H9c2 Cardiomyocytes under Hypoxic Stress: Biological Effects Mediated by Sentinel Downstream Targets

The association between diabetes and cardiovascular diseases is well known. Related diabetes macro- and microangiopathies frequently induce hypoxia and consequently energy failure to satisfy the jeopardized myocardium basal needs. Additionally, it is widely accepted that diabetes impairs endothelial nitric oxide synthase (eNOS) activity, resulting in diminished nitric oxide (NO) bioavailability and consequent endothelial cell dysfunction. In this study, we analyzed the embryonic heart-derived H9c2 cell response to hypoxic stress after administration of a high glucose concentration to reproduce a condition often observed in diabetes. We observed that 24 h hypoxia exposure of H9c2 cells reduced cell viability compared to cells grown in normoxic conditions. Cytotoxicity and early apoptosis were increased after exposure to high glucose administration. In addition, hypoxia induced a RhoA upregulation and a Bcl-2 downregulation and lowered the ERK activation observed in normoxia at both glucose concentrations. Furthermore, a significant cell proliferation rate increases after the 1400W iNOS inhibitor administration was observed. Again, hypoxia increased the expression level of myogenin, a marker of skeletal muscle cell differentiation. The cardiomyocyte gene expression profiles and morphology changes observed in response to pathological stimuli, as hypoxia, could lead to improper ventricular remodeling responsible for heart failure. Therefore, understanding cell signaling events that regulate cardiac response to hypoxia could be useful for the discovery of novel therapeutic approaches able to prevent heart diseases

Minimal flavour violation extensions of the seesaw

We analyze the most natural formulations of the minimal lepton flavour violation hypothesis compatible with a type-I seesaw structure with three heavy singlet neutrinos N, and satisfying the requirement of being predictive, in the sense that all LFV effects can be expressed in terms of low energy observables. We find a new interesting realization based on the flavour group $SU(3)_e\times SU(3)_{\ell+N}$ (being $e$ and $\ell$ respectively the SU(2) singlet and doublet leptons). An intriguing feature of this realization is that, in the normal hierarchy scenario for neutrino masses, it allows for sizeable enhancements of $\mu \to e$ transitions with respect to LFV processes involving the $\tau$ lepton. We also discuss how the symmetries of the type-I seesaw allow for a strong suppression of the N mass scale with respect to the scale of lepton number breaking, without implying a similar suppression for possible mechanisms of N productionComment: 14 pages, 6 figure

Color & Weak triplet scalars, the dimuon asymmetry in BsB_s decay, the top forward-backward asymmetry, and the CDF dijet excess

The new physics required to explain the anomalies recently reported by the D0 and CDF collaborations, namely the top forward-backward asymmetry (FBA), the like-sign dimuon charge asymmetry in semileptonic b decay, and the CDF dijet excess, has to feature an amount of flavor symmetry in order to satisfy the severe constrains arising from flavor violation. In this paper we show that, once baryon number conservation is imposed, color & weak triplet scalars with hypercharge $Y=1/3$ can feature the required flavor structure as a consequence of standard model gauge invariance. The color & weak triplet model can simultaneously explain the top FBA and the dimuon charge asymmetry or the dimuon charge asymmetry and the CDF dijet excess. However, the CDF dijet excess appears to be incompatible with the top FBA in the minimal framework. Our model for the dimuon asymmetry predicts the observed pattern $h_d\ll h_s$ in the region of parameter space required to explain the top FBA, whereas our model for the CDF dijet anomaly is characterized by the absence of beyond the SM b-quark jets in the excess region. Compatibility of the color & weak triplet with the electroweak constraints is also discussed. We show that a Higgs boson mass exceeding the LEP bound is typically favored in this scenario, and that both Higgs production and decay can be significantly altered by the triplet. The most promising collider signature is found if the splitting among the components of the triplet is of weak scale magnitude.Comment: references added, published versio

Array analysis of seismic noise at the Sos Enattos mine, the Italian candidate site for the Einstein Telescope

The area surrounding the dismissed mine of Sos Enattos (Sardinia, Italy) is the Italian candidate site for hosting Einstein Telescope (ET), the third-generation gravitational wave (GW) observatory. One of the goals of ET is to extend the sensitivity down to frequencies well below those currently achieved by GW detectors, i.e. down to 2 Hz. In the bandwidth [1,10] Hz, the seismic noise of anthropogenic origin is expected to represent the major perturbation to the operation of the infrastructure, and the site that will host the future detector must fulfill stringent requirements on seismic disturbances. In this paper we describe the operation of a temporary, 15-element, seismic array deployed in close proximity to the mine. Signals of anthropogenic origin have a transient nature, and their spectra are characterized by a wide spectral lobe spanning the [3,20] Hz frequency interval. Superimposed to this wide lobe are narrow spectral peaks within the [3,8] Hz frequency range. Results from slowness analyses suggest that the origin of these peaks is related to vehicle traffic along the main road running east of the mine. Exploiting the correlation properties of seismic noise, we derive a dispersion curve for Rayleigh waves, which is then inverted for a shallow velocity structure down to depths of ≈≈ 150 m. This data, which is consistent with that derived from analysis of a quarry blast, provide a first assessment of the elastic properties of the rock materials at the site candidate to hosting ET

The Impact of Flavour Changing Neutral Gauge Bosons on B->X_s gamma

The branching ratio of the rare decay B->X_s gamma provides potentially strong constraints on models beyond the Standard Model. Considering a general scenario with new heavy neutral gauge bosons, present in particular in Z' and gauge flavour models, we point out two new contributions to the B->X_s gamma decay. The first one originates from one-loop diagrams mediated by gauge bosons and heavy exotic quarks with electric charge -1/3. The second contribution stems from the QCD mixing of neutral current-current operators generated by heavy neutral gauge bosons and the dipole operators responsible for the B->X_s gamma decay. The latter mixing is calculated here for the first time. We discuss general sum rules which have to be satisfied in any model of this type. We emphasise that the neutral gauge bosons in question could also significantly affect other fermion radiative decays as well as non-leptonic two-body B decays, epsilon'/epsilon, anomalous (g-2)_mu and electric dipole moments.Comment: 31 pages, 5 figures; version published on JHEP; added magic QCD numbers for flavour-violating Z gauge boson contribution to B -> X_s gamm

Platelets and hepatocellular cancer: Bridging the bench to the clinics

Growing interest is recently being focused on the role played by the platelets in favoring hepatocellular cancer (HCC) growth and dissemination. The present review reports in detail both the experimental and clinical evidence published on this topic. Several growth factors and angiogenic molecules specifically secreted by platelets are directly connected with tumor progression and neo-angiogenesis. Among them, we can list the platelet-derived growth factor, the vascular endothelial growth factor, the endothelial growth factor, and serotonin. Platelets are also involved in tumor spread, favoring endothelium permeabilization and tumor cells' extravasation and survival in the bloodstream. From the bench to the clinics, all of these aspects were also investigated in clinical series, showing an evident correlation between platelet count and size of HCC, tumor biological behavior, metastatic spread, and overall survival rates. Moreover, a better understanding of the mechanisms involved in the platelet-tumor axis represents a paramount aspect for optimizing both current tumor treatment and development of new therapeutic strategies against HCC

Minimal Flavour Violation and Neutrino Masses without R-parity

We study the extension of the Minimal Flavour Violation (MFV) hypothesis to the MSSM without R-parity. The novelty of our approach lies in the observation that supersymmetry enhances the global symmetry of the kinetic term and in the fact that we consider as irreducible sources of the flavour symmetry breaking all the couplings of the superpotential including the R-parity violating ones. If R-parity violation is responsible for neutrino masses, our setup can be seen as an extension of MFV to the lepton sector. We analyze two patterns based on the non-abelian flavour symmetries SU(3)^4 \otimes SU(4) and SU(3)^5. In the former case the total lepton number and the lepton flavour number are broken together, while in the latter the lepton number can be broken independently by an abelian spurion, so that visible effects and peculiar correlations can be envisaged in flavour changing charged lepton decays like \ell_i \rightarrow \ell_j \gamma.Comment: 23 pages, 3 figures. References added. Minor changes, to appear in JHE

Nationwide consensus on the clinical management of treatment-resistant depression in Italy: a Delphi panel

Background: Treatment-resistant depression (TRD) is defined by the European Medicines Agency as a lack of clinically meaningful improvement after treatment, with at least two different antidepressants. Individual, familiar, and socio-economic burden of TRD is huge. Given the lack of clear guidelines, the large variability of TRD approaches across different countries and the availability of new medications to meet the need of effective and rapid acting therapeutic strategies, it is important to understand the consensus regarding the clinical characteristics and treatment pathways of patients with TRD in Italian routine clinical practice, particularly in view of the recent availability of esketamine nasal spray. Methods: A Delphi questionnaire with 17 statements (with a 7 points Likert scale for agreement) was administered via a customized web-based platform to Italian psychiatrists with at least 5 years of experience and specific expertise in the field of depression. In the second-round physicians were asked to answer the same statements considering the interquartile range of each question as an index of their colleagues' responses. Stata 16.1 software was used for the analyses. Results: Sixty panellists, representative of the Italian territory, answered the questionnaire at the first round. For 8/17 statements more than 75% of panellists reached agreement and a high consensus as they assigned similar scores; for 4 statements the panellists assigned similar scores but in the middle of the Likert scale showing a moderate agreement with the statement, while for 5 statements there was indecision in the agreement and low consensus with the statement. Conclusions: This Delphi Panel showed that there is a wide heterogeneity in Italy in the management of TRD patients, and a compelling need of standardised strategies and treatments specifically approved for TRD. A high level of consensus and agreement was obtained about the importance of adding lithium and/or antipsychotics as augmentation therapies and in the meantime about the need for long-term maintenance therapy. A high level of consensus and agreement was equally reached for the identification of esketamine nasal spray as the best option for TRD patients and for the possibility to administrate without difficulties esketamine in a community outpatient setting, highlighting the benefit of an appropriate educational support for patients

Twelve Variants Polygenic Score for Low-Density Lipoprotein Cholesterol Distribution in a Large Cohort of Patients With Clinically Diagnosed Familial Hypercholesterolemia With or Without Causative Mutations

: Background A significant proportion of individuals clinically diagnosed with familial hypercholesterolemia (FH), but without any disease-causing mutation, are likely to have polygenic hypercholesterolemia. We evaluated the distribution of a polygenic risk score, consisting of 12 low-density lipoprotein cholesterol (LDL-C)-raising variants (polygenic LDL-C risk score), in subjects with a clinical diagnosis of FH. Methods and Results Within the Lipid Transport Disorders Italian Genetic Network (LIPIGEN) study, 875 patients who were FH-mutation positive (women, 54.75%; mean age, 42.47±15.00 years) and 644 patients who were FH-mutation negative (women, 54.21%; mean age, 49.73±13.54 years) were evaluated. Patients who were FH-mutation negative had lower mean levels of pretreatment LDL-C than patients who were FH-mutation positive (217.14±55.49 versus 270.52±68.59 mg/dL, P<0.0001). The mean value (±SD) of the polygenic LDL-C risk score was 1.00 (±0.18) in patients who were FH-mutation negative and 0.94 (±0.20) in patients who were FH-mutation positive (P<0.0001). In the receiver operating characteristic analysis, the area under the curve for recognizing subjects characterized by polygenic hypercholesterolemia was 0.59 (95% CI, 0.56-0.62), with sensitivity and specificity being 78% and 36%, respectively, at 0.905 as a cutoff value. Higher mean polygenic LDL-C risk score levels were observed among patients who were FH-mutation negative having pretreatment LDL-C levels in the range of 150 to 350 mg/dL (150-249 mg/dL: 1.01 versus 0.91, P<0.0001; 250-349 mg/dL: 1.02 versus 0.95, P=0.0001). A positive correlation between polygenic LDL-C risk score and pretreatment LDL-C levels was observed among patients with FH independently of the presence of causative mutations. Conclusions This analysis confirms the role of polymorphisms in modulating LDL-C levels, even in patients with genetically confirmed FH. More data are needed to support the use of the polygenic score in routine clinical practice