Dual miRNA Targeting Restricts Host Range and Attenuates Neurovirulence of Flaviviruses

Mosquito-borne flaviviruses are among the most significant arboviral pathogens worldwide. Vaccinations and mosquito population control programs remain the most reliable means for flavivirus disease prevention, and live attenuated viruses remain one of the most attractive flavivirus vaccine platforms. Some live attenuated viruses are capable of infecting principle mosquito vectors, as demonstrated in the laboratory, which in combination with their intrinsic genetic instability could potentially lead to a vaccine virus reversion back to wild-type in nature, followed by introduction and dissemination of potentially dangerous viral strains into new geographic locations. To mitigate this risk we developed a microRNA-targeting approach that selectively restricts replication of flavivirus in the mosquito host. Introduction of sequences complementary to a mosquito-specific mir-184 and mir-275 miRNAs individually or in combination into the 3’NCR and/or ORF region resulted in selective restriction of dengue type 4 virus (DEN4) replication in mosquito cell lines and adult Aedes mosquitos. Moreover a combined targeting of DEN4 genome with mosquito-specific and vertebrate CNS-specific mir-124 miRNA can silence viral replication in two evolutionally distant biological systems: mosquitoes and mouse brains. Thus, this approach can reinforce the safety of newly developed or existing vaccines for use in humans and could provide an additional level of biosafety for laboratories using viruses with altered pathogenic or transmissibility characteristics.     

Bifidobacteria-mediated immune system imprinting early in life

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Pharmacologic modulation of RNA splicing enhances anti-tumor immunity

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The Effect of Conflicting Pressures on the Evolution of Division of Labor

Within nature, many groups exhibit division of labor. Individuals in these groups are under seemingly antagonistic pressures to perform the task most directly beneficial to themselves and to potentially perform a less desirable task to ensure the success of the group. Performing experiments to study how these pressures interact in an evolutionary context is challenging with organic systems because of long generation times and difficulties related to group propagation and fine-grained control of within-group and between-group pressures. Here, we use groups of digital organisms (i.e., self-replicating computer programs) to explore how populations respond to antagonistic multilevel selection pressures. Specifically, we impose a within-group pressure to perform a highly-rewarded role and a between-group pressure to perform a diverse suite of roles. Thus, individuals specializing on highly-rewarded roles will have a within-group advantage, but groups of such specialists have a between-group disadvantage. We find that digital groups could evolve to be either single-lineage or multi-lineage, depending on experimental parameters. These group compositions are reminiscent of different kinds of major evolutionary transitions that occur within nature, where either relatives divide labor (fraternal transitions) or multiple different organisms coordinate activities to form a higher-level individual (egalitarian transitions). Regardless of group composition, organisms embraced phenotypic plasticity as a means for genetically similar individuals to perform different roles. Additionally, in multi-lineage groups, organisms from lineages performing highly-rewarded roles also employed reproductive restraint to ensure successful coexistence with organisms from other lineages.     

N-hexyl-O-glucosyl sphingosine, an inhibitor of glucosyl ceramide -glucosidase

A synthetic analog of glucocerebroside, N-hexyl-O-glucosyl sphingosine, was found to inhibit the glucosidase in rat spleen that hydrolyzes glucocerebroside. At a concentration of 1 micro m, the analog inhibited the enzyme by 48%. The mode of action appeared to be competitive, probably aided by tight binding of the amine group to a carboxyl group near the enzyme's active site. Increasing or decreasing the chain length of the n-alkyl group attached to the nitrogen atom led to decreased effectiveness. The inhibitory effect was maximal at pH 7.0, but it was still considerable at the enzyme's optimal pH, 5.0. It is suggested that the compound may be useful for inducing an animal model of Gaucher's disease.     

Descriptive epidemiology of small-bowel atresia in metropolitan Atlanta.

The epidemiological characteristics are presented of 46 children with small-bowel atresia, ascertained over a 6-year period by an active, population-based birth defect surveillance program in Atlanta, Georgia. The malformation occurred at a rate of 2.7/10,000 livebirths. The previously reported association of duodenal atresia and Down syndrome was confirmed was confirmed. No instances of familial association were noted, nor was any excessive prenatal exposure to drugs found. Thirty-two instances of isolated small-bowel atresia were analyzed in detail. The frequency of the isolated defect for blacks was twice that for whites because of a higher rate for black females. The isolated defect was commonest in the winter months. The relation between isolated small-bowel atresia, birth weight, and mortality was discussed. This small series cannot readily be subdivided into distinct epidemiological groups on the basis of the location of the atretic lesions along the length of the small bowel.