Systemic lupus erythematosus (SLE), a worldwide autoimmune disease with high heritability, shows differences in prevalence, severity and age of onset among different ancestral groups. Previous ...genetic studies have focused more on European populations, which appear to be the least affected. Consequently, the genetic variations that underlie the commonalities, differences and treatment options in SLE among ancestral groups have not been well elucidated. To address this, we undertake a genome-wide association study, increasing the sample size of Chinese populations to the level of existing European studies. Thirty-eight novel SLE-associated loci and incomplete sharing of genetic architecture are identified. In addition to the human leukocyte antigen (HLA) region, nine disease loci show clear ancestral differences and implicate antibody production as a potential mechanism for differences in disease manifestation. Polygenic risk scores perform significantly better when trained on ancestry-matched data sets. These analyses help to reveal the genetic basis for disparities in SLE among ancestral groups.
We present the Census of the Local Universe (CLU) narrowband survey to search for emission-line (H ) galaxies. CLU-H has imaged 3π of the sky (26,470 deg2) with four narrowband filters that probe a ...distance out to 200 Mpc. We have obtained spectroscopic follow-up for galaxy candidates in 14 preliminary fields (101.6 deg2) to characterize the limits and completeness of the survey. In these preliminary fields, CLU can identify emission lines down to an H flux limit of 10−14 erg s−1 cm−2 at 90% completeness, and recovers 83% (67%) of the H flux from cataloged galaxies in our search volume at the = 2.5 ( = 5) color excess levels. The contamination from galaxies with no emission lines is 61% (12%) for = 2.5 ( = 5). Also, in the regions of overlap between our preliminary fields and previous emission-line surveys, we recover the majority of the galaxies found in previous surveys and identify an additional 300 galaxies. In total, we find 90 galaxies with no previous distance information, several of which are interesting objects: 7 blue compact dwarfs, 1 green pea, and a Seyfert galaxy; we also identify a known planetary nebula. These objects show that the CLU-H survey can be a discovery machine for objects in our own Galaxy and extreme galaxies out to intermediate redshifts. However, the majority of the CLU-H galaxies identified in this work show properties consistent with normal star-forming galaxies. CLU-H galaxies with new redshifts will be added to existing galaxy catalogs to focus the search for the electromagnetic counterpart to gravitational wave events.
Isoprene has the highest emission into Earth’s atmosphere of any nonmethane hydrocarbon. Atmospheric processing of alkenes, including isoprene, via ozonolysis leads to the formation of zwitterionic ...reactive intermediates, known as Criegee intermediates (CIs). Direct studies have revealed that reactions involving simple CIs can significantly impact the tropospheric oxidizing capacity, enhance particulate formation, and degrade local air quality. Methyl vinyl ketone oxide (MVK-oxide) is a four-carbon, asymmetric, resonance-stabilized CI, produced with 21 to 23% yield fromisoprene ozonolysis, yet its reactivity has not been directly studied. We present direct kinetic measurements of MVK-oxide reactions with key atmospheric species using absorption spectroscopy. Direct UV-Vis absorption spectra from two independent flow cell experiments overlap with the molecular beam UV-Vis-depletion spectra reported recently M. F. Vansco, B. Marchetti, M. I. Lester, J. Chem. Phys. 149, 44309 (2018) but suggest different conformer distributions under jetcooled and thermal conditions. Comparison of the experimental lifetime herein with theory indicates only the syn-conformers are observed; anti-conformers are calculated to be removed much more rapidly via unimolecular decay. We observe experimentally and predict theoretically fast reaction of syn-MVK-oxide with SO₂ and formic acid, similar to smaller alkyl-substituted CIs, and by contrast, slow removal in the presence of water. We determine products through complementary multiplexed photoionization mass spectrometry, observing SO₃ and identifying organic hydroperoxide formation from reaction with SO₂ and formic acid, respectively. The tropospheric implications of these reactions are evaluated using a global chemistry and transport model.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Gene expression analysis is a widely used and powerful method for investigating the transcriptional behavior of biological systems, for classifying cell states in disease, and for many other ...purposes. Recent studies indicate that common assumptions currently embedded in experimental and analytical practices can lead to misinterpretation of global gene expression data. We discuss these assumptions and describe solutions that should minimize erroneous interpretation of gene expression data from multiple analysis platforms.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Polyether-ether-ketone (PEEK) is one of the most common materials used for load-bearing orthopaedic devices due to its radiolucency and favorable mechanical properties. However, current ...smooth-surfaced PEEK implants can lead to fibrous encapsulation and poor osseointegration. This study compared the in vitro and in vivo bone response to two smooth PEEK alternatives: porous PEEK and plasma-sprayed titanium coatings on PEEK. MC3T3 cells were grown on smooth PEEK, porous PEEK, and Ti-coated PEEK for 14 days and assayed for calcium content, osteocalcin, VEGF and ALP activity. Osseointegration was investigated by implanting cylindrical implants into the proximal tibiae of male Sprague Dawley rats for 8 weeks. Bone-implant interfaces were evaluated using μCT, histology and pullout testing. Cells on porous PEEK surfaces produced more calcium, osteocalcin, and VEGF than smooth PEEK and Ti-coated PEEK groups. Bone ingrowth into porous PEEK surfaces was comparable to previously reported porous materials and correlated well between μCT and histology analysis. Porous PEEK implants exhibited greater pullout force, stiffness and energy-to-failure compared to smooth PEEK and Ti-coated PEEK, despite Ti-coated PEEK exhibiting a high degree of bone-implant contact. These results are attributed to increased mechanical interlocking of bone with the porous PEEK implant surface. Overall, porous PEEK was associated with improved osteogenic differentiation in vitro and greater implant fixation in vivo compared to smooth PEEK and Ti-coated PEEK. These results suggest that not all PEEK implants inherently generate a fibrous response and that topography has a central role in determining implant osseointegration.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Highlights • Individuals with asymptomatic malaria are an important reservoir of transmission. • Smear-positive asymptomatics are more infectious to mosquitoes than those with submicroscopic ...infection. • Current efforts to eliminate the malaria reservoir often target those with submicroscopic parasitemia. • The contribution of submicroscopic malaria to transmission needs further evaluation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Designing tight-binding ligands is a primary objective of small-molecule drug discovery. Over the past few decades, free-energy calculations have benefited from improved force fields and sampling ...algorithms, as well as the advent of low-cost parallel computing. However, it has proven to be challenging to reliably achieve the level of accuracy that would be needed to guide lead optimization (∼5× in binding affinity) for a wide range of ligands and protein targets. Not surprisingly, widespread commercial application of free-energy simulations has been limited due to the lack of large-scale validation coupled with the technical challenges traditionally associated with running these types of calculations. Here, we report an approach that achieves an unprecedented level of accuracy across a broad range of target classes and ligands, with retrospective results encompassing 200 ligands and a wide variety of chemical perturbations, many of which involve significant changes in ligand chemical structures. In addition, we have applied the method in prospective drug discovery projects and found a significant improvement in the quality of the compounds synthesized that have been predicted to be potent. Compounds predicted to be potent by this approach have a substantial reduction in false positives relative to compounds synthesized on the basis of other computational or medicinal chemistry approaches. Furthermore, the results are consistent with those obtained from our retrospective studies, demonstrating the robustness and broad range of applicability of this approach, which can be used to drive decisions in lead optimization.
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IJS, KILJ, NUK, PNG, UL, UM
Early insights into the unique structure and properties of native silk suggested that β-sheet nanocrystallites in silk would degrade prior to melting when subjected to thermal processing. Since then, ...canonical approaches for fabricating silk-based materials typically involve solution-derived processing methods, which have inherent limitations with respect to silk protein solubility and stability in solution, and time and cost efficiency. Here we report a thermal processing method for the direct solid-state moulding of regenerated silk into bulk 'parts' or devices with tunable mechanical properties. At elevated temperature and pressure, regenerated amorphous silk nanomaterials with ultralow β-sheet content undergo thermal fusion via molecular rearrangement and self-assembly assisted by bound water to form a robust bulk material that retains biocompatibility, degradability and machinability. This technique reverses presumptions about the limitations of direct thermal processing of silk into a wide range of new material formats and composite materials with tailored properties and functionalities.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Highlights • Myc is a general regulator that binds to established euchromatin in the cell. • Myc acts as a nonlinear amplifier of transcription. • Miz1 and other regulators shape Myc transcriptional ...amplification.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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Despite its widespread clinical use in load-bearing orthopedic implants, polyether-ether-ketone (PEEK) is often associated with poor osseointegration. In this study, a surface-porous ...PEEK material (PEEK-SP) was created using a melt extrusion technique. The porous layer was 399.6±63.3μm thick and possessed a mean pore size of 279.9±31.6μm, strut spacing of 186.8±55.5μm, porosity of 67.3±3.1% and interconnectivity of 99.9±0.1%. Monotonic tensile tests showed that PEEK-SP preserved 73.9% of the strength (71.06±2.17MPa) and 73.4% of the elastic modulus (2.45±0.31GPa) of as-received, injection-molded PEEK. PEEK-SP further demonstrated a fatigue strength of 60.0MPa at one million cycles, preserving 73.4% of the fatigue resistance of injection-molded PEEK. Interfacial shear testing showed the pore layer shear strength to be 23.96±2.26MPa. An osseointegration model in the rat revealed substantial bone formation within the pore layer at 6 and 12weeks via microcomputed tomography and histological evaluation. Ingrown bone was more closely apposed to the pore wall and fibrous tissue growth was reduced in PEEK-SP when compared to non-porous PEEK controls. These results indicate that PEEK-SP could provide improved osseointegration while maintaining the structural integrity necessary for load-bearing orthopedic applications.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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