Hydroxy-Rich Covalent Organic Framework for the Efficient Catalysis of the Cycloaddition of CO2.

The cycloaddition of CO2 with epoxides to cyclic carbonates is one of the most promising and green pathways for CO2 utilization, and the development of highly efficient catalysts remains a challenge. In this work, a novel hydroxy-rich covalent organic framework (TFPB-DHBD-COF) was synthesized, and it served as an efficient heterogeneous catalyst for the reaction of CO2 with 1,2-epoxybutane under mild conditions, providing the desired products in 90% conversion. The abundant hydroxy groups in the pore channels of TFPB-DHBD-COF could not only activate epoxides and CO2 via hydrogen bonding but also obviously enhance its stability through intramolecular five-membered ring hydrogen bonding. Thus, this COF also exhibited outstanding stability and tolerance for diverse substrates. Undoubtedly, this work has enriched the application of tailored COFs in the activation and utilization of CO2.

Dynamic immunogenicity after primary and booster inactivated SARS-CoV-2 vaccination in people living with HIV: A longitudinal observational study.

People living with HIV (PLWH) have poor outcomes from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); vaccination reduces the associated mortality. The humoral immune response dynamics after booster inactivated vaccinations in PLWH remain unclear. In this longitudinal observational study, 100 PLWH after primary inactivated SARS-CoV-2 vaccination were consecutively recruited and followed up. After booster vaccination (BV), neutralizing antibodies (NAbs) were detected at 1 month from all the PLWH, and the titer increased sixfold compared to that associated with the primary vaccination (PV), similar to that in healthy controls after BV. The NAbs titer declined over time after BV, but remained higher at 6 months than after PV. The NAbs response was elevated after BV with CD4 count <200 cells/µL, it was the poorest among the different CD4 cell count subgroups. Similar results were observed for anti-RBD-IgG responses. Moreover, RBD-specific MBCs were significantly elevated after BV in PLWH. No serious AEs were observed after BV in PLWH. In conclusion, booster inactivated SARS-CoV-2 vaccination is well tolerated and can elicit robust and durable humoral responses in PLWH. PLWH may benefit from a third dose of the inactivated vaccine.

A Survey of Transoral Robotic Mechanisms: Distal Dexterity, Variable Stiffness, and Triangulation.

Robot-assisted technologies are being investigated to overcome the limitations of the current solutions for transoral surgeries, which suffer from constrained insertion ports, lengthy and indirect passageways, and narrow anatomical structures. This paper reviews distal dexterity mechanisms, variable stiffness mechanisms, and triangulation mechanisms, which are closely related to the specific technical challenges of transoral robotic surgery (TORS). According to the structure features in moving and orienting end effectors, the distal dexterity designs can be classified into 4 categories: serial mechanism, continuum mechanism, parallel mechanism, and hybrid mechanism. To ensure adequate adaptability, conformability, and safety, surgical robots must have high flexibility, which can be achieved by varying the stiffness. Variable stiffness (VS) mechanisms based on their working principles in TORS include phase-transition-based VS mechanism, jamming-based VS mechanism, and structure-based VS mechanism. Triangulations aim to obtain enough workspace and create adequate traction and counter traction for various operations, including visualization, retraction, dissection, and suturing, with independently controllable manipulators. The merits and demerits of these designs are discussed to provide a reference for developing new surgical robotic systems (SRSs) capable of overcoming the limitations of existing systems and addressing challenges imposed by TORS procedures.

BAX as the mediator of C-MYC sensitizes acute lymphoblastic leukemia to TLR9 agonists.

BACKGROUND: The prognosis of B-cell acute lymphoblastic leukemia (B-ALL) has improved significantly with current first-line therapy, although the recurrence of B-ALL is still a problem. Toll-like receptor 9 (TLR9) agonists have shown good safety and efficiency as immune adjuvants. Apart from their immune regulatory effect, the direct effect of TLR9 agonists on cancer cells with TLR9 expression cannot be ignored. However, the direct effect of TLR9 agonists on B-ALL remains unknown. METHODS: We discussed the relationship between TLR9 expression and the clinical characteristics of B-ALL and explored whether CpG 685 exerts direct apoptotic effect on B-ALL without inhibiting normal B-cell function. By using western blot, co-immunoprecipitation, immunofluorescence co-localization, and chromatin immunoprecipitation, we explored the mechanism of the apoptosis-inducing effect of CpG 685 in treating B-ALL cells. By exploring the mechanism of CpG 685 on B-ALL, the predictive biomarkers of the efficacy of CpG 685 in treating B-ALL were explored. These efficiencies were also confirmed in mouse model as well as clinical samples. RESULTS: High expression of TLR9 in B-ALL patients showed good prognosis. C-MYC-induced BAX activation was the key to the effect of CpG oligodeoxynucleotides against B-ALL. C-MYC overexpression promoted P53 stabilization, enhanced Bcl-2 associated X-protein (BAX) activation, and mediated transcription of the BAX gene. Moreover, combination therapy using CpG 685 and imatinib, a BCR-ABL kinase inhibitor, could reverse resistance to CpG 685 or imatinib alone by promoting BAX activation and overcoming BCR-ABL1-independent PI3K/AKT activation. CONCLUSION: TLR9 is not only a prognostic biomarker but also a potential target for B-ALL therapy. CpG 685 monotherapy might be applicable to Ph- B-ALL patients with C-MYC overexpression and without BAX deletion. CpG 685 may also serve as an effective combinational therapy against Ph+ B-ALL.

CircRNA and miRNA expression analysis in livers of mice with Toxoplasma gondii infection.

Toxoplasmosis is an important zoonotic parasitic disease caused by Toxoplasma gondii (T. gondii). However, the functions of circRNAs and miRNAs in response to T. gondii infection in the livers of mice at acute and chronic stages remain unknown. Here, high-throughput RNA sequencing was performed for detecting the expression of circRNAs and miRNAs in livers of mice infected with 20 T. gondii cysts at the acute and chronic stages, in order to understand the potential molecular mechanisms underlying hepatic toxoplasmosis. Overall, 265 and 97 differentially expressed (DE) circRNAs were found in livers at the acute and chronic infection stages in comparison with controls, respectively. In addition, 171 and 77 DEmiRNAs were found in livers at the acute and chronic infection stages, respectively. Functional annotation showed that some immunity-related Gene ontology terms, such as "positive regulation of cytokine production", "regulation of T cell activation", and "immune receptor activity", were enriched at the two infection stages. Moreover, the pathways "Valine, leucine, and isoleucine degradation", "Fatty acid metabolism", and "Glycine, serine, and threonine metabolism" were involved in liver disease. Remarkably, DEcircRNA 6:124519352|124575359 was significantly correlated with DEmiRNAs mmu-miR-146a-5p and mmu-miR-150-5p in the network that was associated with liver immunity and pathogenesis of disease. This study revealed that the expression profiling of circRNAs in the livers was changed after T. gondii infection, and improved our understanding of the transcriptomic landscape of hepatic toxoplasmosis in mice.

Multiscale Transcriptomic Integration Reveals B-Cell Depletion and T-Cell Mistrafficking in Nasopharyngeal Carcinoma Progression.

Nasopharyngeal carcinoma (NPC), featured by Epstein-Barr virus (EBV) infection and regional epidemiology, is curable when detected early, but highly lethal at an advanced stage. The molecular mechanism of NPC progression toward a clinically uncontrollable stage remains elusive. In this study, we developed a novel computational framework to conduct multiscale transcriptomic analysis during NPC progression. The framework consists of four modules enabling transcriptomic analyses spanning from single-cell, bulk, microenvironment, to cohort scales. The bulk-transcriptomic analysis of 133 NPC or normal samples unraveled leading functional enrichments of cell-cycle acceleration, epithelial-mesenchymal transition, and chemokine-modulated inflammatory response during NPC progression. The chemokine CXCL10 in the NPC microenvironment, discovered by single-cell RNA sequencing data analysis, recruits cytotoxic T cells through interacting with its receptor CXCR3 at early but late stages. This T-cell mistrafficking was featured by the decline of cytotoxic T cells and the increase of regulatory T cells, accompanied with B-cell depletion confirmed by immunohistochemistry staining. The featured immunomodulatory chemokines were commonly upregulated in the majority of cancers associated with viral or bacterial infections.

Posttransplant blockade of CXCR4 improves leukemia complete remission rates and donor stem cell engraftment without aggravating GVHD.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a promising therapeutic option for hematological malignancies, but relapse resulting predominantly from residual disease in the bone marrow (BM) remains the major cause of treatment failure. Using immunodeficient mice grafted with laboratory-generated human B-ALL, our previous study suggested that leukemia cells within the BM are resistant to graft-versus-leukemia (GVL) effects and that mobilization with CXCR4 antagonists may dislodge leukemia cells from the BM, enabling them to be destroyed by GVL effects. In this study, we extended this approach to patient-derived xenograft (PDX) and murine T-ALL and AML models to determine its clinical relevance and effects on GVHD and donor hematopoietic engraftment. We found that posttransplant treatment with the CXCR4 antagonist AMD3100 significantly improved the eradication of leukemia cells in the BM in PDX mice grafted with B-ALL cells from multiple patients. AMD3100 also significantly improved GVL effects in murine T-ALL and AML models and promoted donor hematopoietic engraftment in mice following nonmyeloablative allo-HCT. Furthermore, posttransplant treatment with AMD3100 had no detectable deleterious effect related to acute or chronic GVHD. These findings provide important preclinical data supporting the initiation of clinical trials exploring combination therapy with CXCR4 antagonists and allo-HCT.

A Flexible Transoral Robot Towards COVID-19 Swab Sampling.

There are high risks of infection for surgeons during the face-to-face COVID-19 swab sampling due to the novel coronavirus's infectivity. To address this issue, we propose a flexible transoral robot with a teleoperated configuration for swab sampling. The robot comprises a flexible manipulator, an endoscope with a monitor, and a master device. A 3-prismatic-universal (3-PU) flexible parallel mechanism with 3 degrees of freedom (DOF) is used to realize the manipulator's movements. The flexibility of the manipulator improves the safety of testees. Besides, the master device is similar to the manipulator in structure. It is easy to use for operators. Under the guidance of the vision from the endoscope, the surgeon can operate the master device to control the swab's motion attached to the manipulator for sampling. In this paper, the robotic system, the workspace, and the operation procedure are described in detail. The tongue depressor, which is used to prevent the tongue's interference during the sampling, is also tested. The accuracy of the manipulator under visual guidance is validated intuitively. Finally, the experiment on a human phantom is conducted to demonstrate the feasibility of the robot preliminarily.

Cadaveric feasibility study of a teleoperated parallel continuum robot with variable stiffness for transoral surgery.

Robot-assisted technologies are overcoming the limitations of the current approaches for transoral surgeries, which are suffering from limited vision and workspace. As a result, we develop a novel teleoperated parallel continuum robot with variable stiffness for collision avoidance. This paper focuses on the feasibility study on a cadaveric model for the robotic system as a first trial. We introduce the configuration of the robotic system, the description of the processes of the trial, including the setting of the robotic system, the test of stiffness, and the action of the manipulation. The contact force between the manipulators with different stiffness and the surrounding tissues and a series of surgical operations of the manipulator, including grasping, cutting, pushing, and pulling tissues under the master-slave control mode, were recorded and analyzed. Experimental results suggest that the typical surgical procedure on a cadaveric model was successfully performed. Moreover, the efficacy and feasibility of the developed robotic system are verified to satisfy the requirements of transoral robotic surgery (TORS). Graphical abstract.

A Compliant Transoral Surgical Robotic System Based on a Parallel Flexible Mechanism.

Transoral robotic surgery (TORS) allows for access to oropharyngeal regions in an effective and minimally invasive manner. However, safe TORS access to deep pharyngeal (such as hypopharynx) sites remains a great challenge for current surgical robotic systems. In this work, we introduce a novel continuum robot with an optimized flexible parallel mechanism, to meet stringent requirements imposed by TORS on size, workspace, flexibility, and compliance. The system is comprised of two parts, a guidance part and an execution part, and achieves 11 controllable degrees of freedom. The execution part of the robot, based on the optimized flexible parallel mechanism, is able to reach deep sites in the oropharynx and larynx with the assistance of the continuum guidance part. In addition to the mechanical design, extensive analysis and experiments were carried out. Kinematic models were derived and the reachable workspace of the robot was verified to cover the entire target surgical area. Experimental results indicate that the robot achieves significantly enhanced compliance. Additionally, the designed robot can withstand a load of 1.5 N within the allowable range of the deflection. The positioning errors caused by the interference between different mechanisms can be effectively eliminated using the proposed compensation method. The maximum displacement error of this system under various conditions is less than 2 mm and the maximum bending error is less than 7.5°, which are satisfied for TORS. Cadaver trials were conducted to further demonstrate the feasibility. The reduced setup time and the reduced time to access the target site indicate that the developed surgical robotic system can achieve better operative efficiency in TORS when compared with current systems.

Stretchable Graphene Pressure Sensors with Shar-Pei-like Hierarchical Wrinkles for Collision-Aware Surgical Robotics.

Stretchable skin-like pressure sensing with minimized and distinguishable strain-induced interference is essential for the development of collision-aware surgical robotics to improve the safety and efficiency of minimally invasive surgery in a confined space. Inspired by the multidimensional wrinkles of Shar-Pei dog's skin for tactile sensing, we developed a stretchable pressure sensor consisting of reduced graphene oxide (rGO) electrodes with biomimetic topographies to improve the robot-tissue collision detections. A facile fabrication route for stretchable rGO electrodes was first demonstrated by harnessing the surface instability during the sequential deformation processes. The wrinkle-crumple rGO electrodes exhibited high stretchability (∼100%) and strain-insensitive resistance profiles [a gauge factor (GF) < 0.05], which were next utilized to fabricate piezoresistive pressure sensors. The rGO pressure sensors were highly stretchable and exhibited high sensitivity under uniaxial strains (1.37, 1.30, and 0.98 kPa-1 at 0, 30, and 50% stretching states, respectively) along with distinguishable and reduced stretching responsiveness (a small GF ∼0.2 under 40% strains). The stretchable pressure sensors were next integrated with two surgical robots for the transoral robotic surgery procedure. During the cadaveric testing, the rGO sensors can detect the robot-tissue contacts under joint stretches in real time to enhance the surgeon's awareness for collision avoidance. The stretchable rGO pressure sensor that is highly sensitive under large strains provides great potential in the fields of wearable sensing and collision-aware humanoid robots to improve the human-machine interactions.

Multilateral Teleoperation With New Cooperative Structure Based on Reconfigurable Robots and Type-2 Fuzzy Logic.

This paper develops an innovative multilateral teleoperation system with two haptic devices on the master side and a newly designed reconfigurable multi-fingered robot on the slave side. A novel nonsingular fast terminal sliding-mode algorithm, together with varying dominance factors for cooperation, is proposed to offer this system's fast position and force tracking, as well as an integrated perception for the operator on the reconfigurable slave robot (manipulator). The Type-2 fuzzy model is used to describe the overall system dynamics, and accordingly a new fuzzy-model-based state observer is proposed to compensate for system uncertainties. A sliding-mode adaptive controller is designed to deal with the varying zero drift of the force sensors and force observers. The stability of the closed-loop system under time-varying delays is proved using Lyapunov-Krasovskii functions. Finally, experiments to grasp different objects are performed to verify the effectiveness of this multilateral teleoperation system.

Molecular targeting of VEGF/VEGFR signaling by the anti-VEGF monoclonal antibody BD0801 inhibits the growth and induces apoptosis of human hepatocellular carcinoma cells in vitro and in vivo.

Hepatocellular carcinoma (HCC) is the third-leading cause of cancer-related deaths with 750,000 newly diagnosed cases each year. Surgery, radiotherapy, and chemotherapy constitute the main treatment modalities for HCC, but liver cirrhosis and damage often occur. Molecular targeted drugs have been recently developed to treat HCC. Vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) autocrine signaling is closely related to the growth, progression, and metastasis of HCC, making the VEGF/VEGFR axis an ideal target for the development of molecular targeted agents. Here, we report the effects of the novel anti-VEGF humanized monoclonal antibody BD0801 on the growth of HCC cells in vitro and in vivo as well as the underlying mechanisms. BD0801 significantly inhibited the proliferation of HepG2, SMMC-7721, and Bel7402 cells in vitro, accompanied with an induction of apoptosis and cell cycle arrest at the G1 phase. BD0801 potently suppressed AKT, Erk1/2, and retinoblastoma (Rb) phosphorylation, while increasing p21 and decreasing cyclin D1 protein levels. BD0801 significantly inhibited growth in mouse tumor xenografts and induced cell apoptosis of HepG2 and SMMC-7721 tumor xenografts. Furthermore, BD0801 effectively reduced the vascular density and tumor tissue microvessel density (MVD). Similarly, BD0801 decreased AKT, Erk1/2, and Rb phosphorylation and cyclin D1 expression whereas it increased p21 protein expression in mouse HCC tumor xenografts. Importantly, BD0801 showed a better effect than Bevacizumab (Bev) on the inhibition of cell growth and induction of apoptosis in HCC cells in vitro and in vivo. These findings suggest that BD0801 is a potent anti-VEGF monoclonal antibody for the treatment of HCC.

Fasting Glucose Levels Correlate with Disease Severity of Guillain-Barré Syndrome.

OBJECTIVE: A potential association between diabetes and Guillain-Barré syndrome (GBS) has been indicated by a few case studies. We retrospectively analyzed the clinical features of a large cohort of GBS patients to explore the relationship between the level of fasting plasma glucose (FPG) obtained in the acute phase at admission and the severity of GBS. METHODS: Three hundred and four GBS patients were divided into two groups, one with normal FPG and the other with high FPG levels according to the international standards of FPG. RESULTS: The GBS disability scale score was positively, the Medical Research Council (MRC) sum score was negatively correlated to the level of FPG, but not to blood HBA1c or CSF glucose concentrations. A relatively higher FPG level was observed in older and younger GBS patients, and more often in those with cranial nerve involvement, autonomic deficit, dyspnea and ventilator dependence than in patients without these clinical characteristics. Importantly, higher levels of FPG at admission were associated with poorer short-term prognosis measured by the MRC sum score and the GBS disability scale at discharge. CONCLUSIONS: Our data demonstrates that FPG in the acute phase of GBS correlates with the severity of GBS and may predict the short-term prognosis of GBS.

Involvement of 90-kuD ribosomal S6 kinase in collagen type I expression in rat hepatic fibrosis.

AIM: To investigate the relationship between 90-kuD ribosomal S6 kinase (p90RSK) and collagen type I expression during the development of hepatic fibrosis in vivo and in vitro. METHODS: Rat hepatic fibrosis was induced by intraperitoneal injection of dimethylnitrosamine. The protein expression and cell location of p90RSK and their relationship with collagen type I were determined by co-immunofluoresence and confocal microscopy. Subsequently, RNAi strategy was employed to silence p90RSK mRNA expression in HSC-T6, an activated hepatic stellate cell (HSC) line. The expression of collagen type I in HSC-T6 cells was assessed by Western blotting and real-time polymerase chain reaction. Furthermore, HSCs were transfected with expression vectors or RNAi constructs of p90RSK to increase or decrease the p90RSK expression, then collagen type I promoter activity in the transfected HSCs was examined by reporter assay. Lastly HSC-T6 cells transfected with p90RSK siRNA was treated with or without platelet-derived growth factor (PDGF)-BB at a final concentration of 20 microg/L and the cell growth was determined by MTS conversion. RESULTS: In fibrotic liver tissues, p90RSK was over-expressed in activated HSCs and had a significant positive correlation with collagen type I levels. In HSC-T6 cells transfected with RNAi targeted to p90RSK, the expression of collagen type I was down-regulated (61.8% in mRNA, P < 0.01, 89.1% in protein, P < 0.01). However, collagen type I promoter activity was not increased with over-expression of p90RSK and not decreased with low expression either, compared with controls in the same cell line (P = 0.076). Furthermore, p90RSK siRNA exerted the inhibition of HSC proliferation, and also abolished the effect of PDGF on the HSC proliferation. CONCLUSION: p90RSK is over-expressed in activated HSCs and involved in regulating the abnormal expression of collagen type I through initiating the proliferation of HSCs.