Novel cyclohexyl-amides as potent antibacterials targeting bacterial type IIA topoisomerases

As part of our wider efforts to exploit novel mode of action antibacterials, we have discovered a series of cyclohexyl-amide compounds that has good Gram positive and Gram negative potency. The mechanism of action is via inhibition of bacterial topoisomerases II and IV. We have investigated various subunits in this series and report advanced studies on compound 7 which demonstrates good PK and in vivo efficacy properties.     

Novel amino-piperidines as potent antibacterials targeting bacterial type IIA topoisomerases

We have identified a series of amino-piperidine antibacterials with a good broad spectrum potency. We report the investigation of various subunits in this series and advanced studies on compound 8. Compound 8 possesses good pharmacokinetics, broad spectrum antibacterial activity and demonstrates oral efficacy in a rat lung infection model.     

Global impact of biotech crops: environmental effects, 1996-2010

This paper updates the assessment of the impact commercialized agricultural biotechnology is having on global agriculture, from some important environmental perspectives. It focuses on the impact of changes in pesticide use and greenhouse gas emissions arising from the use of biotech crops. The technology has reduced pesticide spraying by 443 million kg (-9.1%) and, as a result, decreased the environmental impact associated with herbicide and insecticide use on these crops [as measured by the indicator the Environmental Impact Quotient (EIQ)] by 17.9%. The technology has also significantly reduced the release of greenhouse gas emissions from this cropping area, which, in 2010, was equivalent to removing 8.6 million cars from the roads.     

A gene for lymphedema-distichiasis maps to 16q24.3.

Lymphedema-distichiasis (LD) is a dominantly inherited syndrome with onset of lymphedema at or just after puberty. Most affected individuals have distichiasis-fine hairs arising inappropriately from the eyelid meibomian glands-which is evident from birth. A study of three families with LD has shown linkage to chromosome 16q24.3, and subsequent analysis of the region for recombinant genes places the locus between D16S422 and D16S3074, a distance of approximately 16 cM. Possible candidate genes in this interval include the N-proteinase for type 3 collagen, PCOLN3; the metalloprotease PRSM1; and the cell matrix-adhesion regulator, CMAR.     

Growth and mortality of age-0 northern squawfish, Ptychocheilus oregonensis, rearing in shoreline habitats of a Columbia River reservoir

We investigated growth and mortality of age-0 northern squawfish during early rearing in shallow shoreline habitats. Larvae and juveniles (n=22914) were collected by weekly seining at three sample sites in the upper John Day Reservoir, Columbia River, during June through early September 1994–1996. Using a length-based ageing method, it was estimated that the exponential growth rate (G) for a common growth stanza (10–28 mm standard length SL) was significantly higher in 1994 (G=0.047) than in 1996 (G=0.037). Growth rate in 1995 could not be estimated, but was probably intermediate between 1994 and 1996 based on mean standard lengths of fish collected at the end of each sampling season (46.3, 40.0, and 32.0 mm SL in 1994, 1995, and 1996, respectively). For many fish species, variations in early growth can influence survival through size-selective mortality processes. Consistent with this possibility, our estimates of instantaneous mortality rates (Z) demonstrated that larvae and juveniles had significantly higher mortality in 1996 than in 1994 (Z=0.103 in 1994, versus Z=0.138 in 1996). Enhanced growth and lower mortality in 1994 were associated with a number of interrelated environmental conditions – comparatively low flows and turbidities, abundant instream vegetative cover, and high near-shore water temperatures.     

Functional Analysis of the Bacteriophage T4 Rad50 Homolog (gp46) Coiled-coil Domain

Rad50 and Mre11 form a complex involved in the detection and processing of DNA double strand breaks. Rad50 contains an anti-parallel coiled-coil with two absolutely conserved cysteine residues at its apex. These cysteine residues serve as a dimerization domain and bind a Zn²⁺ cation in a tetrathiolate coordination complex known as the zinc-hook. Mutation of the zinc-hook in bacteriophage T4 is lethal, indicating the ability to bind Zn²⁺ is critical for the functioning of the MR complex. In vitro, we found that complex formation between Rad50 and a peptide corresponding to the C-terminal domain of Mre11 enhances the ATPase activity of Rad50, supporting the hypothesis that the coiled-coil is a major conduit for communication between Mre11 and Rad50. We constructed mutations to perturb this domain in the bacteriophage T4 Rad50 homolog. Deletion of the Rad50 coiled-coil and zinc-hook eliminates Mre11 binding and ATPase activation but does not affect its basal activity. Mutation of the zinc-hook or disruption of the coiled-coil does not affect Mre11 or DNA binding, but their activation of Rad50 ATPase activity is abolished. Although these mutants excise a single nucleotide at a normal rate, they lack processivity and have reduced repetitive exonuclease rates. Restricting the mobility of the coiled-coil eliminates ATPase activation and repetitive exonuclease activity, but the ability to support single nucleotide excision is retained. These results suggest that the coiled-coiled domain adopts at least two conformations throughout the ATPase/nuclease cycle, with one conformation supporting enhanced ATPase activity and processivity and the other supporting nucleotide excision.     

Perceptions of obesity in a UK leisure-based population of horse owners

Pregnancy rates with cooled equine semen can be unsatisfactory and show great variation. Information about first cycle pregnancy rates and pregnancy rates per cycle are often lacking from publicly available records. This retrospective cohort study was performed to evaluate the fertility of the Norwegian Coldblooded trotter. The aim of the study was to compare the breeding results after insemination with fresh, extended with those of cooled, shipped semen among Norwegian Coldblooded trotter mares. First cycle pregnancy rate was the main parameter used to measure fertility. Stud-books were collected from four studs from the years 2006–2010. Statistical analyses were done in Stata using Chi square test and multivariable analyses where different models were compared based on Akaike’s information criterion. First cycle pregnancy rate, seasonal pregnancy rate and foaling rate all showed significant differences (P < 0.0001) when comparing mares inseminated at stud with mares inseminated with cooled, shipped semen, favoring artificial insemination (AI) at stud. First cycle pregnancy rate was 55.1 % for mares inseminated at stud with fresh extended semen and 42.2 % for mares inseminated with cooled shipped semen. The overall pregnancy rate per cycle was 84.4 % for AI at stud and 66.9 % for cooled, shipped semen. The parameters stud, mare age, number of inseminations within an estrus cycle and individual stallion were also investigated for influence on fertility. Few retrospective studies include the parameter of first cycle pregnancy rates. Our study does not differ dramatically when comparing seasonal pregnancy rates and foaling rates with similar studies. Fertility parameters for the Norwegian Coldblooded trotter do not differ significantly from most other studies of Coldblooded mares and other mare breeds around the world. But the difference in fertility parameters between AI at stud to AI with cooled semen between our study and others, indicates that higher pregnancy rates in Norwegian Coldblooded trotter may be possible.     

The income and production effects of biotech crops globally 1996-2010

A critical feature in evaluating the global value of crop biotechnology in agriculture must include an assessment of its economic impact at the farm level. This paper follows earlier studies which examined economic impacts on yields, key costs of production, direct farm income, indirect (non-pecuniary) farm level income effects and impacts on the production base of the four main crops of soybeans, corn, cotton and canola. The commercialization of biotech crops is continuing to proceed rapidly, with significant changes in the overall level of adoption and impact taking place in 2010. This updated analysis shows that there have been substantial net economic benefits at the farm level amounting to $14 billion in 2010 and $78.4 billion for the 15-year period (in nominal terms). The non-pecuniary benefits associated with the use of the technology have also had a positive impact on adoption (in the US accounting for the equivalent of 22% of the total US direct farm income benefit). Biotech crops are, moreover, making important contributions to increasing global production levels of the four main crops. They have, for example, now added 97.5 million tons and 159 million tons respectively, to the global production of soybeans and corn since the introduction of the technology in the mid-1990s.     

Variants in CHEK2 other than 1100delC do not make a major contribution to breast cancer susceptibility

We recently reported that a sequence variant in the cell-cycle-checkpoint kinase CHEK2 (CHEK2 1100delC) is a low-penetrance breast cancer-susceptibility allele in noncarriers of BRCA1 or BRCA2 mutations. To investigate whether other CHEK2 variants confer susceptibility to breast cancer, we screened the full CHEK2 coding sequence in BRCA1/2-negative breast cancer cases from 89 pedigrees with three or more cases of breast cancer. We identified one novel germline variant, R117G, in two separate families. To evaluate the possible association of R117G and two germline variants reported elsewhere, R145W and I157T with breast cancer, we screened 737 BRCA1/2-negative familial breast cancer cases from 605 families, 459 BRCA1/2-positive cases from 335 families, and 723 controls from the United Kingdom, the Netherlands, and North America. All three variants were rare in all groups, and none occurred at significantly elevated frequency in familial breast cancer cases compared with controls. These results indicate that 1100delC may be the only CHEK2 allele that makes an appreciable contribution to breast cancer susceptibility.     

Consistent loss of genetic diversity in isolated cutthroat trout populations independent of habitat size and quality

Fragmentation and isolation of wildlife populations has reduced genetic diversity worldwide, leaving many populations vulnerable to inbreeding depression and local extinction. Nonetheless, isolation is protecting many native aquatic species from interactions with invasive species, often making reconnection an unrealistic conservation strategy. Isolation management is widely used to protect extant cutthroat trout (Oncorhynchus clarkii) populations from invasive species. Despite this, few studies have empirically examined how predictor variables including habitat length, population size, time since isolation and habitat quality, relate to levels of genetic diversity in isolated trout populations. We compared allelic richness of cutthroat trout across 14 microsatellite loci in two connected and 12 anthropogenically isolated populations of the Flathead River basin, Montana. Isolated populations in habitat fragments <8 km stream length had reduced genetic diversity, but diversity was not significantly related to any of our predictor variables. To broaden our scope, we analyzed seven geologically isolated populations from the same river basin occupying habitat fragments up to 18 km in length. These populations showed reduced diversity, regardless of fragment size. Furthermore, geologically isolated populations had significantly lower average allelic richness compared to streams recently isolated by anthropogenic activities. These results demonstrate a consistent loss of genetic diversity through time in isolated populations, emphasizing the need to explore strategies to minimize risks of inbreeding depression. Testing conservation theory and subsequent assumptions broadly across taxa is necessary to ensure efficacy of conservation efforts.