Background The Peripheral Myelin Protein 22 (PMP22) gene plays a central role in peripheral nerve myelination, and dosage alterations (deletion, duplication, or point mutation) are established causes of hereditary neuropathies such as Charcot-Marie-Tooth disease type 1 A (CMT1A), CMT1E, and Hereditary Neuropathy with Liability to Pressure Palsies (HNPP). However, its potential contribution to atypical developmental motor phenotypes such as persistent toe-walking (PTW) has not been systematically explored.

Objective To characterize the phenotypic spectrum of pediatric PMP22 variant carriers presenting with PTW and to compare their clinical features with those of established PMP22-related neuropathies.

Methods This retrospective study analyzed 22 children with PMP22 variants (pathogenic, likely pathogenic, or of uncertain significance) identified through a targeted 49-gene next-generation sequencing panel. Detailed phenotypic data were collected across five clinical domains—genetic, developmental, gait and musculoskeletal, neurological, and associated comorbidities—and compared to standardized phenotype frequencies for CMT1A, CMT1E, and HNPP derived from Orphanet and the Human Phenotype Ontology (HPO) databases.

Results Persistent tip-toe gait was universal, accompanied by pes cavus, lumbar hyperlordosis, tremor, and hyporeflexia. Speech and language difficulties were reported in 45 % of cases, and a family history of toe-walking in 40 %. Additional muscle symptoms and neurological findings were reported, developmental disorders were also reported.

Conclusions Children carrying PMP22 variants with PTW exhibit a distinct phenotype differing from classic demyelinating neuropathies. The findings suggest that a subset of idiopathic toe-walking cases may represent a developmental manifestation within the PMP22-related disease spectrum, highlighting the value of genetic testing in reevaluating gait disorders of uncertain etiology.

Metabolic syndromes (MeS), marked by central obesity, high blood pressure, abnormal cholesterol and blood sugar, are key cardiovascular disease (especially coronary artery disease, CAD) risk factors. Genetic studies show MeS-CAD genetic overlap, indicating shared biological pathways. We used Summary-data-based Mendelian Randomization (SMR), Bayesian colocalization (with large GWAS summary stats for MeS/CAD and cis-eQTL data from 3 tissues) and Transcriptome-Wide Association Study (TWAS). We also investigated the effects of gene knockout on mouse phenotypes. SMR found 886/737/192 shared genes in blood/brain cortex/liver; colocalization identified 11/13/5 shared causal genes in these tissues and 46 shared loci (e.g., CAMK1D, OR=1.11; AGPAT1, OR=1.13; FDR<0.05). Moreover, knocking out these genes in mice affected metabolism, adipose tissue, cardiovascular function, glucose homeostasis, and the fat/muscle balance. This study identified common regulatory genes between MeS and CAD, suggesting that targeted therapies or interventions could potentially address both conditions simultaneously, offering prospects for more integrated treatment strategies.

Background Sedentary behavior and obesity are established risk factors for depression. The weight-adjusted-waist index (WWI) is a more accurate obesity measure than body mass index (BMI) or waist circumference (WC). This study aims to investigate if WWI mediates the effect of sedentary behavior on depression.

Methods Data on daily sitting times, WWI and depression symptoms assessed by the Patient Health Questionnaire-9 (PHQ-9) scores were analyzed for this study. WWI was calculated as WC divided by the square root of body weight. Depression was defined as a PHQ-9 score ≥ 10. We used weighted logistic regression and restricted cubic splines (RCS) to examine the linear and nonlinear effects of daily sitting time and WWI on depression. Mediation analysis was performed to determine if WWI mediates the relationship between daily sitting time and depression. Gender-stratified analysis was also conducted.

Results The study included 26,508 participants. Adjusted analyses showed positive associations of both daily sitting time (OR = 1.035, 95 % CI 1.015-1.056) and WWI (OR = 1.345, 95 % CI 1.226-1.476) with depression. Sitting > 8 h/day conferred higher depression risk versus < 4 h/day (OR = 1.268, 95 % CI 1.086-1.481). Similarly, the highest WWI quartile (Q4) had significantly greater risk than the lowest (Q1) (OR = 1.791, 95 % CI 1.429-2.245). WWI significantly mediated the sitting-depression relationship (proportion mediated: 0.075, 95 % CI 0.062-0.212, P < 0.001).

Conclusion Sedentary behavior and WWI both elevate depression likelihood. Furthermore, WWI partially mediates the effect of sedentary behavior on depression, and this mediation effect is independent of gender.

Background/Objectives Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disease driven by the BCR-ABL1 fusion oncogene. Tyrosine kinase inhibitors (TKIs) such as Imatinib mesylate have dramatically improved patient outcomes, yet resistance remains a major obstacle to long-term efficacy. Exosomes, as carriers of bioactive molecules including miRNAs, are increasingly recognized as mediators of drug resistance. CBD has demonstrated antiproliferative and pro-apoptotic effects in several cancer models, but its potential to modulate Imatinib sensitivity or resistance in CML remains unclear. This study aimed to investigate exosomal miRNA signatures associated with Imatinib sensitivity and resistance in the context of treatment with Cannabidiol (CBD), Imatinib mesylate (IM), and their combination.

Methods Following treatment with CBD, IM, and CBD+IM, exosomal miRNA profiles in Imatinib-sensitive (K-562S) and Imatinib-resistant (K-562 R) cell lines were analyzed. Gene Ontology (GO) enrichment and semantic clustering was performed.

Results CBD activated tumor-suppressive and apoptosis-related miRNAs in K-562S cells, whereas K-562 R cells showed a dual response involving oncogenic miRNAs and metabolic regulators. IM induced suppressive cascades in K-562S but caused loss of canonical tumor suppressors in K-562 R. CBD+IM produced synergistic amplification of apoptotic and differentiation-related pathways in sensitive cells, while resistant cells showed partial restoration of apoptosis but persistent loss of tumor suppressors. HMGB1-associated miRNAs were identified, of which suppressed were miR-615-5p, miR-4435, let-7 g-3p, and the miR-548 family, alongside upregulated miR-3191-3p and miR-33a-5p.

Conclusions Circulating miRNAs are valuable biomarkers for TKI resistance in CML. Targeting HMGB1-associated miRNAs, together with combined CBD and IM treatment, may help re-establish apoptotic regulation and overcome resistance mechanisms.

Purpose Persistent toe walking is frequently labeled idiopathic; however, targeted genetic testing in selected cohorts can identify variants in genes implicated in neuromuscular disease. SBF1 is a known cause of autosomal recessive Charcot-Marie-Tooth disease type 4B3 (CMT4B3), whereas the clinical relevance of heterozygous SBF1 variants—particularly variants of uncertain significance (VUS)—remains unclear. We aimed to describe, in an exploratory manner, the clinical features of children with persistent toe walking in whom heterozygous SBF1 variants were identified, and to contextualize these observations using published CMT4B3 families and Human Phenotype Ontology (HPO) feature frequencies.

Methods We retrospectively analyzed children referred to a specialized toe-walking clinic who underwent a standardized blinded clinical assessment and targeted 49-gene next-generation sequencing. Individuals with alternative sequencing approaches or known non-genetic causes of toe walking were excluded. Heterozygous SBF1 variants were summarized using HGVS nomenclature, ACMG classification, population allele frequency, and report date. Phenotypic frequencies were compared with published SBF1-related CMT4B3 families and with HPO-reported feature frequencies for CMT4B3.

Results The cohort comprised 86 children (mean age 9.5 years), all with persistent toe walking. Common findings included skeletal features (e.g., pes cavus and lumbar hyperlordosis), whereas muscle weakness and deep tendon reflex abnormalities were less frequent than reported in recessive CMT4B3 families. Genetic testing identified a spectrum of heterozygous SBF1 variants, predominantly classified as VUS.

Conclusions In this referral-based cohort, heterozygous SBF1 variants were observed in children with persistent toe walking and accompanying mild neuromotor/musculoskeletal features that partially overlap with reported CMT4B3 phenotypes; however, these findings are descriptive and do not establish causality or enrichment. Longitudinal follow-up, segregation/phase determination, and electrophysiological studies are needed to clarify clinical significance, potential biallelic configurations in some individuals, and possible gene-dosage or modifier effects.

Background Dermatomyositis (DM) is an uncommon autoimmune disease that presents challenges due to the lack of reliable biomarkers in clinical practice. Growing evidence suggests that N6-methyladenosine (m6A) is closely associated with the pathogenesis of autoimmune diseases.

Methods Microarray gene expression matrix for GSE46239, GSE128314, and GSE142807 were downloaded from the GEO database. Random forest (RF), support vector machine (SVM), and nomogram models were developed, with their performance subsequently compared. The identification of m6A subtypes, based on differentially expressed m6A regulatory genes, was followed by the classification of gene subtypes according to the differently expressed genes between the m6A subtypes. Both classification systems were subjected to m6A scoring analysis and visualized via a Sankey diagram.

Results We retrieved 99 dermatomyositis samples and 14 healthy samples. Using an RF model, we identified five core genes—IGFBP3, ZCCHC4, HNRNPC, WTAP, and RBM15—and constructed a predictive nomogram model. Two m6A clusters were developed. Cluster A exhibited a significant increase of CD56-bright natural killer cells, immature B cells, plasmacytoid dendritic cells, regulatory T cells, and type 1 T helper cells distinct from cluster B (p < 0.05). Based on 32 significantly distinctly expressed genes between m6A subtypes (p < 0.05), we further reproduced two m6A gene subtypes. The Sankey diagram showed significant concordance among m6A scores, m6A subtypes, and m6A gene subtypes.

Conclusion m6A regulatory genes significantly influence the pathogenesis of dermatomyositis. In this work, we built a predictive nomogram model, comprehensively evaluated two classification methods, and provided new insights for patient classification.