A -translation inhibitor is potentiated by zinc and kills and non-tuberculous mycobacteria.

poses a serious challenge for human health, and new antibiotics with novel targets are needed. Here we demonstrate that an acylaminooxadiazole, MBX-4132, specifically inhibits the -translation ribosome rescue pathway to kill . Our data demonstrate that MBX-4132 is bactericidal against multiple pathogenic mycobacterial species and kills in macrophages.

Thiol Stress Fuels Pyrazinamide Action Against .

Pyrazinamide (PZA) is a cornerstone of first-line antitubercular drug therapy and is unique in its ability to kill nongrowing populations of through disruption of coenzyme A synthesis. Unlike other drugs, PZA action is conditional and requires potentiation by host-relevant environmental stressors, such as low pH and nutrient limitation. Despite its pivotal role in tuberculosis therapy, the mechanistic basis for PZA potentiation remains unknown and the durability of this crucial drug is challenged by the emergent spread of drug resistance.

Cephem-Pyrazinoic Acid Conjugates: Circumventing Resistance in Mycobacterium tuberculosis.

Tuberculosis (TB) is a leading source of infectious disease mortality globally. Antibiotic-resistant strains comprise an estimated 10 % of new TB cases and present an urgent need for novel therapeutics. β-lactam antibiotics have traditionally been ineffective against M.

Numbers matter: how irruptive bark beetles initiate transition to self-sustaining behavior during landscape-altering outbreaks.

Irruptive forest insects such as bark beetles undergo intermittent outbreaks that cause landscape-scale tree mortality. Despite their enormous economic and ecological impacts, we still have only limited understanding of the dynamics by which populations transition from normally stable endemic to irruptive densities. We investigated density-dependent changes in mountain pine beetle reliance on stressed hosts, host selection, spatial configuration of attacks, and the interaction of host selection and spatial configuration by performing a complete census of lodgepole pine across six stands and 6 years.

Synthesis and biological evaluation of orally active prodrugs and analogs of para-aminosalicylic acid (PAS).

Tuberculosis (TB) is one of the world's most deadly infectious diseases resulting in nearly 1.3 million deaths annually and infecting nearly one-quarter of the population. para-Aminosalicylic acid (PAS), an important second-line agent for treating drug-resistant Mycobacterium tuberculosis, has moderate bioavailability and rapid clearance that necessitate high daily doses of up to 12 g per day, which in turn causes severe gastrointestinal disturbances presumably by disruption of gut microbiota and host epithelial cells.

Pyrazinamide Susceptibility Is Driven by Activation of the SigE-Dependent Cell Envelope Stress Response in Mycobacterium tuberculosis.

Pyrazinamide (PZA) plays a crucial role in first-line tuberculosis drug therapy. Unlike other antimicrobial agents, PZA is active against Mycobacterium tuberculosis only at low pH. The basis for this conditional drug susceptibility remains undefined.

When discretionary boundary spanning relationships cease becoming discretionary: The impact of closed ties on informal leadership perceptions.

Organizations have recognized that effective informal leadership is a source of competitive advantage and invest heavily in leadership development efforts. Moreover, because of historical shifts in the nature of work, this informal leadership often takes the form of inter-unit boundary spanning. Because of these two developments, discretionary boundary spanning (DBS) between units has increasingly become a critical, dynamic, bottom-up activity where individuals lacking formal authority step up and take on informal leadership responsibilities.

Climate-induced outbreaks in high-elevation pines are driven primarily by immigration of bark beetles from historical hosts.

Warming temperatures are allowing native insect herbivores to expand into regions that previously exceeded their thermal tolerance, encounter new host species, and pose significant threats to native communities. However, the dynamics of these expansions remain poorly understood, particularly in the extent to which outbreaks remain reliant on emigration from historical hosts or are driven by local reproduction within novel hosts in the expanded range. We tested these non-mutually exclusive hypotheses using spatially explicit data on mountain pine beetle (Dendroctonus ponderosae), which historically undergoes intermittent outbreaks in low-elevation lodgepole pine (Pinus contorta), but is now causing severe mortality in a high-elevation endangered species, whitebark pine (Pinus albicaulis).

Pathogen-specific antimicrobials engineered de novo through membrane-protein biomimicry.

Precision antimicrobials aim to kill pathogens without damaging commensal bacteria in the host, and thereby cure disease without antibiotic-associated dysbiosis. Here we report the de novo design of a synthetic host defence peptide that targets a specific pathogen by mimicking key molecular features of the pathogen's channel-forming membrane proteins. By exploiting physical and structural vulnerabilities within the pathogen's cellular envelope, we designed a peptide sequence that undergoes instructed tryptophan-zippered assembly within the mycolic acid-rich outer membrane of Mycobacterium tuberculosis to specifically kill the pathogen without collateral toxicity towards lung commensal bacteria or host tissue.

The formyl peptide receptor agonist FPRa14 induces differentiation of Neuro2a mouse neuroblastoma cells into multiple distinct morphologies which can be specifically inhibited with FPR antagonists and FPR knockdown using siRNA.

The N-formyl peptide receptors (FPRs) have been identified within neuronal tissues and may serve as yet undetermined functions within the nervous system. The FPRs have been implicated in the progression and invasiveness of neuroblastoma and other cancers. In this study the effects of the synthetic FPR agonist FPRa14, FPR antagonists and FPR knockdown using siRNA on mouse neuroblastoma neuro2a (N2a) cell differentiation plus toxicity were examined.

Spirocyclic and Bicyclic 8-Nitrobenzothiazinones for Tuberculosis with Improved Physicochemical and Pharmacokinetic Properties.

8-Nitrobenzothiazinones (BTZs) typified by the second-generation analogue PBTZ169 are a new class of antitubercular agents. The activity of BTZs and lipophilicity are tightly coupled since the molecular target DprE1 is located in the mycobacterial cell envelope. A series of analogues was designed to address the notorious insolubility of the BTZs while preserving the required lipophilicity.

Investigation of ( S)-(-)-Acidomycin: A Selective Antimycobacterial Natural Product That Inhibits Biotin Synthase.

The synthesis, absolute stereochemical configuration, complete biological characterization, mechanism of action and resistance, and pharmacokinetic properties of ( S)-(-)-acidomycin are described. Acidomycin possesses promising antitubercular activity against a series of contemporary drug susceptible and drug-resistant M. tuberculosis strains (minimum inhibitory concentrations (MICs) = 0.

General mental ability and goal type as antecedents of recurrent adaptive task performance.

Even though considerable work has demonstrated a robust positive relationship between general mental ability (GMA) and task performance, recent work indicates that the expected relationship may not hold in the context of adaptive performance. By integrating the concept of choking, or performing worse than expected, with goal theory, the present work advances a theoretical framework aimed at furthering our understanding of how and when GMA is most likely to meaningfully impact performance. Drawing on this perspective, we propose that the relationship between GMA and adaptive performance is uniquely dependent on the type of goal individuals are striving to achieve.

Methionine Antagonizes -Aminosalicylic Acid Activity via Affecting Folate Precursor Biosynthesis in .

-Aminosalicylic acid (PAS) is a second-line anti-tubercular drug that is used for the treatment of drug-resistant tuberculosis (TB). PAS efficacy in the treatment of TB is limited by its lower potency against relative to many other drugs in the TB treatment arsenal. It is known that intrinsic metabolites, such as, -aminobenzoic acid (PABA) and methionine, antagonize PAS and structurally related anti-folate drugs.

Wearable bluetooth sensors for capturing relational variables and temporal variability in relationships: A construct validation study.

The advent of wearable sensor technologies has the potential to transform organizational research by offering the unprecedented opportunity to collect continuous, objective, highly granular data over extended time periods. Recent evidence has demonstrated the potential utility of Bluetooth-enabled sensors, specifically, in identifying emergent networks via colocation signals in highly controlled contexts with known distances and groups. Although there is proof of concept that wearable Bluetooth sensors may be able to contribute to organizational research in highly controlled contexts, to date there has been no explicit psychometric construct validation effort dedicated to these sensors in field settings.

Pine Engravers Carry Bacterial Communities Whose Members Reduce Concentrations of Host Monoterpenes With Variable Degrees of Redundancy, Specificity, and Capability.

Bark beetles are eruptive forest insects that have the potential to cause landscape level mortality to conifer forests. The pine engraver, Ips pini (Say) (Coleoptera: Curculionidae), is the predominant pest of mature red pine (Pinus resinosa Aiton) plantations throughout the Great Lakes region of North America. Pine engraver attack elicits a localized response by host trees in which concentrations of terpenes rapidly exceed the tolerance levels of beetles and their fungal associates.

Imagining tomorrow's university in an era of open science.

As part of a recent workshop entitled "Imagining Tomorrow's University", we were asked to visualize the future of universities as research becomes increasingly data- and computation-driven, and identify a set of principles characterizing pertinent opportunities and obstacles presented by this shift. In order to establish a holistic view, we take a multilevel approach and examine the impact of open science on individual scholars and how this impacts as well as on the university as a whole. At the university level, open science presents a double-edged sword: when well executed, open science can accelerate the rate of scientific inquiry across the institution and beyond; however, haphazard or half-hearted efforts are likely to squander valuable resources, diminish university productivity and prestige, and potentially do more harm than good.

Personality similarity in negotiations: Testing the dyadic effects of similarity in interpersonal traits and the use of emotional displays on negotiation outcomes.

We build on the small but growing literature documenting personality influences on negotiation by examining how the joint disposition of both negotiators with respect to the interpersonal traits of agreeableness and extraversion influences important negotiation processes and outcomes. Building on similarity-attraction theory, we articulate and demonstrate how being similarly high or similarly low on agreeableness and extraversion leads dyad members to express more positive emotional displays during negotiation. Moreover, because of increased positive emotional displays, we show that dyads with such compositions also tend to reach agreements faster, perceive less relationship conflict, and have more positive impressions of their negotiation partner.

How functional traits, herbivory, and genetic diversity interact in Echinacea: implications for fragmented populations.

Habitat fragmentation produces small, spatially isolated populations that promote inbreeding. Remnant populations often contain inbred and outbred individuals, but it is unclear how inbreeding relative to outbreeding affects the expression of functional traits and biotic interactions such as herbivory. We measured a suite of 12 functional traits and herbivore damage on three genotypic cross types in the prairie forb, Echinacea angustifolia: inbred, and outbred crosses resulting from matings within and between remnant populations.

Underutilization of Radial Access in Patients Undergoing Percutaneous Coronary Intervention for ST-Segment-Elevation Myocardial Infarction: Insights From the Blue Cross Blue Shield of Michigan Cardiovascular Consortium.

Background: The purpose of this study was to evaluate the frequency and temporal trends in use of transradial access (TRA) for percutaneous coronary intervention (PCI) in ST-segment-elevation myocardial infarction (STEMI). The use of TRA has been associated with less bleeding and improved clinical outcomes in patients undergoing PCI for STEMI.

Methods And Results: The frequency of TRA compared with transfemoral access for patients undergoing PCI for STEMI or other indications (non-ST-segment-elevation myocardial infarction, unstable angina, and non-acute coronary syndrome) in The Blue Cross Blue Shield of Michigan Cardiovascular Consortium database between 2010 and 2013 was evaluated.

Cor triatriatum: a reversible cause of severe pulmonary hypertension.

Cor triatriatum sinister is a congenital heart disorder that can lead to progressive dyspnea, pulmonary hypertension, and ultimately right ventricular (RV) failure. We report a case in which symptoms of progressive pulmonary hypertension were initially attributed to asthma, leading to a delayed diagnosis that resulted in suprasystemic pulmonary pressures and RV dysfunction. Rapid symptomatic and hemodynamic improvement was observed after surgical repair, with normalization of pulmonary artery pressures and RV function.

A Practical Approach to Preventing Renal Complications in the Catheterization Laboratory.

Kidney injury following cardiac catheterization is an infrequent, though persistent, complication, which in some cases may be preventable. Patients at increased risk for renal complications following catheterization can be identified through individual and procedural risk factors, and several risk-prediction models are readily available. The authors advocate for the development of an easily implemented and standardized protocol, readily accessible to catheterization laboratory staff, for the identification and treatment of those patients who may be at increased risk for renal complications following cardiac catheterization.

Small sample mediation testing: misplaced confidence in bootstrapped confidence intervals.

Bootstrapping is an analytical tool commonly used in psychology to test the statistical significance of the indirect effect in mediation models. Bootstrapping proponents have particularly advocated for its use for samples of 20-80 cases. This advocacy has been heeded, especially in the Journal of Applied Psychology, as researchers are increasingly utilizing bootstrapping to test mediation with samples in this range.

Source-tract interaction with prescribed vocal fold motion.

An equation describing the time-evolution of glottal volume velocity with specified vocal fold motion is derived when the sub- and supra-glottal vocal tracts are present. The derivation of this Fant equation employs a property explicated in Howe and McGowan [(2011) J. Fluid Mech.

Physician variation in perceived barriers to personal health.

Objective: Physicians' personal health habits are associated with their counseling habits regarding physical activity. We sought to examine physicians' own barriers to a healthy lifestyle by level of training and gender.

Methods: Physicians at a major teaching hospital were surveyed regarding their lifestyle habits and barriers to healthy habits.