RelA/NF-kappaB recruitment on the bax gene promoter antagonizes p73-dependent apoptosis in costimulated T cells

The balance between antiapoptotic and proapoptotic proteins of the Bcl-2 family is critical in determining the fate of T cells in response to death stimuli. Proapoptotic genes, such as bax, are generally regulated by the p53 family of transcription factors, whereas NF-kappaB subunits can activate the transcription of antiapoptotic Bcl-2 members. Here, we show that CD28 activation protects memory T cells from irradiation-induced apoptosis by both upregulating bcl-xL and inhibiting bax gene expression. We found that p73, but not p53, binds to and trans-activates the bax gene promoter in irradiated T cells. The activation of RelA/NF-kappaB subunit in CD28 costimulated T cells and its binding onto the bax gene promoter results in suppression of bax transcription and decrease in both p73 and RNA polymerase II recruitment in vivo. RelA recruitment on the bax gene promoter is also accompanied by the lost of p300 binding and the parallel appearance of histone deacetylase-1-containing complexes. These findings identify RelA/NF-kappaB as a critical regulator of T-cell survival by affecting the balance of Bcl-2 family members

Rainfall rate retrieval in presence of path attenuation using C-band polarimetric weather radars

Weather radar systems are very suitable tools for the monitoring of extreme rainfall events providing measurements with high spatial and temporal resolution over a wide geographical area. Nevertheless, radar rainfall retrieval at C-band is prone to several error sources, such as rain path attenuation which affects the accuracy of inversion algorithms. In this paper, the so-called rain profiling techniques (namely the surface reference method FV and the polarimetric method ZPHI) are applied to correct rain path attenuation and a new neural network algorithm is proposed to estimate the rain rate from the corrected measurements of reflectivity and differential reflectivity. A stochastic model, based on disdrometer measurements, is used to generate realistic range profiles of raindrop size distribution parameters while a T-matrix solution technique is adopted to compute the corresponding polarimetric variables. A sensitivity analysis is performed in order to evaluate the expected errors of these methods. It has been found that the ZPHI method is more reliable than FV, being less sensitive to calibration errors. Moreover, the proposed neural network algorithm has shown more accurate rain rate estimates than the corresponding parametric algorithm, especially in presence of calibration errors

Interactive management control via analytic hierarchy process (AHP). An empirical study in a public university hospital.

Management control in public university hospitals is a challenging task because of continuous changes due to external pressures (e.g. economic pressures, stakeholder focuses and scientific progress) and internal complexities (top management turnover, shared leadership, technological evolution, and researcher oriented mission). Interactive budgeting contributed to improving vertical and horizontal communication between hospital and stakeholders and between different organizational levels. This paper describes an application of Analytic Hierarchy Process (AHP) to enhance interactive budgeting in one of the biggest public university hospital in Italy. AHP improved budget allocation facilitating elicitation and formalization of units’ needs. Furthermore, AHP facilitated vertical communication among manager and stakeholders, as it allowed multilevel hierarchical representation of hospital needs, and horizontal communication among staff of the same hospital, as it allowed units’ need prioritization and standardization, with a scientific multi-criteria approach, without using complex mathematics. Finally, AHP allowed traceability of a complex decision making processes (as budget allocation), this aspect being of paramount importance in public sectors, where managers are called to respond to many different stakeholders about their choices

New insights into the pathogenesis of bullous pemphigoid: 2019 update

There are several lines of evidence indicating that the physiopathological bases of bullous pemphigoid (BP), the most common subepidermal autoimmune bullous disease, are hallmarked by the production of autoantibodies directed against the hemidesmosomal anchoring proteins BP180 and BP230. In contrast to the robustness of the latter assumption, the multifaceted complexity of upstream and downstream mechanisms implied in the pathogenesis of BP remains an area of intense speculation. So far, an imbalance between T regulatory cells and autoreactive T helper (Th) cells has been regarded as the main pathogenic factor triggering the autoimmune response in BP patients. However, the contributory role of signaling pathways fostering the B cell stimulation, such as Toll-like receptor activation, as well as that of ancillary inflammatory mechanisms responsible for blister formation, such as Th17 axis stimulation and the activation of the coagulation cascade, are still a matter of debate. In the same way, the pathomechanisms implied in the loss of dermal-epidermal adhesion secondary to autoantibodies binding are not fully understood. Herein, we review in detail the current concepts and controversies on the complex pathogenesis of BP, shedding light on the most recent theories emerging from the literature

Overview: Tropospheric profiling: state of the art and future challenges – introduction to the AMT special issue

Abstract. This paper introduces the Atmospheric Measurement Techniques special issue on tropospheric profiling, which was conceived to host full papers presenting the results shown at the 9th International Symposium on Tropospheric Profiling (ISTP9). ISTP9 was held in L'Aquila (Italy) from 3 to 7 September 2012, bringing together 150 scientists representing of 28 countries and 3 continents. The tropospheric profiling special issue collects the highlights of ISTP9, reporting recent advances and future challenges in research and technology development

Quenched BKB_K-parameter with the Wilson and Clover actions at β=6.0\beta = 6.0

We present results for the Kaon $B$ parameter from a sample of $200$ configurations using the Wilson action and $460$ configurations using the Clover action, on a $18^3 \times 64$ lattice at $\beta=6.0$. A slight improvement of the chiral behaviour of $B_K$ is observed due to the Clover action. We have also compared the results for $B_K$ obtained from two different procedures for the boosting of the coupling constant $g$. We observe a strong dependence of $B_K$ on the prescription adopted for $g$ in the Wilson case, contrary to the results of the Clover case which are almost unaffected by the choice of $g$. Combining some recently obtained non perturbative estimates for the renormalisation constants with our Clover matrix element, we observe a significant improvement in the chiral behaviour of $B_K$.Comment: 3 pages, Latex, Postscript file with figures available at ftp://hpteo.roma1.infn.it/pub/preprints/lat94/donini ; to appear in Lattice '94, Nucl. Phys. (Proc.Suppl.

Platinum(IV) complexes of trans-1,2-diamino-4-cyclohexene: Prodrugs affording an oxaliplatin analogue that overcomes cancer resistance

Six platinum(IV) compounds derived from an oxaliplatin analogue containing the unsaturated cyclic diamine trans-1,2-diamino-4-cyclohexene (DACHEX), in place of the 1,2-diaminocyclohexane, and a range of axial ligands, were synthesized and characterized. The derivatives with at least one axial chlorido ligand demonstrated solvent-assisted photoreduction. The electrochemical redox behavior was investigated by cyclic voltammetry; all compounds showed reduction potentials suitable for activation in vivo. X-ray photoelectron spectroscopy (XPS) data indicated an X-ray-induced surface reduction of the Pt(IV) substrates, which correlates with the reduction potentials measured by cyclic voltammetry. The cytotoxic activity was assessed in vitro on a panel of human cancer cell lines, also including oxaliplatin-resistant cancer cells, and compared with that of the reference compounds cisplatin and oxaliplatin; all IC50 values were remarkably lower than those elicited by cisplatin and somewhat lower than those of oxaliplatin. Compared to the other Pt(IV) compounds of the series, the bis-benzoate derivative was by far (5–8 times) the most cytotoxic showing that low reduction potential and high lipophilicity are essential for good cytotoxicity. Interestingly, all the complexes proved to be more active than cisplatin and oxaliplatin even in three-dimensional spheroids of A431 human cervical cancer cells

Decay Constants of Heavy-Light Mesons

The decay constants of the heavy-light pseudoscalar mesons are studied in a high statistics run using the Wilson action at $\beta=6.0$ and $\beta=6.2$, and the clover action at $\beta=6.0$. The systematics of $O(a)$ discretisation errors are discussed. Our best estimates of the decay constants are: $f_D$ = 218(9) MeV, $f_D/f_{Ds}$ = 1.11(1) and we obtain preliminary values for $f_B$.Comment: at the Dallas Lattice Conference, October 1993. 3 pages in a single postscript file, uuencoded form. Rome Preprint 93/98

Increased tumor necrosis factor alpha-converting enzyme activity induces insulin resistance and hepatosteatosis in mice

Tumor necrosis factor alpha-converting enzyme (TACE, also known as ADAM17) was recently involved in the pathogenesis of insulin resistance. We observed that TACE activity was significantly higher in livers of mice fed a high-fat diet (HFD) for 1 month, and this activity was increased in liver > white adipose tissue > muscle after 5 months compared with chow control. In mouse hepatocytes, C(2)C(12) myocytes, and 3T3F442A adipocytes, TACE activity was triggered by palmitic acid, lipolysaccharide, high glucose, and high insulin. TACE overexpression significantly impaired insulin-dependent phosphorylation of AKT, GSK3, and FoxO1 in mouse hepatocytes. To test the role of TACE activation in vivo, we used tissue inhibitor of metalloproteinase 3 (Timp3) null mice, because Timp3 is the specific inhibitor of TACE and Timp3(-/-) mice have higher TACE activity compared with wild-type (WT) mice. Timp3(-/-) mice fed a HFD for 5 months are glucose-intolerant and insulin-resistant; they showed macrovesicular steatosis and ballooning degeneration compared with WT mice, which presented only microvesicular steatosis. Shotgun proteomics analysis revealed that Timp3(-/-) liver showed a significant differential expression of 38 proteins, including lower levels of adenosine kinase, methionine adenosysltransferase I/III, and glycine N-methyltransferase and higher levels of liver fatty acid-binding protein 1. These changes in protein levels were also observed in hepatocytes infected with adenovirus encoding TACE. All these proteins play a role in fatty acid uptake, triglyceride synthesis, and methionine metabolism, providing a molecular explanation for the increased hepatosteatosis observed in Timp3(-/-) compared with WT mice. Conclusion: We have identified novel mechanisms, governed by the TACE-Timp3 interaction, involved in the determination of insulin resistance and liver steatosis during overfeeding in mice