Comparative genomics provides insights into chromosomal evolution and immunological adaptation in horseshoe bats
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Neurotensin-neurotensin receptor 2 signaling in adipocytes suppresses food intake through regulating ceramide metabolism
Neurotensin (NTS) is a secretory peptide produced by lymphatic endothelial cells. Our previous study revealed that NTS suppressed the activity of brown adipose tissue via interactions with NTSR2. In the current study, we found that the depletion of Ntsr2 in white adipocytes upregulated food intake, while the local treatment of NTS suppressed food intake. Our mechanistic study revealed that suppression of NTS-NTSR2 signaling enhanced the phosphorylation of ceramide synthetase 2, increased the abundance of its products ceramides C20–C24, and downregulated the production of GDF15 in white adipose tissues, which was responsible for the elevation of food intake. We discovered a potential causal and positive correlation between serum C20–C24 ceramide levels and human food intake in four populations with different ages and ethnic backgrounds. Together, our study shows that NTS-NTSR2 signaling in white adipocytes can regulate food intake via its direct control of lipid metabolism and production of GDF15. The ceramides C20–C24 are key factors regulating food intake in mammals.
Optimising the mainstreaming of renal genomics: Complementing empirical and theoretical strategies for implementation
To identify and develop complementary implementation strategies that support nephrologists in mainstreaming renal genomic testing. Interviews were conducted with individuals nominated as ‘genomics champions’ and ‘embedded genomics experts’ as part of a mainstreaming project to identify initial barriers and investigate empirical strategies for delivering the project at initial stage. Data were mapped onto implementation science framework to identify complementary theoretical strategies. Interviews with 14 genomics champions and embedded genomics experts (genetic counsellors, nephrologists, renal nurses), identified 34 barriers to incorporating genomic testing into routine care, e.g., lack of long-term multidisciplinary team support and role clarity. In total, 25 empirical implementation strategies were identified such as creating new clinical teams. Using the Consolidated Framework for Implementation Research, 10 complementary theoretical implementation strategies were identified. Our study presents a novel approach complementing empirical strategies with theoretical strategies to support nephrologists in incorporating genomic testing into routine practice. Complementary strategies can potentially address barriers and inform future studies when mainstreaming renal genomics. This process underscored the need for integrating collaborative efforts among health professionals, patients, implementation scientists and the health system to overcome identified challenges to mainstream genomic testing. Future research should explore the applicability of these strategies to support mainstreaming genomic testing in different clinical settings.
Chromosomal aberrations and early mortality in a non-mammalian vertebrate: example from pressure-induced triploid Atlantic salmon
In commercial aquaculture, the production of triploid fish is currently the most practical approach to prevent maturation and farm-to-wild introgression following escapes. However, triploids often exhibit poor welfare, and the underlying mechanisms remain unclear. Inheritance issues associated with sub-optimal hydrostatic pressure treatments used to induce triploidy, or the genetic background of parental fish, have been speculated to contribute. We tested this by quantifying the frequency and type of chromosomal aberrations in Atlantic salmon subjected to a gradient of sub-optimal pressure treatments (Experiment 1) and from multiple mothers (Experiment 2). From these experiments, we genotyped a subsample of ~900 eyed eggs and all ~3300 surviving parr across ~20 microsatellites. In contrast to the low frequency of chromosomal aberrations in the diploid (no hydrostatic pressure) and triploid (full 9500 PSI treatment) controls, eyed eggs subjected to sub-optimal pressure treatments (6500–8500 PSI) had a higher incidence of chromosomal aberrations such as aneuploidy and uniparental disomy, corresponding to lower triploidization success and higher egg mortality rates. We also observed maternal effects on triploidization success and incidence of chromosomal aberrations, with certain half-sibling families exhibiting more aberrations than others. Chromosomal aberrations were rare among surviving parr, suggesting a purge of maladapted individuals during early development. This study demonstrates that sub-optimal hydrostatic pressure treatments and maternal effects not only influence the success of triploidization treatments, but may also affect the incidence of chromosomal aberrations and early mortality. The results have important implications for aquaculture breeding programs and their efforts to prevent farm-to-wild introgression.
Modern biology of extrachromosomal DNA: A decade-long voyage of discovery
Genomic instability is a hallmark of cancer and is a major driving force of tumorigenesis. A key manifestation of genomic instability is the formation of extrachromosomal DNAs (ecDNAs) — acentric, circular DNA molecules ranging from 50 kb to 5 Mb in size, distinct from chromosomes. Ontological studies have revealed that ecDNA serves as a carrier of oncogenes, immunoregulatory genes, and enhancers, capable of driving elevated transcription of its cargo genes and cancer heterogeneity, leading to rapid tumor evolution and therapy resistance. Although ecDNA was documented over half a century ago, the past decade has witnessed a surge in breakthrough discoveries about its biological functions. Here, we systematically review the modern biology of ecDNA uncovered over the last ten years, focusing on how discoveries during this pioneering stage have illuminated our understanding of ecDNA-driven transcription, heterogeneity, and cancer progression. Furthermore, we discuss ongoing efforts to target ecDNA as a novel approach to cancer therapy. This burgeoning field is entering a new phase, poised to reshape our knowledge of cancer biology and therapeutic strategies.
Macroevolution along developmental lines of least resistance in fly wings
Evolutionary change requires genetic variation, and a reigning paradigm in biology is that rates of microevolution can be predicted from estimates of available genetic variation within populations. However, the accuracy of such predictions should decay on longer evolutionary timescales, as the influence of genetic constraints diminishes. Here we show that intrinsic developmental variability and standing genetic variation in wing shape in two distantly related flies, Drosophila melanogaster and Sepsis punctum, are aligned and predict deep divergence in the dipteran phylogeny, spanning >900 taxa and 185 million years. This alignment cannot be easily explained by constraint hypotheses unless most of the quantified standing genetic variation is associated with deleterious side effects and is effectively unusable for evolution. However, phenotyping of 71 genetic lines of S. punctum revealed no covariation between wing shape and fitness, lending no support to this hypothesis. We also find little evidence for genetic constraints on the pace of wing shape evolution along the dipteran phylogeny. Instead, correlational selection related to allometric scaling, simultaneously shaping developmental variability and deep divergence in fly wings, emerges as a potential explanation for the observed alignment. This suggests that pervasive natural selection has the potential to shape developmental architectures of some morphological characters such that their intrinsic variability predicts their long-term evolution.
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