Mechanisms of Choice in X-Chromosome Inactivation.

Early in development, placental and marsupial mammals harbouring at least two X chromosomes per nucleus are faced with a choice that affects the rest of their lives: which of those X chromosomes to transcriptionally inactivate. This choice underlies phenotypical diversity in the composition of tissues and organs and in their response to the environment, and can determine whether an individual will be healthy or affected by an X-linked disease. Here, we review our current understanding of the process of choice during X-chromosome inactivation and its implications, focusing on the strategies evolved by different mammalian lineages and on the known and unknown molecular mechanisms and players involved

Mechanisms of Choice in X-Chromosome Inactivation.

Early in development, placental and marsupial mammals harbouring at least two X chromosomes per nucleus are faced with a choice that affects the rest of their lives: which of those X chromosomes to transcriptionally inactivate. This choice underlies phenotypical diversity in the composition of tissues and organs and in their response to the environment, and can determine whether an individual will be healthy or affected by an X-linked disease. Here, we review our current understanding of the process of choice during X-chromosome inactivation and its implications, focusing on the strategies evolved by different mammalian lineages and on the known and unknown molecular mechanisms and players involved

Respiratory Syncytial Virus in Veneto Region: Analysis of Hospital Discharge Records from 2007 to 2021

: Respiratory Syncytial Virus (RSV) is a known cause of acute lower respiratory infections in infants and young children. The present study aims to analyze the temporal trends and characteristics of hospitalization related to RSV in the Veneto region (Italy) in the period between 2007 and 2021. The analysis is performed on all the hospital discharge records (HDRs) of public and accredited private hospitals corresponding to hospitalizations occurring in the Veneto region (Italy). HDRs are considered if they included at least one of the following ICD9-CM codes: 079.6-Respiratory Syncytial Virus (RSV); 466.11-acute bronchiolitis due to RSV; and 480.1-pneumonia due to RSV. Total annual cases, sex, and age-specific rates and trends are evaluated. Overall, an increasing trend in the number of hospitalizations due to RSV was observed between 2007 and 2019, with a slight drop in RSV seasons 2013-2014 and 2014-2015. From March 2020 to September 2021, almost no hospitalization was registered, but in the last quarter of 2021, the number of hospitalizations reached its highest value in the series. Our data confirm the preponderance of RSV hospitalizations in infants and young children, the seasonality of RSV hospitalizations, and acute bronchiolitis as the most frequent diagnosis. Interestingly, the data also show the existence of a significant burden of disease and a non-negligible number of deaths also in older adults. The present study confirms RSV is associated with high rates of hospitalization in infants and sheds light on the burden in the 70+ age group in which a considerable number of deaths was observed, as well as the parallelism with other countries, which is consistent with a wide underdiagnoses issue

Extracellular vesicles from adipose mesenchymal stem cells target inflamed lymph nodes in experimental autoimmune encephalomyelitis

Background aims: Adipose mesenchymal stem cells (ASCs) represent a promising therapeutic approach in inflammatory neurological disorders, including multiple sclerosis (MS). Recent lines of evidence indicate that most biological activities of ASCs are mediated by the delivery of soluble factors enclosed in extracellular vesicles (EVs). Indeed, we have previously demonstrated that small EVs derived from ASCs (ASC-EVs) ameliorate experimental autoimmune encephalomyelitis (EAE), a murine model of MS. The precise mechanisms and molecular/cellular target of EVs during EAE are still unknown. Methods: To investigate the homing of ASC-EVs, we intravenously injected small EVs loaded with ultra-small superparamagnetic iron oxide nanoparticles (USPIO) at disease onset in EAE-induced C57Bl/6J mice. Histochemical analysis and transmission electron microscopy were carried out 48 h after EV treatment. Moreover, to assess the cellular target of EVs, flow cytometry on cells extracted ex vivo from EAE mouse lymph nodes was performed. Results: Histochemical and ultrastructural analysis showed the presence of labeled EVs in lymph nodes but not in lungs and spinal cord of EAE injected mice. Moreover, we identified the cellular target of EVs in EAE lymph nodes by flow cytometry: ASC-EVs were preferentially located in macrophages, with a consistent amount also noted in dendritic cells and CD4+ T lymphocytes. Conclusions: This represents the first direct evidence of the privileged localization of ASC-EVs in draining lymph nodes of EAE after systemic injection. These data provide prominent information on the distribution, uptake and retention of ASC-EVs, which may help in the development of EV-based therapy in MS

Use of GLP-1 analogs in the treatment of obesity: an integrative and systematic review

Obesity is the global epidemic of the 21st century: about 1.5 billion adults worldwide are overweight, and among them, about 200 million men and 300 million women are obese. The prevalence of overweight and obesity is also increasing in children and adolescents in developed (about 25%) and developing countries (about 13%). Obesity has been associated with many comorbidities, including type 2 diabetes mellitus (T2DM), nonalcoholic fatty liver disease (NAFLD), hypertension, chronic kidney disease, cardiovascular disease (CVD), and malignancies, leading to increased mortality observed in obese individuals. Overweight and obesity were estimated to be associated worldwide with 3.4 million deaths, which could also be expressed as 4% of disability-adjusted life-years lost (DALYs). It is also alarming that children with severe obesity are apparently at in- creased risk of premature death. Managing obesity is hard and usually disappointing for both patients and physicians. Weight loss is difficult to achieve and even more difficult to sustain in the long term. When lifestyle modifications fail to achieve the predefined target, anti-obesity medications may be added on, as recommended by all relevant guidelines, including those of the Endocrine Society and recent guidelines for obese with diabetes. Glucagon-like peptide 1 (GLP-1) is an incretin secreted by L-cells in the intestinal mucosa and has been shown to act in the brain and periphery to cause effective weight loss. GLP-1 release is stimulated by food intake and its agonist, exenatide, is the first from the incretin family approved for weight-loss therapy by the Food and Drug Administration (FDA). In overweight and obese adults, it is concluded that the GLP-1 analogs and the Phentermine/Topiramate association proved to be among the best for the effects on weight reduction. Regarding childhood obesity, the FDA recently approved the use of Liraglutide. Schizophrenic patients, a target of studies due to risk factors, benefited from treatment with GLP-1 analogs

Genotype and residual enzyme activity in medium-chain acyl-CoA dehydrogenase (MCAD) deficiency: Are predictions possible?

AbstractMedium‐chain acyl‐CoA dehydrogenase deficiency (MCADD) is the most common defect of mitochondrial β‐oxidation. Confirmation diagnostics after newborn screening (NBS) can be performed either by enzyme testing and/or by sequencing of the ACADM gene. Here, we report the results from enzyme testing in lymphocytes with gene variants from molecular analysis of the ACADM gene and with the initial acylcarnitine concentrations in the NBS sample. From April 2013 to August 2019, in 388 individuals with characteristic acylcarnitine profiles suggestive of MCADD the octanoyl‐CoA‐oxidation was measured in lymphocytes. In those individuals with residual activities 35% excluding MCADD. In the remaining 21 individuals, MCAD residual activity ranged from 30% to 35%. The latter group comprised both heterozygous carriers and individuals carrying two gene variants on different alleles. Twenty new variants could be identified and functionally classified based on their effect on enzyme function. C6 and C8 acylcarnitine species in NBS correlated with MCAD activity and disease severity. MCADD was only confirmed in half of the cases referred suggesting a higher false positive rate than expected. Measurement of the enzyme function in lymphocytes allowed fast confirmation diagnostics and clear determination of the pathogenicity of new gene variants. There is a clear correlation between genotype and enzyme function underlining the reproducibility of the functional measurement in vitro

The RNA polymerase II subunit RPB-9 recruits the integrator complex to terminate Caenorhabditis elegans piRNA transcription.

PIWI-interacting RNAs (piRNAs) are genome-encoded small RNAs that regulate germ cell development and maintain germline integrity in many animals. Mature piRNAs engage Piwi Argonaute proteins to silence complementary transcripts, including transposable elements and endogenous genes. piRNA biogenesis mechanisms are diverse and remain poorly understood. Here, we identify the RNA polymerase II (RNA Pol II) core subunit RPB-9 as required for piRNA-mediated silencing in the nematode Caenorhabditis elegans. We show that rpb-9 initiates heritable piRNA-mediated gene silencing at two DNA transposon families and at a subset of somatic genes in the germline. We provide genetic and biochemical evidence that RPB-9 is required for piRNA biogenesis by recruiting the Integrator complex at piRNA genes, hence promoting transcriptional termination. We conclude that, as a part of its rapid evolution, the piRNA pathway has co-opted an ancient machinery for high-fidelity transcription

Aberrant DNA methylation profiles of inherited and sporadic colorectal cancer

Background: Aberrant DNA methylation has been widely investigated in sporadic colorectal carcinomas (CRCs), and extensive work has been performed to characterize different methylation profiles of CRC. Less information is available about the role of epigenetics in hereditary CRC and about the possible clinical use of epigenetic biomarkers in CRC, regardless of the etiopathogenesis. Long interspersed nucleotide element 1 (LINE-1) hypomethylation and gene-specific hypermethylation of 38 promoters were analyzed in multicenter series of 220 CRCs including 71 Lynch (Lynch colorectal cancer with microsatellite instability (LS-MSI)), 23 CRCs of patients under 40 years in which the main inherited CRC syndromes had been excluded (early-onset colorectal cancer with microsatellite stability (EO-MSS)), and 126 sporadic CRCs, comprising 28 cases with microsatellite instability (S-MSI) and 98 that were microsatellite stable (S-MSS). All tumor methylation patterns were integrated with clinicopathological and genetic characteristics, namely chromosomal instability (CIN), TP53 loss, BRAF, and KRAS mutations. Results: LS-MSI mainly showed absence of extensive DNA hypo-and hypermethylation. LINE-1 hypomethylation was observed in a subset of LS-MSI that were associated with the worse prognosis. Genetically, they commonly displayed G:A transition in the KRAS gene and absence of a CIN phenotype and of TP53 loss. S-MSI exhibited a specific epigenetic profile showing low rates of LINE-1 hypomethylation and extensive gene hypermethylation. S-MSI were mainly characterized by MLH1 methylation, BRAF mutation, and absence of a CIN phenotype and of TP53 loss. By contrast, S-MSS showed a high frequency of LINE-1 hypomethylation and of CIN, and they were associated with a worse prognosis. EO-MSS were a genetically and epigenetically heterogeneous group of CRCs. Like LS-MSI, some EO-MSS displayed low rates of DNA hypo-or hypermethylation and frequent G:A transitions in the KRAS gene, suggesting that a genetic syndrome might still be unrevealed in these patients. By contrast, some EO-MSS showed similar features to those observed in S-MSS, such as LINE-1 hypomethylation, CIN, and TP53 deletion. In all four classes, hypermethylation of ESR1, GATA5, and WT1 was very common. Conclusions: Aberrant DNA methylation analysis allows the identification of different subsets of CRCs. This study confirms the potential utility of methylation tests for early detection of CRC and suggests that LINE-1 hypomethylation may be a useful prognostic marker in both sporadic and inherited CRCs

The histone binding capacity of SPT2 controls chromatin structure and function in Metazoa

Histone chaperones control nucleosome density and chromatin structure. In yeast, the H3-H4 chaperone Spt2 controls histone deposition at active genes but its roles in metazoan chromatin structure and organismal physiology are not known. Here we identify the Caenorhabditis elegans ortholog of SPT2 (CeSPT-2) and show that its ability to bind histones H3-H4 is important for germline development and transgenerational epigenetic gene silencing, and that spt-2 null mutants display signatures of a global stress response. Genome-wide profiling showed that CeSPT-2 binds to a range of highly expressed genes, and we find that spt-2 mutants have increased chromatin accessibility at a subset of these loci. We also show that SPT2 influences chromatin structure and controls the levels of soluble and chromatin-bound H3.3 in human cells. Our work reveals roles for SPT2 in controlling chromatin structure and function in Metazoa.</p