Notch Ankyrin Repeat Domain Variation Influences Leukemogenesis and Myc Transactivation

, cell-based and structural analyses to compare the abilities of activated Notch1-4 to support T cell development, induce T cell acute lymphoblastic leukemia/lymphoma (T-ALL), and maintain T-ALL cell growth and survival., a direct Notch target that has an important role in Notch-associated T-ALL.We conclude that the leukemogenic potentials of Notch receptors vary, and that this functional difference stems in part from divergence among the highly conserved ankyrin repeats, which influence the transactivation of specific target genes involved in leukemogenesis

Phenotype Enhancement Screen of a Regulatory spx Mutant Unveils a Role for the ytpQ Gene in the Control of Iron Homeostasis

Spx is a global regulator of genes that are induced by disulfide stress in Bacillus subtilis. The regulon that it governs is comprised of over 120 genes based on microarray analysis, although it is not known how many of these are under direct Spx control. Most of the Spx-regulated genes (SRGs) are of unknown function, but many encode products that are conserved in low %GC Gram-positive bacteria. Using a gene-disruption library of B. subtilis genomic mutations, the SRGs were screened for phenotypes related to Spx-controlled activities, such as poor growth in minimal medium and sensitivity to methyglyoxal, but nearly all of the SRG mutations showed little if any phenotype. To uncover SRG function, the mutations were rescreened in an spx mutant background to determine which mutant SRG allele would enhance the spx mutant phenotype. One of the SRGs, ytpQ was the site of a mutation that, when combined with an spx null mutation, elevated the severity of the Spx mutant phenotype, as shown by reduced growth in a minimal medium and by hypersensitivity to methyglyoxal. The ytpQ mutant showed elevated oxidative protein damage when exposed to methylglyoxal, and reduced growth rate in liquid culture. Proteomic and transcriptomic data indicated that the ytpQ mutation caused the derepression of the Fur and PerR regulons of B. subtilis. Our study suggests that the ytpQ gene, encoding a conserved DUF1444 protein, functions directly or indirectly in iron homeostasis. The ytpQ mutant phenotype mimics that of a fur mutation, suggesting a condition of low cellular iron. In vitro transcription analysis indicated that Spx stimulates transcription from the ytpPQR operon within which the ytpQ gene resides. The work uncovers a link between Spx and control of iron homeostasis

Synonymous but not the same: the causes and consequences of codon bias

Despite their name, synonymous mutations have significant consequences for cellular processes in all taxa. As a result, an understanding of codon bias is central to fields as diverse as molecular evolution and biotechnology. Although recent advances in sequencing and synthetic biology have helped resolve longstanding questions about codon bias, they have also uncovered striking patterns that suggest new hypotheses about protein synthesis. Ongoing work to quantify the dynamics of initiation and elongation is as important for understanding natural synonymous variation as it is for designing transgenes in applied contexts

Trends in HIV counseling and testing uptake among married individuals in Rakai, Uganda.

BACKGROUND: Despite efforts to promote HIV counseling and testing (HCT) among couples, few couples know their own or their partners' HIV status. We assessed trends in HCT uptake among married individuals in Rakai district, southwestern Uganda. METHODS: We analysed data for 11,268 married individuals aged 15-49 years who were enrolled into the Rakai Community Cohort Study (RCCS) between 2003 and 2009. Married individuals were interviewed separately but were retrospectively linked to their partners at analysis. All participants had serologic samples obtained for HIV testing, and had the option of receiving HCT together (couples' HCT) or separately (individual HCT). Individuals were categorized as concordant HIV-positive if both partners had HIV; concordant HIV-negative if both did not have HIV; or HIV-discordant if only one of the partners had HIV. We used χ2 tests to assess linear trends in individual and couples' HCT uptake in the entire sample and conducted multinomial logistic regression on a sub-sample of 10,712 individuals to assess relative risk ratios (RRR) and 95% Confidence Intervals (95% CI) associated with individual and couples' HCT uptake. Analysis was done using STATA version 11.0. RESULTS: Uptake of couples' HCT was 27.2% in 2003/04, 25.1% in 2005/06, 28.5% in 2006/08 and 27.8% in 2008/09 (χ2 for trend = 2.38; P = 0.12). Uptake of individual HCT was 57.9% in 2003/04, 60.2% in 2005/06, 54.0% in 2006/08 and 54.4% in 2008/09 (χ2 for trend = 8.72; P = 0.003). The proportion of couples who had never tested increased from 14.9% in 2003/04 to 17.8% in 2008/09 (χ2 for trend = 18.16; P < 0.0001). Uptake of couples' HCT was significantly associated with prior HCT (Adjusted [Adj.] RRR = 6.80; 95% CI: 5.44, 8.51) and being 25-34 years of age (Adj. RRR = 1.81; 95% CI: 1.32, 2.50). Uptake of individual HCT was significantly associated with prior HCT (Adj. RRR = 6.26; 95% CI: 4.24, 9.24) and the female partner being HIV-positive (Adj. RRR = 2.46; 95% CI: 1.26, 4.80). CONCLUSION: Uptake of couples' HCT remained consistently low (below 30%) over the years, while uptake of individual HCT declined over time. These findings call for innovative strategies to increase demand for couples' HCT, particularly among younger couples and those with no prior HCT

The promise of solution-processed Fe2GeS4 thin films in iron chalcogenide photovoltaics

The olivine Fe2GeS4, featuring non-toxic elements, cost-effective synthesis, and suitable optoelectronic properties, recently emerged as a promising light-absorbing candidate. Fe2GeS4 precursor powders obtained via a simple solutionbased process were converted to highly crystalline Fe2GeS4 powders upon a thermal treatment in controlled atmosphere. Thin films fabricated by dip coating in the Fe2GeS4 precursor dispersion and subjected to the same thermal treatment render high-purity Fe2GeS4 thin films with a band gap of 1.4 eV, measured by room-temperature photoluminescence. Using Fe2GeS4 thin films as the sole absorber in a solution-based solar cell, open-circuit voltages of 361 mV are observed, while the use of the Fe2GeS4 films as counter electrodes in dyesensitized solar cell constructs enhances the overall power conversion efficiency of the cell by a factor of five. This is the first report of a photovoltaic device based on Fe2GeS4