The effects of NMDA subunit composition on calcium influx and spike timing-dependent plasticity in striatal medium spiny neurons

Calcium through NMDA receptors (NMDARs) is necessary for the long-term potentiation (LTP) of synaptic strength; however, NMDARs differ in several properties that can influence the amount of calcium influx into the spine. These properties, such as sensitivity to magnesium block and conductance decay kinetics, change the receptor's response to spike timing dependent plasticity (STDP) protocols, and thereby shape synaptic integration and information processing. This study investigates the role of GluN2 subunit differences on spine calcium concentration during several STDP protocols in a model of a striatal medium spiny projection neuron (MSPN). The multi-compartment, multi-channel model exhibits firing frequency, spike width, and latency to first spike similar to current clamp data from mouse dorsal striatum MSPN. We find that NMDAR-mediated calcium is dependent on GluN2 subunit type, action potential timing, duration of somatic depolarization, and number of action potentials. Furthermore, the model demonstrates that in MSPNs, GluN2A and GluN2B control which STDP intervals allow for substantial calcium elevation in spines. The model predicts that blocking GluN2B subunits would modulate the range of intervals that cause long term potentiation. We confirmed this prediction experimentally, demonstrating that blocking GluN2B in the striatum, narrows the range of STDP intervals that cause long term potentiation. This ability of the GluN2 subunit to modulate the shape of the STDP curve could underlie the role that GluN2 subunits play in learning and development.     

Oral rabies vaccination of a northern Ohio raccoon population: relevance of population density and prebait serology

Ohio's oral rabies vaccination (ORV) program was established to prevent the westward spread of the raccoon (Procyon lotor) rabies virus (Lyssavirus, Rhabdoviridae) in Ohio, USA. The program, which targets raccoons, distributes vaccine-bait units (VBU) at a target density of 75 units/km2. Few studies have examined the relationship of VBU density and target population density to the prevalence of rabies virus-neutralizing antibodies (RVNA). We conducted experimental VBU distributions in August 2003 and August 2004, 150 km west of the ORV zone where there was no history of raccoon rabies. We measured change in RVNA titers in blood collected from live-trapped raccoons before and after VBU distributions. A closed population mark-recapture estimate of the size of the target population was 91 raccoons/km2, compared to the realized VBU distribution density of 70 units/km2. Surprisingly, 41% of 37 serum samples were RVNA-positive (>or=0.05 IU/ml) before VBU distribution in 2003, but all titers were <0.25 IU/ml. Although viable VBUs were distributed in August 2003, only 21% of 315 samples were RVNA-positive before VBU distribution in 2004, but 9% had titers>or=0.25 IU/ml. Tetracycline (biomarker in bait) prevalence in teeth indicated that 57% of raccoons ingested VBUs after distribution in 2003, and 54% ingested VBUs after distribution in 2004. However, only 8% and 11% of sera were positive for RVNA (>or=0.05 IU/ml) after VBU distribution in 2003 and 2004, respectively. Only 4-5% of sera collected after bait distribution had titers>or=0.25 IU/ml each year. The standard distribution density of 75 VBUs/km2 was insufficient to produce a population-wide immunoprotective response against rabies infection in our high-density target population. Presence of RVNA in a presumed na?ve population before baiting demonstrates that estimating prevalence of RVNA after oral rabies vaccination can be problematic without knowledge of background titers and seasonal changes in prevalence of RVNA before and after baiting.     

Age-specific differences in oncogenic pathway deregulation seen in human breast tumors

Purpose

To define the biology driving the aggressive nature of breast cancer arising in young women.

Experimental Design

Among 784 patients with early stage breast cancer, using prospectively-defined, age-specific cohorts (young ≤45 years; older ≥65 years), 411 eligible patients (n = 200≤45 years; n = 211≥65 years) with clinically-annotated Affymetrix microarray data were identified. GSEA, signatures of oncogenic pathway deregulation and predictors of chemotherapy sensitivity were evaluated within the two age-defined cohorts.

Results

In comparing deregulation of oncogenic pathways between age groups, a higher probability of PI3K (p = 0.006) and Myc (p = 0.03) pathway deregulation was observed in breast tumors arising in younger women. When evaluating unique patterns of pathway deregulation, a low probability of Src and E2F deregulation in tumors of younger women, concurrent with a higher probability of PI3K, Myc, and β-catenin, conferred a worse prognosis (HR = 4.15). In contrast, a higher probability of Src and E2F pathway activation in tumors of older women, with concurrent low probability of PI3K, Myc and β-catenin deregulation, was associated with poorer outcome (HR = 2.7). In multivariate analyses, genomic clusters of pathway deregulation illustrate prognostic value.

Conclusion

Results demonstrate that breast cancer arising in young women represents a distinct biologic entity characterized by unique patterns of deregulated signaling pathways that are prognostic, independent of currently available clinico-pathologic variables. These results should enable refinement of targeted treatment strategies in this clinically challenging situation.     

Protection of specific maternal messenger RNAs by the P body protein CGH-1 (Dhh1/RCK) during Caenorhabditis elegans oogenesis

During oogenesis, numerous messenger RNAs (mRNAs) are maintained in a translationally silenced state. In eukaryotic cells, various translation inhibition and mRNA degradation mechanisms congregate in cytoplasmic processing bodies (P bodies). The P body protein Dhh1 inhibits translation and promotes decapping-mediated mRNA decay together with Pat1 in yeast, and has been implicated in mRNA storage in metazoan oocytes. Here, we have investigated in Caenorhabditis elegans whether Dhh1 and Pat1 generally function together, and how they influence mRNA sequestration during oogenesis. We show that in somatic tissues, the Dhh1 orthologue (CGH-1) forms Pat1 (patr-1)-dependent P bodies that are involved in mRNA decapping. In contrast, during oogenesis, CGH-1 forms patr-1-independent mRNA storage bodies. CGH-1 then associates with translational regulators and a specific set of maternal mRNAs, and prevents those mRNAs from being degraded. Our results identify somatic and germ cell CGH-1 functions that are distinguished by the involvement of PATR-1, and reveal that during oogenesis, numerous translationally regulated mRNAs are specifically protected by a CGH-1-dependent mechanism.     

Efficacy of the Entomopathogenic Fungus, Culicinomyces clavisporus against Larvae of the Biting Midge, Culicoides nubeculosus (Diptera: Ceratopogonidae)

Culicinomyces clavisporus, a fungal pathogen of a wide range of mosquito species, was investigated in relation to potential pathogenicity against Culicoides nubeculosus biting midge larvae. Seven different C. clavisporus strains were assayed. Each showed some degree of activity against C. nubeculosus larvae with LC₅₀ values of between 3.2×10^-5 and 1.1×10^-6 spores/mL; these effects occurred in dose-dependent manners and tended to be delayed until 72-96 h post treatment. The results are discussed in relation to incorporation of C. clavisporus into biocontrol programmes for Culicoides spp.     

Two theories of origin of the land-plant sporophyte: Which is left standing?

Questions concerning the two competing theories of the development of alternating generations in land plants, the homologous theory and the antithetic theory, have never been fully resolved. In the majority of recent accounts there appears to have been increasing de facto support (if one considers the ontogenetic processes and phylogenetic consequences discussed) for the antithetic theory. However, this preference is usually not plainly stated (as such) in these discussions, and some support has also continued for the homologous theory. The crux of both theories (homologous and antithetic) centers upon how the sporophyte may have originated in the life cycle. One problem with the homologous theory is that it is not made explicit how the development of a dependent sporophyte could have occurred in the life cycle (when the precedent organisms are considered to have had free-living, putatively similar, gametophytes and sporophytes). The antithetic theory, by contrast, offers a definite ontogenetic mechanism or process (retention of the zygote on the gametophyte, delay of zygotic meiosis, with zygotic mitoses occurring first) by which a dependent sporophyte might have originated and persisted, in the context of a life cycle formerly lacking a sporophyte generation. Also, a review of a variety of evidence (morphological, cytological, biochemical, etc.) would appear to lend more support to the antithetic theory than to the homologous theory. In discussing types of algae now known to be most clearly related to land plants (i.e., charophytes, particularly advanced forms), the type of life cycle exhibited by these particular algae (haplontic, with zygotic meiosis; no sporophyte present) suggests that only an antithetic origin of the sporophyte in land plants is actually feasible.     

A morphological investigation of Culicoides spp. biting midges (Diptera: Ceratopogonidae) from the Caribbean.

Features of the antennae, maxillary palps, and mouthparts of the females of seven species of Culicoides spp. biting midges collected from a montane rainforest site in Trinidad, West Indies, were studied by light and scanning electron microscopy. Comparisons were made with two British species, Culicoides impunctatus and Culicoides nubeculosus. Species-specific differences were demonstrated in the camber and pitch of mandibular teeth, the size and shape of the subapical labral sensilla, the size and depth of the palpal sensory pit, and the number and shape of heads of the palpal sensilla. Counts of sensilla coeloconica and palpal sensilla were suggested as being contributory features for the prediction of host preference, indicating that Culicoides darlingtonae, Culicoides glabellus, Culicoides insinuatus, Culicoides paraensis, and Culicoides pseudodiabolicus were probably mammalophilic species. The host preferences of Culicoides heliconiae and Culicoides flavivenula could not be determined accurately.     

Inhibition of Helicobacter pylori haemagglutination activity by human salivary mucins

Thirty isolates of Helicobacter pylori from gastric biopsies agglutinated human erythrocyte suspensions. Crude mucin preparations derived from saliva of 20 different donors were examined for their ability to inhibit haemagglutination. All mucin preparations exhibited strong inhibitory activity. Removal of sialic residues from mucin preparations by treatment with neuraminidase resulted in a substantial reduction of their inhibitory activity. The mucin preparations had no bactericidal or aggregation activity for H. pylori. These results are discussed in the context of the role of mucins in colonization of the gastric mucosa by H. pylori.