The discovery of 2-amino-3,5-diarylbenzamide inhibitors of IKK-alpha and IKK-beta kinases

A potent and selective series of 2-amino-3,5-diarylbenzamide inhibitors of IKK-alpha and IKK-beta is described. The most potent compounds are 8h, 8r and 8v, with IKK-beta inhibitory potencies of pIC(50) 7.0, 6.8 and 6.8, respectively. The series has excellent selectivity, both within the IKK family over IKK-epsilon, and across a wide variety of kinase assays. The potency of 8h in the IKK-beta enzyme assay translates to significant cellular activity (pIC(50) 5.7-6.1) in assays of functional and mechanistic relevance.     

Rigor-like structures from muscle myosins reveal key mechanical elements in the transduction pathways of this allosteric motor

Unlike processive cellular motors such as myosin V, whose structure has recently been determined in a "rigor-like" conformation, myosin II from contracting muscle filaments necessarily spends most of its time detached from actin. By using squid and sea scallop sources, however, we have now obtained similar rigor-like atomic structures for muscle myosin heads (S1). The significance of the hallmark closed actin-binding cleft in these crystal structures is supported here by actin/S1-binding studies. These structures reveal how different duty ratios, and hence cellular functions, of the myosin isoforms may be accounted for, in part, on the basis of detailed differences in interdomain contacts. Moreover, the rigor-like position of switch II turns out to be unique for myosin V. The overall arrangements of subdomains in the motor are relatively conserved in each of the known contractile states, and we explore qualitatively the energetics of these states.     

A comprehensive analysis of common copy-number variations in the human genome

Segmental copy-number variations (CNVs) in the human genome are associated with developmental disorders and susceptibility to diseases. More importantly, CNVs may represent a major genetic component of our phenotypic diversity. In this study, using a whole-genome array comparative genomic hybridization assay, we identified 3,654 autosomal segmental CNVs, 800 of which appeared at a frequency of at least 3%. Of these frequent CNVs, 77% are novel. In the 95 individuals analyzed, the two most diverse genomes differed by at least 9 Mb in size or varied by at least 266 loci in content. Approximately 68% of the 800 polymorphic regions overlap with genes, which may reflect human diversity in senses (smell, hearing, taste, and sight), rhesus phenotype, metabolism, and disease susceptibility. Intriguingly, 14 polymorphic regions harbor 21 of the known human microRNAs, raising the possibility of the contribution of microRNAs to phenotypic diversity in humans. This in-depth survey of CNVs across the human genome provides a valuable baseline for studies involving human genetics.     

Rectoanal Junction Colonization of Feedlot Cattle by Escherichia coli O157:H7 and Its Association with Supershedders and Excretion Dynamics

Feedlot cattle were observed for fecal excretion of and rectoanal junction (RAJ) colonization with Escherichia coli O157:H7 to identify potential “supershedders.” RAJ colonization and fecal excretion prevalences were correlated, and E. coli O157:H7 prevalences and counts were significantly greater for RAJ samples. Based on a comparison of RAJ and fecal ratios of E. coli O157:H7/E. coli counts, the RAJ appears to be preferentially colonized by the O157:H7 serotype. Five supershedders were identified based on persistent colonization with high concentrations of E. coli O157:H7. Cattle copenned with supershedders had significantly greater mean pen E. coli O157:H7 RAJ and fecal prevalences than noncopenned cattle. Cumulative fecal E. coli O157:H7 excretion was also significantly higher for pens housing a supershedder. E. coli O157:H7/E. coli count ratios were higher for supershedders than for other cattle, indicating greater proportional colonization. Pulsed-field gel electrophoresis analysis demonstrated that isolates from supershedders and copenned cattle were highly related. Cattle that remained negative for E. coli O157:H7 throughout sampling were five times more likely to have been in a pen that did not house a supershedder. The data from this study support an association between levels of fecal excretion of E. coli O157:H7 and RAJ colonization in pens of feedlot cattle and suggest that the presence of supershedders influences group-level excretion parameters. An improved understanding of individual and population transmission dynamics of E. coli O157:H7 can be used to develop preslaughter- and slaughter-level interventions that reduce contamination of the food chain.     

Vochysia palmirana (Vochysiaceae), a new species from Goiás and Tocantins,Brazil

Vochysia palmirana is described and illustrated as a new species. It is a member of sect.Vochysiella subsect.Decorticantes. It grows in sandy Cerrados of the Central Brazilian Plateau and is similar toV. sessilifolia. A key to the species ofVochysia sect.Vochysiella subsect.Decorticantes is provided.     

Surface re-engineering of pancreatic islets with recombinant azido-thrombomodulin

Chemoselective conjugation of an azido-functionalized thrombomodulin to pancreatic islets was achieved by Staudinger ligation to a surface-bound bifunctional poly(ethylene glycol) linker. The presence of the tethered thrombomodulin resulted in a significant increase in the production of activated protein C with a reduction in islet-mediated thrombogenicity. This report highlights the potential of tissue-targeted chemistry to reduce donor cell mediated procoagulant and proinflammatory responses.     

Male chicks are more costly to rear than females in a monogamous seabird, the Common Murre

Feeding rates and mass loss during chick rearing were comparedfor individually marked parents of male and female Common Murre(Uria aalge) chicks at Great Island, Newfoundland, Canada, from1997–2001. Both parents in this socially monogamous seabirdspecies share parental care duties until colony departure, afterwhich the single chick is fed only by its father. Because murresprovision their single chicks with one clearly visible fishper trip, it is possible to accurately determine whether parentsdifferentially feed male and female chicks. Based on slightlygreater mass of males in adulthood, possibly favored by sexdifferences in breeding roles, we predicted that male nestlingswould be fed more than females. Fathers' feeding rate to sons,but not daughters, increased with chick age, whereas maternalfeeding rate increased with chick age for both sexes. When year-correctedfeeding rates of pairs rearing both sexes were compared, bothmothers and fathers fed their sons significantly more than theirdaughters in the later part of the chick-rearing period. Moreover,parents rearing male chicks lost mass at a significantly higherrate than those rearing females. There was no difference infledging age for sons and daughters. These results indicatethat differential parental allocation occurs and has measurablecosts even in a species with only slight adult sexual dimorphism.     

Spinal loading during manual materials handling in a kneeling posture.

Stooped, restricted, kneeling, and other awkward postures adopted during manual materials handling have frequently been associated with LBP onset. However, lift assessment tools have focused on materials handling performed in an upright, or nearly upright standing posture. Unfortunately, many of the tools designed to analyze standing postures are not easily adapted to jobs requiring restricted postures. Therefore, the objective of this study was to evaluate spinal loading during manual materials handing in kneeling postures and determine if those loads can be predicted using simple regression. An EMG-driven biomechanical model, previously validated for upright lifting, was adapted for use in kneeling tasks. Subjects knelt under a 1.07m ceiling and lifted luggage of six weights (6.8, 10.9, 15.0, 19.1, 23.1 and, 27.2kgf) to one of four destination heights (0, 25.4, 53.3, 78.7cm). Spine loading was significantly affected by both destination height and load weight. Destination height increased compression, AP shear and lateral shear by an average of 14.5, 3.7 and 6.6N respectively per cm height increase. Load weight increased compression, AP shear and lateral shear by an average of 83.8, 27.0 and 13.1N respectively per kgf lifted. Regression equations were developed to predict peak spine loading using subject height, load weight and destination height with R(2) values of 0.62, 0.51 and 0.57 for compression, AP and lateral shear respectively.     

The relevance of pedigrees in the conservation genomics era

Over the past 50 years conservation genetics has developed a substantive toolbox to inform species management. One of the most long-standing tools available to manage genetics—the pedigree—has been widely used to characterize diversity and maximize evolutionary potential in threatened populations. Now, with the ability to use high throughput sequencing to estimate relatedness, inbreeding, and genome-wide functional diversity, some have asked whether it is warranted for conservation biologists to continue collecting and collating pedigrees for species management. In this perspective, we argue that pedigrees remain a relevant tool, and when combined with genomic data, create an invaluable resource for conservation genomic management. Genomic data can address pedigree pitfalls (e.g., founder relatedness, missing data, uncertainty), and in return robust pedigrees allow for more nuanced research design, including well-informed sampling strategies and quantitative analyses (e.g., heritability, linkage) to better inform genomic inquiry. We further contend that building and maintaining pedigrees provides an opportunity to strengthen trusted relationships among conservation researchers, practitioners, Indigenous Peoples, and Local Communities.