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The laboratory mouse is the most widely used animal model for biomedical research, due in part to its well-annotated genome, wealth of genetic resources, and the ability to precisely manipulate its genome. Despite the importance of genetics for mouse research, genetic quality control (QC) is not standardized, in part due to the lack of cost-effective, informative, and robust platforms. Genotyping arrays are standard tools for mouse research and remain an attractive alternative even in the era of high-throughput whole-genome sequencing. Here, we describe the content and performance of a new iteration of the Mouse Universal Genotyping Array (MUGA), MiniMUGA, an array-based genetic QC platform with over 11,000 probes. In addition to robust discrimination between most classical and wild-derived laboratory strains, MiniMUGA was designed to contain features not available in other platforms: (1) chromosomal sex determination, (2) discrimination between substrains from multiple commercial vendors, (3) diagnostic SNPs for popular laboratory strains, (4) detection of constructs used in genetically engineered mice, and (5) an easy-to-interpret report summarizing these results. In-depth annotation of all probes should facilitate custom analyses by individual researchers. To determine the performance of MiniMUGA, we genotyped 6899 samples from a wide variety of genetic backgrounds. The performance of MiniMUGA compares favorably with three previous iterations of the MUGA family of arrays, both in discrimination capabilities and robustness. We have generated publicly available consensus genotypes for 241 inbred strains including classical, wild-derived, and recombinant inbred lines. Here, we also report the detection of a substantial number of XO and XXY individuals across a variety of sample types, new markers that expand the utility of reduced complexity crosses to genetic backgrounds other than C57BL/6, and the robust detection of 17 genetic constructs. We provide preliminary e

The laboratory mouse is the most widely used animal model for biomedical research, due in part to its well-annotated genome, wealth of genetic resources, and the ability to precisely manipulate its genome. Despite the importance of genetics for mouse research, genetic quality control (QC) is not standardized, in part due to the lack of cost-effective, informative, and robust platforms. Genotyping arrays are standard tools for mouse research and remain an attractive alternative even in the era of high-throughput whole-genome sequencing. Here, we describe the content and performance of a new iteration of the Mouse Universal Genotyping Array (MUGA), MiniMUGA, an array-based genetic QC platform with over 11,000 probes. In addition to robust discrimination between most classical and wild-derived laboratory strains, MiniMUGA was designed to contain features not available in other platforms: (1) chromosomal sex determination, (2) discrimination between substrains from multiple commercial vendors, (3) diagnostic SNPs for popular laboratory strains, (4) detection of constructs used in genetically engineered mice, and (5) an easy-to-interpret report summarizing these results. In-depth annotation of all probes should facilitate custom analyses by individual researchers. To determine the performance of MiniMUGA, we genotyped 6899 samples from a wide variety of genetic backgrounds. The performance of MiniMUGA compares favorably with three previous iterations of the MUGA family of arrays, both in discrimination capabilities and robustness. We have generated publicly available consensus genotypes for 241 inbred strains including classical, wild-derived, and recombinant inbred lines. Here, we also report the detection of a substantial number of XO and XXY individuals across a variety of sample types, new markers that expand the utility of reduced complexity crosses to genetic backgrounds other than C57BL/6, and the robust detection of 17 genetic constructs. We provide preliminary e

Plasma concentration of Cystatin C (CysC) level is a biomarker of glomerular filtration rate in the kidney. We use a Systems Genetics approach to investigate the genetic determinants of plasma CysC concentration. To do so we perform Quantitative Trait Loci (QTL) and expression QTL (eQTL) analysis of 120 Diversity Outbred (DO) female mice, 56 weeks of age. We performed network analysis of kidney gene expression to determine if the gene modules with common functions are associated with kidney biomarkers of chronic kidney diseases. Our data demonstrates that plasma concentrations and kidney mRNA levels of CysC are associated with genetic variation and are transcriptionally coregulated by immune genes. Specifically, Type-I interferon signaling genes are coexpressed with Cst3 mRNA levels and associated with CysC concentrations in plasma. Our findings demonstrate the complex control of CysC by genetic polymorphisms and inflammatory pathways.

Gabriel Tremblay1, Tracy Westley1, Joseph C Cappelleri2, Bhakti Arondekar2, Geoffrey Chan2, Timothy J Bell2, Andrew Briggs3 1Purple Squirrel Economics, New York, NY, USA; 2Pfizer Inc, New York, NY, USA; 3William R Lindsay Chair of Health Economics, Health Economics and Technology Assessment, Institute of Health & Wellbeing, University of Glasgow, Glasgow, UKCorrespondence: Gabriel TremblayPurple Squirrel Economics, 4 Lexington Avenue, Suite 15K, New York, NY 10010, USATel +1 646 478 8213Email gabrieltremblay@pshta.comBackground: Until recently, treatments for older patients with AML ineligible to receive intensive chemotherapies were limited to hypomethylating agents, low-dose cytarabine (LDAC), or clinical trials. In 2018, the FDA approved combination glasdegib (GLAS) plus LDAC based on Phase II results demonstrating improved overall survival (OS) versus LDAC alone in previously untreated AML. However, no randomized clinical trials have directly compared GLAS + LDAC with other AML treatments.Objective: Using both indirect treatment comparison (ITC) and simulated treatment comparison (STC), which adjusts for baseline differences between trials, the comparative effectiveness of GLAS + LDAC was compared with hypomethylating agent azacitidine (AZA) or decitabine (DEC).Methods: A systematic literature review identified published trials of AZA or DEC versus LDAC among older AML patients ineligible for high-intensity chemotherapy. In addition to standard and covariate-adjusted ITC, STC was performed following guidance from the NICE Decision Support Unit (DSU). Using individual patient data from the Phase II GLAS + LDAC study, population-specific OS hazard ratios (HR) for GLAS + LDAC versus AZA or DEC were compared. Furthermore, covariate-adjusted ITC (Cox multivariate models) and STC were repeated using GLAS + LDAC versus LDAC data propensity-weighted for within-trial mean cy

Anna Forsythe,1 Christina S Kwon,1 Timothy Bell,2 T Alexander Smith,3 Bhakti Arondekar4 1Purple Squirrel Economics, New York, NY, USA; 2Pfizer Inc, New York, NY, USA; 3Pfizer Ltd, Walton Oaks, UK; 4Pfizer Inc, Collegeville, PA, USA Background: AML is a rapidly progressing bone marrow cancer, with poor survival rates compared to other types of leukemia. IC and NIC as well as BSC treatment options are available; however, there is scant published literature on the impact of disease and treatment on the HRQoL in patients receiving NIC.Aim: This study determined the HRQoL among NIC AML patients.Materials and methods: Embase, Medline, Cochrane database, and conference abstracts were searched using the prespecified PICOS criteria from January 2000 to November 2017 for studies reporting HRQoL and patient preference utilities in NIC AML. Studies on patients with RAEB-t MDS, randomized clinical trials (RCTs), prospective observational studies, and patient surveys were included, while systematic reviews and meta-analyses were used for bibliographic searching.Results: Thirteen records from 12 original studies were identified. These included five records from four RCTs, three prospective studies, four patient survey studies, and one cost-effectiveness analysis. At baseline, NIC AML patients had poor HRQoL scores especially in fatigue (33) and GHS (50) on a 0–100 scale, with higher scores indicating better health. Low baseline HRQoL scores, especially PF and fatigue (<50) were shown to be significant independent predictors of poor survival. Clinical responders demonstrated meaningful improvements, especially in PF and fatigue, along with other health domains after being treated with NIC agents across several studies.Conclusion: HRQoL is poor for patients with NIC AML; measures such as fatigue and PF at baseline have been identified as independent prognostic factors for overall survival with several studies showing improvement in both domains with treatment. RCTs

We measure the mass function for a sample of 840 young star clusters with ages between 10-300 Myr observed by the Panchromatic Hubble Andromeda Treasury (PHAT) survey in M31. The data show clear evidence of a high-mass truncation: only 15 clusters more massive than $10^4$ $M_{\odot}$ are observed, compared to $\sim$100 expected for a canonical $M^{-2}$ pure power-law mass function with the same total number of clusters above the catalog completeness limit. Adopting a Schechter function parameterization, we fit a characteristic truncation mass of $M_c = 8.5^{+2.8}_{-1.8} \times 10^3$ $M_{\odot}$. While previous studies have measured cluster mass function truncations, the characteristic truncation mass we measure is the lowest ever reported. Combining this M31 measurement with previous results, we find that the cluster mass function truncation correlates strongly with the characteristic star formation rate surface density of the host galaxy, where $M_c \propto$ $\langle \Sigma_{\mathrm{SFR}} \rangle^{\sim1.1}$. We also find evidence that suggests the observed $M_c$-$\Sigma_{\mathrm{SFR}}$ relation also applies to globular clusters, linking the two populations via a common formation pathway. If so, globular cluster mass functions could be useful tools for constraining the star formation properties of their progenitor host galaxies in the early Universe., Comment: 15 pages, 7 figures, Accepted by ApJ

We measure the mass function for a sample of 840 young star clusters with ages between 10-300 Myr observed by the Panchromatic Hubble Andromeda Treasury (PHAT) survey in M31. The data show clear evidence of a high-mass truncation: only 15 clusters more massive than $10^4$ $M_{\odot}$ are observed, compared to $\sim$100 expected for a canonical $M^{-2}$ pure power-law mass function with the same total number of clusters above the catalog completeness limit. Adopting a Schechter function parameterization, we fit a characteristic truncation mass of $M_c = 8.5^{+2.8}_{-1.8} \times 10^3$ $M_{\odot}$. While previous studies have measured cluster mass function truncations, the characteristic truncation mass we measure is the lowest ever reported. Combining this M31 measurement with previous results, we find that the cluster mass function truncation correlates strongly with the characteristic star formation rate surface density of the host galaxy, where $M_c \propto$ $\langle \Sigma_{\mathrm{SFR}} \rangle^{\sim1.1}$. We also find evidence that suggests the observed $M_c$-$\Sigma_{\mathrm{SFR}}$ relation also applies to globular clusters, linking the two populations via a common formation pathway. If so, globular cluster mass functions could be useful tools for constraining the star formation properties of their progenitor host galaxies in the early Universe., Comment: 15 pages, 7 figures, Accepted by ApJ

A selective sweep is the result of strong positive selection driving newly occurring or standing genetic variants to fixation, and can dramatically alter the pattern and distribution of allelic diversity in a population. Population-level sequencing data have enabled discoveries of selective sweeps associated with genes involved in recent adaptations in many species. In contrast, much debate but little evidence addresses whether “selfish” genes are capable of fixation – thereby leaving signatures identical to classical selective sweeps – despite being neutral or deleterious to organismal fitness. We previously described R2d2, a large copy-number variant that causes non-random segregation of mouse Chromosome 2 in females due to meiotic drive. Here we show population-genetic data consistent with a selfish sweep driven by alleles of R2d2 with high copy number (R2d2HC) in natural populations. We replicate this finding in multiple closed breeding populations from six outbred backgrounds segregating for R2d2 alleles. We find that R2d2HC rapidly increases in frequency, and in most cases becomes fixed in significantly fewer generations than can be explained by genetic drift. R2d2HC is also associated with significantly reduced litter sizes in heterozygous mothers, making it a true selfish allele. Our data provide direct evidence of populations actively undergoing selfish sweeps, and demonstrate that meiotic drive can rapidly alter the genomic landscape in favor of mutations with neutral or even negative effects on overall Darwinian fitness. Further study will reveal the incidence of selfish sweeps, and will elucidate the relative contributions of selfish genes, adaptation and genetic drift to evolution.

Complex human traits are influenced by variation in regulatory DNA through mechanisms that are not fully understood. Because regulatory elements are conserved between humans and mice, a thorough annotation of cis regulatory variants in mice could aid in further characterizing these mechanisms. Here we provide a detailed portrait of mouse gene expression across multiple tissues in a three-way diallel. Greater than 80% of mouse genes have cis regulatory variation. Effects from these variants influence complex traits and usually extend to the human ortholog. Further, we estimate that at least one in every thousand SNPs creates a cis regulatory effect. We also observe two types of parent-of-origin effects, including classical imprinting and a new global allelic imbalance in expression favoring the paternal allele. We conclude that, as with humans, pervasive regulatory variation influences complex genetic traits in mice and provide a new resource toward understanding the genetic control of transcription in mammals.

Complex human traits are influenced by variation in regulatory DNA through mechanisms that are not fully understood. Because regulatory elements are conserved between humans and mice, a thorough annotation of cis regulatory variants in mice could aid in further characterizing these mechanisms. Here we provide a detailed portrait of mouse gene expression across multiple tissues in a three-way diallel. Greater than 80% of mouse genes have cis regulatory variation. Effects from these variants influence complex traits and usually extend to the human ortholog. Further, we estimate that at least one in every thousand SNPs creates a cis regulatory effect. We also observe two types of parent-of-origin effects, including classical imprinting and a new global allelic imbalance in expression favoring the paternal allele. We conclude that, as with humans, pervasive regulatory variation influences complex genetic traits in mice and provide a new resource toward understanding the genetic control of transcription in mammals.

An exoskeleton platform was developed, prototyped and tested for mobility performance in a beachfront environment. New platform, drive-train, motor-controller and wheel design were employed in the experiment. The objective was to improve on the shortcoming of previous NPS research. Three wheel-designs were tested during fixed pattern tests on grass, concrete and sand. Data suggests that, with regard to power consumption, there is a marginal difference on preferred wheel design. The sparse print round wheel showed promise in heavy vegetation; however, the WhegTM wheel proved to be the most versatile on various terrains. This suggests that a WhegTM wheel with improved round wheel characteristics would be optimal for various beachfront terrains.

Uncertainty associated with ecological forecasts has long been recognized, but forecast accuracy is rarely quantified. We evaluated how well data on 82 populations of 20 species of plants spanning 3 continents explained and predicted plant population dynamics. We parameterized stage-based matrix models with demographic data from individually marked plants and determined how well these models forecast population sizes observed at least 5 years into the future. Simple demographic models forecasted population dynamics poorly; only 40% of observed population sizes fell within our forecasts' 95% confidence limits. However, these models explained population dynamics during the years in which data were collected; observed changes in population size during the data-collection period were strongly positively correlated with population growth rate. Thus, these models are at least a sound way to quantify population status. Poor forecasts were not associated with the number of individual plants or years of data. We tested whether vital rates were density dependent and found both positive and negative density dependence. However, density dependence was not associated with forecast error. Forecast error was significantly associated with environmental differences between the data collection and forecast periods. To forecast population fates, more detailed models, such as those that project how environments are likely to change and how these changes will affect population dynamics, may be needed. Such detailed models are not always feasible. Thus, it may be wiser to make risk-averse decisions than to expect precise forecasts from models. Habilidad de los Modelos Matriciales para Explicar el Pasado y Predecir el Futuro de las Poblaciones de Plantas Resumen La incertidumbre asociada con el pronostico ecologico ha sido reconocida durante un largo tiempo pero rara vez se cuantifica su seguridad. Evaluamos que tan bien la informacion de 82 poblaciones de 20 especies de plantas a lo larg, AuthorCount:20

P>Matrix projection models are among the most widely used tools in plant ecology. However, the way in which plant ecologists use and interpret these models differs from the way in which they are presented in the broader academic literature. In contrast to calls from earlier reviews, most studies of plant populations are based on < 5 matrices and present simple metrics such as deterministic population growth rates. However, plant ecologists also cautioned against literal interpretation of model predictions. Although academic studies have emphasized testing quantitative model predictions, such forecasts are not the way in which plant ecologists find matrix models to be most useful. Improving forecasting ability would necessitate increased model complexity and longer studies. Therefore, in addition to longer term studies with better links to environmental drivers, priorities for research include critically evaluating relative/comparative uses of matrix models and asking how we can use many short-term studies to understand long-term population dynamics., authorCount :16

Stanford University carried out a detailed study of the following topics: 1) the optimum orbit for exciting the magnetospheric cavity resonance by a space-based ELF/VLF transmitter, 2) the antenna type and configuration necessary to excite various cavity modes with the radiated ELF/VLF waves, 3) the effects of Landau damping on the ELF/VLFL waves within the cavity, 4) the effectiveness of the radiated ELF/VLF cavity waves in precipitating energetic radiation belt particles, and 5) the optimum spacecraft orbit, antenna configuration, and ELF/VLF transmitter frequency spectmm for precipitating energetic radiation belt particles over a wide range of energies. In addition, a study was carried out concerning the excitation of the magnetospheric cavity by ground-based VLF transmitters., The original document contains color images.

The Air Force Grant documented here directly resulted in the purchase of hardware eight VLF receivers. Five of these receivers have been deployed successfully and are operating regularly and reliably. The remaining are pending imminent deployment. The new receiver sites have enabled Stanford to jumpstart a fully-funded THY program, with funds from Stanford University and NASA, which will enable a great expansion of this network, and in addition, provides a new dataset which will greatly support Stanford's scientific studies of VLF and magnetospheric and ionospheric physics.

The overall objectives of this work are to: * Quantify the requirements for controlled precipitation of radiation belt particles in order to mitigate space particle effects * Address the issue of coupling of space based antennas to the surrounding magnetoplasma for use in system design * Determine radiated power from single transmitting element The completion of these goals requires the design of antenna-in-plasma codes which simulate the interaction of radiating antennas and the magnetized plasma in which they are immersed. Different codes have been developed that solve various aspects of the coupling problem and that are tailored to the particular physics in the corresponding region of the coupling environment.

Ventricular arrhythmias in patients after total surgical repair of tetralogy of Fallot have been associated with late sudden death. In this large multicenter retrospective study of 359 patients with postoperative tetralogy of Fallot, spontaneous ventricular premature complexes (VPCs) on 24-hour ambulatory electrocardiographic monitoring and laboratory-induced ventricular tachycardia (VT) by electrophysiologic stimulation were analyzed. The mean age at surgical repair was 5 years and the mean follow-up duration after repair was 7 years. Spontaneous VPCs on ambulatory monitoring were found in 48% and induced VT on electrophysiologic stimulation was found in 17% of patients. Both spontaneous VPCs and induced VT were significantly related to delayed age at repair, longer follow-up interval, symptoms of syncope or presyncope and right ventricular systolic hypertension (> 60 mm Hg) (p 8 mm Hg. The VPCs on ambulatory monitoring were more complex with increasing age at repair and follow-up duration. Induction of VT on electrophysiologic stimulation correlated with spontaneous VPCs including VT on 24-hour ambulatory electrocardiographic monitoring. The electrophysiologic stimulation protocol varied and the induction of VT increased with a more aggressive stimulation protocol. While induced sustained monomorphic VT was related to all forms of spontaneous VPCs, induced nonsustained polymorphic VT was related to more complex forms of VPCs on ambulatory monitoring. VT was not induced in asymptomatic patients who had normal 24-hour ambulatory electrocardiographic monitoring and normal right ventricular systolic pressure. Late sudden death occurred in 5 patients, most of whom had spontaneous VPCs on ambulatory monitoring and right ventricular diastolic pressure> 8mm Hg, but none had induced VT with a nonaggressive electrophysiologic protocol.

The overall objectives of this work were to quantify the requirements for controlled precipitation of radiation belt particles in order to mitigate enhanced space particle effects, to address critical issues of antenna-plasma coupling, and to develop a model of the effective radiated power throughout the magnetosphere In carrying out this effort, Stanford University worked closely with AFRL/VSB. During the period of performance, Stanford University concentrated on the critical issues which determine the properties of the ion and electron sheaths which surround dipole antennas in a plasma. The accurate modeling of the ion and electron sheaths and their effects on the far-field pattern of the antenna is necessary in order to simulate the characteristics of an antenna radiating at ELF/VLF frequencies in the magnetosphere, The original document contains color images. All DTIC reproductions will be in black and white.

During the period of performance Stanford University constructed a VLF/ELF receiver to measure the VLF/ELF electromagnetic and quasi-electrostatic fields produced by lightning during Sprite and Blue Jet events, and deployed this instrument in the field to make such measurements. The data acquired in the field was used to characterized the electromagnetic and quasi-electrostatic fields produced by lightning during Sprite and Blue Jet events.

During the period of performance a program of instrument construction, technique development, data acquisition, and data analysis was carried out in order to characterize the auroral electrojet and the ambient and modified D-region directly above and near the HAARP (High Frequency Active Auroral Research Program) facility in Alaska. To accomplish this goal, five VLF D-region diagnostic systems were constructed and deployed in five High Schools near the HAARP facility and along the west coast of Alaska. In addition in order to characterize the auroral electrojet on a continental scale and to allow prediction of its location, four VLF D-region diagnostic systems were constructed and deployed in four High Schools on the east coast of the United States and Canada. Data from the complete array of D-region diagnostic systems was acquired during a number of Fall and Spring HAARP campaigns during the period of performance. This data was then used to determine the state of the D-region above HAARP during the campaigns and to provide information on the location of the auroral electrojet. The salient scientific results from the observations were published in the scientific literature and also reported at the annual RF Ionospheric Interactions Workshop in Santa Fe, New Mexico. In addition a portion of this data formed one of the bases of a Ph.D. dissertation completed at Stanford University.

Intense gamma ray flares and enhanced relativistic electron precipitation can have profound effects upon the characteristics of the nighttime D-region of the ionosphere. We examine recent examples of these phenomena and discuss their effects upon HAARP systems.

An exoskeleton platform was developed, prototyped and tested for mobility performance in a beachfront environment. New platform, drive-train, motor-controller and wheel design were employed in the experiment. The objective was to improve on the shortcoming of previous NPS research. Three wheel-designs were tested during fixed pattern tests on grass, concrete and sand. Data suggests that, with regard to power consumption, there is a marginal difference on preferred wheel design. The sparse print round wheel showed promise in heavy vegetation; however, the WhegTM wheel proved to be the most versatile on various terrains. This suggests that a WhegTM wheel with improved round wheel characteristics would be optimal for various beachfront terrains., http://archive.org/details/seashoreinterfac1094542580, Lieutenant, United States Navy, Approved for public release; distribution is unlimited.

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