4,465 research outputs found
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Structural basis for substrate gripping and translocation by the ClpB AAA+ disaggregase.
Bacterial ClpB and yeast Hsp104 are homologous Hsp100 protein disaggregases that serve critical functions in proteostasis by solubilizing protein aggregates. Two AAA+ nucleotide binding domains (NBDs) power polypeptide translocation through a central channel comprised of a hexameric spiral of protomers that contact substrate via conserved pore-loop interactions. Here we report cryo-EM structures of a hyperactive ClpB variant bound to the model substrate, casein in the presence of slowly hydrolysable ATPγS, which reveal the translocation mechanism. Distinct substrate-gripping interactions are identified for NBD1 and NBD2 pore loops. A trimer of N-terminal domains define a channel entrance that binds the polypeptide substrate adjacent to the topmost NBD1 contact. NBD conformations at the seam interface reveal how ATP hydrolysis-driven substrate disengagement and re-binding are precisely tuned to drive a directional, stepwise translocation cycle
Sotatercept safety and effects on hemoglobin, bone, and vascular calcification
Introduction: Patients with end-stage kidney disease (ESKD) exhibit anemia, chronic kidney disease‒mineral bone disorder (CKD-MBD), and cardiovascular disease. The REN-001 and REN-002 phase II, multicenter, randomized studies examined safety, tolerability, and effects of sotatercept, an ActRIIA-IgG1 fusion protein trap, on hemoglobin concentration; REN-001 also explored effects on bone mineral density (BMD) and abdominal aortic vascular calcification.
Methods: Forty-three patients were treated in REN-001 (dose range: sotatercept 0.3‒0.7 mg/kg or placebo subcutaneously [s.c.] for 200 days) and 50 in REN-002 (dose range: 0.1‒0.4 mg/kg i.v. and 0.13‒0.5 mg/kg s.c. for 99 days).
Results: In REN-001, frequency of achieving target hemoglobin response (\u3e10 g/dl [6.21 mmol/l]) with sotatercept was dose-related and greater than placebo (0.3 mg/kg: 33.3%; 0.5 mg/kg: 62.5%; 0.7 mg/kg: 77.8%; 0.7 mg/kg [doses 1 and 2]/0.4 mg/kg [doses 3‒15]: 33.3%; placebo: 27.3%). REN-002 hemoglobin findings were similar (i.v.: 16.7%-57.1%; s.c.: 11.1%‒42.9%). Dose-related achievement of ≥2% increase in femoral neck cortical BMD was seen among only REN-001 patients receiving sotatercept (0.3‒0.7 mg/kg: 20.0%‒57.1%; placebo: 0.0%). Abdominal aortic vascular calcification was slowed in a dose-related manner, with a ≤15% increase in Agatston score achieved by more REN-001 sotatercept versus placebo patients (60%‒100% vs. 16.7%). The most common adverse events during treatment were hypertension, muscle spasm, headache, arteriovenous fistula site complication, and influenza observed in both treatment and placebo groups.
Conclusion: In patients with ESKD, sotatercept exhibited a favorable safety profile and was associated with trends in dose-related slowing of vascular calcification. Less-consistent trends in improved hemoglobin concentration and BMD were observed
Approaching finite-temperature phase diagrams of strongly correlated materials: a case study for V2O3
Examining phase stabilities and phase equilibria in strongly correlated
materials asks for a next level in the many-body extensions to the
local-density approximation (LDA) beyond mainly spectroscopic assessments. Here
we put the charge-self-consistent LDA+dynamical mean-field theory (DMFT)
methodology based on projected local orbitals for the LDA+DMFT interface and a
tailored pseudopotential framework into action in order to address such
thermodynamics of realistic strongly correlated systems. Namely a case study
for the electronic phase diagram of the well-known prototype Mott-phenomena
system VO at higher temperatures is presented. We are able to describe
the first-order metal-to-insulator transitions with negative pressure and
temperature from the self-consistent computation of the correlated total energy
in line with experimental findings.Comment: 12 pages, 15 figures, new data adde
Effects of lateral diffusion on morphology and dynamics of a microscopic lattice-gas model of pulsed electrodeposition
The influence of nearest-neighbor diffusion on the decay of a metastable
low-coverage phase (monolayer adsorption) in a square lattice-gas model of
electrochemical metal deposition is investigated by kinetic Monte Carlo
simulations. The phase-transformation dynamics are compared to the
well-established Kolmogorov-Johnson-Mehl-Avrami theory. The phase
transformation is accelerated by diffusion, but remains in accord with the
theory for continuous nucleation up to moderate diffusion rates. At very high
diffusion rates the phase-transformation kinetic shows a crossover to
instantaneous nucleation. Then, the probability of medium-sized clusters is
reduced in favor of large clusters. Upon reversal of the supersaturation, the
adsorbate desorbs, but large clusters still tend to grow during the initial
stages of desorption. Calculation of the free energy of subcritical clusters by
enumeration of lattice animals yields a quasi-equilibrium distribution which is
in reasonable agreement with the simulation results. This is an improvement
relative to classical droplet theory, which fails to describe the
distributions, since the macroscopic surface tension is a bad approximation for
small clusters.Comment: Minor corrections and modifications. 15 pages with 10 figures.
Accepted for publication in the Journal of Chemical Physics, see
http://jcp.aip.org/jcp
An Ensemble of Bayesian Neural Networks for Exoplanetary Atmospheric Retrieval
Machine learning is now used in many areas of astrophysics, from detecting
exoplanets in Kepler transit signals to removing telescope systematics. Recent
work demonstrated the potential of using machine learning algorithms for
atmospheric retrieval by implementing a random forest to perform retrievals in
seconds that are consistent with the traditional, computationally-expensive
nested-sampling retrieval method. We expand upon their approach by presenting a
new machine learning model, \texttt{plan-net}, based on an ensemble of Bayesian
neural networks that yields more accurate inferences than the random forest for
the same data set of synthetic transmission spectra. We demonstrate that an
ensemble provides greater accuracy and more robust uncertainties than a single
model. In addition to being the first to use Bayesian neural networks for
atmospheric retrieval, we also introduce a new loss function for Bayesian
neural networks that learns correlations between the model outputs.
Importantly, we show that designing machine learning models to explicitly
incorporate domain-specific knowledge both improves performance and provides
additional insight by inferring the covariance of the retrieved atmospheric
parameters. We apply \texttt{plan-net} to the Hubble Space Telescope Wide Field
Camera 3 transmission spectrum for WASP-12b and retrieve an isothermal
temperature and water abundance consistent with the literature. We highlight
that our method is flexible and can be expanded to higher-resolution spectra
and a larger number of atmospheric parameters
BARCRAWL and BARTAB: software tools for the design and implementation of barcoded primers for highly multiplexed DNA sequencing
<p>Abstract</p> <p>Background</p> <p>Advances in automated DNA sequencing technology have greatly increased the scale of genomic and metagenomic studies. An increasingly popular means of increasing project throughput is by multiplexing samples during the sequencing phase. This can be achieved by covalently linking short, unique "barcode" DNA segments to genomic DNA samples, for instance through incorporation of barcode sequences in PCR primers. Although several strategies have been described to insure that barcode sequences are unique and robust to sequencing errors, these have not been integrated into the overall primer design process, thus potentially introducing bias into PCR amplification and/or sequencing steps.</p> <p>Results</p> <p><it>Barcrawl </it>is a software program that facilitates the design of barcoded primers, for multiplexed high-throughput sequencing. The program <it>bartab </it>can be used to deconvolute DNA sequence datasets produced by the use of multiple barcoded primers. This paper describes the functions implemented by <it>barcrawl </it>and <it>bartab </it>and presents a proof-of-concept case study of both programs in which barcoded rRNA primers were designed and validated by high-throughput sequencing.</p> <p>Conclusion</p> <p><it>Barcrawl </it>and <it>bartab </it>can benefit researchers who are engaged in metagenomic projects that employ multiplexed specimen processing. The source code is released under the GNU general public license and can be accessed at <url>http://www.phyloware.com</url>.</p
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A Smartphone-Based Tool for Rapid, Portable, and Automated Wide-Field Retinal Imaging.
Purpose:High-quality, wide-field retinal imaging is a valuable method for screening preventable, vision-threatening diseases of the retina. Smartphone-based retinal cameras hold promise for increasing access to retinal imaging, but variable image quality and restricted field of view can limit their utility. We developed and clinically tested a smartphone-based system that addresses these challenges with automation-assisted imaging. Methods:The system was designed to improve smartphone retinal imaging by combining automated fixation guidance, photomontage, and multicolored illumination with optimized optics, user-tested ergonomics, and touch-screen interface. System performance was evaluated from images of ophthalmic patients taken by nonophthalmic personnel. Two masked ophthalmologists evaluated images for abnormalities and disease severity. Results:The system automatically generated 100° retinal photomontages from five overlapping images in under 1 minute at full resolution (52.3 pixels per retinal degree) fully on-phone, revealing numerous retinal abnormalities. Feasibility of the system for diabetic retinopathy (DR) screening using the retinal photomontages was performed in 71 diabetics by masked graders. DR grade matched perfectly with dilated clinical examination in 55.1% of eyes and within 1 severity level for 85.2% of eyes. For referral-warranted DR, average sensitivity was 93.3% and specificity 56.8%. Conclusions:Automation-assisted imaging produced high-quality, wide-field retinal images that demonstrate the potential of smartphone-based retinal cameras to be used for retinal disease screening. Translational Relevance:Enhancement of smartphone-based retinal imaging through automation and software intelligence holds great promise for increasing the accessibility of retinal screening
Fast switching devices and induction rf at CLIC
We survey possible applications of fast switching devices and induction rf at the Compact Linear Collider (CLIC). These applications include extraction kickers for the combiner rings, modulators for the drive-beam linac, fast intra-train feedback, induction crab cavities, halo kickers, emergency kickers, long-range beam-beam compensation, damping-ring barrier rf, pulsed linac wigglers, positron capture, and spent-beam handling
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