Although deep learning has revolutionized protein structure prediction, almost all experimentally characterized de novo protein designs have been generated using physically based approaches such as ...Rosetta. Here, we describe a deep learning-based protein sequence design method, ProteinMPNN, that has outstanding performance in both in silico and experimental tests. On native protein backbones, ProteinMPNN has a sequence recovery of 52.4% compared with 32.9% for Rosetta. The amino acid sequence at different positions can be coupled between single or multiple chains, enabling application to a wide range of current protein design challenges. We demonstrate the broad utility and high accuracy of ProteinMPNN using x-ray crystallography, cryo-electron microscopy, and functional studies by rescuing previously failed designs, which were made using Rosetta or AlphaFold, of protein monomers, cyclic homo-oligomers, tetrahedral nanoparticles, and target-binding proteins.
We present the result of an experiment to measure the electric dipole moment (EDM) of the neutron at the Paul Scherrer Institute using Ramsey's method of separated oscillating magnetic fields with ...ultracold neutrons. Our measurement stands in the long history of EDM experiments probing physics violating time-reversal invariance. The salient features of this experiment were the use of a ^{199}Hg comagnetometer and an array of optically pumped cesium vapor magnetometers to cancel and correct for magnetic-field changes. The statistical analysis was performed on blinded datasets by two separate groups, while the estimation of systematic effects profited from an unprecedented knowledge of the magnetic field. The measured value of the neutron EDM is d_{n}=(0.0±1.1_{stat}±0.2_{sys})×10^{-26} e.cm.
We show through first-principles nuclear structure calculations that the special nature of the strong nuclear force determines highly regular patterns heretofore unrecognized in nuclei that can be ...tied to an emergent approximate symmetry. This symmetry is ubiquitous and mathematically tracks with a symplectic symmetry group. This, in turn, has important implications for understanding the physics of nuclei: we find that nuclei are made of only a few equilibrium shapes, deformed or not, with associated vibrations and rotations. It also opens the path for ab initio large-scale modeling of open-shell intermediate-mass nuclei without the need for renormalized interactions and effective charges.
Spermatogenesis in the adult male depends on the action of FSH and androgen. Ablation of either hormone has deleterious effects on Sertoli cell function and the progression of germ cells through ...spermatogenesis. In this study we generated mice lacking both FSH receptors (FSHRKO) and androgen receptors on the Sertoli cell (SCARKO) to examine how FSH and androgen combine to regulate Sertoli cell function and spermatogenesis. Sertoli cell number in FSHRKO-SCARKO mice was reduced by about 50% but was not significantly different from FSHRKO mice. In contrast, total germ cell number in FSHRKO-SCARKO mice was reduced to 2% of control mice (and 20% of SCARKO mice) due to a failure to progress beyond early meiosis. Measurement of Sertoli cell-specific transcript levels showed that about a third were independent of hormonal action on the Sertoli cell, whereas others were predominantly androgen dependent or showed redundant control by FSH and androgen. Results show that FSH and androgen act through redundant, additive, and synergistic regulation of spermatogenesis and Sertoli cell activity. In addition, the Sertoli cell retains a significant capacity for activity, which is independent of direct hormonal regulation.
Patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) have a poor prognosis. The phase III KESTREL study evaluated the efficacy of durvalumab programmed death-ligand ...1 (PD-L1) antibody with or without tremelimumab cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody, versus the EXTREME regimen in patients with R/M HNSCC.
Patients with HNSCC who had not received prior systemic treatment for R/M disease were randomized (2 : 1 : 1) to receive durvalumab 1500 mg every 4 weeks (Q4W) plus tremelimumab 75 mg Q4W (up to four doses), durvalumab monotherapy 1500 mg Q4W, or the EXTREME regimen (platinum, 5-fluorouracil, and cetuximab) until disease progression. Durvalumab efficacy, with or without tremelimumab, versus the EXTREME regimen in patients with PD-L1-high tumors and in all randomized patients was assessed. Safety was also assessed.
Durvalumab and durvalumab plus tremelimumab were not superior to EXTREME for overall survival (OS) in patients with PD-L1-high expression median, 10.9 and 11.2 versus 10.9 months, respectively; hazard ratio (HR) = 0.96; 95% confidence interval (CI) 0.69-1.32; P = 0.787 and HR = 1.05; 95% CI 0.80-1.39, respectively. Durvalumab and durvalumab plus tremelimumab prolonged duration of response versus EXTREME (49.3% and 48.1% versus 9.8% of patients remaining in response at 12 months), correlating with long-term OS for responding patients; however, median progression-free survival was longer with EXTREME (2.8 and 2.8 versus 5.4 months). Exploratory analyses suggested that subsequent immunotherapy use by 24.3% of patients in the EXTREME regimen arm contributed to the similar OS outcomes between arms. Grade 3/4 treatment-related adverse events (TRAEs) for durvalumab, durvalumab plus tremelimumab, and EXTREME were 8.9%, 19.1%, and 53.1%, respectively.
In patients with PD-L1-high expression, OS was comparable between durvalumab and the EXTREME regimen. Durvalumab alone, and with tremelimumab, demonstrated durable responses and reduced TRAEs versus the EXTREME regimen in R/M HNSCC.
•KESTREL assessed first-line durvalumab with or without tremelimumab versus the EXTREME regimen in patients with R/M HNSCC.•Durvalumab ± tremelimumab was not superior to the EXTREME regimen for OS in patients with PD-L1-high expression.•Durvalumab ± tremelimumab produced durable responses and fewer TRAEs versus EXTREME in patients with R/M HNSCC.•Subsequent immunotherapy use may have contributed to longer-than-expected OS in the EXTREME regimen arm.
The quantitative evaluation of optical flow algorithms by Barron et al. (
1994
) led to significant advances in performance. The challenges for optical flow algorithms today go beyond the datasets ...and evaluation methods proposed in that paper. Instead, they center on problems associated with complex natural scenes, including nonrigid motion, real sensor noise, and motion discontinuities. We propose a new set of benchmarks and evaluation methods for the next generation of optical flow algorithms. To that end, we contribute four types of data to test different aspects of optical flow algorithms: (1) sequences with nonrigid motion where the ground-truth flow is determined by tracking hidden fluorescent texture, (2) realistic synthetic sequences, (3) high frame-rate video used to study interpolation error, and (4) modified stereo sequences of static scenes. In addition to the average angular error used by Barron et al., we compute the absolute flow endpoint error, measures for frame interpolation error, improved statistics, and results at motion discontinuities and in textureless regions. In October 2007, we published the performance of several well-known methods on a preliminary version of our data to establish the current state of the art. We also made the data freely available on the web at
http://vision.middlebury.edu/flow/
. Subsequently a number of researchers have uploaded their results to our website and published papers using the data. A significant improvement in performance has already been achieved. In this paper we analyze the results obtained to date and draw a large number of conclusions from them.
Forests are major components of the global carbon cycle, providing substantial feedback to atmospheric greenhouse gas concentrations. Our ability to understand and predict changes in the forest ...carbon cycle--particularly net primary productivity and carbon storage--increasingly relies on models that represent biological processes across several scales of biological organization, from tree leaves to forest stands. Yet, despite advances in our understanding of productivity at the scales of leaves and stands, no consensus exists about the nature of productivity at the scale of the individual tree, in part because we lack a broad empirical assessment of whether rates of absolute tree mass growth (and thus carbon accumulation) decrease, remain constant, or increase as trees increase in size and age. Here we present a global analysis of 403 tropical and temperate tree species, showing that for most species mass growth rate increases continuously with tree size. Thus, large, old trees do not act simply as senescent carbon reservoirs but actively fix large amounts of carbon compared to smaller trees; at the extreme, a single big tree can add the same amount of carbon to the forest within a year as is contained in an entire mid-sized tree. The apparent paradoxes of individual tree growth increasing with tree size despite declining leaf-level and stand-level productivity can be explained, respectively, by increases in a tree's total leaf area that outpace declines in productivity per unit of leaf area and, among other factors, age-related reductions in population density. Our results resolve conflicting assumptions about the nature of tree growth, inform efforts to undertand and model forest carbon dynamics, and have additional implications for theories of resource allocation and plant senescence.
The first major scientific discovery of the Space Age was that the Earth is enshrouded in toroids, or belts, of very high-energy magnetically trapped charged particles. Early observations of the ...radiation environment clearly indicated that the Van Allen belts could be delineated into an inner zone dominated by high-energy protons and an outer zone dominated by high-energy electrons. The energy distribution, spatial extent and particle species makeup of the Van Allen belts has been subsequently explored by several space missions. Recent observations by the NASA dual-spacecraft Van Allen Probes mission have revealed many novel properties of the radiation belts, especially for electrons at highly relativistic and ultra-relativistic kinetic energies. In this review we summarize the space weather impacts of the radiation belts. We demonstrate that many remarkable features of energetic particle changes are driven by strong solar and solar wind forcings. Recent comprehensive data show broadly and in many ways how high energy particles are accelerated, transported, and lost in the magnetosphere due to interplanetary shock wave interactions, coronal mass ejection impacts, and high-speed solar wind streams. We also discuss how radiation belt particles are intimately tied to other parts of the geospace system through atmosphere, ionosphere, and plasmasphere coupling. The new data have in many ways rewritten the textbooks about the radiation belts as a key space weather threat to human technological systems.
Developing expertise in flexible bronchoscopy is limited by inadequate opportunities to train on difficult airways. The new ORSIM bronchoscopy simulator aims to address this by creating virtual ...patients with difficult airways. This study aims to provide evidence on the validity and reliability of the ORSIM for assessment of subjects on both normal and abnormal airway simulations.
Novice, trainee, and expert subjects performed seven simulations of varying difficulty and scored the perceived difficulty for each. Time to completion was measured. Three blinded raters independently scored videos of each subject's performance. We measured inter-rater agreement and the difference in raters’ scores between subject groups.
We recruited 28 study subjects, generating 196 videos for analysis. Expert subjects consistently completed the scenarios faster than novices. Overall performance scores showed significant differences between subject groups (P<0.0001). Inter-rater reliability of scores was >0.8.
Our results provide initial evidence on the validity and reliability of the ORSIM bronchoscopy simulator, supporting its potential value in training and assessment.
PDF
