Contributors to the March Issue/Notes

Notes by Nicholas T. Tsiolis, Robert B. Devine, John A. Berry, John L. Towne, John H. Logan, Jr., August P. Petrillo, Richard A. Molique, and J. Frederick Meister

Contributors to the March Issue/Notes

Notes by Nicholas T. Tsiolis, Robert B. Devine, John A. Berry, John L. Towne, John H. Logan, Jr., August P. Petrillo, Richard A. Molique, and J. Frederick Meister

Rocaglates induce gain-of-function alterations to eIF4A and eIF4F

Rocaglates are a diverse family of biologically active molecules that have gained tremendous interest in recent years due to their promising activities in pre-clinical cancer studies. As a result, this family of compounds has been significantly expanded through the development of efficient synthetic schemes. However, it is unknown whether all of the members of the rocaglate family act through similar mechanisms of action. Here, we present a comprehensive study comparing the biological activities of >200 rocaglates to better understand how the presence of different chemical entities influences their biological activities. Through this, we find that most rocaglates preferentially repress the translation of mRNAs containing purine-rich 5' leaders, but certain rocaglates lack this bias in translation repression. We also uncover an aspect of rocaglate mechanism of action in which the pool of translationally active eIF4F is diminished due to the sequestration of the complex onto RNA.P50 GM067041 - NIGMS NIH HHS; R24 GM111625 - NIGMS NIH HHS; R35 GM118173 - NIGMS NIH HHSPublished versio

Cardioprotective Effects of Cell Permeable NADPH oxidase inhibitors in Myocardial Ischemia/Reperfusion Injury

During myocardial ischemia/reperfusion (I/R), the generation of reactive oxygen species (ROS) contributes to post-reperfused cardiac injury and contractile dysfunction. Activation of NADPH oxidase (NOX) during reperfusion generates ROS, and exacerbates I/R injury. We hypothesize that reducing ROS formation through inhibition of NOX will attenuate myocardial I/R injury in isolated perfused rat hearts subjected to I(30min)/R(45min) compared to untreated I/R hearts. The cell-permeable NOX inhibiting peptide, gp91 ds/tat (RKKRRQRRR-CSTRIRRQL-Amide, MW=2452 g/mol, 20μM, n=5), significantly improved post-reperfused cardiac function compared to controls (n=15,

Electrochemically initiated release: exploring new modalities for controlled drug release

A series of naphthoquinone-aminophenol derivatives have been synthesized on the basis that their conjugation with a suitable drug candidate could provide a means through which the latter could be released upon the imposition of an appropriate oxidation potential. The approach is based on a three component assembly in which the naphthoquinone redox centre serves as a reporter unit allowing electrochemical interrogation without release of the drug. The central aminophenol serves as the tether to which the drug is linked via an ether bond. Upon oxidation of the aminophenol - ether component, transition of the latter to quinone imine results in the release of the drug. The electrochemical properties of the model system are investigated and the impact of the release process on the functional groups intrinsic to the drug component is critically considered

A comparison of taxon co-occurrence patterns for macro- and microorganisms

We examine co-occurrence patterns of microorganisms to evaluate community assembly “rules.” We use methods previously applied to macroorganisms, both to evaluate their applicability to microorganisms and to allow comparison of co-occurrence patterns observed in microorganisms to those found in macroorganisms. We use a null model analysis of 124 incidence matrices from microbial communities, including bacteria, archaea, fungi, and algae, and we compare these results to previously published findings from a meta-analysis of almost 100 macroorganism data sets. We show that assemblages of microorganisms demonstrate nonrandom patterns of co-occurrence that are broadly similar to those found in assemblages of macroorganisms. These results suggest that some taxon co-occurrence patterns may be general characteristics of communities of organisms from all domains of life. We also find that co-occurrence in microbial communities does not vary among taxonomic groups or habitat types. However, we find that the degree of co-occurrence does vary among studies that use different methods to survey microbial communities. Finally, we discuss the potential effects of the undersampling of microbial communities on our results, as well as processes that may contribute to nonrandom patterns of co-occurrence in both macrobial and microbial communities such as competition, habitat filtering, historical effects, and neutral processes

Using a New Odour-Baited Device to Explore Options for Luring and Killing Outdoor-Biting Malaria Vectors: A Report on Design and Field Evaluation of the Mosquito Landing Box.

Mosquitoes that bite people outdoors can sustain malaria transmission even where effective indoor interventions such as bednets or indoor residual spraying are already widely used. Outdoor tools may therefore complement current indoor measures and improve control. We developed and evaluated a prototype mosquito control device, the 'Mosquito Landing Box' (MLB), which is baited with human odours and treated with mosquitocidal agents. The findings are used to explore technical options and challenges relevant to luring and killing outdoor-biting malaria vectors in endemic settings. Field experiments were conducted in Tanzania to assess if wild host-seeking mosquitoes 1) visited the MLBs, 2) stayed long or left shortly after arrival at the device, 3) visited the devices at times when humans were also outdoors, and 4) could be killed by contaminants applied on the devices. Odours suctioned from volunteer-occupied tents were also evaluated as a potential low-cost bait, by comparing baited and unbaited MLBs. There were significantly more Anopheles arabiensis, An. funestus, Culex and Mansonia mosquitoes visiting baited MLB than unbaited controls (P<=0.028). Increasing sampling frequency from every 120 min to 60 and 30 min led to an increase in vector catches of up to 3.6 fold (P<=0.002), indicating that many mosquitoes visited the device but left shortly afterwards. Outdoor host-seeking activity of malaria vectors peaked between 7:30 and 10:30pm, and between 4:30 and 6:00am, matching durations when locals were also outdoors. Maximum mortality of mosquitoes visiting MLBs sprayed or painted with formulations of candidate mosquitocidal agent (pirimiphos-methyl) was 51%. Odours from volunteer occupied tents attracted significantly more mosquitoes to MLBs than controls (P<0.001). While odour-baited devices such as the MLBs clearly have potential against outdoor-biting mosquitoes in communities where LLINs are used, candidate contaminants must be those that are effective at ultra-low doses even after short contact periods, since important vector species such as An. arabiensis make only brief visits to such devices. Natural human odours suctioned from occupied dwellings could constitute affordable sources of attractants to supplement odour baits for the devices. The killing agents used should be environmentally safe, long lasting, and have different modes of action (other than pyrethroids as used on LLINs), to curb the risk of physiological insecticide resistance

Direct rate measurements of eruption plumes at Augustine volcano: A problem of scaling and uncontrolled variables

The March–April 1986 eruption of Augustine Volcano, Alaska, provided an opportunity to directly measure the flux of gas, aerosol, and ash particles during explosive eruption. Most previous direct measurements of volcanic emission rates are on plumes from fuming volcanoes or on very small eruption clouds. Direct measurements during explosive activity are needed to understand the scale relationships between passive degassing or small eruption plumes and highly explosive events. Conditions on April 3, 1986 were ideal: high winds, clear visibility, moderate activity. Three measurements were made: 1) an airborne correlation spectrometer (Cospec) provided mass flux rates of SO2; 2) treated filter samples chemically characterized the plume and 3) a quartz crystal microcascade impactor provided particle size distribution. Atmospheric conditions on April 3 caused the development of a lee wave plume, which allowed us to constrain a model of plume dispersion leading to a forecast map of concentrations of SO2 at greater distances from the vent. On April 3, 1986, the emission rate of SO2 at Augustine was 24,000 t/d, one of the largest direct volcanic rate measurements yet recorded with a Cospec. The results, coupled with analytical results from samples simultaneously collected on filters, allow us to estimate HCl emissions at 10,000 t/d and ash eruption rate at 1.5×106 t/d. Based on other data, this ash eruption rate is about 1/50 of the maximum rate during the March–April activity. Filter samples show that the gas:aerosol proportions for sulfur and chlorine are about 10:1 and 4:1, respectively. By contrast, measurements of Augustine\u27s plume, together with ground-based gas sampling in July 1986 when the volcano was in a posteruptive fuming state, are 380 t/d SO2 and approximately 8000 t/d HCl with no ash emission. The observations of large Cl releases at Augustine support the Cl abundance conclusions of Johnston (1980) based on study of melt inclusions in the 1976 lavas. The results reinforce the need for more measurements during eruptions and for better understanding of scaling of volcanic emissions of various eruptive components