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PubMed2026

Metabolic ketosis attenuates NLRP3 inflammasome activation and is associated with improvements in hepatic steatosis and liver stiffness in MASLD: a pilot randomized controlled trial.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized as a systemic metabolic-inflammatory disorder in which metabolic stress and innate immune activation, particularly through the NLRP3 inflammasome, contribute to disease progression. Metabolic ketosis, characterized by increased levels of circulating ketone bodies, especially β-hydroxybutyrate, has emerged as a promising strategy to modulate substrate utilization, inflammatory signaling, and hepatic injury. However, clinical evidence integrating molecular, metabolic, and hepatic outcomes remains limited. METHODS: In this pilot randomized controlled trial, 20 participants with newly diagnosed MASLD were randomly assigned to either a 3-month intervention with a daily C8-enriched medium-chain fatty acid formulation (m-CAP; meta-Capridin, providing approximately 20 g/day of C8) or a standardized low-carbohydrate dietary protocol. Metabolic indices, inflammatory mediators, adipokines, and hepatic enzymes were assessed. The expression of key inflammasome components (NLRP3, caspase-1, and ASC) was evaluated in peripheral blood mononuclear cells, and hepatic steatosis and liver stiffness were measured via transient elastography. RESULTS: The C8-enriched intervention was associated with increased circulating β-hydroxybutyrate levels, indicating the achievement of nutritional ketosis. Changes over time were observed in metabolic parameters, including fasting serum glucose (p < 0.05), HOMA-IR (p < 0.05), body fat percentage (p < 0.05), and BMI (p < 0.05). Alterations in inflammatory mediators and adipokine-related outcomes were also observed following the intervention. At the molecular level, changes in inflammasome-related markers were detected, including caspase-1 mRNA expression (p < 0.05) and NLRP3 expression at the transcriptional (p < 0.05) and protein levels (p < 0.01), whereas ASC expression remained unchanged. Changes in hepatic steatosis (p < 0.01) and liver stiffness measurements were observed following the intervention. Given the absence of significant Group × Time interactions for several secondary outcomes, these findings should be interpreted as exploratory and hypothesis-generating. CONCLUSIONS: Induction of metabolic ketosis was associated with changes in metabolic, inflammatory, and hepatic parameters in patients with MASLD. The observed associations between ketosis, inflammasome-related markers, and noninvasive liver outcomes warrant further investigation of ketosis-based interventions as adjunctive approaches in MASLD. Larger and longer-term clinical trials are needed to confirm these findings and to determine whether short-term changes in liver stiffness reflect sustained alterations in hepatic status rather than structural fibrosis regression. TRIAL REGISTRATION: Iranian Registry of Clinical Trials (IRCT); Unique identifier: IRCT20170315033086N12; Registration date: 19 September 2024; Registry URL: https://www.irct.ir. IRCT is a primary registry in the WHO Registry Network (https://www.who.int/tools/clinical-trials-registry-platform/network/primary-registries).

Humans↗

PubMed2026

An Update on Inborn Errors of V(D)J Recombination.

V(D)J recombination is the fundamental process by which developing T and B lymphocytes generate diverse antigen receptors, enabling adaptive immunity. This tightly regulated program operates exclusively in lymphoid precursors during G1 phase and depends on the lymphocyte-specific RAG1-RAG2 recombinase to introduce programmed DNA double-strand breaks at recombination signal sequences, followed by repair through the classical nonhomologous end joining (c-NHEJ) pathway. Disruption of any step in this molecular choreography compromises antigen receptor diversity and underlies a spectrum of inborn errors of immunity (IEIs), ranging from severe combined immunodeficiency (SCID) to immune dysregulation with autoimmunity and granulomatous disease. In this review, we place disorders of V(D)J recombination within the broader framework of T-cell development, detailing the temporal waves of recombinase activity, chromatin accessibility, and DNA damage responses that guide thymocyte differentiation. We discuss pathogenic variants affecting the cleavage phase [RAG1, RAG2, and the recently identified RAG cochaperone NudC domain-containing 3 (NUDCD3)], end processing (ARTEMIS), ligation and repair (LIG4, XLF, XRCC4, PRKDC), and genome surveillance pathways (ATM, MRN complex, RNF168), highlighting genotype-phenotype correlations and mechanisms driving immune deficiency and dysregulation. We briefly review recent diagnostic advances, including newborn screening using T-cell receptor excision circles, repertoire sequencing, and functional assays, alongside current therapeutic strategies. Finally, we outline key unanswered questions and argue that continued integration of clinical observation with molecular discovery is essential to improve outcomes and deepen understanding of adaptive immune development.

Humans↗

PubMed2026

Efficient rDNA-mediated multi-copy integration of gene clusters in Aureobasidium melanogenum.

Aureobasidium melanogenum is a promising non-conventional yeast chassis for synthetic biology. However, techniques recombining large genetic fragments, such as gene clusters, are still unavailable, hindering further metabolic reprogramming in this chassis. To achieve multi-copy integration of genes, we employed highly repetitive ribosomal DNA (rDNA) sequences in A. melanogenum as homologous recombination sites for large genetic fragments. First, integration efficiency of three different regions of A. melanogenum rDNA were investigated: RNA polymerase I promoter region (rDNA1, 1.0 kb), partial 26S rDNA region (rDNA2, 1.0 kb), and RNA polymerase I terminator region (rDNA3, 1.0 kb). Our findings revealed that the highest copy numbers and expression stability were observed for the short heterologous green fluorescent protein gene (gfp, 0.7 kb) and the long native polyketide synthase gene (pks, 7.0 kb) after rDNA1-mediated integration. Specifically, the copy numbers reached 7.0 and 8.0 for gfp and pks, respectively, and they remained stably expressed in the genome after 120-h subculturing. Furthermore, an 11.0 kb gene cluster (comprising the native pks, phosphopantetheinyl transferase (npg1), and scytalone dehydratase genes (scd) responsible for melanin biosynthesis) was integrated at the rDNA1 site, resulting in stable recombination with 15.0 copies and an approximately 12-fold increase in melanin production. Overall, the convenience and efficiency of the proposed rDNA-mediated multi-copy insertion strategy will facilitate superior metabolic engineering of A. melanogenum chassis cells.

Multigene Family↗

PubMed2026

Spatially confined electrochemical strategy with DNA-assembled nanogaps for SNP detection.

Accurate detection of low-abundance single nucleotide polymorphisms (SNPs) against a large excess of homologous wild-type sequences requires both selective molecular recognition and effective transduction of small sequence differences into measurable signals. Here, we report a spatially confined electrochemical strategy that couples sequence-selective recognition with size-dependent mass-transport gating. DNA-hybridization-driven self-assembly of gold nanoparticles (AuNPs) forms a three-dimensional self-assembled electrode (3D-SAE) with a DNA-defined interparticle architecture. Competitive probes (SP/WP) convert single-base recognition into distinct molecular-size states: the SNP-associated pathway preferentially triggers a hybridization chain reaction (HCR), generating bulky AuNP-anchored HCR/methylene blue complexes (Au@HCR/MB) with reduced electrochemical accessibility through the porous 3D-SAE, whereas the wild-type pathway does not trigger HCR and maintains a high-current response from more readily accessible MB-containing species. Thus, sequence recognition is translated into a molecular-size difference and subsequently into an electrochemical signal through differential mass transport. Under buffer conditions, the platform achieved a statistically estimated detection limit of ∼0.47 fM and a quantitative range of 1 fM-100 pM. It discriminated a 0.1% mutant abundance in a fragmented genomic-DNA background. The downstream signal-transduction chemistry is enzyme-free and isothermal. This work establishes a mechanistical recognition-size-conversion-mass-transport-gating architecture for electrochemical nucleic acid analysis.

Polymorphism, Single Nucleotide↗

PubMed2026

Protein sorting and proteostasis mechanisms in CFTR-related exocrine pancreas dysfunction: A systematic narrative review.

The pancreas consists of exocrine and endocrine compartments. In the exocrine pancreas, cystic fibrosis transmembrane conductance regulator (CFTR) functions mainly in ductal epithelial cells as a chloride and bicarbonate channel. Its activity depends on proper protein folding, trafficking, and localization to the apical membrane. This systematic narrative review aims to synthesize the available evidence on the role of protein sorting machinery in CFTR channelopathies and its contribution to exocrine pancreatic dysfunction. A thorough search was conducted using PRISMA criteria on PubMed, Wiley Online Library, and Scopus for studies published in English between January 2000 and November 2025. Twenty studies that met the inclusion criteria were included in this review. Pathogenic CFTR variants impair protein folding, endoplasmic reticulum (ER) exit, and endosomal recycling, resulting in reduced apical membrane expression and stability. These defects disrupt the localization of associated transporters and secretory proteins, impair ductal bicarbonate secretion, alter zymogen handling, and promote acinar injury, although these claims are supported mainly by indirect experimental models and therefore require clinical confirmation. CFTR channelopathies in the exocrine pancreas encompass both ion transport defects and broader disruptions of protein sorting machinery. CFTR may contribute to the assembly, stabilization, or localization of selected apical transport complexes, and its loss can secondarily alter epithelial organization. Therapeutic approaches targeting both channel correction and intracellular trafficking may improve pancreatic function and mitigate disease progression.

Humans↗

PubMed2026

ChIP-seq profiling identifies diapause-regulated H3K27me3 targets in the fat body of Culex pipiens.

Culex pipiens, a principal vector of significant arboviruses, survives winter through diapause, a hormonally controlled inactive phase that enhances endurance under severe cold circumstances. Recent data suggests that epigenetic processes, namely histone post-translational modifications (hPTMs), play a crucial role in regulating seasonal dormancy. Prior studies from our laboratory indicated a decrease in the methylation of Histone 3 (H3K27me3) in diapausing fat body tissue, associated with elevated expression of the histone demethylase UTX. Nonetheless, the precise genomic areas impacted by these chromatin alterations remained unidentified. We used chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq) to delineate the genome-wide distribution of H3K27me3 across fat body chromatin in diapausing (D) and non-diapausing (ND) female Cx. pipiens. Notably, the higher signal at transcription start sites (TSSs) reflects localized redistribution rather than a global decrease, as diapausing fat bodies retain less H3K27me3 overall but concentrate it at promoters. To investigate the functional significance of these chromatin alterations, we confirmed a number of target loci via ChIP-qPCR and assessed gene expression with qRT-PCR. We identified many critical genes that were markedly increased in diapausing mosquitoes, exhibiting an inverse relation to H3K27me3 enrichment. Our data demonstrates different H3K27me3 chromatin landscapes between diapausing and non-diapausing Cx. pipiens, corroborating a hypothesis of selective, locus-specific repression in the non-diapause state and its targeted removal during diapause to permit activation of dormancy-associated genes. These results suggest that chromatin remodeling is a core driver of the diapause switch.

Animals↗

PubMed2026

Intraspecific variation in Bothrops neuwiedi snake venom: Influence of age and sex.

Snake venom is a complex mixture of molecules and is subject to intraspecific variations due to the influence of abiotic and/or biotic factors, one of which is the animal's ontogeny. Some studies have already shown the influence of age on the composition and properties of snake venom, but these variations are not uniform, and each species may exhibit a specific pattern of variation. Therefore, this study aimed to analyze the influence of age on the venom of Bothrops neuwiedi, using 5 age groups, differentiating between males and females. To this end, we analyzed the protein profile of these venoms (using SDS-PAGE, HPLC, and proteomic analyses); enzymatic activities (PLA2, LAAO, and proteolytic activities); coagulant activity, in vivo assays (MDH; LD50 and ED50), and immunorecognition tests (Western blotting and ELISA). Protein profile analysis showed that males exhibited a gradual increase in SVMP and PLA2 concentrations. Both sexes showed a decrease in CTL concentration and a loss of PLA2 activity, which occurred more gradually in males. Proteolytic activity did not show clear ontogenetic differences, but both sexes showed activity peaks in the 2-year-old and senile groups, with females exhibiting higher proteolytic activity than males. Regarding LAAO activity, it increased in males and decreased in females. Although the LD50 did not show age-dependent differences, the venom from the 1-year-old group took longer to cause death in mice but showed a higher hemorrhagic activity than seniles. Furthermore, more antivenom was needed to neutralize the venom from the 1-year-old group than the venom from the senile group; despite this, immunorecognition tests did not show significant ontogenetic variations. In conclusion, the venom of the snake B. neuwiedi undergoes ontogenetic variations with certain sexual differences, showing some peculiarities that have not been found in ontogenetic analyses of other species of the same genus.

Animals↗

PubMed2026

Spermidine and melatonin ameliorate heat stress-induced decline in sheep semen quality.

Heat stress impairs reproductive performance in sheep through endocrine disruption and oxidative stress. This study evaluated the protective effects of spermidine (SPD) and melatonin (MT) supplementation on semen quality in Dorper rams during summer. Twenty-four rams were randomly assigned to a control group, an SPD group (5 mg/kg, dietary supplementation), or an MT group (60 mg, subcutaneous implantation) and treated for 60 days. The temperature-humidity index (THI) was monitored throughout the experimental period. Compared with the control group, MT significantly reduced serum cortisol concentration on day 30 (P < 0.05), whereas no significant differences were observed at the other sampling time points. Serum testosterone, spermidine, and melatonin concentrations remained unchanged throughout the study (P > 0.05). SPD supplementation significantly increased ejaculate volume on day 35 and sperm motility on day 42 (P < 0.05), whereas MT did not significantly affect these parameters. Neither treatment reduced the overall sperm abnormality rate. However, both SPD and MT significantly decreased the proportion of acephalic and decaudated sperm on day 56 (P < 0.05). Neither treatment significantly affected pregnancy rate, delivery rate, or the expression of PMFBP1 and SUN5 proteins in semen (P > 0.05). Regarding oxidative stress, MT significantly downregulated CAT protein expression (P < 0.05), whereas SPD significantly reduced MDA content and SOD1 protein expression (P < 0.05); MT showed similar but non-significant trends for these two markers (P > 0.05). Collectively, these findings demonstrate that SPD and MT exert distinct protective effects against heat stress, with SPD improving selected semen quality traits and both treatments reducing sperm head-tail separation, although these benefits did not translate into improved reproductive performance.

Animals↗

PubMed2026

Surface shaving proteomics reveals a parasite-encoded protein embedded in the spore filaments of Ameson portunus.

The surfaces of microsporidian spores are frequently adorned with filamentous appendages of unknown origin and function. Although some studies suggest that these structures may be host-acquired, the absence of identified parasite-encoded components has hindered our understanding of their biogenesis and role in infection. Here, we applied surface shaving proteomics to profile the surface-exposed proteins of Ameson portunus -a microsporidian pathogen causing severe myopathy in portunid crabs. Our analysis identified 120 candidate surface proteins. Nineteen of these were highly enriched by both direct shaving and SDS-assisted methods, representing a high-confidence surfome. Among these, a previously uncharacterized protein, designated 8-2.11, was confirmed via immunofluorescence assay and immunoelectron microscopy. It was expressed early in development stage and specifically localized to the spore wall and hair-like projections (HLPs) of microsporidia. Notably, polyclonal antibodies against recombinant 8-2.11 recognized a native protein in spores, specifically labeled the HLP structures, and showed no cross-reactivity with host cells. Our results provide the first evidence of a parasite-encoded protein that is integral to HLP formation, challenging the prevailing hypothesis that these surface filaments are solely host-derived. This study establishes surface shaving as a powerful tool for microsporidian research and highlights 8-2.11 as a promising candidate for future functional studies on spore surface biology and host-parasite interactions.

Animals↗

PubMed2026

Single-cell RNA sequencing provides further insights into the immunostimulatory action of freeze-dried Lactiplantibacillus plantarum on Penaeus vannamei shrimp.

Immunostimulation through dietary interventions opened new avenues in developing disease control and prevention tools for shrimp aquaculture. We have previously shown that feeding with freeze-dried Lactiplantibacillus plantarum (LAB) increased disease resistance of Penaeus vannamei against both Vibrio parahaemolyticus and white spot syndrome virus (WSSV) based on bulk RNA sequencing of shrimp gills. This tissue participates in ion transport and serves as a first line of defense against environmental stressors and pathogenic infections. However, characterization of their cell composition and functions remains limited. Here, we implemented a single-cell RNA sequencing approach to further gather insights into how feeding with freeze-dried LAB modulates host immunity which may not be evident with bulk RNA sequencing approach. A total of five clusters with unique transcriptional signatures were identified, corresponding to pillar cells, septal cells, and sessile hemocytes. Pseudo-bulk analyses at global- and cluster-levels showed differential expression of genes related to host immunity and metabolism. We further revealed how overall transcriptomic changes are not exclusively caused by gene expression changes but may also be driven by cell population dynamics. This study highlighted how single-cell RNA sequencing approach may shed light on the mechanisms of action of immunostimulants which may be masked in bulk transcriptome analyses.

Animals↗

PubMed2026

Tranexamic acid protects human dermal fibroblasts from D-galactose-induced senescence via the GPR30/MAPK pathway.

BACKGROUND: Tranexamic acid (TXA) is widely used for pigmentary disorders, but its anti-ageing potential remains unclear. This study aimed to evaluate whether topical 3% TXA improves early periorbital wrinkles in women with facial melasma and to investigate whether TXA protects human dermal fibroblasts from D-galactose-induced senescence via the GPR30/MAPK pathway. METHODS: Fifty women with melasma were randomized to 3% TXA serum plus moisturizer or moisturizer alone for 8 weeks, with follow-up to week 12. Periorbital wrinkles were graded using a modified Fitzpatrick Wrinkle Scale (MFWS). Separately, D-gal-induced senescence in HDFs was assessed via viability, SA-β-gal activity, senescence markers, ROS, antioxidant enzymes, SASP/ECM gene expression, and MAPK activation. GPR30 involvement was examined using antagonist G15, shRNA knockdown, and molecular docking. RESULTS: Topical TXA produced significantly greater MFWS reductions versus moisturizer alone at weeks 4, 8, and 12, with benefit persisting post-treatment. In HDFs, TXA preserved viability, reduced SA-β-gal positivity, attenuated p21/p16, restored Lamin B1, decreased ROS, and rescued antioxidant activities. TXA downregulated IL-6, IL-8, MMP1, and MMP3, and suppressed D-gal-induced ERK, JNK, and p38 phosphorylation. These effects were weakened by G15 or GPR30 knockdown; docking supported a stable TXA-GPR30 interaction. CONCLUSIONS: TXA showed clinical anti-wrinkle activity in melasma patients and protected HDFs from D-gal-induced senescence, partly via GPR30-dependent modulation of oxidative stress, SASP/ECM expression, and MAPK signalling. TXA is a promising candidate for skin ageing intervention.

Humans↗

PubMed2026

Circular RNAs in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive loss of motor neurons, with most cases lacking a clear genetic basis. Emerging evidence highlights the involvement of non-coding RNAs, particularly circular RNAs (circRNAs), in disease onset and progression. Here, we investigated circRNAs implicated in ALS and related motor neuron diseases (MNDs). Here, we provide a general overview of circular RNA metabolism and cellular functions. We then present our systematic literature review that identified ALS-associated circRNAs, followed by in silico analyses of 15 circular RNA candidates that were selected based on the most compelling data regarding ALS. Our results revealed that several circular RNAs regulate ALS-related genes, such as unfolded protein response, oxidative stress, cell cycle regulation, and apoptosis. Protein-RNA interaction analysis further showed that ALS-related circRNAs can sponge 20 RNA-binding proteins. Additionally, molecular docking analysis demonstrated that ALS-associated FUS variants significantly alter its binding affinity to circular RNAs. RNA-seq data from ALS patients confirmed significant alterations in the expression of host genes of ALS-related circRNAs and hub proteins in ALS-affected CNS tissues. Collectively, our findings identify circRNAs as potential key contributors to ALS pathogenesis.

Amyotrophic Lateral Sclerosis↗

PubMed2026

Integrated multi-omics profiling of amniotic fluid identifies predictive biomarkers for fetal growth restriction trajectories.

BACKGROUND: Fetal growth restriction (FGR) is a complex condition with highly heterogeneous clinical outcomes, making prenatal distinction between transient and persistent growth failure challenging. This study aims to identify amniotic fluid (AF) biomarkers capable of differentiating distinct FGR trajectories and characterizing persistent growth failure mechanisms. METHODS: Integrated proteomic and metabolomic profiling was performed on AF samples from transient FGR (n = 11), persistent FGR (n = 9), and healthy controls (n = 13). Diagnostic and prognostic models were developed using multivariate analysis. Selected protein candidates were validated via ELISA in an independent cohort (n = 69). RESULTS: Multi-omics analysis revealed distinct molecular signatures for FGR stratification. A two-protein diagnostic panel (PDGFA and phospho-STAT5A) achieved an AUC of 1.000 in the discovery stage and 0.780 in the external validation cohort. For prognostic assessment, a molecular signature including IREB2, HLA-C, and PLXNB2 accurately predicted persistent growth failure from transient recovery (AUC = 0.966). Cross-platform integration highlighted the mass spectrometry-derived WASHC2C as a central hub protein with a significant progressive increase across the control, transient, and persistent groups (p < 0.001). CONCLUSIONS: This study establishes a multi-omics framework for prenatal FGR stratification. Our findings identify distinct molecular signatures reflecting the intrauterine environment and provide high-performance molecular tools for predicting divergent fetal growth trajectories to guide personalized clinical decision-making.

Humans↗

PubMed2026

Maternal transfer of nonylphenol drives oxidative, immune, and epigenetic dysregulation in zebrafish offspring.

Nonylphenol (NP), a widespread surfactant and endocrine-disrupting pollutant, poses significant ecological and public health risks globally; however, its transgenerational effects remain poorly understood. Using zebrafish (Danio rerio), we compared chronic maternal NP exposure (50 and 100 µg/L, 28 days) with acute embryonic exposure (0.22 µmol/L) during 0-3 days post-fertilization (dpf) to delineate mechanistic differences in toxicity. Maternal NP exposure produced severe developmental defects in offspring, including edema, axial curvature, impaired swim bladder inflation, reduced growth, cardiac dysfunction, and decreased viability. These phenotypes were accompanied by systemic molecular disruptions including oxidative stress, altered estrogen receptor (ER) expression, dysregulated mitogen-activated protein kinase (MAPK) signaling, and suppressed innate immune response characterized by attenuated neutrophil/macrophage density, reduced CD68 and complement protein C3 expression, diminished nitrite load, and downregulation of pro-inflammatory mediators at both transcript and protein levels. Maternal exposure further induced apoptosis and persistent epigenetic reprogramming (alterations in DNA methylation and histone-modifying enzymes), hallmarks of transgenerational toxicity. In contrast, direct embryonic NP exposure elicited morphological abnormalities without significant lethality, accompanied by induction of pro-inflammatory cytokines, nitric oxide (NO) synthesis, and MAPK activation, reflecting an augmented inflammatory response. These mechanistic contrasts reveal that maternal NP exposure is a potent driver of systemic, heritable molecular reprogramming, whereas embryonic exposure triggers acute inflammatory pathways. Together, our findings underscore the global relevance of NP as a transgenerational toxicant, advocating for its urgent inclusion in ecotoxicological risk assessments and regulatory frameworks.

Animals↗

PubMed2026

Identification of CXCL13 as an agonist and CXCL11 as an inverse agonist for the viral G protein-coupled receptor ORF74.

Kaposi's sarcoma-associated herpesvirus (KSHV) establishes latent infection in humans, but under conditions of immune suppression, it may reactivate and contribute to severe diseases, including Kaposi's sarcoma (KS) and B-cell malignancies. The KSHV genome encodes a single G protein-coupled receptor (GPCR), open reading frame 74 (ORF74), which shows homology to human chemokine receptors. Since its identification in 1996, ORF74 has subsequently been shown to interact with a broad range of human CXC chemokines, as well as CCL1 and the viral chemokine vCCL2. Compared with many human chemokine receptors, ORF74 displays high basal activity. These properties allow ORF74 to deregulate host cellular pathways through constitutive and chemokine-modulated signaling. In this study, we evaluated several human chemokines that, to our knowledge, had not previously been tested in ORF74-dependent cellular assays. Whereas CXCL9, CXCL14, CXCL16 and CXCL17 did not interact with ORF74, CXCL13 was identified as an additional ORF74 agonist and CXCL11 as an inverse agonist. CXCL13 dose-dependently induced ORF74-mediated Ca2+ release, β-arrestin1/2 recruitment and chemotaxis, and enhanced basal nuclear factor κB (NF-κB) activity in ORF74-expressing cells. In contrast, CXCL11 showed no detectable ORF74 agonist activity in the calcium mobilization or chemotaxis assay, but antagonized CXCL1-induced responses in both readouts. CXCL11 also elicited inverse agonist-like responses in β-arrestin1/2 recruitment assays and reduced basal NF-κB signaling. Our study thus reveals CXCL13 and CXCL11 as two additional chemokine ligands for ORF74, further expanding the pharmacological profile of this viral GPCR.

Humans↗

PubMed2026

Dynamic lysine acetylation and succinylation of platelet proteins regulates platelet storage lesion: mechanistic insights from multi-omics.

OBJECTIVES: Platelet storage lesion (PSL) severely impairs platelet function during storage, presenting a major hurdle in transfusion medicine; however, the dynamic interplay between global proteomic changes and post-translational modifications (PTMs) underlying these functional deteriorations remains insufficiently characterized. Here, we report the first comprehensive multi-omics analysis integrating global proteomics, acetylomics, and succinylomics to dissect the molecular dynamics during platelet storage. METHODS: We performed quantification of global proteomics, acetylome and succinylome based on TMT-labeled LC-MS/MS analysis, combined with antibody-affinity enrichment and purification. Dynamic molecular changes and functional transformation of platelet were also characterized under proper conditions stored for 1, 3, 5, 7 days, respectively. RESULTS: We systematically characterized 3,609 proteins, 1,308 acetylation sites, and 1,947 succinylation sites across multiple storage time points (D1, D3, D5, D7). We distinct temporal patterns of post-translational modifications, with succinylation showing more extensive coverage than acetylation in platelets. Pathway enrichment analysis revealed extensive metabolic reprogramming involving complement activation, energy metabolism, and cellular detoxification processes. The identification of specific motif patterns provided mechanistic insights into the functional specificity of these modifications. Random forest machine learning identified 20 core regulatory proteins representing critical nodes in PSL development. Furthermore, we employed real - time quantitative polymerase chain reaction (RT - QPCR) to measure the expression levels of key genes related to platelet function and PTM - associated pathways. CONCLUSION: By mapping the interplay between proteomic abundance shifts and PTM dynamics, this study provides a multidimensional understanding of PSL, establishing a foundational framework for optimizing storage protocols and enhancing transfusion safety.

Blood Platelets↗

PubMed2026

TWIST2-dependent transcriptional activation of TPI1 mediates TGF-β1-driven fibroblast activation in pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease characterized by aberrant profibrotic signaling and excessive extracellular matrix deposition, accompanied by fibroblast-to-myofibroblast transition. Despite extensive investigation, the molecular mechanisms underlying IPF pathogenesis remain incompletely understood. Here, we investigated the role of triosephosphate isomerase 1 (TPI1) in IPF progression and its regulation by transforming growth factor-β (TGF-β) signaling. Loss-of-function analyses identified TPI1 as a downstream effector of TGF-β1, as its knockdown markedly suppressed fibrotic marker expression, fibroblast proliferation, and migration. Mechanistically, TWIST2 was shown to function as a direct transcriptional regulator of TPI1, binding to its promoter and promoting transcriptional activation. Rescue experiments further confirmed that the TWIST2-TPI1 axis is central to the progression of pulmonary fibrosis. Notably, knockdown of either TPI1 or TWIST2 effectively attenuated TGF-β1-induced fibrotic phenotypes. Collectively, these findings define the TGF-β1/TWIST2/TPI1 signaling axis as an important regulator of pathogenic fibroblast behavior and pro-fibrotic responses through transcriptional control of TPI1, highlighting its potential as a therapeutic target for IPF.

Twist-Related Protein 1↗

PubMed2026

Combining neuromelanin-sensitive MRI and quantitative susceptibility mapping for enhanced diagnosis and differentiation of parkinson's disease: A systematic review.

BACKGROUND: Loss of dopaminergic neurones and iron deposition in the substantia nigra pars compacta (SNpc) are two major pathological hallmarks of Parkinson's disease (PD). Such changes can be visualised by advanced techniques including neuromelanin-sensitive MRI (NM-MRI) and quantitative susceptibility mapping (QSM). This systematic review investigates the diagnostic performance and methodological development of the integrated use of NM-MRI and QSM in PD. METHODS: The systematic search was performed in four databases (Scopus, PubMed, ScienceDirect, and Web of Science) according to the PRISMA 2020 guidelines until July 2026. Bias was assessed using QUADAS-2 and certainty of evidence was assessed using GRADE. RESULTS: Seventeen studies with 2228 participants were included. Combined NM-MRI and QSM consistently showed reduced neuromelanin volume/contrast and increased iron deposition in the SNpc of PD patients compared to healthy controls. Multimodal integration yielded a significant improvement in diagnostic accuracy (AUC values 0.86-0.99), and was able to successfully differentiate PD. Recent methodological advances included simultaneous acquisition sequences (e.g. MTC-GRE, STAGE, setMag) and AI-driven automated segmentation, which led to significantly reduced scan times and improved reproducibility. CONCLUSION: The combination of NM-MRI and QSM has a synergistic effect and provides powerful complementary biomarkers for the diagnosis and differential diagnosis of PD.

Humans↗