In the past few decades, many ingenious efforts have been made in the development of free-energy simulation methods. Because complex systems often undergo nontrivial structural transition during ...state switching, achieving efficient free-energy calculation can be challenging. As identified earlier, the "Hamiltonian" lagging, which reveals the fact that necessary structural relaxation falls behind the order parameter move, has been a primary problem for generally low free-energy simulation efficiency. Here, we propose an algorithm by achieving a random walk in both the order parameter space and its generalized force space; thereby, the order parameter move and the required conformational relaxation can be efficiently synchronized. As demonstrated in both the alchemical transition and the conformational transition, a leapfrog improvement in free-energy simulation efficiency can be obtained; for instance, (i) it allows us to solve a notoriously challenging problem: accurately predicting the pKa value of a buried titratable residue, Asp-66, in the interior of the V66E staphylococcal nuclease mutant, and (ii) it allows us to gain superior efficiency over the metadynamics algorithm.
Patients with relapsed or refractory mantle-cell lymphoma who have disease progression during or after the receipt of Bruton's tyrosine kinase (BTK) inhibitor therapy have a poor prognosis. KTE-X19, ...an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, may have benefit in patients with relapsed or refractory mantle-cell lymphoma.
In a multicenter, phase 2 trial, we evaluated KTE-X19 in patients with relapsed or refractory mantle-cell lymphoma. Patients had disease that had relapsed or was refractory after the receipt of up to five previous therapies; all patients had to have received BTK inhibitor therapy previously. Patients underwent leukapheresis and optional bridging therapy, followed by conditioning chemotherapy and a single infusion of KTE-X19 at a dose of 2×10
CAR T cells per kilogram of body weight. The primary end point was the percentage of patients with an objective response (complete or partial response) as assessed by an independent radiologic review committee according to the Lugano classification. Per the protocol, the primary efficacy analysis was to be conducted after 60 patients had been treated and followed for 7 months.
A total of 74 patients were enrolled. KTE-X19 was manufactured for 71 patients and administered to 68. The primary efficacy analysis showed that 93% (95% confidence interval CI, 84 to 98) of the 60 patients in the primary efficacy analysis had an objective response; 67% (95% CI, 53 to 78) had a complete response. In an intention-to-treat analysis involving all 74 patients, 85% had an objective response; 59% had a complete response. At a median follow-up of 12.3 months (range, 7.0 to 32.3), 57% of the 60 patients in the primary efficacy analysis were in remission. At 12 months, the estimated progression-free survival and overall survival were 61% and 83%, respectively. Common adverse events of grade 3 or higher were cytopenias (in 94% of the patients) and infections (in 32%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 15% and 31% of patients, respectively; none were fatal. Two grade 5 infectious adverse events occurred.
KTE-X19 induced durable remissions in a majority of patients with relapsed or refractory mantle-cell lymphoma. The therapy led to serious and life-threatening toxic effects that were consistent with those reported with other CAR T-cell therapies. (Funded by Kite, a Gilead company; ZUMA-2 ClinicalTrials.gov number, NCT02601313.).
Automotive millimeter-wave (MMW) radar is essential in autonomous vehicles due to its robustness in all weather conditions. Traditional commercial automotive radars are limited by their resolution, ...which makes the object classification task difficult. Thus, the concept of a new generation of four-dimensional (4D) imaging radar was proposed. It has high azimuth and elevation resolution and contains Doppler information to produce a high-quality point cloud. In this paper, we propose an object classification network named Radar Transformer. The algorithm takes the attention mechanism as the core and adopts the combination of vector attention and scalar attention to make full use of the spatial information, Doppler information, and reflection intensity information of the radar point cloud to realize the deep fusion of local attention features and global attention features. We generated an imaging radar classification dataset and completed manual annotation. The experimental results show that our proposed method achieved an overall classification accuracy of 94.9%, which is more suitable for processing radar point clouds than the popular deep learning frameworks and shows promising performance.
Hand gesture recognition technology plays an important role in human-computer interaction and in-vehicle entertainment. Under in-vehicle conditions, it is a great challenge to design gesture ...recognition systems due to variable driving conditions, complex backgrounds, and diversified gestures. In this paper, we propose a gesture recognition system based on frequency-modulated continuous-wave (FMCW) radar and transformer for an in-vehicle environment. Firstly, the original range-Doppler maps (RDMs), range-azimuth maps (RAMs), and range-elevation maps (REMs) of the time sequence of each gesture are obtained by radar signal processing. Then we preprocess the obtained data frames by region of interest (ROI) extraction, vibration removal algorithm, background removal algorithm, and standardization. We propose a transformer-based radar gesture recognition network named RGTNet. It fully extracts and fuses the spatial-temporal information of radar feature maps to complete the classification of various gestures. The experimental results show that our method can better complete the eight gesture classification tasks in the in-vehicle environment. The recognition accuracy is 97.56%.
Traffic participant classification is critical in autonomous driving perception. Millimetre wave radio detection and ranging (RADAR) is a cost‐effective and robust means of performing this task in ...adverse traffic scenarios such as inclement weather (e.g. fog, snow, and rain) and poor lighting conditions. Compared to commercial two‐dimensional RADAR, the new generation of three‐dimensional (3D) RADAR can obtain height information about targets as well as their dense point clouds, greatly improving target classification capabilities. This study proposes a multi‐objective classification method for traffic participants based on 3D RADAR point clouds. First, a 22‐dimensional feature vector of the 3D RADAR point cloud distribution was extracted to describe the shape, discrete, Doppler, and reflection intensity features of the targets. Then, dynamic and static datasets containing five classes of targets were produced, creating a 10k frame. Extensive experiments were conducted to build machine learning classifiers. The experimental results show that the trained classifiers can achieve over 92% classification accuracy when the targets are classified into five groups and over 95% classification accuracy when the targets are classified into four groups. The proposed method can guide the design of safer and more efficient intelligent driving systems.
A direct‐infusion electrospray ionization triple–quadrupole mass spectrometry method with multiple reaction monitoring (MRM) was employed to measure 264 lipid analytes extracted from leaves of ...Arabidopsis thaliana subjected to mechanical wounding. The method provided precise measurements with an average coefficient of variation of 6.1%. Lipid classes analyzed comprised galactolipids and phospholipids (including monoacyl molecular species, molecular species with oxidized acyl chains, phosphatidic acids (PAs)), tri‐ and tetra‐galactosyldiacylglycerols (TrGDGs and TeGDGs), head‐group‐acylated galactolipids, and head‐group‐acylated phosphatidylglycerol (acPG), sulfoquinovosyldiacylglycerols (SQDGs), sphingolipids, di‐ and tri‐acylglycerols (DAGs and TAGs), and sterol derivatives. Of the 264 lipid analytes, 254 changed significantly in response to wounding. In general, levels of structural lipids decreased, whereas monoacyl molecular species, galactolipids and phosphatidylglycerols (PGs) with oxidized fatty acyl chains, PAs, TrGDGs, TeGDGs, TAGs, head‐group‐acylated galactolipids, acPG, and some sterol derivatives increased, many transiently. The observed changes are consistent with activation of lipid oxidizing, hydrolyzing, glycosylating, and acylating activities in the wounding response. Correlation analysis of the levels of lipid analytes across individual control and treated plants was used to construct a lipid dendrogram and to define clusters and sub‐clusters of lipid analytes, each composed of a group of lipids which occurred in a coordinated manner. Current knowledge of metabolism supports the notion that observed sub‐clusters comprise lipids generated by a common enzyme and/or metabolically downstream of a common enzyme. This work demonstrates that co‐occurrence analysis, based on correlation of lipid levels among plants, is a powerful approach to defining lipids generated in vivo by a common enzymatic pathway.
This paper presents a target tracking algorithm based on 4D millimeter-wave radar point cloud information for autonomous driving applications, which addresses the limitations of traditional 2 + 1D ...radar systems by using higher resolution target point cloud information that enables more accurate motion state estimation and target contour information. The proposed algorithm includes several steps, starting with the estimation of the ego vehicle’s velocity information using the radial velocity information of the millimeter-wave radar point cloud. Different clustering suggestions are then obtained using a density-based clustering method, and correlation regions of the targets are obtained based on these clustering suggestions. The binary Bayesian filtering method is then used to determine whether the targets are dynamic or static targets based on their distribution characteristics. For dynamic targets, Kalman filtering is used to estimate and update the state of the target using trajectory and velocity information, while for static targets, the rolling ball method is used to estimate and update the shape contour boundary of the target. Unassociated measurements are estimated for the contour and initialized for the trajectory, and unassociated trajectory targets are selectively retained and deleted. The effectiveness of the proposed method is verified using real data. Overall, the proposed target tracking algorithm based on 4D millimeter-wave radar point cloud information has the potential to improve the accuracy and reliability of target tracking in autonomous driving applications, providing more comprehensive motion state and target contour information for better decision making.
The genetic architecture of many phenotypic traits is such that genes often contribute to multiple traits, and mutations in these genes can therefore affect multiple phenotypes. These pleiotropic ...interactions often manifest as tradeoffs between traits where improvement in one property entails a cost in another. The life cycles of many pathogens include periods of growth within a host punctuated with transmission events, such as passage through a digestive tract or a passive stage of exposure in the environment. Populations exposed to such fluctuating selective pressures are expected to acquire mutations showing tradeoffs between reproduction within and survival outside of a host. We selected for individual mutations under fluctuating selective pressures for a ssDNA microvirid bacteriophage by alternating selection for increased growth rate with selection on biophysical properties of the phage capsid in high-temperature or low-pH conditions. Surprisingly, none of the seven unique mutations identified showed a pleiotropic cost; they all improved both growth rate and pH or temperature stability, suggesting that single mutations even in a simple genetic system can simultaneously improve two distinct traits. Selection on growth rate alone revealed tradeoffs, but some mutations still benefited both traits. Tradeoffs were therefore prevalent when selection acted on a single trait, but payoffs resulted when multiple traits were selected for simultaneously. We employed a molecular-dynamics simulation method to determine the mechanisms underlying beneficial effects for three heat-shock mutations. All three mutations significantly enhanced the affinities of protein-protein interfacial bindings, thereby improving capsid stability. The ancestral residues at the mutation sites did not contribute to protein-protein interfacial binding, indicating that these sites acquired a new function. Computational models, such as those used here, may be used in future work not only as predictive tools for mutational effects on protein stability but, ultimately, for evolution.
The orthogonal space random walk (OSRW) method, which enables synchronous acceleration of the motions of a focused region and its coupled environment, was recently introduced to enhance sampling for ...free energy simulations. In the present work, the OSRW algorithm is generalized to be the orthogonal space tempering (OST) method via the introduction of the orthogonal space sampling temperature. Moreover, a double-integration recursion method is developed to enable practically efficient and robust OST free energy calculations, and the algorithm is augmented by a novel θ-dynamics approach to realize both the uniform sampling of order parameter spaces and rigorous end point constraints. In the present work, the double-integration OST method is employed to perform alchemical free energy simulations, specifically to calculate the free energy difference between benzyl phosphonate and difluorobenzyl phosphonate in aqueous solution, to estimate the solvation free energy of the octanol molecule, and to predict the nontrivial Barnase–Barstar binding affinity change induced by the Barnase N58A mutation. As demonstrated in these model studies, the DI-OST method can robustly enable practically efficient free energy predictions, particularly when strongly coupled slow environmental transitions are involved.
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