Coronary artery disease-associated genetic variants and biomarkers of inflammation

Introduction: Genetic constitution and inflammation both contribute to development of coronary artery disease (CAD). Several CAD-associated single-nucleotide polymorphisms (SNPs) have recently been identified, but their functions are largely unknown. We investigated the associations between CAD-associated SNPs and five CAD-related inflammatory biomarkers. Methods: We genotyped 45 CAD-associated SNPs in 701 stable CAD patients in whom levels of high-sensitivity C-reactive protein (hsRCP), interleukin-6, calprotectin, fibrinogen and complement component 3 levels had previously been measured. A genetic risk score was calculated to assess the combined risk associated with all the genetic variants. A multiple linear regression model was used to assess associations between the genetic risk score, single SNPs, and the five inflammatory biomarkers. Results: The minor allele (G) (CAD risk allele) of rs2075650 (TOMM40/APOE) was associated with lower levels of high-sensitivity C-reactive protein (effect per risk allele: -0.37 mg/l [95%CI -0.56 to -0.18 mg/l]). The inflammatory markers tested showed no association with the remaining 44 SNPs or with the genetic risk score. Conclusions: In stable CAD patients, the risk allele of a common CAD-associated marker at the TOMM40/APOE locus was associated with lower hsCRP levels. No other genetic variants or the combined effect of all variants were associated with the five inflammatory biomarkers

Local delivery of novel MRTF/SRF inhibitors prevents scar tissue formation in a preclinical model of fibrosis

The myocardin-related transcription factor/serum response factor (MRTF/SRF) pathway represents a promising therapeutic target to prevent fibrosis. We have tested the effects of new pharmacological inhibitors of MRTF/SRF signalling in a preclinical model of fibrosis. CCG-222740, a novel MRTF/SRF inhibitor, markedly decreased SRF reporter gene activity and showed a greater inhibitory effect on MRTF/SRF target genes than the previously described MRTF-A inhibitor CCG-203971. CCG-222740 was also five times more potent, with an IC50 of 5 μM, in a fibroblast-mediated collagen contraction assay, was less cytotoxic, and a more potent inhibitor of alpha-smooth muscle actin protein expression than CCG-203971. Local delivery of CCG-222740 and CCG-203971 in a validated and clinically relevant rabbit model of scar tissue formation after glaucoma filtration surgery increased the long-term success of the surgery by 67% (P < 0.0005) and 33% (P < 0.01), respectively, and significantly decreased fibrosis and scarring histologically. Unlike mitomycin-C, neither CCG-222740 nor CCG-203971 caused any detectable epithelial toxicity or systemic side effects with very low drug levels measured in the aqueous, vitreous, and serum. We conclude that inhibitors of MRTF/SRF-regulated gene transcription such as CCG-222740, potentially represent a new therapeutic strategy to prevent scar tissue formation in the eye and other tissues

Excitations in the deformed D1D5 CFT

We perform some simple computations for the first order deformation of the D1D5 CFT off its orbifold point. It had been shown earlier that under this deformation the vacuum state changes to a squeezed state (with the further action of a supercharge). We now start with states containing one or two initial quanta and write down the corresponding states obtained under the action of deformation operator. The result is relevant to the evolution of an initial excitation in the CFT dual to the near extremal D1D5 black hole: when a left and a right moving excitation collide in the CFT, the deformation operator spreads their energy over a larger number of quanta, thus evolving the state towards the infrared.Comment: 26 pages, Latex, 4 figure

Deforming the D1D5 CFT away from the orbifold point

The D1D5 brane bound state is believed to have an `orbifold point' in its moduli space which is the analogue of the free Yang Mills theory for the D3 brane bound state. The supergravity geometry generated by D1 and D5 branes is described by a different point in moduli space, and in moving towards this point we have to deform the CFT by a marginal operator: the `twist' which links together two copies of the CFT. In this paper we find the effect of this deformation operator on the simplest physical state of the CFT -- the Ramond vacuum. The twist deformation leads to a final state that is populated by pairs of excitations like those in a squeezed state. We find the coefficients characterizing the distribution of these particle pairs (for both bosons and fermions) and thus write this final state in closed form.Comment: 30 pages, 4 figures, Late

Intertwining Relations for the Deformed D1D5 CFT

The Higgs branch of the D1D5 system flows in the infrared to a two-dimensional N=(4,4) SCFT. This system is believed to have an "orbifold point" in its moduli space where the SCFT is a free sigma model with target space the symmetric product of copies of four-tori; however, at the orbifold point gravity is strongly coupled and to reach the supergravity point one needs to turn on the four exactly marginal deformations corresponding to the blow-up modes of the orbifold SCFT. Recently, technology has been developed for studying these deformations and perturbing the D1D5 CFT off its orbifold point. We present a new method for computing the general effect of a single application of the deformation operators. The method takes the form of intertwining relations that map operators in the untwisted sector before application of the deformation operator to operators in the 2-twisted sector after the application of the deformation operator. This method is computationally more direct, and may be of theoretical interest. This line of inquiry should ultimately have relevance for black hole physics.Comment: latex, 23 pages, 3 figure

Emission from the D1D5 CFT: Higher Twists

We study a certain class of nonextremal D1D5 geometries and their ergoregion emission. Using a detailed CFT computation and the formalism developed in arXiv:0906.2015 [hep-th], we compute the full spectrum and rate of emission from the geometries and find exact agreement with the gravity answer. Previously, only part of the spectrum had been reproduced using a CFT description. We close with a discussion of the context and significance of the calculation.Comment: 39 pages, 6 figures, late

Virtual screening for inhibitors of the human TSLP:TSLPR interaction

The pro-inflammatory cytokine thymic stromal lymphopoietin (TSLP) plays a pivotal role in the pathophysiology of various allergy disorders that are mediated by type 2 helper T cell (Th2) responses, such as asthma and atopic dermatitis. TSLP forms a ternary complex with the TSLP receptor (TSLPR) and the interleukin-7-receptor subunit alpha (IL-7Ra), thereby activating a signaling cascade that culminates in the release of pro-inflammatory mediators. In this study, we conducted an in silico characterization of the TSLP: TSLPR complex to investigate the drugability of this complex. Two commercially available fragment libraries were screened computationally for possible inhibitors and a selection of fragments was subsequently tested in vitro. The screening setup consisted of two orthogonal assays measuring TSLP binding to TSLPR: a BLI-based assay and a biochemical assay based on a TSLP: alkaline phosphatase fusion protein. Four fragments pertaining to diverse chemical classes were identified to reduce TSLP: TSLPR complex formation to less than 75% in millimolar concentrations. We have used unbiased molecular dynamics simulations to develop a Markov state model that characterized the binding pathway of the most interesting compound. This work provides a proof-ofprinciple for use of fragments in the inhibition of TSLP: TSLPR complexation

Neurogenic diabetes insipidus presenting in a patient with subacute liver failure: a case report

<p>Abstract</p> <p>Introduction</p> <p>To the best of our knowledge, this is the first report in the literature of development of neurogenic diabetes insipidus in a patient with subacute liver failure.</p> <p>Case presentation</p> <p>A 25-year-old man presented with subacute liver failure. While awaiting a liver transplant, the patient developed cerebral edema, which resulted in neurogenic diabetes insipidus secondary to cerebral edema. The patient died before the liver transplantation could be carried out.</p> <p>Conclusion</p> <p>Neurogenic diabetes insipidus is well recognized in the neurosurgical population as a consequence of cerebral edema and increased intracranial pressure, both of which occur commonly in patients with subacute liver failure.</p

A General Black String and its Microscopics

Using G2(2) dualities we construct the most general black string solution of minimal five-dimensional ungauged supergravity. The black string has five independent parameters, namely, the magnetic one-brane charge, smeared electric zero-brane charge, boost along the string direction, energy above the BPS bound, and rotation in the transverse space. In one extremal limit it reduces to the three parameter supersymmetric string of five-dimensional minimal supergravity; in another extremal limit it reduces to the three parameter non-supersymmetric extremal string of five-dimensional minimal supergravity. It also admits an extremal limit when it has maximal rotation in the four-dimensional transverse space. The decoupling limit of our general black string is a BTZ black hole times a two sphere. The macroscopic entropy of the string is reproduced by the Maldacena-Strominger-Witten CFT in appropriate ranges of the parameters. When the pressureless condition is imposed, our string describes the infinite radius limit of the most general class of black rings of minimal supergravity. We discuss implications our solution has for extremal and non-extremal black rings of minimal supergravity.Comment: 35 pages; 3 figures; v2 section 4.1.1 rewritten + minor changes + ref adde

Cardy and Kerr

The Kerr/CFT correspondence employs the Cardy formula to compute the entropy of the left moving CFT states. This computation, which correctly reproduces the Bekenstein--Hawking entropy of the four-dimensional extremal Kerr black hole, is performed in a regime where the temperature is of order unity rather than in a high-temperature regime. We show that the comparison of the entropy of the extreme Kerr black hole and the entropy in the CFT can be understood within the Cardy regime by considering a D0-D6 system with the same entropic properties.Comment: 20 pages; LaTeX; JHEP format; v.2 references added, v.3 Section 4 adde