Substituted oxazole benzenesulfonamides as potent human beta3 adrenergic receptor agonists

As a part of our investigation into the development of orally bioavailable beta3 adrenergic receptor agonists, we have identified a series of substituted oxazole derivatives that are potent beta3 agonists with excellent selectivity against other beta receptors. Several of these compounds showed excellent oral bioavailability in dogs. One example, cyclopentylethyloxazole 5f is a potent beta3 agonist (EC50 = 14 nM, 84% activation) with 340-fold and 160-fold selectivity over beta1 and beta2 receptors, respectively, and has 38% oral bioavailability in dogs.     

Whole-Genome Resequencing Reveals Extensive Natural Variation in the Model Green Alga Chlamydomonas reinhardtii

We performed whole-genome resequencing of 12 field isolates and eight commonly studied laboratory strains of the model organism Chlamydomonas reinhardtii to characterize genomic diversity and provide a resource for studies of natural variation. Our data support previous observations that Chlamydomonas is among the most diverse eukaryotic species. Nucleotide diversity is ∼3% and is geographically structured in North America with some evidence of admixture among sampling locales. Examination of predicted loss-of-function mutations in field isolates indicates conservation of genes associated with core cellular functions, while genes in large gene families and poorly characterized genes show a greater incidence of major effect mutations. De novo assembly of unmapped reads recovered genes in the field isolates that are absent from the CC-503 assembly. The laboratory reference strains show a genomic pattern of polymorphism consistent with their origin as the recombinant progeny of a diploid zygospore. Large duplications or amplifications are a prominent feature of laboratory strains and appear to have originated under laboratory culture. Extensive natural variation offers a new source of genetic diversity for studies of Chlamydomonas, including naturally occurring alleles that may prove useful in studies of gene function and the dissection of quantitative genetic traits.     

Increasement of Heterologous Expression of Recombinant Vit v 1 in Pichia pastoris KM71 by Nonionic Detergents as a Cost-effective Approach

Applied Biochemistry and Microbiology - Vit v 1 as a lipid-transfer protein is a major allergen of grapes (Vitis vinifera) that elicits food allergy in many patients in Iran. Todays, recombinant...     

Dual cytoplasmic and nuclear distribution of the novel arsenite-stimulated human ATPase (hASNA-I)

The arsenite-stimulated human ATPase (hASNA-I) protein is a distinct human ATPase whose cDNA was cloned by sequence homology to the Escherichia coli ATPase arsA. Its subcellular localization in human malignant melanoma T289 cells was examined to gain insight into the role of hASNA-I in the physiology of human cells. Immunocytochemical staining using the specific anti-hASNA-I monoclonal antibody 5G8 showed a cytoplasmic, perinuclear, and nucleolar distribution. Subcellular fractionation indicated that the cytoplasmic hASNA-I was soluble and that the perinuclear distribution was due to association with the nuclear membrane rather than with the endoplasmic reticulum. Its presence in the nucleolus was confirmed by showing colocalization with an antibody of known nucleolar specificity. Further immunocytochemical analysis showed that the hASNA-I at the nuclear membrane was associated with invaginations into the nucleus in interphase cells. These results indicate that hASNA-I is a paralogue of the bacterial ArsA protein and suggest that it plays a role in the nucleocytoplasmic transport of a nucleolar component. J. Cell. Biochem. 71:1–10, 1998. © 1998 Wiley-Liss, Inc.     

Factors affecting the in vitro rapid germination of Taxus embryos and the evaluation of taxol content in the plantlets

A simple and efficient in vitro method for breaking the dormancy of Taxus baccata L. cv. Stricta seeds was investigated. The highest rate of germination (100%) of embryos isolated from seeds, which had been washed with running tap water for 7 days, was obtained after 7 days of culture on modified Murashige and Skoog or Heller media. The taxol equivalent content in 2-month-old Taxus plantlets was investigated using anti-taxol polyclonal antibodies. The results showed that the taxol equivalent content varied, depending on Taxus species and on the individuals in the same taxon.     

Design and synthesis of brain penetrant selective JNK inhibitors with improved pharmacokinetic properties for the prevention of neurodegeneration

The SAR of a series of brain penetrant, trisubstituted thiophene based JNK inhibitors with improved pharmacokinetic properties is described. These compounds were designed based on information derived from metabolite identification studies which led to compounds such as 42 with lower clearance, greater brain exposure and longer half life compared to earlier analogs.     

Carbon Sequestration in the New Jersey Pine Barrens Under Different Scenarios of Fire Management

The New Jersey Pine Barrens (NJPB) is the largest forested area along the northeastern coast of the United States. The NJPB are dominated by pine (Pinus spp.) and oak (Quercus spp.) stands that are fragmented and subject to frequent disturbance and forest management. Over long time periods (>50 years), the balance between oak and pine dominance is determined by fire frequency. As a consequence, the ability of the NJPB to sequester carbon may be contingent upon management activities as well as patterns of historic land use. We simulated 100 years of carbon change using three scenarios: (1) contemporary management as reflected in the recent (1991–2006) fire records, (2) an increase in the fire ignitions within the wildland urban interface areas of the NJPB reflecting increased prescribed fires, and (3) a longer response time to wildfires, reflecting a more liberal burning policy by the New Jersey Forest Fire Service. We used the LANDIS-II model coupled with CENTURY and the Dynamic Fire and Dynamic Biomass Fuels extensions to estimate forest carbon sequestration based on these three scenarios. Calibration and validation via comparison to monthly flux tower data indicated that the model reasonably captured the timing and magnitude of net ecosystem exchange in the absence of Gypsy moth defoliation (r ² = 0.89). Under all scenarios, our simulations suggest that forests of the NJPB will continue to accumulate carbon over the next 100 years under current climatic conditions. Although aboveground net primary productivity, live carbon, and detrital carbon were roughly constant or increased only modestly, soil organic carbon continued to increase through time for all forest types except the highly xeric pine plains. Our simulated changes in management reflected only minor alterations to the fire regime and thus management may have only minor effects on total forest carbon budgets in the immediate future particularly when compared to recovery from historic disturbance patterns.     

Dispersal history of a globally introduced carnivore,the small Indian mongoose Urva auropunctata,with an emphasis on the Caribbean region

Biological Invasions - The small Indian mongoose has been introduced into several important hotspots of biodiversity and is considered the wild carnivore with the greatest negative impact on...     

Massage therapy for osteoarthritis of the knee: a randomized dose-finding trial

Background

In a previous trial of massage for osteoarthritis (OA) of the knee, we demonstrated feasibility, safety and possible efficacy, with benefits that persisted at least 8 weeks beyond treatment termination.

Methods

We performed a RCT to identify the optimal dose of massage within an 8-week treatment regimen and to further examine durability of response. Participants were 125 adults with OA of the knee, randomized to one of four 8-week regimens of a standardized Swedish massage regimen (30 or 60 min weekly or biweekly) or to a Usual Care control. Outcomes included the Western Ontario and McMaster Universities Arthritis Index (WOMAC), visual analog pain scale, range of motion, and time to walk 50 feet, assessed at baseline, 8-, 16-, and 24-weeks.

Results

WOMAC Global scores improved significantly (24.0 points, 95% CI ranged from 15.3–32.7) in the 60-minute massage groups compared to Usual Care (6.3 points, 95% CI 0.1–12.8) at the primary endpoint of 8-weeks. WOMAC subscales of pain and functionality, as well as the visual analog pain scale also demonstrated significant improvements in the 60-minute doses compared to usual care. No significant differences were seen in range of motion at 8-weeks, and no significant effects were seen in any outcome measure at 24-weeks compared to usual care. A dose-response curve based on WOMAC Global scores shows increasing effect with greater total time of massage, but with a plateau at the 60-minute/week dose.

Conclusion

Given the superior convenience of a once-weekly protocol, cost savings, and consistency with a typical real-world massage protocol, the 60-minute once weekly dose was determined to be optimal, establishing a standard for future trials.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00970008","term_id":"NCT00970008"}}NCT00970008     

Design and synthesis of cell potent BACE-1 inhibitors: Structure–activity relationship of P1′ substituents

Using structure-guided design, hydroxyethylamine BACE-1 inhibitors were optimized to nanomolar Aβ cellular inhibition with selectivity against cathepsin-D. X-ray crystallography illuminated the S1′ residues critical to this effort, which culminated in compounds 56 and 57 that exhibited potency and selectivity but poor permeability and high P-gp efflux.