Behavioural and neurochemical correlates of drugs acting at imidazoline and a2-adrenoceptor binding sites

A number of agents with differing selectivity profiles for the non-a2 adrenoceptor binding site (NAIBS), imidazoline preferring receptor (IPR) and a2-adrenoceptor were employed in a series of behavioural and neurochemical experiments to determine a functional role for the former two sites. The highly selective NAIBS ligand RX801 077 produced an increase in rat brain extracellular noradrenaline (NA) levels, as determined by the technique of in vivo microdialysis, which may underlie its ability to produce a discriminable cue in the same species. This increase in NA may be due to a suggested link between the NAIBS and the monoamine oxidase inhibitor (MAOI) activity of RX801 077. For instance, the RX801 077 cue was substituted for by the MAOI drugs pargyline and moclobemide, which themselves down regulate NAIBS when administered chronically. RX811 059 substituted for the RX801 077 cue which may be due its ability to stimulate NA release via its activity as a highly selective a2-adrenoceptor antagonist. An effect upon NA output may also explain the ability of RX801 077 to 'mimic' the anti-immobility effect of the antidepressant drug desmethylimipramine (DMJ) in the forced swimming test. Further studies are therefore required to examine a possible role for the NAIBS in the treatment of depression. Discriminable cues were also produced by RX811 059 and the a2- adrenoceptor agonist clonidine, probably as a consequence of their respective ability to stimulate and inhibit NA output via their opposing activity at a2-adrenoceptors. The IPR has been suggested to play a role in mediating the hypotensive effect of clonidine, although a precise role was unable to be established for this site in the present studies due to the unavailability of highly selective IPA agents.

The HLA-A2-supermotif:a QSAR definition

Identification of epitopes capable of binding multiple HLA types will significantly rationalise the development of epitope-based vaccines. A quantitative method assessing the contribution of each amino acid at each position was applied to over 500 nonamer peptides binding to 5 MHC alleles — A*0201, A*0202, A*0203, A*0206 and A*6802 — which together define the HLA-A2-like supertype. FXIGXI (L)IFV was identified as a supermotif for the A2-supertype based on the contributions of the common preferred amino acids at each of the nine positions. The results indicate that HLA-A*6802 is an intermediate allele standing between A2 and A3 supertypes: at anchor position 2 it is closer to A3 and at anchor position 9 it is nearer to A2. Models are available free on-line at http://www.jenner.ac.uk/MHCPred and can be used for binding affinity prediction.

Induction de la capacitation des spermatozoïdes épididymaires porcins par pB1 et BSP-A1/-A2, des protéines de la famille des protéines BSP

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Induction de la capacitation des spermatozoïdes épididymaires porcins par pB1 et BSP-A1/-A2, des protéines de la famille des protéines BSP

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Particle flux measured on deep sea sediment trap VP-2_trap (Appendix A2.7)

A 17 month record of vertical particle flux of dry weight, carbonate and organic carbon were 25.8, 9.4 and 2.4g/m**2/y, respectively. Parallel to trap deployments, pelagic system structure was recorded with high vertical and temporal resolution. Within a distinct seasonal cycle of vertical particle flux, zooplankton faecal pellets of various sizes, shapes and contents were collected by the traps in different proportions and quantities throughout the year (range: 0-4,500 10**3/m**2/d). The remains of different groups of organisms showed distinct seasonal variations in abundance. In early summer there was a small maximum in the diatom flux and this was followed by pulses of tinntinids, radiolarians, foraminiferans and pteropods between July and November. Food web interactions in the water column were important in controlling the quality and quantity of sinking materials. For example, changes in the population structure of dominant herbivores, the break-down of regenerating summer populations of microflagellates and protozooplankton and the collapse of a pteropod dominated community, each resulted in marked sedimentation pulses. These data from the Norwegian Sea indicate those mechanisms which either accelerate or counteract loss of material via sedimentation. These involve variations in the structure of the pelagic system and they operatè on long (e.g. annual plankton succession) and short (e.g. the end of new production, sporadic grazing of swarm feeders) time scales. Connecting investigation of the water column with a high resolution in time in parallel with drifting sediment trap deployments and shipboard experiments with the dominant zooplankters is a promising approach for giving a better understanding of both the origin and the fate of material sinking to the sea floor.

Trace element composition of IODP Site 304-U1309 and 305-U1309 (Table A2)

IODP Site U1309 was drilled at Atlantis Massif, an oceanic core complex, at 30°N on the Mid-Atlantic Ridge (MAR). We present the results of a bulk rock geochemical study (major and trace elements) carried out on 228 samples representative of the different lithologies sampled at this location. Over 96% of Hole U1309D is made up of gabbroic rocks. Diabases and basalts cross-cut the upper part of the section; they have depleted MORB compositions similar to basalts sampled at MAR 30°N. Relics of mantle were recovered at shallow depth. Mantle peridotites show petrographic and geochemical evidence of extensive melt-rock interactions. Gabbroic rocks comprise: olivine-rich troctolites (> 70% modal olivine) and troctolites having high Mg# (82-89), high Ni (up to 2300 ppm) and depleted trace element compositions (Yb 0.06-0.8 ppm); olivine gabbros and gabbros (including gabbronorites) with Mg# of 60-86 and low trace element contents (Yb 0.125-2.5 ppm); and oxide gabbros and leucocratic dykes with low Mg# (< 50), low Ni (~65 ppm) and high trace element contents (Yb up to 26 ppm). Troctolites and gabbros are amongst the most primitive and depleted oceanic gabbroic rocks. The main geochemical characteristics of Site U1309 gabbroic rocks are consistent with a formation as a cumulate sequence after a common parental MORB melt, although (lack of systematic) downhole variations indicate that the gabbroic series were built by multiple magma injections. In detail, textural and geochemical variations in olivine-rich troctolites and gabbronorites suggest chemical interaction (assimilation?) between the parental melt and the intruded lithosphere. Site U1309 gabbroic rocks do not represent the complementary magmatic product of 30°N volcanics, although they sample the same mantle source. The bulk trace element composition of Site U1309 gabbroic rocks is similar to primitive MORB melt compositions; this implies that there was no large scale removal of melts from this gabbro section. The occurrence of such a large magmatic sequence implies that a high magmatic activity is associated with the formation of Atlantis Massif. Our results suggest that almost all melts feeding this magmatic system stays trapped into the intruded lithosphere.

Thromboxane A2 receptor (TBXA2R) is a potent survival factor for triple negative breast cancers (TNBCs)

Triple Negative Breast Cancer (TNBC) is defined by the lack of ERα, PR expression and HER2 overexpression and is the breast cancer subtype with the poorest clinical outcomes. Our aim was to identify genes driving TNBC proliferation and/or survival which could represent novel therapeutic targets. We performed microarray profiling of primary TNBCs and generated differential genelists based on clinical outcomes following the chemotherapy regimen FEC (5-Fluorouracil/Epirubicin/Cyclophosphamide -‘good’ outcome no relapse > 3 years; ‘poor’ outcome relapse < 3 years). Elevated expression of thromboxane A2 receptor (TBXA2R) was observed in ‘good’ outcome TNBCs. TBXA2R expression was higher specifically in TNBC cell lines and TBXA2R knockdowns consistently showed dramatic cell killing in TNBC cells. TBXA2R mRNA and promoter activities were up-regulated following BRCA1 knockdown, with c-Myc being required for BRCA1-mediated transcriptional repression. We demonstrated that TBXA2R enhanced TNBC cell migration, invasion and activated Rho signalling, phenotypes which could be reversed using Rho-associated Kinase (ROCK) inhibitors. TBXA2R also protected TNBC cells from DNA damage by negatively regulating reactive oxygen species levels. In summary, TBXA2R is a novel breast cancer-associated gene required for the survival and migratory behaviour of a subset of TNBCs and could provide opportunities to develop novel, more effective treatments.

Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer's disease.

Genome-wide association studies (GWAS) have identified several risk variants for late-onset Alzheimer's disease (LOAD)1, 2. These common variants have replicable but small effects on LOAD risk and generally do not have obvious functional effects. Low-frequency coding variants, not detected by GWAS, are predicted to include functional variants with larger effects on risk. To identify low-frequency coding variants with large effects on LOAD risk, we carried out whole-exome sequencing (WES) in 14 large LOAD families and follow-up analyses of the candidate variants in several large LOAD case–control data sets. A rare variant in PLD3 (phospholipase D3; Val232Met) segregated with disease status in two independent families and doubled risk for Alzheimer’s disease in seven independent case–control series with a total of more than 11,000 cases and controls of European descent. Gene-based burden analyses in 4,387 cases and controls of European descent and 302 African American cases and controls, with complete sequence data for PLD3, reveal that several variants in this gene increase risk for Alzheimer’s disease in both populations. PLD3 is highly expressed in brain regions that are vulnerable to Alzheimer’s disease pathology, including hippocampus and cortex, and is expressed at significantly lower levels in neurons from Alzheimer’s disease brains compared to control brains. Overexpression of PLD3 leads to a significant decrease in intracellular amyloid-β precursor protein (APP) and extracellular Aβ42 and Aβ40 (the 42- and 40-residue isoforms of the amyloid-β peptide), and knockdown of PLD3 leads to a significant increase in extracellular Aβ42 and Aβ40. Together, our genetic and functional data indicate that carriers of PLD3 coding variants have a twofold increased risk for LOAD and that PLD3 influences APP processing. This study provides an example of how densely affected families may help to identify rare variants with large effects on risk for disease or other complex traits.