| 1. |
- Flannick, Jason, et al.
(author)
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Data Descriptor : Sequence data and association statistics from 12,940 type 2 diabetes cases and controls
- 2017
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In: Scientific Data. - : Springer Science and Business Media LLC. - 2052-4463. ; 4
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Journal article (peer-reviewed)abstract
- To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1-5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low-frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (> 80% of low-frequency coding variants in similar to ~82 K Europeans via the exome chip, and similar to ~90% of low-frequency non-coding variants in similar to ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D.
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| 2. |
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| 3. |
- Fuchsberger, Christian, et al.
(author)
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The genetic architecture of type 2 diabetes
- 2016
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 536:7614, s. 41-47
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Journal article (peer-reviewed)abstract
- The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.
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| 4. |
- Hoffmann, Samantha L., et al.
(author)
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OPTICAL IDENTIFICATION OF CEPHEIDS IN 19 HOST GALAXIES OF TYPE Ia SUPERNOVAE AND NGC 4258 WITH THE HUBBLE SPACE TELESCOPE
- 2016
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In: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 830:1
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Journal article (peer-reviewed)abstract
- We present results of an optical search conducted as part of the SH0ES project (Supernovae and H-0 for the Equation of State of dark energy) for Cepheid variable stars using the Hubble Space Telescope (HST) in 19 hosts of Type Ia supernovae (SNe Ia) and the maser-host galaxy NGC 4258. The targets include nine newly imaged SN. Ia hosts using a novel strategy based on a long-pass filter that minimizes the number of HST orbits required to detect and accurately determine Cepheid properties. We carried out a homogeneous reduction and analysis of all observations, including new universal variability searches in all SN. Ia hosts, which yielded a total of 2200 variables with well-defined selection criteria, the largest such sample identified outside the Local Group. These objects are used in a companion paper to determine the local value of H-0 with a total uncertainty of 2.4%.
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| 5. |
- Espinet-Gonzalez, Pilar, et al.
(author)
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Radiation Tolerant Nanowire Array Solar Cells
- 2019
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In: ACS Nano. - : American Chemical Society (ACS). - 1936-0851 .- 1936-086X. ; 13:11, s. 12860-12869
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Journal article (peer-reviewed)abstract
- Space power systems require photovoltaics that are lightweight, efficient, reliable, and capable of operating for years or decades in space environment. Current solar panels use planar multijunction, III-V based solar cells with very high efficiency, but their specific power (power to weight ratio) is limited by the added mass of radiation shielding (e.g., coverglass) required to protect the cells from the high-energy particle radiation that occurs in space. Here, we demonstrate that III-V nanowire-array solar cells have dramatically superior radiation performance relative to planar solar cell designs and show this for multiple cell geometries and materials, including GaAs and InP. Nanowire cells exhibit damage thresholds ranging from ∼10-40 times higher than planar control solar cells when subjected to irradiation by 100-350 keV protons and 1 MeV electrons. Using Monte Carlo simulations, we show that this improvement is due in part to a reduction in the displacement density within the wires arising from their nanoscale dimensions. Radiation tolerance, combined with the efficient optical absorption and the improving performance of nanowire photovoltaics, indicates that nanowire arrays could provide a pathway to realize high-specific-power, substrate-free, III-V space solar cells with substantially reduced shielding requirements. More broadly, the exceptional reduction in radiation damage suggests that nanowire architectures may be useful in improving the radiation tolerance of other electronic and optoelectronic devices.
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| 6. |
- Heid, Iris M, et al.
(author)
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Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution
- 2010
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 949-960
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Journal article (peer-reviewed)abstract
- Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
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| 7. |
- Hsiao, Tiger Yu-Yang, et al.
(author)
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JWST Reveals a Possible z similar to 11 Galaxy Merger in Triply Lensed MACS0647-JD
- 2023
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In: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8205 .- 2041-8213. ; 949:2
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Journal article (peer-reviewed)abstract
- MACS0647-JD is a triply lensed z similar to 11 galaxy originally discovered with the Hubble Space Telescope. The three lensed images are magnified by factors of similar to 8, 5, and 2 to AB mag 25.1, 25.6, and 26.6 at 3.5 mu m. The brightest is over a magnitude brighter than other galaxies recently discovered at similar redshifts z > 10 with JWST. Here, we report new JWST imaging that clearly resolves MACS0647-JD as having two components that are either merging galaxies or stellar complexes within a single galaxy. The brighter larger component "A" is intrinsically very blue (ss similar to-2.6 +/- 0.1), likely due to very recent star formation and no dust, and is spatially extended with an effective radius similar to 70 +/- 24 pc. The smaller component "B" (r similar to 20-+ 58 pc) appears redder (ss similar to-2 +/- 0.2), likely because it is older (100-200 Myr) with mild dust extinction (AV similar to 0.1 mag). With an estimated stellar mass ratio of roughly 2:1 and physical projected separation similar to 400 pc, we may be witnessing a galaxy merger 430 million years after the Big Bang. We identify galaxies with similar colors in a high-redshift simulation, finding their star formation histories to be dissimilar, which is also suggested by the spectral energy distribution fitting, suggesting they formed further apart. We also identify a candidate companion galaxy "C" similar to 3 kpc away, likely destined to merge with A and B. Upcoming JWST Near Infrared Spectrograph observations planned for 2023 January will deliver spectroscopic redshifts and more physical properties for these tiny magnified distant galaxies observed in the early universe.
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| 8. |
- Katsiotis, Christos S.
(author)
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Additive Manufacturing and Mesoporous Materials for Pharmaceutical Applications
- 2024
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Doctoral thesis (other academic/artistic)abstract
- Additive Manufacturing (AM), over the past decade, has evolved into a versatile technology with significant applications in pharmaceutical research. This technology enables the production of drug formulations tailored to individual patients, offering customization in both dosage and dissolution profiles. While challenges in mass production persist, 3D printing, particularly through techniques like Fused Deposition Modeling (FDM) and Semi Solid Extrusion (SSE), proves ideal for crafting smaller batches of personalized dosage forms.A prevalent issue in drug development revolves around poor water solubility, impacting bioavailability upon oral administration. To combat this, the integration of mesoporous materials emerges as a promising strategy to enhance the dissolution of poorly water-soluble drugs. Here, the applicability of mesoporous materials is explored, as well as their incorporation with various AM techniques. Overall, the thesis dives into the investigation of combinatorial formulations, incorporating at least one 3D printed component to address specific requirements in drug delivery. By combining FDM with Selective Laser Sintering (SLS), a hybrid two-compartmental formulation is developed. The durable FDM-printed shell regulates buffer medium access to the contained SLS-produced inserts loaded with the drug. Varying printing parameters and insert combinations within the shell showcase the adjustability and flexibility of this hybrid approach.Tablets with different infill percentages, containing drug-loaded mesoporous materials, are developed. Poorly water-soluble drugs are successfully amorphized within mesoporous material pores, formulated into filaments through Hot Melt Extrusion (HME), and printed via FDM. These tablets exhibit improved dissolution compared to the crystalline drug, with the dissolution behavior regulated also by the infill percentage.The study explores the impact of drug-loaded mesoporous materials on HME-produced filament properties, studying their effect on maximum tensile strength and Young’s modulus. The relationship between these properties and filament printability is investigated. Additionally, a protective effect of mesoporous materials on drugs from thermal degradation is revealed.For Semi Solid Extrusion (SSE) manufactured formulations, a paste is developed, comprising mesoporous material loaded with a poorly water-soluble drug and an excipient. This paste demonstrates favorable rheological properties and easy extrudability via a syringe. The formulation proves versatile for printing dosage forms for both oral and rectal administration, with the printed tablet and suppository exhibiting effective drug release.In conclusion, this work presents valuable strategies for developing patient-tailored dosage forms, addressing specific pharmaceutical challenges like poor solubility. The integration of mesoporous materials and various 3D printing techniques showcases a promising direction for personalized medicine in the pharmaceutical field.
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| 9. |
- Orho-Melander, Marju, et al.
(author)
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Common Missense Variant in the Glucokinase Regulatory Protein Gene Is Associated With Increased Plasma Triglyceride and C-Reactive Protein but Lower Fasting Glucose Concentrations
- 2008
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In: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 57:11, s. 3112-3121
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Journal article (peer-reviewed)abstract
- OBJECTIVE-Using the genome-wide association approach, we recently identified the glucokinase regulatory protein gene (GCKR, rs780094) region as a novel quantitative trait locus for plasma triglyceride concentration in Europeans. Here, we sought to study the association of GCKR variants with metabolic phenotypes, including measures of glucose homeostasis, to evaluate the GCYR locus in samples of non-European ancestry and to fine-map across the associated genomic interval. RESEARCH DESIGN AND METHODS-We performed association studies in 12 independent cohorts comprising >45,000 individuals representing several ancestral groups (whites from Northern and Southern Europe, whites from the U.S., African Americans from the U.S., Hispanics of Caribbean origin, and Chinese, Malays, and Asian Indians from Singapore). We conducted genetic fine-mapping across the similar to 417-kb region of linkage disequilibrium. spanning GCKR and 16 other genes on chromosome 2p23 by imputing untyped HapMap single nucleotide polymorphisms (SNPs) and genotyping 104 SNPs across the associated genomic interval. RESULTS-We provide comprehensive evidence that GCYR rs780094 is associated with opposite effects on fasting plasma triglyceride (P-meta = 3 x 10(-56)) and glucose (P-meta = 1 x 10(-13)) concentrations. In addition, we confirmed recent reports that the same SNP is associated with C-reactive protein (CRP) level (P = 5 x 10(-5)). Both fine-mapping approaches revealed a common missense GCKR variant (rs1260326, Pro446Leu, 34% frequency, r(2) = 0.93 with rs780094) as the strongest association signal in the region. CONCLUSIONS-These findings point to a molecular mechanism in humans by which higher triglycerides and CRP can be coupled with lower plasma glucose concentrations and position GCKR in central pathways regulating both hepatic triglyceride and glucose metabolism. Diabetes 57:3112-3121, 2008
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| 10. |
- Palmer, Nicholette D, et al.
(author)
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A genome-wide association search for type 2 diabetes genes in African Americans.
- 2012
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In: PloS one. - San Francisco : Public Library of Science (PLoS). - 1932-6203. ; 7:1, s. e29202-
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Journal article (peer-reviewed)abstract
- African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.
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| 11. |
- Scott, Robert A., et al.
(author)
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Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways
- 2012
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:9, s. 991-1005
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Journal article (peer-reviewed)abstract
- Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.
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| 12. |
- Speliotes, Elizabeth K., et al.
(author)
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Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index
- 2010
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 937-948
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Journal article (peer-reviewed)abstract
- Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ~2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10−8), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
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| 13. |
- Viñuela, Ana, et al.
(author)
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Genetic variant effects on gene expression in human pancreatic islets and their implications for T2D
- 2020
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1, s. 4912-4912
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Journal article (peer-reviewed)abstract
- Most signals detected by genome-wide association studies map to non-coding sequence and their tissue-specific effects influence transcriptional regulation. However, key tissues and cell-types required for functional inference are absent from large-scale resources. Here we explore the relationship between genetic variants influencing predisposition to type 2 diabetes (T2D) and related glycemic traits, and human pancreatic islet transcription using data from 420 donors. We find: (a) 7741 cis-eQTLs in islets with a replication rate across 44 GTEx tissues between 40% and 73%; (b) marked overlap between islet cis-eQTL signals and active regulatory sequences in islets, with reduced eQTL effect size observed in the stretch enhancers most strongly implicated in GWAS signal location; (c) enrichment of islet cis-eQTL signals with T2D risk variants identified in genome-wide association studies; and (d) colocalization between 47 islet cis-eQTLs and variants influencing T2D or glycemic traits, including DGKB and TCF7L2. Our findings illustrate the advantages of performing functional and regulatory studies in disease relevant tissues.
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| 14. |
- Voight, Benjamin F., et al.
(author)
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Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis
- 2010
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:7, s. 579-589
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Journal article (peer-reviewed)abstract
- By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P < 5 x 10(-8). These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits.
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| 15. |
- Welch, Brian, et al.
(author)
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JWST Imaging of Earendel, the Extremely Magnified Star at Redshift z=6.2
- 2022
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In: Astrophysical Journal Letters. - : Institute of Physics (IOP). - 2041-8205 .- 2041-8213. ; 940
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Journal article (peer-reviewed)abstract
- The gravitationally lensed star WHL 0137-LS, nicknamed Earendel, was identified with a photometric redshift z (phot) = 6.2 +/- 0.1 based on images taken with the Hubble Space Telescope. Here we present James Webb Space Telescope (JWST) Near Infrared Camera images of Earendel in eight filters spanning 0.8-5.0 mu m. In these higher-resolution images, Earendel remains a single unresolved point source on the lensing critical curve, increasing the lower limit on the lensing magnification to mu > 4000 and restricting the source plane radius further to r < 0.02 pc, or similar to 4000 au. These new observations strengthen the conclusion that Earendel is best explained by an individual star or multiple star system and support the previous photometric redshift estimate. Fitting grids of stellar spectra to our photometry yields a stellar temperature of T (eff) similar to 13,000-16,000 K, assuming the light is dominated by a single star. The delensed bolometric luminosity in this case ranges from log(L)=5.8 L-theta, which is in the range where one expects luminous blue variable stars. Follow-up observations, including JWST NIRSpec scheduled for late 2022, are needed to further unravel the nature of this object, which presents a unique opportunity to study massive stars in the first billion years of the universe.
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| 16. |
- Windhorst, Rogier A., et al.
(author)
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JWST PEARLS. Prime extragalactic areas for reionization and lensing science : project overview and first results
- 2023
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In: Astronomical Journal. - : Institute of Physics (IOP). - 0004-6256 .- 1538-3881. ; 165:1
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Journal article (peer-reviewed)abstract
- We give an overview and describe the rationale, methods, and first results from NIRCam images of the JWST “Prime Extragalactic Areas for Reionization and Lensing Science” (PEARLS) project. PEARLS uses up to eight NIRCam filters to survey several prime extragalactic survey areas: two fields at the North Ecliptic Pole (NEP); seven gravitationally lensing clusters; two high redshift protoclusters; and the iconic backlit VV 191 galaxy system to map its dust attenuation. PEARLS also includes NIRISS spectra for one of the NEP fields and NIRSpec spectra of two high-redshift quasars. The main goal of PEARLS is to study the epoch of galaxy assembly, active galactic nucleus (AGN) growth, and First Light. Five fields—the JWST NEP Time-Domain Field (TDF), IRAC Dark Field, and three lensing clusters—will be observed in up to four epochs over a year. The cadence and sensitivity of the imaging data are ideally suited to find faint variable objects such as weak AGN, high-redshift supernovae, and cluster caustic transits. Both NEP fields have sightlines through our Galaxy, providing significant numbers of very faint brown dwarfs whose proper motions can be studied. Observations from the first spoke in the NEP TDF are public. This paper presents our first PEARLS observations, their NIRCam data reduction and analysis, our first object catalogs, the 0.9–4.5 μm galaxy counts and Integrated Galaxy Light. We assess the JWST sky brightness in 13 NIRCam filters, yielding our first constraints to diffuse light at 0.9–4.5 μm. PEARLS is designed to be of lasting benefit to the community.
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| 17. |
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