Transcriptional response to alcohol exposure in Drosophila melanogaster

Background  

Alcoholism presents widespread social and human health problems. Alcohol sensitivity, the development of tolerance to alcohol and susceptibility to addiction vary in the population. Genetic factors that predispose to alcoholism remain largely unknown due to extensive genetic and environmental variation in human populations. Drosophila, however, allows studies on genetically identical individuals in controlled environments. Although addiction to alcohol has not been demonstrated in Drosophila, flies show responses to alcohol exposure that resemble human intoxication, including hyperactivity, loss of postural control, sedation, and exposure-dependent development of tolerance.     

Bacterial swimming strategies and turbulence

Most bacteria in the ocean can be motile. Chemotaxis allows bacteria to detect nutrient gradients, and hence motility is believed to serve as a method of approaching sources of food. This picture is well established in a stagnant environment. In the ocean a shear microenvironment is associated with turbulence. This shear flow prevents clustering of bacteria around local nutrient sources if they swim in the commonly assumed "run-and-tumble" strategy. Recent observations, however, indicate a "back-and-forth" swimming behavior for marine bacteria. In a theoretical study we compare the two bacterial swimming strategies in a realistic ocean environment. The "back-and-forth" strategy is found to enable the bacteria to stay close to a nutrient source even under high shear. Furthermore, rotational diffusion driven by thermal noise can significantly enhance the efficiency of this strategy. The superiority of the "back-and-forth" strategy suggests that bacterial motility has a control function rather than an approach function under turbulent conditions.     

The question of uniqueness of ancient bacteria

Microorganisms are associated with a variety of ancient geological materials. However, conclusive proof that these organisms are as old as the geological material and not more recent introductions has generally been lacking. Over the years, numerous reports of the isolation of ancient bacteria from geological materials have appeared. Most of these have suffered from the fact that the protocol for the surface sterilization of the sample was either poorly defined, inadequate or rarely included data to validate the overall effectiveness of the sterilization protocol. With proper sterility validation and isolation protocol, a legitimate claim for the isolation of an ancient microbe can be made. Biochemical, physiological, or morphological data indicate that these ancient microbes are not significantly different from modern isolates. As the role (decomposition) of modern and ancient microbes has not changed over time, it is probably unreasonable to expect these organisms to be vastly different. A discussion on the reasons for the homogeneity of ancient and modern microbes is presented. Journal of Industrial Microbiology & Biotechnology (2002) 28, 32–41 DOI: 10.1038/sj/jim/7000174 Received 20 May 2001/ Accepted in revised form 16 June 2001     

A cyclin D-Cdk4 activity required for G2 phase cell cycle progression is inhibited in ultraviolet radiation-induced G2 phase delay.

Cyclin D-Cdk4 complexes have a demonstrated role in G1 phase, regulating the function of the retinoblastoma susceptibility gene product (Rb). Previously, we have shown that following treatment with low doses of UV radiation, cell lines that express wild-type p16 and Cdk4 responded with a G2 phase cell cycle delay. The UV-responsive lines contained elevated levels of p16 post-treatment, and the accumulation of p16 correlated with the G2 delay. Here we report that in UV-irradiated HeLa and A2058 cells, p16 bound Cdk4 and Cdk6 complexes with increased avidity and inhibited a cyclin D3-Cdk4 complex normally activated in late S/early G2 phase. Activation of this complex was correlated with the caffeine-induced release from the UV-induced G2 delay and a decrease in the level of p16 bound to Cdk4. Finally, overexpression of a dominant-negative mutant of Cdk4 blocked cells in G2 phase. These data indicate that the cyclin D3-Cdk4 activity is necessary for cell cycle progression through G2 phase into mitosis and that the increased binding of p16 blocks this activity and G2 phase progression after UV exposure.     

Cross-species analysis of genetically engineered mouse models of MAPK-driven colorectal cancer identifies hallmarks of the human disease

Effective treatment options for advanced colorectal cancer (CRC) are limited, survival rates are poor and this disease continues to be a leading cause of cancer-related deaths worldwide. Despite being a highly heterogeneous disease, a large subset of individuals with sporadic CRC typically harbor relatively few established ‘driver’ lesions. Here, we describe a collection of genetically engineered mouse models (GEMMs) of sporadic CRC that combine lesions frequently altered in human patients, including well-characterized tumor suppressors and activators of MAPK signaling. Primary tumors from these models were profiled, and individual GEMM tumors segregated into groups based on their genotypes. Unique allelic and genotypic expression signatures were generated from these GEMMs and applied to clinically annotated human CRC patient samples. We provide evidence that a Kras signature derived from these GEMMs is capable of distinguishing human tumors harboring KRAS mutation, and tracks with poor prognosis in two independent human patient cohorts. Furthermore, the analysis of a panel of human CRC cell lines suggests that high expression of the GEMM Kras signature correlates with sensitivity to targeted pathway inhibitors. Together, these findings implicate GEMMs as powerful preclinical tools with the capacity to recapitulate relevant human disease biology, and support the use of genetic signatures generated in these models to facilitate future drug discovery and validation efforts.KEY WORDS: KRAS, BRAF, MAPK, Colorectal cancer, GEMM, Genomic signatures     

The genetic basis of alcoholism: multiple phenotypes,many genes,complex networks

Alcoholism is a significant public health problem. A picture of the genetic architecture underlying alcohol-related phenotypes is emerging from genome-wide association studies and work on genetically tractable model organisms.     

Effects of oncogenic p110alpha subunit mutations on the lipid kinase activity of phosphoinositide 3-kinase

The PIK3CA gene, encoding the p110alpha catalytic subunit of Class IA PI3Ks (phosphoinositide 3-kinases), is frequently mutated in many human tumours. The three most common tumour-derived alleles of p110alpha, H1047R, E542K and E545K, were shown to potently activate PI3K signalling in human epithelial cells. In the present study, we examine the biochemical activity of the recombinantly purified PI3K oncogenic mutants. The kinetic characterizations of the wt (wild-type) and the three 'hot spot' PI3K mutants show that the mutants all have approx. 2-fold increase in lipid kinase activities. Interestingly, the phosphorylated IRS-1 (insulin receptor substrate-1) protein shows activation of the lipid kinase activity for the wt and H1047R but not E542K and E545K PI3Kalpha, suggesting that these mutations represent different mechanisms of lipid kinase activation and hence transforming activity in cancer cells.