The total burden of rare,non-synonymous exome genetic variants is not associated with childhood or late-life cognitive ability

Human cognitive ability shows consistent, positive associations with fitness components across the life-course. Underlying genetic variation should therefore be depleted by selection, which is not observed. Genetic variation in general cognitive ability (intelligence) could be maintained by a mutation–selection balance, with rare variants contributing to its genetic architecture. This study examines the association between the total number of rare stop-gain/loss, splice and missense exonic variants and cognitive ability in childhood and old age in the same individuals. Exome array data were obtained in the Lothian Birth Cohorts of 1921 and 1936 (combined N = 1596). General cognitive ability was assessed at age 11 years and in late life (79 and 70 years, respectively) and was modelled against the total number of stop-gain/loss, splice, and missense exonic variants, with minor allele frequency less than or equal to 0.01, using linear regression adjusted for age and sex. In both cohorts and in both the childhood and late-life models, there were no significant associations between rare variant burden in the exome and cognitive ability that survived correction for multiple testing. Contrary to our a priori hypothesis, we observed no evidence for an association between the total number of rare exonic variants and either childhood cognitive ability or late-life cognitive ability.     

Photometric elisa calibration for antibody assay

Summary The calibration of a quantitative ELISA assay for monoclonal antibodies based on a photometric measurement may be carried out using a cubic polynomial function of the logarithm of the antibody concentration, The fit is good and the error structure is well suited to the least squares fit method. The antibody concentrations are obtained from the roots of the calibration equation calculated by the cubic formulae.     

Dasatinib Inhibits CXCR4 Signaling in Chronic Lymphocytic Leukaemia Cells and Impairs Migration Towards CXCL12

Chemokines and their ligands play a critical role in enabling chronic lymphocytic leukaemia (CLL) cells access to protective microenvironmental niches within tissues, ultimately resulting in chemoresistance and relapse: disruption of these signaling pathways has become a novel therapeutic approach in CLL. The tyrosine kinase inhibitor dasatinib inhibits migration of several cell lines from solid-organ tumours, but effects on CLL cells have not been reported. We studied the effect of clinically achievable concentrations of dasatinib on signaling induced by the chemokine CXCL12 through its'' receptor CXCR4, which is highly expressed on CLL cells. Dasatinib pre-treatment inhibited Akt and ERK phosphorylation in CLL cells upon stimulation with CXCL12. Dasatinib also significantly diminished the rapid increase in actin polymerisation observed in CLL cells following CXCL12 stimulation. Moreover, the drug significantly inhibited chemotaxis in a transwell assay, and reduced the percentage of cells able to migrate beneath a CXCL12-expressing murine stromal cell line. Dasatinib also abrogated the anti-apoptotic effect of prolonged CXCL12 stimulation on cultured CLL cells. These data suggest that dasatinib, akin to other small molecule kinase inhibitors targeting the B-cell receptor signaling pathway, may redistribute CLL cells from protective tissue niches to the peripheral blood, and support the investigation of dasatinib in combination strategies.     

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.     

Treatment of Early Breast Cancer: A Report after Ten Years of a Clinical Trial

A controlled clinical trial has been carried out to compare radical mastectomy with wide excision (extended tylectomy) in the treatment of early breast cancer. Only patients aged 50 and over were included and 370 entered the trial during a period of 10 years. Postoperative radiotherapy was given in each case. In patients with clinically involved axillary nodes there was a significantly higher incidence of local and distant recurrence in those having a wide excision, and the survival of these patients was significantly less than those who had a radical mastectomy. In patients with clinically uninvolved nodes, although there was a significantly higher incidence of local recurrence in those having a wide excision, there was no increased incidence of distant recurrence and the survival rate was similar to those having a radical mastectomy.