Scn4b regulates the hypnotic effects of ethanol and other sedative drugs

The voltage‐gated sodium channel subunit β4 (SCN4B) regulates neuronal activity by modulating channel gating and has been implicated in ethanol consumption in rodent models and human alcoholics. However, the functional role for Scn4b in ethanol‐mediated behaviors is unknown. We determined if genetic global knockout (KO) or targeted knockdown of Scn4b in the central nucleus of the amygdala (CeA) altered ethanol drinking or related behaviors. We used four different ethanol consumption procedures (continuous and intermittent two‐bottle choice (2BC), drinking‐in‐the dark and chronic intermittent ethanol vapor) and found that male and female Scn4b KO mice did not differ from their wild‐type (WT) littermates in ethanol consumption in any of the tests. Knockdown of Scn4b mRNA in the CeA also did not alter 2BC ethanol drinking. However, Scn4b KO mice showed longer duration of the loss of righting reflex induced by ethanol, gaboxadol, pentobarbital and ketamine. KO mice showed slower recovery to basal levels of handling‐induced convulsions after ethanol injection, which is consistent with the increased sedative effects observed in these mice. However, Scn4b KO mice did not differ in the severity of acute ethanol withdrawal. Acoustic startle responses, ethanol‐induced hypothermia and clearance of blood ethanol also did not differ between the genotypes. There were also no functional differences in the membrane properties or excitability of CeA neurons from Scn4b KO and WT mice. Although we found no evidence that Scn4b regulates ethanol consumption in mice, it was involved in the acute hypnotic effects of ethanol and other sedatives.     

Association between Recruitment Methods and Attrition in Internet-Based Studies

Internet-based systems for epidemiological studies have advantages over traditional approaches as they can potentially recruit and monitor a wider range of individuals in a relatively inexpensive fashion. We studied the association between communication strategies used for recruitment (offline, online, face-to-face) and follow-up participation in nine Internet-based cohorts: the Influenzanet network of platforms for influenza surveillance which includes seven cohorts in seven different European countries, the Italian birth cohort Ninfea and the New Zealand birth cohort ELF. Follow-up participation varied from 43% to 89% depending on the cohort. Although there were heterogeneities among studies, participants who became aware of the study through an online communication campaign compared with those through traditional offline media seemed to have a lower follow-up participation in 8 out of 9 cohorts. There were no clear differences in participation between participants enrolled face-to-face and those enrolled through other offline strategies. An Internet-based campaign for Internet-based epidemiological studies seems to be less effective than an offline one in enrolling volunteers who keep participating in follow-up questionnaires. This suggests that even for Internet-based epidemiological studies an offline enrollment campaign would be helpful in order to achieve a higher participation proportion and limit the cohort attrition.     

Persistence and Change in Community Composition of Reef Corals through Present,Past, and Future Climates

The reduction in coral cover on many contemporary tropical reefs suggests a different set of coral community assemblages will dominate future reefs. To evaluate the capacity of reef corals to persist over various time scales, we examined coral community dynamics in contemporary, fossil, and simulated future coral reef ecosystems. Based on studies between 1987 and 2012 at two locations in the Caribbean, and between 1981 and 2013 at five locations in the Indo-Pacific, we show that many coral genera declined in abundance, some showed no change in abundance, and a few coral genera increased in abundance. Whether the abundance of a genus declined, increased, or was conserved, was independent of coral family. An analysis of fossil-reef communities in the Caribbean revealed changes in numerical dominance and relative abundances of coral genera, and demonstrated that neither dominance nor taxon was associated with persistence. As coral family was a poor predictor of performance on contemporary reefs, a trait-based, dynamic, multi-patch model was developed to explore the phenotypic basis of ecological performance in a warmer future. Sensitivity analyses revealed that upon exposure to thermal stress, thermal tolerance, growth rate, and longevity were the most important predictors of coral persistence. Together, our results underscore the high variation in the rates and direction of change in coral abundances on contemporary and fossil reefs. Given this variation, it remains possible that coral reefs will be populated by a subset of the present coral fauna in a future that is warmer than the recent past.     

The discovery of glycine and related amino acid-based factor Xa inhibitors

Herein, we report on the identification of three potent glycine and related amino acid-based series of FXa inhibitors containing a neutral P1 chlorophenyl pharmacophore. A X-ray crystal structure has shown that constrained glycine derivatives with optimized N-substitution can greatly increase hydrophobic interactions in the FXa active site. Also, the substitution of a pyridone ring for a phenylsulfone ring in the P4 sidechain resulted in an inhibitor with enhanced oral bioavailability.     

Primary antibody-forming cells and secondary B cells are generated from separate precursor cell subpopulations

Two precursor cell subpopulations have been isolated from the spleen cells of nonimmune mice. The major B cell subpopulation binds high levels of the J11D monoclonal antibody and, upon T cell-dependent antigenic stimulation, gives rise to primary antibody-forming cell clones but not secondary B cells. A minority of the 10%-14% of Ia+ precursors that bind low levels of J11D (J11Dlo) also generate antibody-forming cell clones after primary stimulation. However, over 70% of J11Dlo precursors yield no primary antibody-forming cell clones but instead give rise to secondarily responsive B cells. The existence of a distinct precursor cell subpopulation that is responsible for the generation of B cell memory is further evidenced by the distribution of variable region clonotypes among J11Dlo primary precursors, which resembles the clonotype patterns of secondary B cells, and by the accumulation of somatic mutations in their clonal progeny.     

The role of glyceraldehyde 3-phosphate dehydrogenase (GapA-1) in <Emphasis Type="Italic">Neisseria meningitidis</Emphasis> adherence to human cells

Background  

Glyceraldehyde 3-phosphate dehydrogenases (GAPDHs) are cytoplasmic glycolytic enzymes, which although lacking identifiable secretion signals, have also been found localized to the surface of several bacteria (and some eukaryotic organisms); where in some cases they have been shown to contribute to the colonization and invasion of host tissues. Neisseria meningitidis is an obligate human nasopharyngeal commensal which can cause life-threatening infections including septicaemia and meningitis. N. meningitidis has two genes, gapA-1 and gapA-2, encoding GAPDH enzymes. GapA-1 has previously been shown to be up-regulated on bacterial contact with host epithelial cells and is accessible to antibodies on the surface of capsule-permeabilized meningococcal cells. The aims of this study were: 1) to determine whether GapA-1 was expressed across different strains of N. meningitidis; 2) to determine whether GapA-1 surface accessibility to antibodies was dependant on the presence of capsule; 3) to determine whether GapA-1 can influence the interaction of meningococci and host cells, particularly in the key stages of adhesion and invasion.     

DAG, a gene required for chloroplast differentiation and palisade development in Antirrhinum majus.

We have identified a mutation at the DAG locus of Antirrhinum majus which blocks the development of chloroplasts to give white leaves with green revertant sectors. The green areas contain normal chloroplasts whereas the white areas have small plastids that resemble proplastids. The cotyledons of dark-grown dag mutant seedlings have plastids which also resemble proplastids. The palisade cells in the white areas of dag mutant leaves also lack their characteristic columnar shape. The DAG locus was cloned by transposon tagging: DAG encodes a novel protein with a predicted Mr of 26k, which is targeted to the plastids. Cleavage of its predicted transit peptide gives a mature protein of Mr 20k. Screening of databases and analysis of Southern blots gave evidence that DAG belongs to a protein family with homology to several proteins of unknown function from plants. Expression of DAG is required for expression of nuclear genes affecting the chloroplasts, such as CAB and RBCS, and also for expression of the plastidial gene RPOB encoding the plastidial RNA polymerase beta subunit, indicating that it functions very early in chloroplast development.     

The impact of specific and non-specific immunity on the ecology of Streptococcus pneumoniae and the implications for vaccination

More than 90 capsular serotypes of Streptococcus pneumoniae coexist despite competing for nasopharyngeal carriage and a gradient in fitness. The underlying mechanisms for this are poorly understood and make assessment of the likely population impact of vaccination challenging. We use an individual-based simulation model to generalize widely used deterministic models for pneumococcal competition and show that in these models short-term serotype-specific and serotype non-specific immunity could constitute the mechanism governing between-host competition and coexistence. We find that non-specific immunity induces between-host competition and that serotype-specific immunity limits a type''s competitive advantage and allows stable coexistence of multiple serotypes. Serotypes carried at low prevalence show high variance in carriage levels, which would result in apparent outbreaks if they were highly pathogenic. Vaccination against few serotypes can lead to elimination of the vaccine types and induces replacement by others. However, in simulations where the elimination of the targeted types is achieved only by a combination of vaccine effects and the competitive pressure of the non-vaccine types, a universal vaccine with similar-type-specific effectiveness can fail to eliminate pneumococcal carriage and offers limited herd immunity. Hence, if vaccine effects are insufficient to control the majority of serotypes at the same time, then exploiting the competitive pressure by selective vaccination can help control the most pathogenic serotypes.