cooler temperatures promote sugar accumulation, while excessive shading hinders carbon assimilation and the development of flavor precursors. Postharvest processing significantly influences flavor, where microbial or enzymatic treatments enhance sensory attributes. In addition, methods like natural, washed, or honey processing modulate various nonvolatile compounds, impacting lipid emulsification and aroma retention. Multi-omics analyses suggest that MYB proteins play a key role in regulating pathways involved in caffeine, chlorogenic acids, and terpenes. Effective hermetic packaging prevents oxidation, thereby preserving freshness. Overall, superior coffee quality stems from synergistic interactions across genetic, ecological, agronomic, and processing factors, highlighting the need for the development of an integrated strategy to support the sustainable production of premium coffee. Full article

This work investigated the membrane fouling mechanisms during the microfiltration of oat protein–β-glucan complexes. Microfiltration experiments were conducted under various pH conditions, protein-to-polysaccharide ratios, and ionic strengths. The fouling behavior was analyzed using multiple membrane fouling models to systematically elucidate the relationships among the particle characteristics, rheological behaviors, and membrane fouling. When the pH was adjusted to 7.8, the multimodal particle size distribution of the complexes promoted the formation of a loosely structured cake layer on the membrane surface, accompanied by partial obstruction of membrane pore entrances. On the contrary, the complexes, shown as having a monomodal particle size distribution and similar particle size to the membrane pore, formed compact cake layers and strong membrane fouling resistance. At pH 4.8, protein hydrophobic aggregation generated large particulate clusters that formed a loose cake layer during microfiltration, resulting in a decrease in membrane fouling resistance. Increasing the β-glucan content reduced membrane resistance through enhancing steric hindrance and hydrophilicity. This research provides a theoretical foundation for optimizing membrane separation process parameters in the production of diversified oat-based products. Full article

Sporulation represents a complex metabolic reprogramming process in bacteria. In this study, we used CRISPR-Cpf1 to knock out spoIIE and rsfA in Bacillus licheniformis. The ΔspoIIE strain completely lost sporulataion capacity, while ΔrsfA showed a 25% reduction. Although viable cell counts decreased by 80.7% and 45.7%, respectively, glucose consumption and 2,3-butanediol synthesis remained unchanged, and acetoin synthesis increased by 19% in ΔspoIIE. Per-cell metabolic rates were significantly enhanced: glucose uptake increased 2.7–3.4-fold, acetoin synthesis 2.3–4.2-fold, 2,3-butanediol synthesis 1.7-fold, and heterologous protein expression 10–15-fold. These findings demonstrate that blocking sporulation liberates metabolic resources and enhances the specific productivity of vegetative cells, providing a strategy for engineering high-performance B. licheniformis cell factories. Full article

Skin aging is a complex biological process triggered by intrinsic and extrinsic factors, causing structural and functional deterioration, and its mitigation is a priority in cosmetology and functional food science. Skin fibroblasts, which mediate skin repair, wound healing and inflammation, are closely associated with aging. Sea cucumber collagen peptides exhibit prominent anti-aging, immunomodulatory and antioxidant properties, yet their mechanisms in ameliorating skin aging remain elusive, necessitating further exploration. This study verified the anti-skin aging efficacy of sea cucumber collagen peptides in D-galactose-induced aging mice, and explored whether the mechanism involves regulating endoplasmic reticulum (ER) stress in skin fibroblasts. Aging mice were gavaged with sea cucumber collagen peptides; skin moisture, barrier function and hydroxyproline content were measured, and skin morphology was observed. Immunofluorescence and Western Blot were used to detect ER stress-related proteins. Results showed that sea cucumber collagen peptides significantly improved aging mouse skin barrier function, elevated water and collagen fiber contents, and ameliorated the status of fibroblasts and prickle cells. The underlying mechanism may involve inhibiting ER stress in skin fibroblasts and enhancing prickle cell function. These findings confirm the peptides’ high bioavailability and potential as anti-aging functional food ingredients, providing insights for skin aging prevention. Full article