Thresholds of uncertainty : radiation and responsibility in the fallout controversy

The public controversy over possible health hazards from radioactive fallout from atomic bomb testing began in 1954, shortly after a thermonuclear test by the United States spread fallout world wide. In the dissertation, I address two of the fundamental questions of the fallout controversy: Was there a threshold of radiation exposure below which there would be no significant injury? What was the role of a responsible scientist in a public scientific debate? Genetics and medicine were the scientific fields most directly involved in the debate over the biological effects of radiation. Geneticists' prewar experiences with radiation led them to believe that there was no safe level of radiation exposure and that any amount of radiation would cause a proportional amount of genetic injury. In contrast to geneticists, physicians and medical researchers generally believed that there was a threshold for somatic injury from radiation. One theme of the dissertation is an examination of how different scientific conceptual and methodological approaches affected how geneticists and medical researchers evaluated the possible health effects of fallout. Geneticists and physicians differed not only in their evaluations of radiation hazards, but also in their views of how the debate over fallout should be conducted. A central question of the fallout debate was how a responsible scientist should act in a public policy controversy involving scientific issues upon which the scientific community had not yet reached a consensus. Based on their assumption that any increase in radiation exposure was harmful, most geneticists believed that they had a responsibility to speak out publicly about the deleterious effects of radiation. Physicians, who believed in the likelihood of a threshold for significant radiation-induced injury, generally adopted the opposite view. They believed that public discussion of possible, but improbable, radiation hazards was irresponsible because it risked creating irrational public fear of radiation exposure. In my dissertation, I examine how the different positions of geneticists and physicians over what constituted responsible public scientific debate affected the rhetoric of the controversy, as well as the implications of the debate in matters of politics and policy

Fixing DNA breaks during class switch recombination

Immunoglobulin (Ig) class switch recombination (CSR) involves the breakage and subsequent repair of two DNA sequences, known as switch (S) regions, which flank IgH constant region exons. The resolution of CSR-associated breaks is thought to require the nonhomologous end-joining (NHEJ) DNA repair pathway, but the role of the NHEJ factor DNA-dependent protein kinase catalytic subunit (DNA-PKcs) in this process has been unclear. A new study, in which broken IgH-containing chromosomes in switching B cells were visualized directly, clearly demonstrated that DNA-PKcs and, unexpectedly, the nuclease Artemis are involved in the resolution of switch breaks

Science, service, and specialized agriculture : the re-invention of the maraschino cherry

From 1925 to 1930, Ernest H. Wiegand, a professor of Horticultural Products at Oregon State Agricultural College, developed an improved brining process for cherries. Brined cherries are used in the production of maraschino and glacé cherries, which already had a sizable market in the United States by the 1920s. This thesis examines the scientific, economic, and geographic circumstances that played a role in the development of the new process. The institutionalization of agricultural science in the Land-Grant Colleges and experiment stations in the United States created a favorable context for the development of a new brining process. The scientists associated with these institutions were "service-oriented,"both in ideology and practice. They generally tailored their research programs to meet the needs of their agricultural lay-constituency. This service-orientation has been present in agricultural science since its origins in the eighteenth century. Oregon State Agricultural College and its associated experiment station exemplified this dedication to service. In developing a brining process more suitable to large-scale commercial production, Wiegand was responding to the needs of local cherry growers, whose needs were determined by the demands and problems inherent in specialized agriculture. As a result of the improved brining process and tariff protection, Northwest cherry growers were able to successfully compete in the brined cherry market, a market previously closed to them

Incorporation of dUTP does not mediate mutation of A:T base pairs in Ig genes in vivo

Activation-induced cytidine deaminase (AID) protein initiates Ig gene mutation by deaminating cytosines, converting them into uracils. Excision of AID-induced uracils by uracil-N-glycosylase is responsible for most transversion mutations at G:C base pairs. On the other hand, processing of AID-induced G:U mismatches by mismatch repair factors is responsible for most mutation at Ig A:T base pairs. Why mismatch processing should be error prone is unknown. One theory proposes that long patch excision in G1-phase leads to dUTP-incorporation opposite adenines as a result of the higher G1-phase ratio of nuclear dUTP to dTTP. Subsequent base excision at the A:U base pairs produced could then create non-instructional templates leading to permanent mutations at A:T base pairs (1). This compelling theory has remained untested. We have developed a method to rapidly modify DNA repair pathways in mutating mouse B cells in vivo by transducing Ig knock-in splenic mouse B cells with GFP-tagged retroviruses, then adoptively transferring GFP+ cells, along with appropriate antigen, into primed congenic hosts. We have used this method to show that dUTP-incorporation is unlikely to be the cause of AID-induced mutation of A:T base pairs, and instead propose that A:T mutations might arise as an indirect consequence of nucleotide paucity during AID-induced DNA repair

Morphological variation in the genus Chlorocebus: Ecogeographic and anthropogenically mediated variation in body mass, postcranial morphology, and growth

Objectives Direct comparative work in morphology and growth on widely dispersed wild primate taxa is rarely accomplished, yet critical to understanding ecogeographic variation, plastic local variation in response to human impacts, and variation in patterns of growth and sexual dimorphism. We investigated population variation in morphology and growth in response to geographic variables (i.e., latitude, altitude), climatic variables (i.e., temperature and rainfall), and human impacts in the vervet monkey (Chlorocebus spp.). Methods We trapped over 1,600 wild vervets from across Sub‐Saharan Africa and the Caribbean, and compared measurements of body mass, body length, and relative thigh, leg, and foot length in four well‐represented geographic samples: Ethiopia, Kenya, South Africa, and St. Kitts & Nevis. Results We found significant variation in body mass and length consistent with Bergmann\u27s Rule in adult females, and in adult males when excluding the St. Kitts & Nevis population, which was more sexually dimorphic. Contrary to Rensch\u27s Rule, although the South African population had the largest average body size, it was the least dimorphic. There was significant, although very small, variation in all limb segments in support for Allen\u27s Rule. Females in high human impact areas were heavier than those with moderate exposures, while those in low human impact areas were lighter; human impacts had no effect on males. Conclusions Vervet monkeys appear to have adapted to local climate as predicted by Bergmann\u27s and, less consistently, Allen\u27s Rule, while also responding in predicted ways to human impacts. To better understand deviations from predicted patterns will require further comparative work in vervets

DNA-Dependent Protein Kinase Inhibits AID-Induced Antibody Gene Conversion

Affinity maturation and class switching of antibodies requires activation-induced cytidine deaminase (AID)-dependent hypermutation of Ig V(D)J rearrangements and Ig S regions, respectively, in activated B cells. AID deaminates deoxycytidine bases in Ig genes, converting them into deoxyuridines. In V(D)J regions, subsequent excision of the deaminated bases by uracil-DNA glycosylase, or by mismatch repair, leads to further point mutation or gene conversion, depending on the species. In Ig S regions, nicking at the abasic sites produced by AID and uracil-DNA glycosylases results in staggered double-strand breaks, whose repair by nonhomologous end joining mediates Ig class switching. We have tested whether nonhomologous end joining also plays a role in V(D)J hypermutation using chicken DT40 cells deficient for Ku70 or the DNA-dependent protein kinase catalytic subunit (DNA-PKcs). Inactivation of the Ku70 or DNA-PKcs genes in DT40 cells elevated the rate of AID-induced gene conversion as much as 5-fold. Furthermore, DNA-PKcs-deficiency appeared to reduce point mutation. The data provide strong evidence that double-strand DNA ends capable of recruiting the DNA-dependent protein kinase complex are important intermediates in Ig V gene conversion

Effects of short-term treatment with atorvastatin in smokers with asthma - a randomized controlled trial

<b>Background</b> The immune modulating properties of statins may benefit smokers with asthma. We tested the hypothesis that short-term treatment with atorvastatin improves lung function or indices of asthma control in smokers with asthma.<p></p> <b>Methods</b> Seventy one smokers with mild to moderate asthma were recruited to a randomized double-blind parallel group trial comparing treatment with atorvastatin (40 mg per day) versus placebo for 4 weeks. After 4 weeks treatment inhaled beclometasone (400 ug per day) was added to both treatment arms for a further 4 weeks. The primary outcome was morning peak expiratory flow after 4 weeks treatment. Secondary outcome measures included indices of asthma control and airway inflammation.<p></p> <b>Results</b> At 4 weeks, there was no improvement in the atorvastatin group compared to the placebo group in morning peak expiratory flow [-10.67 L/min, 95% CI -38.70 to 17.37, p=0.449], but there was an improvement with atorvastatin in asthma quality of life score [0.52, 95% CI 0.17 to 0.87 p=0.005]. There was no significant improvement with atorvastatin and inhaled beclometasone compared to inhaled beclometasone alone in outcome measures at 8 weeks.<p></p> <b>Conclusions</b> Short-term treatment with atorvastatin does not alter lung function but may improve asthma quality of life in smokers with mild to moderate asthma. Clinicaltrials.gov identifier: NCT0046382