In Vivo RNAi Screening Identifies a Leukemia-Specific Dependence on Integrin Beta 3 Signaling

We used an in vivo small hairpin RNA (shRNA) screening approach to identify genes that are essential for MLL-AF9 acute myeloid leukemia (AML). We found that Integrin Beta 3 (Itgb3) is essential for murine leukemia cells in vivo and for human leukemia cells in xenotransplantation studies. In leukemia cells, Itgb3 knockdown impaired homing, downregulated LSC transcriptional programs, and induced differentiation via the intracellular kinase Syk. In contrast, loss of Itgb3 in normal hematopoietic stem and progenitor cells did not affect engraftment, reconstitution, or differentiation. Finally, using an Itgb3 knockout mouse model, we confirmed that Itgb3 is dispensable for normal hematopoiesis but is required for leukemogenesis. Our results establish the significance of the Itgb3 signaling pathway as a potential therapeutic target in AML.National Institutes of Health (U.S.) (Harvard Stem Cell Institute. GlaxoSmithKline. Grant P01 CA108631)National Institutes of Health (U.S.) (Harvard Stem Cell Institute. GlaxoSmithKline. Grant RC1 CA145229)National Institutes of Health (U.S.) (Harvard Stem Cell Institute. GlaxoSmithKline. Grant R01 CA140292)National Institutes of Health (U.S.) (Harvard Stem Cell Institute. GlaxoSmithKline. Grant CA148180

Energy Requirements for Biomass Harvest and Densification

This research quantified the unit and bulk density of several biomass crops across a variety of harvest and processing methods, as well as the energy and fuel requirements for these operations. A load density of approximately 240 kg·m−3 is needed to reach the legal weight limit of most transporters. Of the three types of balers studied, only the high density (HD) large square baler achieved this target density. However, the specific energy and fuel requirements increased exponentially with bale density, and at the maximum densities for corn stover and switchgrass, the dry basis energy and fuel requirements ranged from 4.0 to 5.0 kW·h·Mg−1 and 1.2 to 1.4 L·Mg−1, respectively. Throughputs of tub grinders when grinding bales was less than any other harvesting or processing methods investigated, so specific energy and fuel requirements were high and ranged from 13 to 32 kW·h·Mg−1 and 5.0 to 11.3 L·Mg−1, respectively. Gross size-reduction by pre-cutting at baling increased bale density by less than 6% and increased baling energy requirements by 11% to 22%, but pre-cut bales increased the tub grinder throughput by 25% to 45% and reduced specific fuel consumption for grinding by 20% to 53%. Given the improvement in tub grinder operation, pre-cutting bales should be considered as a means to increase grinder throughput. Additional research is needed to determine the energy required to grind high density pre-cut bales at high throughputs so that better estimates of total energy required for a high density bale system can be made. An alternative bulk feedstock system was investigated that involved chopping moist biomass crops with a precision-cut forage harvester, compacting the bulk material in a silo bag, and then segmenting the densified material into modules optimized for efficient transport. The specific fuel use for chopping and then compacting biomass crops in the silo bag ranged from 1.6 to 3.0 L·Mg−1 and 0.5 to 1.3 L·Mg−1, respectively. At the proposed moistures, the compacted density in the silo bags was sufficient to achieve weight-limited transport although there would be less dry matter (DM) shipped than with the high density dry bale system. Additional development work is needed to create transportable modules from the compacted silo bag. The overall results of this research will allow more accurate estimates of biomass logistics costs based on product density and energy expenditures

An Apparatus and Method for Evaluating Particle-Size Distribution of Small Grain Crop Residues

Size-reduction of small grain residue is required on the combine harvester to promote uniform distribution of residue across the full harvested width. However, unnecessary size reduction increases energy expenditures that can reduce harvester capacity. To objectively quantify the degree of residue processing, an apparatus and method was developed for evaluating particle-size distribution of small grain crop residue. The apparatus consisted of a pre-screener to sort long particles and an oscillating cascade of three screens which separated material into four additional fractions. The separation process was continuous, so large volume samples could be separated more quickly than batch systems. The developed system was used to evaluate wheat residue which was processed to various extents by a combine residue chopper in two experiments. Statistically significant (p < 0.05) differences between variably processed wheat residues were found using the developed apparatus and methodology. The separated wheat residue was partitioned into three particle-size ranges of less than 50 mm, 50 to 125 mm, and greater than 125 mm. Samples of 3 to 4 kg could be completely analyzed in less than 10 min

Impact—Shredding Processing of Whole-Plant Corn: Machine Performance, Physical Properties, and In Situ Ruminant Digestion

An intensive processing mechanism that combined impact and shredding was applied to create physical disruption of whole-plant corn as a means to increase in situ dry matter (DM) digestion in lactating dairy cows. A ratio of treatment leachate conductivity relative to that of an ultimately processed treatment, defined as a processing level index, was used to quantify material physical disruption. Two processing levels were compared to a control treatment, which applied conventional chopping and kernel processing. The non-grain fraction was substantially size-reduced by processing such that only 28% to 51% by mass of this material remained greater than 6.4 mm length. After processing with the experimental processor, greater than 85% of kernels passed through a 4.75 mm screen, and the corn silage processing score (CSPS) was 18 to 27 percentage points greater than the control. The highly fiberized material was more compliant; thus, compacted density was 9% to 17% greater than the control. During in situ digestion experiments, processing significantly increased the rapidly soluble DM fraction by 10 percentage points and the extent of DM disappearance by 5 percentage points through 16 h incubation

An Introductory Tutorial on Cardiovascular Pharmacogenetics for Healthcare Providers

10.1002/cpt.2957CLINICAL PHARMACOLOGY & THERAPEUTICS1142275-28

An Introductory Tutorial on Cardiovascular Pharmacogenetics for Healthcare Providers

Pharmacogenetics can improve clinical outcomes by reducing adverse drug effects and enhancing therapeutic efficacy for commonly used drugs that treat a wide range of cardiovascular diseases. One of the major barriers to the clinical implementation of cardiovascular pharmacogenetics is limited education on this field for current healthcare providers and students. The abundance of pharmacogenetic literature underscores its promise, but it can also be challenging to learn such a wealth of information. Moreover, current clinical recommendations for cardiovascular pharmacogenetics can be confusing because they are outdated, incomplete, or inconsistent. A myriad of misconceptions about the promise and feasibility of cardiovascular pharmacogenetics among healthcare providers also has halted clinical implementation. Therefore, the main goal of this tutorial is to provide introductory education on the use of cardiovascular pharmacogenetics in clinical practice. The target audience is any healthcare provider (or student) with patients that use or have indications for cardiovascular drugs. This tutorial is organized into the following 6 steps: (1) understand basic concepts in pharmacogenetics; (2) gain foundational knowledge of cardiovascular pharmacogenetics; (3) learn the different organizations that release cardiovascular pharmacogenetic guidelines and recommendations; (4) know the current cardiovascular drugs/drug classes to focus on clinically and the supporting evidence; (5) discuss an example patient case of cardiovascular pharmacogenetics; and (6) develop an appreciation for emerging areas in cardiovascular pharmacogenetics. Ultimately, improved education among healthcare providers on cardiovascular pharmacogenetics will lead to a greater understanding for its potential in improving outcomes for a leading cause of morbidity and mortality