Generation Foundation

This study integrates multimodal metabolomic data from three platforms—LC–MS, GC–MS, and NMR—to systematically identify biomarkers distinguishing breast cancer subtypes. A feedforward attention-based deep learning model effectively selected 99 significant metabolites, outperforming traditional static methods in classification performance and biomarker consistency. By combining data from diverse platforms, the approach captured a comprehensive metabolic profile while maintaining biological relevance. Self-organizing map analysis revealed distinct metabolic signatures for each subtype, highlighting critical pathways. Group 1 (ER/PR-positive, HER2-negative) exhibited elevated serine, tyrosine, and 2-aminoadipic acid levels, indicating enhanced amino acid metabolism supporting nucleotide synthesis and redox balance. Group 3 (triple-negative breast cancer) displayed increased TCA cycle intermediates, such as α-ketoglutarate and malate, reflecting a metabolic shift toward energy production and biosynthesis to sustain aggressive proliferation. In Group 4 (HER2-enriched), elevated phosphatidylcholines and phosphatidylethanolamines suggested upregulated mono-unsaturated phospholipid biosynthesis. The study provides a framework for leveraging multimodal data integration, attention-based feature selection, and self-organizing map analysis to identify biologically meaningful biomarkers.

Abstract Background We previously reported that a major portion of trinucleotide two-repeat units (TTUs) are sites of unequal crossover and consequent colonization, that are massively spread and shared across the genomes of human and several other primates. These sites underscore the preference of AT- over CG-rich sequences, as recombination sites. Methods Here we extended our study to dinucleotides of AT/TA and CG/GC. An algorithm was designed to extract genomic regions with a higher probability of recombination. To this end, the algorithm consisted of dinucleotide 3-repeat units (D3Us), a portion of which was hypothesized to be the basic overlapping units, resulting from unequal crossover between dinucleotide two-repeat units (D2Us). We mapped TATATA, ATATAT, CGCGCG, and GCGCGC across the human genome, and analyzed their colonization (distance between consecutive D3Us < 500 bp). We also studied several colonies of various sizes in up to 100 vertebrates, using the UCSC and ENSEMBL Genome Browsers. Results We found 3,989,861 AT/TA and 95,849 CG/GC D3Us across the human genome, the majority of which resided in over 480,000 colonies, ubiquitously spread along all chromosomes. The AT/TA colonies were significantly larger and more intricate than CG/GC colonies. These colonies were mainly specific to, or of their largest size in human. D2Us and D3Us were the primary sites of unequal crossover in these colonies, resulting in the emergence of primary recombinants (overlaps among AT/TA repeats), ranging from 5- to 15-bp, and a vast repertoire of secondary recombinants (recombination among pure and primary recombinants), and eventually, colonies of exceeding intricacy and significance, based on Poisson distribution. Conclusion We report ubiquitous and intricate colonies of exceeding significance, in which D2Us and D3Us were the primary sites of unequal crossover and recombination. Across vertebrates, these colonies reached their maximum size in human. It is plausible that minimal DNA repeat sequences, such as D2Us, D3Us, and TTUs, mark recombination a ubiquitous rule across the human genome. This phenomenon may transform our perception of recombination, its magnitude, and biological and evolutionary consequences.

microRNAs (miRNAs) have a serious and dynamic function in spermatogenesis. These molecules have been recognized as crucial parts of the control of gene activity, and their involvement in the regulation of target genes has been extensively studied. This research aimed to determine the expression of CRISP3 and miR-493-5p, miR-204-5p, and miR-182-5p in the seminal plasma fluid and spermatozoa and to examine the relationship between CRISP3 and the mentioned miRNAs in 57 infertile men with Asthenozoospermia (AZ) (n = 19), Teratoasthenozoospermia (TAZ) (n = 19), and Normozoospermia (NZ) (n = 19).The selection of these three miRNAs, miR-493-5p, miR-204-5p, and miR-182-5p, was conducted using computational prediction algorithms. These miRNAs were nominated as CRISP3-associated miRNAs that can target CRISP3. We performed the quantitative real-time polymerase chain reaction (qRT-PCR) method to determine the levels of the studied miRNA expression. In the following stage, the expression of two protein isoforms of CRISP3, targeted by these miRNAs, was quantified using western blotting. The results demonstrate significant differences in the levels of miR-182-5p, miR-204-5p, miR-493-5p, and CRISP3 isoforms among the patient groups. In TAZ individuals, miR-182-5p and miR-204-5p expression decreased, while miR-493-5p expression increased compared to the control samples. Additionally, significant differences were observed in the expression levels of unglycosylated and glycosylated CRISP3 isoforms between the AZ and NZ groups. Correlation analysis revealed associations between miRNA expression and the expression of CRISP3 isoforms in the patient groups. Additionally, there were correlations between the expression of CRISP3 isoforms and sperm motility and morphology. These results offer valuable insights into the underlying molecular processes associated with male infertility.

Abstract CG-rich trinucleotide short tandem repeats (STRs) are linked with human cognition and various neurodevelopmental, neurological, and movement disorders. However, the fundamental two-repeat units of these STRs remain unexplored. On a genome-wide scale, here we mapped the two-repeat units of all combinations of CG-rich trinucleotides in human. We found 81,118 colonies (distance between each unit <500 bp). Subsequently, we performed a comparative genomics study of several large and medium-sized colonies of significant occurrence based on Poisson distribution, in other primates and mouse. We discovered that some of those colonies were shared, with extensive dynamicity, as phylogenetically distant as in mouse. We detected pure units and units that were overlaps of those pure units across the colonies, indicative of unequal crossing over and recombination at those units. We provide example models of some of the potential evolutionary implications of the colonies, such as mechanisms for the emergence and propagation of non-coding RNAs, as well as a defense system against transposable elements, through recombination-coupled inactivating mutations and methylation. In conclusion, we report extensively dynamic trans-species colonies of CG-rich trinucleotide two-repeat units, and indication of crossing over and recombination at those units. Whereas the bulk of literature supports the hypothesis that recombination hotspots rarely (if at all) occur at the same locus between human and chimpanzee, here we propose that sharing such loci may extend beyond primates, and include mouse. Based on the ubiquity, abundance, significant occurrence, and envisioned events and mechanisms associated with the identified colonies, we predict the identified colonies of phenomenal biological and evolutionary consequences.

Abstract Background Hereditary ichthyosis is a clinically and genetically heterogeneous disorder of keratinization, characterized by cutaneous hyperkeratosis of the skin. Mutations in over 50 genes have been identified to be associated with hereditary ichthyosis. Establishing an accurate diagnosis is important for genetic counseling and patient management. Objective We aimed to assess the clinical applicability of whole-exome sequencing (WES) in the molecular diagnosis of hereditary ichthyosis. Methods During a 1-year period, index cases of 5 unrelated families clinically diagnosed with hereditary ichthyosis went through WES, followed by extensive segregation analysis to assess the pathogenicity of the detected variants, and prenatal diagnosis, where indicated. Results In this case series, we identified 2 homozygous variants (c.655A > G and c.797A > G) and one heterozygous (c.428G > A) variant in TGM1 and 2 homozygous variants (c.527 + 2T > G and c.1654G > T) in ALOX12B, 4 of which were novel. The variants were all pathogenic/likely pathogenic according to the ACMG classification and segregation analysis, except for c.797A > G in TGM1 which was a variant of unknown clinical significance. Prenatal diagnosis was performed in Family 1 with c.655A > G in TGM1 and Family 2 with c.527 + 2T > G in ALOX12B. Conclusion Our findings further support that WES is an effective diagnostic tool for the accurate and rapid identification of causative variants in hereditary ichthyosis.

Mulibrey Nanism is a rare multisystem disorder inherited in an autosomal recessive manner caused by mutations in the TRIM37 gene. Most of the reported cases are from Finland, but this condition has rarely occurred in other countries. Although the clinical diagnosis of Mulibrey nanism is a challenge during the first months of life, the disease can be suspected clinically due to the distinctive features of the patients. A 4-year-old female with pneumonia, cardiomyopathy, growth retardation, peripheral edema, and characteristic craniofacial features was referred to Tehran Hope Generation Foundation Genetic diagnosis Center, in October 2021. Genomic DNA was isolated from peripheral blood samples of the patient and her parents and Whole exome sequencing was performed for the patient. Whole exome sequencing revealed a homozygous G>A splice site variant (TRIM37; c.370-1G>A). Sanger sequencing confirmed the segregation of the variant with phenotype in this family. Whole exome sequencing can be helpful in the diagnosis of the patients suspecting to Mulibrey nanism and lacking sufficient clinical presentation according to the diagnostic algorithm.

PurposeOocytes and spermatozoa are electrogenic cells with the ability to respond to electrical stimuli and modulate their electrical properties accordingly. Determination of the ionic events during the gamete maturation helps to design suitable culture media for gametes in assisted reproductive technology (ART). The present systematic review focuses on the electrophysiology of human gametes during different stages of maturation and also during fertilization.Materials and MethodsThe reports published in the English language between January 2000 and July 2021 were extracted from various electronic scientific databases following the PRISMA checklist using specific MeSH keywords.ResultsSubsequent to the screening process with defined inclusion and exclusion criteria, 60 articles have been included in this review. Among them, 11 articles were directly related to the electrophysiology of human oocytes and 49 physiology department to the electrophysiology of human spermatozoa.ConclusionsGametes generate electrical currents by ionic exchange, particularly Na+, K+, Cl-, H+, Zn2+, Cu2+, Se2+, Mg2+, HCO3-, and Ca2+ through specific ion channels in different stages of gamete maturation. The ionic concentrations, pH, and other physicochemical variables are modulated during the gametogenesis, maturation, activation, and the fertilization process following gamete function and metabolism. The electrical properties of human gametes change during different stages of maturation. Although it is demonstrated that the electrical properties are significant regulators of cell signaling and are fundamental to gamete maturation and fertilization, their exact roles in these processes are still poorly understood. Further research is required to unveil the intricate electrophysiological processes of human gamete maturation.