76555 research outputs found
Sort by
Modest increase in the de novo single-nucleotide mutation rate in house mice born by assisted reproduction.
No full textApproximately 2.6% of live births in the United States are conceived using assisted reproductive technologies (ARTs). Although some ARTs, including in vitro fertilization (IVF) and intracytoplasmic sperm injection, are known to alter the epigenetic landscape of early embryonic development, their impact on DNA sequence stability is unclear. Here, we leverage the strengths of the laboratory mouse model system to investigate whether a standard ART series (ovarian hyperstimulation, gamete isolation, IVF, embryo culture, and embryo transfer) affects genome stability. Age-matched cohorts of 12 ART-derived and 16 naturally conceived C57BL/6J inbred mice were reared in a controlled setting and whole-genome-sequenced to ∼50× coverage. Using a rigorous pipeline for de novo single-nucleotide variant (dnSNV) discovery, we observe a ∼30% (95% CI: 4.5%–56%) increase in the dnSNV rate with ART compared with naturally conceived mice (P = 0.017). Analysis of the dnSNV mutation spectrum identifies signatures attributable to germline DNA repair activity but reveals no differentially enriched signatures between cohorts. We observe no enrichment of dnSNVs in specific genomic contexts, suggesting that the observed rate increase in ART-derived mice is a general genome-wide phenomenon. Together, our findings show that ART is moderately mutagenic in house mice and motivate future work to define the procedure(s) associated with this increased mutational vulnerability. Although we caution that our findings cannot be immediately translated to humans, they nonetheless emphasize a pressing need for investigations on the potential mutagenicity of ART in our species
Educational efficacy of training videos and simulators for teaching basic mouse experimental skills to novice veterinary students.
No full textAlternative educational tools, such as training videos and simulators, are recommended in the education of laboratory animal science. However, evidence supporting their educational utility in the training of rodent experimental techniques remains limited. In this study, we assessed the utility of alternative educational tools in the practice of laboratory animal science for novice veterinary students. 149 students participated in a stepwise program beginning with lectures, followed by preparatory learning sessions using training videos and two types of mouse simulators (a silicone-based model and fabric toy mouse), and then hands-on training with live mice. The program covered basic techniques: habituation, restraint, and vaginal smear sampling for estrous cycle determination. A survey-based evaluation was conducted to assess the educational utility of alternative educational tools. The contribution of each preparatory resource (videos, lectures, simulators, printed materials, and notes) to skill acquisition was evaluated, showing that videos, lectures, and printed materials highly contributed. The training videos were rated as more necessary than the simulators for skill acquisition. Psychological evaluation showed that 84% of students experienced anxiety before practice. A positive correlation was found between anxiety levels and frequency of use for all three tools, and students reported that all tools were effective in reducing anxiety during practice. All techniques showed high proficiency rates. Our findings suggest that integrating alternative tools with live-animal training promotes technical skill acquisition, enhances psychological readiness, and supports 3Rs-based laboratory animal practice
Overcoming EGFR-Mediated Dendritic Cell Dysfunction to Enhance Anti-tumor Immunity in EGFR-Mutant NSCLC by Precisely Targeting CD73 With pH-responsive Nanocarriers.
No full textEGFR mutations remain a major challenge in immunotherapy for non-small cell lung cancer (NSCLC), with poor responses to immune checkpoint inhibitors driven by mechanisms associated with EGFR mutation-mediated tumor microenvironment (TME) modulation. This study reveals that EGFR mutations prominently impaired dendritic cell (DC) maturation, disrupting their capacity to effectively prime CD8+ T cells and thereby compromising anti-tumor immune responses. By application of clinical specimen analyses, multi-omics approaches, and in vivo mouse models, this work demonstrates that EGFR mutations elicited adenosine production through the ERK/c-Jun signaling axis in tumor cells, establishing an immunosuppressive TME that impeded maturation and antigen presentation of DCs, and in turn weakened CD8+ T cell activation. To overcome the EGFR mutation-induced immunosuppression, this work next develops F127 ZIF-8 AB680 , a pH-responsive and tumor-selective nanodrug specifically designed to target the CD73-adenosine pathway within the acidic TME. This nanodrug significantly improves the therapeutic efficacy of PD-1 blockade, leading to robust tumor growth inhibition and prolonged survival of mice in EGFR-mutant NSCLC models. Leveraging the advanced nanotechnology, this newly designed pH-sensitive nanocarrier introduces a precise CD73/adenosine inhibition within the acidic TME that reprograms the immune landscape in EGFR-mutant NSCLC, which represents a promising therapeutic strategy to overcome immunotherapy resistance in NSCLC
An ITPR1 Variant in the IP3-ITPR1 Binding Pocket Associated With a Clinical Phenotype of Athetoid Cerebral Palsy.
No full textA de novo, missense variant in ITPR1-inositol 1,4,5-trisphosphate receptor type 1 (ITPR1), p.(Tyr567Cys), was identified by trio whole-genome sequencing in an individual diagnosed with Spinocerebellar ataxia 29 (SCA29) who was affected by cerebral palsy and global developmental delay. The variant affects a residue involved in Inositol 1,4,5-trisphosphate (IP3)-ITPR1 binding. Genotype-Phenotype correlation analysis of the set of missense variants affecting nine residues involved in IP3-ITPR1 binding in the current case and 170 reports of individuals with ITPR1 variants showed a significantly higher frequency of phenotypic features related to neurodevelopmental delay in these variants than in other ITPR1 variants. Our proband was diagnosed with cerebral palsy, as were five other published individuals diagnosed with SCA29. Two of these individuals were siblings who were found to have the variant p.(Arg269Trp), also located in the IP3-ITPR1 binding pocket. These observations suggest that genotype-phenotype correlations exist in the ITPR1 gene and underscore the importance of data sharing and reuse to elucidate the natural history of rare neurodevelopmental diseases
Perspectives from the 2025 ISCBI/ISCI joint workshop on genetic stability, clonal monitoring, ethical data governance, and global inclusion in stem cell banking.
No full textTwo international stem cell consortia, the International Stem Cell Initiative (ISCI) and the International Stem Cell Biobanking Initiative (ISCBI, www.iscbi.org ) held a workshop on June 15th 2025 in Hong Kong on genetic variants in human pluripotent stem cell (hPSC) lines and accurate and standardized documentation of donor/hPSC genetic information including ethnicity. The occurrence and detection of genetic variants is a key issue for assuring reproducible stem cell research data and the safety of stem cell derived medicinal products. Presentations by leading experts addressed the nature of hPSC genetic variants, their detection and accurate recording of genetic data and ethnicity. The audience of stem cell researchers, cell banking directors and experts in ethic, policy and stem cell databases, from 13 countries across the globe, discussed progression of the ISCI consortium\u27s efforts in providing further data and thought leadership on the management of genetic variants, and the challenges for standardizing biobanking approaches for hPSC genetic data including ethnicity. This paper records the key elements of this discussion and the conclusions and consensus reached and ongoing work to provide guidance for hPSC biobanks
Intrinsic-dimension analysis for guiding dimensionality reduction and data fusion in multi-omics data processing.
Full text linkMulti-omics data have revolutionized biomedical research by providing a comprehensive understanding of biological systems and the molecular mechanisms of disease development. However, analyzing multi-omics data is challenging due to high dimensionality and limited sample sizes, necessitating proper data-reduction pipelines to ensure reliable analyses. Additionally, its multimodal nature requires effective data-integration pipelines. While several dimensionality reduction and data fusion algorithms have been proposed, crucial aspects are often overlooked. Specifically, the choice of projection space dimension is typically heuristic and uniformly applied across all omics, neglecting the unique high dimension small sample size challenges faced by individual omics. This paper introduces a novel multi-modal dimensionality reduction pipeline tailored to individual views. By leveraging intrinsic dimensionality estimators, we assess the curse-of-dimensionality impact on each view and propose a two-step reduction strategy for significantly affected views, combining feature selection with feature extraction. Compared to traditional uniform reduction pipelines in a crucial and supervised multi-omics analysis setting, our approach shows significant improvement. Additionally, we explore three effective unsupervised multi-omics data fusion methods rooted in the main data fusion strategies to gain insights into their performance under crucial, yet overlooked, settings
Virtual Cancer Genomics: An Accessible and Effective Approach to Research Training for Undergraduates.
Full text linkTo diversify the cancer research workforce, it is necessary to broaden the accessibility of audience appropriate training programs. Cancer research training opportunities for undergraduates are often geographically bound and have limited enrollment capacities. To address this problem, the Genomic Education team at The Jackson Laboratory designed a free, 2-week, virtual short course in cancer genomics open to students across the USA. Each summer students learn foundational concepts in cancer genomics while gaining valuable exposure to a range of careers in the field. We developed recruitment strategies prioritizing students who are underrepresented in research and successfully scaled the course without compromising the student experience by creating tiered levels of engagement and flexibility through a mix of synchronous and interactive asynchronous activities. This approach accommodates students who work or are otherwise unable to participate in mentored research away from their home institution. In addition to 1-h live sessions designed for didactic content delivery and interaction with researchers and clinicians, the course offers participants in the highest tier of engagement collaboration in small groups on an inquiry project at the intersection of cancer genomics and patient care. Formal assessment of student attitudes indicates significant benefits and gains from participation in this course. Greater than ninety percent of surveyed students indicated the course was an effective way to learn about cancer genomics, had a positive effect on their interest in science, and provided clarification of their career path, which attests to the value of creating accessible training formats for undergraduates who wish to engage in biomedicine
Antisense oligonucleotide-mediated TRA2β poison exon inclusion induces the expression of a lncRNA with anti-tumor effects.
Full text linkUpregulated expression of the oncogenic splicing factor TRA2β occurs in human tumors partly through decreased inclusion of its autoregulatory non-coding poison exon (PE). Here, we reveal that low TRA2β-PE inclusion negatively impacts patient survival across several tumor types. We demonstrate the ability of splice-switching antisense oligonucleotides (ASOs) to promote TRA2β-PE inclusion and lower TRA2β protein levels in pre-clinical cancer models. TRA2β-PE-targeting ASOs induce anti-cancer phenotypes and widespread transcriptomic alterations with functional impact on RNA processing, mTOR, and p53 signaling pathways. Surprisingly, the effect of TRA2β-PE-targeting ASOs on cell viability are not phenocopied by TRA2β knockdown. Mechanistically, we find that the ASO functions by both decreasing TRA2β protein and inducing the expression of TRA2β-PE-containing transcripts that act as long non-coding RNAs to sequester nuclear proteins. Finally, TRA2β-PE-targeting ASOs are toxic to preclinical 3D organoid and in vivo patient-derived xenograft models. Together, we demonstrate that TRA2β-PE acts both as a regulator of protein expression and a long-noncoding RNA to control cancer cell growth. Drugging oncogenic splicing factors using PE-targeting ASOs is a promising therapeutic strategy
MorPhiC Consortium: towards functional characterization of all human genes.
No full textRecent advances in functional genomics and human cellular models have substantially enhanced our understanding of the structure and regulation of the human genome. However, our grasp of the molecular functions of human genes remains incomplete and biased towards specific gene classes. The Molecular Phenotypes of Null Alleles in Cells (MorPhiC) Consortium aims to address this gap by creating a comprehensive catalogue of the molecular and cellular phenotypes associated with null alleles of all human genes using in vitro multicellular systems. In this Perspective, we present the strategic vision of the MorPhiC Consortium and discuss various strategies for generating null alleles, as well as the challenges involved. We describe the cellular models and scalable phenotypic readouts that will be used in the consortium\u27s initial phase, focusing on 1,000 protein-coding genes. The resulting molecular and cellular data will be compiled into a catalogue of null-allele phenotypes. The methodologies developed in this phase will establish best practices for extending these approaches to all human protein-coding genes. The resources generated-including engineered cell lines, plasmids, phenotypic data, genomic information and computational tools-will be made available to the broader research community to facilitate deeper insights into human gene functions