miR-196b target screen reveals mechanisms maintaining leukemia stemness with therapeutic potential.

We have shown that antagomiR inhibition of miRNA miR-21 and miR-196b activity is sufficient to ablate MLL-AF9 leukemia stem cells (LSC) in vivo. Here, we used an shRNA screening approach to mimic miRNA activity on experimentally verified miR-196b targets to identify functionally important and therapeutically relevant pathways downstream of oncogenic miRNA in MLL-r AML. We found Cdkn1b (p27Kip1) is a direct miR-196b target whose repression enhanced an embryonic stem cell–like signature associated with decreased leukemia latency and increased numbers of leukemia stem cells in vivo. Conversely, elevation of p27Kip1 significantly reduced MLL-r leukemia self-renewal, promoted monocytic differentiation of leukemic blasts, and induced cell death. Antagonism of miR-196b activity or pharmacologic inhibition of the Cks1-Skp2–containing SCF E3-ubiquitin ligase complex increased p27Kip1 and inhibited human AML growth. This work illustrates that understanding oncogenic miRNA target pathways can identify actionable targets in leukemia

Elucidating the structural basis for differing enzyme inhibitor potency by cryo-EM

Histidine biosynthesis is an essential process in plants and microorganisms, making it an attractive target for the development of herbicides and antibacterial agents. Imidazoleglycerol-phosphate dehydratase (IGPD), a key enzyme within this pathway, has been biochemically characterized in both Saccharomyces cerevisiae (Sc_IGPD) and Arabidopsis thaliana (At_IGPD). The plant enzyme, having been the focus of in-depth structural analysis as part of an inhibitor development program, has revealed details about the reaction mechanism of IGPD, whereas the yeast enzyme has proven intractable to crystallography studies. The structure–activity relationship of potent triazole-phosphonate inhibitors of IGPD has been determined in both homologs, revealing that the lead inhibitor (C348) is an order of magnitude more potent against Sc_IGPD than At_IGPD; however, the molecular basis of this difference has not been established. Here we have used single-particle electron microscopy (EM) to study structural differences between the At and Sc_IGPD homologs, which could influence the difference in inhibitor potency. The resulting EM maps at ∼3 Å are sufficient to de novo build the protein structure and identify the inhibitor binding site, which has been validated against the crystal structure of the At_IGPD/C348 complex. The structure of Sc_IGPD reveals that a 24-amino acid insertion forms an extended loop region on the enzyme surface that lies adjacent to the active site, forming interactions with the substrate/inhibitor binding loop that may influence inhibitor potency. Overall, this study provides insights into the IGPD family and demonstrates the power of using an EM approach to study inhibitor binding

Why are the K dwarfs in the Pleiades so Blue?

The K dwarfs in the Pleiades fall nearly one half magnitude below a main sequence isochrone when plotted in a color-magnitude diagram utilizing V magnitude as the luminosity index and B-V as the color index. This peculiarity has been known for forty years but has gone unexplained and mostly ignored. When compared to Praesepe members, the Pleiades K dwarfs again are subluminous (or blue) in a color-magnitude diagram using B-V as the color index. However, using V-I as the color index, stars in the two clusters are coincident to M_V ~ 10; using V-K as the color index, Pleiades late K and M stars fall above the main sequence locus defined by Praesepe members. We believe that the anomalous spectral energy distributions for the Pleiades K dwarfs, as compared to older clusters, are a consequence of rapid stellar rotation and may be primarily due to spottedness. If so, the required areal filling factor for the cool component has to be very large (=> 50%). Weak-lined T Tauri stars have similar color anomalies, and we suspect this is a common feature of all very young K dwarfs (sp. type > K3). The peculiar spectral energy distribution needs to be considered in deriving accurate pre-main sequence isochrone-fitting ages for clusters like the Pleiades since the age derived will depend on the temperature index used.Comment: 41 pages, 15 figures, AASTeX5.0. Accepted 05 May 2003; Scheduled for publication in the Astronomical Journal (August 2003

Development of a triclosan scaffold which allows for adaptations on both the A- and B-ring for transport peptides

The enoyl acyl-carrier protein reductase (ENR) enzyme is harbored within the apicoplast of apicomplexan parasites providing a significant challenge for drug delivery, which may be overcome through the addition of transductive peptides, which facilitates crossing the apicoplast membranes. The binding site of triclosan, a potent ENR inhibitor, is occluded from the solvent making the attachment of these linkers challenging. Herein, we have produced 3 new triclosan analogs with bulky A- and B-ring motifs, which protrude into the solvent allowing for the future attachment of molecular transporters for delivery

Leveraging the Power of SAR Observations for Forest Monitoring Systems

Earth observations from Synthetic Aperture Radar (SAR) can provide unique information related to forest structure and condition. Despite the many advantages of SAR, particularly where clouds impede optical observations, a knowledge gap has prevented the applied remote sensing community from harnessing its full potential. Here, we discuss the results of a collaboration between SERVIR, a joint program between NASA and the U.S. Agency for International Development (USAID), and SilvaCarbon, the United States' contribution to the Global Forest Observation Initiative, to build global capacity in using SAR for forest monitoring and biomass estimation. This includes primarily the creation of 1) The SAR Handbook: Comprehensive Methodologies for Forest Monitoring and Biomass Estimation, 2) a series of international hands-on trainings and training materials, 3) quick-reference guides illustrating SAR concepts, and 4) animated videos explaining how SAR works. The SERVIR-Global community joined efforts to develop a hands-on guide to support decision-makers in the forestry community to leverage the power of SAR technology to better protect and manage forest resources. We worked with world-renowned SAR experts to provide targeted trainings and develop the SAR Handbook. This handbook consists of approachable theoretical background and applied content that contributes to filling the knowledge gap in the applied use of SAR technology for forestry applications. We hope that forest managers and remote sensing specialists will use these materials to benefit from currently available SAR datasets, as well as prepare for future SAR missions, such as NISAR and BIOMASS. Since its release on April 11, 2019, the SAR Handbook has been accessed more than 100,000 times in less than a month, demonstrating the remote sensing community's urgent need and interest to learn and use SAR

AMI-LA radio continuum observations of Spitzer c2d small clouds and cores: Perseus region

We present deep radio continuum observations of the cores identified as deeply embedded young stellar objects in the Perseus molecular cloud by the Spitzer c2d programme at a wavelength of 1.8 cm with the Arcminute Microkelvin Imager Large Array (AMI-LA). We detect 72% of Class 0 objects from this sample and 31% of Class I objects. No starless cores are detected. We use the flux densities measured from these data to improve constraints on the correlations between radio luminosity and bolometric luminosity, infrared luminosity and, where measured, outflow force. We discuss the differing behaviour of these objects as a function of protostellar class and investigate the differences in radio emission as a function of core mass. Two of four possible very low luminosity objects (VeLLOs) are detected at 1.8 cm.Comment: 18 pages, 9 figures, accepted MNRA

How to Leverage the Power of SAR Observations for Forest Monitoring Systems

Earth observations from Synthetic Aperture Radar (SAR) can provide unique observations related to forest structure and condition. Furthermore, SAR has many potential applications in forest monitoring systems, particularly where clouds have impeded optical observations. Currently, there is a reliable, freely-available, provision of SAR datasets, such as Sentinel-1, and there are plans to have more observations in the near- future (NISAR, BIOMASS). Given SARs enhanced earth observation characteristics, there is broad interest in using SAR datasets for decision support systems, such as deforestation early warning systems. However, applications of SAR are still underutilized. What is preventing users from using SAR data in their decision support systems? This study documents the experiences and lessons learned from the SERVIR network on the main limitations of incorporating SAR datasets into existing forest monitoring systems. This research also focuses on the major technical and scientific barriers we experience and best practices to address them. The results of this study are part of the SERVIR- SilvaCarbon collaboration. The primary goal of this collaboration is to build capacity in the applied use of SAR for forest monitoring and biomass estimation. The products of this effort aim to start closing the gap between SAR-science and forest applications. We will also present results to generate applied-ready knowledge for SAR

Ross, Macdonald, and a Theory for the Dynamics and Control of Mosquito-Transmitted Pathogens

Ronald Ross and George Macdonald are credited with developing a mathematical model of mosquito-borne pathogen transmission. A systematic historical review suggests that several mathematicians and scientists contributed to development of the Ross-Macdonald model over a period of 70 years. Ross developed two different mathematical models, Macdonald a third, and various “Ross-Macdonald” mathematical models exist. Ross-Macdonald models are best defined by a consensus set of assumptions. The mathematical model is just one part of a theory for the dynamics and control of mosquito-transmitted pathogens that also includes epidemiological and entomological concepts and metrics for measuring transmission. All the basic elements of the theory had fallen into place by the end of the Global Malaria Eradication Programme (GMEP, 1955–1969) with the concept of vectorial capacity, methods for measuring key components of transmission by mosquitoes, and a quantitative theory of vector control. The Ross-Macdonald theory has since played a central role in development of research on mosquito-borne pathogen transmission and the development of strategies for mosquito-borne disease prevention

Leveraging the Power of SAR Observations for Forest Monitoring Systems

Earth observations from Synthetic Aperture Radar (SAR) can provide unique information related to forest structure and condition. Despite the many advantages of SAR, particularly where clouds impede optical observations, a knowledge gap has prevented the applied remote sensing community from harnessing its full potential. Here, we discuss the results of a collaboration between SERVIR, a joint program between NASA and the U.S. Agency for International Development (USAID), and SilvaCarbon, the United States contribution to the Global Forest Observation Initiative, to build global capacity in using SAR for forest monitoring and biomass estimation. This includes primarily the creation of 1) The SAR Handbook: Comprehensive Methodologies for Forest Monitoring and Biomass Estimation, 2) a series of international hands-on trainings and training materials, 3) quick-reference guides illustrating SAR concepts, and 4) animated videos explaining how SAR works. The SERVIR-Global community joined efforts to develop a hands-on guide to support decision-makers in the forestry community to leverage the power of SAR technology to better protect and manage forest resources. We worked with world-renowned SAR experts to provide targeted trainings and develop the SAR Handbook. This handbook consists of approachable theoretical background and applied content that contributes to filling the knowledge gap in the applied use of SAR technology for forestry applications. We hope that forest managers and remote sensing specialists will use these materials to benefit from currently available SAR datasets, as well as prepare for future SAR missions, such as NISAR and BIOMASS. Since its release on April 11, 2019, the SAR Handbook has been accessed more than 100,000 times in less than a month, demonstrating the remote sensing communitys urgent need and interest to learn and use SAR