Credibility and Policy Convergence: Evidence from U.S. House Roll Call Voting Records

Traditional models of politician behavior predict complete or partial policy convergence, whereby electoral competition compels partisan politicians to choose positions more moderate than their most-preferred policies. Alternatively, if politicians cannot overcome the inability to make binding pre-commitments to policies, the expected result is complete policy divergence. By exploiting a regression discontinuity (RD) design inherent in the Congressional electoral system, this paper empirically tests the strong predictions of the complete divergence hypothesis against the alternative of partial convergence within the context of Representatives' roll call voting behavior in the U.S. House (1946-1994). The RD design implies that which party wins a district seat is quasi-randomly assigned among elections that turn out to be 'close'. We use this variation to examine if Representatives' roll call voting patterns do not respond to large exogenous changes in the probability of winning the election, the strong prediction of complete policy divergence. The evidence is more consistent with full divergence and less consistent with partial convergence, suggestive that the difficulty of establishing credible commitments to policies is an important real-world phenomenon.

Natural product libraries: Assembly, maintenance, and screening

This review discusses successful strategies and potential pitfalls to assembling a natural product-based library suitable for high-throughput screening. Specific extraction methods for plants, microorganisms, and marine invertebrates are detailed, along with methods for generating a fractionated sub-library. The best methods to store, maintain and prepare the library for screening are addressed, as well as recommendations on how to develop a robust high-throughput assay. Finally, the logistics of moving from an assay hit to pure bioactive compound are discussed

Ramoplanin at bactericidal concentrations induces bacterial membrane depolarization in Staphylococcus aureus

Ramoplanin is an actinomycetes-derived antibiotic with broad-spectrum activity against Gram-positive bacteria that has been evaluated in clinical trials for the treatment of gastrointestinal vancomycin-resistant enterococci (VRE) and Clostridium difficile infections. Recent studies have proposed that ramoplanin binds to bacterial membranes as a C2 symmetrical dimer that can sequester Lipid II, which causes inhibition of cell wall peptidoglycan biosynthesis and cell death. In this study, ramoplanin was shown to bind to anionic and zwitterionic membrane mimetics with a higher affinity for anionic membranes and to induce membrane depolarization of methicillin-susceptible Staphylococcus aureus (MSSA) ATCC 25923 at concentrations at or above the minimal bactericidal concentration (MBC). The ultrastructural effects of ramoplanin on S. aureus were also examined by transmission electron microscopy (TEM), and this showed dramatic changes to bacterial cell morphology. The correlation observed between membrane depolarization and bacterial cell viability suggests that this mechanism may contribute to the bactericidal activity of ramoplanin

Association Between High Perceived Stress Over Time and Incident Hypertension in Black Adults: Findings From the Jackson Heart Study.

Background Chronic psychological stress has been associated with hypertension, but few studies have examined this relationship in blacks. We examined the association between perceived stress levels assessed annually for up to 13 years and incident hypertension in the Jackson Heart Study, a community-based cohort of blacks. Methods and Results Analyses included 1829 participants without hypertension at baseline (Exam 1, 2000-2004). Incident hypertension was defined as blood pressure≥140/90 mm Hg or antihypertensive medication use at Exam 2 (2005-2008) or Exam 3 (2009-2012). Each follow-up interval at risk of hypertension was categorized as low, moderate, or high perceived stress based on the number of annual assessments between exams in which participants reported "a lot" or "extreme" stress over the previous year (low, 0 high stress ratings; moderate, 1 high stress rating; high, ≥2 high stress ratings). During follow-up (median, 7.0 years), hypertension incidence was 48.5%. Hypertension developed in 30.6% of intervals with low perceived stress, 34.6% of intervals with moderate perceived stress, and 38.2% of intervals with high perceived stress. Age-, sex-, and time-adjusted risk ratios (95% CI) associated with moderate and high perceived stress versus low perceived stress were 1.19 (1.04-1.37) and 1.37 (1.20-1.57), respectively (P trend<0.001). The association was present after adjustment for demographic, clinical, and behavioral factors and baseline stress (P trend=0.001). Conclusions In a community-based cohort of blacks, higher perceived stress over time was associated with an increased risk of developing hypertension. Evaluating stress levels over time and intervening when high perceived stress is persistent may reduce hypertension risk

A National Strategy for the Conservation of Native Freshwater Mollusks

In 1998, a strategy document outlining the most pressing issues facing the conservation of freshwater mussels was published (NNMCC 1998). Beginning in 2011, the Freshwater Mollusk Conservation Society began updating that strategy, including broadening the scope to include freshwater snails. Although both strategy documents contained 10 issues that were deemed priorities for mollusk conservation, the identity of these issues has changed. For example, some issues (e.g., controlling dreissenid mussels, technology to propagate and reintroduce mussels, techniques to translocate adult mussels) were identified in the 1998 strategy, but are less prominent in the revised strategy, due to changing priorities and progress that has been made on these issues. In contrast, some issues (e.g., biology, ecology, habitat, funding) remain prominent concerns facing mollusk conservation in both strategies. In addition, the revised strategy contains a few issues (e.g., newly emerging stressors, education and training of the next generation of resource managers) that were not explicitly present in the 1998 strategy. The revised strategy states that to effectively conserve freshwater mollusks, we need to (1) increase knowledge of their distribution and taxonomy at multiple scales; (2) address the impacts of past, ongoing, and newly emerging stressors; (3) understand and conserve the quantity and quality of suitable habitat; (4) understand their ecology at the individual, population, and community levels; (5) restore abundant and diverse populations until they are self-sustaining; (6) identify the ecosystem services provided by mollusks and their habitats; (7) strengthen advocacy for mollusks and their habitats; (8) educate and train the conservation community and future generations of resource managers and researchers; (9) seek long-term funding to support conservation efforts; and (10) coordinate development of an updated and revised strategy every 15 years. Collectively addressing these issues should strengthen conservation efforts for North American freshwater mollusks

Antimicrobial octapeptin C4 analogues active against Cryptococcus species

Resistance to antimicrobials is a growing problem in both developed and developing countries. In nations where AIDS is most prevalent, the human fungal pathogen Cryptococcus neoformans is a significant contributor to mortality, and its growing resistance to current antifungals an ever-expanding threat. We investigated octapeptin C4, from the cationic cyclic lipopeptide class of antimicrobials, as a potential new antifungal. Octapeptin C4 was a potent, selective inhibitor of this fungal pathogen with minimum inhibitory concentration of 1.56 μg/mL. Further testing of octapeptin C4 against 40 clinical isolates of C. neoformans var. grubii or neoformans showed MIC 1.56-3.13 μg/mL while 20 clinical isolates of C. neoformans var. gattii had MIC 0.78-12.5 μg/mL. In each case MIC values for octapeptin C4 were equivalent to, or better than, current antifungal drugs fluconazole and amphotericin B. The negatively charged polysaccharide capsule of C. neoformans influences the pathogens sensitivity to octapeptin C4 while degree of melanisation had little effect. Testing synthetic octapeptin C4 derivatives provided insight into the structure activity relationships, revealing that the lipophilic amino acid moieties are more important to the activity than the cationic diaminobutyric acid groups. Octapeptins have promising potential for development as anticryptococcal therapeutic agents

Mucin binding reduces colistin antimicrobial activity

Colistin has found increasing use in treating drug-resistant bacterial lung infections, but potential interactions with pulmonary biomolecules have not been investigated. We postulated that colistin, like aminoglycoside antibiotics, may bind to secretory mucin in sputum or epithelial mucin that lines airways, reducing free drug levels. To test this hypothesis, we measured binding of colistin and other antibiotics to porcine mucin, a family of densely glycosylated proteins used as a surrogate for human sputum and airway mucin. Antibiotics were incubated in dialysis tubing with or without mucin, and concentrations of unbound antibiotics able to penetrate the dialysis tubing were measured over time using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The percentage of antibiotic measured in the dialysate after 4 h in the presence of mucin, relative to the amount without mucin, was 15% for colistin, 16% for polymyxin B, 19% for tobramycin, 52% for ciprofloxacin, and 78% for daptomycin. Antibiotics with the strongest mucin binding had an overall polybasic positive charge, whereas those with comparatively little binding were less basic. When comparing MICs measured with or without added mucin, colistin and polymyxin B showed >100-fold increases in MICs for multiple Gram-negative bacteria. Preclinical evaluation of mucin binding should become a standard procedure when considering the potential pulmonary use of new or existing antibiotics, particularly those with a polybasic overall charge. In the airways, mucin binding may reduce the antibacterial efficacy of inhaled or intravenously administered colistin, and the presence of sub-MIC effective antibiotic concentrations could result in the development of antibiotic resistance

Biofluid spectroscopic disease diagnostics : a review on the processes and spectral impact of drying

The complex patterns observed from evaporated liquid drops have been examined extensively over the last 20 years. Complete understanding of drop deposition is vital in many medical processes, and one which is essential to the translation of biofluid spectroscopic disease diagnostics. The promising use of spectroscopy in disease diagnosis has been hindered by the complicated patterns left by dried biological fluids which may inhibit the clinical translation of this technology. Coffee ring formation, cracking and gelation patterns have all been observed in biofluid drops, and with surface homogeneity being a key element to many spectroscopic techniques, experimental issues have been found to arise. A better understanding of the fundamental processes involved in a drying droplet could allow efficient progression in this research field, and ultimately benefit the population with the development of a reliable cancer diagnostic

Bioprocess monitoring applications of an innovative ATR-FTIR spectroscopy platform

Pharmaceutical manufacturing is reliant upon bioprocessing approaches to generate the range of therapeutic products that are available today. The high cost of production, susceptibility to process failure, and requirement to achieve consistent, high-quality product means that process monitoring is paramount during manufacturing. Process analytic technologies (PAT) are key to ensuring high quality product is produced at all stages of development. Spectroscopy-based technologies are well suited as PAT approaches as they are non-destructive and require minimum sample preparation. This study explored the use of a novel attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy platform, which utilises disposable internal reflection elements (IREs), as a method of upstream bioprocess monitoring. The platform was used to characterise organism health and to quantify cellular metabolites in growth media using quantification models to predict glucose and lactic acid levels both singularly and combined. Separation of the healthy and nutrient deficient cells within PC space was clearly apparent, indicating this technique could be used to characterise these classes. For the metabolite quantification, the binary models yielded R2 values of 0.969 for glucose, 0.976 for lactic acid. When quantifying the metabolites in tandem using a multi-output partial least squares model, the corresponding R2 value was 0.980. This initial study highlights the suitability of the platform for bioprocess monitoring and paves the way for future in-line developments