Quality Control and Nonclinical Research on CAR-T Cell Products: General Principles and Key Issues

Adoptive cell therapy using chimeric antigen receptor T (CAR-T) cells, which is a promising cancer immunotherapy strategy, has been developing very rapidly in recent years. CAR-T cells are genetically modified T cells that can specifically recognize tumor specific antigens on the surface of tumor cells, and then effectively kill tumor cells. At present, exciting results are being achieved in clinical applications of CAR-T cells for patients with hematological malignancies. The research and development of CAR-T cells for various targets and for the treatment of solid tumors have become a hot topic worldwide, so an increasing number of investigational new drug applications (INDAs) and new drug applications (NDAs) of CAR-T cell products are expected to be submitted in future. The quality control and nonclinical research of these products are of great significance in ensuring the safety and effectiveness of these products;however, they also present great challenges and difficulties. This article discusses the general principles of and key issues regarding the quality control and nonclinical research of CAR-T cell products based on their product characteristics and on relevant guidelines for gene and cell therapy products.

Pressure relief of underground ammunition storage under missile accidental ignition

Safety of underground ammunition storage is an important issue,especially during the accidental ignition of missiles.This work investigates the pressure and temperature distribution of the multi-layer underground ammunition storage with a pressure relief duct during the accidental ignition process of the missile.A large-scale experiment was carried out using a multi-layered restricted space with a pressure relief duct to simulate the underground ammunition store and a solid rocket motor to simulate the accidental ignition of the missile.The results show that when the motor gas mass flow increased by5.6 times,the maximum pressure of the ammunition storage increased by 5.87 times.At a certain motor flow rate,when the pressure relief exhaust area at the end of the relief duct was reduced by 1/2,the maximum pressure on the first layer did not change.But the rate of pressure relief was reduced and the time delayed for the pressure of ammunition store to drop to zero.In this experiment,when the motor ignition position was located in to the third layer ammunition chamber,the maximum pressure was reduced by 32.9%and also reduced the rate of change of pressure.In addition,for the experimental conditions,the theoretical analysis of the pressure relief of the ammunition storage is given by a simplified model.Based on the findings,some suggestions to the safety protection design of ammunition store are proposed.

An Overview of Privacy Preserving Schemes for Industrial Internet of Things

The concept of Internet of Everything is like a revolutionary storm,bringing the whole society closer together.Internet of Things(IoT)has played a vital role in the process.With the rise of the concept of Industry 4.0,intelligent transformation is taking place in the industrial field.As a new concept,an industrial IoT system has also attracted the attention of industry and academia.In an actual industrial scenario,a large number of devices will generate numerous industrial datasets.The computing efficiency of an industrial IoT system is greatly improved with the help of using either cloud computing or edge computing.However,privacy issues may seriously harmed interests of users.In this article,we summarize privacy issues in a cloud-or an edge-based industrial IoT system.The privacy analysis includes data privacy,location privacy,query and identity privacy.In addition,we also review privacy solutions when applying software defined network and blockchain under the above two systems.Next,we analyze the computational complexity and privacy protection performance of these solutions.Finally,we discuss open issues to facilitate further studies.

Study on Prediction and Application of Human Body Feeling Temperature

[Objective]The study aimed to forecast human body feeling temperature.[Method]Using air temperature data outside shutter boxes of cement and asphalt underlying surface at 1.5 m and conventional observation data from 2008 to 2010 as well as T639 and Japan numerical forecast product,the characteristics of the minimum temperature in winter half year and the maximum temperature in summer half year in Changzhou were analyzed,and the prediction equation of the maximum temperature from May to September as well as year-round comfort prediction index were established.Moreover,the announcement platform of human body feeling temperature was developed to forecast it.[Result]There remained a tiny discrepancy in the winter minimum temperature between inside and outside shutter box,and days with the minimum temperature difference lower than 2℃accounted for 94.3%of total days.However,the summer maximum temperature difference between inside and outside shutter box was larger,and days with the maximum temperature difference higher than 2℃accounted for 82.0%,while the maximum difference was 5.5℃.The prediction accuracy of the inside maximum temperature was 78%.Wind was considered as the primary factor based on the effective temperature,and comfort index forecast and service were determined based on human feelings,dress,meteorological care and so forth.Both human body feeling temperature and comfort index forecast were released in the temperature forecast service.[Conclusion]The prediction of human body feeling temperature could provide scientific references for people's dress and traveling in daily life.

Theoretical Research on R245fa Condensation Heat Transfer inside a Horizontal Tube

Numerical simulation on R245fa condensation inside an inner diameter of 8 mm horizontal tube is researched in this paper. The effect of variation in velocity, condensation temperature and superheat of inlet steam and variation in cooling water temperature on heat transfer coefficient are investigated as a parametric study. Condensation process of steam has been successfully modeled by applying a user defined function (UDF) added to the commercial computational fluid dynamics (CFD) package. By analyzing the corresponding condensate contours and the curves of local heat transfer coefficient, the relationships between condensation heat transfer coefficient and various parameters of R245fa inside horizontal tube are obtained. It shows that the heat transfer coefficient increases by the increase in velocity, condensation temperature and superheat of inlet steam and the decrease in cooling water temperature. The errors between the heat transfer coefficient of simulation result and model of Wang and Shah are within ±30%. The parametric study will provide the basis for designing efficient heat exchangers of R245fa.

Information behaviors of Chinese K-12physical education teachers:A survey study

Purpose:Given the unique characteristics of physical education(PE) teaching in K-12education,PE teachers' information behaviors deserve special attention.This article reports a survey study of PE teachers' information behaviors,covering information literacy skills and behaviors of information seeking and information use.Design/methodology/approach:A questionnaire survey was conducted of K-12 PE teachers in the Tianjin municipal region of China,with a response rate of 61.9%.Findings:PE teachers lack skills with information retrieval systems in general.The Internet continues to be their primary information source,and they rely more on personal collection and colleagues than the school library for teaching materials.They rarely develop a searching strategy,employ querying tactics,or use advanced search functions,and they tend to be content with finding a few relevant articles.Research limitations:The survey is limited to the Tianjin municipal region in scope.Though attempting to reach 210 participants from 40 schools,it yielded only 130 valid responses.A larger survey covering more regions and with greater responses may be useful.Practical implications:Insights from this study inform the educational and on-job training of K-12 PE teachers to improve their information literacy skills.Originality/value:Little research exists on PE teachers' behaviors of information seeking.This study bridges the gap and enriches our understanding of K-12 teachers' information behaviors.

虫媒病毒感染传播及跨界免疫适应机制

基于第323期“双清论坛”,本文在介绍虫媒病领域的研究背景下,从媒介生物学、虫媒病毒学和病毒—虫媒—宿主互作三个方面梳理了我国在医学、动物及植物虫媒病毒领域的研究进展,涉及病毒感染媒介的分子机制、虫媒病毒的免疫互作机制、病毒跨界传播机制以及虫媒病健康绿色防控的新方法,凝练出该领域亟需解决的关键科学问题,提出我国未来5~10年虫媒病领域的发展目标。

Immunity-and-matrix-regulatory cells enhance cartilage regeneration for meniscus injuries: a phase I dose-escalation trial

Immunity-and-matrix-regulatory cells(IMRCs)derived from human embryonic stem cells have unique abilities in modulating immunity and regulating the extracellular matrix,which could be mass-produced with stable biological properties.Despite resemblance to mesenchymal stem cells(MSCs)in terms of self-renew and tri-lineage differentiation,the ability of IMRCs to repair the meniscus and the underlying mechanism remains undetermined.Here,we showed that IMRCs demonstrated stronger immunomodulatory and pro-regenerative potential than umbilical cord MSCs when stimulated by synovial fluid from patients with meniscus injury.Following injection into the knees of rabbits with meniscal injury,IMRCs enhanced endogenous fibrocartilage regeneration.In the dose-escalating phase I clinical trial(NCT03839238)with eighteen patients recruited,we found that intra-articular IMRCs injection in patients was safe over 12 months post-grafting.Furthermore,the effective results of magnetic resonance imaging(MRI)of meniscus repair and knee functional scores suggested that 5×107 cells are optimal for meniscus injury treatment.In summary,we present the first report of a phase I clinical trial using IMRCs to treat meniscus injury.Our results demonstrated that intra-articular injection of IMRCs is a safe and effective therapy by providing a permissive niche for cartilage regeneration.

Motion equations of hemispherical resonator and analysis of frequency split caused by slight mass non-uniformity

The mass non-uniformity of hemispherical resonator is one of reasons for frequency split,and frequency split can cause gyroscope to drift.Therefore,it is of great significance to analyze the relationship between mass non-uniformity and frequency split,which can provide a theoretical basis for mass balance of imperfect resonator.The starting point of error mechanism analysis for gyroscope is the motion equations of resonator.Firstly,based on the Kirchhoff-Love hypothesis in the elastic thin shell theory,the geometric deformation equations of resonator are deduced.Secondly,the deformation energy equation of resonator is derived according to the vibration mode and relationship between the stress and strain of hemispherical thin shell.Thirdly,the kinetic energy equation of resonator is deduced by the Coriolis theorem.Finally,the motion equations of resonator are established by the Lagrange mechanics principle.The theoretical values of precession factor and natural frequency are calculated by the motion equations,which are substantially consistent with the ones by the finite element method and practical measurement,the errors are within a reasonable range.Simultaneously,the varying trend of natural frequency with respect to the geometrical and physical parameters of resonator by the motion equations is consistent with that by the finite element analysis.The above conclusions prove the correctness and rationality of motion equations.Similarly,the motion equations of resonator with mass non-uniformity are established by the same modeling method in case of ignoring the input angular rate and damping,and the state equations with respect to the velocity and displacement of vibration system are derived,then twonatural frequencies are solved by the characteristic equation.It is concluded that one of reasons for frequency split is the 4 th harmonic of mass non-uniformity,and thus much attention should be paid to minimizing the 4 th harmonic of mass non-uniformity in the course of mass balancing for imperfect resonator.

Designing specific bacterial 16S primers to sequence and quantitate plant endo-bacteriome

Plant endophytic bacteria colonize the internal tissues of plants and interact with plants closely.The past two decades have witnessed the increasing application of next-generation 16S r RNA gene sequencing in the investigation of bacterial communities.However,deciphering plant endo-bacterial communities by this method is difficult because of the co-amplification of massive plant organellar DNAs with bacterial 16S.Here,we designed polymerase chain reaction(PCR) primer sets,including799F/1107R,322F/796R,and 322F-Dr/796Rs(primer pair 322F/796R with a penultimate-base substitution in 322F),that can specifically amplify bacterial 16S from plant total DNAs.We computationally and experimentally evaluated the specificity,coverage,and accuracy of the newly designed primer sets.Both 799F/1107R and 322F-Dr/796Rs produced plant DNA-free 16S amplicon libraries or reduced plant DNA contamination to lower than 5% for the plant materials with extremely-low-abundance bacterial communities.The primer set 322F-A/796R was used through absolute quantitative PCR to quantitate the population size of rice leaf or root endo-bacteriome,which revealed 10^(6)–10^(7) and 10^(9)–10^(10) bacteria per gram fresh weight,respectively.These 16S primer sets and amplification methods enable the simple and inexpensive next-generation sequencing and quantification of plant endo-bacteriome,which will significantly advance studies on the plant-related microbiome.

Simultaneous Determination of Pinoresinol Di-gluco-pyranoside and Pinoresinol Glucoside in Rat Plasma by HPLC-tandem MS/MS for Pharmacokinetic Study

Objective Pinoresinol di-glucopyranoside(PDG) is one of the main active lignans of Eucommiae Cortex considered to be a high-quality antihypertensive drug. In this study the pharmacokinetic process of PDG and its primary in vivo metabolite pinoresinol glucoside(PG) in the portal and jugular vein were surveyed and evaluated simultaneously. Methods A sensitive high-performance liquid chromatography coupled with tandem quadruple mass spectrometry(HPLC-MS/MS) method and sample preparation protocol were developed and validated in method of selectivity, sensitivity, precision, stability, and extraction recovery for the simultaneous determination of PDG and its primary metabolite PG in rat plasma. The double intubation technique was used to simultaneously collect blood from common jugular vein and hepatic portal vein after single ig administration of PDG. Results Using this method, the quantification linearity ranges of PDG and PG in rat plasma were both 0.05-100 ng/mL. This method was successfully applied to the evaluation of the absolute oral bioavailability of PDG and determination of the pharmacokinetic properties of PDG and PG after ig administration of single dose in rats. The bioavailability of PDG at common jugular vein was 51.3% compared to that of 91.6% at hepatic portal vein. Conclusion We conclude that liver is the major conversion site of PDG to PG.

Laodelphax striatellus Atg8 facilitates Rice stripe virus infection in an autophagy-independent manner

Rice stripe virus(RSV)is the causative agent of rice stripe disease and is completely dependent on insect vectors for its plant-to-plant transmission.Laodelphax striatellus is the major insect vector for RSV.In this study,we explored the interactions be-tween RSV infection and L.striatellus autophagy,a potential intrinsic antiviral mechanism in insects.We found that L.striatellus autophagic activity did not affect RSV infection;however,the autophagy related-8(Atg8)gene significantly enhanced virus infection.Dur-ing RSV initial infection within the L.striatellus midgut,silencing of Atg8 expression significantly decreased the phosphorylation of c-Jun N-terminal kinase(p-JNK);however,when RSV infection is absent,silencing of Atg8 did not alter p-JNK levels.Thesc results indicated that Atg8 might activate the JNK machinery by allowing more virus infection into cells.We further revealed that Atg8-deficiency significantly decreased RSV accumu-lation on the surface of the insect midgut epithelial cells,suggesting a receptor trafficking function of the y-aminobutyric acid receptor-associated protein family.Using the RSV ovary entry as a model,in which vitellogenin receptor(V gR)mediates RSV cell entry,we clarified that Atg8-deficiency decreased the abundance of V gR localizing on the cytomem-brane and disturbed the attachment of RSV in the germarium zones.Collectively,these results revealed an autophagy-independent function of L.striatellus Atg8 that enhances RSV initial infection by increasing virus attachment on the infection sites.

A Cross-Layer Cooperative Jamming Scheme for Social Internet of Things

In this paper,we design a friendly jammer selection scheme for the social Internet of Things(IoT).A typical social IoT is composed of a cellular network with underlaying Device-to-Device(D2D)communications.In our scheme,we consider signal characteristics over a physical layer and social attribute information of an application layer simultaneously.Using signal characteristics,one of the D2D gadgets is selected as a friendly jammer to improve the secrecy performance of a cellular device.In return,the selected D2D gadget is allowed to reuse spectrum resources of the cellular device.Using social relationship,we analyze and quantify the social intimacy degree among the nodes in IoT to design an adaptive communication time threshold.Applying an artificial intelligence forecasting model,we further forecast and update the intimacy degree,and then screen and filter potential devices to effectively reduce the detection and calculation costs.Finally,we propose an optimal scheme to integrate the virtual social relationship with actual communication systems.To select the optimal D2D gadget as a friendly jammer,we apply Kuhn-Munkres(KM)algorithm to solve the maximization problem of social intimacy and cooperative jamming.Comprehensive numerical results are presented to validate the performance of our scheme.

Monitoring unbound warfarin in drug combination therapy by pharmacokinetics and fluorospectrometry

Objective: Monitoring the unbound drug concentration in blood in combination therapy is necessary,because its concentration determines the efficacy of drug therapy. This study was designed to explore the effect of Dan Hong Injection(DHI) on the unbound warfarin using two approaches including an in vivo pharmacokinetic and in vitro fluorescence studies.Methods: The effect of DHI on the pharmacokinetic properties of the unbound warfarin was investigated by a microdialysis sampling method coupled with LC–MS/MS. The effect of DHI and salvianolic acid B(Sa B) on warfarin binding with bovine serum albumin(BSA) was conducted by fluorescence spectrometry.Results: The AUC_(0-tn)of warfarin with DHI group was higher than that of warfarin alone group. The result showed that DHI could increase the concentration of unbound warfarin in rat blood, which may be due to the competition between warfarin and DHI as well as its components binding to serum albumin. The competition process was demonstrated by fluorescence study.Conclusion: Combination therapy of DHI with warfarin could enhance the release profile of warfarin from serum protein.

Standing wave drift of hemispherical resonator with quality factor non-uniformity under a ring electrode excitation

Hemispherical Resonator Gyroscope(HRG)is a classical high precision Coriolis Vibration Gyroscope(CVG),which performs attitude estimation of carrier by detecting the precession of standing wave of resonator,thus,the drift of standing wave of resonator has a great influence on the output accuracy of gyroscope,where the quality factor non-uniformity of resonator is one of main error sources.Ring electrode is a classical excitation structure of HRG because the standing wave can precess freely under its excitation,which makes the gyroscope have more accurate scale factor,larger measurement range and better dynamic characteristics.In this paper,the equations of motion of an ideal resonator excited by a ring electrode are derived by the elastic thin shell theory and Lagrange mechanical principle,then the corresponding equivalent mechanical model is established.According to the“average method”,it can be seen that the ideal resonator excited by the ring electrode works in integral mode,and any position in the circumferential direction of resonator can be a working point,which means that the quality factor non-uniformity has a great effect on the drift of standing wave.Therefore,the equations of motion of resonator with quality factor non-uniformity under the ring electrode excitation are deduced by the equivalent mechanical model,and the drift model of standing wave is established by the“average method”,it can be found that both the amplitude of quality factor non-uniformity and angle between the“inherent damping axis”and antinode axis of standing wave can affect the drift rate of standing wave.Moreover,the drift model indicates that if the input angular rate does not reach the threshold,the precession angular rate of standing wave will appear“self-locking”phenomenon,that is,the gyroscope will lose the integral effect.