Orbital operations study. Appendix B: Operational procedures

Operational procedures for each alternate approach for each interfacing activity of the orbital operations study are presented. The applicability of the procedures to interfacing element pairs is identified

Prion protein repeat expansion results in increased aggregation and reveals phenotypic variability

Mammalian prion diseases are fatal neurodegenerative disorders dependent on the prion protein PrP. Expansion of the oligopeptide repeats (ORE) found in PrP is associated with inherited prion diseases. Patients with ORE frequently harbor PrP aggregates, but other factors may contribute to pathology, as they often present with unexplained phenotypic variability. We created chimeric yeast-mammalian prion proteins to examine the influence of the PrP ORE on prion properties in yeast. Remarkably, all chimeric proteins maintained prion characteristics. The largest repeat expansion chimera displayed a higher propensity to maintain a self-propagating aggregated state. Strikingly, the repeat expansion conferred increased conformational flexibility, as observed by enhanced phenotypic variation. Furthermore, the repeat expansion chimera displayed an increased rate of prion conversion, but only in the presence of another aggregate, the [RNQ(+)] prion. We suggest that the PrP ORE increases the conformational flexibility of the prion protein, thereby enhancing the formation of multiple distinct aggregate structures and allowing more frequent prion conversion. Both of these characteristics may contribute to the phenotypic variability associated with PrP repeat expansion diseases

Diabetes by Air, Land, and Sea: Effect of Deployments on HbA1c and BMI

INTRODUCTION: Service members (SMs) in the United States (U.S.) Armed Forces have diabetes mellitus at a rate of 2-3%. Despite having a chronic medical condition, they have deployed to environments with limited medical support. Given the scarcity of data describing how they fare in these settings, we conducted a retrospective study analyzing the changes in glycated hemoglobin (HbA1c) and body mass index (BMI) before and after deployment. MATERIALS AND METHODS: SMs from the U.S. Army, Air Force, Navy, and Marine Corps with diabetes who deployed overseas were identified through the Military Health System (MHS) Management Analysis and Reporting Tool and the Defense Manpower Data Center. Laboratory and pharmaceutical data were obtained from the MHS Composite Health Care System and the Pharmacy Data Transaction Service, respectively. Paired t-tests were conducted to calculate changes in HbA1c and BMI before and after deployment. RESULTS: SMs with diabetes completed 11,325 deployments of greater than 90 days from 2005 to 2017. Of these, 474 (4.2%) SMs had both HbA1c and BMI measurements within 90 days prior to departure and within 90 days of return. Most (84.2%) required diabetes medications: metformin in 67.3%, sulfonylureas in 19.0%, dipeptidyl peptidase-4 inhibitors in 13.9%, and insulin in 5.5%. Most SMs deployed with an HbA1c \u3c 7.0% (67.1%), with a mean predeployment HbA1c of 6.8%. Twenty percent deployed with an HbA1c between 7.0 and 7.9%, 7.2% deployed with an HbA1c between 8.0 and 8.9%, and 5.7% deployed with an HbA1c of 9.0% or higher. In the overall population and within each military service, there was no significant change in HbA1c before and after deployment. However, those with predeployment HbA1c \u3c 7.0% experienced a rise in HbA1c from 6.2 to 6.5% (P \u3c 0.001), whereas those with predeployment HbA1c values ≥7.0% experienced a decline from 8.0 to 7.5% (P \u3c 0.001). Those who deployed between 91 and 135 days had a decline in HbA1c from 7.1 to 6.7% (P = 0.010), but no significant changes were demonstrated in those with longer deployment durations. BMI declined from 29.6 to 29.3 kg/m2 (P \u3c 0.001), with other significant changes seen among those in the Army, Navy, and deployment durations up to 315 days. CONCLUSIONS: Most SMs had an HbA1c \u3c 7.0%, suggesting that military providers appropriately selected well-managed SMs for deployment. HbA1c did not seem to deteriorate during deployment, but they also did not improve despite a reduction in BMI. Concerning trends included the deployment of some SMs with much higher HbA1c, utilization of medications with adverse safety profiles, and the lack of HbA1c and BMI evaluation proximal to deployment departures and returns. However, for SMs meeting adequate glycemic targets, we demonstrated that HbA1c remained stable, supporting the notion that some SMs may safely deploy with diabetes. Improvement in BMI may compensate for factors promoting hyperglycemia in a deployed setting, such as changes in diet and medication availability. Future research should analyze in a prospective fashion, where a more complete array of diabetes and readiness-related measures to comprehensively evaluate the safety of deploying SMs with diabetes

Genomic alterations indicate tumor origin and varied metastatic potential of disseminated cells from prostate-cancer patients

Disseminated epithelial cells can be isolated from the bone marrow of a far greater fraction of prostate-cancer patients than the fraction of patients who progress to metastatic disease. To provide a better understanding of these cells, we have characterized their genomic alterations. We first present an array comparative genomic hybridization method capable of detecting genomic changes in the small number of disseminated cells (10-20) that can typically be obtained from bone-marrow aspirates of prostate-cancer patients. We show multiple regions of copy-number change, including alterations common in prostate cancer, such as 8p loss, 8q gain, and gain encompassing the androgen-receptor gene on Xq, in the disseminated cell pools from 11 metastatic patients. We found fewer and less striking genomic alterations in the 48 pools of disseminated cells from patients with organ-confined disease. However, we identify changes shared by these samples with their corresponding primary tumors and prostate-cancer alterations reported in the literature, evidence that these cells, like those in advanced disease, are disseminated tumor cells (DTCs). We also demonstrate that DTCs from patients with advanced and localized disease share several abnormalities, including losses containing cell-adhesion genes and alterations reported to associate with progressive disease. These shared alterations might confer the capability to disseminate or establish secondary disease. Overall, the spectrum of genomic deviations is evidence for metastatic capacity in advanced-disease DTCs and variation in that capacity in DTCs from localized disease. Our analysis lays the foundation for elucidation of the relationship between DTC genomic alterations and progressive prostate cancer

Assessment of Inactivating Stop Codon Mutations in Forty Saccharomyces cerevisiae Strains: Implications for [PSI+] Prion- Mediated Phenotypes

The yeast prion [PSI+] has been implicated in the generation of novel phenotypes by a mechanism involving a reduction in translation fidelity causing readthrough of naturally occurring stop codons. Some [PSI+] associated phenotypes may also be generated due to readthrough of inactivating stop codon mutations (ISCMs). Using next generation sequencing we have sequenced the genomes of two Saccharomyces cerevisiae strains that are commonly used for the study of the yeast [PSI+] prion. We have identified approximately 26,000 and 6,500 single nucleotide polymorphisms (SNPs) in strains 74-D694 and G600 respectively, compared to reference strain S288C. In addition to SNPs that produce non-synonymous amino acid changes we have also identified a number of SNPs that cause potential ISCMs in these strains, one of which we show is associated with a [PSI+]-dependent stress resistance phenotype in strain G600. We identified twenty-two potential ISCMs in strain 74-D694, present in genes involved in a variety of cellular processes including nitrogen metabolism, signal transduction and oxidative stress response. The presence of ISCMs in a subset of these genes provides possible explanations for previously identified [PSI+]-associated phenotypes in this strain. A comparison of ISCMs in strains G600 and 74-D694 with S. cerevisiae strains sequenced as part of the Saccharomyces Genome Resequencing Project (SGRP) shows much variation in the generation of strain-specific ISCMs and suggests this process is possible under complex genetic control. Additionally we have identified a major difference in the abilities of strains G600 and 74-D694 to grow at elevated temperatures. However, this difference appears unrelated to novel SNPs identified in strain 74-D694 present in proteins involved in the heat shock response, but may be attributed to other SNP differences in genes previously identified as playing a role in high temperature growth

Dynamics of railway freight vehicles

This paper summarises the historical development of railway freight vehicles and how vehicle designers have tackled the difficult challenges of producing running gear which can accommodate the very high tare to laden mass of typical freight wagons whilst maintaining stable running at the maximum required speed and good curving performance. The most common current freight bogies are described in detail and recent improvements in techniques used to simulate the dynamic behaviour of railway vehicles are summarised and examples of how these have been used to improve freight vehicle dynamic behaviour are included. A number of recent developments and innovative components and sub systems are outlined and finally two new developments are presented in more detail: the LEILA bogie and the SUSTRAIL bogie

Pesticides and health: A review of evidence on health effects, valuation of risks, and benefit‐cost analysis

In this paper, we provide reviews of recent scientific findings on health effects and preference valuation of health risks related to pesticides, and the role of benefit‐cost analysis in policies related to pesticides. Our reviews reveal that whereas the focus of the health literature has been on individuals with direct exposure to pesticides, e.g. farmers, the literature on preference elicitation has focused on those with indirect exposure, e.g. consumers. Our discussion of pesticides policies emphasizes the need to clarify the rationale for regulation and the role of risk perceptions in benefit‐cost analysis, and stress the importance of inter‐disciplinary research in this area

On the occurrence of cytochrome P450 in viruses

Author Posting. © The Author(s), 2019. This is the author's version of the work. It is posted here by permission of National Academy of Sciences for personal use, not for redistribution. The definitive version was published in Proceedings of the National Academy of Sciences of the United States of America 116(25), (2019):12343-12352, doi:10.1073/pnas.1901080116.Genes encoding cytochrome P450 (CYP; P450) enzymes occur widely in the Archaea, Bacteria, and Eukarya, where they play important roles in metabolism of endogenous regulatory molecules and exogenous chemicals. We now report that genes for multiple and unique P450s occur commonly in giant viruses in the Mimiviridae, Pandoraviridae, and other families in the proposed order Megavirales. P450 genes were also identified in a herpesvirus (Ranid herpesvirus 3) and a phage (Mycobacterium phage Adler). The Adler phage P450 was classified as CYP102L1, and the crystal structure of the open form was solved at 2.5 Å. Genes encoding known redox partners for P450s (cytochrome P450 reductase, ferredoxin and ferredoxin reductase, and flavodoxin and flavodoxin reductase) were not found in any viral genome so far described, implying that host redox partners may drive viral P450 activities. Giant virus P450 proteins share no more than 25% identity with the P450 gene products we identified in Acanthamoeba castellanii, an amoeba host for many giant viruses. Thus, the origin of the unique P450 genes in giant viruses remains unknown. If giant virus P450 genes were acquired from a host, we suggest it could have been from an as yet unknown and possibly ancient host. These studies expand the horizon in the evolution and diversity of the enormously important P450 superfamily. Determining the origin and function of P450s in giant viruses may help to discern the origin of the giant viruses themselves.We thank Dr. David Nes (Texas Tech University) for providing sterols and Dr. Matthieu Legendre and Dr. Chantal Abergel (CNRS, Marseille) for access to the P. celtis sequences. Drs. Irina Arkhipova, Mark Hahn, Judith Luborsky, and Ann Bucklin commented on the manuscript. The research was supported by a USA-UK Fulbright Scholarship and a Royal Society grant (to D.C.L.), the Boston University Superfund Research Program [NIH Grant 5P42ES007381 (to J.J.S. and J.V.G.) and NIH Grant 5U41HG003345 (to J.V.G.)], the European Regional Development Fund and Welsh Government Project BEACON (S.L.K.), the Woods Hole Center for Oceans and Human Health [NIH Grant P01ES021923 and National Science Foundation Grant OCE-1314642 (to J.J.S.)], and NIH Grant R01GM53753 (to T.L.P.).2019-12-0

Search for squarks and gluinos in events with isolated leptons, jets and missing transverse momentum at s√=8 TeV with the ATLAS detector

The results of a search for supersymmetry in final states containing at least one isolated lepton (electron or muon), jets and large missing transverse momentum with the ATLAS detector at the Large Hadron Collider are reported. The search is based on proton-proton collision data at a centre-of-mass energy s√=8 TeV collected in 2012, corresponding to an integrated luminosity of 20 fb−1. No significant excess above the Standard Model expectation is observed. Limits are set on supersymmetric particle masses for various supersymmetric models. Depending on the model, the search excludes gluino masses up to 1.32 TeV and squark masses up to 840 GeV. Limits are also set on the parameters of a minimal universal extra dimension model, excluding a compactification radius of 1/R c = 950 GeV for a cut-off scale times radius (ΛR c) of approximately 30