Collaboration of signal transducer and activator of transcription 1 (STAT1) and BRCA1 in differential regulation of IFN-γ target genes

Most of the activities of IFN-γ are the result of STAT1-mediated transcriptional responses. In this study, we show that the BRCA1 tumor suppressor acts in concert with STAT1 to differentially activate transcription of a subset of IFN-γ target genes and mediates growth inhibition by this cytokine. After IFN-γ treatment, induction of the cyclin-dependent kinase inhibitor, p21WAF1, was synergistically activated by BRCA1, whereas the IRF-1 gene was unaffected. Importantly, the differential induction of p21WAF1 was impaired in breast cancer cells homozygous for the mutant BRCA1 5382C allele. Biochemical analysis illustrated that the mechanism of this transcriptional synergy involves interaction between BRCA1 aa 502–802 and the C-terminal transcriptional activation domain of STAT1 including Ser-727 whose phosphorylation is crucial for transcriptional activation. Significantly, STAT1 proteins mutated at Ser-727 bind poorly to BRCA1, reinforcing the importance of Ser-727 in the recruitment of transcriptional coactivators by STAT proteins. These findings reveal a novel mechanism for BRCA1 function in the IFN-γ-dependent tumor surveillance system.

A first trial of retrospective collaboration for positional cloning in complex inheritance: Assay of the cytokine region on chromosome 5 by the Consortium on Asthma Genetics (COAG)

The central problem of complex inheritance is to map oligogenes for disease susceptibility, integrating linkage and association over samples that differ in several ways. Combination of evidence over multiple samples with 1,037 families supports loci contributing to asthma susceptibility in the cytokine region on 5q [maximum logarithm of odds (lod) = 2.61 near IL-4], but no evidence for atopy. The principal problems with retrospective collaboration on linkage appear to have been solved, providing far more information than a single study. A multipoint lod table evaluated at commonly agreed reference loci is required for both collaboration and metaanalysis, but variations in ascertainment, pedigree structure, phenotype definition, and marker selection are tolerated. These methods are invariant with statistical methods that increase the power of lods and are applicable to all diseases, motivating collaboration rather than competition. In contrast to linkage, positional cloning by allelic association has yet to be extended to multiple samples, a prerequisite for efficient combination with linkage and the greatest current challenge to genetic epidemiology.

Global warming in the twenty-first century: An alternative scenario

A common view is that the current global warming rate will continue or accelerate. But we argue that rapid warming in recent decades has been driven mainly by non-CO2 greenhouse gases (GHGs), such as chlorofluorocarbons, CH4, and N2O, not by the products of fossil fuel burning, CO2 and aerosols, the positive and negative climate forcings of which are partially offsetting. The growth rate of non-CO2 GHGs has declined in the past decade. If sources of CH4 and O3 precursors were reduced in the future, the change in climate forcing by non-CO2 GHGs in the next 50 years could be near zero. Combined with a reduction of black carbon emissions and plausible success in slowing CO2 emissions, this reduction of non-CO2 GHGs could lead to a decline in the rate of global warming, reducing the danger of dramatic climate change. Such a focus on air pollution has practical benefits that unite the interests of developed and developing countries. However, assessment of ongoing and future climate change requires composition-specific long-term global monitoring of aerosol properties.

A “midinfrared” scenario for cuprate superconductivity

I conjecture that the mechanism of superconductivity in the cuprates is a saving, due to the improved screening resulting from Cooper pair formation, of the part of the Coulomb energy associated with long wavelengths and midinfrared frequencies. This scenario is shown to provide a plausible explanation of the trend of transition temperature with layering structure in the Ca-spaced compounds and to predict a spectacularly large decrease in the electron-energy-loss spectroscopy cross-section in the midinfrared region on transition to the superconducting state, as well as less spectacular but still surprisingly large changes in the optical behavior. Existing experimental results appear to be consistent with this picture.