Abstract
In recent years, immunotherapy represented by immune checkpoint inhibitors (ICIs) has led to unprecedented breakthroughs in cancer treatment. However, the fact that many tumors respond ...poorly or even not to ICIs, partly caused by the absence of tumor-infiltrating lymphocytes (TILs), significantly limits the application of ICIs. Converting these immune “cold” tumors into “hot” tumors that may respond to ICIs is an unsolved question in cancer immunotherapy. Since it is a general characteristic of cancers to resist apoptosis, induction of non-apoptotic regulated cell death (RCD) is emerging as a new cancer treatment strategy. Recently, several studies have revealed the interaction between non-apoptotic RCD and antitumor immunity. Specifically, autophagy, ferroptosis, pyroptosis, and necroptosis exhibit synergistic antitumor immune responses while possibly exerting inhibitory effects on antitumor immune responses. Thus, targeted therapies (inducers or inhibitors) against autophagy, ferroptosis, pyroptosis, and necroptosis in combination with immunotherapy may exert potent antitumor activity, even in tumors resistant to ICIs. This review summarizes the multilevel relationship between antitumor immunity and non-apoptotic RCD, including autophagy, ferroptosis, pyroptosis, and necroptosis, and the potential targeting application of non-apoptotic RCD to improve the efficacy of immunotherapy in malignancy.
Soft robots have unique advantages over traditional rigid robots and have broad application prospects in many fields, such as pipe inspections. Several of the reported pipe-crawling soft robots have ...long actuation periods and small locomotion speeds. Moreover, they lack active steering property to adapt to complex piping systems, such as T-shaped pipes. To solve the above problems, this paper proposes a novel parallel-pipe-crawling pneumatic soft robot consisting of three extensible pneumatic soft actuators and two flexible feet. The parallel structure and flexible feet allow the robot to reduce the number of steps in a crawling cycle. The extensible actuator allows the robot to change its body shape for active steering property. However, a complete mathematical model for soft robots with parallel structure is hard to establish. In this paper, the phenomenological modeling method is used to realize a mathematical model with high precision, limited calculation, and easy engineering applicability of the pipe-crawling soft robot. Then, the prototype of the robot is fabricated with the optimal structural parameters selected by finite element simulations. The static identification experiment shows that the average errors of the extended length and output force are 0.51 mm and 0.28 N, respectively. The crawling experiments in various scenarios show that the horizontal crawling speed is higher than 15 mm/s, the maximum load is 2.456 kg, and the minimum turning radius is 38.2 mm. The robot shows great potential for inspecting in complex pipes with high crawling efficiency, excellent flexibility, and strong adaptability by switching its crawling gaits.
The endocrine hormone fibroblast growth factor 21 (FGF21) is a powerful modulator of glucose and lipid metabolism and a promising drug for type 2 diabetes. Here we identify FGF21 as a potent ...regulator of skeletal homeostasis. Both genetic and pharmacologic FGF21 gain of function lead to a striking decrease in bone mass. In contrast, FGF21 loss of function leads to a reciprocal high-bone-mass phenotype. Mechanistically, FGF21 inhibits osteoblastogenesis and stimulates adipogenesis from bone marrow mesenchymal stem cells by potentiating the activity of peroxisome proliferator-activated receptor γ (PPAR-γ). Consequently, FGF21 deletion prevents the deleterious bone loss side effect of the PPAR-γ agonist rosiglitazone. Therefore, FGF21 is a critical rheostat for bone turnover and a key integrator of bone and energy metabolism. These results reveal that skeletal fragility may be an undesirable consequence of chronic FGF21 administration.
Background Human reproduction depends on the fusion of a mature oocyte with a sperm cell to form a fertilized egg. The genetic events that lead to the arrest of human oocyte maturation are unknown. ...Methods We sequenced the exomes of five members of a four-generation family, three of whom had infertility due to oocyte meiosis I arrest. We performed Sanger sequencing of a candidate gene, TUBB8, in DNA samples from these members, additional family members, and members of 23 other affected families. The expression of TUBB8 and all other β-tubulin isotypes was assessed in human oocytes, early embryos, sperm cells, and several somatic tissues by means of a quantitative reverse-transcriptase-polymerase-chain-reaction assay. We evaluated the effect of the TUBB8 mutations on the assembly of the heterodimer consisting of one α-tubulin polypeptide and one β-tubulin polypeptide (α/β-tubulin heterodimer) in vitro, on microtubule architecture in HeLa cells, on microtubule dynamics in yeast cells, and on spindle assembly in mouse and human oocytes. Results We identified seven mutations in the primate-specific gene TUBB8 that were responsible for oocyte meiosis I arrest in 7 of the 24 families. TUBB8 expression is unique to oocytes and the early embryo, in which this gene accounts for almost all the expressed β-tubulin. The mutations affect chaperone-dependent folding and assembly of the α/β-tubulin heterodimer, disrupt microtubule behavior on expression in cultured cells, alter microtubule dynamics in vivo, and cause catastrophic spindle-assembly defects and maturation arrest on expression in mouse and human oocytes. Conclusions TUBB8 mutations have dominant-negative effects that disrupt microtubule behavior and oocyte meiotic spindle assembly and maturation, causing female infertility. (Funded by the National Basic Research Program of China and others.).
Background:
Baicalin (BCL), a candidate drug for ischemic stroke, has been indicated to protect neurons by promoting brain-derived neurotrophic factor (BDNF). However, the cellular source of BDNF ...release promoted by baicalin and its detailed protective mechanism after ischemia/reperfusion remains to be studied. The aim of this study was to investigate the neuroprotective mechanisms of baicalin against oxygen–glucose deprivation/reoxygenation (OGD/R) in a neuron–astrocyte coculture system and to explore whether the BDNF-TrkB pathway is involved.
Methods and Results:
A neuron–astrocyte coculture system was established to elucidate the role of astrocytes in neurons under OGD/R conditions. The results demonstrated that astrocytes became reactive astrocytes and released more BDNF in the coculture system to attenuate neuronal apoptosis and injury after OGD/R. BCL maintained the characteristics of reactive astrocytes and obviously increased the expression of cyclic AMP response element-binding protein (CREB) and the levels of BDNF in the coculture system after OGD/R. To further verify whether BDNF binding to its receptor tyrosine kinase receptor B (TrkB) was required for the neuroprotective effect of baicalin, we examined the effect of ANA-12, an antagonist of TrkB, on NA system injury, including oxidative stress, inflammation, and apoptosis induced by OGD/R. The results showed that treatment of NA systems with ANA-12 significantly attenuated the neuroprotection of BCL. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathways are two important downstream cascades of signaling pathways activated by BDNF binding to TrkB. We investigated the expressions of TrkB, PI3K, Akt, MAPK, and ERK. The results demonstrated that baicalin significantly increased the expressions of TrkB, PI3K/AKT, and MAPK/ERK.
Conclusion:
The neuroprotective effects of baicalin against oxidative stress, inflammation, and apoptosis were improved by astrocytes, mainly mediated by increasing the release of BDNF and its associated receptor TrkB and downstream signaling regulators PI3K/Akt and MAPK/ERK1/2.
La2O3/Bi2O3 photocatalysts were prepared by impregnation of Bi2O3 with an aqueous solution of lanthanum precursor followed by calcination at different temperatures. The composite materials were used ...for the first time for the photocatalytic removal of Hg0 from a simulated flue gas under UV light irradiation. The results showed that the sample containing 6 wt.% La2O3 and calcined at 500°C has the highest dispersion of the active sites, which was promoted by the strong interaction with the support (i.e., the formation of Bi-O-La species). Since they are fully accessible on the surface, the material also exhibits excellent optical properties while the heterojunction formed in La2O3/Bi2O3 promotes the separation and migration of photoelectron-hole pairs and thus Hg0 oxidation efficiency is enhanced. The effects of the various factors (e.g., the reaction temperature and composition of the simulated flue gas (i.e., O2, NO, H2O, and SO2)) on the efficiency of the Hg0 photocatalytic oxidation were investigated. The results demonstrated that O2 and SO2 enhanced the efficiency of the reaction while the reaction temperature, NO, and H2O had an inhibitory effect.
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It has been suggested that a vascular-like cell has multipotent regenerative and mesenchymal lineage relationships. The identity of this stem/progenitor cell has remained elusive. We report here that ...adult central nervous system (CNS) capillaries contain a distinct population of microvascular cells, the pericyte that are nestin/NG2 positive and in response to basic fibroblast growth factor (bFGF) differentiate into cells of neural lineage. In their microvascular location, pericytes express nestin and NG2 proteoglycan. In serum containing media primary (0 to 7 day old) CNS pericytes are nestin positive, NG2 positive, alpha smooth muscle actin (αSMA) positive, and do not bind the endothelial cell specific griffonia symplicifolia agglutinin (GSA). In serum containing media, pericytes do not undergo neurogenesis but are induced to express αSMA. In bFGF containing media without serum, CNS pericytes form small clusters and multicellular spheres. Differentiated spheres expressed neuronal and glial cell markers. After disruption and serial dilution, differentiated spheres were capable of self-renewal. When differentiated spheres were disrupted and cultured in the presence of serum, multiple adherent cell populations were identified by dual and triple immunocytochemistry. Cells expressing markers characteristic of pericytes, neurons, and glial cells were generated. Many of the cells exhibited dual expression of differentiation markers. With prolonged culture fully differentiated cells of neural lineage were present. Results indicate that adult CNS microvascular pericytes have neural stem cell capability.
This paper focuses on vessel detection through the fusion of synthetic aperture radar (SAR) images acquired from spaceborne–airborne collaborative observations. The vessel target detection task ...becomes more challenging when it features inshore interferences and structured and shaped targets. We propose a new method, based on target proposal and polarization information exploitation (TPPIE), to fuse the spaceborne–airborne collaborative SAR images for accurate vessel detection. First, a new triple-state proposal matrix (TSPM) is generated by combining the normed gradient-based target proposal and the edge-based morphological candidate map. The TSPM can be used to extract the potential target regions, as well as filtering out the sea clutter and inshore interference regions. Second, we present a new polarization feature, named the absolute polarization ratio (APR), to exploit the intensity information of dual-polarization SAR images. In the APR map, the vessel target regions are further enhanced. Third, the final fused image with enhanced targets and suppressed backgrounds (i.e., improved target-to-clutter ratio; TCR) is attained by taking the Hadamard product of the intersected TSPM from multiple sources and the composite map exploiting the APR feature. Experimental analyses using Gaofen-3 satellite and unmanned aerial vehicle (UAV) SAR imagery indicate that the proposed TPPIE fusion method can yield higher TCRs for fused images and better detection performance for vessel targets, compared to commonly used image fusion approaches.
A hyper-redundant flexible manipulator is characterized by high degree(s) of freedom (DoF), flexibility, and environmental adaptability. It has been used for missions in complex and unknown spaces, ...such as debris rescue and pipeline inspection, where the manipulator is not intelligent enough to face complex situations. Therefore, human intervention is required to assist in decision-making and control. In this paper, we designed an interactive navigation method based on mixed reality (MR) of a hyper-redundant flexible manipulator in an unknown space. A novel teleoperation system frame is put forward. An MR-based interface was developed to provide a virtual model of the remote workspace and virtual interactive interface, allowing the operator to observe the real-time situation from a third perspective and issue commands to the manipulator. As for environmental modeling, a simultaneous localization and mapping (SLAM) algorithm based on an RGB-D camera is applied. Additionally, a path-finding and obstacle avoidance method based on artificial potential field (APF) is introduced to ensure that the manipulator can move automatically under the artificial command in the remote space without collision. The results of the simulations and experiments validate that the system exhibits good real-time performance, accuracy, security, and user-friendliness.
HCN was removed by the combined action of catalytic hydrolysis and catalytic oxidation on the Mn/TiO2-Al2O3 catalyst. Mn was mainly present in the form of Mn2+, Mn3+, and Mn4+ on the surface of ...catalyst and chemisorbed oxygen played a major role in the HCN catalytic oxidation process. During the reaction, part of NH3 was adsorbed by Brönsted and Lewis acid sites. NH3 adsorbed on Lewis acid sites participated in NH3-SCR, which reduced the amount of NOx produced and resulted in a high N2 yield.
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•The Mn/TiO2-Al2O3 catalyst synthesized by sol–gol method was used to remove HCN.•The maximum yield of N2 was 68.02% without the participation of water vapor.•NH3 comes from the decomposition of HCN adsorbed on Lewis acid sites resulted in a high N2 yield.
The manganese-modified titania-alumina (Mn/TiO2-Al2O3) catalyst synthesized by sol–gol method was used to remove hydrogen cyanide (HCN) from simulated flue gas. Further, effects of the mass ratios of Ti/Al, Mn loading, calcination temperature, and relative humidity on HCN conversion efficiency and catalytic activity were systematically investigated. The results indicated that the Mn/TiO2-Al2O3 catalyst exhibited significantly enhanced HCN removal efficiency, and the maximum yield of N2 increased to 68.02% without the participation of water vapor. When water vapor was added into the flue gas, the yield of N2 decreased and the formation of NOx was also inhibited. The XRD and XPS results indicated that Mn was mainly present in the form of Mn2+, Mn3+, and Mn4+ on the surface of catalyst and chemisorbed oxygen played a major role in the HCN catalytic oxidation process. The results of DSC-TGA analysis and H2-TPR indicated that the catalyst also exhibited a good thermal and chemical stability. NH3-TPD and CO2-TPD indicated that the surface of the catalyst mainly contained acidic sites. During the reaction, part of NH3 was adsorbed by Brönsted and Lewis acid sites. NH3 adsorbed on Lewis acid sites participated in NH3-SCR, which reduced the amount of NOx produced and resulted in a high N2 yield.
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