LBJ and Vietnam: A Conversation

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The Lessons of History? Debating the Vietnam and Iraq Wars

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Changing Course in Vietnam — or Not

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The Prisoner of Events in Vietnam

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CIA Study: “Consequences to the US of Communist Domination of Mainland Southeast Asia,” October 13, 1950

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Meso-scale controlled motion for a microfluidic drop ejector.

The objective of this LDRD was to develop a uniquely capable, novel droplet solution based manufacturing system built around a new MEMS drop ejector. The development all the working subsystems required was completed, leaving the integration of these subsystems into a working prototype still left to accomplish. This LDRD report will focus on the three main subsystems: (1) MEMS drop ejector--the MEMS ''sideshooter'' effectively ejected 0.25 pl drops at 10 m/s, (2) packaging--a compact ejector package based on a modified EMDIP (Electro-Microfluidic Dual In-line Package--SAND2002-1941) was fabricated, and (3) a vision/stage system allowing precise ejector package positioning in 3 dimensions above a target was developed

Blazars in the Fermi Era: The OVRO 40-m Telescope Monitoring Program

The Large Area Telescope (LAT) aboard the Fermi Gamma-ray Space Telescope provides an unprecedented opportunity to study gamma-ray blazars. To capitalize on this opportunity, beginning in late 2007, about a year before the start of LAT science operations, we began a large-scale, fast-cadence 15 GHz radio monitoring program with the 40-m telescope at the Owens Valley Radio Observatory (OVRO). This program began with the 1158 northern (declination>-20 deg) sources from the Candidate Gamma-ray Blazar Survey (CGRaBS) and now encompasses over 1500 sources, each observed twice per week with a ~4 mJy (minimum) and 3% (typical) uncertainty. Here, we describe this monitoring program and our methods, and present radio light curves from the first two years (2008 and 2009). As a first application, we combine these data with a novel measure of light curve variability amplitude, the intrinsic modulation index, through a likelihood analysis to examine the variability properties of subpopulations of our sample. We demonstrate that, with high significance (7-sigma), gamma-ray-loud blazars detected by the LAT during its first 11 months of operation vary with about a factor of two greater amplitude than do the gamma-ray-quiet blazars in our sample. We also find a significant (3-sigma) difference between variability amplitude in BL Lacertae objects and flat-spectrum radio quasars (FSRQs), with the former exhibiting larger variability amplitudes. Finally, low-redshift (z<1) FSRQs are found to vary more strongly than high-redshift FSRQs, with 3-sigma significance. These findings represent an important step toward understanding why some blazars emit gamma-rays while others, with apparently similar properties, remain silent.Comment: 23 pages, 24 figures. Submitted to ApJ

Is oxidative damage the fundamental pathogenic mechanism of Alzheimer’s and other neurodegenerative diseases?

In less than a decade, beginning with the demonstration by Floyd, Stadtman, Markesbery et al. [1] of increased reactive carbonyls in the brains of patients with Alzheimer’s disease (AD), oxidative damage has been established as a feature of the disease. Here, we review the types of oxidative damage seen in AD, sites involved, possible origin, relationship to lesions, and compensatory changes, and we also consider other neurodegenerative diseases where oxidative stress has been implicated. Although much data remain to be collected, the broad spectrum of changes found in AD are only seen, albeit to a lesser extent, in normal aging with other neurodegenerative diseases showing distinct spectrums of change.Work in the authors’ laboratories is supported by funding from the National Institutes of Health (NS38648, AG19356, AG14249) and the Alzheimer’s Association (IIRG-98-136, ZEN-99-1789, IIRG-00-2163-Stephanie B. Overstreet Scholars, IIRG-98-140, TLL-99-1872).Peer reviewe

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P<1×10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development