Manual abort guidance from the midcourse region of a lunar mission

Manual abort guidance from midcourse region of lunar missio

Development of oxide dispersion strengthened turbine blade alloy by mechanical alloying

There were three nickel-base alloys containing up to 18 wt. % of refractory metal examined initially for oxide dispersion strengthening. To provide greater processing freedom, however, a leaner alloy was finally selected. This base alloy, alloy D, contained 0.05C/15Cr / 2Mo/4W/2Ta/4.5Al/2.Ti/015Zr/0.01-B/Bal. Ni. Following alloy selection, the effect of extrusion, heat treatment, and oxide volume fraction and size on microstructure and properties were examined. The optimum structure was achieved in zone annealed alloy D which contained 2.5 vol. % of 35 mm Y2O3 and which was extruded 16:1 at 1038 C

Recombination events among virulence genes in malaria parasites are associated with G-quadruplex-forming DNA motifs

Background Malaria parasites of the genus Plasmodium possess large hyper-variable families of antigen-encoding genes. These are often variantly-expressed and are major virulence factors for immune evasion and the maintenance of chronic infections. Recombination and diversification of these gene families occurs readily, and may be promoted by G-quadruplex (G4) DNA motifs within and close to the variant genes. G4s have been shown to cause replication fork stalling, DNA breakage and recombination in model systems, but these motifs remain largely unstudied in Plasmodium. Results We examined the nature and distribution of putative G4-forming sequences in multiple Plasmodium genomes, finding that their co-distribution with variant gene families is conserved across different Plasmodium species that have different types of variant gene families. In P. falciparum, where a large set of recombination events that occurred over time in cultured parasites has been mapped, we found a strong spatial association between these recombination events and putative G4-forming sequences. Finally, we searched Plasmodium genomes for the three classes of helicase that can unwind G4s: Plasmodium spp. have no identifiable homologue of the highly efficient G4 helicase PIF1, but they do encode two putative RecQ helicases and one homologue of the RAD3-family helicase FANCJ. Conclusions Our analyses, conducted at the whole-genome level in multiple species of Plasmodium, support the concept that G4s are likely to be involved in recombination and diversification of antigen-encoding gene families in this important protozoan pathogen

Multiplex analysis of mitochondrial DNA pathogenic and polymorphic sequence variants

The mitochondrial DNA (mtDNA) encompasses two classes of functionally important sequence variants: recent pathogenic mutations and ancient adaptive polymorphisms. To rapidly and cheaply evaluate both classes of single nucleotide variants (SNVs), we have developed an integrated system in which mtDNA SNVs are analyzed by multiplex primer extension using the SNaPshot system. A multiplex PCR amplification strategy was used to amplify the entire mtDNA, a computer program identifies optimal extension primers, and a complete global haplotyping system is also proposed. This system genotypes SNVs on multiplexed mtDNA PCR products or directly from enriched mtDNA samples and can quantify heteroplasmic variants down to 0.8% using a standard curve. With this system, we have developed assays for testing the common pathogenic mutations in four multiplex panels: two genotype the 13 most common pathogenic mtDNA mutations and two genotype the 10 most common Leber Hereditary Optic Neuropathy mutations along with haplogroups J and T. We use a hierarchal system of 140 SNVs to delineate the major global mtDNA haplogroups based on a global phylogenetic tree of coding region polymorphisms. This system should permit rapid and inexpensive genotyping of pathogenic and lineage-specific mtDNA SNVs by clinical and research laboratories

Ternatin and improved synthetic variants kill cancer cells by targeting the elongation factor-1A ternary complex.

Cyclic peptide natural products have evolved to exploit diverse protein targets, many of which control essential cellular processes. Inspired by a series of cyclic peptides with partially elucidated structures, we designed synthetic variants of ternatin, a cytotoxic and anti-adipogenic natural product whose molecular mode of action was unknown. The new ternatin variants are cytotoxic toward cancer cells, with up to 500-fold greater potency than ternatin itself. Using a ternatin photo-affinity probe, we identify the translation elongation factor-1A ternary complex (eEF1A·GTP·aminoacyl-tRNA) as a specific target and demonstrate competitive binding by the unrelated natural products, didemnin and cytotrienin. Mutations in domain III of eEF1A prevent ternatin binding and confer resistance to its cytotoxic effects, implicating the adjacent hydrophobic surface as a functional hot spot for eEF1A modulation. We conclude that the eukaryotic elongation factor-1A and its ternary complex with GTP and aminoacyl-tRNA are common targets for the evolution of cytotoxic natural products

Detection and sequencing of phosphopeptides affinity bound to immobilized metal ion beads by matrix-assisted laser desorption/ionization mass spectrometry

AbstractConsecutive enzymatic reactions of analytes which are affinity bound to immobilized metal ion beads with subsequent direct analysis of the products by matrix-assisted laser desorption/ionization mass spectrometry have been used for detecting phosphorylation sites. The usefulness of this method was demonstrated by analyzing two commercially available phosphoproteins, β-casein and α-casein, as well as one phosphopeptide from a kinase reaction mixture. Agarose loaded with either Fe3+ or Ga3+ was used to isolate phosphopeptides from the protein digest. Results from using either metal ion were complementary. Less overall suppression effect was achieved when Ga3+-loaded agarose was used to isolate phosphopeptides. The selectivity for monophosphorylated peptides, however, was better with Fe3+-loaded agarose. This technique is easy to use and has the ability to analyze extremely complicated phosphopeptide mixtures. Moreover, it eliminates the need for prior high-performance liquid chromatography separation or radiolabeling, thus greatly simplifying the sample preparation

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

The importance of decision intent within descriptions of pragmatic trials

ACKNOWLEGEMENTS This work is supported by the Canadian Institutes of Health Research through the Project Grant competition (competitive, peer-reviewed), award number PJT-153045. CRediT authorship contribution statement Stuart G. Nicholls: Writing - review & editing. Merrick Zwarenstein: Writing - review & editing. Spencer Phillips Hey: Writing - review & editing. Bruno Giraudeau: Writing - review & editing. Marion K. Campbell: Writing - review & editing. Monica Taljaard: Writing - review & editing.Peer reviewedPostprin

Office design and health: a systematic review

Aim: To carry out a systematic review of recent research into the effects of workplace design, comparing individual with shared workspaces, on the health of employees. Methods: The research question was "Does workplace design (specifically individual offices compared with shared workspaces) affect the health of workers?" A literature search limited to articles published between 2000 and 2017 was undertaken. A systematic review was carried out, and the findings of the reviewed studies grouped into themes according to the primary outcomes measured in the studies. Results: The literature search identified 15 relevant studies addressing health effects of shared or open-plan offices compared with individual offices. Our systematic review found that, compared with individual offices, shared or open-plan office space is not beneficial to employees' health, with consistent findings of deleterious effects on staff health, wellbeing and productivity. Our findings are also consistent with those of earlier reviews. Conclusion: These findings have public health implications for the New Zealand workforce. Decisions about workplace design should include weighing the short-term financial benefits of open-plan or shared workspaces against the significant harms, including increased sickness absence, lower job satisfaction and productivity, and possible threats to recruitment and retention of staff