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The 4-trifluoromethyl analog 4c shown moderate activity against Pim-1, but was surprisingly effective when tested against Pim-3 (residual activities 51% and 24%, respectively) The overall yield for the preparation of the C8 methyl derivative 17 from the common aldehyde starting material was 18%

(2010). detected in 25 calves that died of infection, suggesting that most deaths due to are the result of acute disease from primary exposure. and and for 10?min. Sera were aspirated with sterile pipettes and stored in 18?mL Nunc cryovials at ?40?C before moving them to long-term storage at ?80?C until testing. Species-specific antibody-capture ELISAs for and were carried out according to LAMC2 previously described methods (Katende and ELISA was ?20?PP, while for and ELISA the cut-off was ?15?PP. Seroconversion rule A seroconversion rule was employed that relied on PP results from two consecutive 5-weekly routine visits. For a calf to be defined as having seroconverted, the rule required that the PP value for the seroconversion visit sample was greater than the cut-off value as defined above and greater than the previous visit (a rising titre). Under the rule, calves that were seropositive due to the presence of maternal antibodies were not classed as seroconverted, but calves which seroconverted during the period when maternal antibodies were present were identified. Cause of death Full post-mortem examinations were carried out on calves that died. Gross abnormalities were noted and tissue samples were taken both into formalin and frozen for future analysis. Full histological examination was carried out on all available tissue. Most ECF cases were confirmed from macroscopic and microscopic examination of lung tissue, in addition to ante-mortem clinical indicators and post-mortem observations of the animal. Final diagnoses of death were made by a committee of experts using all available diagnostic material. Where no diagnosis could be confirmed, the death was classified as due to unknown cause. A more detailed description of the mortality in the cohort is in Bronsvoort (James and DebRoy, 2012), (Chongsuvivatwong, 2010), (Wickham, 2007), (Wickham, 2009) and (Therneau and Lumley, 2010). The population-based estimates of seroprevalences for calves were determined using a weighted adjustment for the number of breeding dams in each sub-location and the LY2603618 (IC-83) s.e. was adjusted for clustering by sub-location using the R survey package (Lumley, 2004, 2012). The by-week baseline hazard (risk per unit time) of seroconversion to each parasite conditional on not having seroconverted previously was estimated using a time-discrete hazard model described by Singer and Willett (2003). This analysis was based on time to first occurrence of seroconversion, thus it only included observations up to and including the time of first seroconversion (if it occurred). Ethics statement This project was approved by the University of Edinburgh Ethics Committee, the Kenyan Department of Veterinary Services and by ILRI’s LY2603618 (IC-83) Institute Animal Care and Use Committee. Standard, peripheral venepuncture techniques were used to collect the blood samples. The calves were restrained by professional animal health assistants and veterinary surgeons, and a veterinary surgeon was available to examine any sick calf reported by recruited farmers. Any calves which were in severe distress due to trauma or disease were humanely euthanized by a veterinary surgeon. All farmers gave informed consent in their own language before recruitment of their calves began. The Ethical Review Committee of the University of Edinburgh (Animal (Scientific Procedures) Act, 1986) took into account the ethical issues enshrined in the Animals (Scientific Procedures) Act and approved the work LY2603618 (IC-83) (reference number OS 03-06). RESULTS Longitudinal assessment of the serological response to and and and 275 (50%) to When these natural numbers are adjusted for deaths and censoring and also for the different populace sizes in each sub-location, the estimates (with 95% confidence intervals) for cumulative seroconversion at 51 weeks are 859% (784C897) for and 569% (528C609) for was sustained following initial exposure, although a substantial number of calves also became seronegative. There was a particularly rapid decrease in antibody levels for and to by 1 year is about the same, Fig. 2 shows that seroconversion to.