An orally available,brain-penetrant CAMKK2 inhibitor reduces food intake in rodent model

Hypothalamic CAMKK2 represents a potential mechanism for chemically affecting satiety and promoting weight loss in clinically obese patients. Single-digit nanomolar inhibitors of CAMKK2 were identified in three related ATP-competitive series. Limited optimization of kinase selectivity, solubility, and pharmacokinetic properties were undertaken on all three series, as SAR was often transferrable. Ultimately, a 2,4-diaryl 7-azaindole was optimized to afford a tool molecule that potently inhibits AMPK phosphorylation in a hypothalamus-derived cell line, is orally bioavailable, and crosses the blood–brain barrier. When dosed orally in rodents, compound 4?t limited ghrelin-induced food intake.     

Density and genetic structure of black bears in coastal South Carolina

The frequency of black bear (Ursus americanus) sightings, vehicle collisions, and nuisance incidents in the coastal region of South Carolina has increased over the past 4 decades. To develop the statewide Black Bear Management and Conservation Strategy, the South Carolina Department of Natural Resources needed reliable information for the coastal population. Because no such data were available, we initiated a study to determine population density and genetic structure of black bears. We selected 2 study areas that were representative of the major habitat types in the study region: Lewis Ocean Bay consisted primarily of Carolina Bays and pocosin habitats, whereas Carvers Bay was representative of extensive pine plantations commonly found in the region. We established hair snares on both study areas to obtain DNA from hair samples during 8 weekly sampling periods in 2008 and again in 2009. We used genotypes to obtain capture histories of sampled bears. We estimated density using spatially explicit capture–recapture (SECR) models and used information-theoretic procedures to fit parameters for capture heterogeneity and behavioral responses and to test if density and model parameters varied by year. Model-averaged density was 0.046 bears/km² (SE = 0.011) for Carvers Bay and 0.339 bears/km² (SE = 0.056) for Lewis Ocean Bay. Next, we sampled habitat covariates for all locations in the SECR sampling grid to derive spatially explicit estimates of density based on habitat characteristics. Addition of habitat covariates had substantial support, and accounted for differences in density between Carvers Bay and Lewis Ocean Bay; black bear density showed a negative association with the area of pine forests (4.5-km² scale) and a marginal, positive association with the area of pocosin habitat (0.3-km² scale). Bear density was not associated with pine forest at a smaller scale (0.3-km²), nor with major road density or an index of largest patch size. Predicted bear densities were low throughout the coastal region and only a few larger areas had high predicted densities, most of which were centered on public lands (e.g., Francis Marion National Forest, Lewis Ocean Bay). We sampled a third bear population in the Green Swamp area of North Carolina for genetic structure analyses and found no evidence of historic fragmentation among the 3 sampled populations. Neither did we find evidence of more recent barriers to gene exchange; with the exception of 1 recent migrant, Bayesian population assignment techniques identified only a single population cluster that incorporated all 3 sampled areas. Bears in the region may best be managed as 1 population. If the goal is to maintain or increase bear densities, demographic connectivity of high-density areas within the low-density landscape matrix is a key consideration and managers would need to mitigate potential impacts of planned highway expansions and anticipated development. Because the distribution of black bears in coastal South Carolina is not fully known, the regional map of potential black bear density can be used to identify focal areas for management and sites that should be surveyed for occupancy or where more intensive studies are needed. © 2012 The Wildlife Society.     

Simultaneous improvement in productivity,water use,and albedo through crop structural modification

Spanning 15% of the global ice‐free terrestrial surface, agricultural lands provide an immense and near‐term opportunity to address climate change, food, and water security challenges. Through the computationally informed breeding of canopy structural traits away from those of modern cultivars, we show that solutions exist that increase productivity and water use efficiency, while increasing land‐surface reflectivity to offset greenhouse gas warming. Plants have evolved to maximize capture of radiation in the upper leaves, thus shading competitors. While important for survival in the wild, this is suboptimal in monoculture crop fields for maximizing productivity and other biogeophysical services. Crop progenitors evolved over the last 25 million years in an atmosphere with less than half the [CO₂] projected for 2050. By altering leaf photosynthetic rates, rising [CO₂] and temperature may also alter the optimal canopy form. Here using soybean, the world's most important protein crop, as an example we show by applying optimization routines to a micrometeorological leaf canopy model linked to a steady‐state model of photosynthesis, that significant gains in production, water use, and reflectivity are possible with no additional demand on resources. By modifying total canopy leaf area, its vertical profile and angular distribution, and shortwave radiation reflectivity, all traits available in most major crop germplasm collections, increases in productivity (7%) are possible with no change in water use or albedo. Alternatively, improvements in water use (13%) or albedo (34%) can likewise be made with no loss of productivity, under Corn Belt climate conditions.     

Sepsis induces apoptosis and profound depletion of splenic interdigitating and follicular dendritic cells

Dendritic cells are a phenotypically diverse group of APC that have unique capabilities to regulate the activity and survival of B and T cells. Although proper function of dendritic cells is essential to host control of invading pathogens, few studies have examined the impact of sepsis on dendritic cells. The purpose of this study was to determine the effect of sepsis on splenic interdigitating dendritic cells (IDCs) and follicular dendritic cells (FDCs) using a clinically relevant animal model. Immunohistochemical staining for FDCs showed that sepsis induced an initial marked expansion in FDCs that peaked at 36 h after onset. The FDCs expanded to fill the entire lymphoid zone otherwise occupied by B cells. Between 36 and 48 h after sepsis, there was a profound caspase 3 mediated apoptosis induced depletion of FDCs such that only a small contingent of cells remained. In contrast to the initial increase in FDCs, IDC numbers were decreased to approximately 50% of control by 12 h after onset of sepsis. IDC death occurred by caspase 3-mediated apoptosis. Such profound apoptosis induced loss of FDCs and IDCs may significantly compromise B and T cell function and impair the ability of the host to survive sepsis.     

A covariotide model explains apparent phylogenetic structure of oxygenic photosynthetic lineages

The aims of the work were (1) to develop statistical tests to identify whether substitution takes place under a covariotide model in sequences used for phylogenetic inference and (2) to determine the influence of covariotide substitution on phylogenetic trees inferred for photosynthetic and other organisms. (Covariotide and covarion models are ones in which sites that are variable in some parts of the underlying tree are invariable in others and vice versa.) Two tests were developed. The first was a contingency test, and the second was an inequality test comparing the expected number of variable sites in two groups with the observed number. Application of these tests to 16S rDNA and tufA sequences from a range of nonphotosynthetic prokaryotes and oxygenic photosynthetic prokaryotes and eukaryotes suggests the occurrence of a covariotide mechanism. The degree of support for partitioning of taxa in reconstructed trees involving these organisms was determined in the presence or absence of sites showing particular substitution patterns. This analysis showed that the support for splits between (1) photosynthetic eukaryotes and prokaryotes and (2) photosynthetic and nonphotosynthetic organisms could be accounted for by patterns arising from covariotide substitution. We show that the additional problem of compositional bias in sequence data needs to be considered in the context of patterns of covariotide/covarion substitution. We argue that while covariotide or covarion substitution may give rise to phylogenetically informative patterns in sequence data, this may not always be so.      

2-Amino-4,6-diarylpyridines as novel ligands for the estrogen receptor.

We have prepared a novel series of 2-amino-4,6-diarylpyridines that function as ligands of estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta). These compounds bind to both ERalpha and ERbeta with a modest selectivity for the alpha subtype. The most potent of these analogues, compound 19, has a K(i)=20nM at ERalpha. These molecules represent a novel template for designing potentially useful ligands for the estrogen receptor.     

Influence of nutrients and currents on the genomic composition of microbes across an upwelling mosaic

Metagenomic data sets were generated from samples collected along a coastal to open ocean transect between Southern California Bight and California Current waters during a seasonal upwelling event, providing an opportunity to examine the impact of episodic pulses of cold nutrient-rich water into surface ocean microbial communities. The data set consists of ∼5.8 million predicted proteins across seven sites, from three different size classes: 0.1–0.8, 0.8–3.0 and 3.0–200.0 μm. Taxonomic and metabolic analyses suggest that sequences from the 0.1–0.8 μm size class correlated with their position along the upwelling mosaic. However, taxonomic profiles of bacteria from the larger size classes (0.8–200 μm) were less constrained by habitat and characterized by an increase in Cyanobacteria, Bacteroidetes, Flavobacteria and double-stranded DNA viral sequences. Functional annotation of transmembrane proteins indicate that sites comprised of organisms with small genomes have an enrichment of transporters with substrate specificities for amino acids, iron and cadmium, whereas organisms with larger genomes have a higher percentage of transporters for ammonium and potassium. Eukaryotic-type glutamine synthetase (GS) II proteins were identified and taxonomically classified as viral, most closely related to the GSII in Mimivirus, suggesting that marine Mimivirus-like particles may have played a role in the transfer of GSII gene functions. Additionally, a Planctomycete bloom was sampled from one upwelling site providing a rare opportunity to assess the genomic composition of a marine Planctomycete population. The significant correlations observed between genomic properties, community structure and nutrient availability provide insights into habitat-driven dynamics among oligotrophic versus upwelled marine waters adjoining each other spatially.     

禾木科植物染色体消除型远缘杂交的研究进展

植物远缘杂交是作物育种中广泛应用的技术。除了核型稳定的种间杂交可以获得杂种以外,还可以利用核型不稳定的种间杂交后父本染色体消除的现象,通过胚培养和染色体加倍处理获得加倍单倍体(     

Oscillatory Transpiration and Water Uptake of Avena Plants IV. Transpiratory Response to Sine Shaped Light Cycles

The transpiration rate of individual 6-day-old oat plants was forced to oscillate by cyclic sine-shaped changes in the leaf irradiance (frequency 2 cycles h^?1, amplitude and average value 1.4 mW cm^?2, red light 620–800 nm). By means of a specially designed cuvette with three chambers the transpiration rate from three different segments of the leaf could be measured simultaneously. The leaf segments were illuminated individually and the illumination on each leaf segment could be modulated independently. The experiments showed that there was a strong correlation between the transpiration rates from the different leaf segments, dependent on a coupling mechanism in the plant. The coupling phenomenon disappeared when the root system was eliminated or when the water potential of the root medium was lowered. It was experimentally shown that CO₂ diffusion in the leaf could not be the primary cause for the coupling. Therefore the stomatal dependence on the leaf water potential was considered the most probable reason for the coupling. The frequency of the forcing light cycles could be linearly changed during an experiment and this swept-frequency technique was used to obtain a frequency response of one single oat plant. The technique made it also possible to study the strength of the coupling between different leaf segments.