Selective and Genetic Constraints on Pneumococcal Serotype Switching

Streptococcus pneumoniae isolates typically express one of over 90 immunologically distinguishable polysaccharide capsules (serotypes), which can be classified into “serogroups” based on cross-reactivity with certain antibodies. Pneumococci can alter their serotype through recombinations affecting the capsule polysaccharide synthesis (cps) locus. Twenty such “serotype switching” events were fully characterised using a collection of 616 whole genome sequences from systematic surveys of pneumococcal carriage. Eleven of these were within-serogroup switches, representing a highly significant (p < 0.0001) enrichment based on the observed serotype distribution. Whereas the recombinations resulting in between-serogroup switches all spanned the entire cps locus, some of those that caused within-serogroup switches did not. However, higher rates of within-serogroup switching could not be fully explained by either more frequent, shorter recombinations, nor by genetic linkage to genes involved in β–lactam resistance. This suggested the observed pattern was a consequence of selection for preserving serogroup. Phenotyping of strains constructed to express different serotypes in common genetic backgrounds was used to test whether genotypes were physiologically adapted to particular serogroups. These data were consistent with epistatic interactions between the cps locus and the rest of the genome that were specific to serotype, but not serogroup, meaning they were unlikely to account for the observed distribution of capsule types. Exclusion of these genetic and physiological hypotheses suggested future work should focus on alternative mechanisms, such as host immunity spanning multiple serotypes within the same serogroup, which might explain the observed pattern.     

The Gender Gap in Second Language Acquisition: Gender Differences in the Acquisition of Dutch among Immigrants from 88 Countries with 49 Mother Tongues

Gender differences were analyzed across countries of origin and continents, and across mother tongues and language families, using a large-scale database, containing information on 27,119 adult learners of Dutch as a second language. Female learners consistently outperformed male learners in speaking and writing proficiency in Dutch as a second language. This gender gap remained remarkably robust and constant when other learner characteristics were taken into account, such as education, age of arrival, length of residence and hours studying Dutch. For reading and listening skills in Dutch, no gender gap was found. In addition, we found a general gender by education effect for all four language skills in Dutch for speaking, writing, reading, and listening. Female language learners turned out to profit more from higher educational training than male learners do in adult second language acquisition. These findings do not seem to match nurture-oriented explanatory frameworks based for instance on a human capital approach or gender-specific acculturation processes. Rather, they seem to corroborate a nature-based, gene-environment correlational framework in which language proficiency being a genetically-influenced ability interacting with environmental factors such as motivation, orientation, education, and learner strategies that still mediate between endowment and acquiring language proficiency at an adult stage.     

Endogenous Murine BST-2/Tetherin Is Not a Major Restriction Factor of Influenza A Virus Infection

BST-2 (tetherin, CD317, HM1.24) restricts virus growth by tethering enveloped viruses to the cell surface. The role of BST-2 during influenza A virus infection (IAV) is controversial. Here, we assessed the capacity of endogenous BST-2 to restrict IAV in primary murine cells. IAV infection increased BST-2 surface expression by primary macrophages, but not alveolar epithelial cells (AEC). BST-2-deficient AEC and macrophages displayed no difference in susceptibility to IAV infection relative to wild type cells. Furthermore, BST-2 played little role in infectious IAV release from either AEC or macrophages. To examine BST-2 during IAV infection in vivo, we infected BST-2-deficient mice. No difference in weight loss or in viral loads in the lungs and/or nasal tissues were detected between BST-2-deficient and wild type animals. This study rules out a major role for endogenous BST-2 in modulating IAV in the mouse model of infection.     

Production of a highly glucose tolerant β-glucosidase by Paecilomyces variotii MG3: optimization of fermentation conditions using Plackett–Burman and Box–Behnken experimental designs

β-Glucosidases (β-d-glucoside glucohydrolase, 3.2.1.21) are a group of enzymes mainly involved in the hydrolysis of β-glycosidic bonds connecting carbohydrate residues in different classes of β-d glycosides. During cellulose degradation they convert cellobiose and cellooligosaccharides produced by the endo and exoglucanases to glucose. Most of the microbial β-glucosidases are inhibited by glucose. This limits their application in commercial scale cellulose degradation ventures. Solid state fermentation production of a highly glucose tolerant β-glucosidase by a novel isolate of Paecilomyces was optimized using a two step statistical experiment design. In the first step which employed a Plackett–Burman design, the effects of parameters such as moisture, temperature, pH, inoculum concentration, incubation time and different concentrations of (NH₄)₂SO₄, KH₂PO₄, NaCl, peptone and cellobiose were evaluated. The parameters with significant influence on the process were selected and fine tuned in the second step using a Box–Behnken design. The model obtained was validated and a peptone concentration of 2 g/l, inoculum concentration of 1.2 × 10⁶ spores/ml and an incubation period of 96 h were found to be optimum for the maximum production of the enzyme. The optimization resulted in a doubling of the enzyme production by the fungus.     

N-substituted pyrrolidines and tetrahydrofurans as novel AMPAR positive modulators

A series of novel AMPA receptor positive modulators displaying CNS penetration have been discovered with sub-micromolar activity and good selectivity over the cardiac channel receptor, hERG. We describe here the synthesis of these compounds which are biaryl pyrrolidine and tetrahydrofuran sulfonamides and disclose their activities against the human GluA2 flip isoform homotetrameric receptor.     

Time to articulate a vision for the future of plant proteomics - A global perspective: An initiative for establishing the International Plant Proteomics Organization (INPPO)

Given the essential role of proteomics in understanding the biology of plants, we are establishing a global plant proteomics organization to properly organize, preserve and disseminate collected information on plant proteomics. We call this organization 'International Plant Proteomics Organization (INPPO; http://www.inppo.com).' Ten initiatives of INPPO are outlined along with how to address them in multiple phases. As our vision is global, we sincerely hope the scientific communities around the world will come together to support and join INPPO.     

Membrane targeting and pore formation by the type III secretion system translocon

The type III secretion system (T3SS) is a complex macromolecular machinery employed by a number of Gram-negative species to initiate infection. Toxins secreted through the system are synthesized in the bacterial cytoplasm and utilize the T3SS to pass through both bacterial membranes and the periplasm, thus being introduced directly into the eukaryotic cytoplasm. A key element of the T3SS of all bacterial pathogens is the translocon, which comprises a pore that is inserted into the membrane of the target cell, allowing toxin injection. Three macromolecular partners associate to form the translocon: two are hydrophobic and one is hydrophilic, and the latter also associates with the T3SS needle. In this review, we discuss recent advances on the biochemical and structural characterization of the proteins involved in translocon formation, as well as their participation in the modification of intracellular signalling pathways upon infection. Models of translocon assembly and regulation are also discussed.     

Reactive oxygen species production and mitochondrial dysfunction contribute to quercetin induced death in Leishmania amazonensis

Background

Leishmaniasis, a parasitic disease caused by protozoa of the genus Leishmania, affects more than 12 million people worldwide. Quercetin has generated considerable interest as a pharmaceutical compound with a wide range of therapeutic activities. One such activity is exhibited against the bloodstream parasite Trypanosoma brucei and amastigotes of Leishmania donovani. However, the mechanism of protozoan action of quercetin has not been studied.

Methodology/Principal Findings

In the present study, we report here the mechanism for the antileishmanial activity of quercetin against Leishmania amazonensis promastigotes. Quercetin inhibited L. amazonensis promastigote growth in a dose- and time- dependent manner beginning at 48 hours of treatment and with maximum growth inhibition observed at 96 hours. The IC₅₀ for quercetin at 48 hours was 31.4 µM. Quercetin increased ROS generation in a dose-dependent manner after 48 hours of treatment. The antioxidant GSH and NAC each significantly reduced quercetin-induced cell death. In addition, quercetin caused mitochondrial dysfunction due to collapse of mitochondrial membrane potential.

Conclusions/Significance

The effects of several drugs that interfere directly with mitochondrial physiology in parasites such as Leishmania have been described. The unique mitochondrial features of Leishmania make this organelle an ideal drug target while minimizing toxicity. Quercetin has been described as a pro-oxidant, generating ROS which are responsible for cell death in some cancer cells. Mitochondrial membrane potential loss can be brought about by ROS added directly in vitro or induced by chemical agents. Taken together, our results demonstrate that quercetin eventually exerts its antileishmanial effect on L. amazonensis promastigotes due to the generation of ROS and disrupted parasite mitochondrial function.