Synergy of Immunostimulatory Genetherapy with Immune Checkpoint Blockade Motivates Immune Response to Eliminate Cancer

Normalizing the tumor-induced immune deficiency in the immunosuppressive tumor microenvironment (TME) through increasing the efficient infiltration and activation of antitumoral immunity in TME is the core of promising immunotherapy. Herein, a Cyclo(Arg-Gly-Asp-d -Phe-Lys) (RGD) peptides-modified combinatorial immunotherapy system based on the self-assembly of the nanoparticles named RGD-DMA composed of RGD-PEG-PLA, methoxy poly(ethylene glycol)-poly(lactide) (MPEG-PLA) and 1,2-Dioleoyl-3-trimethylammonium-propane (DOTAP) is used to codeliver the immunostimulatory chemokine CCL19-encoding plasmid DNA (CCL19 pDNA) and immune checkpoint ligand PD-L1 inhibitor (BMS-1). The RGD-DMA/pCCL19-BMS-1 system not only exhibited significant inhibition of tumor progression but also induced locally high concentrations of immunostimulatory cytokines at tumor sites without causing an obviously systemic inflammatory response. The immunosuppressive TME is efficaciously reshaped by the coadministration of RGD-DMA/pCCL19 and BMS-1, as indicated by the activated T lymphocytes, increased intratumoral-infiltration of mature dendritic cells (DCs), and the repolarization of macrophages from pro-tumoral M2-phenotype toward tumoricidal M1-phenotype. The upregulated PD-L1 expression at tumor sites caused by the increased IFN-γ levels after immunostimulatory gene therapy further demonstrated the synergistic effects of BMS-1 in counteracting the inhibitory role of PD-L1 expression in antitumor immunity. Therefore, the combination of immunostimulating therapy and immune checkpoint inhibitor that synergistically target multiple immune regulatory pathways demonstrates significant potential as a novel immunotherapy approach.     

Learn from the past – sequentially one-to-one video deblurring network

With the growing availability of hand-held cameras in recent years, more and more images and videos are taken at any time and any place. However, they usually suffer from undesirable blur due to camera shake or object motion in the scene. In recent years, a few modern video deblurring methods are proposed and achieve impressive performance. However, they are still not suitable for practical applications as high computational cost or using future information as input. To address the issues, we propose a sequentially one-to-one video deblurring network (SOON) which can deblur effectively without any future information. It transfers both spatial and temporal information to the next frame by utilizing the recurrent architecture. In addition, we design a novel Spatio-Temporal Attention module to nudge the network to focus on the meaningful and essential features in the past. Extensive experiments demonstrate that the proposed method outperforms the state-of-the-art deblurring methods, both quantitatively and qualitatively, on various challenging real-world deblurring datasets. Moreover, as our method deblurs in an online manner and is potentially real-time, it is more suitable for practical applications.     

Smart-microstructures of composites for electrical contacts with frameless packing of Cr and W in copper

W₄₅Cu₅₅, Cr₆₅Cu₃₅, and Cr₃₂W₁₄Cu₅₄ alloys were obtained in order to study the mechanism of “smart response” of the structure of these alloys when using them as arc-resistant circuit-breakers. These alloys differ from industrial ones with frameless packing of Cr and W phases in the copper matrix. The alloy production method is based on the infiltration of copper melt into a mixture of non-compacted Cr and W powders under vibration exposure (80 Hz). The research results show an increase in the arc resistance of contacts when changing from “frame” packing of W to “frameless,” as well as the decisive role of Cr in the processes of self-dispersion of arc-resistant phases and passivation of W and Cu. Based on the obtained results, conclusions are drawn about the advantage of frameless packing of arc-resistant phases in copper and the reasons for the “smart behavior” of the structure of Cr-containing contacts in response to functional loads in the presence of oxygen and an inert atmosphere.     

Microstructure,tribological behavior and magnetic properties of Fe−Ni−TiO2 composite coatings synthesized via pulse frequency variation

The Fe−Ni−TiO₂ nanocomposite coatings were electrodeposited by pulse frequency variation. The results showed that the nanocomposite with a very dense coating surface and a nanocrystalline structure was produced at higher frequencies. By increasing the pulse frequency from 10 to 500 Hz, the iron and TiO₂ nanoparticles contentswere increased in expense of nickel content. XRD patterns showed that by increasing the frequency to 500 Hz, an enhancement ofBCC phase was observed and the grain size of deposits was reduced to 35 nm. The microhardness and the surface roughness were increased to 647 HV and 125 nm at 500 Hz due to the grain size reduction and higher incorporation of TiO₂ nanoparticles into the Fe−Ni matrix (5.13 wt.%). Moreover, the friction coefficient and wear rate values were decreased by increasing the pulse frequency;while the saturation magnetization and coercivity values of the composite deposits were increased.     

Studies on waterline corrosion processes and corrosion product characteristics of carbon steel in 3.5 wt% NaCl solution

The waterline corrosion behaviors of carbon steel partially immersed in a 3.5 wt% NaCl solution were investigated using the wire beam electrode technique, and the effects of corrosion products on the processes of waterline corrosion were analyzed. The results demonstrated that the initial stage and development stage of waterline corrosion were mainly controlled by the concentration and diffusion of dissolved oxygen, respectively, and the deceleration stage of waterline corrosion was mainly affected by corrosion products. The main component of the yellow corrosion products was γ-FeOOH, and γ-FeOOH that exhibited a high reduction reactivity could be involved in the cathodic reaction. The black corrosion products were mainly composed of Fe₃O₄ with strong thermodynamic stability and the processes of dissolved oxygen diffusion and ion transports were obviously affected due to the continuous accumulation of Fe₃O₄ on the surface of the electrodes. Polarity reversals were observed on the single electrodes below the waterline, but the reasons for the phenomena were different from each other.     

CNBP Binds and Unfolds In Vitro G-Quadruplexes Formed in the SARS-CoV-2 Positive and Negative Genome Strands

The Coronavirus Disease 2019 (COVID-19) pandemic has become a global health emergency with no effective medical treatment and with incipient vaccines. It is caused by a new positive-sense RNA virus called severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2). G-quadruplexes (G4s) are nucleic acid secondary structures involved in the control of a variety of biological processes including viral replication. Using several G4 prediction tools, we identified highly putative G4 sequences (PQSs) within the positive-sense (+gRNA) and negative-sense (−gRNA) RNA strands of SARS-CoV-2 conserved in related betacoronaviruses. By using multiple biophysical techniques, we confirmed the formation of two G4s in the +gRNA and provide the first evidence of G4 formation by two PQSs in the −gRNA of SARS-CoV-2. Finally, biophysical and molecular approaches were used to demonstrate for the first time that CNBP, the main human cellular protein bound to SARS-CoV-2 RNA genome, binds and promotes the unfolding of G4s formed by both strands of SARS-CoV-2 RNA genome. Our results suggest that G4s found in SARS-CoV-2 RNA genome and its negative-sense replicative intermediates, as well as the cellular proteins that interact with them, are relevant factors for viral genes expression and replication cycle, and may constitute interesting targets for antiviral drugs development.     

42CrMo钢加热过程中的奥氏体晶粒尺寸演变

通过金相试验方法测定42CrMo钢在890~930 ℃下保温10~240 min后的晶粒尺寸。结果表明,42CrMo钢在加热到试验温度890~930 ℃时已经完全奥氏体化,保温过程中的晶粒生长属于正常生长;加热温度对晶粒尺寸的影响较大,保温时间对晶粒尺寸的影响较小;随保温时间的延长晶粒生长缓慢,晶粒尺寸与保温时间满足指数小于1的函数关系。基于试验数据,通过线性回归得到晶粒长大的Beck模型参数,通过非线性回归得到Sellars和Anelli模型参数,3个模型的预测精度都较好,而Anelli模型的适用性要高于Beck模型和Sellars模型,故在预测42CrMo钢的奥氏体晶粒长大规律时宜使用Anelli模型。     

风机主轴锻件锻后热处理工艺优化

通过对42CrMo4风机主轴结构尺寸、性能要求、材质特点等方面进行分析,对原有锻后热处理工艺进行优化,制定出既能达到锻后热处理效果又经济节能的工艺参数。     

Novel KCND3 Variant Underlying Nonprogressive Congenital Ataxia or SCA19/22 Disrupt KV4.3 Protein Expression and K+ Currents with Variable Effects on Channel Properties

KCND3 encodes the voltage-gated potassium channel K_V4.3 that is highly expressed in the cerebellum, where it regulates dendritic excitability and calcium influx. Loss-of-function K_V4.3 mutations have been associated with dominant spinocerebellar ataxia (SCA19/22). By targeted NGS sequencing, we identified two novel KCND3 missense variants of the K_V4.3 channel: p.S347W identified in a patient with adult-onset pure cerebellar syndrome and p.W359G detected in a child with congenital nonprogressive ataxia. Neuroimaging showed mild cerebellar atrophy in both patients. We performed a two-electrode voltage-clamp recording of K_V4.3 currents in Xenopus oocytes: both the p.G345V (previously reported in a SCA19/22 family) and p.S347W mutants exhibited reduced peak currents by 50%, while no K+ current was detectable for the p.W359G mutant. We assessed the effect of the mutations on channel gating by measuring steady-state voltage-dependent activation and inactivation properties: no significant alterations were detected in p.G345V and p.S347W disease-associated variants, compared to controls. K_V4.3 expression studies in HEK293T cells showed 53% (p.G345V), 45% (p.S347W) and 75% (p.W359G) reductions in mutant protein levels compared with the wildtype. The present study broadens the spectrum of the known phenotypes and identifies additional variants for KCND3-related disorders, outlining the importance of SCA gene screening in early-onset and congenital ataxia.     

Sintering behavior of Ni–Zn ferrite powders prepared by molten-salt synthesis

Ni_0.5Zn_0.5Fe₂O₄ powders were prepared by a novel molten-salt synthesis method. The effects of calcination processes of the powders on their sintering behaviors were investigated. Compared with the synthesis by traditional solid-state reaction, the proposed molten-salt method can significantly reduce the synthesis temperature of Ni_0.5Zn_0.5Fe₂O₄ from 800 to 550°C below, and the prepared powders have relatively high sintering activity at low temperature, which can thus decrease the sintering temperature. However, the abnormal growth of grains is easy to occur during sintering, thus resulting in uneven grain size. In particular, during the molten-salt synthesis, the holding time for calcination is a dominant factor affecting the activity and crystallization degree of the resultant powders. From the point of view of increasing the density of sintered bodies, the optimal conditions for synthesizing Ni_0.5Zn_0.5Fe₂O₄ powder by the proposed molten-salt synthesis is 400°C for 6 h. In addition, the saturate magnetization of the finally obtained ferrite ceramics has nothing to do with the preparation processes, while their coercivity depends on their densification and grain size caused by their different processing routes.