Identification of 2-Aminothiazole-4-Carboxylate Derivatives Active against Mycobacterium tuberculosis H37Rv and the β-Ketoacyl-ACP Synthase mtFabH

Background Tuberculosis (TB) is a disease which kills two million people every year and infects approximately over one-third of the world's population. The difficulty in managing tuberculosis is the prolonged treatment duration, the emergence of drug resistance and co-infection with HIV/AIDS. Tuberculosis control requires new drugs that act at novel drug targets to help combat resistant forms of Mycobacterium tuberculosis and reduce treatment duration. Methodology/Principal Findings Our approach was to modify the naturally occurring and synthetically challenging antibiotic thiolactomycin (TLM) to the more tractable 2-aminothiazole-4-carboxylate scaffold to generate compounds that mimic TLM's novel mode of action. We report here the identification of a series of compounds possessing excellent activity against M. tuberculosis H37Rv and, dissociatively, against the β-ketoacyl synthase enzyme mtFabH which is targeted by TLM. Specifically, methyl 2-amino-5-benzylthiazole-4-carboxylate was found to inhibit M. tuberculosis H37Rv with an MIC of 0.06 µg/ml (240 nM), but showed no activity against mtFabH, whereas methyl 2-(2-bromoacetamido)-5-(3-chlorophenyl)t​hiazole-4-carboxylateinhibited mtFabH with an IC50 of 0.95±0.05 µg/ml (2.43±0.13 µM) but was not active against the whole cell organism. Conclusions/Significance These findings clearly identify the 2-aminothiazole-4-carboxylate scaffold as a promising new template towards the discovery of a new class of anti-tubercular agents

Female University Students’ Experiences of Hookah Smoking: Cool Habit and Non-predictable Imminent Consequences and Risks

Aim: The purpose of this study is to describe the perceptions of and reasons for adopting Hookah smoking among female university students.  Background: Debates on risk and harm of Hookah smoking existed among female university students.   There is a dearth of studies describing the daily experience and the causative factors for Hookah smoking among female university students.  Methods: A descriptive qualitative design was used for this study. A purposive sample of 14 female university students participated through face-to-face interviews.  Results: The study results included six main themes, Hookah smoking is cool and entertaining, attracting factors for Hookah smoking, Hookah smoking versus Cigarette smoking, sociocultural acceptance for female Hookah Smoking, imminent hazardous consequences of Hookah smoking, and strategies to combat Hookah smoking among females students.  Conclusion: Hookah smoking has become culturally accepted by female university students. Serious attention and initiatives should be considered to enhance female internal awareness to prevent peer pressure to start Hookah smoking. This habit started at home, became accepted by parents, and is now accepted in public places.  Relevance to clinical practice and education: Nurses and policymakers should address the triggering factors for increased Hookah smoking among adults. Nurses should use effective approaches for combating Hookah smoking at different community settings. Also, they should conduct and implement culturally competent preventive programs to combat Hookah smoking in different settings and among all age groups specifically university and school students. Additionally, it is significant to enforce legislations and policies for the prevention of smoking Hookah among adults.&nbsp

Syrian Refugees and the Digital Passage to Europe: Smartphone Infrastructures and Affordances

This research examines the role of smartphones in refugees’ journeys. It traces the risks and possibilities afforded by smartphones for facilitating information, communication, and migration flows in the digital passage to Europe. For the Syrian and Iraqi refugee respondents in this France-based qualitative study, smartphones are lifelines, as important as water and food. They afford the planning, navigation, and documentation of journeys, enabling regular contact with family, friends, smugglers, and those who help them. However, refugees are simultaneously exposed to new forms of exploitation and surveillance with smartphones as migrations are financialised by smugglers and criminalized by European policies, and the digital passage is dependent on a contingent range of sociotechnical and material assemblages. Through an infrastructural lens, we capture the dialectical dynamics of opportunity and vulnerability, and the forms of resilience and solidarity, that arise as forced migration and digital connectivity coincide

The Nondeterministic Waiting Time Algorithm: A Review

We present briefly the Nondeterministic Waiting Time algorithm. Our technique for the simulation of biochemical reaction networks has the ability to mimic the Gillespie Algorithm for some networks and solutions to ordinary differential equations for other networks, depending on the rules of the system, the kinetic rates and numbers of molecules. We provide a full description of the algorithm as well as specifics on its implementation. Some results for two well-known models are reported. We have used the algorithm to explore Fas-mediated apoptosis models in cancerous and HIV-1 infected T cells

Passive acoustic tracking of the three-dimensional movements and acoustic behaviour of toothed whales in close proximity to static nets

Funding: Department for Environment, Food and Rural Affairs, UK Government (Grant Number(s): ME6052; Grant recipient(s): Jamie Macaulay, Allen Kingston, Simon Northridge, Alexander Coram). University of St Andrews.1. Entanglement in net fisheries (static and drift) is the largest known cause of direct anthropogenic mortality to many small cetacean species, including harbour porpoise (Phocoena phocoena), in UK waters. Despite this, little is known about the behaviour of small cetaceans in proximity to nets. 2. We have developed a passive acoustic monitoring (PAM) system for tracking the fine-scale three-dimensional (3D) movements of echolocating cetaceans around actively fishing nets by localising their acoustic clicks. The system consists of two compact four-channel acoustic recorders with sample-synchronised sensor packages that use 3D motion tracking technology to accurately calculate log orientation, depth, water temperature and ambient light level. Two recorders were used in tandem, with each one attached to and floating above the net floatline. The system can be deployed during normal fishing operations by a trained researcher or experienced fisheries observer. Recordings were analysed in PAMGuard software and the 3D positions of echolocating animals in the vicinity of the system were calculated using an acoustic particle filter-based localisation method. 3. We present findings from four deployments in UK waters (each 1–2 days in duration) in which 12 distinct harbour porpoise encounters yielded a sufficient number of detected clicks to track their movements around the net. The tracks show a variety of behaviours, including multiple instances of animals actively foraging in close proximity to the fishing net. 4. We show that a relatively inexpensive PAM system, which is practical to deploy from active fishing vessels, is capable of providing highly detailed data on harbour porpoise behaviour around nets. As harbour porpoises are the one of the most difficult species to localise, this methodology is likely to be suitable for elucidating the behaviour of many other toothed whale species in a variety of situations.Publisher PDFPeer reviewe

Global parameter identification of stochastic reaction networks from single trajectories

We consider the problem of inferring the unknown parameters of a stochastic biochemical network model from a single measured time-course of the concentration of some of the involved species. Such measurements are available, e.g., from live-cell fluorescence microscopy in image-based systems biology. In addition, fluctuation time-courses from, e.g., fluorescence correlation spectroscopy provide additional information about the system dynamics that can be used to more robustly infer parameters than when considering only mean concentrations. Estimating model parameters from a single experimental trajectory enables single-cell measurements and quantification of cell--cell variability. We propose a novel combination of an adaptive Monte Carlo sampler, called Gaussian Adaptation, and efficient exact stochastic simulation algorithms that allows parameter identification from single stochastic trajectories. We benchmark the proposed method on a linear and a non-linear reaction network at steady state and during transient phases. In addition, we demonstrate that the present method also provides an ellipsoidal volume estimate of the viable part of parameter space and is able to estimate the physical volume of the compartment in which the observed reactions take place.Comment: Article in print as a book chapter in Springer's "Advances in Systems Biology

Simple, Fast and Accurate Implementation of the Diffusion Approximation Algorithm for Stochastic Ion Channels with Multiple States

The phenomena that emerge from the interaction of the stochastic opening and closing of ion channels (channel noise) with the non-linear neural dynamics are essential to our understanding of the operation of the nervous system. The effects that channel noise can have on neural dynamics are generally studied using numerical simulations of stochastic models. Algorithms based on discrete Markov Chains (MC) seem to be the most reliable and trustworthy, but even optimized algorithms come with a non-negligible computational cost. Diffusion Approximation (DA) methods use Stochastic Differential Equations (SDE) to approximate the behavior of a number of MCs, considerably speeding up simulation times. However, model comparisons have suggested that DA methods did not lead to the same results as in MC modeling in terms of channel noise statistics and effects on excitability. Recently, it was shown that the difference arose because MCs were modeled with coupled activation subunits, while the DA was modeled using uncoupled activation subunits. Implementations of DA with coupled subunits, in the context of a specific kinetic scheme, yielded similar results to MC. However, it remained unclear how to generalize these implementations to different kinetic schemes, or whether they were faster than MC algorithms. Additionally, a steady state approximation was used for the stochastic terms, which, as we show here, can introduce significant inaccuracies. We derived the SDE explicitly for any given ion channel kinetic scheme. The resulting generic equations were surprisingly simple and interpretable - allowing an easy and efficient DA implementation. The algorithm was tested in a voltage clamp simulation and in two different current clamp simulations, yielding the same results as MC modeling. Also, the simulation efficiency of this DA method demonstrated considerable superiority over MC methods.Comment: 32 text pages, 10 figures, 1 supplementary text + figur

Characterization of the domestic goat γδ T cell receptor gene loci and gene usage

Goats and cattle diverged 30 million years ago but retain similarities in immune system genes. Here, the caprine T cell receptor (TCR) gene loci and transcription of its genes were examined and compared to cattle. We annotated the TCR loci using an improved genome assembly (ARS1) of a highly homozygous San Clemente goat. This assembly has already proven useful for describing other immune system genes including antibody and leucocyte receptors. Both the TCRγ (TRG) and TCRδ (TRD) loci were similarly organized in goats as in cattle and the gene sequences were highly conserved. However, the number of genes varied slightly as a result of duplications and differences occurred in mutations resulting in pseudogenes. WC1+ γδ T cells in cattle have been shown to use TCRγ genes from only one of the six available cassettes. The structure of that Cγ gene product is unique and may be necessary to interact with WC1 for signal transduction following antigen ligation. Using RT-PCR and PacBio sequencing, we observed the same restriction for goat WC1+ γδ T cells. In contrast, caprine WC1+ and WC1− γδ T cell populations had a diverse TCRδ gene usage although the propensity for particular gene usage differed between the two cell populations. Noncanonical recombination signal sequences (RSS) largely correlated with restricted expression of TCRγ and δ genes. Finally, caprine γδ T cells were found to incorporate multiple TRD diversity gene sequences in a single transcript, an unusual feature among mammals but also previously observed in cattle