A novel series of IKKβ inhibitors part II: description of a potent and pharmacologically active series of analogs

A novel series of (E)-1-((2-(1-methyl-1H-imidazol-5-yl) quinolin-4-yl) methylene) thiosemicarbazides was discovered as potent inhibitors of IKKβ. In this Letter we document our efforts at further optimization of this series, culminating in 2 with submicromolar potency in a HWB assay and efficacy in a CIA mouse model.     

Durable broad-spectrum powdery mildew resistance in pea er1 plants is conferred by natural loss-of-function mutations in PsMLO1

Loss-of-function alleles of plant-specific MLO (Mildew Resistance Locus O) genes confer broad-spectrum powdery mildew resistance in monocot (barley) and dicot (Arabidopsis thaliana, tomato) plants. Recessively inherited powdery mildew resistance in pea (Pisum sativum) er1 plants is, in many aspects, reminiscent of mlo-conditioned powdery mildew immunity, yet the underlying gene has remained elusive to date. We used a polymerase chain reaction (PCR)-based approach to amplify a candidate MLO cDNA from wild-type (Er1) pea. Sequence analysis of the PsMLO1 candidate gene in two natural er1 accessions from Asia and two er1-containing pea cultivars with a New World origin revealed, in each case, detrimental nucleotide polymorphisms in PsMLO1, suggesting that PsMLO1 is Er1. We corroborated this hypothesis by restoration of susceptibility on transient expression of PsMLO1 in the leaves of two resistant er1 accessions. Orthologous legume MLO genes from Medicago truncatula and Lotus japonicus likewise complemented the er1 phenotype. All tested er1 genotypes showed unaltered colonization with the arbuscular mycorrhizal fungus, Glomus intraradices, and with nitrogen-fixing rhizobial bacteria. Our data demonstrate that PsMLO1 is Er1 and that the loss of PsMLO1 function conditions durable broad-spectrum powdery mildew resistance in pea.     

Multiple loci are associated with white blood cell phenotypes

White blood cell (WBC) count is a common clinical measure from complete blood count assays, and it varies widely among healthy individuals. Total WBC count and its constituent subtypes have been shown to be moderately heritable, with the heritability estimates varying across cell types. We studied 19,509 subjects from seven cohorts in a discovery analysis, and 11,823 subjects from ten cohorts for replication analyses, to determine genetic factors influencing variability within the normal hematological range for total WBC count and five WBC subtype measures. Cohort specific data was supplied by the CHARGE, HeamGen, and INGI consortia, as well as independent collaborative studies. We identified and replicated ten associations with total WBC count and five WBC subtypes at seven different genomic loci (total WBC count-6p21 in the HLA region, 17q21 near ORMDL3, and CSF3; neutrophil count-17q21; basophil count- 3p21 near RPN1 and C3orf27; lymphocyte count-6p21, 19p13 at EPS15L1; monocyte count-2q31 at ITGA4, 3q21, 8q24 an intergenic region, 9q31 near EDG2), including three previously reported associations and seven novel associations. To investigate functional relationships among variants contributing to variability in the six WBC traits, we utilized gene expression- and pathways-based analyses. We implemented gene-clustering algorithms to evaluate functional connectivity among implicated loci and showed functional relationships across cell types. Gene expression data from whole blood was utilized to show that significant biological consequences can be extracted from our genome-wide analyses, with effect estimates for significant loci from the meta-analyses being highly corellated with the proximal gene expression. In addition, collaborative efforts between the groups contributing to this study and related studies conducted by the COGENT and RIKEN groups allowed for the examination of effect homogeneity for genome-wide significant associations across populations of diverse ancestral backgrounds.     

OTUbase: an R infrastructure package for operational taxonomic unit data

SUMMARY: OTUbase is an R package designed to facilitate the analysis of operational taxonomic unit (OTU) data and sequence classification (taxonomic) data. Currently there are programs that will cluster sequence data into OTUs and/or classify sequence data into known taxonomies. However, there is a need for software that can take the summarized output of these programs and organize it into easily accessed and manipulated formats. OTUbase provides this structure and organization within R, to allow researchers to easily manipulate the data with the rich library of R packages currently available for additional analysis. AVAILABILITY: OTUbase is an R package available through Bioconductor. It can be found at http://www.bioconductor.org/packages/release/bioc/html/OTUbase.html.     

A new approach to determining environmental flow requirements: Sustaining the natural values of floodplains of the southern Murray‐Darling Basin

Summary Large overbank flood events play an important role in maintaining large‐scale ecological processes and connectivity along and across the floodplains and between the rivers and their floodplains in the southern Murray‐Darling Basin. However, the regulation of rivers means that extensive overbank flooding can only occur in the rare circumstance of extreme flood events. Recent environmental water allocations have focussed on the largest floodplain blocks (‘icon’ sites) and a small set of specific values (e.g. colonial nesting waterbirds), as well as on trialling fine‐scale manipulation of infrastructure (e.g. pumping) to water relatively small areas. There has been no comprehensive systematic assessment of the entire floodplain and its wider set of flood‐dependent natural assets (such as ecosystems and species; herein referred to as ‘natural values’) to maximise the effectiveness of environmental water use and to catalogue values likely to be lost. This paper describes an assessment of some 220 000 ha found to support flood‐dependent natural values in Victoria. We mapped the geographic distribution and estimated components of the flooding requirements (natural flooding frequency, and maximum period without flooding and minimum duration of each flooding event before significant deterioration) for each natural value. Using an example of one stretch of the River Murray, we show how the resultant spatial data can be used with floodplain inundation modelling to compare the outcomes of real or planned environmental watering events; potentially providing tools for management agencies to conserve a wider range of floodplain values than is currently the case. That is, water managers and the public can see what ecosystems and threatened species are intended to be maintained by environmental watering and what values are intended to be abandoned across the whole floodplain, rather than just seeing the small subset of values and ‘icon’ sites that are intended to be maintained. Examples are provided to illustrate how information about the location, water requirements and extent covered by potential floods for specific values can be used to build adaptive watering strategies for areas as large as the whole floodplain.