Probe Branes, Time-dependent Couplings and Thermalization in AdS/CFT

We present holographic descriptions of thermalization in conformal field theories using probe D-branes in AdS X S space-times. We find that the induced metrics on Dp-brane worldvolumes which are rotating in an internal sphere direction have horizons with characteristic Hawking temperatures even if there is no black hole in the bulk AdS. The AdS/CFT correspondence applied to such systems indeed reveals thermal properties such as Brownian motions and AC conductivities in the dual conformal field theories. We also use this framework to holographically analyze time-dependent systems undergoing a quantum quench, where parameters in quantum field theories, such as a mass or a coupling constant, are suddenly changed. We confirm that this leads to thermal behavior by demonstrating the formation of apparent horizons in the induced metric after a certain time.Comment: LaTeX, 47 pages, 14 figures; Typos corrected and references added (v2); minor corrections, references added(v3

Moduli and electromagnetic black brane holography

We investigate the thermodynamic and hydrodynamic properties of 4-dimensional gauge theories with finite electric charge density in the presence of a constant magnetic field. Their gravity duals are planar magnetically and electrically charged AdS black holes in theories that contain a gauge Chern-Simons term. We present a careful analysis of the near horizon geometry of these black branes at finite and zero temperature for the case of a scalar field non-minimally coupled to the electromagnetic field. With the knowledge of the near horizon data, we obtain analytic expressions for the shear viscosity coefficient and entropy density, and also study the effect of a generic set of four derivative interactions on their ratio. We also comment on the attractor flows of the extremal solutions.Comment: 39 pages, no figures; v2: minor changes, refs. added; v3: typo fixed; v4: a proof for decoupling of the viscosity mode added in appendix, matches the published versio

A manifestly MHV Lagrangian for N=4 Yang-Mills

We derive a manifestly MHV Lagrangian for the N=4 supersymmetric Yang-Mills theory in light-cone superspace. This is achieved by constructing a canonical redefinition which maps the N=4 superfield and its conjugate to a new pair of superfields. In terms of these new superfields the N=4 Lagrangian takes a (non-polynomial) manifestly MHV form, containing vertices involving two superfields of negative helicity and an arbitrary number of superfields of positive helicity. We also discuss constraints satisfied by the new superfields, which ensure that they describe the correct degrees of freedom in the N=4 supermultiplet. We test our derivation by showing that an expansion of our superspace Lagrangian in component fields reproduces the correct gluon MHV vertices.Comment: 37 pages, 1 figure. v2: minor changes, references adde

MicroRNAs in pulmonary arterial remodeling

Pulmonary arterial remodeling is a presently irreversible pathologic hallmark of pulmonary arterial hypertension (PAH). This complex disease involves pathogenic dysregulation of all cell types within the small pulmonary arteries contributing to vascular remodeling leading to intimal lesions, resulting in elevated pulmonary vascular resistance and right heart dysfunction. Mutations within the bone morphogenetic protein receptor 2 gene, leading to dysregulated proliferation of pulmonary artery smooth muscle cells, have been identified as being responsible for heritable PAH. Indeed, the disease is characterized by excessive cellular proliferation and resistance to apoptosis of smooth muscle and endothelial cells. Significant gene dysregulation at the transcriptional and signaling level has been identified. MicroRNAs are small non-coding RNA molecules that negatively regulate gene expression and have the ability to target numerous genes, therefore potentially controlling a host of gene regulatory and signaling pathways. The major role of miRNAs in pulmonary arterial remodeling is still relatively unknown although research data is emerging apace. Modulation of miRNAs represents a possible therapeutic target for altering the remodeling phenotype in the pulmonary vasculature. This review will focus on the role of miRNAs in regulating smooth muscle and endothelial cell phenotypes and their influence on pulmonary remodeling in the setting of PAH

Effects of inaccuracies in arterial path length measurement on differences in MRI and tonometry measured pulse wave velocity

Abstract Background Carotid-femoral pulse wave velocity (cf-PWV) and aortic PWV measured using MRI (MRI-PWV) show good correlation, but with a significant and consistent bias across studies. The aim of the current study was to evaluate whether the differences between cf.-PWV and MRI-PWV can be accounted for by inaccuracies of currently used distance measurements. Methods One hundred fourteen study participants were recruited into one of 4 groups: Type 2 diabetes melltus (T2DM) with cardiovascular disease (CVD) (n = 23), T2DM without CVD (n = 41), CVD without T2DM (n = 25) and a control group (n = 25). All participants underwent cf.-PWV, cardiac MRI and whole body MR angiography(WB-MRA). 90 study participants also underwent aortic PWV using MRI. cf.-PWVEXT was performed using a SphygmoCor device (Atcor Medical, West Ryde, Australia). The true intra-arterial pathlength was measured using the WB-MRA and then used to recalculate the cf.-PWVEXT to give a cf.-PWVMRA. Results Distance measurements were significantly lower on WB-MRA than on external tape measure (mean diff = −85.4 ± 54.0 mm,p < 0.001). MRI-PWV was significantly lower than cf.-PWVEXT (MRI-PWV = 8.1 ± 2.9 vs. cf.-PWVEXT = 10.9 ± 2.7 ms−1,p < 0.001). When cf.-PWV was recalculated using the inter-arterial distance from WB-MRA, this difference was significantly reduced but not lost (MRI-PWV = 8.1 ± 2.9 ms−1 vs. cf.-PWVMRA 9.1 ± 2.1 ms−1, mean diff = −0.96 ± 2.52 ms−1,p = 0.001). Recalculation of the PWV increased correlation with age and pulse pressure. Conclusion Differences in cf.-PWV and MRI PWV can be predominantly but not entirely explained by inaccuracies introduced by the use of simple surface measurements to represent the convoluted arterial path between the carotid and femoral arteries

Interim heterogeneity changes measured using entropy texture features on T2- weighted MRI at 3.0 T predict pathological response to neoadjuvant chemotherapy in primary breast cancer

Objectives: This study investigated whether interim changes in hetereogeneity (measured using entropy features) on magnetic resonance images (MRI) were associated with pathological residual cancer burden (RCB) at final surgery in patients receiving neoadjuvant chemotherapy (NAC) for primary breast cancer.Methods: Institutional review board approval was waived for this retrospective study of 88 consenting women (age:30-79). Scanning was performed on a 3.0T MRI scanner prior to NAC (baseline) and after 2-3 cycles of treatment (interim). Entropy was derived from the grey-level co-occurrence matrix, on slice-matched baseline/interim T2- weighted images. Response, assessed using RCB score on surgically resected specimens, was compared statistically with entropy/heterogeneity changes and ROC analysis performed. Prediction of pCR within each tumour immunophenotype was evaluated.Results: Mean entropy percent differences between examinations, by response category, were: pCR:32.8%, RCB-I:10.5%, RCB-II:9.7% and RCB-III:3.0%. Prediction of ultimate pCR from coarse entropy changes between baseline/interim MRI across all lesions yielded 85.2% accuracy (area under ROC curve:0.845). Excellent sensitivity/specificity was obtained for pCR prediction within each immunophenotype: ER+: 100%/100%; HER2+: 83.3%/95.7%, TNBC: 87.5%/80.0%.Conclusions: Lesion T2 heterogeneity changes are associated with response to NAC using RCB scores, particularly for pCR, and can be useful in prediction across all immunophenotypes with good diagnostic accuracy

Interventional radiology virtual simulator for liver biopsy

Purpose Training in Interventional Radiology currently uses the apprenticeship model, where clinical and technical skills of invasive procedures are learnt during practice in patients. This apprenticeship training method is increasingly limited by regulatory restrictions on working hours, concerns over patient risk through trainees’ inexperience and the variable exposure to case mix and emergencies during training. To address this, we have developed a computer-based simulation of visceral needle puncture procedures. Methods A real-time framework has been built that includes: segmentation, physically based modelling, haptics rendering, pseudo-ultrasound generation and the concept of a physical mannequin. It is the result of a close collaboration between different universities, involving computer scientists, clinicians, clinical engineers and occupational psychologists. Results The technical implementation of the framework is a robust and real-time simulation environment combining a physical platform and an immersive computerized virtual environment. The face, content and construct validation have been previously assessed, showing the reliability and effectiveness of this framework, as well as its potential for teaching visceral needle puncture. Conclusion A simulator for ultrasound-guided liver biopsy has been developed. It includes functionalities and metrics extracted from cognitive task analysis. This framework can be useful during training, particularly given the known difficulties in gaining significant practice of core skills in patients

Performance of swabs, lavage, and diluents to quantify biomarkers of female genital tract soluble mucosal mediators

Background: Measurement of immune mediators and antimicrobial activity in female genital tract secretions may provide biomarkers predictive of risk for HIV-1 acquisition and surrogate markers of microbicide safety. However, optimal methods for sample collection do not exist. This study compared collection methods. Methods: Secretions were collected from 48 women (24 with bacterial vaginosis [BV]) using vaginal and endocervical Dacron and flocked swabs. Cervicovaginal lavage (CVL) was collected with 10 mL of Normosol-R (n = 20), saline (n = 14), or water (n = 14). The concentration of gluconate in Normosol-R CVL was determined to estimate the dilution factor. Cytokine and antimicrobial mediators were measured by Luminex or ELISA and corrected for protein content. Endogenous anti-HIV-1 and anti-E. coli activity were measured by TZM-bl assay or E. coli growth. Results: Higher concentrations of protein were recovered by CVL, despite a 10-fold dilution of secretions, as compared to swab eluents. After protein correction, endocervical swabs recovered the highest mediator levels regardless of BV status. Endocervical and vaginal flocked swabs recovered significantly higher levels of anti-HIV-1 and anti-E. coli activity than Dacron swabs (P<0.001). BV had a significant effect on CVL mediator recovery. Normosol-R tended to recover higher levels of most mediators among women with BV, whereas saline or water tended to recover higher levels among women without BV. Saline recovered the highest levels of anti-HIV-1 activity regardless of BV status. Conclusions: Endocervical swabs and CVL collected with saline provide the best recovery of most mediators and would be the optimal sampling method(s) for clinical trials. © 2011 Dezzutti et al

The wonders of flap endonucleases: structure, function, mechanism and regulation.

Processing of Okazaki fragments to complete lagging strand DNA synthesis requires coordination among several proteins. RNA primers and DNA synthesised by DNA polymerase α are displaced by DNA polymerase δ to create bifurcated nucleic acid structures known as 5'-flaps. These 5'-flaps are removed by Flap Endonuclease 1 (FEN), a structure-specific nuclease whose divalent metal ion-dependent phosphodiesterase activity cleaves 5'-flaps with exquisite specificity. FENs are paradigms for the 5' nuclease superfamily, whose members perform a wide variety of roles in nucleic acid metabolism using a similar nuclease core domain that displays common biochemical properties and structural features. A detailed review of FEN structure is undertaken to show how DNA substrate recognition occurs and how FEN achieves cleavage at a single phosphate diester. A proposed double nucleotide unpairing trap (DoNUT) is discussed with regards to FEN and has relevance to the wider 5' nuclease superfamily. The homotrimeric proliferating cell nuclear antigen protein (PCNA) coordinates the actions of DNA polymerase, FEN and DNA ligase by facilitating the hand-off intermediates between each protein during Okazaki fragment maturation to maximise through-put and minimise consequences of intermediates being released into the wider cellular environment. FEN has numerous partner proteins that modulate and control its action during DNA replication and is also controlled by several post-translational modification events, all acting in concert to maintain precise and appropriate cleavage of Okazaki fragment intermediates during DNA replication

Cellular Active N-Hydroxyurea FEN1 Inhibitors Block Substrate Entry to the Active Site

The structure-specific nuclease human flap endonuclease-1 (hFEN1) plays a key role in DNA replication and repair and may be of interest as an oncology target. We present the first crystal structure of inhibitor-bound hFEN1 and show a cyclic N-hydroxyurea bound in the active site coordinated to two magnesium ions. Three such compounds had similar IC50 values but differed subtly in mode of action. One had comparable affinity for protein and protein– substrate complex and prevented reaction by binding to active site catalytic metal ions, blocking the unpairing of substrate DNA necessary for reaction. Other compounds were more competitive with substrate. Cellular thermal shift data showed engagement of both inhibitor types with hFEN1 in cells with activation of the DNA damage response evident upon treatment. However, cellular EC50s were significantly higher than in vitro inhibition constants and the implications of this for exploitation of hFEN1 as a drug target are discussed