Modeling expression quantitative trait loci in data combining ethnic populations

Background  

Combining data from different ethnic populations in a study can increase efficacy of methods designed to identify expression quantitative trait loci (eQTL) compared to analyzing each population independently. In such studies, however, the genetic diversity of minor allele frequencies among populations has rarely been taken into account. Due to the fact that allele frequency diversity and population-level expression differences are present in populations, a consensus regarding the optimal statistical approach for analysis of eQTL in data combining different populations remains inconclusive.     

Slow oscillations as a probe of the dynamics of the locus coeruleus-frontal cortex interaction in anesthetized rats

Multiunit or single unit activity recorded simultaneously from frontal cortex (FC) and locus coeruleus (LC) under ketamine anesthesia revealed that both regions show slow oscillatory activity, together or separately. If, however, both regions are engaged in this oscillatory activity, there is a systematic relationship between their phases with peak LC firing always following FC firing by 200–400 ms. This was confirmed by cross-correlational analyses, which indicated that the two structures temporarily form a resonant system. The FC-LC resonant state is, however, loose enough to remain open to other intrinsic or extrinsic influences, keeping the measured frequencies of oscillations at each site slightly different, as demonstrated by a delailed analysis of the autocorrelograms. An injection of lidocaine at the frontal cortex site, while sharply reducing the prefrontal activity to essentially zero, leads to an increase of the LC activity and to a modification of the shape of the LC autocorrelogram, but does not change appreciably the phase relationship between the activity in the two structures during the diminishing activity in FC.     

Preservation of extracellular space during fixation of the brain for electron microscopy

Adult mammalian brain contains about 20% extracellular space, but fixatives cause the cellular processes to ingest the extracellular fluid, and the space is not preserved in electron micrographs prepared by any of the conventional methods. This distortion can be prevented by replacing part of the sodium chloride in the extracellular fluid by an impermeant solute such as sucrose. To do this, the blood-brain barrier can be opened by vascular perfusion at 300 mmHg pressure, or the barrier can be bypassed by immersion of thin slices of fresh brain in the impermeant solution. In either case, addition of aldehyde fixatives and conventional processing then leads to the preservation of extracellular space in electron micrographs. Both procedures are as easy to use for routine fixation as conventional methods. In well fixed tissue the cellular processes are different in size, shape and electron density from the inflated profiles seen after the ingestion of extracellular fluid that accompanies conventional fixation. Moreover, extracellular space is found to separate widely some cellular elements, while leaving others contiguous.     

Evaluation of High-Throughput Genomic Assays for the Fc Gamma Receptor Locus

Cancer immunotherapy has been revolutionised by the use monoclonal antibodies (mAb) that function through their interaction with Fc gamma receptors (FcγRs). The low-affinity FcγR genes are highly homologous, map to a complex locus at 1p23 and harbour single nucleotide polymorphisms (SNPs) and copy number variation (CNV) that can impact on receptor function and response to therapeutic mAbs. This complexity can hinder accurate characterisation of the locus. We therefore evaluated and optimised a suite of assays for the genomic analysis of the FcγR locus amenable to peripheral blood mononuclear cells and formalin-fixed paraffin-embedded (FFPE) material that can be employed in a high-throughput manner. Assessment of TaqMan genotyping for FCGR2A-131H/R, FCGR3A-158F/V and FCGR2B-232I/T SNPs demonstrated the need for additional methods to discriminate genotypes for the FCGR3A-158F/V and FCGR2B-232I/T SNPs due to sequence homology and CNV in the region. A multiplex ligation-dependent probe amplification assay provided high quality SNP and CNV data in PBMC cases, but there was greater data variability in FFPE material in a manner that was predicted by the BIOMED-2 multiplex PCR protocol. In conclusion, we have evaluated a suite of assays for the genomic analysis of the FcγR locus that are scalable for application in large clinical trials of mAb therapy. These assays will ultimately help establish the importance of FcγR genetics in predicting response to antibody therapeutics.     

Family friction as ΔNp73 antagonises p73 and p53

p53 and its homolog p73 are responsible for guarding the genome and regulating cellular responses to genotoxic damage. However, life is never simple and in fact multiple isoforms of each gene exist which may have opposing functions. ΔNp73 is a truncated isoform of p73 which lacks the N-terminal transactivation domain and is up-regulated in a number of diverse primary tumour types. Although its exact cellular function is unclear, upregulation of ΔNp73 has been linked to various pro-tumour activities. Here we review the current literature surrounding this mysterious protein and reveal its potentially important functions in tumourigenesis and treatment resistance.