Aim: Skeletal muscle unloading leads to the upregulation of proteolytic gene expression, downregulation of protein synthesis markers, and the development of muscle atrophy. These changes are accompanied by alterations in calcium signaling. We investigated the role of Inositol 1,4,5-triphosphate (IP3) receptors (IP3Rs) in regulating calcium signaling and controlling gene expression in skeletal muscles during unloading.
Methods: Male Wistar rats were randomly assigned to 4 groups (n = 8 per group). C - vivarium control; C+2APB - vivarium control with daily intraperitoneal injections of the IP3 receptor inhibitor 2-aminoethoxydiphenyl borate
Results: Three days of unloading resulted in a significant increase in nuclear phosphorylated Ca2+/calmodulin-dependent protein kinase II (p-CaMK II) content and calcineurin (CaN) expression compared to the C group (P < 0.05); this effect was prevented in the HU+2APB group. In HU+2APB rats, the decline in soleus muscle weight-to-body weight ratio was partially prevented, and the downregulation of protein synthesis markers (as seen in the HU group) was also prevented. However, proteolytic signaling markers were equally upregulated in the HU+2APB and HU groups compared to C.
Conclusion: IP3 receptor inhibition during 3-day hind limb suspension in rats partially prevented the decline in
The study by Li et al., “Single-cell transcriptome analysis reveals the association between histone lactylation and cisplatin resistance in bladder cancer”, investigated how histone lactylation contributes to cisplatin resistance in bladder cancer (BCa). Using high-resolution single-cell lineage tracing, the authors identified a distinct subpopulation of BCa cells with enhanced glycolytic metabolism that exhibited significant cisplatin resistance. Further analyses showed significant enrichment of histone H3 lysine 18 lactylation (H3K18la) at the promoter regions of the transcription factors YY1 and YBX1, which promoted their expression and facilitated the development of a drug-resistant phenotype. This study was the first to combine single-cell omics with lactylation modification mechanisms, providing new insights into strategies for overcoming cisplatin resistance in BCa. Nonetheless, potential limitations of the study should be carefully considered.
This study, “Alveolar fibroblast lineage orchestrates lung inflammation and fibrosis”, provides important new insights into the varied functions of alveolar fibroblasts. It highlights their key involvement in maintaining the stability of pulmonary alveoli and in regulating the prolonged tissue response to injury. Using a Scube2-creER system, the investigators achieved precise labeling of alveolar fibroblasts, thereby overcoming the limitations of previous methodologies that lacked the specificity to distinguish fibroblast subpopulations in different anatomical niches. By integrating lineage tracing, single-cell RNA sequencing, and targeted functional ablation assays, the study delineated the transition of inflammatory fibroblasts into a pro-fibrotic phenotype. These approaches further revealed the pivotal role of TGFβ in driving this fibrogenic conversion. This commentary will critically analyze these findings, discuss their significance, and explore future prospects.
Spinal muscular atrophy (SMA) is a progressive neuromuscular degenerative disorder caused by mutations in the survival motor neuron 1 (SMN1) gene, leading to insufficient production of the survival motor neuron (SMN) protein. The nearly identical SMN2 gene modifies disease severity but generates only limited amounts of functional SMN protein due to a C-to-T transition in exon 7 that disrupts proper splicing. This review summarizes advances in understanding SMN2 splicing regulation and post-transcriptional modification in SMA pathogenesis. It discusses the roles of cis- and trans-acting elements in exon 7 inclusion, as well as the impact of epigenetic mechanisms such as histone acetylation and DNA methylation on SMN2 expression. This review also examines available therapeutic strategies, including antisense oligonucleotides (Nusinersen), small-molecule splicing modulators (Risdiplam and Branaplam), and gene therapy (Onasemnogene abeparvovec). Emerging approaches such as CRISPR/Cas9 genome editing and nanotechnology-based delivery systems are also highlighted. In addition, this review explores translational research using animal models, iPSC-derived neurons, and multi-omics approaches. Finally, it emphasizes the need for integrated therapeutic strategies that address both SMN-dependent and -independent pathways to improve treatment outcomes.
The SLC6A4 gene, which encodes the serotonin (5-hydroxytryptamine; 5-HT) transporter, plays an important role in the pathogenesis of mental disorders by regulating serotonin reuptake in the synaptic cleft. This review summarizes current evidence on the associations of SLC6A4 polymorphisms, epigenetic modifications, and neuroimaging findings with schizophrenia (SCZ), major depressive disorder (MDD), bipolar disorder (BD), and other psychiatric conditions. Studies have shown that the impact of SLC6A4 polymorphisms varies across ethnic groups and populations. Epigenetic studies indicate that DNA methylation in the promoter and exon regions of SLC6A4 can inhibit gene expression and exacerbate imbalances in the 5-HT signaling pathway, which are closely related to negative symptoms in SCZ, childhood trauma, and gender-specific risks for MDD. Neuroimaging evidence further suggests that SLC6A4 polymorphisms and methylation status are significantly associated with brain structural and functional abnormalities, pointing to a multidimensional mechanism involving ontogeny, epigenetics, and neural networks. Moreover, alterations in SLC6A4 have also been implicated in BD and attention-deficit/hyperactivity disorder. Despite significant progress, challenges remain, including ethnic biases in study populations, discrepancies between epigenetic patterns in peripheral and central nervous systems, and unclear mechanisms underlying gene-environment interactions. Future research should integrate multi-omics approaches, large cross-ethnic cohorts, and gender-stratified analyses to elucidate the precise regulatory network of SLC6A4 in mental disorders.
Background: Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease characterized by joint destruction and functional impairment. Tumor Necrosis Factor inhibitors (TNFi) are widely used biologic therapies for RA; however, patient outcomes show significant individual variation. Genetic factors, including polymorphisms in the PTPRC gene, have been investigated as potential predictors of TNFi efficacy, but results remain inconsistent.
Methods: We conducted a systematic review and meta-analysis following PRISMA guidelines to evaluate the association between PTPRC polymorphisms and TNFi treatment response in RA patients. A comprehensive search was performed in PubMed and Scopus databases up to April 2025. Studies were screened and quality assessed using the Q-Genie tool. Meta-analyses employed Mantel-Haenszel methods with fixed and random effects models.
Results: Five studies met eligibility criteria, including data from 12 European cohorts totaling 1,543 RA patients. The main polymorphism assessed was rs10919563. Meta-analysis revealed the rs10919563 A allele was significantly associated with increased odds of non-response to TNFi (allelic model OR: 1.94; 95%CI: 1.31-2.88). The recessive models supported these findings, and no publication bias was detected.
Conclusions: Our results consolidate evidence supporting the PTPRC rs10919563 polymorphism as a potential predictive genetic biomarker for TNFi efficacy in RA, which could be integrated into personalized treatment strategies. Further studies are required to validate clinical utility across diverse populations.
Duchenne muscular dystrophy (DMD) is an X-linked, progressive muscle disorder caused by pathogenic variants in the DMD gene and resulting in a complete loss of dystrophin protein expression. As of now, there is no cure for DMD, and despite improvements in standard of care, there are significant unmet needs for disease modifying treatments. This article provides an overview of emerging therapies aimed at dystrophin restoration, emphasizing exon skipping and gene therapy, within the rapidly evolving landscape for Duchenne muscular dystrophy.
Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) have transformed the therapeutic landscape of non-small cell lung cancer (NSCLC), producing durable responses in a subset of patients. Yet for most, clinical benefit is undermined by the development of acquired resistance (AR), a phenomenon that continues to limit the long-term success of immunotherapy. Recent analyses have drawn attention to persistent interferon-γ (IFN-γ) signaling as a paradoxical hallmark of AR: a cytokine typically associated with effective antitumor immunity that, when chronically engaged, sustains immune dysfunction. In this commentary, we synthesize existing literature to expand upon this model. We review molecular and cellular mechanisms by which chronic IFN-γ drives resistance through the signal transducer and activator of transcription 1 (STAT1)/interferon regulatory factor 1 (IRF1) axis, epigenetic stabilization of exhaustion, antigen-presentation loss, and metabolic suppression. We extend the discussion to innate immunity, bystander T-cell responses, and stromal regulation, emphasizing spatial heterogeneity as a critical mediator of IFN-γ biology. Finally, we explore translational strategies - including rational checkpoint combinations, radiotherapy-immunotherapy sequencing, epigenetic modulation, and innate immune engagement - that may reprogram IFN-γ-permissive resistance states. We argue that IFN-γ persistence should not be viewed as an isolated mechanism but as a central hub in a broader resistance network, and we propose a phenotype-guided framework for therapeutic intervention in AR NSCLC.
Artificial intelligence (AI) is transforming forensic genetics through groundbreaking applications in (1) population structure analysis and biogeographical ancestry inference; (2) microbial detection and body fluid identification; (3) allele recognition and mixture interpretation; (4) age inference and phenotype prediction, (5) kinship analysis; and (6) other emerging domains, such as bloodstain deposition time and transcriptomic analysis. While promising efficiency and enhanced accuracy, its integration also raises ethical, legal, and social concerns. This opinion piece critically explores both the promise and perils of AI in forensic genetics, calling for urgent action to (1) build secure and trustworthy AI systems; (2) develop agile and effective regulatory frameworks; (3) uphold ethical integrity and human-centered design; and (4) foster global collaboration to meet cross-border challenges. Together, these principles are essential to ensuring that AI’s integration into forensic science advances both technological progress and the pursuit of justice.
Aim: Tibial muscular dystrophy (TMD; MIM#600334, ORPHA:609) is an adult-onset, slowly progressive distal myopathy resulting from dominant variants in exon 364 of the TTN gene. The Finnish founder variant (FINmaj), characterized by an 11-bp insertion/deletion, causes autosomal dominant (AD) TMD in heterozygous individuals. Our aim was to assess the prevalence and origin of the FINmaj variant within the Estonian population.
Methods: We reanalyzed next-generation sequencing panels and whole-exome sequencing data from 2014 to 2025 to identify individuals carrying the FINmaj variant. The study included three cohorts: Tartu University Hospital (n = 15,178), West Tallinn Central Hospital (n = 52), and the Estonian Genome Center (n = 4,776). Most carriers of the FINmaj variant underwent muscle magnetic resonance imaging (MRI) and haplotype analysis.
Results: We identified 13 individuals from five families with the heterozygous FINmaj variant, including two individuals with autosomal recessive limb-girdle muscular dystrophy-10 and eleven with AD TMD. By the age of 50, all patients diagnosed with TMD showed symptoms of distal myopathy and characteristic MRI findings. The carrier frequency of the FINmaj variant in the Estonian cohort was one in 3,036, with no carriers in the Estonian Genome Center cohort. The average haplotype length was estimated to be ~4.1 Mb in Estonians, compared to
Conclusion: AD TMD is one of the most prevalent but underdiagnosed hereditary muscle diseases in the Estonian population. Since Estonian patients exhibit an estimated shorter haplotype length than Finnish patients, the FINmaj variant likely originated in Estonia before spreading to Finland.
Breast cancer (BC) remains a major contributor to cancer-related morbidity and mortality among women globally. While systemic therapies have significantly advanced, the emergence of drug resistance continues to hinder durable clinical benefit, leading to treatment failure and disease relapse. Long non-coding RNAs (lncRNAs) have gained recognition as key regulators in BC biology and therapeutic response, with growing evidence implicating them in resistance to chemotherapy, endocrine therapy, targeted agents, and immunotherapy. This review provides a detailed overview of the molecular mechanisms through which specific lncRNAs promote resistance, emphasizing their roles in modulating processes such as programmed cell death, epithelial-mesenchymal transition, and remodeling of the tumor microenvironment. We further highlight common regulatory axes - such as competing endogenous RNA networks and the phosphatidylinositol 3-kinase/protein kinase B pathway - that serve as converging points across distinct resistance mechanisms. In addition, we discuss recent progress in harnessing lncRNAs as liquid biopsy biomarkers and examine the key challenges and opportunities in translating lncRNA-based targets into therapeutic strategies. Together, these insights offer a foundation for future research aimed at overcoming drug resistance in BC through novel lncRNA-centered interventions.
Aim: Duchenne muscular dystrophy (DMD) is a rare genetic condition that results in a lack of dystrophin protein due to a series of mutations. Current treatment strategies for DMD remain limited, highlighting the urgent need for novel therapeutic options. This study aimed to identify drugs that can be repositioned using DMD-specific molecular network signatures and potential diagnostic biomarkers, using a holistic, multi-omics data-integration approach.
Methods: We have examined messenger RNA expression datasets GSE109178, GSE70955, and GSE38417 to identify differentially expressed genes (DEGs) using adjusted P-value < 0.001 and |log2(fold change)| > 1 as the cut-off criteria. A total of 285 DEGs were identified as common across all three datasets. Principal component analyses were carried out using 33 hub genes identified from three-layered (protein-protein interaction, transcription factor, and microRNA) biological network constructions.
Results: The discrimination effect of these hub genes was found to be significantly higher between DMD patients and healthy controls. Therefore, these hub genes might be proposed as potential DMD-specific network biomarkers. Also, a drug repositioning analysis was conducted, revealing that celastrol, emetine dihydrochloride hydrate, radicicol, withaferin-A, and apigenin triacetate were reported as potential drugs for the management of DMD pathogenesis. The docking analysis with these repositioned drug candidates showed significant binding affinities among 17 network biomarkers (SQSTM1, PML, SPTAN1, SPTBN1, KIAA1429, SOX4, SP1, SPP1, NFKB1, TP53, NKX3-1, CIITA, ARL6IP1, IGFBP5, OCIAD2, RAP2B, and NFIB).
Conclusion: Celastrol and emetine dihydrochloride hydrate were the two repurposed small molecules that demonstrated effective docking results compared with inhibitors of hub genes and with the clinically used DMD-specific drug vamolorone. Further studies should be conducted to recapitulate these findings through in vitro and in vivo studies.