102 research outputs found
A study of handling cytotoxic drugs and risk of birth defects in offspring of female veterinarians
We examined the association of occupational exposure to handling cytotoxic drugs at work with risk of birth defects among a cohort of female veterinarians. This study is a follow up survey of 321 female participants (633 pregnancies) who participated in the Health Risks of Australian Veterinarian project. Data on pregnancies and exposure during each pregnancy was obtained by self-administered mailed questionnaire. Female veterinarians handling cytotoxic drugs during their pregnancy had a two-fold increased risk of birth defects in their offspring (RR = 2.08, 95% CI (1.05–4.15)). Results were consistent in subgroup analysis of those who graduated during the period of 1961 to 1980 (RR = 5.04, 95% CI (1.81, 14.03) and in those working specifically in small and large animal practice. There was no increased risk in the subgroup that graduated after 1980. Women with unplanned pregnancies were more likely to handle cytotoxic drugs on a daily basis (RR = 1.86, 95% CI, 1.00–3.48) and had a higher increased risk of birth defects than those who planned their pregnancies in recent graduates and in those who worked specifically in small animal practice (RR = 2.53, 95% CI, 1.18–5.42). This study suggests that the adverse effects of handling cytotoxic drugs in pregnant women may include an increased risk of birth defects. Pregnancy intention status is an important health behavior and should be considered in prenatal programs
Unexpected Changes in the Population of Coordination Isomers for the Lanthanide Ion Complexes of DOTMA–Tetraglycinate
[Abstract] Lanthanide complexes with DOTA–tetraglycinate (DOTA-(gly)4) heavily favor the square antiprismatic (SAP) coordination isomer in aqueous solution, a structural feature that has made them useful as water-based paraCEST agents. In an effort to create amide-based paraCEST agents with rapid water exchange rates, we prepared the analogous tetraglycinate complexes with DOTMA, a ligand known to favor the twisted square antiprismatic (TSAP) coordination structures. Unexpectedly, NMR investigations show that the LnDOTMA–(gly)4 complexes, like the LnDOTA–(gly)4 complexes, also favor the SAP isomers in solution. This observation led to density functional theory (DFT) calculations in order to identify the energy terms that favor the SAP structures in lanthanide
complexes formed with macrocyclic DOTA– and DOTMA–tetraamide ligands. The DFT calculations revealed that, regardless the nature of the ligand, the TSAP isomers present more negative hydration energies than the SAP counterparts. The extent to which the TSAP isomer is stabilized varies, however, depending on the ligand structure, resulting in different isomeric populations in solution.Estados Unidos. National Institutes of Health; CA115531Estados Unidos. National Institutes of Health; EB015908Estados Unidos. National Institutes of Health; EB004582Estados Unidos. Robert A. Welch Foundation; AT-584Ministerio de EconomÃa y Competitividad; CTQ2013-43243-PMinisterio de EconomÃa y Competitividad; CTQ2015-71211-RED
A p53-independent role for the MDM2 antagonist Nutlin-3 in DNA damage response initiation.
BACKGROUND: The mammalian DNA-damage response (DDR) has evolved to protect genome stability and maximize cell survival following DNA-damage. One of the key regulators of the DDR is p53, itself tightly regulated by MDM2. Following double-strand DNA breaks (DSBs), mediators including ATM are recruited to the site of DNA-damage. Subsequent phosphorylation of p53 by ATM and ATM-induced CHK2 results in p53 stabilization, ultimately intensifying transcription of p53-responsive genes involved in DNA repair, cell-cycle checkpoint control and apoptosis.
METHODS: In the current study, we investigated the stabilization and activation of p53 and associated DDR proteins in response to treatment of human colorectal cancer cells (HCT116p53+/+) with the MDM2 antagonist, Nutlin-3.
RESULTS: Using immunoblotting, Nutlin-3 was observed to stabilize p53, and activate p53 target proteins. Unexpectedly, Nutlin-3 also mediated phosphorylation of p53 at key DNA-damage-specific serine residues (Ser15, 20 and 37). Furthermore, Nutlin-3 induced activation of CHK2 and ATM - proteins required for DNA-damage-dependent phosphorylation and activation of p53, and the phosphorylation of BRCA1 and H2AX - proteins known to be activated specifically in response to DNA damage. Indeed, using immunofluorescent labeling, Nutlin-3 was seen to induce formation of γH2AX foci, an early hallmark of the DDR. Moreover, Nutlin-3 induced phosphorylation of key DDR proteins, initiated cell cycle arrest and led to formation of γH2AX foci in cells lacking p53, whilst γH2AX foci were also noted in MDM2-deficient cells.
CONCLUSION: To our knowledge, this is the first solid evidence showing a secondary role for Nutlin-3 as a DDR triggering agent, independent of p53 status, and unrelated to its role as an MDM2 antagonist
The study of aquaculture potential of Bojnord and Jajarm cities (Northern Khorasan province)
This study investigates the potential of Bojnord and Jarjam cities (Northern Khorasan province) for developments of Aquaculture. First of all, the current condition of Aquacture and fish farms were montiroed and recorde. Then, the information on geology, weather and climate as well as water resources data were gathered and evaluated. Climatology, geology and distribution of water reseources (i.e. reviers, springs, wells, and aqueducts) were prepared using GIS software. Evaluation of selected water resources in study area revealed suitability for culture of cold water fishes. Potentialities of the water resources for aquacture production were determined according to the latest guidline of Shilat organization. The maps of production potentialities were prepared for each water resources
Study on biological status of the Gorgan Bay
Present study carried out between September 2011 and October 2012 in 19 sampling sites in order to investigate the trophy level, productivity, and natural dominant living conditions in the Gorgan Bay. According to the provided maps from the shoreline, depth, and sediment, the total area and volume of Gorgan Bay is 466 square meters and 905.33 million cubic meters respectively. Also the physic-chemical parameters including: water temperature, EC, salinity, transparency, DO, BOD_5, pH, Ammonia, Nitrate, Total hardness, Total alkalinity, and phosphate are determined and studies. 3 main phylum, 12 orders, 6 classes, and 12 families from bottom living organisms (macro-benthos) were identified in this region. Standard deviation in TSI was from minimum 37 in March up to maximum 65 in September and the annual average was 53. According to the average TSI in different months, for five months namely as March, April, June, August, and February the dominant situation was eutrophy. For the rest of months namely as May, September, October, November, December, and January the dominant situation was Meso-trophic in the Bay. Based on calculation, minimum and maximum productivity in the Bay were 92.26 and 700.66 Kg per hectare in October and July respectively. The annual average of productivity was 195.10 Kg per hectare
Recurrent Modification of a Conserved Cis-Regulatory Element Underlies Fruit Fly Pigmentation Diversity
The development of morphological traits occurs through the collective action of networks of genes connected at the level of gene expression. As any node in a network may be a target of evolutionary change, the recurrent targeting of the same node would indicate that the path of evolution is biased for the relevant trait and network. Although examples of parallel evolution have implicated recurrent modification of the same gene and cis-regulatory element (CRE), little is known about the mutational and molecular paths of parallel CRE evolution. In Drosophila melanogaster fruit flies, the Bric-à -brac (Bab) transcription factors control the development of a suite of sexually dimorphic traits on the posterior abdomen. Female-specific Bab expression is regulated by the dimorphic element, a CRE that possesses direct inputs from body plan (ABD-B) and sex-determination (DSX) transcription factors. Here, we find that the recurrent evolutionary modification of this CRE underlies both intraspecific and interspecific variation in female pigmentation in the melanogaster species group. By reconstructing the sequence and regulatory activity of the ancestral Drosophila melanogaster dimorphic element, we demonstrate that a handful of mutations were sufficient to create independent CRE alleles with differing activities. Moreover, intraspecific and interspecific dimorphic element evolution proceeded with little to no alterations to the known body plan and sex-determination regulatory linkages. Collectively, our findings represent an example where the paths of evolution appear biased to a specific CRE, and drastic changes in function were accompanied by deep conservation of key regulatory linkages. © 2013 Rogers et al
A glial amino-acid transporter controls synapse strength and courtship in Drosophila
Mate choice is an evolutionarily critical decision that requires the detection of multiple sex-specific signals followed by central integration of these signals to direct appropriate behavior. The mechanisms controlling mate choice remain poorly understood. Here, we show that the glial amino-acid transporter genderblind controls whether Drosophila melanogaster males will attempt to mate with other males. Genderblind (gb) mutant males showed no alteration in heterosexual courtship or copulation, but were attracted to normally unappealing male species-specific chemosensory cues. As a result, genderblind mutant males courted and attempted to copulate with other Drosophila males. This homosexual behavior could be induced within hours using inducible RNAi, suggesting that genderblind controls nervous system function rather than its development. Consistent with this, and indicating that glial genderblind regulates ambient extracellular glutamate to suppress glutamatergic synapse strength in vivo, homosexual behavior could be turned on and off by altering glutamatergic transmission pharmacologically and/or genetically
Rapid Evolution of Sex Pheromone-Producing Enzyme Expression in Drosophila
Rapid evolution of gene expression patterns responsible for pheromone production in 24 species of Drosophila was mapped to simple mutations within the regulatory domain of the desatF gene
How does exposure to pesticides vary in space and time for residents living near to treated orchards?
This study investigated changes over 25 years (1987-2012) in pesticide usage in orchards in England and Wales and associated changes to exposure and risk for resident pregnant women living 100 and 1000 m downwind of treated areas. A model was developed to estimate aggregated daily exposure to pesticides via inhaled vapour and indirect dermal contact with contaminated ground, whilst risk was expressed as a hazard quotient (HQ) for reproductive and/or developmental endpoints. Results show the largest changes occurred between 1987 and 1996 with total pesticide usage reduced by ca. 25%, exposure per unit of pesticide applied slightly increased, and a reduction in risk per unit exposure by factors of 1.4 to 5. Thereafter, there were no consistent changes in use between 1996 and 2012, with an increase in number of applications to each crop balanced by a decrease in average application rate. Exposure per unit of pesticide applied decreased consistently over this period such that values in 2012 for this metric were 48-65% of those in 1987, and there were further smaller decreases in risk per unit exposure. All aggregated hazard quotients were two to three orders of magnitude smaller than one, despite the inherent simplifications of assuming co-occurrence of exposure to all pesticides and additivity of effects. Hazard quotients at 1000 m were 5 to 30 times smaller than those at 100 m. There were clear signals of the impact of regulatory intervention in improving the fate and hazard profiles of pesticides over the period investigated
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