Analysis of expansion of myeloid progenitors in mice to identify leukemic susceptibility genes

The myeloid progenitor cell compartment (MPC) exhibits pronounced expansion in human myeloid leukemias. It is becoming more apparent that progression of myelodysplastic syndromes and myeloproliferative diseases to acute myelogenous leukemia is the result of defects in progenitor cell maturation. The MPC of bone marrow was analyzed in mice using a cell culture assay for measuring the relative frequency of proliferative myeloid progenitors. Response to the cytokines SCF, IL-3, and GM-CSF was determined by this assay for the leukemic mouse strain BXH-2 and ten other inbred mouse strains. Significant differences were found to exist among ten inbred mouse strains in the nature of their MPC in bone marrow, indicating the presence of genetic polymorphisms responsible for the divergence. The SWR/J and FVB/J strains show consistently low frequencies of myeloid progenitors, while the DBA/2J and SJL/J inbred strains show consistently high frequencies of myeloid progenitors within the bone marrow compartment. In addition, in silico linkage disequilibrium analysis was conducted to identify possible chromosomal regions responsible for the phenotypic variation. Given the importance of this cell compartment in leukemia progression and the soon to be released genomic sequence of 15 mouse strains, these differences may provide a valuable tool for research into leukemia.     

The NUG1 GTPase reveals and N-terminal RNA-binding domain that is essential for association with 60 S pre-ribosomal particles

The putative yeast GTPase Nug1, which is associated with several pre-60 S particles in the nucleolus and nucleoplasm, consists of an N-terminal domain, which is found only in eukaryotic orthologues, and middle and C-terminal domains that are conserved throughout eukaryotes, bacteria, and archaea. Here, we analyzed the role of the eukaryote-specific Nug1 N-domain (Nug1-N). We show that the essential Nug1-N is sufficient and necessary for nucle(ol)ar targeting and association with pre-60 S particles. Nug1-N exhibits RNA binding activity and is genetically linked in an allele-specific way to the pre-60 S factors Noc2, Noc3, and Dbp10. In contrast, the middle domain, which exhibits a circularly permuted GTPase fold and an intrinsic GTP hydrolysis activity in vitro, is not essential for cell growth. The conserved Nug1 C-domain, which has a yet uncharacterized fold, is also essential for ribosome biogenesis. Our findings suggest that Nug1 associates with pre-60 S subunits via its essential N-terminal RNA-binding domain and exerts a non-essential regulative role in pre-60 S subunit biogenesis via its central GTPase domain.     

Effects of ribose as an ergogenic aid

The amount of adenosine triphosphate (ATP) stored in the muscle available for immediate use is limited, and once used, must be resynthesized in the muscle. Ribose, a naturally occurring pentose sugar, helps resynthesize ATP for use in muscles. There have been claims that ribose supplements increase ATP levels and improve performance. Other studies have provided mixed results on the effectiveness of ribose as an ergogenic aid at high doses. None of these studies have compared the impact of the recommended dose of ribose on athletes and nonathletes under exercise conditions that are most conducive for effectiveness. The purpose of this study was to evaluate the effectiveness of ribose as an ergogenic aid at the dose recommended for supplements currently on the market during an exercise trial to maximize its efficacy. Male subjects (n = 11) performed 2 trials 1 week apart. Each trial consisted of three 30-second Wingate tests with a 2-minute recovery between each test. Trials were counterbalanced, with 1 trial being performed with 625 mg of ribose and the other with a placebo. Peak power, mean power, and percent decrease in power were recorded during each Wingate test. Repeated-measures analysis of variance (p > 0.05) found no significant differences between ribose and placebo. These results suggest that ribose had no effect on performance when taken orally, at the dose suggested by the distributor.     

Fluctuations in densities of the invasive gill parasite Centrocestus formosanus (Trematoda: Heterophyidae) in the Comal River, Comal County, Texas, U.S.A

Centrocestus formosanus (Trematoda: Heterophyidae) is an invasive fish parasite in the Comal River, Texas, and is considered a threat to the federally endangered fountain darter, Etheostoma fonticola . Monitoring densities of C. formosanus cercariae is crucial to determining levels of infection pressure. We sampled 3 sites in the Comal River during 2 sampling periods, the first during 2006-2007, and again during 2009-2010. Two of the sites were located in the upstream reach of Landa Lake, sites HS and LA, and the third site was located downstream of Landa Lake in the old channel of the river. Cercariae densities were highest at the downstream most site (EA), followed by sites LA and HS, during both sampling periods, but a significant decline in cercariae density was observed between the first and second sampling periods. Several abiotic factors were monitored, including total stream discharge, wading discharge, temperature, and dissolved oxygen, but no river-wide trends were observed. Therefore, we speculate that these factors do not adequately explain the observed long-term decline in cercariae density. We propose that the decline is simply a reflection of a typical pattern followed by most invasive species as they gradually become integrated into the local community following an initial explosive growth in population size. Although cercariae densities may be abating, fountain darters in the Comal River are still threatened by the parasite, and conservation efforts must focus on reducing levels of infection pressure from the parasite whenever possible.     

Inhibitors of the acetyltransferase domain of N-acetylglucosamine-1-phosphate-uridylyltransferase/glucosamine-1-phosphate-acetyltransferase (GlmU). Part 2: Optimization of physical properties leading to antibacterial aryl sulfonamides

A previously described aryl sulfonamide series, originally found through HTS, targets GlmU, a bifunctional essential enzyme involved in bacterial cell wall synthesis. Using structure-guided design, the potency of enzyme inhibition was increased in multiple isozymes from different bacterial species. Unsuitable physical properties (low Log D and high molecular weight) of those compounds prevented them from entering the cytoplasm of bacteria and inhibiting cell growth. Further modifications described herein led to compounds that possessed antibacterial activity, which was shown to occur through inhibition of GlmU. The left-hand side amide and the right-hand side sulfonamides were modified such that enzyme inhibitory activity was maintained (IC₅₀ <0.1 μM against GlmU isozymes from Gram-negative organisms), and the lipophilicity was increased giving compounds with Log D ?1 to 3. Antibacterial activity in an efflux-pump deficient mutant of Haemophilus influenzae resulted for compounds such as 13.