Exploiting the WH/ZH symmetry in the search for New Physics

We suggest to isolate the loop-induced gluon-initiated component ($gg\to ZH$) for associated $ZH$ production by using the similarity of the Drell-Yan-like component for $ZH$ production to the $WH$ process. We argue that the cross-section ratio of the latter two processes can be predicted with high theoretical accuracy. Comparing it to the experimental $ZH/WH$ cross-section ratio should allow to probe for New Physics in the $gg\to ZH$ component at the HL-LHC. We consider typical BSM scenarios in order to exemplify the effect they would have on the proposed observable.Comment: 22 pages, 10 figures. v2: Minor changes; matches published versio

Structural and functional diversity of ferredoxin-NADP+ reductases

Although all ferredoxin-NADP+ reductases (FNRs) catalyze the same reaction, i.e. the transfer of reducing equivalents between NADP(H) and ferredoxin, they belong to two unrelated families of proteins: the plant-type and the glutathione reductase-type of FNRs. Aim of this review is to provide a general classification scheme for these enzymes, to be used as a framework for the comparison of their properties. Furthermore, we report on some recent findings, which significantly increased the understanding of the structure–function relationships of FNRs, i.e. the ability of adrenodoxin reductase and its homologs to catalyze the oxidation of NADP+ to its 4-oxo derivative, and the properties of plant-type FNRs from non-photosynthetic organisms. Plant-type FNRs from bacteria and Apicomplexan parasites provide examples of novel ways of FAD- and NADP(H)-binding. The recent characterization of an FNR from Plasmodium falciparum brings these enzymes into the field of drug design

Is renalase a novel player in catecholaminergic signaling? The mystery of the catalytic activity of an intriguing new flavoenzyme

Renalase is a flavoprotein recently discovered in humans, preferentially expressed in the proximal tubules of the kidney and secreted in blood and urine. It is highly conserved in vertebrates, with homologs identified in eukaryotic and prokaryotic organisms. Several genetic, epidemiological, clinical and experimental studies show that renalase plays a role in the modulation of the functions of the cardiovascular system, being particularly active in decreasing the catecholaminergic tone, in lowering blood pressure and in exerting a protective action against myocardial ischemic damage. Deficient renalase synthesis might be the cause of the high occurrence of hypertension and adverse cardiac events in kidney disease patients. Very recently, recombinant human renalase has been structurally and functionally characterized in vitro. Results show that it belongs to the p-hydroxybenzoate hydroxylase structural family of flavoenzymes, contains non-covalently bound FAD with redox features suggestive of a dehydrogenase activity, and is not a catecholamine-degrading enzyme, either through oxidase or NAD(P)H-dependent monooxygenase reactions. The biochemical data now available will hopefully provide the basis for a systematic and rational quest toward the identification of the reaction catalyzed by renalase and of the molecular mechanism of its physiological action, which in turn are expected to favor the development of novel therapeutic tools for the treatment of kidney and cardiovascular diseases

Interactive effects between carbon allotrope fillers on the mechanical reinforcement of polyisoprene based nanocomposites

Interactive effects of carbon allotropes on the mechanical reinforcement of polymer nanocomposites were investigated. Carbon nanotubes (CNT) and nano-graphite with high shape anisotropy (nanoG) were melt blended with poly(1,4- cis-isoprene), as the only fillers or in combination with carbon black (CB), measuring the shear modulus at low strain amplitudes for peroxide crosslinked composites. The nanofiller was found to increase the low amplitude storage modulus of the matrix, with or without CB, by a factor depending on nanofiller type and content. This factor, fingerprint of the nanofiller, was higher for CNT than for nanoG. The filler-polymer interfacial area was able to correlate modulus data of composites with CNT, CB and with the hybrid filler system, leading to the construction of a common master curve. © BME-PT

Curcumin and Novel Synthetic Analogs in Cell-Based Studies of Alzheimer's Disease

Alzheimer's disease (AD) is a chronic neurodegenerative disorder that is associated with the most common type of dementia and is characterized by the presence of deposits of the protein fragment amyloid beta (A\u3b2) in the brain. The natural product mixture of curcuminoids that improves certain defects in innate immune cells of AD patients may selectively enhance A\u3b2 phagocytosis by alteration of gene transcription. In this work, we evaluated the protective effects of curcuminoids in cells from AD patients by investigating the effect on NF-\u3baB and BACE1 signaling pathways. These results were compared to the gene expression profile of the clearance of A\u3b2. The minor curcumin constituent, bisdemethoxycurcumin (BDC) showed the most potent protective action to decrease levels of NF-\u3baB and BACE1, decrease the inflammatory cascade and diminish A\u3b2 aggregates in cells from AD patients. Moreover, mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase (MGAT3) and vitamin D receptor (VDR) gene mRNAs were up-regulated in peripheral blood mononuclear cells from AD patients treated with BDC. BDC treatment impacts both gene expression including Mannosyl (Beta-1,4-)-Glycoprotein Beta-1,4-N-Acetylglucosaminyltransferase, Vitamin D and Toll like receptor mRNA and A\u3b2 phagocytosis. The observation of down-regulation of BACE1 and NF-\u3baB following administration of BDC to cells from AD patients as a model system may have utility in the treatment of asymptomatic AD patients

sp2 carbon allotropes in elastomer matrix: from master curves for the mechanical reinforcement to lightweight materials

This work presents high surface area sp2 carbon allotropes as important tools to design and prepare lightweight materials. Composites were prepared based on either carbon black (CB) or carbon nanotubes (CNT) or hybrid CB/CNT filler systems, with either poly(1,4-cis-isoprene) or poly(styrene-co-butadiene) as the polymer matrix. A correlation was established between the specific interfacial area (i.a.), i.e. the surface made available by the filler per unit volume of composite, and the initial modulus of the composite (G′γmin), determined through dynamic mechanical shear tests. Experimental points could be fitted with a common line, a sort of master curve, up to about 30.2 and 9.8 mass% as CB and CNT content, respectively. The equation of such master curve allowed to correlate modulus and density of the composite. Thanks to the mastercurve, composites with the same modulus and lower density could be designed by substituting part of CB with lower amount of the carbon allotrope with larger surface area, CNT. This work establishes a quantitative correlation as a tool to design lightweight materials and paves the way for large scale application in polymer matrices of innovative sp2 carbon allotropes

Specialized dynamical properties of promiscuous residues revealed by simulated conformational ensembles

The ability to interact with different partners is one of the most important features in proteins. Proteins that bind a large number of partners (hubs) have been often associated with intrinsic disorder. However, many examples exist of hubs with an ordered structure, and evidence of a general mechanism promoting promiscuity in ordered proteins is still elusive. An intriguing hypothesis is that promiscuous binding sites have specific dynamical properties, distinct from the rest of the interface and pre-existing in the protein isolated state. Here, we present the first comprehensive study of the intrinsic dynamics of promiscuous residues in a large protein data set. Different computational methods, from coarse-grained elastic models to geometry-based sampling methods and to full-atom Molecular Dynamics simulations, were used to generate conformational ensembles for the isolated proteins. The flexibility and dynamic correlations of interface residues with a different degree of binding promiscuity were calculated and compared considering side chain and backbone motions, the latter both on a local and on a global scale. The study revealed that (a) promiscuous residues tend to be more flexible than nonpromiscuous ones, (b) this additional flexibility has a higher degree of organization, and (c) evolutionary conservation and binding promiscuity have opposite effects on intrinsic dynamics. Findings on simulated ensembles were also validated on ensembles of experimental structures extracted from the Protein Data Bank (PDB). Additionally, the low occurrence of single nucleotide polymorphisms observed for promiscuous residues indicated a tendency to preserve binding diversity at these positions. A case study on two ubiquitin-like proteins exemplifies how binding promiscuity in evolutionary related proteins can be modulated by the fine-tuning of the interface dynamics. The interplay between promiscuity and flexibility highlighted here can inspire new directions in protein-protein interaction prediction and design methods. © 2013 American Chemical Society

Anisotropic properties of elastomeric nanocomposites based on natural rubber and sp2carbon allotropes

This work provides a comprehensive investigation of the anisotropic mechanical and electrical properties of elastomeric nanocomposites based on natural rubber and sp2carbon allotropes. They can be either nanometric and with high shape anisotropy like Carbon Nanotubes (CNT) and lamellar nanographite, or nanostructured and nearly isometric like carbon black. Studies were performed on calendered and compression molded plates. A complete mechanical characterization along all main directions could be performed by a non-standard testing approach. Composites with nanometric, high aspect ratio fillers gave rise to remarkable mechanical anisotropy, revealing an orthotropic and transversally isotropic response: modulus values were very similar in the sheet plane and much larger (almost twice as much) in the orthogonal direction. The electrical anisotropy achieved its maximum at lower CNT content. Composites with carbon black did not reveal mechanical anisotropy, while, quite strikingly, a very large electrical anisotropy was observed for carbon black content close to the percolation threshold. These results provide insights into the anisotropic behavior of nanofilled elastomers, and could pave the way to their exploitation in advanced engineering design and biomimicking biomedical applications

Comparative analysis of homology models of the Ah receptor ligand binding domain: Verification of structure-function predictions by site-directed mutagenesis of a nonfunctional receptor

The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor that mediates the biological and toxic effects of a wide variety of structurally diverse chemicals, including the toxic environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). While significant interspecies differences in AHR ligand binding specificity, selectivity, and response have been observed, the structural determinants responsible for those differences have not been determined, and homology models of the AHR ligand-binding domain (LBD) are available for only a few species. Here we describe the development and comparative analysis of homology models of the LBD of 16 AHRs from 12 mammalian and nonmammalian species and identify the specific residues contained within their ligand binding cavities. The ligand-binding cavity of the fish AHR exhibits differences from those of mammalian and avian AHRs, suggesting a slightly different TCDD binding mode. Comparison of the internal cavity in the LBD model of zebrafish (zf) AHR2, which binds TCDD with high affinity, to that of zfAHR1a, which does not bind TCDD, revealed that the latter has a dramatically shortened binding cavity due to the side chains of three residues (Tyr296, Thr386, and His388) that reduce the amount of internal space available to TCDD. Mutagenesis of two of these residues in zfAHR1a to those present in zfAHR2 (Y296H and T386A) restored the ability of zfAHR1a to bind TCDD and to exhibit TCDD-dependent binding to DNA. These results demonstrate the importance of these two amino acids and highlight the predictive potential of comparative analysis of homology models from diverse species. The availability of these AHR LBD homology models will facilitate in-depth comparative studies of AHR ligand binding and ligand-dependent AHR activation and provide a novel avenue for examining species-specific differences in AHR responsiveness. © 2013 American Chemical Society