Experimental investigation and analysis of two sources of nozzle-thrust misalignment

Asymmetry of nozzle's throat produces oscillatory type net side-force axial profile. Using mean values of localized static pressure and Mach number, scaling laws for flat-plate supersonic flow over protrusion are applied to nozzle expansion cone irregularities to give approximate indication of perturbed-pressure profiles and induced side forces

The Otto-engine-equivalent vehicle concept

A vehicle comparison methodology based on the Otto-Engine Equivalent (OEE) vehicle concept is described. As an illustration of this methodology, the concept is used to make projections of the fuel economy potential of passenger cars using various alternative power systems. Sensitivities of OEE vehicle results to assumptions made in the calculational procedure are discussed. Factors considered include engine torque boundary, rear axle ratio, performance criteria, engine transient response, and transmission shift logic

Cold-flow experimental investigation and analysis of two sources of nozzle thrust misalignment

Cold flow investigation and analysis of two nozzle thrust misalignmen

Efficient CRISPR-rAAV engineering of endogenous genes to study protein function by allele-specific RNAi.

Gene knockout strategies, RNAi and rescue experiments are all employed to study mammalian gene function. However, the disadvantages of these approaches include: loss of function adaptation, reduced viability and gene overexpression that rarely matches endogenous levels. Here, we developed an endogenous gene knockdown/rescue strategy that combines RNAi selectivity with a highly efficient CRISPR directed recombinant Adeno-Associated Virus (rAAV) mediated gene targeting approach to introduce allele-specific mutations plus an allele-selective siRNA Sensitive (siSN) site that allows for studying gene mutations while maintaining endogenous expression and regulation of the gene of interest. CRISPR/Cas9 plus rAAV targeted gene-replacement and introduction of allele-specific RNAi sensitivity mutations in the CDK2 and CDK1 genes resulted in a >85% site-specific recombination of Neo-resistant clones versus ∼8% for rAAV alone. RNAi knockdown of wild type (WT) Cdk2 with siWT in heterozygotic knockin cells resulted in the mutant Cdk2 phenotype cell cycle arrest, whereas allele specific knockdown of mutant CDK2 with siSN resulted in a wild type phenotype. Together, these observations demonstrate the ability of CRISPR plus rAAV to efficiently recombine a genomic locus and tag it with a selective siRNA sequence that allows for allele-selective phenotypic assays of the gene of interest while it remains expressed and regulated under endogenous control mechanisms

Site Selective Antibody-Oligonucleotide Conjugation via Microbial Transglutaminase.

Nucleic Acid Therapeutics (NATs), including siRNAs and AntiSense Oligonucleotides (ASOs), have great potential to drug the undruggable genome. Targeting siRNAs and ASOs to specific cell types of interest has driven dramatic improvement in efficacy and reduction in toxicity. Indeed, conjugation of tris-GalNAc to siRNAs and ASOs has shown clinical efficacy in targeting diseases driven by liver hepatocytes. However, targeting non-hepatic diseases with oligonucleotide therapeutics has remained problematic for several reasons, including targeting specific cell types and endosomal escape. Monoclonal antibody (mAb) targeting of siRNAs and ASOs has the potential to deliver these drugs to a variety of specific cell and tissue types. However, most conjugation strategies rely on random chemical conjugation through lysine or cysteine residues resulting in conjugate heterogeneity and a distribution of Drug:Antibody Ratios (DAR). To produce homogeneous DAR-2 conjugates with two siRNAs per mAb, we developed a novel two-step conjugation procedure involving microbial transglutaminase (MTGase) tagging of the antibody C-terminus with an azide-functionalized linker peptide that can be subsequently conjugated to dibenzylcyclooctyne (DBCO) bearing oligonucleotides through azide-alkyne cycloaddition. Antibody-siRNA (and ASO) conjugates (ARCs) produced using this strategy are soluble, chemically defined targeted oligonucleotide therapeutics that have the potential to greatly increase the number of targetable cell types

Measuring the Effects of Thread Placement on the Kendall Square KSR1

This paper describes a measurement study of the effects of thread placement on memory access times on the Kendall Square multiprocessor, the KSRl. The KSRl uses a conventional shared memory programming model in a distributed memory architecture. The architecture is based on a ring of rings of 64-bit superscalar microprocessors. The KSRl has a Cache-Only Memory Architecture (COMA). Memory consists of the local cache memoria attached to each processor. Whenever an address is accessed, the data item is automatically copied to the local cache memory module, 80 that access times for subsequent references will be minimal. If a local cache has space allocated for a particular data item, but does not have a current valid copy of that data item, then it is possible for the cache to acquire a valid read-only copy before it is requested by the local processor due to a request by a different processor that happens to pass by on the ring. This automatic prefetching can greatly reduce the average time for a thread to acquire data items. Because of the automatic prefetching, the time required to obtain a valid copy of a data item does not depend simply on the distance from the owner of the data item, but also depends on the placement and number of other processing threads which ehare the same data item. Also, the strategic placement of processing threads helps programs take advantage of the unique features of the memory architecture which help eliminate memory access bottlenecks for shared data sets. Experiments run on the KSRl across a wide variety of thread configurations show that shared memory access is accelerated through strategic placement of threads which share data. The results indicate strategies for improving the performance of applications programs, and illustrate that KSRl memory access times can remain nearly constant even when the number of participating threads increases

Modelling the social and structural determinants of tuberculosis: opportunities and challenges

INTRODUCTION: Despite the close link between tuberculosis (TB) and poverty, most mathematical models of TB have not addressed underlying social and structural determinants. OBJECTIVE: To review studies employing mathematical modelling to evaluate the epidemiological impact of the structural determinants of TB. METHODS: We systematically searched PubMed and personal libraries to identify eligible articles. We extracted data on the modelling techniques employed, research question, types of structural determinants modelled and setting. RESULTS: From 232 records identified, we included eight articles published between 2008 and 2015; six employed population-based dynamic TB transmission models and two non-dynamic analytic models. Seven studies focused on proximal TB determinants (four on nutritional status, one on wealth, one on indoor air pollution, and one examined overcrowding, socio-economic and nutritional status), and one focused on macro-economic influences. CONCLUSIONS: Few modelling studies have attempted to evaluate structural determinants of TB, resulting in key knowledge gaps. Despite the challenges of modelling such a complex system, models must broaden their scope to remain useful for policy making. Given the intersectoral nature of the interrelations between structural determinants and TB outcomes, this work will require multidisciplinary collaborations. A useful starting point would be to focus on developing relatively simple models that can strengthen our knowledge regarding the potential effect of the structural determinants on TB outcomes