Segmental aneuploidies with 1 Mb resolution in human preimplantation blastocysts

PurposeThis study aimed to investigate the spectrum and characteristics of segmental aneuploidies (SAs) of <10 megabase (Mb) length in human preimplantation blastocysts.MethodsPreimplantation genetic testing for aneuploidy was performed in 15,411 blastocysts from 5171 patients using a validated 1 Mb resolution platform. The characteristics and spectrum of SAs, including the incidence, sizes, type, inheritance pattern, clinical significance, and embryo distribution, were studied.ResultsIn total, 6.4% of the 15,411 blastocysts carried SAs of >10 Mb, 4.9% of embryos had SAs ranging between 1 to 10 Mb, and 84.3% of 1 to 10 Mb SAs were <5 Mb in size. Inheritance pattern analysis indicated that approximately 63.8% of 1 to 10 Mb SAs were inherited and were predominantly 1 to 3 Mb in size. Furthermore, 18.4% of inherited SAs and 51.9% de novo 1 to 10 Mb SAs were pathogenic or likely pathogenic (P/LP). Different from whole-chromosome aneuploidies, reanalysis indicated that 50% of the de novo 1 to 10 Mb SAs and 70% of the >10 Mb SAs arose from mitotic errors.ConclusionBased on the established platform, 1 to 10 Mb SAs are common in blastocysts and include a subset of P/LP SAs. Inheritance pattern analysis and clinical interpretation based on the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines contributed to determine the P/LP SAs.     

NAFLD: genetics and its clinical implications

Worldwide non-alcoholic fatty liver disease (NAFLD) is recognized as the most common type of liver disease and its burden increasing at an alarming rate. NAFLD entails steatosis, fibrosis, cirrhosis, and, finally, hepatocellular carcinoma (HCC). The substantial inter-patient variation during disease progression is the hallmark of individuals with NAFLD. The variability of NAFLD development and related complications among individuals is determined by genetic and environmental factors. Genome-wide association studies (GWAS) have discovered reproducible and robust associations between gene variants such as PNPLA3, TM6SF2, HSD17B13, MBOAT7, GCKR and NAFLD. Evidences have provided the new insights into the NAFLD biology and underlined potential pharmaceutical targets. Ideally, the candidate genes associated with the hereditability of NAFLD are mainly involved in assembly of lipid droplets, lipid remodeling, lipoprotein packing and secretion, redox status mitochondria, and de novo lipogenesis. In recent years, the ability to translate genetics into a clinical context has emerged substantially by combining genetic variants primarily associated with NAFLD into polygenic risk scores (PRS). These score in combination with metabolic factors could be utilized to identify the severe liver diseases in patients with the gene regulatory networks (GRNs). Hereby, we even have highlighted the current understanding related to the schedule therapeutic approach of an individual based on microbial colonization and dysbiosis reversal as a therapy for NAFLD. The premise of this review is to concentrate on the potential of genetic factors and their translation into the design of novel therapeutics, as well as their implications for future research into personalized medications using microbiota.     

STING pathway stimulation results in a differentially activated innate immune phenotype associated with low nitric oxide and enhanced antibody titers in young and aged mice

BackgroundOne of the most concerning public health issues, related to vaccination and disease prevention, is the inability to induce durable immune responses following a single-dose immunization. In this regard, the nature of the inflammatory environment induced by vaccine adjuvants can negatively impact the resulting immune response. To address these concerns, new strategies to vaccine design are needed in order to improve the outcomes of immune responses, particularly in immunologically disadvantaged populations.MethodsComparisons of the scope of innate immune activation induced by TLR agonists versus cyclic dinucleotides (CDNs) was performed. Their effects on the activation characteristics (e.g., metabolism, cytokine secretion) of bone marrow derived dendritic cells (BMDCs) were studied. In addition, the differential effects on in vivo induction of antibody responses were measured.ResultsAs compared to TLR ligands, the stimulation of BMDCs with CDNs induced distinctly different metabolic outcomes. Marked differences were observed in the production of nitric oxide (NO) and the cytokine BAFF. These distinct differences were correlated with improved (i.e., more rapid and persistent) vaccine antibody responses in both aged and young mice.ConclusionsOur results illustrate that the innate immune pathway targeted by adjuvants can critically impact the outcome of the immune response post-vaccination. Specifically, CDN stimulation of APCs induced an activation phenotype that was characterized by decreased innate effector molecule production (e.g., NO) and increased BAFF. This was attributed to the induction of an innate inflammatory environment that enabled the host to make the most of the existing B lymphocyte potential. The use of adjuvants that differentially engage mechanisms of innate immune activation would be particularly advantageous for the generation of robust, single dose vaccines. The results of this study demonstrated that CDNs induced differential innate activation and enhanced vaccine induced antibody responses in both young and aged mice.     

Genetic recombination as a major cause of mutagenesis in the human globin gene clusters

ObjectivesHomologous recombination is a frequent phenomenon in multigene families and as such it occurs several times in both the α- and β-like globin gene families. In numerous occasions, genetic recombination has been previously implicated as a major mechanism that drives mutagenesis in the human globin gene clusters, either in the form of unequal crossover or gene conversion. Unequal crossover results in the increase or decrease of the human globin gene copies, accompanied in the majority of cases with minor phenotypic consequences, while gene conversion contributes either to maintaining sequence homogeneity or generating sequence diversity. The role of genetic recombination, particularly gene conversion in the evolution of the human globin gene families has been discussed elsewhere.ConclusionHere, we summarize our current knowledge and review existing experimental evidence outlining the role of genetic recombination in the mutagenic process in the human globin gene families.     

Gene-based therapeutic strategies for Human Lipoprotein Lipase (LPL) deficiency: Rationale and prospects for alteration of atherogenic risk

Lipoprotein lipase (LPL) plays a critical role in the regulation of total body lipoprotein and energy metabolism. This is evident in patients presenting with significant morbidity from profound hypertiglyceridemia due to complete LPL deficiency, such as infantile onset failure to thrive, hepatosplenomegaly, eruptive xanthomata, lipemia retinalis and chronic progressive pancreatitis. In addition, gene mutations leading to partial LPL deficiency may be common in the population and carriers often present with combined hyperlipidemia and hypercholesterolemia, which would be predicted to increase atherogenic risk. Conventional therapy by diet or lipid-lowering agents is often ineffective. The development of an alternative gene transfer-based therapy to potentiate LPL activity in patients with either complete or partial LPL deficiency would represent a major advance for persons suffering from this disorder. We report the current status of our efforts to develop and test a comprehensive series of vectors and delivery systems for LPL gene transfer and expression in somatic cells in vitro, and ultimately in vivo, in a well-characterized naturally occurring feline model with LPL deficiency.