Minimal Super Technicolor

We introduce novel extensions of the Standard Model featuring a supersymmetric technicolor sector. First we consider N=4 Super Yang-Mills which breaks to N=1 via the electroweak (EW) interactions and coupling to the MSSM. This is a well defined, economical and calculable extension of the SM involving the smallest number of fields. It constitutes an explicit example of a natural supersymmetric conformal extension of the Standard Model featuring a well defined connection to string theory. It allows to interpolate, depending on how we break the underlying supersymmetry, between unparticle physics and Minimal Walking Technicolor. As a second alternative we consider other N =1 extensions of the Minimal Walking Technicolor model. The new models allow all the standard model matter fields to acquire a mass.Comment: Improved version demonstrating that this extension is phenomenologically viable. No Landau pole exists in the theory to two loops level. This is the first theory showing that supersymmetry can solve the flavor problem when coupled to low energy technicolo

P3‐179: ABERRANT PERK ACTIVATION IS ASSOCIATED WITH THE DEPLETION OF NRF2 SIGNALING AND THE INCREASE OF OXIDATIVE BURDEN IN DS PATHOLOGY

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23-valent pneumococcal polysaccharide vaccine (PPV23) for the prevention of invasive pneumococcal diseases (IPDs) in the elderly: is it really effective?

Introduction. Incidence of invasive pneumococcal diseases (IPDs) in Italy is constantly increasing and that is particularly true among the elderly. 23-valent polysaccharide pneumococcal vac- cine (PPV23) is recommended to this age group and offered in all Italian regions. However, efficacy of PPV23 on preventing IPDs is debated. We therefore performed a review of the most recent avail- able meta-analyses in order to assess the efficacy of PPVs. Methods. The literature search was conducted using PubMed and Scopus search engines. We used the following keywords: ?pneu- mococcal?, ?polysaccharide?, ?vaccine?, ?efficacy?, ?elderly?, ?meta analysis?. Only meta-analyses published in the last 7 years were selected. We examined the results of the selected meta-anal- yses and assessed their quality according to the PRISMA recom- mendations. Results. The search returned 16 results in PubMed and 12 in Scopus: among them we selected 3 meta-analyses. According to our quality assessment, all meta-analyses showed generally posi- tive results and almost all items of the PRISMA checklist were respected. However, the research protocol and the registration number were absent in all the 3 revisions and the flow-chart was not shown in Moberley?s and Melegaro?s works. In the study by Huss et al. the relative risk of developing IPDs among vaccinated subjects was 0.90 (95%CI: 0.46-1.77, I2 4.9%), indicating a very slight benefit after vaccination. This contrasts with the results of the Cochrane Review by Moberley et al., in which the PPVs showed a protective efficacy in reducing the risk of IPDs of 74% (OR 0.26, 95%CI: 0.15-0.46) with no statistical heterogeneity (I2 0%). Melegaro et al. found a reduction not statistically signifi- cant of the incidence of IPD of 65% (OR 0.35; 95%CI 0.08-1.49) among healthy elderly, while the global estimate of vaccine efficacy among high risk elderly was minimal (OR 0.80; 95%CI 0.22-2.88). Conclusions. Most of the studies suggest that the PPVs confer low protection against IPDs. Anyhow, their methodological het- erogeneity does not allow definitive conclusions. While waiting to see the results of new trials about the efficacy of PPVs, in particular of PPV23, and the extension of the use of conjugate vaccine among the population over 65, stakeholders should be aware of the results of the meta-analyses discussed in this paper during the implementation of the vaccination programs for the elderly in Public Health. The full article is free available on www.jpmh.or

Phylogenetic analysis in the clinical risk management of an outbreak of hepatitis C virus infection among transfused thalassaemia patients in Italy

Background: Occurrence of hepatitis C virus (HCV) infection is reduced by effective risk management procedures, but patient-to-patient transmission continues to be reported in healthcare settings. Aim: To report the use of phylogenetic analysis in the clinical risk management of an HCV outbreak among 128 thalassaemia outpatients followed at a thalassaemia centre of an Italian hospital. Methods: Epidemiological investigation and root-cause analysis were performed. All patients with acute hepatitis and known chronic infection were tested for HCV RNA, HCV genotyping, and NS3, NS5A, and NS5B HCV genomic region sequencing. To identify transmission clusters, phylogenetic trees were built for each gene employing Bayesian methods. Findings: All patients with acute hepatitis were infected with HCV genotype 1b. Root-cause analysis, including a lookback procedure, excluded blood donors as the source of HCV transmission. The phylogenetic analysis, conducted on seven patients with acute infection and eight patients with chronic infection, highlighted four transmission clusters including at least one patient with chronic and one patient with acute HCV infection. All patients in the same cluster received a blood transfusion during the same day. Two patients with acute hepatitis spontaneously cleared HCV within four weeks and nine patients received ledipasvir plus sofosbuvir for six weeks, all achieving a sustained virological response. Conclusion: Combined use of root-cause analysis and molecular epidemiology was effective in ascertaining the origin of the HCV outbreak. Antiviral therapy avoided the chronic progression of the infection and further spread in care units and in the family environment

Quercetin Reduces Lipid Accumulation in a Cell Model of NAFLD by Inhibiting De Novo Fatty Acid Synthesis through the Acetyl‐CoA Carboxylase 1/AMPK/PP2A Axis

none6noDysregulation of de novo lipogenesis (DNL) has recently gained strong attention as being one of the critical factors that contribute to the assessment of non‐alcoholic fatty liver disease (NAFLD). NAFLD is often diagnosed in patients with dyslipidemias and type 2 diabetes; thus, an interesting correlation can be deduced between high hematic free fatty acids and glucose excess in the DNL dysregulation. In the present study, we report that, in a cellular model of NAFLD, the coexistence of elevated glucose and FFA conditions caused the highest cellular lipid accumulation. Deepening the molecular mechanisms of the DNL dysregulation—RT‐qPCR and immunoblot analysis demonstrated increased expression of mitochondrial citrate carrier (CiC), cytosolic acetyl‐ CoA carboxylase 1 (ACACA), and diacylglycerol acyltransferase 2 (DGAT2) involved in fatty acids and triglycerides synthesis, respectively. XBP‐1, an endoplasmic reticulum stress marker, and SREBP‐1 were the transcription factors connected to the DNL activation. Quercetin (Que), a flavonoid with strong antioxidant properties, and noticeably reduced the lipid accumulation and the expression of SREBP‐1 and XBP‐1, as well as of their lipogenic gene targets in steatotic cells. The anti‐lipogenic action of Que mainly occurs through a strong phosphorylation of ACACA, which catalyzes the committing step in the DNL pathway. The high level of ACACA phosphorylation in Que‐treated cells was explained by the intervention of AMPK together with the reduction of enzymatic activity of PP2A phosphatase. Overall, our findings highlight a direct anti‐lipogenic effect of Que exerted through inhibition of the DNL pathway by acting on ACACA/AMPK/PP2A axis; thus, suggesting this flavonoid as a promising molecule for the NAFLD treatment.openGnoni A.; Di Chiara Stanca B.; Giannotti L.; Gnoni G.V.; Siculella L.; Damiano F.Gnoni, A.; Di Chiara Stanca, B.; Giannotti, L.; Gnoni, G. V.; Siculella, L.; Damiano, F

Pathogenesis and molecular mechanisms of anderson–fabry disease and possible new molecular addressed therapeutic strategies

Anderson–Fabry disease (AFD) is a rare disease with an incidenceof approxi-mately 1:117,000 male births. Lysosomal accumulation of globotriaosylceramide (Gb3) is the element characterizing Fabry disease due to a hereditary deficiency α-galactosidase A (GLA) enzyme. The accumulation of Gb3 causes lysosomal dysfunction that compromises cell signaling pathways. Deposition of sphingolipids occurs in the autonomic nervous system, dorsal root ganglia, kidney epithelial cells, vascular system cells, and myocardial cells, resulting in organ failure. This manuscript will review the molecular pathogenetic pathways involved in Anderson–Fabry disease and in its organ damage. Some studies reported that inhibition of mitochondrial function and energy metabolism plays a signif-icant role in AFD cardiomyopathy and in kidney disease of AFD patients. Furthermore, mitochondrial dysfunction has been reported as linked to the dysregulation of the au-tophagy–lysosomal pathway which inhibits the mechanistic target of rapamycin kinase (mTOR) mediated control of mitochondrial metabolism in AFD cells. Cerebrovascular complications due to AFD are caused by cerebral micro vessel stenosis. These are caused by wall thickening resulting from the intramural accumulation of glycolipids, luminal oc-clusion or thrombosis. Other pathogenetic mechanisms involved in organ damage linked to Gb3 accumulation are endocytosis and lysosomal degradation of endothelial calcium-activated intermediate-conductance potassium ion channel 3.1 (KCa3.1) via a clathrin-de-pendent process. This process represents a crucial event in endothelial dysfunction. Several studies have identified the deacylated form of Gb3, globotriaosylsphingosine (Lyso-Gb3), as the main catabolite that increases in plasma and urine in patients with AFD. The mean concentrations of Gb3 in all organs and plasma of Galactosidase A knockout mice were significantly higher than those of wild-type mice. The distributions of Gb3 isoforms vary from organ to organ. Various Gb3 isoforms were observed mainly in the kidneys, and kidney-specific Gb3 isoforms were hydroxylated. Furthermore, the action of Gb3 on the KCa3.1 channel suggests a possible contribution of this interaction to the Fabry disease process, as this channel is expressed in various cells, including endothelial cells, fibro-blasts, smooth muscle cells in proliferation, microglia, and lymphocytes. These molecular pathways could be considered a potential therapeutic target to correct the enzyme in ad-dition to the traditional enzyme replacement therapies (ERT) or drug chaperone therapy