N-Heterocyclic Carbene-Catalyzed Regio- and Enantioselective C7-Alkylation of 4-Aminoindoles with α-Bromoenals.

The first carbene-catalyzed regio- and enantioselective indole C7-alkylation reaction between 4-aminoindoles and α-bromoenals is disclosed. The corresponding indole products could be obtained in moderate to good yields with good to excellent enantioselectivities. The evaluation of antibacterial activity against Psa revealed that nine of the C7-functionalized indoles exhibited superior inhibitory activities compared to the positive controls TC and BT. Our approach provides an efficient strategy to introduce a chiral chain into the C7 position of indole compounds, with potential applications evaluated in pesticide development.

An improved Bi-LSTM method based on heterogeneous features fusion and attention mechanism for ECG recognition.

Electrocardiogram (ECG) plays a critical role in early prevention and diagnosis of cardiovascular diseases. However, extracting powerful deep features from ECG signal for recognition is still a challenging problem today due to the variable abnormal rhythms and noise distribution. This work proposes a Bi-LSTM algorithm based on heterogeneous features fusion and attention mechanism (HFFAM + Bi-LSTM). Combining the empirical features and the features learned by the deep learning network, HFFAM + Bi-LSTM can comprehensively extract the temporal frequency information and spatial structure information of the ECG signal. Meanwhile, a novel attention mechanism based on improved DTW (AM-DTW) is designed to analyze and control the fusion process of features. The role of AM-DTW in HFFAM + Bi-LSTM is twofold, one is to measure the feature similarity between ECG signal sets with different labels using the improved DTW, and the other is to distinguish the features into isomorphic and heterogeneous features as well as adaptive weighting of the features. It is worth mentioning that overly similar isomorphic features are filtered out to further optimize the algorithm. Thus, HFFAM + Bi-LSTM has the advantage of strengthening the heterogeneous information in the feature subspace while accounting for the isomorphic features. The accuracy of HFFAM + Bi-LSTM reaches up to 98.1 % and 97.1 % on the simulated and real datasets, respectively. Compared to the all benchmark models, the classification accuracy of HFFAM + Bi-LSTM is 1.3 % higher than the best. The experiments also demonstrate that HFFAM + Bi-LSTM has better performance compared with existing methods, which provides a new scheme for automatic detection of ECG signal.

Bio-Inspired Proprioceptive Touch of a Soft Finger with Inner-Finger Kinesthetic Perception.

In-hand object pose estimation is challenging for humans and robots due to occlusion caused by the hand and object. This paper proposes a soft finger that integrates inner vision with kinesthetic sensing to estimate object pose inspired by human fingers. The soft finger has a flexible skeleton and skin that adapts to different objects, and the skeleton deformations during interaction provide contact information obtained by the image from the inner camera. The proposed framework is an end-to-end method that uses raw images from soft fingers to estimate in-hand object pose. It consists of an encoder for kinesthetic information processing and an object pose and category estimator. The framework was tested on seven objects, achieving an impressive error of 2.02 mm and 11.34 degrees for pose error and 99.05% for classification.

A novel post-processing strategy to improve the accuracy of complete-arch intraoral scanning for implants: an in vitro study.

OBJECTIVES: To develop a new post-processing strategy that utilizes an auxiliary device to adjust intraoral scans and improve the accuracy of 3D models of complete-arch dental implants. MATERIALS AND METHODS: An edentulous resin model with 6 dental implants was prepared. An auxiliary device, consisting of an opaque base and artificial landmarks, was fabricated and mounted onto the resin model. Twenty intraoral scans (raw scans) were taken using this setup. A new post-processing strategy was proposed to adjust the raw scans using reverse engineering software (verified group). Additionally, ten conventional gypsum casts were duplicated and digitized using a laboratory scanner. The linear and angular trueness and precision of the models were evaluated and compared. The effect of the proposed strategy on the accuracy of complete-arch intraoral scans was analyzed using one-way ANOVA. RESULTS: The linear trueness (29.7 µm) and precision (24.8 µm) of the verified group were significantly better than the raw scans (46.6 µm, 44.7 µm) and conventional casts (51.3 µm, 36.5 µm), particularly in cross-arch sites. However, the angular trueness (0.114°) and precision (0.085°) of the conventional casts were significantly better than both the verified models (0.298°, 0.168°) and the raw scans (0.288°, 0.202°). CONCLUSIONS: The novel post-processing strategy is effective in enhancing the linear accuracy of complete-arch implant IO scans, especially in cross-arch sites. However, further improvement is needed to eliminate the angular deviations. CLINICAL SIGNIFICANCE: Errors generated from intraoral scanning in complete edentulous arches exceed the clinical threshold. The elimination of stitching errors in the raw scans particularly in the cross-arch sites, through the proposed post-processing strategy would enhance the accuracy of complete-arch implant prostheses.

Bridging Locomotion and Manipulation Using Reconfigurable Robotic Limbs via Reinforcement Learning.

Locomotion and manipulation are two essential skills in robotics but are often divided or decoupled into two separate problems. It is widely accepted that the topological duality between multi-legged locomotion and multi-fingered manipulation shares an intrinsic model. However, a lack of research remains to identify the data-driven evidence for further research. This paper explores a unified formulation of the loco-manipulation problem using reinforcement learning (RL) by reconfiguring robotic limbs with an overconstrained design into multi-legged and multi-fingered robots. Such design reconfiguration allows for adopting a co-training architecture for reinforcement learning towards a unified loco-manipulation policy. As a result, we find data-driven evidence to support the transferability between locomotion and manipulation skills using a single RL policy with a multilayer perceptron or graph neural network. We also demonstrate the Sim2Real transfer of the learned loco-manipulation skills in a robotic prototype. This work expands the knowledge frontiers on loco-manipulation transferability with learning-based evidence applied in a novel platform with overconstrained robotic limbs.

Carbene-Catalyzed Activation of C-Si Bonds for Chemo- and Enantioselective Cross Brook-Benzoin Reaction.

The first carbene-catalyzed asymmetric chemoselective cross silyl benzoin (Brook-Benzoin) reaction has been developed. Key steps of this reaction involve activation of the carbon-silicon bond of an acylsilane by a chiral N-heterocyclic carbene (NHC) catalyst to form a silyl acyl anion intermediate. These acyl anions then undergo an addition reaction with indole aldehydes in a highly chemo- and enantioselective manner to afford α-silyloxy ketones with excellent optical purities. The reaction mechanism of this cross Brook-Benzoin reaction was investigated through both experimental and computational methods. The chiral α-hydroxy ketone derivatives obtained by this approach show promising, agrochemically interesting activity against harmful plant bacteria.

DeepClaw 2.0: A Data Collection Platform for Learning Human Manipulation.

Besides direct interaction, human hands are also skilled at using tools to manipulate objects for typical life and work tasks. This paper proposes DeepClaw 2.0 as a low-cost, open-sourced data collection platform for learning human manipulation. We use an RGB-D camera to visually track the motion and deformation of a pair of soft finger networks on a modified kitchen tong operated by human teachers. These fingers can be easily integrated with robotic grippers to bridge the structural mismatch between humans and robots during learning. The deformation of soft finger networks, which reveals tactile information in contact-rich manipulation, is captured passively. We collected a comprehensive sample dataset involving five human demonstrators in ten manipulation tasks with five trials per task. As a low-cost, open-sourced platform, we also developed an intuitive interface that converts the raw sensor data into state-action data for imitation learning problems. For learning-by-demonstration problems, we further demonstrated our dataset's potential by using real robotic hardware to collect joint actuation data or using a simulated environment when limited access to the hardware.

[Efficacy and Safety of Cladribine-based Intensified Conditioning Regimen in Hematopoietic Stem Cell Transplantation in Patients with High-Risk Acute Myeloid Leukemia].

OBJECTIVE: To investigate the efficacy, safety and the risk factors affecting prognosis of high-risk acute myeloid leukemia (AML) patients treated by cladribine-based intensified conditioning regimen. METHODS: The clinical data of 28 patients with high-risk AML treated by cladribine in combination with busulfan plus cyclophosphamide (BuCy) intensified conditioning regimen before allogeneic hematopoietic stem cell transplantation (allo-HSCT) in Zhujiang Hospital, Southern Medical University from October 2016 to June 2020 were analyzed retrospectively. The overall survival (OS) rate, cumulative progression-free survival (PFS) rate, relapse rate, non-relapse mortality (NRM), regimen related toxicity (RRT) and risk factors affecting prognosis of the patients were analyzed. RESULTS: The 1-year OS and PFS of the patients after implantation was (78.8±8.6)% and (79.8±8.1)%, while the 1-year cumulative relapse rate and NRM of the patients was 9.3% and 22.0%, respectively. The 1-year expected OS of MRD- high-risk patients before HSCT was 100%. The 1-year expected OS and PFS of the patients in pre-transplant relapse group was (46.9±18.7)% and (50.0±17.7)%, respectively. The incidence of I/II grade RRT was 39.3%. NO III/IV grade RRT were found in 28 patients. Multivariate analysis showed that pre-transplant relapse was the independent risk factor affecting OS and PFS of the patients. CONCLUSION: The intensified conditioning regimen of cladribine in combination with BuCy can reduce the relapse rate of high-risk AML transplantation, and its RRT is mild, exhibiting good safety. MRD- high-risk patients before HSCT can achieve better transplant benefits, but the prognosis of patients with relapse before transplantation is not significantly improved. Therefore, for non-relapsed high-risk AML patients, this intensified conditioning regimen deserves to be considered.

Soft magnetic skin for super-resolution tactile sensing with force self-decoupling.

Human skin can sense subtle changes of both normal and shear forces (i.e., self-decoupled) and perceive stimuli with finer resolution than the average spacing between mechanoreceptors (i.e., super-resolved). By contrast, existing tactile sensors for robotic applications are inferior, lacking accurate force decoupling and proper spatial resolution at the same time. Here, we present a soft tactile sensor with self-decoupling and super-resolution abilities by designing a sinusoidally magnetized flexible film (with the thickness ~0.5 millimeters), whose deformation can be detected by a Hall sensor according to the change of magnetic flux densities under external forces. The sensor can accurately measure the normal force and the shear force (demonstrated in one dimension) with a single unit and achieve a 60-fold super-resolved accuracy enhanced by deep learning. By mounting our sensor at the fingertip of a robotic gripper, we show that robots can accomplish challenging tasks such as stably grasping fragile objects under external disturbance and threading a needle via teleoperation. This research provides new insight into tactile sensor design and could be beneficial to various applications in robotics field, such as adaptive grasping, dexterous manipulation, and human-robot interaction.

Preclinical and clinical advances in dual-target chimeric antigen receptor therapy for hematological malignancies.

In recent years, the excellent curative effect of CD19-specific chimeric antigen receptor (CAR) T-cell therapy has brought hope to patients with relapsing or refractory B-cell hematological malignancies, however relapse after CAR T-cell infusion has hindered the widespread clinical application of this immunotherapy and targeted antigen-negative relapse has caused widespread concern. Consequently, strategies for increasing targeted antigens have been created. In addition to the most widely applied target, namely CD19, researchers have further explored the possibility of other targets, such as CD20, CD22, CD33, and CD123, and have tested a series of combination antigen CAR T-cell therapies. Here, we summarize the current preclinical and clinical studies of dual-target CAR T cells.

Rigid-Soft Interactive Design of a Lobster-Inspired Finger Surface for Enhanced Grasping Underwater.

Bio-inspirations from soft-bodied animals provide a rich design source for soft robots, yet limited literature explored the potential enhancement from rigid-bodied ones. This paper draws inspiration from the tooth profiles of the rigid claws of the Boston Lobster, aiming at an enhanced soft finger surface for underwater grasping using an iterative design process. The lobsters distinguish themselves from other marine animals with a pair of claws capable of dexterous object manipulation both on land and underwater. We proposed a 3-stage design iteration process that involves raw imitation, design parametric exploration, and bionic parametric exploitation on the original tooth profiles on the claws of the Boston Lobster. Eventually, 7 finger surface designs were generated and fabricated with soft silicone. We validated each design stage through many vision-based robotic grasping attempts against selected objects from the Evolved Grasping Analysis Dataset (EGAD). Over 14,000 grasp attempts were accumulated on land (71.4%) and underwater (28.6%), where we selected the optimal design through an on-land experiment and further tested its capability underwater. As a result, we observed an 18.2% improvement in grasping success rate at most from a resultant bionic finger surface design, compared with those without the surface, and a 10.4% improvement at most compared with the validation design from the previous literature. Results from this paper are relevant and consistent with the bioresearch earlier in 1911, showing the value of bionics. The results indicate the capability and competence of the optimal bionic finger surface design in an amphibious environment, which can contribute to future research in enhanced underwater grasping using soft robots.

Phase I Trial of Fourth-Generation Anti-CD19 Chimeric Antigen Receptor T Cells Against Relapsed or Refractory B Cell Non-Hodgkin Lymphomas.

Background: The administration of second- or third-generation anti-CD19 chimeric antigen receptor (CAR) T cells has remarkably improved the survival of patients with relapsed or refractory B cell malignancies. However, there are limited clinical results from fourth-generation CAR-T cell therapy, and the factors affecting response rate and survival have not been fully determined. Methods: Lymphoma patients with progression or relapse after intensive treatments, including hematopoietic stem cell transplantation, and life expectancy >2 months were enrolled in the study. Peripheral lymphocytes were collected through apheresis, and magnetically selected T cells were lentivirally transduced with a 4th-generation CAR featuring an anti-CD19 CAR and the iCasp9 suicide switch (4SCAR19). The patients received 4SCAR19 T cell infusion after approximately seven days of expansion and a conditioning regimen comprising cyclophosphamide/fludarabine. The efficacy, safety, and risk factors were evaluated. Results: A total of 21 patients with relapsed/refractory B cell non-Hodgkin lymphoma were enrolled and received 4SCAR19 T cell infusions at a median dose of 8.9×105 CAR-T cells/kg. The overall response rate was 67% [95% confidence interval (CI), 43 to 85], with 43% of patients achieving a complete response and 24% having a partial response. The overall and complete response rates were 58 and 33% in the diffuse large B-cell lymphoma (DLBCL) group and 78 and 56% in the non-DLBCL group, respectively. The median overall survival was 23.8 months (95% CI, not reached), with a median follow-up of 13.7 months. Factors affecting overall survival were International Prognostic Index (IPI), disease type, and remission status after CAR-T cell treatment. The most common adverse events of grade 3 or 4 during treatment were neutropenia (76%), leukopenia (71%), and thrombocytopenia (29%). The incidence of cytokine release syndrome (CRS) was 14%, and all cases were grade 1. One patient developed grade 3 neurotoxicity. No deaths were attributed to infusion of 4SCAR19 T cells, CRS, or neurotoxicity. Conclusions: In this study, patients with relapsed or refractory B cell non-Hodgkin's lymphoma who received 4SCAR19 T cell therapy had durable responses and few of adverse events. The IPI model is suitable for evaluating the prognosis of patients receiving CAR-T cell therapy. Trial registration: Chinese Clinical Trial Registry (http://www.chictr.org.cn): ChiCTR-OOC-16007779.

[Efficacy and Prognosis of Allogeneic Hematopoietic Stem Cell Transplantation for Acute Monocytic Leukemia Patients].

OBJECTIVE: To investigate the efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the treatment of acute monocytic leukemia (AML-M5) and the related factors that affecting the prognosis of the patients. METHODS: The clinical data of 71 patients with AML-M5 treated with allo-HSCT in Zhujiang Hospital Affiliated to Southern Medical University from April 2009 to October 2019 were collected and retrospectively analyzed. The incidence of graft-versus-host disease (GVHD), cumulative overall survival (OS) rate, cumulative progression-free survival (PFS) rate, transplantation-related mortality (TRM), relapse rate and the risk factors affecting prognosis in the patients were analyzed. RESULTS: 66 patients obtained hematopoietic reconstruction after transplantation, the median time of granulocyte implantation was 12 (9-26) d, and the median time of megakaryocytic implantation was 13 (8-72) d. The incidence of acute GVHD and chronic GVHD was 33.8% (24/71) and 36.6% (26/71), respectively. The median follow-up time was 13.81 (0.16 to 112.54) months; the median OS and PFS was 31.27 and 26.07 months, respectively. The cumulative OS of the patients in 1 and 3 years after transplantation was 64.9% and 48.6%, respectively, and the cumulative PFS of the patients in 1 and 3 years was 55.0% and 39.5%, respectively. The cumulative relapse rate of the patients in 1 and 3 years was 24% and 40%, respectively. Multivariate analysis showed that pre-transplantation relapse was the independent risk factor affecting OS (HR=2.32, 95%CI:1.17-4.62, P=0.02) and PFS (HR=3.08, 95%CI:1.61-5.90, P=0.001) of the patients; invasive fungal disease after transplantation was the independent risk factor affecting OS (HR=2.71, 95% CI:1.32-5.56, P=0.007) and PFS (HR=2.87, 95%CI=1.40-5.86, P=0.004) of the patients; FLT3 mutation was the independent risk factor affecting PFS (HR=2.13, 95%CI=1.07-4.24, P=0.03) of the patients. CONCLUSION: AML-M5 is the intermediate or high-risk leukemia, and allo-HSCT can improve the survival prognosis of the patients. Pre-transplantation relapse and invasive fungal disease after transplantation are the important factors affecting the efficacy of allo-HSCT in patients with AML-M5.

Flange-Based Hand-Eye Calibration Using a 3D Camera With High Resolution, Accuracy, and Frame Rate.

Point cloud data provides three-dimensional (3D) measurement of the geometric details in the physical world, which relies heavily on the quality of the machine vision system. In this paper, we explore the potentials of a 3D scanner of high quality (15 million points per second), accuracy (up to 0.150 mm), and frame rate (up to 20 FPS) during static and dynamic measurements of the robot flange for direct hand-eye calibration and trajectory error tracking. With the availability of high-quality point cloud data, we can exploit the standardized geometric features on the robot flange for 3D measurement, which are directly accessible for hand-eye calibration problems. In the meanwhile, we tested the proposed flange-based calibration methods in a dynamic setting to capture point cloud data in a high frame rate. We found that our proposed method works robustly even in dynamic environments, enabling a versatile hand-eye calibration during motion. Furthermore, capturing high-quality point cloud data in real-time opens new doors for the use of 3D scanners, capable of detecting sensitive anomalies of refined details even in motion trajectories. Codes and sample data of this calibration method is provided at Github (https://github.com/ancorasir/flange_handeye_calibration).

NeoPeptide: an immunoinformatic database of T-cell-defined neoantigens.

Therapeutic vaccines represent a promising immunotherapeutic modality against cancer. Discovery and validation of antigens is the key to develop effective anti-cancer vaccines. Neoantigens, arising from somatic mutations in individual cancers, are considered as ideal cancer vaccine targets because of their immunogenicity and lack of expression in normal tissues. However, only few databases support convenient access to these neoantigens for use in vaccines. To address this gap, we developed a web-accessible database, called NeoPeptide, which contains most of the important characteristics of neoantigens (such as mutation site, subunit sequence, major histocompatibility complex restriction) derived from published literature and other immunological resources. NeoPeptide also provides links to resources for further characterization of the novel features of these neoantigens. NeoPeptide will be regularly updated with newly identified and published neoantigens. Our work will help researchers in identifying neoantigens in different cancers and hasten the search for appropriate cancer vaccine candidates.

Fiber-Reinforced Origamic Robotic Actuator.

A novel pneumatic soft linear actuator Fiber-reinforced Origamic Robotic Actuator (FORA) is proposed with significant improvements on the popular McKibben-type actuators, offering nearly doubled motion range, substantially improved force profile, and significantly lower actuation pressure. The desirable feature set is made possible by a novel soft origamic chamber that expands radially while contracts axially when pressurized. Combining this new origamic chamber with a reinforcing fiber mesh, FORA generates very high traction force (over 150N) and very large contractile motion (over 50%) at very low input pressure (100 kPa). We developed quasi-static analytical models both to characterize the motion and forces and as guidelines for actuator design. Fabrication of FORA mostly involves consumer-grade three-dimensional (3D) printing. We provide a detailed list of materials and dimensions. Fabricated FORAs were tested on a dedicated platform against commercially available pneumatic artificial muscles from Shadow and Festo to showcase its superior performances and validate the analytical models with very good agreements. Finally, a robotic joint was developed driven by two antagonistic FORAs, to showcase the benefits of the performance improvements. With its simple structure, fully characterized mechanism, easy fabrication procedure, and highly desirable performance, FORA could be easily customized to application requirements and fabricated by anyone with access to a 3D printer. This will pave the way to the wider adaptation and application of soft robotic systems.

Allogeneic Hematopoietic Stem Cell Transplant for Severe Aplastic Anemia: Current State and Future Directions.

Acquired severe aplastic anemia (SAA) is a rare and life-threatening bone marrow failure syndrome characterized by cytotoxic T-cells excessive activity, hematopoietic precursors decrease and peripheral blood (PB) pancytopenia. Patients with severe aplastic anemia (SAA) die 1 to 2 years after diagnosis due to fatal infections and/or hemorrhagic complications if they do not undergo any effective treatment. Nowadays, Immunosuppressive therapy (IST) and allogeneic hematopoietic stem cell transplantation (HSCT) are still the standard treatment for SAA. For patients younger than 40 years old, allogeneic HSCT is often the best choice. Recently, outcomes of matched unrelated donor and haploidentical donor transplantation have significantly improved, notably in some cases which are comparable to the result of matched related donor transplantation. Mixed chimerism status is more common in SAA post-transplantation patients, which is effected by conditioning regimen used in transplantation and is closely relevant to donor cells rejection and secondary graft failure. In this article, we briefly have reviewed the current state and future directions for SAA HSCT, and have shared our SAA data and transplant experience of the recent decade. We have analyzed the impact of conditioning regimen on engraftment and chimerism status in SAA transplantation, and have compiled our findings in this report.

A Neural Network With Logical Reasoning Based on Auxiliary Inputs.

This paper describes a neural network design using auxiliary inputs, namely the indicators, that act as the hints to explain the predicted outcome through logical reasoning, mimicking the human behavior of deductive reasoning. Besides the original network input and output, we add an auxiliary input that reflects the specific logic of the data to formulate a reasoning process for cross-validation. We found that one can design either meaningful indicators, or even meaningless ones, when using such auxiliary inputs, upon which one can use as the basis of reasoning to explain the predicted outputs. As a result, one can formulate different reasonings to explain the predicted results by designing different sets of auxiliary inputs without the loss of trustworthiness of the outcome. This is similar to human explanation process where one can explain the same observation from different perspectives with reasons. We demonstrate our network concept by using the MNIST data with different sets of auxiliary inputs, where a series of design guidelines are concluded. Later, we validated our results by using a set of images taken from a robotic grasping platform. We found that our network enhanced the last 1-2% of the prediction accuracy while eliminating questionable predictions with self-conflicting logics. Future application of our network with auxiliary inputs can be applied to robotic detection problems such as autonomous object grasping, where the logical reasoning can be introduced to optimize robotic learning.

Sunitinib Induces NK-κB-dependent NKG2D Ligand Expression in Nasopharyngeal Carcinoma and Hepatoma Cells.

Multitargeted tyrosine kinase inhibitors (MTKIs) have been shown to combine with natural killer (NK) cell adoptive transfer for the treatment in various cancers. MTKIs sensitize cancer cells to NK cell therapy through upregulation of nature killer group 2 member D ligands (NKG2DLs) on tumor cells. However, the molecular mechanism of MTKIs-mediated upregulation of NKG2DLs is still unknown. In this study, we confirmed sunitinib induced downregulation of its targets, such as vascular endothelial growth factor, platelet-derived growth factor, and c-kit in multiple-drug-resistant nasopharyngeal carcinoma cell line CNE2/DDP and hepatoma cell line HepG2. Then, we further showed sunitinib induced cell proliferation inhibition, apoptosis, and DNA damage in CNE2/DDP and HepG2 cells. Coculture experiments showed that sunitinib-treated CNE2/DDP and HepG2 cells were able to increase the activation and cytotoxicity of NK cells. Quantitative polymerase chain reaction results showed that sunitinib upregulated NKG2DLs, apoptotic genes, DNA damage repair genes, and nuclear factor (NF)-κß family genes. Silencing of NF-κß1, NF-κß2, or RelB (NF-κß pathway) inhibited sunitinib-induced upregulation of NKG2DLs. Taken together, we concluded that sunitinib upregulated NKG2DLs through NF-κß signaling noncanonical pathway which might mediate higher cytotoxic sensitivity of CNE2/DDP and HepG2 cells to NK cells.