Computing paths and cycles in biological interaction graphs

<p>Abstract</p> <p>Background</p> <p>Interaction graphs (signed directed graphs) provide an important qualitative modeling approach for Systems Biology. They enable the analysis of causal relationships in cellular networks and can even be useful for predicting qualitative aspects of systems dynamics. Fundamental issues in the analysis of interaction graphs are the enumeration of paths and cycles (feedback loops) and the calculation of shortest positive/negative paths. These computational problems have been discussed only to a minor extent in the context of Systems Biology and in particular the shortest signed paths problem requires algorithmic developments.</p> <p>Results</p> <p>We first review algorithms for the enumeration of paths and cycles and show that these algorithms are superior to a recently proposed enumeration approach based on elementary-modes computation. The main part of this work deals with the computation of shortest positive/negative paths, an NP-complete problem for which only very few algorithms are described in the literature. We propose extensions and several new algorithm variants for computing either exact results or approximations. Benchmarks with various concrete biological networks show that exact results can sometimes be obtained in networks with several hundred nodes. A class of even larger graphs can still be treated exactly by a new algorithm combining exhaustive and simple search strategies. For graphs, where the computation of exact solutions becomes time-consuming or infeasible, we devised an approximative algorithm with polynomial complexity. Strikingly, in realistic networks (where a comparison with exact results was possible) this algorithm delivered results that are very close or equal to the exact values. This phenomenon can probably be attributed to the particular topology of cellular signaling and regulatory networks which contain a relatively low number of negative feedback loops.</p> <p>Conclusion</p> <p>The calculation of shortest positive/negative paths and cycles in interaction graphs is an important method for network analysis in Systems Biology. This contribution draws the attention of the community to this important computational problem and provides a number of new algorithms, partially specifically tailored for biological interaction graphs. All algorithms have been implemented in the <it>CellNetAnalyzer </it>framework which can be downloaded for academic use at <url>http://www.mpi-magdeburg.mpg.de/projects/cna/cna.html</url>.</p

Counter-current chromatography for the separation of terpenoids: A comprehensive review with respect to the solvent systems employed

Copyright @ 2014 The Authors.This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.Natural products extracts are commonly highly complex mixtures of active compounds and consequently their purification becomes a particularly challenging task. The development of a purification protocol to extract a single active component from the many hundreds that are often present in the mixture is something that can take months or even years to achieve, thus it is important for the natural product chemist to have, at their disposal, a broad range of diverse purification techniques. Counter-current chromatography (CCC) is one such separation technique utilising two immiscible phases, one as the stationary phase (retained in a spinning coil by centrifugal forces) and the second as the mobile phase. The method benefits from a number of advantages when compared with the more traditional liquid-solid separation methods, such as no irreversible adsorption, total recovery of the injected sample, minimal tailing of peaks, low risk of sample denaturation, the ability to accept particulates, and a low solvent consumption. The selection of an appropriate two-phase solvent system is critical to the running of CCC since this is both the mobile and the stationary phase of the system. However, this is also by far the most time consuming aspect of the technique and the one that most inhibits its general take-up. In recent years, numerous natural product purifications have been published using CCC from almost every country across the globe. Many of these papers are devoted to terpenoids-one of the most diverse groups. Naturally occurring terpenoids provide opportunities to discover new drugs but many of them are available at very low levels in nature and a huge number of them still remain unexplored. The collective knowledge on performing successful CCC separations of terpenoids has been gathered and reviewed by the authors, in order to create a comprehensive document that will be of great assistance in performing future purifications. © 2014 The Author(s)

Therapy with un-engineered naïve rat umbilical cord matrix stem cells markedly inhibits growth of murine lung adenocarcinoma

<p>Abstract</p> <p>Background</p> <p>Lung cancer remains the leading cause of cancer-related mortality despite continuous efforts to find effective treatments. Data from the American Cancer Society indicate that while the overall incidence of lung cancer is declining, it continues to rise in women. Stem cell-based therapy has been an emerging strategy to treat various diseases. The purpose of this paper is to determine the efficacy of an intrinsic anti-cancer effect of rat umbilical cord matrix stem cells (UCMSCs) on lung cancer.</p> <p>Methods</p> <p>A mouse syngeneic lung carcinoma model was used to test the basic ability of UCMSCs to control the growth of lung cancer. Lung tumors were experimentally induced by tail vein administration of Lewis lung carcinoma (LLC) cells derived from the lung of C57BL/6 mouse. Rat UCMSCs were then administered intratracheally five days later or intravenously on days 5 and 7. The tumor burdens were determined by measuring lung weight three weeks after the treatment.</p> <p>Results</p> <p>Co-culture of rat UCMSCs with LLC significantly attenuated the proliferation of LLC cells as monitored by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), a tetrazole cell proliferation assay, thymidine uptake, and direct cell counts. <it>In vitro </it>colony assays with rat UCMSCs as feeder layers markedly reduced LLC colony size and number. Co-culture of rat UCMSCs with LLCs causes G0/G1 arrest of cancer cells. This is evident in the decrease of cyclin A and CDK2 expression. The <it>in vivo </it>studies showed that rat UCMSC treatment significantly decreased tumor weight and the total tumor mass. Histological study revealed that intratracheally or systemically administered rat UCMSCs homed to tumor areas and survived for at least 3 weeks without any evidence of differentiation or adverse effects.</p> <p>Conclusions</p> <p>These results indicate that rat UCMSCs alone remarkably attenuate the growth of lung carcinoma cells <it>in vitro </it>and in a mouse syngeneic lung carcinoma graft model and could be used for targeted cytotherapy for lung cancer.</p

A Screening Pipeline for Antiparasitic Agents Targeting Cryptosporidium Inosine Monophosphate Dehydrogenase

Persistent diarrhea is a leading cause of illness and death among impoverished children, and a growing share of this disease burden can be attributed to the parasite Cryptosporidium. There are no vaccines to prevent Cryptosporidium infection, and the treatment options are limited and unreliable. Critically, no effective treatment exists for children or adults suffering from AIDS. Cryptosporidium presents many technical obstacles for drug discovery; perhaps the most important roadblock is the difficulty of monitoring drug action. Here we have developed a set of methods to accelerate the drug discovery process for cryptosporidiosis. We exploit the opportunities for experimental manipulation in the related parasite Toxoplasma to genetically engineer a Cryptosporidium model. This new model parasite mirrors the metabolism of Cryptosporidium for a particularly promising drug target that supplies the building blocks for DNA and RNA. Drug effectiveness can be assayed through simple fluorescence measurements for many candidates. Using this assay as an initial filter, and adapting other assays to a high throughput format, we identify several novel chemical compounds that exhibit markedly improved anti-cryptosporidial activity and excellent selectivity

Methods of model reduction for large-scale biological systems: a survey of current methods and trends

Complex models of biochemical reaction systems have become increasingly common in the systems biology literature. The complexity of such models can present a number of obstacles for their practical use, often making problems difficult to intuit or computationally intractable. Methods of model reduction can be employed to alleviate the issue of complexity by seeking to eliminate those portions of a reaction network that have little or no effect upon the outcomes of interest, hence yielding simplified systems that retain an accurate predictive capacity. This review paper seeks to provide a brief overview of a range of such methods and their application in the context of biochemical reaction network models. To achieve this, we provide a brief mathematical account of the main methods including timescale exploitation approaches, reduction via sensitivity analysis, optimisation methods, lumping, and singular value decomposition-based approaches. Methods are reviewed in the context of large-scale systems biology type models, and future areas of research are briefly discussed

The SCIDOTS Project: Evidence of benefits of an integrated tobacco cessation intervention in tuberculosis care on treatment outcomes

<p>Abstract</p> <p>Background</p> <p>There is substantial evidence to support the association between tuberculosis (TB) and tobacco smoking and that the smoking-related immunological abnormalities in TB are reversible within six weeks of cessation. Therefore, connecting TB and tobacco cessation interventions may produce significant benefits and positively impact TB treatment outcomes. However, no study has extensively documented the evidence of benefits of such integration. SCIDOTS Project is a study from the context of a developing nation aimed to determine this.</p> <p>Methods</p> <p>An integrated TB-tobacco intervention was provided by trained TB directly observed therapy short-course (DOTS) providers at five chest clinics in Malaysia. The study was a prospective non-randomized controlled intervention using quasi-experimental design. Using Transtheoretical Model approach, 120 eligible participants who were current smokers at the time of TB diagnosis were assigned to either of two treatment groups: conventional TB DOTS plus smoking cessation intervention (integrated intervention or SCIDOTS group) or conventional TB DOTS alone (comparison or DOTS group). At baseline, newly diagnosed TB patients considering quitting smoking within the next 30 days were placed in the integrated intervention group, while those who were contemplating quitting were assigned to the comparison group. Eleven sessions of individualized cognitive behavioral therapy with or without nicotine replacement therapy were provided to each participant in the integrated intervention group. The impacts of the novel approach on biochemically validated smoking cessation and TB treatment outcomes were measured periodically as appropriate.</p> <p>Results</p> <p>A linear effect on both 7-day point prevalence abstinence and continuous abstinence was observed over time in the intervention group. At the end of 6 months, patients who received the integrated intervention had significantly higher rate of success in quitting smoking when compared with those who received the conventional TB treatment alone (77.5% vs. 8.7%; p < 0.001). Furthermore, at the end of TB treatment (6 months or later), there were significantly higher rates of treatment default (15.2% vs. 2.5%; p = 0.019) and treatment failure (6.5% vs. 0%; p = 0.019) in the DOTS group than in the SCIDOTS group.</p> <p>Conclusion</p> <p>This study provides evidence that connecting TB-tobacco treatment strategy is significant among TB patients who are smokers. The findings suggest that the integrated approach may be beneficial and confer advantages on short-term outcomes and possibly on future lung health of TB patients who quit smoking. This study may have important implications on health policy and clinical practice related to TB management among tobacco users.</p

Withanolides and related steroids

Since the isolation of the first withanolides in the mid-1960s, over 600 new members of this group of compounds have been described, with most from genera of the plant family Solanaceae. The basic structure of withaferin A, a C28 ergostane with a modified side chain forming a δ-lactone between carbons 22 and 26, was considered for many years the basic template for the withanolides. Nowadays, a considerable number of related structures are also considered part of the withanolide class; among them are those containing γ-lactones in the side chain that have come to be at least as common as the δ-lactones. The reduced versions (γ and δ-lactols) are also known. Further structural variations include modified skeletons (including C27 compounds), aromatic rings and additional rings, which may coexist in a single plant species. Seasonal and geographical variations have also been described in the concentration levels and types of withanolides that may occur, especially in the Jaborosa and Salpichroa genera, and biogenetic relationships among those withanolides may be inferred from the structural variations detected. Withania is the parent genus of the withanolides and a special section is devoted to the new structures isolated from species in this genus. Following this, all other new structures are grouped by structural types. Many withanolides have shown a variety of interesting biological activities ranging from antitumor, cytotoxic and potential cancer chemopreventive effects, to feeding deterrence for several insects as well as selective phytotoxicity towards monocotyledoneous and dicotyledoneous species. Trypanocidal, leishmanicidal, antibacterial, and antifungal activities have also been reported. A comprehensive description of the different activities and their significance has been included in this chapter. The final section is devoted to chemotaxonomic implications of withanolide distribution within the Solanaceae. Overall, this chapter covers the advances in the chemistry and biology of withanolides over the last 16 years.Fil: Misico, Rosana Isabel. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos Aplicados a la Química Orgánica (i); ArgentinaFil: Nicotra, V.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Instituto Multidisciplinario de Biología Vegetal (p); Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Química Orgánica; ArgentinaFil: Oberti, Juan Carlos María. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Instituto Multidisciplinario de Biología Vegetal (p); Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Química Orgánica; ArgentinaFil: Barboza, Gloria Estela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Instituto Multidisciplinario de Biología Vegetal (p); Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacia; ArgentinaFil: Gil, Roberto Ricardo. University Of Carnegie Mellon; Estados UnidosFil: Burton, Gerardo. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos Aplicados a la Química Orgánica (i); Argentin

Using an equity-based framework for evaluating publicly funded health insurance programmes as an instrument of UHC in Chhattisgarh State, India

Universal health coverage (UHC) has provided the impetus for the introduction of publicly funded health insurance (PFHI) schemes in the mixed health systems of India and many other low- and middle-income countries. There is a need for a holistic understanding of the pathways of impact of PFHI schemes, including their role in promoting equity of access. Methods: This paper applies an equity-oriented evaluation framework to assess the impacts of PFHI schemes in Chhattisgarh State by synthesising literature from various sources and highlighting knowledge gaps. Data were collected from an extensive review of publications on PFHI schemes in Chhattisgarh since 2009, including empirical studies from the first author's PhD and grey literature such as programme evaluation reports, media articles and civil society campaign documents. The framework was constructed using concepts and frameworks from the health policy and systems research literature on UHC, access and health system building blocks, and is underpinned by the values of equity, human rights and the right to health

Management strategy for facial arteriovenous malformations

Arteriovenous malformations (AVMs) are uncommon errors of vascular morphogenesis; haemodynamically, they are high-flow lesions. Approximately 50% of AVMs are located in the craniofacial region. Subtotal excision or proximal ligation of the feeding vessel frequently results in rapid progression of the AVMs. Hence, the correct treatment consists of highly selective embolisation (super-selective) followed by complete resection 24-48 hours later. We treated 20 patients with facial arteriovenous malformation by using this method. Most of the lesions (80%) were located within the cheek and lip. There were no procedure related complications and cosmetic results were excellent