International Precision Child Health Partnership (IPCHiP): an initiative to accelerate discovery and improve outcomes in rare pediatric disease

npj Genomic Medicine, Год журнала: 2025, Номер 10(1)

Опубликована: Фев. 27, 2025

Advances in genomic technologies have revolutionized the diagnosis of rare genetic diseases, leading to emergence precision therapies. However, there remains significant effort ahead ensure promise medicine translates improved outcomes. Here, we discuss challenges advancing child health and highlight how international collaborations such as International Precision Child Health Partnership, which embed research into clinical care, can maximize benefits for children globally.

Язык: Английский

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Divergent B-cell and cytotoxic TNK cell activation signatures in HLA-B27-associated ankylosing spondylitis and acute anterior uveitis

Frontiers in Immunology, Год журнала: 2025, Номер 16

Опубликована: Март 7, 2025

Ankylosing spondylitis (AS), also known as radiographic axial spondyloarthritis (r-axSpA), is an immune-mediated inflammatory disorder frequently associated with acute anterior uveitis (AAU). Both conditions share a strong association the genetic risk factor, human leukocyte antigen (HLA)-B27. However, immunophenotype underlying HLA-B27-associated AS and/or AAU pathophysiology remains known. Using cellular indexing of transcriptomes and epitopes (CITE-Seq) in well-characterized cohort 25 subjects-including (HLA-B27pos), AS+AAU HCs (HLA-B27neg); N = 5/group-we identified transcriptomic differences at single-cell level, along differentially expressed cell surface markers. Our study elucidates both shared distinct immune alterations linked to HLA-B27 disease. Furthermore, we employed sparse decomposition arrays (SDA) analysis, unsupervised machine learning method, examine high-dimensional transcriptional landscape our data identify complex nonlinear relationships. HLA-B27- disease-specific AAU. The profiles closely resembled those AS, suggesting plays dominant role dysregulation. SDA analysis further revealed dysregulated B-cell maturation activation subjects, whereas subjects exhibited enrichment cytotoxic effector function T NK cells. myeloid activation, key process initiating sustaining inflammation. Additionally, showed dampening homeostatic function, i.e., balance between identifying actively eliminating foreign pathogens while preventing response against self-antigens, that inflammation may arise from In conclusion, results highlight overlapping involvement, immunophenotypic responses, such decrease naive B cells reduction CD8/NK population subjects. These set mediators driving pathogenesis. Future studies incorporating HLA-B27-negative patients, validation dysfunction these diseases, provide novel biomarkers therapeutic targets.

Язык: Английский

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The Role of the Sirtuin Family Histone Deacetylases in Acute Myeloid Leukemia—A Promising Road Ahead

Cancers, Год журнала: 2025, Номер 17(6), С. 1009 - 1009

Опубликована: Март 17, 2025

Acute myeloid leukemia (AML) corresponds to a heterogeneous group of clonal hematopoietic diseases, which are characterized by uncontrolled proliferation malignant transformed precursors and their inability differentiate into mature blood cells. The prognosis AML depends on many variables, including the genetic features disease. Treatment outcomes, despite introduction new targeted therapies, still unsatisfactory. Recently, there have been an increasing number reports enzymatic proteins sirtuin family potential importance in cancer general. Sirtuins 7 (SIRT1-7) NAD+-dependent histone deacetylases with pleiotropic effects metabolism, aging processes, cell survival. They not only responsible for post-translational modification histones but also play various biochemical functions interact other regulating survival, such as p53. Thus, role key mechanisms tumorigenesis makes them worthwhile topic AML. Different sirtuins shown act oppositely depending biological context, mechanism requires further exploration. This review provides comprehensive description significance light current state knowledge. It focuses particular molecular regulated signaling pathways involved leukemogenesis, well clinical aspects therapeutic targets

Язык: Английский

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Epigenetic Regulation of Chromatin Functions by MicroRNAs and Long Noncoding RNAs and Implications in Human Diseases

Biomedicines, Год журнала: 2025, Номер 13(3), С. 725 - 725

Опубликована: Март 16, 2025

The bulk of RNA produced from the genome complex organisms consists a very large number transcripts lacking protein translational potential and collectively known as noncoding RNAs (ncRNAs). Initially thought to be mere products spurious transcriptional noise, ncRNAs are now universally recognized pivotal players in cell regulatory networks across broad spectrum biological processes. Owing their critical roles, ncRNA dysfunction is closely associated with etiopathogenesis various human malignancies, including cancer. As such, represent valuable diagnostic biomarkers well targets for innovative therapeutic intervention. In this review, we focus on microRNAs (miRNAs) long (lncRNAs), two most extensively studied classes field biology. After outlining key concepts miRNA lncRNA biogenesis pathways, examine multiple roles mediating epigenetic regulation gene expression chromatin organization. Finally, by providing numerous examples specific miRNAs lncRNAs, discuss how dysregulation these mechanisms contributes onset and/or progression diseases.

Язык: Английский

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Conservation assessment of human splice site annotation based on a 470-genome alignment

Nucleic Acids Research, Год журнала: 2025, Номер 53(6)

Опубликована: Фев. 25, 2025

Abstract Despite many improvements over the years, annotation of human genome remains imperfect. The use evolutionarily conserved sequences provides a strategy for selecting high-confidence subset annotation. Using latest whole-genome alignment, we found that splice sites from protein-coding genes in high-quality MANE are consistently across >350 species. We also studied RefSeq, GENCODE, and CHESS databases not present MANE. In addition, analyzed completeness alignment with respect to annotations described method would allow us fix up 60% missing alignments exons. trained logistic regression classifier distinguish between conservation exhibited by versus chosen randomly neutrally evolving sequences. classified our model as well-supported have lower single nucleotide polymorphism rates better transcriptomic evidence. then computed transcripts using only “well-supported” or ones This is enriched major gene catalogs appear be under purifying selection more likely correct functionally relevant.

Язык: Английский

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