Spatial and temporal patterns of urea content in a eutrophic stream continuum on the Northern Great Plains

Biogeochemistry - Urea can degrade water quality and stimulate toxic phytoplankton in P-rich lakes, yet little is known of its sources, abundance, or transportation in lotic systems, particularly...     

Identification of Novel Small Molecule Inhibitors of Oncogenic RET Kinase

Oncogenic mutation of the RET receptor tyrosine kinase is observed in several human malignancies. Here, we describe three novel type II RET tyrosine kinase inhibitors (TKI), ALW-II-41-27, XMD15-44 and HG-6-63-01, that inhibit the cellular activity of oncogenic RET mutants at two digit nanomolar concentration. These three compounds shared a 3-trifluoromethyl-4-methylpiperazinephenyl pharmacophore that stabilizes the ‘DFG-out’ inactive conformation of RET activation loop. They blocked RET-mediated signaling and proliferation with an IC50 in the nM range in fibroblasts transformed by the RET/C634R and RET/M918T oncogenes. They also inhibited autophosphorylation of several additional oncogenic RET-derived point mutants and chimeric oncogenes. At a concentration of 10 nM, ALW-II-41-27, XMD15-44 and HG-6-63-01 inhibited RET kinase and signaling in human thyroid cancer cell lines carrying oncogenic RET alleles; they also inhibited proliferation of cancer, but not non-tumoral Nthy-ori-3-1, thyroid cells, with an IC50 in the nM range. The three compounds were capable of inhibiting the ‘gatekeeper’ V804M mutant which confers substantial resistance to established RET inhibitors. In conclusion, we have identified a type II TKI scaffold, shared by ALW-II-41-27, XMD15-44 and HG-6-63-01, that may be used as novel lead for the development of novel agents for the treatment of cancers harboring oncogenic activation of RET.     

Estimating utilization distributions with kernel versus local convex hull methods

Estimates of utilization distributions (UDs) are used in analyses of home-range area, habitat and resource selection, and social interactions. We simulated data from 12 parent UDs, representing 3 series of increasingly intense space-use patterns (clustering of points around a home site, restriction of locations to a network of nodes and corridors, and dominance of a central hole in the UD) and compared the ability of kernel density estimation (KDE) and local convex hull (LCH) construction to reconstruct known UDs from samples of 10, 50, 250, and 1,000 location points. For KDE, we considered 4 bandwidth selectors: the reference bandwidth, least-squares cross-validation (LSCV), direct plug-in (DPI), and solve-the-equation (STE). For the sample sizes and UD patterns tested here, KDE achieved significantly higher volume-of-intersection (VI) scores with known parent UDs than did LCH; KDE also provided less biased home-range area estimates under many conditions. However, LCH minimized the UD volume that occurred outside the true home range boundary (V_out). Among the KDE bandwidth estimators, relative performance depended on the type and intensity of space use patterns, sample size, and the metric used to evaluate performance. Biologists should use KDE for UD and home range estimation within a probabilistic context, unless their objective is to exclude potentially unused areas by defining the area delimited by data. © 2011 The Wildlife Society.     

Discovery of pyrimidine benzimidazoles as Src-family selective Lck inhibitors. Part II

A series of 4-amino-6-benzimidazole-pyrimidines was designed to target lymphocyte-specific tyrosine kinase (Lck), a member of the Src-family kinases (SFKs). These type II inhibitors were optimized using a cellular Lck-dependent proliferation assay and are capable of inhibiting Lck at single-digit nanomolar concentrations. This scaffold is likely to serve a valuable template for developing potent inhibitors of a number of SFKs.     

Factors Associated with Post-Seasonal Serological Titer and Risk Factors for Infection with the Pandemic A/H1N1 Virus in the French General Population

The CoPanFlu-France cohort of households was set up in 2009 to study the risk factors for infection by the pandemic influenza virus (H1N1pdm) in the French general population. The authors developed an integrative data-driven approach to identify individual, collective and environmental factors associated with the post-seasonal serological H1N1pdm geometric mean titer, and derived a nested case-control analysis to identify risk factors for infection during the first season. This analysis included 1377 subjects (601 households). The GMT for the general population was 47.1 (95% confidence interval (CI): 45.1, 49.2). According to a multivariable analysis, pandemic vaccination, seasonal vaccination in 2009, recent history of influenza-like illness, asthma, chronic obstructive pulmonary disease, social contacts at school and use of public transports by the local population were associated with a higher GMT, whereas history of smoking was associated with a lower GMT. Additionally, young age at inclusion and risk perception of exposure to the virus at work were identified as possible risk factors, whereas presence of an air humidifier in the living room was a possible protective factor. These findings will be interpreted in light of the longitudinal analyses of this ongoing cohort.     

Antihypertensive drug Valsartan promotes dendritic spine density by altering AMPA receptor trafficking

Recent studies demonstrated that the antihypertensive drug Valsartan improved spatial and episodic memory in mouse models of Alzheimer’s Disease (AD) and human subjects with hypertension. However, the molecular mechanism by which Valsartan can regulate cognitive function is still unknown. Here, we investigated the effect of Valsartan on dendritic spine formation in primary hippocampal neurons, which is correlated with learning and memory. Interestingly, we found that Valsartan promotes spinogenesis in developing and mature neurons. In addition, we found that Valsartan increases the puncta number of PSD-95 and trends toward an increase in the puncta number of synaptophysin. Moreover, Valsartan increased the cell surface levels of AMPA receptors and selectively altered the levels of spinogenesis-related proteins, including CaMKIIα and phospho-CDK5. These data suggest that Valsartan may promote spinogenesis by enhancing AMPA receptor trafficking and synaptic plasticity signaling.     

Dissecting Functions of the Conserved Oligomeric Golgi Tethering Complex Using a Cell‐Free Assay

Vesicle transport sorts proteins between compartments and is thereby responsible for generating the non‐uniform protein distribution along the eukaryotic secretory and endocytic pathways. The mechanistic details of specific vesicle targeting are not yet well characterized at the molecular level. We have developed a cell‐free assay that reconstitutes vesicle targeting utilizing the recycling of resident enzymes within the Golgi apparatus. The assay has physiological properties, and could be used to show that the two lobes of the conserved oligomeric Golgi tethering complex play antagonistic roles in trans‐Golgi vesicle targeting. Moreover, we can show that the assay is sensitive to several different congenital defects that disrupt Golgi function and therefore cause glycosylation disorders. Consequently, this assay will allow mechanistic insight into the targeting step of vesicle transport at the Golgi, and could also be useful for characterizing some novel cases of congenital glycosylation disorders.      

Acute Respiratory Failure in Critically Ill Patients with Interstitial Lung Disease

Background

Patients with chronic known or unknown interstitial lung disease (ILD) may present with severe respiratory flares that require intensive management. Outcome data in these patients are scarce.

Patients and Methods

Clinical and radiological features were collected in 83 patients with ILD-associated acute respiratory failure (ARF). Determinants of hospital mortality and response to corticosteroid therapy were identified by logistic regression.

Results

Hospital and 1-year mortality rates were 41% and 54% respectively. Pulmonary hypertension, computed tomography (CT) fibrosis and acute kidney injury were independently associated with mortality (odds ratio (OR) 4.55; 95% confidence interval (95%CI) (1.20–17.33); OR, 7.68; (1.78–33.22) and OR 10.60; (2.25–49.97) respectively). Response to steroids was higher in patients with shorter time from hospital admission to corticosteroid therapy. Patients with fibrosis on CT had lower response to steroids (OR, 0.03; (0.005–0.21)). In mechanically ventilated patients, overdistension induced by high PEEP settings was associated with CT fibrosis and hospital mortality.

Conclusion

Mortality is high in ILD-associated ARF. CT and echocardiography are valuable prognostic tools. Prompt corticosteroid therapy may improve survival.