Background: Thyroid disorders and Alzheimer's disease (AD) have been linked epidemiologically, but whether AD brain tissue and thyroid tissue affected by Hashimoto's thyroiditis (HT) share molecular features remains unclear. Methods: Differential expression was estimated in AD (GSE122063) and HT (GSE138198) discovery cohorts using limma, with donor-level blocking and adjustment for age, sex and post-mortem interval where available. Shared genes were tested against chance within the genes measured in both cohorts, separately for each direction of change; characterized by enrichment analysis; related to marker-based cell-state scores; and evaluated in two AD cohorts, three thyroid cohorts including one with concurrently collected normal thyroid (GSE165724), and a single-nucleus AD dataset (GSE138852). Results: The discovery analyses identified 3593 AD- and 3806 HT-associated genes. The overlap was direction-specific: genes upregulated in both diseases exceeded chance (117 vs. 83.2 expected; p = 8.9 & times; 10-5), whereas the other direction combinations did not. Co-upregulated genes were enriched for MHC class II antigen presentation (FDR = 0.004), complement (FDR = 0.002), microglial activation (FDR = 0.017) and T-cell activation (FDR = 1.7 & times; 10-4), and recurred in two independent thyroid datasets and the within-study LT+ versus LT- comparison, with less consistent, region-dependent recurrence in AD cohorts. This shared component tracked immune cell-state signals-glial/myeloid activation in AD and lymphocytic infiltration in HT. Fourteen co-upregulated genes, including ITGAX, CD22 and BST2, met prespecified recurrence and detectability criteria. Conclusions: AD brain tissue and thyroid tissue affected by HT exhibit a co-upregulated immune and antigen-presentation transcriptional program that reflects immune activation in both tissues. These overlapping features are associative and do not establish a causal relationship between AD and HT.
Background/Objectives: Fruit quality in melon is determined by complex traits including sugar accumulation, aroma, flesh color, ripening behavior and disease resistance. Conventional genomic selection provides limited mechanistic interpretation, especially for regulatory and de novo variants. We adapted the EVEE interpretable embedding-probing framework to melon using PlantCAD2 as a frozen DNA language model backbone. Methods: The model was not fine-tuned or further pre-trained. Instead, lightweight probes were trained on fixed embeddings derived from sequence windows surrounding genetic variants. The pipeline integrated supervised variant-effect prediction, functional perturbation profiling, training-free masked log-likelihood ratio scoring, and cis-regulatory element generation. We applied the framework to 32,268 public genotyping-by-sequencing (GBS) SNPs from a melon diversity panel. A total of 30,052 variants were successfully encoded and analyzed. Results: Of these, 31.9% were classified as high predicted functional effect under the GWAS-proximal probe. We adopted a rigorous independent split based on chromosome and locus blocks to ensure test variants and training variants occupy distinct linkage-disequilibrium blocks. In this setting, the covariance probe yields an AUROC of approximately 0.51 with a 95% confidence interval covering 0.50, indicating no predictive advantage over random guessing. The full-cohort AUROC value of 0.748 reported earlier is attributed to linkage-disequilibrium leakage and overlapping positive samples between datasets, and thus does not reflect true independent generalization. The 17-class structural annotation probe reached 95.97% per-position accuracy. Functional perturbation signals were enriched in intronic, coding, and proximal promoter regions, consistent with known regulatory architectures in melon. Using the masked language model head with Gibbs sampling, we generated 76 candidate 400 bp cis-regulatory elements associated with sugar metabolism pathways. A posterior consistency check against 18 published GWAS/QTL loci showed effect-score patterns broadly concordant with reported loci; this is a consistency analysis against known loci, not an independent prospective validation. Variants in the CmTST2 region exhibited elevated mean effect scores of 0.7922 compared with the genome-wide background of 0.406. Conclusions: Overall, this study provides a computational, hypothesis-generating framework in which a frozen plant DNA language model combined with lightweight probes prioritizes melon variants and generates candidate regulatory sequences; all outputs are unverified in-silico predictions requiring experimental validation before any functional or breeding use. Because every variant is scored independently from its local sequence context, the framework necessarily treats genetically linked, network-dependent traits as single-locus effects and does not model epistasis, pathway-level interactions, or genotype-by-environment effects; the outputs are sequence-level priors, not phenotype predictions. The results support a generalizable framework for model-guided functional genomics and precision breeding in Cucurbitaceae crops.
Background/Objectives: Friedreich's ataxia in considered the most common form of autosomal recessive ataxia; however, it's prevalence in the Russian Federation remains poorly studied. Methods: The study included 974 patient samples referred for analysis of the expanded GAA repeat in intron 1 of the FXN gene, as well as 319 healthy individuals participating in a biomaterial donation program for IVF, using PCR-AFLP and fragment analysis with labeled primers. Sanger sequencing of the FXN gene was additionally performed for six patients who exhibited a heterozygous expanded allele. Results: The diagnosis of FRDA was confirmed in 142 patients: 139 of them had homozygous GAA repeat expansions, the most common mutation type in this disorder, while in 3 cases a heterozygous expansion was associated with a pathogenic point mutation in the FXN gene on the second allele. For 28 probands, biallelic GAA expansions in FXN were subsequently confirmed in their affected relatives. Among the 319 healthy donors, only 2 carriers of a pathogenic expansion were identified. Conclusions: This paper presents the results of a long-term study on the molecular genetic causes of FRDA in Russian Federation, yielding an estimated frequency of 1:102,000 individuals for the disease associated with GAA repeat expansion.
Background and Objectives: Autosomal recessive cutis laxa (ARCL) is a genetically heterogeneous group of connective-tissue disorders characterized by loose, inelastic skin and variable systemic involvement. Biallelic variants in PYCR1 are associated with PYCR1-related ARCL, including ARCL type IIB (OMIM #612940) and type IIIB (OMIM #614438). We aimed to characterize the clinical and molecular findings in one affected family and provide segregation and variant-specific functional evidence for two previously unreported PYCR1 variants. Methods: The proband and family underwent whole-exome sequencing with copy-number analysis and Sanger confirmation. The splice-site variant was evaluated by qualitative RT-PCR and Sanger sequencing of endogenous peripheral-blood PYCR1 transcripts, whereas the frameshift variant was studied in a heterologous expression system by qPCR and Western blotting. Neuroimaging, exploratory EEG spectral analysis, and public developmental transcriptomic/single-cell resources were used for complementary phenotypic context. Results: The 16-year-old proband had thin lax skin with prominent superficial veins, generalized joint hypermobility, facial dysmorphism, reduced muscle bulk, and motor developmental delay. Chinese WAIS-IV showed a markedly uneven profile (VCI 52; PRI 94; FSIQ 75). Two previously unreported PYCR1 variants were identified in trans: maternally inherited NM_006907.4:c.139-1G>A and paternally inherited NM_006907.4:c.724_725del, p.(Leu242AlafsTer31). Endogenous RNA analysis identified exon 3 skipping associated with c.139-1G>A (r.139_318del), predicting p.(Met48_Lys107del). The c.724_725del construct showed consistently reduced steady-state abundance of the truncated PYCR1 protein relative to WT across three independent experiments. Both variants were classified as likely pathogenic using the ACMG/AMP framework with relevant ClinGen refinements. Brain MRI revealed irregular morphology of the anterior corpus callosum. Discussion: These two previously unreported variants extend the PYCR1 variant spectrum and are supported by complementary segregation, RNA-level, and protein-level evidence. The neurodevelopmental observations provide additional phenotypic context and are interpreted descriptively.
Background: Endurance performance reflects integrated cardiorespiratory, metabolic and musculoskeletal traits with substantial heritability, yet sex-balanced studies that simultaneously deep-phenotype athletes and genotype candidate loci against trained comparators remain scarce. Objective: We aim to characterize the integrated physiological profile and genotype distributions at five endurance-relevant polymorphisms in elite versus recreationally trained runners. Methods: Eighty runners (20 elite male, 20 elite female, 20 recreational male, 20 recreational female) completed graded treadmill testing with breath-by-breath gas exchange and capillary blood lactate sampling, together with whole-body dual-energy X-ray absorptiometry. A sub-sample of 40 participants (10 per subgroup) underwent next-generation sequencing of ACTN3 R577X, VEGFA rs699947, PPARGC1A Gly482Ser, ACE I/D and PPARG Pro12Ala. Physiology was compared using one-way ANOVA with Tukey's HSD and Cohen's d; genotype distributions were compared using Monte Carlo exact tests with Benjamini-Hochberg correction. Results: Elite runners exhibited higher VO2max (elite male 71.8 +/- 4.9; elite female 65.3 +/- 3.6 mL & centerdot;kg(-1)& centerdot;min(-1); both vs. same-sex controls, p < 0.001; eta(2) = 0.62), superior running economy (eta(2) = 0.76), lactate thresholds shifted rightward by similar to 1 km & centerdot;h(-1), and more favorable body composition (lean mass eta(2) = 0.80; body fat eta(2) = 0.48). Principal component analysis separated elites from recreational runners along PC1 (40.1% variance) in both sexes. Effect-allele frequencies were numerically higher in elites at every locus (odds ratios 1.48-2.03), but no genotype & times; group association survived correction (all q >= 0.82). Conclusions: Elite endurance status was robustly distinguished by an integrated physiological phenotype with large effect sizes. Effect-allele frequencies at five candidate loci were numerically higher in the expected direction but did not reach statistical significance; given the small genotyped sub-sample, these genetic data are purely exploratory and hypothesis-generating and require replication in adequately powered cohorts.
