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Mechanisms of tandem duplication in the cancer genome.
No full textTandem duplications (TD) are among the most frequent type of structural variant (SV) in the cancer genome. They are characterized by a single breakpoint junction that defines the boundaries and the size of the duplicated segment. Cancer-associated TDs often increase oncogene copy number or disrupt tumor suppressor gene function, and thus have important roles in tumor evolution. TDs in cancer genomes fall into three classes, defined by the size of duplications, and are associated with distinct genetic drivers. In this review, we survey key features of cancer-related TDs and consider possible underlying mechanisms in relation to stressed DNA replication and the 3D organization of the S phase genome
Rapid changes in plasma corticosterone and medial amygdala transcriptome profiles during social status change reveal molecular pathways associated with a major life history transition in mouse dominance hierarchies.
Full text linkSocial hierarchies are a common form of social organization across species. Although hierarchies are largely stable across time, animals may socially ascend or descend within hierarchies depending on environmental and social challenges. Here, we develop a novel paradigm to study social ascent and descent within male CD-1 mouse social hierarchies. We show that mice of all social ranks rapidly establish new stable social hierarchies when placed in novel social groups with animals of equivalent social status. Seventy minutes following social hierarchy formation, males that were socially dominant prior to being placed into new social hierarchies exhibit higher increases in plasma corticosterone and vastly greater transcriptional changes in the medial amygdala (MeA), which is central to the regulation of social behavior, compared to males who were socially subordinate prior to being placed into a new hierarchy. Specifically, the loss of social status in a new hierarchy (social descent) is associated with reductions in MeA expression of myelination and oligodendrocyte differentiation genes. Maintaining high social status is associated with high expression of genes related to cholinergic signaling in the MeA. Conversely, gaining social status in a new hierarchy (social ascent) is related to relatively few unique rapid changes in the MeA. We also identify novel genes associated with social transition that show common changes in expression when animals undergo either social descent or social ascent compared to maintaining their status. Two genes, Myosin binding protein C1 (Mybpc1) and μ-Crystallin (Crym), associated with vasoactive intestinal polypeptide (VIP) and thyroid hormone pathways respectively, are highly upregulated in socially transitioning individuals. Further, increases in genes associated with synaptic plasticity, excitatory glutamatergic signaling and learning and memory pathways were observed in transitioning animals suggesting that these processes may support rapid social status changes
Genetic variation modulates susceptibility to aberrant DNA hypomethylation and imprint deregulation in naive pluripotent stem cells.
Full text linkNaive pluripotent stem cells (nPSCs) frequently undergo pathological loss of DNA methylation at imprinted gene loci, posing a hurdle for biomedical applications and underscoring the need to identify underlying causes. We show that nPSCs from inbred mouse strains exhibit strain-specific susceptibility to locus-specific deregulation of imprinting marks during reprogramming and upon exposure to a mitogen-activated protein kinase (MAPK) inhibitor, a common approach to maintain naive pluripotency. Analysis of genetically diverse nPSCs from the Diversity Outbred (DO) stock confirms the impact of genetic variation on epigenome stability, which we leverage to identify trans-acting quantitative trait loci (QTLs) that modulate DNA methylation levels at specific targets or genome-wide. Analysis of multi-target QTLs on chromosomes 4 and 17 suggests candidate transcriptional regulators contributing to DNA methylation maintenance in nPSCs. We propose that genetic variants represent biomarkers to identify pluripotent cell lines with desirable properties and may allow the targeted engineering of nPSCs with stable epigenomes
A comprehensive atlas of AAV tropism in the mouse.
No full textGene therapy with adeno-associated virus (AAV) vectors requires knowledge of their tropism within the body. Here we analyze the tropism of 10 naturally occurring AAV serotypes (AAV3B, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAVrh8, AAVrh10, and AAVrh74) following systemic delivery into male and female mice. A transgene-expressing ZsGreen and Cre recombinase was used to identify transduction in a cell-dependent manner based on fluorescence. Cre-driven activation of tdTomato fluorescence offered superior sensitivity for transduced cells. All serotypes except AAV3B and AAV4 had high liver tropism. Fluorescence activation revealed transduction of unexpected tissues, including adrenals, testes, and ovaries. Rare transduced cells within tissues were also readily visualized. Biodistribution of AAV genomes correlated with fluorescence, except in immune tissues. AAV4 was found to have a pan-endothelial tropism while also targeting pancreatic beta cells. This public resource enables selection of the best AAV serotypes for basic science and preclinical applications in mice
Integrating exposomics into biomedicine.
No full textAssessing a full range of environmental exposures will improve human health
Systematic optimization and prediction of cre recombinase for precise genome editing in mice.
Full text linkBACKGROUND: The Cre-Lox system is a powerful tool in mouse genetics, enabling precise spatiotemporal control of gene expression and conditional knockout models. Since its development, it has transformed genome editing by facilitating targeted deletions, translocations, inversions, and complex modifications-double-floxed inverse orientation. Its utility extends beyond mice to rats, pigs, and zebrafish. However, challenges such as high costs, lengthy timelines, and unpredictable recombination remain, highlighting the need for ongoing improvements to enhance efficiency, reliability, and applicability across genetic models.
RESULTS: In this study, we perform a systematic analysis of Cre-mediated recombination in mice, creating 11 new strains with conditional alleles at the Rosa26 locus, using the C57BL/6J background. Factors influencing recombination efficiency include inter-loxP distance, mutant loxP sites, zygosity, chromosomal location, and breeder age. Our results demonstrate that the choice of Cre-driver strain plays a significant role in recombination efficiency. Optimal recombination is achieved when loxP sites are spaced by less than 4 kb and mutant loxP sites by 3 kb. Complete recombination fails with wildtype loxP sites spaced ≥ 15 kb or mutant lox71/66 sites spaced ≥ 7 kb. The best recombination efficiency is observed in breeders aged 8-20 weeks and when using heterozygous floxed alleles.
CONCLUSION: The Cre-Lox system remains indispensable for genetic engineering, offering flexibility beyond standalone applications by integrating with CRISPR-based methods to expand its utility. Despite challenges, our findings provide a framework for optimizing Cre-mediated recombination. By refining Cre-Lox strategies, this knowledge enhances experimental precision, improves reproducibility, and ultimately reduces the time and cost of genome modification
Harnessing the human gut microbiota: an emerging frontier in combatting multidrug-resistant bacteria.
Full text linkAntimicrobial resistance (AMR) has become a major and escalating global health threat, undermining the effectiveness of current antibiotic and antimicrobial therapies. The rise of multidrug-resistant bacteria has led to increasingly difficult-to-treat infections, resulting in higher morbidity, mortality, and healthcare costs. Tackling this crisis requires the development of novel antimicrobial agents, optimization of current therapeutic strategies, and global initiatives in infection surveillance and control. Recent studies highlight the crucial role of the human gut microbiota in defending against AMR pathogens. A balanced microbiota protects the body through mechanisms such as colonization resistance, positioning it as a key ally in the fight against AMR. In contrast, gut dysbiosis disrupts this defense, thereby facilitating the persistence, colonization, and dissemination of resistant pathogens. This review will explore how gut microbiota influence drug-resistant bacterial infections, its involvement in various types of AMR-related infections, and the potential for novel microbiota-targeted therapies, such as fecal microbiota transplantation, prebiotics, probiotics, phage therapy. Elucidating the interactions between gut microbiota and AMR pathogens will provide critical insights for developing novel therapeutic strategies to prevent and treat AMR infections. While previous reviews have focused on the general impact of the microbiota on human health, this review will specifically look at the latest research on the interactions between the gut microbiota and the evolution and spread of AMR, highlighting potential therapeutic strategies
TLR4 deficiency does not alter glaucomatous progression in a mouse model of chronic glaucoma.
Full text linkGlaucoma is a leading cause of irreversible blindness worldwide. Toll-like receptor 4 (TLR4) is a pattern-recognition transmembrane receptor that induces neuroinflammatory processes in response to injury. Tlr4 is highly expressed in ocular tissues and is known to modulate inflammatory processes in both anterior and posterior segment tissues. TLR4 activation can lead to mitochondrial dysfunction and metabolic deficits in inflammatory disorders. Due to its effects on inflammation and metabolism, TLR4 is a candidate to participate in glaucoma pathogenesis. It has been suggested as a therapeutic target based on studies using acute models, such as experimentally raising IOP to ischemia-inducing levels. Nevertheless, its role in chronic glaucoma needs further evaluation. In the current study, we investigated the role of TLR4 in an inherited mouse model of chronic glaucoma, DBA/2J. To do this, we analyzed the effect of Tlr4 knockout (Tlr4−/−) on glaucoma in DBA/2J mice. Our studies found no significant differences in intraocular pressure, iris disease, or glaucomatous progression in Tlr4−/− compared to Tlr4+/+ DBA/2J mice. Our data do not support a role for TLR4 as a treatment target in chronic glaucoma
Complete sequencing of ape genomes.
Full text linkThe most dynamic and repetitive regions of great ape genomes have traditionally been excluded from comparative studies. Consequently, our understanding of the evolution of our species is incomplete. Here we present haplotype-resolved reference genomes and comparative analyses of six ape species: chimpanzee, bonobo, gorilla, Bornean orangutan, Sumatran orangutan and siamang. We achieve chromosome-level contiguity with substantial sequence accuracy (\u3c 1 error in 2.7 megabases) and completely sequence 215 gapless chromosomes telomere-to-telomere. We resolve challenging regions, such as the major histocompatibility complex and immunoglobulin loci, to provide in-depth evolutionary insights. Comparative analyses enabled investigations of the evolution and diversity of regions previously uncharacterized or incompletely studied without bias from mapping to the human reference genome. Such regions include newly minted gene families in lineage-specific segmental duplications, centromeric DNA, acrocentric chromosomes and subterminal heterochromatin. This resource serves as a comprehensive baseline for future evolutionary studies of humans and our closest living ape relatives