Molecular Imaging in TB: From the Bench to the Clinic

Despite all efforts, tuberculosis (TB) still constitutes a serious global health threat with 9.4 million new cases and 1.7 million deaths worldwide in 2009 (World Health Organisation,2010). Furthermore, an estimated one third of the worlds’ population is infected with the bacterium responsible, Mycobacterium tuberculosis. The main handicaps in fighting TB include a vaccine which works poorly in the most affected populations, and an arduous treatment regimen, involving a combination of several drugs taken over many months. This is further complicated by the emergence of multi-drug resistant (MDR) and extensively drug-resistant (XDR) M. tuberculosis strains, which require even longer treatment times with less well-tolerated drugs. Eradication of TB will require the development of new drugs and vaccines, alongside improved methods for diagnosis and monitoring treatment efficacy. With the vast burden of disease falling in resource poor settings, the challenge will also be to develop methodologies that can be deployed with minimal investment in infrastructure, maintenance and staff expertise. Recent decades have seen the emergence of the new discipline of molecular imaging. In essence, molecular imaging enables the non-invasive visualisation, characterisation, and quantification of biological processes taking place within intact living subjects, be it a mouse or man (Filippi & Rocca, 2011; Horky & Treves, 2011; Pysz et al., 2010; Sandhu et al., 2010). Imaging has long been applied to managing TB; simple chest x-rays have allowed clinicians to visualise TB in people for over a century (Singh & Nath, 1994). However, the new molecular imaging techniques are revolutionising medical research, with the potential to translate into significant changes in clinical practice. In this chapter we describe the new generation of imaging modalities and how these are being applied to eradicating TB, from the laboratory bench and in to the clinic

M2I-1 disrupts the in vivo interaction between CDC20 and MAD2 and increases the sensitivities of cancer cell lines to anti-mitotic drugs via MCL-1s

Background Drugs such as taxanes, epothilones, and vinca alkaloids are widely used in the treatment of breast, ovarian, and lung cancers but come with major side effects such as neuropathy and loss of neutrophils and as single agents have a lack of efficacy. M2I-1 (MAD2 inhibitor-1) has been shown to disrupt the CDC20-MAD2 interaction, and consequently, the assembly of the mitotic checkpoint complex (MCC). Results We report here that M2I-1 can significantly increase the sensitivity of several cancer cell lines to anti-mitotic drugs, with cell death occurring after a prolonged mitotic arrest. In the presence of nocodazole or taxol combined with M2I-1 cell death is triggered by the premature degradation of Cyclin B1, the perturbation of the microtubule network, and an increase in the level of the pro-apoptotic protein MCL-1s combined with a marginal increase in the level of NOXA. The elevated level of MCL-1s and the marginally increased NOXA antagonized the increased level of MCL-1, a pro-survival protein of the Bcl-2 family. Conclusion Our results provide some important molecular mechanisms for understanding the relationship between the mitotic checkpoint and programmed cell death and demonstrate that M2I-1 exhibits antitumor activity in the presence of current anti-mitotic drugs such as taxol and nocodazole and has the potential to be developed as an anticancer agent

Rare-Event Sampling: Occupation-Based Performance Measures for Parallel Tempering and Infinite Swapping Monte Carlo Methods

In the present paper we identify a rigorous property of a number of tempering-based Monte Carlo sampling methods, including parallel tempering as well as partial and infinite swapping. Based on this property we develop a variety of performance measures for such rare-event sampling methods that are broadly applicable, informative, and straightforward to implement. We illustrate the use of these performance measures with a series of applications involving the equilibrium properties of simple Lennard-Jones clusters, applications for which the performance levels of partial and infinite swapping approaches are found to be higher than those of conventional parallel tempering.Comment: 18 figure

VEGETATION SYNTAXONOMY AND LAND MANAGEMENT EFFECT ON METHANE AND CARBON DIOXIDE EMISSIONS FROM WETLANDS: A CASE STUDY FROM TIDAL SALT AND BRACKISH MARSH

Carbon dioxide (CO 2 ) and methane (CH 4 ) emission from wetlands significantly contribute to climate change andglobal warming. The interaction between among vegetation type, various environmental factors, andmanagement regimes such as grazing and mowing is considered important in the calculation of CO 2 and CH 4 gasflux for an ecosystem. In this study, vegetation composition, CH 4 and CO 2 flux, soil characteristics, airtemperature and humidity from the brackish marsh and salt marsh wetland ecosystems on Terschelling Islandin Northern Holland were measured. We aimed to investigate the relationship between vegetation composition, grazing, and mowing on CH 4 and CO 2 emission. The abundance and number of plant species werehigher in brackish than in salt marsh. Grazing was found to influence species richness, 39 species being found ina grazed site of brackish marsh compared to 31 species in a similar ungrazed site. CO 2 fluxes in salt and brackishmarsh were found to be similar while CH 4 flux in the salt marsh was found to be lower than in the brackishmarsh. Within the brackish marsh, a higher methane emission was recorded in the grazed zone. However theoverall effect of grazing and mowing was found to be negligible for CH 4 flux but is suggested to clearly reduceCO 2 flux in both the salt and brackish marsh

An Infinite Swapping Approach to the Rare-Event Sampling Problem

We describe a new approach to the rare-event Monte Carlo sampling problem. This technique utilizes a symmetrization strategy to create probability distributions that are more highly connected and thus more easily sampled than their original, potentially sparse counterparts. After discussing the formal outline of the approach and devising techniques for its practical implementation, we illustrate the utility of the technique with a series of numerical applications to Lennard-Jones clusters of varying complexity and rare-event character.Comment: 24 pages, 16 figure

Digital Transformation: An Overview of the Current State of the Art of Research

The increasing digitalization of economies has highlighted the importance of digital transformation and how it can help businesses stay competitive in the market. However, disruptive changes not only occur at the company level; they also have environmental, societal, and institutional implications. This is the reason why during the past two decades the research on digital transformation has received growing attention, with a wide range of topics investigated in the literature. The following aims to provide insight regarding the current state of the literature on digital transformation (DT) by conducting a systematic literature review. An analysis of co-occurrence using the software VOSviewer was conducted to graphically visualize the literature’s node network. Approached this way, the systematic literature review displays major research avenues of digital transformation that consider technology as the main driver of these changes. This paper qualitatively classifies the literature on digital business transformation into three different clusters based on technological, business, and societal impacts. Several research gaps identified in the literature on DT are proposed as futures lines of research which could provide useful insights to the government and private sectors in order to adapt to the disruptive changes found in business as a result of this phenomenon, as well as to reduce its negative impacts on society and the environment

Developmental Programming of Obesity and Liver Metabolism by Maternal Perinatal Nutrition Involves the Melanocortin System

Maternal obesity predisposes offspring to metabolic dysfunction and Non-Alcoholic Fatty Liver Disease (NAFLD). Melanocortin-4 receptor (Mc4r)-deficient mouse models exhibit obesity during adulthood. Here, we aim to determine the influence of the Mc4r gene on the liver of mice subjected to perinatal diet-induced obesity. Female mice heterozygous for Mc4r fed an obesogenic or a control diet for 5 weeks were mated with heterozygous males, with the same diet continued throughout pregnancy and lactation, generating four offspring groups: control wild type (C_wt), control knockout (C_KO), obese wild type (Ob_wt), and obese knockout (Ob_KO). At 21 days, offspring were genotyped, weaned onto a control diet, and sacrificed at 6 months old. Offspring phenotypic characteristics, plasma biochemical profile, liver histology, and hepatic gene expression were analyzed. Mc4r_ko offspring showed higher body, liver and adipose tissue weights respect to the wild type animals. Histological examination showed mild hepatic steatosis in offspring group C_KO. The expression of hepatic genes involved in regulating inflammation, fibrosis, and immune cell infiltration were upregulated by the absence of the Mc4r gene. These results demonstrate that maternal obesogenic feeding during the perinatal period programs offspring obesity development with involvement of the Mc4r system

MedVir: an interactive representation system of multidimensional medical data applied to Traumatic Brain Injury's rehabilitation prediction

Clinicians could model the brain injury of a patient through his brain activity. However, how this model is defined and how it changes when the patient is recovering are questions yet unanswered. In this paper, the use of MedVir framework is proposed with the aim of answering these questions. Based on complex data mining techniques, this provides not only the differentiation between TBI patients and control subjects (with a 72% of accuracy using 0.632 Bootstrap validation), but also the ability to detect whether a patient may recover or not, and all of that in a quick and easy way through a visualization technique which allows interaction

Levels of dioxin-like PCBs in low-volume serum samples of male patients attending fertility clinics

An accurate and easy method for the extraction, cleanup, and HRGC-HRMS analysis of dioxin-like PCBs (DL-PCBs) in low-volume serum samples (1 mL) was developed. Serum samples were extracted several times using n-hexane and purified by acid washing. Recovery rates of labeled congeners ranged from 70 to 110 % and the limits of detection were below 1 pg/g on lipid basis. Although human studies are limited and contradictory, several studies have shown that DL-PCBs can have adverse effects on the male reproductive system. In this way, the present method was applied to 21 serum samples of male patients attending fertility clinics. The total levels obtained for the patients ranged from 6.90 to 84.1 pg WHO-TEQ/g lipid, with a mean value of 20.3 pg WHO-TEQ/g lipid. The predominant PCBs (the sum of PCB 118, 156, and 105) contributed 67 % to the mean concentration of total DL-PCBs in the samples analyzed.Support for this work was provided by the CTQ2013-41006-R project from the Ministry of Economy and Competitiveness (Spain), the PROMETEOII/2014/007 project from the Valencian Community Government (Spain), and the Chair of Human Fertility of the University of Alicante (Spain)