Scanning tunneling microscopy of deoxyribonucleic acid during replication

Scanning tunneling microscopy was used to produce topographic images of uncoated and unlabeled deoxyribonucleic acid (DNA) in air, on a graphite substrate. The images show for the first time a DNA molecule that had been isolated while it was replicating

Evaluating Differences in the Active-Site Electronics of Supported Au Nanoparticle Catalysts Using Hammett and DFT Studies

Supported metal catalysts, which are composed of metal nanoparticles dispersed on metal oxides or other high-surface-area materials, are ubiquitous in industrially catalysed reactions. Identifying and characterizing the catalytic active sites on these materials still remains a substantial challenge, even though it is required to guide rational design of practical heterogeneous catalysts. Metal-support interactions have an enormous impact on the chemistry of the catalytic active site and can determine the optimum support for a reaction; however, few direct probes of these interactions are available. Here we show how benzyl alcohol oxidation Hammett studies can be used to characterize differences in the catalytic activity of Au nanoparticles hosted on various metal-oxide supports. We combine reactivity analysis with density functional theory calculations to demonstrate that the slope of experimental Hammett plots is affected by electron donation from the underlying oxide support to the Au particles

Wide-Field InfraRed Survey Telescope (WFIRST) Final Report

In December 2010, NASA created a Science Definition Team (SDT) for WFIRST, the Wide Field Infra-Red Survey Telescope, recommended by the Astro 2010 Decadal Survey as the highest priority for a large space mission. The SDT was chartered to work with the WFIRST Project Office at GSFC and the Program Office at JPL to produce a Design Reference Mission (DRM) for WFIRST. Part of the original charge was to produce an interim design reference mission by mid-2011. That document was delivered to NASA and widely circulated within the astronomical community. In late 2011 the Astrophysics Division augmented its original charge, asking for two design reference missions. The first of these, DRM1, was to be a finalized version of the interim DRM, reducing overall mission costs where possible. The second of these, DRM2, was to identify and eliminate capabilities that overlapped with those of NASA's James Webb Space Telescope (henceforth JWST), ESA's Euclid mission, and the NSF's ground-based Large Synoptic Survey Telescope (henceforth LSST), and again to reduce overall mission cost, while staying faithful to NWNH. This report presents both DRM1 and DRM2.Comment: 102 pages, 57 figures, 17 table

Impaired Autophagy of an Intracellular Pathogen Induced by a Crohn's Disease Associated ATG16L1 Variant

The genetic risk factors predisposing individuals to the development of inflammatory bowel disease are beginning to be deciphered by genome-wide association studies. Surprisingly, these new data point towards a critical role of autophagy in the pathogenesis of Crohn's disease. A single common coding variant in the autophagy protein ATG16L1 predisposes individuals to the development of Crohn's disease: while ATG16L1 encoding threonine at amino acid position 300 (ATG16L1*300T) confers protection, ATG16L1 encoding for alanine instead of threonine (ATG16L1*300A, also known as T300A) mediates risk towards the development of Crohn's disease. Here we report that, in human epithelial cells, the Crohn's disease-associated ATG16L1 coding variant shows impairment in the capture of internalized Salmonella within autophagosomes. Thus, we propose that the association of ATG16L1*300A with increased risk of Crohn's disease is due to impaired bacterial handling and lowered rates of bacterial capture by autophagy

Ulcerative colitis-risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study.

Ulcerative colitis is a chronic inflammatory disease of the colon that presents as diarrhea and gastrointestinal bleeding. We performed a genome-wide association study using DNA samples from 1,052 individuals with ulcerative colitis and preexisting data from 2,571 controls, all of European ancestry. In an analysis that controlled for gender and population structure, ulcerative colitis loci attaining genome-wide significance and subsequent replication in two independent populations were identified on chromosomes 1p36 (rs6426833, combined P = 5.1 x 10(-13), combined odds ratio OR = 0.73) and 12q15 (rs1558744, combined P = 2.5 x 10(-12), combined OR = 1.35). In addition, combined genome-wide significant evidence for association was found in a region spanning BTNL2 to HLA-DQB1 on chromosome 6p21 (rs2395185, combined P = 1.0 x 10(-16), combined OR = 0.66) and at the IL23R locus on chromosome 1p31 (rs11209026, combined P = 1.3 x 10(-8), combined OR = 0.56; rs10889677, combined P = 1.3 x 10(-8), combined OR = 1.29)

Wide-Field Infrared Survey Telescope (WFIRST) Interim Report

The New Worlds, New Horizons (NWNH) in Astronomy and Astrophysics 2010 Decadal Survey prioritized the community consensus for ground-based and space-based observatories. Recognizing that many of the community s key questions could be answered with a wide-field infrared survey telescope in space, and that the decade would be one of budget austerity, WFIRST was top ranked in the large space mission category. In addition to the powerful new science that could be accomplished with a wide-field infrared telescope, the WFIRST mission was determined to be both technologically ready and only a small fraction of the cost of previous flagship missions, such as HST or JWST. In response to the top ranking by the community, NASA formed the WFIRST Science Definition Team (SDT) and Project Office. The SDT was charged with fleshing out the NWNH scientific requirements to a greater level of detail. NWNH evaluated the risk and cost of the JDEM-Omega mission design, as submitted by NASA, and stated that it should serve as the basis for the WFIRST mission. The SDT and Project Office were charged with developing a mission optimized for achieving the science goals laid out by the NWNH re-port. The SDT and Project Office opted to use the JDEM-Omega hardware configuration as an initial start-ing point for the hardware implementation. JDEM-Omega and WFIRST both have an infrared imager with a filter wheel, as well as counter-dispersed moderate resolution spectrometers. The primary advantage of space observations is being above the Earth's atmosphere, which absorbs, scatters, warps and emits light. Observing from above the atmosphere enables WFIRST to obtain precision infrared measurements of the shapes of galaxies for weak lensing, infrared light-curves of supernovae and exoplanet microlensing events with low systematic errors, and infrared measurements of the H hydrogen line to be cleanly detected in the 1<z<2 redshift range important for baryon acoustic oscillation (BAO) dark energy measurements. The Infrared Astronomical Satellite (IRAS), the Cosmic Background Explorer (COBE), Herschel, Spitzer, and Wide-field Infrared Sur-vey Explorer (WISE) are all space missions that have produced stunning new scientific advances by going to space to observe in the infrared. This interim report describes progress as of June 2011 on developing a requirements flowdown and an evaluation of scientific performance. An Interim Design Reference Mission (IDRM) configuration is presented that is based on the specifications of NWNH with some refinements to optimize the design in accordance with the new scientific requirements. Analysis of this WFIRST IDRM concept is in progress to ensure the capability of the observatory is compatible with the science requirements. The SDT and Project will continue to refine the mission concept over the coming year as design, analysis and simulation work are completed, resulting in the SDT s WFIRST Design Reference Mission (DRM) by the end of 2012

The Complex and Important Cellular and Metabolic Functions of Saturated Fatty Acids

This review summarizes recent findings on the metabolism and biological functions of saturated fatty acids (SFA). Some of these findings show that SFA may have important and specific roles in the cells. Elucidated biochemical mechanisms like protein acylation (N-myristoylation, S-palmitoylation) and regulation of gene transcription are presented. In terms of physiology, SFA are involved for instance in lipogenesis, fat deposition, polyunsaturated fatty acids bioavailability and apoptosis. The variety of their functions demonstrates that SFA should no longer be considered as a single group

New methodology for specific inhalation challenges with occupational agents

<p>Abstract</p> <p>Background</p> <p>Inhalation challenges are used for diagnosing occupational asthma (OA). The initial methodology consisted of a "realistic" exposure without monitoring nor controlling exposure. Our aim was to design an equipment, called the GenaSIC, that allows the generation of various agents regardless of the formulation and to assess the feasibility of its use in patients investigated for OA.</p> <p>Results</p> <p>GenaSIC can generate lactose, flour, malt, isocyanates, formaldehyde and N-butyl acetate with precise and fairly stable concentrations. Using N-butyl-acetate as a control agent and real time measurement, we show that normal breathing has a negligible effect on the concentration. We exposed forty-four different subjects to a control agent and/or to a suspected occupational agent. Nineteen of the subjects were only exposed to N-butyl acetate as a control agent without experiencing any significant irritant effect (no significant changes in spirometry thereafter). Eight subjects who were exposed to both N-butyl acetate and formaldehyde did not show significant reactions. Seven subjects were exposed to dry particles (flour in six instances, malt in the other) and five showed immediate asthmatic reactions which changes in FEV1 from 20% to a maximum of 28%. Finally, ten subjects were exposed to isocyanates, four of whom showed a positive reaction, including one subject with immediate maximum changes in FEV1 of 22%.</p> <p>Conclusion</p> <p>GenaSIC offers the possibility of reliable and safe exposures to dry particles, formaldehyde and isocyanates in the investigation of OA.</p

Identification of Two Independent Risk Factors for Lupus within the MHC in United Kingdom Families

The association of the major histocompatibility complex (MHC) with SLE is well established yet the causal variants arising from this region remain to be identified, largely due to inadequate study design and the strong linkage disequilibrium demonstrated by genes across this locus. The majority of studies thus far have identified strong association with classical class II alleles, in particular HLA-DRB1*0301 and HLA-DRB1*1501. Additional associations have been reported with class III alleles; specifically, complement C4 null alleles and a tumor necrosis factor promoter SNP (TNF-308G/A). However, the relative effects of these class II and class III variants have not been determined. We have thus used a family-based approach to map association signals across the MHC class II and class III regions in a cohort of 314 complete United Kingdom Caucasian SLE trios by typing tagging SNPs together with classical typing of the HLA-DRB1 locus. Using TDT and conditional regression analyses, we have demonstrated the presence of two distinct and independent association signals in SLE: HLA-DRB1*0301 (nominal p = 4.9 × 10−8, permuted p < 0.0001, OR = 2.3) and the T allele of SNP rs419788 (nominal p = 4.3 × 10−8, permuted p < 0.0001, OR = 2.0) in intron 6 of the class III region gene SKIV2L. Assessment of genotypic risk demonstrates a likely dominant model of inheritance for HLA-DRB1*0301, while rs419788-T confers susceptibility in an additive manner. Furthermore, by comparing transmitted and untransmitted parental chromosomes, we have delimited our class II signal to a 180 kb region encompassing the alleles HLA-DRB1*0301-HLA-DQA1*0501-HLA-DQB1*0201 alone. Our class III signal importantly excludes independent association at the TNF promoter polymorphism, TNF-308G/A, in our SLE cohort and provides a potentially novel locus for future genetic and functional studies

SNP-specific extraction of haplotype-resolved targeted genomic regions

The availability of genotyping platforms for comprehensive genetic analysis of complex traits has resulted in a plethora of studies reporting the association of specific single-nucleotide polymorphisms (SNPs) with common diseases or drug responses. However, detailed genetic analysis of these associated regions that would correlate particular polymorphisms to phenotypes has lagged. This is primarily due to the lack of technologies that provide additional sequence information about genomic regions surrounding specific SNPs, preferably in haploid form. Enrichment methods for resequencing should have the specificity to provide DNA linked to SNPs of interest with sufficient quality to be used in a cost-effective and high-throughput manner. We describe a simple, automated method of targeting specific sequences of genomic DNA that can directly be used in downstream applications. The method isolates haploid chromosomal regions flanking targeted SNPs by hybridizing and enzymatically elongating oligonucleotides with biotinylated nucleotides based on their selective binding to unique sequence elements that differentiate one allele from any other differing sequence. The targeted genomic region is captured by streptavidin-coated magnetic particles and analyzed by standard genotyping, sequencing or microarray analysis. We applied this technology to determine contiguous molecular haplotypes across a ∼150 kb genomic region of the major histocompatibility complex