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Metabolomic and lipidomic atlas of human hair across its length.
No full textThe stable structure and growth cycle of human hair enables the accumulation of both endogenous and exogenous compounds, making hair an ideal matrix for long-term profiling. However, its exact molecular composition, shaped by root-to-tip variations, remains poorly understood. Here, we present a metabolome and lipidome atlas of human hair originating from a healthy cohort. The Human Hair Atlas maps over 1200 unique molecular species and highlights compounds prone to significant longitudinal variations. Metabolite and lipid levels vary by up to 50% along the length of the hair, underscoring the importance of accounting for segmental differences. We categorized 122 molecules as exposome-related compounds, primarily from personal care products, facilitating biological interpretation. The Human Hair Atlas is publicly accessible ( https://metabolomics.cloud/hair/ ), providing a resource to stimulate research in hair metabolomics, lipidomics, and exposomics, and to explore the potential of hair as a complementary matrix in clinical studies
Rapid Changes in Cholinergic Signaling, Myelination, and Thyroid Signaling Pathway Gene Expression in Amygdala Subnuclei in Response to Social Status Maintenance and Reorganization.
No full textMale CD-1 mice form linear social hierarchies and can rapidly reform them following social reorganization. Through tag-based sequencing in the medial amygdala (MeA), we identified several genes regulating cholinergic signaling, myelination, and thyroid signaling that rapidly shift expression 70 min after animals change social status. Here, we further characterize the expression patterns of individual genes within these pathways in both stable and reorganized hierarchies. We find that genes related to cholinergic signaling show higher expression in the MeA of dominant males in stable hierarchies as well as when reestablishing dominance in reorganized hierarchies. Dominant males also show higher levels of myelination-related genes than socially descending males when reestablishing their social status during social reorganization but less so in stable groups. Conversely, thyroid signaling genes show higher expression in the MeA in subordinate males and previously dominant males who are socially descending. Using RNAscope, we were able to demonstrate broadly similar patterns of gene expression immediately following social reorganization across the MeA, basolateral, and central amygdala for seven genes of interest (chat, slc5a7, ache, mbp, mog, crym, and mybpc1). High levels of coexpression of cholinergic signaling and myelination gene expression in dominant males suggest that these processes work together to promote resilience to the social challenge and promote dominance. In summary, we demonstrate that rapid changes in amygdala gene expression in each pathway are associated with the formation and maintenance of dominance and subordinate social status in stable and reorganized environments
Identifying genetic determinants of outer retinal function in mice using a large-scale gene-targeted screen.
No full textElectroretinography (ERG) provides a noninvasive functional measure of multiple cell types of the outer retina. We conducted an ERG-based screen of 530 single-gene knockout mouse strains generated as part of the International Mouse Phenotyping Consortium, representing 2.5% of all protein-coding genes, to identify genetic variants affecting retinal function. We identified 30 strains with significantly altered ERG amplitudes. Two of the genes identified, Cfap418 and Syne2, have been previously reported with outer retinal dysfunction, thereby serving as internal controls that validate our screening protocol. Of the remaining 28 genes newly associated with altered retinal function, the majority lacked a contemporaneous histopathology correlate, highlighting the importance of ERG in early detection of functional abnormalities. A rare homozygous missense variant in FCHSD2, the human orthologue of one of the 28 genes identified, was found in a patient presenting with retinal degeneration that lacked a molecular diagnosis. This report represents a useful resource for future investigations into the molecular mechanisms driving inherited retinal diseases and demonstrates the power of large-scale ERG screening in identifying novel genetic determinants of retinal function
Harmonizing mouse anatomy terminology: a common language?
No full textThe mouse remains the principal animal model for investigating human diseases due, among other reasons, to its anatomical similarities to humans. Despite its widespread use, the assumption that mouse anatomy is a fully established field with standardized and universally accepted terminology is misleading. Many phenotypic anatomical annotations do not refer to the authority or origin of the terminology used, while others inappropriately adopt outdated or human-centric nomenclature. This inconsistency is further exacerbated by the limited availability of comprehensive anatomical references, often compelling researchers to rely on do-it-yourself anatomical interpretations when characterizing disease models-an approach that increases the risk of inaccuracies in the absence of expert anatomical guidance. To address this critical gap, we propose the formation of expert working groups comprising comparative anatomists and disease model developers. These groups would be responsible for systematically reviewing the anatomical literature of each mouse organ system and producing consensus-based terminologies aligned with the Nomina Anatomica Veterinaria (NAV), the authoritative standard for quadrupedal species. Such harmonization efforts would not only improve the consistency and reliability of anatomical descriptions in mouse models but also enhance the integration and interoperability of anatomical data across biomedical ontologies and databases, facilitating more robust data mining and translational research
Opportunities and considerations for using artificial intelligence in bioinformatics education.
No full textArtificial intelligence (AI) tools and techniques are undoubtedly being used in bioinformatics education, reflecting broader trends in education. However, many instructors and learners may be unaware of the full scope of potential uses for these tools within bioinformatics education, as well as effective practices for using them. Building on discussions held at the 6th Global Bioinformatics Education Summit, this perspective article provides insights about ways that AI might be used to generate or adapt instructional content, provide personalized help for learners, and automate assessment and grading. Additionally, we highlight AI skills that are important for bioinformatics learners to develop in order to effectively use AI as a bioinformatics learning tool. We highlight currently available tools in the quickly evolving AI landscape and suggest ways that instructors or learners might use such tools. Furthermore, we discuss key considerations and challenges associated with integrating AI into bioinformatics education, including ethical implications, potential biases, and the need to critically evaluate AI-generated content. Finally, we highlight the need for further research to better understand how AI tools are being used in practice and empower their effective and responsible use in bioinformatics education
Alternative splicing of transposable elements in human breast cancer.
Full text linkTransposable elements (TEs) drive genome evolution and can affect gene expression through diverse mechanisms. In breast cancer, disrupted regulation of TE sequences may facilitate tumor-specific transcriptomic alterations. We examine 142,514 full-length isoforms derived from long-read RNA sequencing (LR-seq) of 30 breast samples to investigate the effects of TEs on the breast cancer transcriptome. Approximately half of these isoforms contain TE sequences, and these contribute to half of the novel annotated splice junctions. We quantify splicing of these LR-seq derived isoforms in 1,135 breast tumors from The Cancer Genome Atlas (TCGA) and 1,329 healthy tissue samples from the Genotype-Tissue Expression (GTEx), and find 300 TE-overlapping tumor-specific splicing events. Some splicing events are enriched in specific breast cancer subtypes - for example, a TE-driven transcription start site upstream of ERBB2 in HER2 + tumors, and several TE-mediated splicing events are associated with patient survival and poor prognosis. The full-length sequences we capture with LR-seq reveal thousands of isoforms with signatures of RNA editing, including a novel isoform belonging to RHOA; a gene previously implicated in tumor progression. We utilize our full-length isoforms to discover polymorphic TE insertions that alter splicing and validate one of these events in breast cancer cell lines. Together, our results demonstrate the widespread effects of dysregulated TEs on breast cancer transcriptomes and highlight the advantages of long-read isoform sequencing for understanding TE biology. TE-derived isoforms may alter the expression of genes important in cancer and can potentially be used as novel, disease-specific therapeutic targets or biomarkers.One sentence summary: Transposable elements generate alternative isoforms and alter post-transcriptional regulation in human breast cancer
A New Targeted Transgenic Mouse Line for the Study of Protocadherin γC4.
No full textThe γ-protocadherins (γ-Pcdhs) comprise 22 homophilic cell adhesion molecule isoforms, expressed from the Pcdhg gene cluster via promoter choice mechanisms that serve many crucial functions during neural development. Emerging evidence supports the hypothesis that distinct isoforms have unique functions. The γC4 isoform, which is expressed from the Pcdhgc4 promoter and includes its unique variable exon, is the sole γ-Pcdh isoform essential for the postnatal survival in mice. Here we describe a new mouse line (C4-GFP) in which Pcdhgc4 with a C-terminal GFP tag is expressed from the Rosa26 locus following excision of a lox-Stop-lox cassette by Cre recombinase. We report that restricted expression of this transgene in the nervous system using Nestin-Cre is sufficient to rescue the neonatal lethality of mice mutant for Pcdhgc4. This new line will be a vital tool for dissecting mechanisms underlying the functions of this essential cell adhesion molecule gene, mutations in which have been associated with neurodevelopmental disorders in humans
Structural polymorphism and diversity of human segmental duplications.
Full text linkSegmental duplications (SDs) contribute significantly to human disease, evolution and diversity but have been difficult to resolve at the sequence level. We present a population genetics survey of SDs by analyzing 170 human genome assemblies (from 85 samples representing 38 Africans and 47 non-Africans) in which the majority of autosomal SDs are fully resolved using long-read sequence assembly. Excluding the acrocentric short arms and sex chromosomes, we identify 173.2 Mb of duplicated sequence (47.4 Mb not present in the telomere-to-telomere reference) distinguishing fixed from structurally polymorphic events. We find that intrachromosomal SDs are among the most variable, with rare events mapping near their progenitor sequences. African genomes harbor significantly more intrachromosomal SDs and are more likely to have recently duplicated gene families with higher copy numbers than non-African samples. Comparison to a resource of 563 million full-length isoform sequencing reads identifies 201 novel, potentially protein-coding genes corresponding to these copy number polymorphic SDs
Extracellular peroxiredoxin 5 exacerbates atherosclerosis via the TLR4/MyD88 pathway.
No full textBACKGROUNGD AND AIMS: Peroxiredoxin 5 (PRDX5), an atypical 2-Cys peroxiredoxin (PRDX), is known to regulate global oxidative stresses and inflammatory responses. Inflammation and oxidative stress are pivotal factors in the development of atherosclerosis, especially in the context of vascular endothelial dysfunction. However, effects of PRDX5 on atherosclerosis remain unclear. This study aimed to elucidate the role of PRDX5 in the pathogenesis of atherosclerosis.
METHODS: For in vivo analysis, normal chow diet 60-week old Apolipoprotein E knockout (ApoE
RESULTS: We observed elevated PRDX5 expression under atherosclerotic conditions in both humans and mice. Unexpectedly, Prdx5
CONCLUSIONS: These data demonstrate that extracellular PRDX5 contributes to endothelial inflammation, promoting macrophage accumulation in the atherosclerotic aorta through activation of TLR4/MyD88/NF-κB and P38 signaling pathways, thereby exacerbating the progression of atherosclerosis