Age acquired skewed X chromosome inactivation is associated with adverse health outcomes in humans

Background: Ageing is a heterogenous process characterised by cellular and molecular hallmarks, including changes to haematopoietic stem cells and is a primary risk factor for chronic diseases. X chromosome inactivation (XCI) randomly transcriptionally silences either the maternal or paternal X in each cell of 46, XX females to balance the gene expression with 46, XY males. Age acquired XCI-skew describes the preferential selection of cells across a tissue resulting in an imbalance of XCI, which is particularly prevalent in blood tissues of ageing females, and yet its clinical consequences are unknown. Methods: We assayed XCI in 1575 females from the TwinsUK population cohort using DNA extracted from whole blood. We employed prospective, cross-sectional, and intra-twin study designs to characterise the relationship of XCI-skew with molecular and cellular measures of ageing, cardiovascular disease risk, and cancer diagnosis. Results: We demonstrate that XCI-skew is independent of traditional markers of biological ageing and is associated with a haematopoietic bias towards the myeloid lineage. Using an atherosclerotic cardiovascular disease risk score, which captures traditional risk factors, XCI-skew is associated with an increased cardiovascular disease risk both cross-sectionally and within XCI-skew discordant twin pairs. In a prospective 10 year follow-up study, XCI-skew is predictive of future cancer incidence. Conclusions: Our study demonstrates that age acquired XCI-skew captures changes to the haematopoietic stem cell population and has clinical potential as a unique biomarker of chronic disease risk

Acute Delta Hepatitis in Italy spanning three decades (1991–2019): Evidence for the effectiveness of the hepatitis B vaccination campaign

Updated incidence data of acute Delta virus hepatitis (HDV) are lacking worldwide. Our aim was to evaluate incidence of and risk factors for acute HDV in Italy after the introduction of the compulsory vaccination against hepatitis B virus (HBV) in 1991. Data were obtained from the National Surveillance System of acute viral hepatitis (SEIEVA). Independent predictors of HDV were assessed by logistic-regression analysis. The incidence of acute HDV per 1-million population declined from 3.2 cases in 1987 to 0.04 in 2019, parallel to that of acute HBV per 100,000 from 10.0 to 0.39 cases during the same period. The median age of cases increased from 27 years in the decade 1991-1999 to 44 years in the decade 2010-2019 (p < .001). Over the same period, the male/female ratio decreased from 3.8 to 2.1, the proportion of coinfections increased from 55% to 75% (p = .003) and that of HBsAg positive acute hepatitis tested for by IgM anti-HDV linearly decreased from 50.1% to 34.1% (p < .001). People born abroad accounted for 24.6% of cases in 2004-2010 and 32.1% in 2011-2019. In the period 2010-2019, risky sexual behaviour (O.R. 4.2; 95%CI: 1.4-12.8) was the sole independent predictor of acute HDV; conversely intravenous drug use was no longer associated (O.R. 1.25; 95%CI: 0.15-10.22) with this. In conclusion, HBV vaccination was an effective measure to control acute HDV. Intravenous drug use is no longer an efficient mode of HDV spread. Testing for IgM-anti HDV is a grey area requiring alert. Acute HDV in foreigners should be monitored in the years to come

Brain energy rescue:an emerging therapeutic concept for neurodegenerative disorders of ageing

The brain requires a continuous supply of energy in the form of ATP, most of which is produced from glucose by oxidative phosphorylation in mitochondria, complemented by aerobic glycolysis in the cytoplasm. When glucose levels are limited, ketone bodies generated in the liver and lactate derived from exercising skeletal muscle can also become important energy substrates for the brain. In neurodegenerative disorders of ageing, brain glucose metabolism deteriorates in a progressive, region-specific and disease-specific manner — a problem that is best characterized in Alzheimer disease, where it begins presymptomatically. This Review discusses the status and prospects of therapeutic strategies for countering neurodegenerative disorders of ageing by improving, preserving or rescuing brain energetics. The approaches described include restoring oxidative phosphorylation and glycolysis, increasing insulin sensitivity, correcting mitochondrial dysfunction, ketone-based interventions, acting via hormones that modulate cerebral energetics, RNA therapeutics and complementary multimodal lifestyle changes

Environmental Enrichment Induces Changes in Long-Term Memory for Social Transmission of Food Preference in Aged Mice through a Mechanism Associated with Epigenetic Processes

Decline in declarative learning and memory performance is a typical feature of normal aging processes. Exposure of aged animals to an enriched environment (EE) counteracts this decline, an effect correlated with reduction of age-related changes in hippocampal dendritic branching, spine density, neurogenesis, gliogenesis, and neural plasticity, including its epigenetic underpinnings. Declarative memories depend on the medial temporal lobe system, including the hippocampus, for their formation, but, over days to weeks, they become increasingly dependent on other brain regions such as the neocortex and in particular the prefrontal cortex (PFC), a process known as system consolidation. Recently, it has been shown that early tagging of cortical networks is a crucial neurobiological process for remote memory formation and that this tagging involves epigenetic mechanisms in the recipient orbitofrontal (OFC) areas. Whether EE can enhance system consolidation in aged animals has not been tested; in particular, whether the early tagging mechanisms in OFC areas are deficient in aged animals and whether EE can ameliorate them is not known. This study aimed at testing whether EE could affect system consolidation in aged mice using the social transmission of food preference paradigm, which involves an ethologically based form of associative olfactory memory. We found that only EE mice successfully performed the remote memory recall task, showed neuronal activation in OFC, assessed with c-fos immunohistochemistry and early tagging of OFC, assessed with histone H3 acetylation, suggesting a defective system consolidation and early OFC tagging in aged mice which are ameliorated by EE

Hb(\u3b1\u3b1,\u3b2\u3b2): a novel fusion construct for a dimeric, four domain hemoglobin

Hemoglobin-based blood substitutes are one of the options available to derive a resuscitating fluid taking into account clinical and physiological demands. In this paper we investigated a novel protein, Hb(\u3b1\u3b1,\u3b2\u3b2) obtained as a combination of two homodimers \u3b12 and \u3b22 both derived from a fusion gene containing two alfa chains or two beta chains respectively coupled via a specific linker. The construct here described is thus a novel heterodimeric hemoglobin carrying four heme groups. The protein cannot dissociate into dimers, as demonstrated by its absence of reactivity versus haptoglobin, and is expected to have a relatively long circulating half-life. The modification does not increase the autoxidation rate, but increases the oxygen affinity, due to a destabilization of the T quaternary state. Characterization of the biochemical properties of this protein in comparison with HbA is reported

Improved Doxorubicin Encapsulation and Pharmacokinetics of Ferritin-Fusion Protein Nanocarriers Bearing Proline, Serine, and Alanine Elements

A novel human ferritin-based nanocarrier, composed of 24 modified monomers able to auto-assemble into a modified protein cage, was produced and used as selective carrier of anti-tumor payloads. Each modified monomer derives from the genetic fusion of two distinct modules, namely the heavy chain of human ferritin (HFt) and a stabilizing/protective PAS polypeptide sequence rich in proline (P), serine (S), and alanine (A) residues. Two genetically fused protein constructs containing PAS polymers with 40- and 75-residue lengths, respectively, were compared. They were produced and purified as recombinant proteins in Escherichia coli at high yields. Both preparations were highly soluble and stable in vitro as well as in mouse plasma. Size-exclusion chromatography, dynamic light scattering, and transmission electron microscopy results indicated that PASylated ferritins are fully assembled and highly monodispersed. In addition, yields and stability of encapsulated doxorubicin were significantly better for both HFt-PAS proteins than for wild-type HFt. Importantly, PAS sequences considerably prolonged the half-life of HFt in the mouse bloodstream. Finally, our doxorubicin-loaded nanocages preserved the pharmacological activity of the drug. Taken together, these results indicate that both of the developed HFt-PAS fusion proteins are promising nanocarriers for future applications in cancer therapy

Usefulness of Addition of Magnetic Resonance Imaging to Echocardiographic Imaging to Predict Left Ventricular Reverse Remodeling in Patients With Nonischemic Cardiomyopathyhttps://arts.units.it/submit?resume=115962#

Defining short-term prognosis in nonischemic cardiomyopathy (NICM) is challenging in clinical practice. Although left ventricular reverse remodeling (LVRR) is a key prognostic marker in NICM there are few parameters able to predict it. We investigated whether a complete structural and functional cardiac magnetic resonance imaging (cMRI) evaluation was incremental to the classic clinical-echocardiographic approach in predicting LVRR in a large cohort of NICM patients receiving evidence-based treatment. Patients with a recent diagnosis of NICM (<3 months) who underwent complete clinical, echocardiographic and cMRI assessment were consecutively enrolled from 2008 to 2016. LVRR was defined as an increase in 6510 points or normalization of left ventricular ejection fraction, associated with a 6510% reduction or normalization of left ventricular end-diastolic diameter at midterm (median time 20 months) echocardiographic follow-up. Among 80 NICM patients included in the study, LVRR was observed in 43 (54%). At multivariate analysis, the clinical-echocardiographic evaluation failed to identify independent predictors of LVRR. However, absence of late gadolinium enhancement (odds ratio [OR] 9.07; confidence interval [CI] 2.7 to 13.1; p value 0.0003), left ventricular mass (OR 1.018; CI 1.001 to 1.036; p value 0.045) and peak circumferential strain (OR 1.213; CI 1.011 to 1.470; p value 0.049) assessed by cMRI were independently associated with LVRR. A model for LVRR prediction based on cMRI and clinical-echocardiographic parameters performed significantly better than the clinical-echocardiographic model alone (area under curve 0.84 vs 0.72; p value 0.023). In conclusion, an integrated imaging approach with the addition of a structural and functional cMRI study to the standard-of-care evaluation improves the prediction of LVRR in a large cohort of patients with recently diagnosed NICM receiving evidence-based treatment

Selective delivery of doxorubicin by novel stimuli-sensitive nano-ferritins overcomes tumor refractoriness

Human ferritin heavy chain (HFt) has been demonstrated to possess considerable potential for targeted delivery of drugs and diagnostic agents to cancer cells. Here, we report the development of a novel HFt-based genetic construct (HFt-MP-PAS) containing a short peptide linker (MP) between each HFt subunit and an outer shielding polypeptide sequence rich in proline (P), serine (S) and alanine (A) residues (PAS). The peptide linker contains a matrix-metalloproteinases (MMPs) cleavage site that permits the protective PAS shield to be removed by tumor-driven proteolytic cleavage within the tumor microenvironment. For the first time HFt-MP-PAS ability to deliver doxorubicin to cancer cells, subcellular localization, and therapeutic efficacy on a xenogeneic mouse model of a highly refractory to conventional chemotherapeutics type of cancer were evaluated. HFt-MP-PAS-DOXO performance was compared with the novel albumin-based drug delivery system INNO-206, currently in phase III clinical trials. The results of this work provide solid evidence indicating that the stimuli-sensitive, long-circulating HFt-MP-PAS nanocarriers described herein have the potential to be exploited in cancer therapy

Key Role of Sequencing to Trace Hepatitis A Viruses Circulating in Italy During a Large Multi-Country European Foodborne Outbreak in 2013.

Foodborne Hepatitis A Virus (HAV) outbreaks are being recognized as an emerging public health problem in industrialized countries. In 2013 three foodborne HAV outbreaks occurred in Europe and one in USA. During the largest of the three European outbreaks, most cases occurred in Italy (>1,200 cases as of March 31, 2014). A national Task Force was established at the beginning of the outbreak by the Ministry of Health. Mixed frozen berries were early demonstrated to be the source of infection by the identity of viral sequences in patients and in food. In the present study the molecular characterization of HAV isolates from 355 Italian cases is reported.Molecular characterization was carried out by PCR/sequencing (VP1/2A region), comparison with reference strains and phylogenetic analysis.A unique strain was responsible for most characterized cases (235/355, 66.1%). Molecular data had a key role in tracing this outbreak, allowing 110 out of the 235 outbreak cases (46.8%) to be recognized in absence of any other link. The data also showed background circulation of further unrelated strains, both autochthonous and travel related, whose sequence comparison highlighted minor outbreaks and small clusters, most of them unrecognized on the basis of epidemiological data. Phylogenetic analysis showed most isolates from travel related cases clustering with reference strains originating from the same geographical area of travel.In conclusion, the study documents, in a real outbreak context, the crucial role of molecular analysis in investigating an old but re-emerging pathogen. Improving the molecular knowledge of HAV strains, both autochthonous and circulating in countries from which potentially contaminated foods are imported, will become increasingly important to control outbreaks by supporting trace back activities, aiming to identify the geographical source(s) of contaminated food, as well as public health interventions