Cord blood IgG and the risk of severe Plasmodium falciparum malaria in the first year of life

Young infants are less susceptible to severe episodes of malaria but the targets and mechanisms of protection are not clear. Cord blood antibodies may play an important role in mediating protection but many studies have examined their association with the outcome of infection or non-severe malaria. Here, we investigated whether cord blood IgG to Plasmodium falciparum merozoite antigens and antibody-mediated effector functions were associated with reduced odds of developing severe malaria at different time points during the first year of life. We conducted a case-control study of well-defined severe falciparum malaria nested within a longitudinal birth cohort of Kenyan children. We measured cord blood total IgG levels against five recombinant merozoite antigens and antibody function in the growth inhibition activity and neutrophil antibody-dependent respiratory burst assays. We also assessed the decay of maternal antibodies during the first 6months of life. The mean antibody half-life range was 2.51months (95% confidence interval (CI): 2.19-2.92) to 4.91months (95% CI: 4.47-6.07). The rate of decline of maternal antibodies was inversely proportional to the starting concentration. The functional assay of antibody-dependent respiratory burst activity predicted significantly reduced odds of developing severe malaria during the first 6months of life (Odds ratio (OR) 0.07, 95% CI: 0.007-0.74, P=0.007). Identification of the targets of antibodies mediating antibody-dependent respiratory burst activity could contribute to the development of malaria vaccines that protect against severe episodes of malaria in early infancy

MicroRNAs and their isomiRs function cooperatively to target common biological pathways

Background: Variants of microRNAs (miRNAs), called isomiRs, are commonly reported in deep-sequencing studies; however, the functional significance of these variants remains controversial. Observational studies show that isomiR patterns are non-random, hinting that these molecules could be regulated and therefore functional, although no conclusive biological role has been demonstrated for these molecules. Results: To assess the biological relevance of isomiRs, we have performed ultra-deep miRNA-seq on ten adult human tissues, and created an analysis pipeline called miRNA-MATE to align, annotate, and analyze miRNAs and their isomiRs. We find that isomiRs share sequence and expression characteristics with canonical miRNAs, and are generally strongly correlated with canonical miRNA expression. A large proportion of isomiRs potentially derive from AGO2 cleavage independent of Dicer. We isolated polyribosome-associated mRNA, captured the mRNA-bound miRNAs, and found that isomiRs and canonical miRNAs are equally associated with translational machinery. Finally, we transfected cells with biotinylated RNA duplexes encoding isomiRs or their canonical counterparts and directly assayed their mRNA targets. These studies allow us to experimentally determine genome-wide mRNA targets, and these experiments showed substantial overlap in functional mRNA networks suppressed by both canonical miRNAs and their isomiRs. Conclusions: Together, these results find isomiRs to be biologically relevant and functionally cooperative partners of canonical miRNAs that act coordinately to target pathways of functionally related genes. This work exposes the complexity of the miRNA-transcriptome, and helps explain a major miRNA paradox: how specific regulation of biological processes can occur when the specificity of miRNA targeting is mediated by only 6 to 11 nucleotides

Inactivation of a Single Copy of Crebbp Selectively Alters Pre-mRNA Processing in Mouse Hematopoietic Stem Cells

Global expression analysis of fetal liver hematopoietic stem cells (FL HSCs) revealed the presence of unspliced pre-mRNA for a number of genes in normal FL HSCs. In a subset of these genes, Crebbp+/− FL HSCs had less unprocessed pre-mRNA without a corresponding reduction in total mRNA levels. Among the genes thus identified were the key regulators of HSC function Itga4, Msi2 and Tcf4. A similar but much weaker effect was apparent in Ep300+/− FL HSCs, indicating that, in this context as in others, the two paralogs are not interchangeable. As a group, the down-regulated intronic probe sets could discriminate adult HSCs from more mature cell types, suggesting that the underlying mechanism is regulated with differentiation stage and is active in both fetal and adult hematopoiesis. Consistent with increased myelopoiesis in Crebbp hemizygous mice, targeted reduction of CREBBP abundance by shRNA in the multipotent EML cell line triggered spontaneous myeloid differentiation in the absence of the normally required inductive signals. In addition, differences in protein levels between phenotypically distinct EML subpopulations were better predicted by taking into account not only the total mRNA signal but also the amount of unspliced message present. CREBBP thus appears to selectively influence the timing and degree of pre-mRNA processing of genes essential for HSC regulation and thereby has the potential to alter subsequent cell fate decisions in HSCs

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Networking of Autonomous Small Unmanned Aerial Systems (SUAS)

The development of a network between autonomous Small Unmanned Aerial Systems (SUAS) will advance the robotics industry and increase the usage and effectiveness of robotic systems. Multiple networked aerial robots can divide labor to decrease mission time; relay signals of robots outside the signal range for the ability to broadcast real-time data; provide the ability to change mission parameters and division of labor if new robots enter the mission zone or an assigned robot experiences a critical failure. Ignite Grant Awar

EAG responses from gravid female moths to test compounds.

<p>EAG responses recorded from two-day old mated female NOW moth antennae. Dose dependence responses (<i>N</i> = 9) for compounds <b>6</b>, <b>8</b>, <b>9</b>, and <b>12</b> at concentrations 10 µg/μl (≈10,000 ppm), 1 µg/μl (≈1,000 ppm), and 0.1 µg/μl (≈100 ppm). There were significantly higher responses for compounds <b>8</b>, <b>9</b>, and <b>12</b> as compared to the hexane controls at concentrations 10 µg/μl (<i>P</i> = 0.0001; Tukey's Multiple Comparison Test) and 1 µg/μl (<i>P</i> = 0.0001). EAG responses at concentration of 0.1 µg/μl were not significantly different (<i>P</i>>0.05) from hexane controls. Compound <b>6</b> did not show EAG activity (<i>P</i>>0.05). <i>Inset</i> Representative EAG traces of hexane control (H) and compound <b>9</b> (9) at 10 µg/μl. The solid line above the traces represents stimulus duration (500 ms). The time and voltage scales are shown at the bottom left of the graph.</p

In-depth field evaluations of an active compound.

<p>This second field trial was performed in Arbuckle, CA from September 14th, 2012 through October 18th, 2012. In these direct comparison compound <b>9</b> was highly significant (<i>P</i> = 0.0001; Mann-Whitney Test, <i>N = 34</i>).</p

Multiple-choice field evaluations of compounds pre-screened by EAG and indoor bioassay.

<p>This first trial was conducted in Arbuckle, CA from May 13th, 2012 through June 9th, 2012. The number of eggs laid on black egg traps baited with compound <b>9</b> was significantly lower than those oviposited on control (hexane) traps (<i>P</i> = 0.003; Dunn's Multiple Comparisons Test). Oviposition in traps baited with compound <b>8</b> was not significantly different (<i>P</i>>0.05) from those on control traps. Lastly, there was no significant difference between the two treatments: compounds <b>8</b> and <b>9</b> (<i>P</i>>0.05; <i>N = 30</i>).</p

Raw Data

Here we provide the raw data for each figure

Small-cage two-choice laboratory oviposition assay.

<p>For each compound tested there were four cages each with twenty two-day old mated female NOW moths replicated three times from three different cohorts (<i>N</i> = 12). Gravid female moths laid significantly fewer eggs on those black egg traps treated with compound <b>8</b> (<i>P</i> = 0.03) as well as compound <b>9</b> (<i>P</i> = 0.003; analyzed via the Mann-Whitney Test) when compared to traps treated with hexane (controls). No significant differences were observed for oviposition on black egg traps spiked with compound <b>6</b> (<i>P</i> = 0.95) or compound <b>12</b> (<i>P</i> = 1.0) as compared to control traps.</p