356 research outputs found
Heterometallic lanthanide complexes with site-specific binding that enable simultaneous visible and NIR-emission
Macrocyclic lanthanide complexes have become widely developed due to their distinctive luminescence characteristics and wide range of applications in biological imaging. However, systems with sufficient brightness and metal selectivity can be difficult to produce on a molecular scale. Presented herein is the stepwise introduction of differing lanthanide ions in a bis-DO3A/DTPA scaffold to afford three trinuclear bimetallic [Ln2Ln’] lanthanide complexes with site-specific, controlled binding [(Yb2Tb), (Eu2Tb), (Yb2Eu)]. The complexes display simultaneous emission from all LnIII centers across the visible (TbIII, EuIII) and near infra-red (YbIII) spectrum when excited via phenyl ligand sensitization at a wide range of temperatures and are consequently of interest for exploiting imaging in the near infra-red II biological window. Analysis of lifetime data over a range of excitation regimes reveals intermetallic communication between TbIII and EuIII centers and further develops the understanding of multimetallic lanthanide complexes
MADNESS: A Multiresolution, Adaptive Numerical Environment for Scientific Simulation
MADNESS (multiresolution adaptive numerical environment for scientific
simulation) is a high-level software environment for solving integral and
differential equations in many dimensions that uses adaptive and fast harmonic
analysis methods with guaranteed precision based on multiresolution analysis
and separated representations. Underpinning the numerical capabilities is a
powerful petascale parallel programming environment that aims to increase both
programmer productivity and code scalability. This paper describes the features
and capabilities of MADNESS and briefly discusses some current applications in
chemistry and several areas of physics
Variant-specific inflation factors for assessing population stratification at the phenotypic variance level
In modern Whole Genome Sequencing (WGS) epidemiological studies, participant-level data from multiple studies are often pooled and results are obtained from a single analysis. We consider the impact of differential phenotype variances by study, which we term \u27variance stratification\u27. Unaccounted for, variance stratification can lead to both decreased statistical power, and increased false positives rates, depending on how allele frequencies, sample sizes, and phenotypic variances vary across the studies that are pooled. We develop a procedure to compute variant-specific inflation factors, and show how it can be used for diagnosis of genetic association analyses on pooled individual level data from multiple studies. We describe a WGS-appropriate analysis approach, implemented in freely-available software, which allows study-specific variances and thereby improves performance in practice. We illustrate the variance stratification problem, its solutions, and the proposed diagnostic procedure, in simulations and in data from the Trans-Omics for Precision Medicine Whole Genome Sequencing Program (TOPMed), used in association tests for hemoglobin concentrations and BMI
Genetic and seasonal determinants of vitamin D status in Confederated Salish and Kootenai Tribes (CSKT) participants
Background: Vitamin D is a hormone produced in the skin upon ultraviolet B (UVB) radiation. Vitamin D is a crucial regulator of calcium and phosphate levels for bone mineralization and other physiological roles. Vitamin D levels vary globally in human populations due to genetics, geography, and other demographic factors. It is estimated that 20-85 % of the variability in vitamin D levels is driven by genetic variation. To improve our understanding of contributors to vitamin D levels, we conducted a candidate-gene study in partnership with the Confederated Salish and Kootenai Tribes (CSKT).
Methods: We recruited 472 CSKT study participants on the Flathead Reservation in Montana. Demographic factors included age, BMI, and gender (185 male and 287 female; ≥ 18 years old). Genomic DNA and plasma were isolated from whole blood. We sequenced 14 vitamin D regulatory candidate genes: CASR, CUBN, CYP2R1, CYP3A4,CYP24A1, CYP27B1, DHCR7, GC, RXRA, RXRB, RXRG, SULT2A1, UGT1A4, and VDR. We also measured plasma levels of vitamin D and vitamin D metabolites by liquid chromatography/mass-spectrometry (LC/MS), including the clinical marker of vitamin D status, 25-hydroxyvitamin D3 [25(OH)D3]. We tested demographic factors as well as common and rare genetic variants for statistical associations with vitamin D levels using bioinformatics software and R statistical programming language code.
Results: We identified 7,370 total genetic variants with 8% (n = 585) of them being novel. We identified 60 genetic variants that may be of clinical significance (disease associated or predicted to influence medication response). Vitamin D levels were below sufficiency [25(OH)D3 + 25(OH)D2 levels \u3c 20 ng/mL] in 56 % of CSKT participants across the year. We observed seasonal vitamin D and metabolite level fluctuations in a seasonal, sinusoidal statistical model with peak concentrations in June – August and trough concentrations in December – February. In linear regression analysis, we found that age, BMI, season, and 5 variants in CUBN and CYP3A4 were significantly associated with 25(OH)D3 concentration (p-value\u3c 0.05). In logistic regression, we found that 4 variants in CUBN, CYP3A4, and UGT1A4 were associated with 25(OH)D sufficiency status [25(OH)D3 + 25(OH)D2 levels of 20 ng/mL] (p-value\u3c 0.05). Multivariate linear regression analysis revealed that genetic variation alone explained ~13% of the variability in 25(OH)D3 concentration in CSKT participants. Genetic variation and environmental factors together explained ~23 % of the variability in 25(OH)D3 concentration in CSKT participants. It is likely that genetic variation in additional genes and other environmental factors (e.g., dietary vitamin D intake) that were not included in this study explain the remaining variability in 25(OH)D3 concentration.
Conclusion: This research addresses the need for increased inclusion of American Indian and Alaska Natives in precision medicine health research. We are the first to describe the contribution of season and genetics to vitamin D levels in an American Indian population. Our next steps will be to use these findings to perform mechanistic studies and develop interventional strategies for the CSKT people
The Lick AGN Monitoring Project: Reverberation Mapping of Optical Hydrogen and Helium Recombination Lines
We have recently completed a 64-night spectroscopic monitoring campaign at
the Lick Observatory 3-m Shane telescope with the aim of measuring the masses
of the black holes in 12 nearby (z < 0.05) Seyfert 1 galaxies with expected
masses in the range ~10^6-10^7M_sun and also the well-studied nearby active
galactic nucleus (AGN) NGC 5548. Nine of the objects in the sample (including
NGC 5548) showed optical variability of sufficient strength during the
monitoring campaign to allow for a time lag to be measured between the
continuum fluctuations and the response to these fluctuations in the broad
Hbeta emission, which we have previously reported. We present here the light
curves for the Halpha, Hgamma, HeII 4686, and HeI 5876 emission lines and the
time lags for the emission-line responses relative to changes in the continuum
flux. Combining each emission-line time lag with the measured width of the line
in the variable part of the spectrum, we determine a virial mass of the central
supermassive black hole from several independent emission lines. We find that
the masses are generally consistent within the uncertainties. The time-lag
response as a function of velocity across the Balmer line profiles is examined
for six of the AGNs. Finally we compare several trends seen in the dataset
against the predictions from photoionization calculations as presented by
Korista & Goad. We confirm several of their predictions, including an increase
in responsivity and a decrease in the mean time lag as the excitation and
ionization level for the species increases. Further confirmation of
photoionization predictions for broad-line gas behavior will require additional
monitoring programs for these AGNs while they are in different luminosity
states. [abridged]Comment: 37 pages, 18 figures and 15 tables, accepted for publication in the
Astrophysical Journa
Structural Basis for Enhanced HIV-1 Neutralization by a Dimeric Immunoglobulin G Form of the Glycan-Recognizing Antibody 2G12
The human immunoglobulin G (IgG) 2G12 recognizes high-mannose carbohydrates on the HIV type 1 (HIV-1) envelope glycoprotein gp120. Its two antigen-binding fragments (Fabs) are intramolecularly domain exchanged, resulting in a rigid (Fab)_2 unit including a third antigen-binding interface not found in antibodies with flexible Fab arms. We determined crystal structures of dimeric 2G12 IgG created by intermolecular domain exchange, which exhibits increased breadth and >50-fold increased neutralization potency compared with monomeric 2G12. The four Fab and two fragment crystalline (Fc) regions of dimeric 2G12 were localized at low resolution in two independent structures, revealing IgG dimers with two (Fab)_2 arms analogous to the Fabs of conventional monomeric IgGs. Structures revealed three conformationally distinct dimers, demonstrating flexibility of the (Fab)_2-Fc connections that was confirmed by electron microscopy, small-angle X-ray scattering, and binding studies. We conclude that intermolecular domain exchange, flexibility, and bivalent binding to allow avidity effects are responsible for the increased potency and breadth of dimeric 2G12
The Atacama Cosmology Telescope: Two-Season ACTPol Lensing Power Spectrum
We report a measurement of the power spectrum of cosmic microwave background
(CMB) lensing from two seasons of Atacama Cosmology Telescope Polarimeter
(ACTPol) CMB data. The CMB lensing power spectrum is extracted from both
temperature and polarization data using quadratic estimators. We obtain results
that are consistent with the expectation from the best-fit Planck LCDM model
over a range of multipoles L=80-2100, with an amplitude of lensing A_lens =
1.06 +/- 0.15 (stat.) +/- 0.06 (sys.) relative to Planck. Our measurement of
the CMB lensing power spectrum gives sigma_8 Omega_m^0.25 = 0.643 +/- 0.054;
including baryon acoustic oscillation scale data, we constrain the amplitude of
density fluctuations to be sigma_8 = 0.831 +/- 0.053. We also update
constraints on the neutrino mass sum. We verify our lensing measurement with a
number of null tests and systematic checks, finding no evidence of significant
systematic errors. This measurement relies on a small fraction of the ACTPol
data already taken; more precise lensing results can therefore be expected from
the full ACTPol dataset.Comment: 17 pages, 11 figures, to be submitted to Physical Review
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