Plausible blockers of Spike RBD in SARS-CoV2-molecular design and underlying interaction dynamics from high-level structural descriptors

COVID-19 is characterized by an unprecedented abrupt increase in the viral transmission rate (SARS-CoV-2) relative to its pandemic evolutionary ancestor, SARS-CoV (2003). The complex molecular cascade of events related to the viral pathogenicity is triggered by the Spike protein upon interacting with the ACE2 receptor on human lung cells through its receptor binding domain (RBDSpike). One potential therapeutic strategy to combat COVID-19 could thus be limiting the infection by blocking this key interaction. In this current study, we adopt a protein design approach to predict and propose non-virulent structural mimics of the RBDSpike which can potentially serve as its competitive inhibitors in binding to ACE2. The RBDSpike is an independently foldable protein domain, resilient to conformational changes upon mutations and therefore an attractive target for strategic re-design. Interestingly, in spite of displaying an optimal shape fit between their interacting surfaces (attributed to a consequently high mutual affinity), the RBDSpike-ACE2 interaction appears to have a quasi-stable character due to a poor electrostatic match at their interface. Structural analyses of homologous protein complexes reveal that the ACE2 binding site of RBDSpike has an unusually high degree of solvent-exposed hydrophobic residues, attributed to key evolutionary changes, making it inherently "reaction-prone." The designed mimics aimed to block the viral entry by occupying the available binding sites on ACE2, are tested to have signatures of stable high-affinity binding with ACE2 (cross-validated by appropriate free energy estimates), overriding the native quasi-stable feature. The results show the apt of directly adapting natural examples in rational protein design, wherein, homology-based threading coupled with strategic "hydrophobic ↔ polar" mutations serve as a potential breakthrough

Small Hairy Black Holes in Global AdS Spacetime

We study small charged black holes in global AdS spacetime in the presence of a charged massless minimally coupled scalar field. In a certain parameter range these black holes suffer from well known superradiant instabilities. We demonstrate that the end point of the resultant tachyon condensation process is a hairy black hole which we construct analytically in a perturbative expansion in the black hole radius. At leading order our solution is a small undeformed RNAdS black hole immersed into a charged scalar condensate that fills the AdS `box'. These hairy black hole solutions appear in a two parameter family labelled by their mass and charge. Their mass is bounded from below by a function of their charge; at the lower bound a hairy black hole reduces to a regular horizon free soliton which can also be thought of as a nonlinear Bose condensate. We compute the microcanonical phase diagram of our system at small mass, and demonstrate that it exhibits a second order `phase transition' between the RNAdS black hole and the hairy black hole phases.Comment: 68+1 pages, 18 figures, JHEP format. v2 : small typos corrected and a reference adde

Writhe in the Stretch-Twist-Fold Dynamo

This is an Author's Original Manuscript of an article whose final and definitive form, the Version of Record, has been published in Geophysical and Astrophysical Fluid Dynamics (2008) Copyright © 2008 Taylor & Francis, available online at: http://www.tandfonline.com/10.1080/03091920802531791This article looks at the influence of writhe in the stretch-twist-fold dynamo. We consider a thin flux tube distorted by simple stretch, twist, and fold motions and calculate the helicity and energy spectra. The writhe number assists in the calculations, as it tells us how much the internal twist changes as the tube is distorted. In addition it provides a valuable diagnostic for the degree of distortion. Non mirror-symmetric dynamos typically generate magnetic helicity of one sign on large-scales and the opposite sign on small scales. The calculations presented here confirm the hypothesis that the large-scale helicity corresponds to writhe and the small scale corresponds to twist. In addition, the writhe helicity spectrum exhibits an interesting oscillatory behavior. The technique of calculating Fourier spectra for the writhe helicity may be useful in other areas of research, for example, the study of highly coiled molecules

A scalar field condensation instability of rotating anti-de Sitter black holes

Near-extreme Reissner-Nordstrom-anti-de Sitter black holes are unstable against the condensation of an uncharged scalar field with mass close to the Breitenlohner-Freedman bound. It is shown that a similar instability afflicts near-extreme large rotating AdS black holes, and near-extreme hyperbolic Schwarzschild-AdS black holes. The resulting nonlinear hairy black hole solutions are determined numerically. Some stability results for (possibly charged) scalar fields in black hole backgrounds are proved. For most of the extreme black holes we consider, these demonstrate stability if the ``effective mass" respects the near-horizon BF bound. Small spherical Reissner-Nordstrom-AdS black holes are an interesting exception to this result.Comment: 34 pages; 13 figure

Comments on black holes in bubbling spacetimes

In five-dimensional minimal supergravity, there are spherical black holes with nontrivial topology outside the horizon which have the same conserved charges at infinity as the BMPV solution. We show that some of these black holes have greater entropy than the BMPV solution. These spacetimes are all asymptotically flat, stationary, and supersymmetric. We also show that there is a limit in which the black hole shrinks to zero size and the solution becomes a nonsingular "bubbling" geometry. Thus, these solutions provide explicit analytic examples of placing black holes inside solitons.Comment: 17 pages, 5 figures; v2: references adde

Neutrophils in cancer: neutral no more

Neutrophils are indispensable antagonists of microbial infection and facilitators of wound healing. In the cancer setting, a newfound appreciation for neutrophils has come into view. The traditionally held belief that neutrophils are inert bystanders is being challenged by the recent literature. Emerging evidence indicates that tumours manipulate neutrophils, sometimes early in their differentiation process, to create diverse phenotypic and functional polarization states able to alter tumour behaviour. In this Review, we discuss the involvement of neutrophils in cancer initiation and progression, and their potential as clinical biomarkers and therapeutic targets

Hairy black holes and solitons in global AdS 5

We use a mix of analytic and numerical methods to exhaustively study a class of asymptotically global AdS solitons and hairy black hole solutions in negative cosmological constant Einstein Maxwell gravity coupled to a charged massless scalar field. Our results depend sensitively on the charge 'e' of the scalar field. The solitonic branch of solutions we study hit the Chandrashekhar limit at finite mass at small 'e', but extends to arbitrarily large mass at larger 'e'. At low values of 'e' no hairy black holes exist. At intermediate values of 'e' hairy black holes exist above a critical charge. At large 'e' hairy black holes exist at all values of the charge. The lowest mass hairy black holes is a smooth zero entropy soliton at small charge, but a (probably) singular nonzero entropy hairy black hole at larger charge. In a phase diagram of solutions, the hairy black holes merge with the familiar Reissner-Nordstrom-AdS black holes along a curve that is determined by the onset of the superradiant instability in the latter family.Comment: 80 pages. 25 Figures. RevTex4 format. v2: added discussions on second soliton branch and on planar limit; matches published versio

Latexin expression is downregulated in human gastric carcinomas and exhibits tumor suppressor potential

<p>Abstract</p> <p>Background</p> <p>Latexin, also known as endogenous carboxypeptidase inhibitor (CPI), has been found to inhibit mouse stem cell populations and lymphoma cell proliferation, demonstrating its potential role as a tumor suppressor. Our previous study also suggested a correlation between latexin expression and malignant transformation of immortalized human gastric epithelial cells. Here, we examined latexin expression in human gastric carcinomas and investigated the effect of differential latexin expression on proliferation of gastric cancer cells <it>in vitro </it>and <it>in vivo</it>.</p> <p>Methods</p> <p>Monoclonal antibody against human latexin was prepared and immunohistochemical analysis was performed to detect latexin expression in 41 paired gastric carcinomas and adjacent normal control tissues. Human gastric cancer cells MGC803 (latexin negative) stably transfected with LXN gene and BGC823 cells (latexin positive) stably transfected with antisense LXN gene were established for anchorage-dependent colony formation assay and tumorigenesis assay in nude mice. Differentially expressed genes in response to exogeneous latexin expression were screened using microarray analysis and identified by RT-PCR. Bisulfite sequencing was performed to analyze the correlation of the methylation status of LXN promoter with latexin expression in cell lines.</p> <p>Results</p> <p>Immunohistochemical analysis showed significantly reduced latexin expression in gastric carcinomas (6/41, 14.6%) compared to control tissues (31/41, 75.6%) (<it>P </it>< 0.05). Overexpression of LXN gene in MGC803 cells inhibited colony formation and tumor growth in nude mice. Conversely, BGC823 cells transfected with antisense LXN gene exhibited enhanced tumor growth and colony formation. Additionally, several tumor related genes, including Maspin, WFDC1, SLPI, S100P, and PDGFRB, were shown to be differentially expressed in MGC803 cells in response to latexin expression. Differential expression of Maspin and S100P was also identified in BGC823 cells while latexin expression was downregulated. Further bisulfite sequencing of the LXN gene promoter indicated CpG hypermethylation was correlated with silencing of latexin expression in human cells.</p> <p>Conclusions</p> <p>Latexin expression was reduced in human gastric cancers compared with their normal control tissues. The cellular and molecular evidences demonstrated the inhibitory effect of latexin in human gastric cancer cell growth and tumorigenicity. These results strongly suggest the possible involvement of latexin expression in tumor suppression.</p

Novel Combination of Sorafenib and Celecoxib Provides Synergistic Anti-Proliferative and Pro-Apoptotic Effects in Human Liver Cancer Cells

Molecular targeted therapy has shown promise as a treatment for advanced hepatocellular carcinoma (HCC). Sorafenib, a multikinase inhibitor, recently received FDA approval for the treatment of advanced HCC. However, although sorafenib is well tolerated, concern for its safety has been expressed. Celecoxib (Celebrex®) is a selective cyclooxygenase-2 (COX-2) inhibitor which exhibits antitumor effects in human HCC cells. The present study examined the interaction between celecoxib and sorafenib in two human liver tumor cell lines HepG2 and Huh7. Our data showed that each inhibitor alone reduced cell growth and the combination of celecoxib with sorafenib synergistically inhibited cell growth and increased apoptosis. To better understand the molecular mechanisms underlying the synergistic antitumor activity of the combination, we investigated the expression profile of the combination-treated liver cancer cell lines using microarray analysis. Combination treatment significantly altered expression levels of 1,986 and 2,483 transcripts in HepG2 and Huh7 cells, respectively. Genes functionally involved in cell death, signal transduction and regulation of transcription were predominantly up-regulated, while genes implicated in metabolism, cell-cycle control and DNA replication and repair were mainly down-regulated upon treatment. However, combination-treated HCC cell lines displayed specificity in the expression and activity of crucial factors involved in hepatocarcinogenesis. The altered expression of some of these genes was confirmed by semi-quantitative and quantitative RT-PCR and by Western blotting. Many novel genes emerged from our transcriptomic analyses, and further functional analyses may determine whether these genes can serve as potential molecular targets for more effective anti-HCC strategies