Small molecule antagonists of the CCR2b receptor. Part 2: Discovery process and initial structure-activity relationships of diamine derivatives

Structure-activity relationships (SAR) of a weakly active class of CCR2b inhibitors were utilized to initiate a lead evolution program employing the Drug Discovery Engine. Several alternative structural series have been discovered that display nanomolar activity in the CCR2b binding and CCR2b-mediated chemotaxis assays.     

Woodland caribou habitat selection patterns in relation to predation risk and forage abundance depend on reproductive state

The ideal free distribution assumes that animals select habitats that are beneficial to their fitness. When the needs of dependent offspring differ from those of the parent, ideal habitat selection patterns could vary with the presence or absence of offspring. We test whether habitat selection depends on reproductive state due to top‐down or bottom‐up influences on the fitness of woodland caribou (Rangifer tarandus caribou), a threatened, wide‐ranging herbivore. We combined established methods of fitting resource and step selection functions derived from locations of collared animals in Ontario with newer techniques, including identifying calf status from video collar footage and seasonal habitat selection analysis through latent selection difference functions. We found that females with calves avoided predation risk and proximity to roads more strongly than females without calves within their seasonal ranges. At the local scale, females with calves avoided predation more strongly than females without calves. Females with calves increased predation avoidance but not selection for food availability upon calving, whereas females without calves increased selection for food availability across the same season. These behavioral responses suggest that habitat selection by woodland caribou is influenced by reproductive state, such that females with calves at heel use habitat selection to offset the increased vulnerability of their offspring to predation risk.     

Topoisomerase 3α Is Required for Decatenation and Segregation of Human mtDNA

1. Download high-res image (186KB)
2. Download full-size image

     

Diet and dental topography in pitheciine seed predators

Pitheciines (Pithecia, Chiropotes, and Cacajao) are a specialized clade of Neotropical seed predators that exhibit postcanine teeth with low and rounded cusps and highly crenulated occlusal surface enamel. Data on feeding ecology show that Pithecia consumes proportionally more leaves than other pitheciine species, and comparative studies demonstrate its greater molar relief and relative shearing potential. However, data on pitheciine food mechanics show that Pithecia masticates seeds with greater crushing resistance than those preferred by Chiropotes. This variation predicts an opposing morphology characterized by low and more rounded occlusal surfaces in Pithecia. We build on previous research using new methods for molar surface shape quantification by examining pitheciine second molar shearing crest length, occlusal relief, surface complexity, and surface curvature relative to nonseed specializing platyrrhines and within the context of the observed interspecific variation in pitheciine feeding ecology. Consistent with the previous analyses, our findings demonstrate that pitheciine molars exhibit low shearing, relief, and curvature compared with nonseed predators, independent of phylogeny. Pitheciines also exhibit highly “complex” occlusal topography that promotes the efficient breakdown of tough seed tissues. Overall, Pithecia, Chiropotes, and Cacajao share a similar topographic pattern, suggesting adaptation to foods with similar structural and/or mechanical properties. However, Cacajao differs in surface complexity, which reflects some variation in its feeding ecology. Contrary to the predictions, Pithecia and Chiropotes do not differ in any of the topographic variables examined. The range of demands imposed on the postcanine teeth of Pithecia might therefore select for an average topography, one that converges on that of Chiropotes. Am J Phys Anthropol, 2013. © 2012 Wiley Periodicals, Inc.     

Hepatitis C Virus Variants with Decreased Sensitivity to Direct-Acting Antivirals (DAAs) Were Rarely Observed in DAA-Naive Patients prior to Treatment

The prevalence of naturally occurring hepatitis C virus (HCV) variants that are less sensitive to direct-acting antiviral (DAA) inhibitors has not been fully characterized. We used population sequence analysis to assess the frequency of such variants in plasma samples from 3,447 DAA-naive patients with genotype 1 HCV. In general, HCV variants with lower-level resistance (3- to 25-fold increased 50% inhibitor concentration [IC₅₀]) to telaprevir were observed as the dominant species in 0 to 3% of patients, depending on the specific variant, whereas higher-level resistant variants (>25-fold-increased IC₅₀) were not observed. Specific variants resistant to NS5A inhibitors were predominant in up to 6% of patients. Most variants resistant to nucleo(s/t)ide active-site NS5B polymerase inhibitors were not observed, whereas variants resistant to non-nucleoside allosteric inhibitors were observed in up to 18% of patients. The presence of DAA-resistant variants in NS5A, NS5B, or NS3 (including telaprevir-resistant variants), in baseline samples of treatment-naive patients receiving a telaprevir-based regimen in phase 3 studies did not affect the sustained viral response (SVR). Treatment-naive patients with viral populations containing the telaprevir-resistant variants NS3 V36M, T54S, or R155K at baseline achieved a 74% SVR rate, whereas patients with no resistant variants detected prior to treatment achieved a 76% SVR rate. The effect of specific resistant variant frequency on response to various DAA treatments in different patient populations, including interferon nonresponders, should be further studied.     

The white race is shrinking: Perceptions of race in Canada and some speculations on the political economy of race classification

Movements for the recognition and official establishment of particular languages in India, among the many hundreds that have been identified and classified by linguists, grammarians, and census takers, have been prominent and recurring features of politics in the subcontinent for a century-and-a-half. These movements have invariably been competitive in character, demanding preference for one, and displacement of other, actual or potential rivals. Further, they have sometimes been associated with hostile and venomous characterizations of both a rival language and its speakers, leading to intercommunal/interethnic violence. Despite the turbulent history of such movements in modern India, viable compromises have been reached concerning the status of the multiplicity of Indian languages and their hierarchical ordering for various purposes. These compromises, however, have profound consequences for the life chances, including the empowerment and disempowerment, of all India’s citizens. These consequences have only recently begun to attract scholarly attention.     

Dance Education Matters: Rebuilding Postsecondary Dance Education for Twenty-First Century Relevance and Resonance

Postsecondary dance education is at a crucial juncture in its history in academe. Emerging from women's physical education programs in the 1930s, the profession's realignment with the arts broadly and arts-based education specifically has been characterized by ambitious goals and steady growth through the 1990s. However, a number of critical developments over the past decade have displaced many previous gains and undermined the overall stability and integrity of the field. Four primary challenges are investigated in this article: curricular equity, expansive dance education programs, graduate study opportunities, and national leadership. I urge dance educators and administrators to re-envision and expand P–12 dance education in the liberal arts tradition to include private studio, commercial-sector dance in community and related teaching professions. This article provides recommendations and strategies for developing relevant and resonant twenty-first-century dance education programs beyond current confines.     

Prokaryotic Super Program Advisory Committee DOE Joint Genome Institute,Walnut Creek,CA, March 27, 2013

The Prokaryotic Super Program Advisory Committee met on March 27, 2013 for their annual review the Prokaryotic Super Program at the DOE Joint Genome Institute. As is the case with any site visit or program review, the objective is to evaluate progress in meeting organizational objectives, provide feedback to from the user-community and to assist the JGI in formulating plans for the coming year. The advisors want to commend the JGI for its central role in developing new technologies and capabilities, and for catalyzing the formation of new collaborative user communities. Highlights of the post-meeting exchanges among the advisors focused on the importance of programmatic initiatives including:• GEBA, which serves as a phylogenetic “base-map” on which our knowledge of functional diversity can be layered.• FEBA, which promises to provide new insights into the physiological capabilities of prokaryotes under highly standardized conditions.• Single-cell genomics technology, which is seen to significantly enhance our ability to interpret genomic and metagenomic data and broaden the scope of the GEBA program to encompass at least a part of the microbial “dark-matter”.• IMG, which is seen to play a central role in JGI programs and is viewed as a strategically important asset in the JGI portfolio.On this latter point, the committee encourages the formation of a strategic relationship between IMG and the Kbase to ensure that the intelligence, deep knowledge and experience captured in the former is not lost. The committee strongly urges the DOE to continue its support for maintaining this critical resource.     

In vitro and in vivo application of RNA interference for targeting genes involved in peritrophic matrix synthesis in a lepidopteran system

Abstract The midgut of most insects is lined with a semipermeable acellular tube, the peritrophic matrix (PM), composed of chitin and proteins. Although various genes encoding PM proteins have been characterized, our understanding of their roles in PM structure and function is very limited. One promising approach for obtaining functional information is RNA interference, which has been used to reduce the levels of specific mRNAs using double‐stranded RNAs administered to larvae by either injection or feeding. Although this method is well documented in dipterans and coleopterans, reports of its success in lepidopterans are varied. In the current study, the silencing midgut genes encoding PM proteins (insect intestinal mucin 1, insect intestinal mucin 4, PM protein 1) and the chitin biosynthetic or modifying enzymes (chitin synthase‐B and chitin deacetylase 1) in a noctuid lepidopteran, Mamestra configurata, was examined in vitro and in vivo. In vitro studies in primary midgut epithelial cell preparations revealed an acute and rapid silencing (by 24 h) for the gene encoding chitin deacetylase 1 and a slower rate of silencing (by 72 h) for the gene encoding PM protein 1. Genes encoding insect intestinal mucins were slightly silenced by 72 h, whereas no silencing was detected for the gene encoding chitin synthase‐B. In vivo experiments focused on chitin deacetylase 1, as the gene was silenced to the greatest extent in vitro. Continuous feeding of neonates and fourth instar larvae with double‐stranded RNA resulted in silencing of chitin deacetylase 1 by 24 and 36 h, respectively. Feeding a single dose to neonates also resulted in silencing by 24 h. The current study demonstrates that genes encoding PM proteins can be silenced and outlines conditions for RNA interference by per os feeding in lepidopterans.