Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis

The establishment of neural circuitry requires vast numbers of synapses to be generated during a specific window of brain development, but it is not known why the developing mammalian brain has a much greater capacity to generate new synapses than the adult brain. Here we report that immature but not mature astrocytes express thrombospondins (TSPs)-1 and -2 and that these TSPs promote CNS synaptogenesis in vitro and in vivo. TSPs induce ultrastructurally normal synapses that are presynaptically active but postsynaptically silent and work in concert with other, as yet unidentified, astrocyte-derived signals to produce functional synapses. These studies identify TSPs as CNS synaptogenic proteins, provide evidence that astrocytes are important contributors to synaptogenesis within the developing CNS, and suggest that TSP-1 and -2 act as a permissive switch that times CNS synaptogenesis by enabling neuronal molecules to assemble into synapses within a specific window of CNS development.     

Four diterpenoid inhibitors of Cdc25B phosphatase from a marine anemone

Three new diterpenoids and one known diterpenoid have been isolated from a sea anemone of the order Actiniara, and the structures of the new compounds, actiniarins A-C (1-3) were established on the basis of extensive 1D and 2D NMR spectroscopic data interpretation. Compound 1 has a six-membered ring hemiacetal ring, and the equilibrium of this ring is discussed. All the isolates were evaluated for their inhibition of Cdc25B and for cytotoxicity against the A2780 ovarian cancer cell line.     

Salmonella enterica serotype Typhimurium MisL is an intestinal colonization factor that binds fibronectin

MisL is an autotransporter protein encoded by Salmonella pathogenicity island 3 (SPI3). To investigate the role of MisL in Salmonella enterica serotype Typhimurium (S. Typhimurium) pathogenesis, we characterized its function during infection of mice and identified a host receptor for this adhesin. In a mouse model of S. Typhimurium intestinal persistence, a misL mutant was shed with the faeces in significantly lower numbers than the wild type and was impaired in its ability to colonize the cecum. Previous studies have implicated binding of extracellular matrix proteins as a possible mechanism for S. Typhimurium intestinal persistence. A gluthathione-S-transferase (GST) fusion protein to the MisL passenger domain (GST-MisL(29-281)) was constructed to investigate binding to extracellular matrix proteins. In a solid-phase binding assay the purified GST-MisL(29-281) fusion protein bound to fibronectin and collagen IV, but not to collagen I. MisL expression was not detected by Western blot in S. Typhimurium grown under standard laboratory conditions. However, when expression of the cloned misL gene was driven by the Escherichia coli arabinose promoter, MisL could be detected in the S. Typhimurium outer membrane by Western blot and on the bacterial cell surface by flow cytometry. Expression of MisL enabled S. Typhimurium to bind fibronectin to its cell surface, resulting in attachment to fibronectin-coated glass slides and in increased invasiveness for human epithelial cells derived from colonic carcinoma (T84 cells). These data identify MisL as an extracellular matrix adhesin involved in intestinal colonization.     

Synthetic peptide approach to the analysis of kinase activities of avian EGF receptor and v-erbB protein

Analysis of the structure and function of a protein such as the epidermal growth factor receptor is facilitated by the use of antibodies directed against discrete portions of the protein. Here, we describe the characterization and use of antibodies directed against synthetic peptides corresponding to specific portions of the epidermal growth factor receptor and/or v-erbB protein. In particular, one useful antiserum has allowed us to compare the protein kinase activities of the epidermal growth factor receptor and the v-erbB proteins and to conclude that the v-erbB protein is a protein-tyrosine specific kinase as is its homologue the avian epidermal growth factor receptor.     

Functional SARS-CoV-2-Specific Immune Memory Persists after Mild COVID-19

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Fuel Use and Greenhouse Gas Emissions from Offshore Fisheries of the Republic of Korea

Greenhouse Gas (GHG) emissions from the offshore fisheries industry in the Republic of Korea (Korea) were examined in response to growing concerns about global warming and the contribution of emissions from different industrial sectors. Fuel usage and GHG emissions (CO₂, CH₄, N₂O) were analysed using the ‘Tier 1’ method provided by the Intergovernmental Panel on Climate Change (IPCC) from the offshore fishery, which is the primary domestic seafood production sector in Korea. In 2013, fuel usage in the offshore fishery accounted for 59.7% (557,463 KL) of total fuel consumption of fishing vessels in Korea. Fuel consumption and thus GHG emissions were not stable through time in this industry, increasing by 2.4% p.a. for three consecutive years, from 2011 to 2013, despite a decrease in the number of vessels operating. GHG emissions generated in offshore fisheries also changed through time and increased from 1,442,975 tCO₂e/year in 2011 to 1,477,279 tCO₂e/year in 2013. Changes in both fuel use and GHG emissions per kg offshore fish production appeared to be associated with decreasing catch rates by the fleet, which in turn were a reflection of decrease in fish biomass. Another important feature of GHG emissions in this industry was the high variation in GHG emission per kg fish product among different fishing methods. The long line fishery had approximately three times the emissions of the average production while the jigging fishery was more than two times higher than the average. Lowest emissions were from the trawl sector, which is regarded as having greatest environmental impact using traditional biodiversity metrics although had lowest environmental impact in terms of fuel and GHG emission metrics used in this study. The observed deterioration in fuel efficiency of the offshore fishery each year is of concern but also demonstrates that fuel efficiency can change, which shows there is opportunity to improve efficiency with changes to fishery management and harvesting operations.     

National Trends in the Ambulatory Treatment of Hypertension in the United States, 1997-2012

Importance

Hypertension is common and costly. Over the past decade, new antihypertensive therapies have been developed, several have lost patent protection and additional evidence regarding the safety and effectiveness of these agents has accrued.

Objective

To examine trends in the use of antihypertensive therapies in the United States between 1997 and 2012.

Design, Setting and Participants

We used nationally representative audit data from the IMS Health National Disease and Therapeutic Index to examine the ambulatory pharmacologic treatment of hypertension.

Outcome Measures

Our primary unit of analysis was a visit where hypertension was a reported diagnosis and treated with a pharmacotherapy (treatment visit). We restricted analyses to the use of six therapeutic classes of antihypertensive medications among individuals 18 years or older.

Results

Annual hypertension treatment visits increased from 56.9 million treatment visits (95% confidence intervals [CI], 53.9–59.8) in 1997 to 83.3 million visits (CI 79.2–87.3) in 2008, then declined steadily to 70.9 million visits (CI 66.7–75.0) by 2012. Angiotensin receptor blocker utilization increased substantially from 3% of treatment visits in 1997 to 18% by 2012, whereas calcium channel blocker use decreased from 27% to 18% of visits. Rates of diuretic and beta-blocker use remained stable and represented 24%–30% and 14–16% of visits, respectively. Use of direct renin inhibitor accounted for fewer than 2% of annual visits. The proportion of visits treated using fixed-dose combination therapies increased from 28% to 37% of visits.

Conclusions

Several important changes have occurred in the landscape of antihypertensive treatment in the United States during the past decade. Despite their novel mechanism of action, the adoption rate of direct renin inhibitors remains low.     

Phenotype Ontologies and Cross-Species Analysis for Translational Research

The use of model organisms as tools for the investigation of human genetic variation has significantly and rapidly advanced our understanding of the aetiologies underlying hereditary traits. However, while equivalences in the DNA sequence of two species may be readily inferred through evolutionary models, the identification of equivalence in the phenotypic consequences resulting from comparable genetic variation is far from straightforward, limiting the value of the modelling paradigm. In this review, we provide an overview of the emerging statistical and computational approaches to objectively identify phenotypic equivalence between human and model organisms with examples from the vertebrate models, mouse and zebrafish. Firstly, we discuss enrichment approaches, which deem the most frequent phenotype among the orthologues of a set of genes associated with a common human phenotype as the orthologous phenotype, or phenolog, in the model species. Secondly, we introduce and discuss computational reasoning approaches to identify phenotypic equivalences made possible through the development of intra- and interspecies ontologies. Finally, we consider the particular challenges involved in modelling neuropsychiatric disorders, which illustrate many of the remaining difficulties in developing comprehensive and unequivocal interspecies phenotype mappings.