Drug Discovery Using Chemical Systems Biology: Repositioning the Safe Medicine Comtan to Treat Multi-Drug and Extensively Drug Resistant Tuberculosis

The rise of multi-drug resistant (MDR) and extensively drug resistant (XDR) tuberculosis around the world, including in industrialized nations, poses a great threat to human health and defines a need to develop new, effective and inexpensive anti-tubercular agents. Previously we developed a chemical systems biology approach to identify off-targets of major pharmaceuticals on a proteome-wide scale. In this paper we further demonstrate the value of this approach through the discovery that existing commercially available drugs, prescribed for the treatment of Parkinson's disease, have the potential to treat MDR and XDR tuberculosis. These drugs, entacapone and tolcapone, are predicted to bind to the enzyme InhA and directly inhibit substrate binding. The prediction is validated by in vitro and InhA kinetic assays using tablets of Comtan, whose active component is entacapone. The minimal inhibition concentration (MIC99) of entacapone for Mycobacterium tuberculosis (M.tuberculosis) is approximately 260.0 µM, well below the toxicity concentration determined by an in vitro cytotoxicity model using a human neuroblastoma cell line. Moreover, kinetic assays indicate that Comtan inhibits InhA activity by 47.0% at an entacapone concentration of approximately 80 µM. Thus the active component in Comtan represents a promising lead compound for developing a new class of anti-tubercular therapeutics with excellent safety profiles. More generally, the protocol described in this paper can be included in a drug discovery pipeline in an effort to discover novel drug leads with desired safety profiles, and therefore accelerate the development of new drugs

Ten Simple Rules for Getting Help from Online Scientific Communities

The increasing complexity of research requires scientists to work at the intersection of multiple fields and to face problems for which their formal education has not prepared them. For example, biologists with no or little background in programming are now often using complex scripts to handle the results from their experiments; vice versa, programmers wishing to enter the world of bioinformatics must know about biochemistry, genetics, and other fields. In this context, communication tools such as mailing lists, web forums, and online communities acquire increasing importance. These tools permit scientists to quickly contact people skilled in a specialized field. A question posed properly to the right online scientific community can help in solving difficult problems, often faster than screening literature or writing to publication authors. The growth of active online scientific communities, such as those listed in Table S1, demonstrates how these tools are becoming an important source of support for an increasing number of researchers. Nevertheless, making proper use of these resources is not easy. Adhering to the social norms of World Wide Web communication—loosely termed “netiquette”—is both important and non-trivial. In this article, we take inspiration from our experience on Internet-shared scientific knowledge, and from similar documents such as “Asking the Questions the Smart Way” and “Getting Answers”, to provide guidelines and suggestions on how to use online communities to solve scientific problems

Development of a training program to support health care professionals to deliver the SPACE for COPD self-management program

Open access journalBackground: With the growing burden of COPD and associated morbidity and mortality, a need for self-management has been identified. The Self-management Programme of Activity, Coping and Education for Chronic Obstructive Pulmonary Disease (SPACE for COPD) manual was developed to support self-management in COPD patients. Currently, there is no literature available regarding health care professionals’ training needs when supporting patients with COPD on self-management. Aim: This study sought to identify these needs to inform, design and develop a training program for health care professionals being trained to deliver a self-management program in COPD. Methods: Fourteen health care professionals from both primary and secondary care COPD services participated in face-to-face semistructured interviews. Thematic analysis was used to produce a framework and identify training needs and views on delivery of the SPACE for COPD self-management program. Components of training were web-based knowledge training, with pre- and posttraining knowledge questionnaires, and a 1-day program to introduce the self-management manual. Feedback was given after training to guide the development of the training program. Results: Health care professionals were able to identify areas where they required increased knowledge to support patients. This was overwhelming in aspects of COPD seen to be outside of their current clinical role. Skills in goal setting and behavioral change were not elicited as a training need, suggesting a lack of understanding of components of supporting self-management. An increase in knowledge of COPD was demonstrated following the training program. Conclusion: Both knowledge and skill gaps existed in those who would deliver self-management. Analysis of this has enabled a training program to be designed to address these gaps and enable health care professionals to support patients in self-management. Keywords: self-management, COPD, health care professionals, trainin

Multiple effects of silymarin on the hepatitis C virus lifecycle

Silymarin, an extract from milk thistle (Silybum marianum), and its purified flavonolignans have been recently shown to inhibit hepatitis C virus (HCV) infection, both in vitro and in vivo. In the current study, we further characterized silymarin's antiviral actions. Silymarin had antiviral effects against hepatitis C virus cell culture (HCVcc) infection that included inhibition of virus entry, RNA and protein expression, and infectious virus production. Silymarin did not block HCVcc binding to cells but inhibited the entry of several viral pseudoparticles (pp), and fusion of HCVpp with liposomes. Silymarin but not silibinin inhibited genotype 2a NS5B RNA-dependent RNA polymerase (RdRp) activity at concentrations 5 to 10 times higher than required for anti-HCVcc effects. Furthermore, silymarin had inefficient activity on the genotype 1b BK and four 1b RDRPs derived from HCV-infected patients. Moreover, silymarin did not inhibit HCV replication in five independent genotype 1a, 1b, and 2a replicon cell lines that did not produce infectious virus. Silymarin inhibited microsomal triglyceride transfer protein activity, apolipoprotein B secretion, and infectious virion production into culture supernatants. Silymarin also blocked cell-to-cell spread of virus. CONCLUSION: Although inhibition of in vitro NS5B polymerase activity is demonstrable, the mechanisms of silymarin's antiviral action appear to include blocking of virus entry and transmission, possibly by targeting the host cell

Generalized Interpolation Material Point Approach to High Melting Explosive with Cavities Under Shock

Criterion for contacting is critically important for the Generalized Interpolation Material Point(GIMP) method. We present an improved criterion by adding a switching function. With the method dynamical response of high melting explosive(HMX) with cavities under shock is investigated. The physical model used in the present work is an elastic-to-plastic and thermal-dynamical model with Mie-Gr\"uneissen equation of state. We mainly concern the influence of various parameters, including the impacting velocity $v$, cavity size $R$, etc, to the dynamical and thermodynamical behaviors of the material. For the colliding of two bodies with a cavity in each, a secondary impacting is observed. Correspondingly, the separation distance $D$ of the two bodies has a maximum value $D_{\max}$ in between the initial and second impacts. When the initial impacting velocity $v$ is not large enough, the cavity collapses in a nearly symmetric fashion, the maximum separation distance $D_{\max}$ increases with $v$. When the initial shock wave is strong enough to collapse the cavity asymmetrically along the shock direction, the variation of $D_{\max}$ with $v$ does not show monotonic behavior. Our numerical results show clear indication that the existence of cavities in explosive helps the creation of ``hot spots''.Comment: Figs.2,4,7,11 in JPG format; Accepted for publication in J. Phys. D: Applied Physic

Signal Processing

Contains research objectives and reports on two research projects.Joint Services Electronics Programs (U. S. Army, U. S. Navy, and U. S. Air Force) under Contract DA 28-043-AMC-02536(E

Plus One: Managing the relationship

Plus One: HIV sero-discordant relationships among black African people in England (NAHIP) Duration: September 2010 - November 2011 Plus One involved in-depth, face-to-face interviews with black African people living in England who were in relationships where one person had diagnosed HIV and the other did not (ie. HIV serodiscordant)

Plus One: External Influences

Plus One: HIV sero-discordant relationships among black African people in England (NAHIP) Duration: September 2010 - November 2011 Plus One involved in-depth, face-to-face interviews with black African people living in England who were in relationships where one person had diagnosed HIV and the other did not (ie. HIV serodiscordant). Catherine Dodds, Peter , Annabel , Edith , John , Lawrence , Pamela , Kathie & Gary

Plus One: Sex and risk

Plus One: HIV sero-discordant relationships among black African people in England (NAHIP) Duration: September 2010 - November 2011 Plus One involved in-depth, face-to-face interviews with black African people living in England who were in relationships where one person had diagnosed HIV and the other did not (ie. HIV serodiscordant)

H-ATLAS: a candidate high redshift cluster/protocluster of star-forming galaxies

We investigate the region around the Planck-detected z=3.26 gravitationally lensed galaxy HATLAS J114637.9-001132 (hereinafter HATLAS12-00) using both archival Herschel data from the H-ATLAS survey and using submm data obtained with both LABOCA and SCUBA2. The lensed source is found to be surrounded by a strong overdensity of both Herschel-SPIRE sources and submm sources. We detect 17 bright (S870 >~7 mJy) sources at >4sigma closer than 5 arcmin to the lensed object at 850/870 microns. Ten of these sources have good cross-identifications with objects detected by Herschel-SPIRE which have redder colours than other sources in the field, with 350 micron flux > 250 micron flux, suggesting that they lie at high redshift. Submillimeter Array (SMA) observations localise one of these companions to ~1 arcsecond, allowing unambiguous cross identification with a 3.6 and 4.5 micron Spitzer source. The optical/near-IR spectral energy distribution (SED) of this source is measured by further observations and found to be consistent with z>2, but incompatible with lower redshifts. We conclude that this system may be a galaxy cluster/protocluster or larger scale structure that contains a number of galaxies undergoing starbursts at the same time