Zero Sound in Strange Metallic Holography

One way to model the strange metal phase of certain materials is via a holographic description in terms of probe D-branes in a Lifshitz spacetime, characterised by a dynamical exponent z. The background geometry is dual to a strongly-interacting quantum critical theory while the probe D-branes are dual to a finite density of charge carriers that can exhibit the characteristic properties of strange metals. We compute holographically the low-frequency and low-momentum form of the charge density and current retarded Green's functions in these systems for massless charge carriers. The results reveal a quasi-particle excitation when z<2, which in analogy with Landau Fermi liquids we call zero sound. The real part of the dispersion relation depends on momentum k linearly, while the imaginary part goes as k^2/z. When z is greater than or equal to 2 the zero sound is not a well-defined quasi-particle. We also compute the frequency-dependent conductivity in arbitrary spacetime dimensions. Using that as a measure of the charge current spectral function, we find that the zero sound appears only when the spectral function consists of a single delta function at zero frequency.Comment: 20 pages, v2 minor corrections, extended discussion in sections 5 and 6, added one footnote and four references, version published in JHE

Target enzyme mutations are the molecular basis for resistance towards pharmacological inhibition of nicotinamide phosphoribosyltransferase

<p>Abstract</p> <p>Background</p> <p>Inhibitors of nicotinamide phosphoribosyltransferase (NAMPT) are promising cancer drugs currently in clinical trials in oncology, including APO866, CHS-828 and the CHS-828 prodrug EB1627/GMX1777, but cancer cell resistance to these drugs has not been studied in detail.</p> <p>Methods</p> <p>Here, we introduce an analogue of CHS-828 called TP201565 with increased potency in cellular assays. Further, we describe and characterize a panel of cell lines with acquired stable resistance towards several NAMPT inhibitors of 18 to 20,000 fold compared to their parental cell lines.</p> <p>Results</p> <p>We find that 4 out of 5 of the resistant sublines display mutations of NAMPT located in the vicinity of the active site or in the dimer interface of NAMPT. Furthermore, we show that these mutations are responsible for the resistance observed. All the resistant cell lines formed xenograft tumours <it>in vivo</it>. Also, we confirm CHS-828 and TP201565 as competitive inhibitors of NAMPT through docking studies and by NAMPT precipitation from cellular lysate by an analogue of TP201565 linked to sepharose. The NAMPT precipitation could be inhibited by addition of APO866.</p> <p>Conclusion</p> <p>We found that CHS-828 and TP201565 are competitive inhibitors of NAMPT and that acquired resistance towards NAMPT inhibitors can be expected primarily to be caused by mutations in NAMPT.</p

The Impact of Smoking on Clinical and Therapeutic Effects in Asthmatics

Smoking is associated with poor symptom control and impaired therapeutic responses in asthma. A total of 843 patients with asthma were recruited. The patients received treatment for 1 yr according to the severity of their asthma. We compared the forced expiratory volume in 1 sec (FEV1), the ratio of FEV1 to forced vital capaity (FVC), atopy, total IgE, emphysema on high-resolution computed tomography (HRCT), the number of near-fatal asthma attacks, and physiological fixed airway obstruction between the smoking and nonsmoking groups. The study population consisted of 159 (18.8%) current smokers, 157 (18.7%) ex-smokers, and 525 (62.5%) nonsmokers. Although the prevalence of atopy was not different between the smoking and nonsmoking groups, the total IgE was higher among the smokers than the nonsmokers. Compared with the nonsmoking group, the smokers had a lower FEV1 % predicted and forced expiratory flow between 25 and 75% of FVC. A greater prevalence of emphysema and a significantly higher number of asthmatic patients with fixed airway obstruction were detected in the smoking versus nonsmoking group. The 37.5% of asthmatic patients who were former or current smokers showed decreased pulmonary function and increased IgE, emphysema on HRCT, and fixed airway obstruction, indicating that smoking can modulate the clinical and therapeutic responses in asthma

Holographic flows and thermodynamics of Polyakov loop impurities

We study holographic probes dual to heavy quark impurities interpo- lating between fundamental and symmetric/antisymmetric tensor representations in strongly coupled N = 4 supersymmetric gauge theory. These correspond to non- conformal D3- and D5-brane probe embeddings in AdS_5 × S^5 exhibiting flows on their world-volumes. By examining the asymptotic regimes of the embeddings and the one-point function of static fields sourced by the boundary impurity, we con- clude that the D5-brane embedding describes the screening of fundamental quarks in the UV into an antisymmetric source in the IR, whilst the non-conformal, D3- brane solution interpolates between the symmetric representation in the UV and fundamental sources in the IR. The D5-brane embeddings exhibit nontrivial ther- modynamics with multiple branches of solutions, whilst the thermal analogue of the interpolating D3-brane solution does not appear to exist

DMSO and Betaine Greatly Improve Amplification of GC-Rich Constructs in De Novo Synthesis

In Synthetic Biology, de novo synthesis of GC-rich constructs poses a major challenge because of secondary structure formation and mispriming. While there are many web-based tools for codon optimizing difficult regions, no method currently exists that allows for potentially phenotypically important sequence conservation. Therefore, to overcome these limitations in researching GC-rich genes and their non-coding elements, we explored the use of DMSO and betaine in two conventional methods of assembly and amplification. For this study, we compared the polymerase (PCA) and ligase-based (LCR) methods for construction of two GC-rich gene fragments implicated in tumorigenesis, IGF2R and BRAF. Though we found no benefit in employing either DMSO or betaine during the assembly steps, both additives greatly improved target product specificity and yield during PCR amplification. Of the methods tested, LCR assembly proved far superior to PCA, generating a much more stable template to amplify from. We further report that DMSO and betaine are highly compatible with all other reaction components of gene synthesis and do not require any additional protocol modifications. Furthermore, we believe either additive will allow for the production of a wide variety of GC-rich gene constructs without the need for expensive and time-consuming sample extraction and purification prior to downstream application

Risk of Myocardial Infarction in Parents of HIV-infected Individuals: a population-based Cohort Study

<p>Abstract</p> <p>Background</p> <p>Previous studies have indicated an increased risk of myocardial infarction (MI) in HIV infected individuals especially after start of highly active antiretroviral therapy (HAART). It is however controversial whether the increased risk of atherosclerotic disease is exclusively associated with the HIV disease and HAART or whether life-style related or genetic factors also increase the risk in this population. To establish whether the increased risk of myocardial infarction in HIV patients partly reflects an increased risk of MI in their families, we estimated the relative risk of MI in parents of HIV-infected individuals.</p> <p>Methods</p> <p>From the Danish HIV Cohort Study and the Danish Civil Registration System we identified the parents of all HIV-infected patients born in Denmark after 1952 in whom a Danish born mother was identifiable. For each HIV patient, 4 matched population controls and their parents were identified. Cumulative incidence functions were constructed to illustrate time to first MI of the parents as registered in the Danish National Hospital Registry. Incidence rate ratios (IRR) were estimated by Cox's regression analyses. Due to the confidential type of the analysed data the study was approved by the Danish Data Protection Agency.</p> <p>Results</p> <p>2,269 mothers and 2,022 fathers of HIV patients as well as 9,076 mothers and 8,460 fathers of control subjects were identified. We observed an increased risk of MI in mothers of HIV patients (adjusted IRR, 1.31; 95% CI: 1.08-1.60). The strongest association was seen in case the offspring was infected heterosexually (adjusted IRR, 1.59; 95% CI: 1.07-2.35) or by IV drug abuse (IVD) (adjusted IRR, 1.63; 95% CI: 1.02-2.60). In fathers of HIV patients the risk of MI was only increased if the offspring was infected by IVD (adjusted IRR, 1.42; 95% CI: 1.01-2.00).</p> <p>Conclusion</p> <p>Mothers of HIV-infected patients have an increased risk of MI. We presume that this stems from family related life style risk factors, some of which may also influence the risk of MI in HIV-infected patients.</p

Effects of a training program after surgically treated ankle fracture: a prospective randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>Despite conflicting results after surgically treated ankle fractures few studies have evaluated the effects of different types of training programs performed after plaster removal. The aim of this study was to evaluate the effects of a 12-week standardised but individually suited training program (training group) versus usual care (control group) after plaster removal in adults with surgically treated ankle fractures.</p> <p>Methods</p> <p>In total, 110 men and women, 18-64 years of age, with surgically treated ankle fracture were included and randomised to either a 12-week training program or to a control group. Six and twelve months after the injury the subjects were examined by the same physiotherapist who was blinded to the treatment group. The main outcome measure was the Olerud-Molander Ankle Score (OMAS) which rates symptoms and subjectively scored function. Secondary outcome measures were: quality of life (SF-36), timed walking tests, ankle mobility tests, muscle strength tests and radiological status.</p> <p>Results</p> <p>52 patients were randomised to the training group and 58 to the control group. Five patients dropped out before the six-month follow-up resulting in 50 patients in the training group and 55 in the control group. Nine patients dropped out between the six- and twelve-month follow-up resulting in 48 patients in both groups. When analysing the results in a mixed model analysis on repeated measures including interaction between age-group and treatment effect the training group demonstrated significantly improved results compared to the control group in subjects younger than 40 years of age regarding OMAS (p = 0.028), muscle strength in the plantar flexors (p = 0.029) and dorsiflexors (p = 0.030).</p> <p>Conclusion</p> <p>The results of this study suggest that when adjusting for interaction between age-group and treatment effect the training model employed in this study was superior to usual care in patients under the age of 40. However, as only three out of nine outcome measures showed a difference, the beneficial effect from an additional standardised individually suited training program can be expected to be limited. There is need for further studies to elucidate how a training program should be designed to increase and optimise function in patients middle-aged or older.</p> <p>Trial Registration</p> <p>Current Controlled Trials ACTRN12609000327280</p

Lkb1 and Pten Synergise to Suppress mTOR-Mediated Tumorigenesis and Epithelial-Mesenchymal Transition in the Mouse Bladder

The AKT/PI3K/mTOR pathway is frequently altered in a range of human tumours, including bladder cancer. Here we report the phenotype of mice characterised by deletion of two key players in mTOR regulation, Pten and Lkb1, in a range of tissues including the mouse urothelium. Despite widespread recombination within the range of epithelial tissues, the primary phenotype we observe is the rapid onset of bladder tumorigenesis, with median onset of approximately 100 days. Single deletion of either Pten or Lkb1 had no effect on bladder cell proliferation or tumour formation. However, simultaneous deletion of Lkb1 and Pten led to an upregulation of the mTOR pathway and the hypoxia marker GLUT1, increased bladder epithelial cell proliferation and ultimately tumorigenesis. Bladder tissue also exhibited characteristic features of epithelial-mesenchymal transition, with loss of the epithelial markers E-cadherin and the tight junction protein ZO-1, and increases in the mesenchymal marker vimentin as well as nuclear localization of epithelial-mesenchymal transition (EMT) regulator Snail. We show that these effects were all dependent upon mTOR activity, as rapamycin treatment blocked both EMT and tumorigenesis. Our data therefore establish clear synergy between Lkb1 and Pten in controlling the mTOR pathway within bladder epithelium, and show that loss of this control leads to the disturbance of epithelial structure, EMT and ultimately tumorigenesis

Synthesising Corporate Responsibility on Organisational and Societal Levels of Analysis: An Integrative Perspective

This article develops an integrative perspective on corporate responsibility by synthesising competing perspectives on the responsibility of the corporation at the organisational and societal levels of analysis. We review three major corporate responsibility perspectives, which we refer to as economic, critical, and politico-ethical. We analyse the major potential uses and pitfalls of the perspectives, and integrate the debate on these two levels. Our synthesis concludes that when a society has a robust division of moral labour in place, the responsibility of a corporation may be economic (as suggested under the economic perspective) without jeopardising democracy and sustainability (as reported under the critical perspective). Moreover, the economic role of corporations neither signifies the absence of deliberative democratic mechanisms nor business practices extending beyond compliance (as called for under the politico-ethical perspective). The study underscores the value of integrating different perspectives and multiple levels of analysis to present comprehensive descriptions and prescriptions of the responsibility phenomenon