Potential peptidic proteasome inhibitors by incorporation of an electrophilic trap based on amino acid derived α-substituted sulfonyl fluorides

Peptido sulfonyl fluoride derivatives were designed and synthesized containing a substituent on the alpha position (αPSFs) with respect to the sulfonyl fluoride electrophilic trap. The chemical reactivity of these α-substituted amino sulfonyl fluorides was studied and compared with the previously described β-substituted amino sulfonyl fluorides in order to get a deeper insight into the importance of the immediate structural environment of the sulfonyl fluoride moiety. Unfortunately, the poor solubility of the resulting αPSFs precluded a proper evaluation of their biological activity

Proteasome inhibition by new dual warhead containing peptido vinyl sulfonyl fluorides

The success of inhibition of the proteasome by formation of covalent bonds is a major victory over the long held-view that this would lead to binding the wrong targets and undoubtedly lead to toxicity. Great challenges are now found in uncovering ensembles of new moieties capable of forming long lasting ties. We have introduced peptido sulfonyl fluorides for this purpose. Tuning the reactivity of this electrophilic trap may be crucial for modulating the biological action. Here we describe incorporation of a vinyl moiety into a peptido sulfonyl fluoride backbone, which should lead to a combined attack of the proteasome active site threonine on the double bond and the sulfonyl fluoride. Although this led to strong proteasome inhibitors, in vitro studies did not unambiguously demonstrate the formation of the proposed seven-membered ring structure. Possibly, formation of a seven-membered covalent adduct with the proteosomal active site threonine can only be achieved within the context of the enzyme. Nevertheless, this dual warhead concept may provide exclusive possibilities for duration and selectivity of proteasome inhibition

Higgs boson masses and B-physics constraints in Non-Minimal Flavor Violating SUSY scenarios

Journal of High Energy Physics 2012.5 (2012): 015 reproduced by permission of Scuola Internazionale Superiore di Studi Avanzati (SISSA)We present one-loop corrections to the Higgs boson masses in the MSSM with Non-Minimal Flavor Violation. The flavor violation is generated from the hypothesis of general flavor mixing in the squark emass matrices, and these are parametrized by a complete set of δ xY ij (X, Y = L,R; i, j = t,c,u or b, s, d). We calculate the corrections to the Higgs masses in terms of these δ xY ij taking into account all relevant restrictions from B-physics data. This includes constraints from BR(B → X sγ), BR(B s → μ +μ -) and ΔM Bs. After taking into account these constraints we find sizable corrections to the Higgs boson masses, in the case of the lightest MSSM Higgs boson mass exceeding tens of GeV. These corrections are found mainly for the low tan β case. In the case of a Higgs boson mass measurement these corrections might be used to set further constraints on δf YThe work of S.H. was supported in part by CICYT (grant FPA 2007-66387), in part by CICYT (grant FPA 2010-22163-C02-01) and by the Spanish MICINN’s Consolider-Ingenio 2010 Program under grant MultiDark CSD2009-00064. The work of M.H. and M.A.-C. was partially supported by CICYT (grant FPA2009-09017) and the Comunidad de Madrid project HEPHACOS, S2009/ESP-1473. The work of S.P. was supported by a Ramón y Cajal contract from MEC (Spain) (PDRYC-2006-000930) and partially by CICYT (grant FPA2009-09638), the Comunidad de Aragón project DCYT-DGA E24/2 and the Generalitat de Catalunya project 2009SGR502. The work is also supported in part by the European Community’s Marie-Curie Research Training Network under contract MRTNCT-2006-035505 ‘Tools and Precision Calculations for Physics Discoveries at Colliders’ and also by the Spanish Consolider-Ingenio 2010 Programme CPAN (CSD2007-00042

Chandra observations of the luminous infrared galaxy NGC 3256

We present a detailed analysis of high-resolution Chandra observations of the merger system NGC 3256, the most infrared-luminous galaxy in the nearby universe. The X-ray data show that several discrete sources embedded in complex diffuse emission contribute 20 per cent of the total emission in the 0.5–10 keV energy range). The compact sources are hard and extremely bright and their emission is probably dominated by accretion-driven processes. Both galaxy nuclei are detected with LX3–10×1040 erg s1. No evidence is found for the presence of an active nucleus in the southern nucleus, contrary to previous speculation. Once the discrete sources are removed, the diffuse component has a soft spectrum that can be modelled by the superposition of three thermal plasma components with temperatures kT=0.6, 0.9 and 3.9 keV. Alternatively, the latter component can be described as a power law with index Γ3. Some evidence is found for a radial gradient of the amount of absorption and temperature of the diffuse component. We compare the X-ray emission with optical, Hα and NICMOS images of NGC 3256 and find a good correlation between the inferred optical/near-infrared and X-ray extinctions. Although inverse Compton scattering could be important in explaining the hard X-rays seen in the compact sources associated with the nuclei, the observed diffuse emission is probably of thermal origin. The observed X-ray characteristics support a scenario in which the powerful X-ray emission is driven solely by the current episode of star formation

The Hierarchy Principle and the Large Mass Limit of the Linear Sigma Model

In perturbation theory we study the matching in four dimensions between the linear sigma model in the large mass limit and the renormalized nonlinear sigma model in the recently proposed flat connection formalism. We consider both the chiral limit and the strong coupling limit of the linear sigma model. Our formalism extends to Green functions with an arbitrary number of pion legs,at one loop level,on the basis of the hierarchy as an efficient unifying principle that governs both limits. While the chiral limit is straightforward, the matching in the strong coupling limit requires careful use of the normalization conditions of the linear theory, in order to exploit the functional equation and the complete set of local solutions of its linearized form.Comment: Latex, 41 pages, corrected typos, final version accepted by IJT

Flood frequency analysis of historical flood data under stationary and non-stationary modelling

Historical records are an important source of information on extreme and rare floods and fundamental to establish a reliable flood return frequency. The use of long historical records for flood frequency analysis brings in the question of flood stationarity, since climatic and land-use conditions can affect the relevance of past flooding as a predictor of future flooding. In this paper, a detailed 400 yr flood record from the Tagus River in Aranjuez (central Spain) was analysed under stationary and non-stationary flood frequency approaches, to assess their contribution within hazard studies. Historical flood records in Aranjuez were obtained from documents (Proceedings of the City Council, diaries, chronicles, memoirs, etc.), epigraphic marks, and indirect historical sources and reports. The water levels associated with different floods (derived from descriptions or epigraphic marks) were computed into discharge values using a one-dimensional hydraulic model. Secular variations in flood magnitude and frequency, found to respond to climate and environmental drivers, showed a good correlation between high values of historical flood discharges and a negative mode of the North Atlantic Oscillation (NAO) index. Over the systematic gauge record (1913–2008), an abrupt change on flood magnitude was produced in 1957 due to constructions of three major reservoirs in the Tagus headwaters (Bolarque, Entrepeñas and Buendia) controlling 80% of the watershed surface draining to Aranjuez. Two different models were used for the flood frequency analysis: (a) a stationary model estimating statistical distributions incorporating imprecise and categorical data based on maximum likelihood estimators, and (b) a time-varying model based on "generalized additive models for location, scale and shape" (GAMLSS) modelling, which incorporates external covariates related to climate variability (NAO index) and catchment hydrology factors (in this paper a reservoir index; RI). Flood frequency analysis using documentary data (plus gauged records) improved the estimates of the probabilities of rare floods (return intervals of 100 yr and higher). Under non-stationary modelling flood occurrence associated with an exceedance probability of 0.01 (i.e. return period of 100 yr) has changed over the last 500 yr due to decadal and multi-decadal variability of the NAO. Yet, frequency analysis under stationary models was successful in providing an average discharge around which value flood quantiles estimated by non-stationary models fluctuate through time

New insights on the seismogenic potential of the Eastern Betic Shear Zone (SE Iberia): Quaternary activity and paleoseismicity of the SW segment of the Carrascoy Fault Zone

The Carrascoy Fault (CAF) is one of the main active faults that form part of the Eastern Betic Shear Zone, a 450 km fault system that accommodates most of the convergence between the Eurasian (Iberia) and Nubian plates in the Betic Cordillera, south Spain. Although the CAF represents a major earthquake threat to the nearby City of Murcia, studies on its Quaternary tectonics and seismogenic potential are scarce to date. We present evidence that supports the division of the CAF into two overlapping segments with contrasting tectonic structure, Quaternary activity, and landform control: a SW segment, characterized by a broad fold-and-thrust zone similar to the forebergs defined in the Gobi-Altai region, and a NE segment, characterized by a sharp mountain front controlled by strike-slip tectonics. We attribute the differentiation into these two segments to the stresses associated with topography, which in turn is a consequence of the shortening component, at the middle Pleistocene, after circa 217.4 ka. For the SW segment we infer the occurrence of 9 to 11, Mw 6.7 paleoearthquakes in the last 30.2 kyr, and a slip rate of 0.37 ± 0.08 m/kyr. We date the occurrence of the last surface rupture event after 2750 B.P., and we estimate an average recurrence period of major events of 3.3 ± 0.7 kyrThis work was supported by SISMOGEN (IGME, 2279) and FASEGEO (CGL2009-09726) research projects and a technical assistance of the Civil Protection Service of Murci

Influence of tumor characteristics on the outcome of liver transplantation among

Hepatocellular carcinoma (HCC) may recur after liver transplantation (LT), mainly in patients with multinodular and large tumors. However, factors predictive of outcome after LT in patients with small tumors remain ill defined. We investigated which factors were related to mortality or tumor recurrence among 47 liver transplant recipients with liver cirrhosis and HCC and compared them with 107 patients with liver cirrhosis without tumor who underwent LT in the same period. Patients with HCC were older (P <.001), more frequently had cirrhosis of a viral origin (P <.001), and had lower Child-Pugh scores (P <.001) than patients without tumor. Survival of patients with and without tumor was not significantly different (P =.20). Among patients with HCC, those with lower recurrence-free survival rates had liver cirrhosis of a viral origin, vascular invasion, bilobar disease, and tumor-node-metastasis (TNM) stage IV. At multivariate analysis, the only factor associated with mortality or recurrence was TNM stage IV (P =.02). Our results suggest that in patients with HCC and TNM stage IV, LT might be contraindicate

Upholding the unified model for Active Galactic Nuclei: VLT/FORS2 spectropolarimetry of Seyfert 2 galaxies

The origin of the unification model for Active Galactic Nuclei (AGN) was the detection of broad hydrogen recombination lines in the optical polarized spectrum of the Seyfert 2 galaxy (Sy2) NGC 1068. Since then, a search for the hidden broad-line region (HBLR) of nearby Sy2s started, but polarized broad lines have only been detected in ?30–40% of the nearby Sy2s observed to date. Here we present new VLT/FORS2 optical spectropolarimetry of a sample of 15 Sy2s, including Compton-thin and Compton-thick sources. The sample includes six galaxies without previously published spectropolarimetry, some of them normally treated as non-hidden BLR (NHBLR) objects in the literature, four classified as NHBLR, and five as HBLR based on previous data. We report ?4? detections of a HBLR in 11 of these galaxies (73% of the sample) and a tentative detection in NGC 5793, which is Compton-thick according to the analysis of X-ray data performed here. Our results confirm that at least some NHBLRs are misclassified, bringing previous publications reporting differences between HBLR and NHBLR objects into question. We detect broad H? and H? components in polarized light for 10 targets, and just broad H? for NGC 5793 and NGC 6300, with line widths ranging between 2100 and 9600 km s?1. High bolometric luminosities and low column densities are associated with higher polarization degrees, but not necessarily with the detection of the scattered broad components

The emission regions in X-ray binaries: dipping as a diagnostic

X-ray dipping in the black hole binary Cygnus X-1, the Galactic jet source GRO J1655-40 and in low mass X-ray binaries is discussed. It is shown that spectral analysis strongly constrains emission models. Measurement of dip ingress/egress times allows the sizes of extended emission regions to be determined, notably for the Accretion Disk Corona which is responsible for Comptonization in X-ray binaries. In LMXB, the radius of the ADC is shown to be between ~ 10^9 and ~ 5x10^10 cm, an appreciable fraction of the accretion disk radius. This is inconsistent with Comptonization models requiring a localized Comptonizing region, for example, in the immediate neighbourhood of the neutron star. Results from a survey of LMXB using ASCA and BeppoSAX reveal an approximate equality between the height of the blackbody emission region on the neutron star and the height of the inner radiatively-supported disk, suggesting either that there is a direct causal link, such as a radial accretion flow between the inner disk edge and the star, or an indirect link, as in the case of accretion flow creep on the surface of the neutron star as suggested by Inogamov & Sunyaev. Finally, the survey shows that the blackbody cannot originate on the accretion disk as the required inner radii in many sources are substantially less than the neutron star radius.Comment: solicited review paper presented at COSPAR 2000 "X-ray and Gamma-ray Signatures of Black Holes and Weakly Magnetized Neutron Stars"; accepted for publication in Advances in Space Research (2nd affiliation added