Crystallographic Investigations of Biotin and Carboxybiotin Derivatives a

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73473/1/j.1749-6632.1985.tb18435.x.pd

Code wars: steganography, signals intelligence, and terrorism

This paper describes and discusses the process of secret communication known as steganography. The argument advanced here is that terrorists are unlikely to be employing digital steganography to facilitate secret intra-group communication as has been claimed. This is because terrorist use of digital steganography is both technically and operationally implausible. The position adopted in this paper is that terrorists are likely to employ low-tech steganography such as semagrams and null ciphers instead

Milestones: a Rapid Assessment Method for the Clinical Competency Committee

INTRODUCTION: Educational milestones are now used to assess the developmental progress of all U.S. graduate medical residents during training. Twice annually, each program\u27s Clinical Competency Committee (CCC) makes these determinations and reports its findings to the Accreditation Council for Graduate Medical Education (ACGME). The ideal way to conduct the CCC is not known. After finding that deliberations reliant upon the new milestones were time intensive, our internal medicine residency program tested an approach designed to produce rapid but accurate assessments. MATERIAL AND METHODS: For this study, we modified our usual CCC process to include pre-meeting faculty ratings of resident milestones progress with in-meeting reconciliation of their ratings. Data were considered largely via standard report and presented in a pre-arranged pattern. Participants were surveyed regarding their perceptions of data management strategies and use of milestones. Reliability of competence assessments was estimated by comparing pre-/post-intervention class rank lists produced by individual committee members with a master class rank list produced by the collective CCC after full deliberation. RESULTS: Use of the study CCC approach reduced committee deliberation time from 25 min to 9 min per resident (p \u3c 0.001). Committee members believed milestones improved their ability to identify and assess expected elements of competency development (p = 0.026). Individual committee member assessments of trainee progress agreed well with collective CCC assessments. CONCLUSIONS: Modification of the clinical competency process to include pre-meeting competence ratings with in-meeting reconciliation of these ratings led to shorter deliberation times, improved evaluator satisfaction and resulted in reliable milestone assessments

An Economic Framework for Evaluating Personalized Medicine

Individual variation accounts for a wide range of medical and economic consequences, from inefficiencies in drug discovery and development to ineffectiveness of drug treatment to drug-induced morbidity and mortality. Addressing these consequences could benefit patients, health care providers and payers, and the pharmaceutical industry. When appropriate markers are known, diagnostic tests allow precise diagnosis and dosing, prediction of disease progression, prediction of treatment response and prediction of adverse drug reactions for individual patients. There may also be substantial savings realized by eliminating costs associated with failed treatment. We developed an analytical framework for analyzing the potential value of using a diagnostic test in clinical practice. Our framework determines the economic consequences of implementing pharmacogenomics in the clinic using a diagnostic test to predict drug response. We offer an empirical test of these ideas: we calculated the cost offset realized by predicting the likelihood of response to an alternative existing treatment using a hypothetical pharmacogenomic test in an asthma population. Because the diagnostic test is hypothetical, our framework is general and could be applied to other indications where diagnostic tests have not been developed. Our results could potentially guide future economic evaluation of new diagnostic tests. Importantly, they may also influence biomarker discovery strategies to ensure consistency between market priorities and the future stream of product introductions

Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use.

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders1. They are heritable2,3 and etiologically related4,5 behaviors that have been resistant to gene discovery efforts6-11. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures

Changing Patterns of Microhabitat Utilization by the Threespot Damselfish, Stegastes planifrons, on Caribbean Reefs

Background: The threespot damselfish, Stegastes planifrons (Cuvier), is important in mediating interactions among corals, algae, and herbivores on Caribbean coral reefs. The preferred microhabitat of S. planifrons is thickets of the branching staghorn coral Acropora cervicornis. Within the past few decades, mass mortality of A. cervicornis from white-band disease and other factors has rendered this coral a minor ecological component throughout most of its range. Methodology/Principal Findings: Survey data from Jamaica (heavily fished), Florida and the Bahamas (moderately fished), the Cayman Islands (lightly to moderately fished), and Belize (lightly fished) indicate that distributional patterns of S. planifrons are positively correlated with live coral cover and topographic complexity. Our results suggest that speciesspecific microhabitat preferences and the availability of topographically complex microhabitats are more important than the abundance of predatory fish as proximal controls on S. planifrons distribution and abundance. Conclusions/Significance: The loss of the primary microhabitat of S. planifrons—A. cervicornis—has forced a shift in the distribution and recruitment of these damselfish onto remaining high-structured corals, especially the Montastraea annulari

Trehalose-6-phosphate-mediated toxicity determines essentiality of OtsB2 in Mycobacterium tuberculosis in vitro and in mice

Trehalose biosynthesis is considered an attractive target for the development of antimicrobials against fungal, helminthic and bacterial pathogens including Mycobacterium tuberculosis. The most common biosynthetic route involves trehalose-6-phosphate (T6P) synthase OtsA and T6P phosphatase OtsB that generate trehalose from ADP/UDP-glucose and glucose-6-phosphate. In order to assess the drug target potential of T6P phosphatase, we generated a conditional mutant of M. tuberculosis allowing the regulated gene silencing of the T6P phosphatase gene otsB2. We found that otsB2 is essential for growth of M. tuberculosis in vitro as well as for the acute infection phase in mice following aerosol infection. By contrast, otsB2 is not essential for the chronic infection phase in mice, highlighting the substantial remodelling of trehalose metabolism during infection by M. tuberculosis. Blocking OtsB2 resulted in the accumulation of its substrate T6P, which appears to be toxic, leading to the self-poisoning of cells. Accordingly, blocking T6P production in a ΔotsA mutant abrogated otsB2 essentiality. T6P accumulation elicited a global upregulation of more than 800 genes, which might result from an increase in RNA stability implied by the enhanced neutralization of toxins exhibiting ribonuclease activity. Surprisingly, overlap with the stress response caused by the accumulation of another toxic sugar phosphate molecule, maltose-1-phosphate, was minimal. A genome-wide screen for synthetic lethal interactions with otsA identified numerous genes, revealing additional potential drug targets synergistic with OtsB2 suitable for combination therapies that would minimize the emergence of resistance to OtsB2 inhibitors

Evolution of Alternative Splicing Regulation: Changes in Predicted Exonic Splicing Regulators Are Not Associated with Changes in Alternative Splicing Levels in Primates

Alternative splicing is tightly regulated in a spatio-temporal and quantitative manner. This regulation is achieved by a complex interplay between spliceosomal (trans) factors that bind to different sequence (cis) elements. cis-elements reside in both introns and exons and may either enhance or silence splicing. Differential combinations of cis-elements allows for a huge diversity of overall splicing signals, together comprising a complex ‘splicing code’. Many cis-elements have been identified, and their effects on exon inclusion levels demonstrated in reporter systems. However, the impact of interspecific differences in these elements on the evolution of alternative splicing levels has not yet been investigated at genomic level. Here we study the effect of interspecific differences in predicted exonic splicing regulators (ESRs) on exon inclusion levels in human and chimpanzee. For this purpose, we compiled and studied comprehensive datasets of predicted ESRs, identified by several computational and experimental approaches, as well as microarray data for changes in alternative splicing levels between human and chimpanzee. Surprisingly, we found no association between changes in predicted ESRs and changes in alternative splicing levels. This observation holds across different ESR exon positions, exon lengths, and 5′ splice site strengths. We suggest that this lack of association is mainly due to the great importance of context for ESR functionality: many ESR-like motifs in primates may have little or no effect on splicing, and thus interspecific changes at short-time scales may primarily occur in these effectively neutral ESRs. These results underscore the difficulties of using current computational ESR prediction algorithms to identify truly functionally important motifs, and provide a cautionary tale for studies of the effect of SNPs on splicing in human disease