Host transcription in active and latent tuberculosis

A recent study has identified a transcriptional signature for active tuberculosis, suggesting that the distinction between active and latent forms may not be absolute

Kentucky Law Survey: Criminal Procedure

Significant criminal procedure decisions of the Kentucky appellate courts for the period July 1, 1982 to July 1, 1983, have been selected for discussion in this Survey. Included in this survey is an extensive discussion of selected cases in the areas of warrants, competency of counsel, pretrial discovery of witness statements, venue, belated attacks on criminal convictions, and the right to talk to an attorney before taking a breathalyzer test

Attitudes towards clinical services among people who self-harm: systematic review.

BACKGROUND: Self-harm is increasingly common in many countries, is often repeated and may have other negative outcomes. AIMS: To systematically review people's attitudes towards clinical services following self-harm in order to inform service design and improvement. METHOD: A search of electronic databases was conducted and experts in the field were contacted in order to identify relevant worldwide qualitative or quantitative studies. Data were extracted independently by two reviewers with more weight given to studies of greater quality and relevance. RESULTS: Thirty-one studies met the inclusion criteria. Despite variations in healthcare systems and setting, participants' experiences were remarkably similar. Poor communication between patients and staff and a perceived lack of staff knowledge with regard to self-harm were common themes. Many participants suggested that psychosocial assessments and access to after-care needed to be improved. CONCLUSIONS: Specific aspects of care that might increase service user satisfaction and treatment adherence include staff knowledge, communication and better after-care arrangements. A standard protocol could aid regular audits of users' experiences of services

Cyclic AMP Regulation of Protein Lysine Acetylation in Mycobacterium Tuberculosis

Protein lysine acetylation networks can regulate central processes such as carbon metabolism and gene expression in bacteria. In Escherichia coli, cyclic-AMP (cAMP) regulates protein lysine acetyltransferase (PAT) activity at the transcriptional level, but in Mycobacterium tuberculosis, fusion of a cyclic-nucleotide binding domain to a Gcn5-like PAT domain enables direct cAMP control of protein acetylation. Here we describe the allosteric activation mechanism of M. tuberculosis PAT. The crystal structures of the auto-inhibited and cAMP-activated PAT reveal that cAMP binds to a cryptic site in the regulatory domain over 32 Å from the catalytic site. An extensive conformational rearrangement relieves auto-inhibition by a substrate-mimicking lid that covers the protein-substrate binding surface. A steric double latch couples the domains by harnessing a classic, cAMP-mediated, conformational switch. The structures suggest general features that enable the evolution of long-range communication between linked domains

Feedback Control as a Framework for Understanding Tradeoffs in Biology

Control theory arose from a need to control synthetic systems. From regulating steam engines to tuning radios to devices capable of autonomous movement, it provided a formal mathematical basis for understanding the role of feedback in the stability (or change) of dynamical systems. It provides a framework for understanding any system with feedback regulation, including biological ones such as regulatory gene networks, cellular metabolic systems, sensorimotor dynamics of moving animals, and even ecological or evolutionary dynamics of organisms and populations. Here we focus on four case studies of the sensorimotor dynamics of animals, each of which involves the application of principles from control theory to probe stability and feedback in an organism's response to perturbations. We use examples from aquatic (electric fish station keeping and jamming avoidance), terrestrial (cockroach wall following) and aerial environments (flight control in moths) to highlight how one can use control theory to understand how feedback mechanisms interact with the physical dynamics of animals to determine their stability and response to sensory inputs and perturbations. Each case study is cast as a control problem with sensory input, neural processing, and motor dynamics, the output of which feeds back to the sensory inputs. Collectively, the interaction of these systems in a closed loop determines the behavior of the entire system.Comment: Submitted to Integr Comp Bio

Modelling multi-scale state-switching functional data with hidden Markov models

Data sets comprised of sequences of curves sampled at high frequencies in time are increasingly common in practice, but they can exhibit complicated dependence structures that cannot be modelled using common methods of Functional Data Analysis (FDA). We detail a hierarchical approach which treats the curves as observations from a hidden Markov model (HMM). The distribution of each curve is then defined by another fine-scale model which may involve auto-regression and require data transformations using moving-window summary statistics or Fourier analysis. This approach is broadly applicable to sequences of curves exhibiting intricate dependence structures. As a case study, we use this framework to model the fine-scale kinematic movement of a northern resident killer whale (Orcinus orca) off the coast of British Columbia, Canada. Through simulations, we show that our model produces more interpretable state estimation and more accurate parameter estimates compared to existing methods.Comment: 23 pages, 8 figures, 2 tables. Supplementary material appended to submissio

The mutation rate of mycobacterial repetitive unit loci in strains of M. tuberculosis from cynomolgus macaque infection

Background: Mycobacterial interspersed repetitive units (MIRUs) are minisatellites within the Mycobacterium tuberculosis (Mtb) genome. Copy number variation (CNV) in MIRU loci is used for epidemiological typing, making the rate of variation important for tracking the transmission of Mtb strains. In this study, we developed and assessed a whole-genome sequencing (WGS) approach to detect MIRU CNV in Mtb. We applied this methodology to a panel of Mtb strains isolated from the macaque model of tuberculosis (TB), the animal model that best mimics human disease. From these data, we have estimated the rate of MIRU variation in the host environment, providing a benchmark rate for future epidemiologic work. Results: We assessed variation at the 24 MIRU loci used for typing in a set of Mtb strains isolated from infected cynomolgus macaques. We previously performed WGS of these strains and here have applied both read depth (RD) and paired-end mapping (PEM) metrics to identify putative copy number variants. To assess the relative power of these approaches, all MIRU loci were resequenced using Sanger sequencing. We detected two insertion/deletion events both of which could be identified as candidates by PEM criteria. With these data, we estimate a MIRU mutation rate of 2.70 × 10-03 (95% CI: 3.30 × 10-04- 9.80 × 10-03) per locus, per year. Conclusion: Our results represent the first experimental estimate of the MIRU mutation rate in Mtb. This rate is comparable to the highest previous estimates gathered from epidemiologic data and meta-analyses. Our findings allow for a more rigorous interpretation of data gathered from MIRU typing

Protein Complexes and Proteolytic Activation of the Cell Wall Hydrolase RipA Regulate Septal Resolution in Mycobacteria

Peptidoglycan hydrolases are a double-edged sword. They are required for normal cell division, but when dysregulated can become autolysins lethal to bacteria. How bacteria ensure that peptidoglycan hydrolases function only in the correct spatial and temporal context remains largely unknown. Here, we demonstrate that dysregulation converts the essential mycobacterial peptidoglycan hydrolase RipA to an autolysin that compromises cellular structural integrity. We find that mycobacteria control RipA activity through two interconnected levels of regulation in vivo—protein interactions coordinate PG hydrolysis, while proteolysis is necessary for RipA enzymatic activity. Dysregulation of RipA protein complexes by treatment with a peptidoglycan synthase inhibitor leads to excessive RipA activity and impairment of correct morphology. Furthermore, expression of a RipA dominant negative mutant or of differentially processed RipA homologues reveals that RipA is produced as a zymogen, requiring proteolytic processing for activity. The amount of RipA processing differs between fast-growing and slow-growing mycobacteria and correlates with the requirement for peptidoglycan hydrolase activity in these species. Together, the complex picture of RipA regulation is a part of a growing paradigm for careful control of cell wall hydrolysis by bacteria during growth, and may represent a novel target for chemotherapy development