2022 Chinese expert consensus and guidelines on clinical management of toxicity in anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma

Adoptive cellular immunotherapy with chimeric antigen receptor(CAR)T cells has emerged as a novel modality for treating relapsed and/or refractory B-cell non-Hodgkin lymphoma(B-NHL).With increasing approval of CAR T-cell products and advances in CAR T cell therapy,CAR T cells are expected to be used in a growing number of cases.However,CAR T-cell-associated toxicities can be severe or even fatal,thus compromising the survival benefit from this therapy.Standardizing and studying the clinical management of these toxicities are imperative.In contrast to other hematological malignancies,such as acute lymphoblastic leukemia and multiple myeloma,anti-CD19 CAR T-cell-associated toxicities in B-NHL have several distinctive features,most notably local cytokine-release syndrome(CRS).However,previously published guidelines have provided few specific recommendations for the grading and management of toxicities associated with CAR T-cell treatment for B-NHL.Consequently,we developed this consensus for the prevention,recognition,and management of these toxicities,on the basis of published literature regarding the management of anti-CD19 CAR T-cell-associated toxicities and the clinical experience of multiple Chinese institutions.This consensus refines a grading system and classification of CRS in B-NHL and corresponding measures for CRS management,and delineates comprehensive principles and exploratory recommendations for managing anti-CD19 CAR T-cell-associated toxicities in addition to CRS.

Epigenetic modification associated with climate regulates betulin biosynthesis in birch

The Betula genus contains pentacyclic triterpenoid betulin known for its environmental adaptation and medicinal properties.However,the mechanisms underlying betulin biosynthesis responding to climate change remain unclear.In this study,the role of epigenetic modification(DNA methylation) in betulin biosynthesis was examined and how climatic factors influence it.Whole-genome bisulfite sequencing was performed for greenhouse-grown Chinese white birch(Betula platyphylla Sukaczev) treated with DNA methylation inhibitor zebularine(ZEB) and a natural birch population in Northeast China.ZEB treatment significantly affected the CHH methylation level of transposable elements and betulin content in a hormesis dose-dependent manner.The methylation and expression of bHLH9,a key transcriptional factor controlling betulin biosynthesis,were also consistently affected by ZEB treatment as a hormetic dose-response.In the natural population,there was a positive correlation between promoter methylation of bHLH9 and summer precipitation,while winter temperature was negatively correlated.Thus climate-dependent methylation of bHLH9 regulates the expression of downstream genes involved in betulin biosynthesis.This study highlights the role of environmental signals to induce epigenetic changes that result in betulin production,possibly helping to develop resilient plants to combat ongoing climate change and enhance secondary metabolite production.

An Overview of Sequential Approximation in Topology Optimization of Continuum Structure

This paper offers an extensive overview of the utilization of sequential approximate optimization approaches in the context of numerically simulated large-scale continuum structures.These structures,commonly encountered in engineering applications,often involve complex objective and constraint functions that cannot be readily expressed as explicit functions of the design variables.As a result,sequential approximation techniques have emerged as the preferred strategy for addressing a wide array of topology optimization challenges.Over the past several decades,topology optimization methods have been advanced remarkably and successfully applied to solve engineering problems incorporating diverse physical backgrounds.In comparison to the large-scale equation solution,sensitivity analysis,graphics post-processing,etc.,the progress of the sequential approximation functions and their corresponding optimizersmake sluggish progress.Researchers,particularly novices,pay special attention to their difficulties with a particular problem.Thus,this paper provides an overview of sequential approximation functions,related literature on topology optimization methods,and their applications.Starting from optimality criteria and sequential linear programming,the other sequential approximate optimizations are introduced by employing Taylor expansion and intervening variables.In addition,recent advancements have led to the emergence of approaches such as Augmented Lagrange,sequential approximate integer,and non-gradient approximation are also introduced.By highlighting real-world applications and case studies,the paper not only demonstrates the practical relevance of these methods but also underscores the need for continued exploration in this area.Furthermore,to provide a comprehensive overview,this paper offers several novel developments that aim to illuminate potential directions for future research.

Microstructure evolution of AZ91 alloy processed by a combination method of equal channel angular pressing and rolling

In the present work,AZ91 alloy was successfully processed by equal channel angular pressing(ECAP)for up to 16 passes and rolling(R)for multiple passes with a total reduction of 75%in addition to a combination method with ECAP plus rolling(ECAP+R).The effects of various processes(ECAP,R and ECAP+R)on microstructure evolution were analyzed and the influence of ECAP process on the rolling performance was examined.The result shows that ECAP contributed to a homogenous grain structure and formed a texture with higher Schmidt factors that was easy for rolling.A plate with smoother surface and reduced edge cracks was observed in the ECAP+R process than in the single R process.Although the microstructure of the alloy was similar after ECAP+R and R process,the sample of ECAP+R was more refined and had stronger second phase precipitation than the sample of R,which resulted in better rolling characteristics,along with the external surfaces.

Analysis of genetic diversity and differentiation of artificial populations of yellowhorn(Xanthoceras sorbifolium) in China using ISSR markers

Yellowhorn （Xanthoceras sorbifolium Bunge） is a drought-tolerant tree in the family Sapindaceae that is native to northeastern China. Its remarkably oil-rich seeds are a reliable biodiesel source. An inter simple sequence repeat （ISSR） analysis showed genetic variation among four artificial populations in China： two in Inner Mongolia （IM）, one in Liaoning （LN）, and one in Shandong （SD）. The average percentage of polymorphic loci was 81.25 % for these four populations. The Forest Farm in SD showed the highest number of effective alleles （Ne）, Shannon index （I）, and expected heterozygosity （He）, i.e., 1.598, 0.470, and 0.325, respectively, but the lowest number of alleles （Na） as 1.600. Based on an analysis of molecular variance, 23 % of the total genetic variation was found among populations, and 77 % within populations. A principal coordinate analysis revealed two groups （Group 1： Lindonglinchang, Jianping Agriculture Research Station and Forest Farm; Group 2： Jinjilinchang）. Understanding the genetic diversity among artificial yellowhorn populations in China, detected using ISSRs, will be useful for yellowhorn conservation and improvement. Additional arti-ficial and natural populations need to be included in the future for a country-wide perspective.

Characterization and potential diagnostic application of monoclonal antibodies specific to rabies virus

Objective：Rabies is invariably a fatal encephalomyelitis that is considered to be a serious public health problem.It is necessary to develop standard rabies virus diagnostic tools,especially for diagnosing the strains prevalent in China.Methods：Monoclonal antibodies（MAbs）specific to rabies virus were produced and characterized by enzyme linked immunosorbent assay（ELISA）,isotyping,affinity assay,immunofluorescence assay（IFA）,and immunocytochemistry.The MAb,whose affinity was higher for antigen,was used to establish an antigen captureELISA（AC-ELISA）detection system and test the efficiency by using clinical samples.Results：The heavy chain subclasses of two MAbs were all determined to be IgG2a.The 3C7 MAb showed stronger reactivity with rabies virus protein than the 2C5 MAb in an ELISA analysis,whereas the 3C7 MAb showed the highest affinity for antigen.IFA and immunocytochemistry results also indicated that the two MAbs could recognize rabies virus protein in its native form in cell samples.Data obtained using clinical samples showed that rabies virus could be detected by AC-ELISA detection system using the 3C7 MAb.Conclusion：It was potentially useful for the further development of highly sensitive,easily handled,and relatively rapid detection kits/tools for rabies surveillance in those areas where rabies is endemic,especially in China.

A novel cold-inducible promoter,PThCAP from Tamarix hispida,confers cold tolerance in transgenic Arabidopsis thaliana

Our previous studies have revealed that the Th CAP gene plays a vital role in transgenic Populus(P.davidiana 9 P.bolleana) in response to cold stress.However,the regulatory mechanism of Th CAP gene expression has been unclear.In this study,the 50 flanking region of the Th CAP promoter(PTh CAP) was cloned using a genomewalking method.By analyzing cis-acting regulatory elements of PTh CAP,a DRE motif and MYC and MYB elements were found to be located in the promoter.To identify the regulatory elements that control the expression of the Th CAP gene promoter,a series of deletion derivatives ofPTh CAP,P1–P5,from the translation start code(-1538,-1190,-900,-718 and-375 bp),were fused to the GUS reporter gene,and then each deletion was stably introduced into Arabidopsis thaliana plants.Deletion analysis of the promoter suggested that only the P2 fragment had strong GUS expression in leaves and roots of A.thaliana exposed to low temperature stress.These results suggest that this290-bp region(-1190 to-900 bp),as an important part in PTh CAP,was associated with cold tolerance of A.thaliana.Our results provide evidence for the regulatory mechanism of Th CAP gene involved in the response to cold stress,and that the gene is promising candidate gene for genetic improvement of crops.

Four-wave mixing in silicon-nanocrystal embedded high-index doped silica micro-ring resonator

A nonlinear integrated optical platform that allows the fabrication of waveguide circuits with different material composition,and at small dimensions,offers advantages in terms of field enhancement and increased interaction length,thereby facilitating the observation of nonlinear optics effects at a much lower power level.To enhance the nonlinearity of the conventional waveguide structure,in this work,we propose and demonstrate a microstructured waveguide where silicon rich layer is embedded in the core of the conventional waveguide in order to increase its nonlinearity.By embedding a 20 nm thin film of silicon nanocrystal(Si-nc),we achieve a twofold increase of the nonlinear parameter,γ.The linear relationship between the fourwave mixing conversion efficiency and pump power reveals the negligible nonlinear absorption and small dispersion in the micro-ring resonators.This simple approach of embedding an ultra-thin Si-nc layer into conventional high-index doped silica dramatically increases its nonlinear performance,and could potentially find applications in all-optical processing functions.

真实世界遗传学高危的急性髓系白血病患者临床结局分析

目的:观察标准化疗诱导的预后不良组急性髓系白血病(acute myeloid leukemia,AML)的临床特征。方法:回顾性分析南方医科大学珠江医院2016年1月至2020年12月收治的98例首个疗程使用标准方案化疗的预后不良组AML患者的临床和实验室资料。结果:预后不良组AML患者中位年龄为37(18~67)岁,其中男性占61.2%。复杂核型(30.0%)、+8(20.0%)、单体核型(18.9%)是最常见的细胞遗传学异常,FLT3-ITD(34.1%)、ASXL1(20.5%)、RUNX1(15.9%)、DNMT3A(15.9%)、TET2(15.9%)是最常见的基因突变,其首疗程完全缓解率为37.8%。中位总生存期(median overall survival,m OS)和中位无事件生存期(median event-free survival,mEFS)分别是17个月和6个月,中位无复发生存期(median relapse-free survival,mRFS)为12个月。移植方面,有55例患者进行了异基因造血干细胞移植,中位随访16个月,m OS尚未达到,显著高于未移植组的9个月(P<0.001)。移植后1年及2年累积复发率分别是22.7%及31.8%,1年的非复发死亡率为15.8%。此外,对于34例首个疗程诱导后评估为未缓解的患者,不同方案的治疗效果比较显示:CAG±去甲基化药物方案相较于标准“3+7”方案具有更高的再诱导完全缓解率(77.8%vs.23.1%;P=0.027)。结论:预后不良组AML患者缓解率低,复发率高,生存期短。对于首疗程诱导化疗效果较差的预后不良组AML,CAG联合去甲基化药物是一种可考虑的再诱导方案。

CircPTEN-MT from PTEN regulates mitochondrial energy metabolism

Phosphatase and tensin homolog(PTEN)is a multifunctional gene involved in a variety of physiological and pathological processes.Circular RNAs(circRNAs)are generated from back-splicing events during mRNA processing and participate in cell biological processes through binding to RNAs or proteins.However,PTEN-related circRNAs are largely unknown.Here,we report that circPTEN-mitochondria(MT)(hsa_circ_0002934)is a circular RNA encoded by exons 3,4,and 5 of PTEN and is a critical regulator of mitochondrial energy metabolism.CircPTEN-MT is localized to mitochondria and physically associated with leucine-rich pentatricopeptide repeat-containing protein(LRPPRC),which regulates posttranscriptional gene expression in mitochondria.Knocking down circPTEN-MT reduces the interaction of LRPPRC and steroid receptor RNA activator(SRA)stem-loop interacting RNA binding protein(SLIRP)and inhibits the polyadenylation of mitochondrial mRNA,which decreases the mRNA level of the mitochondrial complex I subunit and reduces mitochondrial membrane potential and adenosine triphosphate production.Our data demonstrate that circPTEN-MT is an important regulator of cellular energy metabolism.This study expands our understanding of the role of PTEN,which produces both linear and circular RNAs with different and independent functions.

Design and test of the plant-correcting reel for harvesting lodging garlic plants

Crops are prone to lodging with the decline of stem moisture and the intervention of other factors in the mature harvest period,such as garlic,which is difficult to harvest mechanically.To solve this problem,the plant-correcting reel for harvesting lodging garlic plants,bumped and deformed with plants many times to pull and lift them into a conveyor,is proposed in this study.We analyzed the motion trajectory equation and key influencing factors of the reel and defined the lifting and plant-correcting stages as three processes of contact,stirring and release.For example,the contact deformation model and system energy equations were established in the contact process.Besides,in the stirring process,the garlic plant-correcting conditions were established through the dynamic simulation test analysis of garlic seedling trajectories and the deflection model of garlic stem was constructed.Furthermore,in the release process,the expressions of rubber bars rotation and garlic plant offset bending curvature were constructed and the optimal number and distribution form of bars were determined.Meanwhile,the mechanism and key operating parameters of the auxiliary lifting mechanism of the divider were established.Through the single-factor test,the influence of reel speed,forward speed and reel height on the success feeding rate was analyzed under different bars distribution forms;Through multi-factor experiments,the interaction contour map of various factors was constructed.When reel speed,forward speed and reel height were 3 rad/s,3.5 m/s,and 540 mm,the feeding success rate was 98.73%.The optimization factors were tested and verified,which met the operational requirements of a high feeding success rate and low loss rate of garlic harvest.This study combines laboratory virtual as well as field experiments and analyzes of trajectory of bars,contact deformation and deflection model of garlic plant,and reel rotation and garlic plant offset bending curvature to solve the problem of garlic lodging mechanized harvest and yield reduction.

Role of hydrogen peroxide in stress-induced programmed cell death during somatic embryogenesis in Fraxinus mandshurica

We examined how reactive oxygen species, in the form of hydrogen peroxide (H2O2), affect osmotic stress–induced programmed cell death during somatic embryogenesis from cotyledon explants of Manchurian ash (Fraxinus mandshurica Rupr.). We found that substantial osmotic stress was essential for Manchurian ash somatic cells to obtain embryogenic competence. The explant cells displayed hallmarks of programmed cell death, chromatin condensation, and DNA fragmentation to oligonucleotides during somatic embryogenesis. Increasing concentrations of plant growth regulators and sucrose in the medium increased osmotic stress thereby inducing H2O2 accumulation in the explant cells. We found that H2O2 concentration was significantly decreased in explant cells when the induction medium was modified, i.e., when reducing the concentration of sucrose, which reduces the osmotic pressure of the medium, or by withdrawing plant growth regulators at mid-culture. These treatments also decreased the proportion of explant cells undergoing programmed cell death. Accordingly, a decreased rate of somatic embryo induction was observed. These results show that PCD occurred during tissue browning and death of some explant cells during somatic embryogenesis in F. mandshurica. The ROS contributed to PCD in abiotic stress stimulated F. mandshurica cells.

The efficacy of NP11-4-derived immunotoxin scFv-artesunate in reducing hepatic fibrosis inducedby Schistosoma japonicum in mice

Schistosomiasis is one of the most prevalent parasitic diseases in China, and hepatic fibrosis caused by schistosome infection is the principal cause of death. The aim of this study was to evaluate the efficacy of NPll-4- derived immunotoxin scFv-artesunate on Schistosoma japonicum-induced hepatic fibrosis. A single-chain variable fragment （scFv） was generated from the murine anti-Schistosoma japonicum （S. japanicum） monoclonal antibody NP11-4. The scFv was expressed as a soluble protein and purified by Ni-affinity chromatography. After conjuga- tion with artesunate, the binding ability with soluble egg antigens （SEA） was determined by an enzyme-linked immunosorbent assay （ELISA）. The biological activity of purified scFv, scFv-artesunate （immunotoxin）, and artesunate was detected in vivo. Image-Pro Plus software was used to analyze the size of egg granuloma and the extent of liver fibrosis. The recombinant scFv expession vector was constructed and expressed successfully. After purification by a His-trap Ni-affinity column, the scFv yield was approximately 0.8 mg/L of culture medium. ELISA results showed that chemical conjugation did not affect the binding activity of the immunotoxin. Our animal experiments indicated that the immunotoxin could significantly reduce the size of egg granuloma in the liver and inhibit hepatic fibrosis. The immunotoxin could be used as a promising candidate in the targeted therapy of S. .japonicum-induced hepatic fibrosis.

C60 Fullerenes Suppress Reactive Oxygen Species Toxicity Damage in Boar Sperm

We report the carboxylated C60 improved the survival and quality of boar sperm during liquid storage at 4°C and thus propose the use of carboxylated C60 as a novel antioxidant semen extender supplement.Our results demonstrated that the sperm treated with 2μg mL?1 carboxylated C60 had higher motility than the control group(58.6%and 35.4%,respectively;P?0.05).Moreover,after incubation with carboxylated C60 for 10 days,acrosome integrity and mitochondrial activity of sperm increased by 18.1%and 34%,respectively,compared with that in the control group.Similarly,the antioxidation abilities and adenosine triphosphate levels in boar sperm treated with carboxylated C60 significantly increased(P?0.05)compared with those in the control group.The presence of carboxylated C60 in semen extender increases sperm motility probably by suppressing reactive oxygen species(ROS)toxicity damage.Interestingly,carboxylated C60 could protect boar sperm from oxidative stress and energy deficiency by inhibiting the ROS-induced protein dephosphorylation via the cAMP-PKA signaling pathway.In addition,the safety of carboxylated C60 as an alternative antioxidant was also comprehensively evaluated by assessing the mean litter size and number of live offspring in the carboxylated C60 treatment group.Our findings confirm carboxylated C60 as a novel antioxidant agent and suggest its use as a semen extender supplement for assisted reproductive technology in domestic animals.

Design and Optimization of Planting Process Parameters for 2ZYX-2 Type Green Onion Ditching and Transplanting Machine

Considering the current low level of mechanization for domestic green onion planting and the high labor intensity of artificial planting,a 2ZYX-2 green onion ditching and transplanting machine,which can complete ditching,ridging,transplanting,repression,soil covering and other operations,is designed in this study.The Central Composite test design method was carried out with the speed of the transplanting machine,the depth of the opener and the horizontal position of the opener as the experimental factors and with the qualification ratio of perpendicularity,the variation coefficient of the plant spacing and the qualification ratio of the planting depth as the test index.Through the analysis of the model interaction and response surface,the change laws that the influence the machine’s forward speed,the depth of the opener and the horizontal position of the opener were studied.The regression model was optimized by Design-Expert 8.0.6 software,and the accuracy of the predicted results was verified by experiments.The optimal working parameters showed that the forward speed of the machine was 0.06 m/s,the depth of the opener was 102 mm,and the horizontal position of the opener was 29 mm.Under conditions of optimal working parameters,the qualification rate of the verticality was 86.83%,the coefficient of variation for the plant spacing was 2.77,and the pass rate of planting depth was 88.26%.The research related to the thesis can provide a reference for the mechanized planting of green onion,which is of great significance to the cost-effectiveness of the green onion industry.

Identifying candidate genes and patterns of heat-stress response in rice using a genome-wide association study and transcriptome analyses

Because high temperatures impair rice production,it is desirable to elucidate the regulatory mechanisms involved in rice response to heat stress.The objectives of this study were to identify candidate genes and characterize their response patterns during rice adaptation to high temperatures at the seedling stage.Ten heat-associated quantitative-trait loci were identified in a genome-wide association study.Comparison of transcript abundances in heat-sensitive and heat-tolerant rice pools under heat stress revealed approximately 400 differentially expressed genes.The expression of genes from heatsensitive accessions changed more than those from heat-tolerant accessions under heat stress.Alternative splicing(AS)events responded to heat stress in rice.The types of AS variants significant different between the heat-sensitive and heat-tolerant accessions.Expression patterns differing between the heat-sensitive and heat-tolerant accessions were identified for genes known to be involved in heat stress.We identified eleven genes associated with rice heat stress response.These genes could be pyramided to breed heat-tolerant rice accessions.

Athermal third harmonic generation in micro‐ring resonators

Nonlinear high-harmonic generation in micro-resonators is a common technique used to extend the operating range of applications such as self-referencing systems and coherent communications in the visible region.However,the generated high-harmonic emissions are subject to a resonance shift with a change in temperature.We present a comprehensive study of the thermal behavior induced phase mismatch that shows this resonance shift can be compensated by a combination of the linear and nonlinear thermo-optics effects.Using this model,we predict and experimentally demonstrate visible third harmonic modes having temperature dependent wavelength shifts between−2.84 pm/ºC and 2.35 pm/ºC when pumped at the L-band.Besides providing a new way to achieve athermal operation,this also allows one to measure the thermal coefficients and Q-factor of the visible modes.Through steady state analysis,we have also identified the existence of stable athermal third harmonic generation and experimentally demonstrated orthogonally pumped visible third harmonic modes with a temperature dependent wavelength shift of 0.05 pm/ºC over a temperature range of 12ºC.Our findings promise a configurable and active temperature dependent wavelength shift compensation scheme for highly efficient and precise visible emission generation for potential 2f–3f self-referencing in metrology,biological and chemical sensing applications.

A Novel Feature Aggregation Approach for Image Retrieval Using Local and Global Features

The current deep convolution features based on retrievalmethods cannot fully use the characteristics of the salient image regions.Also,they cannot effectively suppress the background noises,so it is a challenging task to retrieve objects in cluttered scenarios.To solve the problem,we propose a new image retrieval method that employs a novel feature aggregation approach with an attention mechanism and utilizes a combination of local and global features.The method first extracts global and local features of the input image and then selects keypoints from local features by using the attention mechanism.After that,the feature aggregation mechanism aggregates the keypoints to a compact vector representation according to the scores evaluated by the attention mechanism.The core of the aggregation mechanism is to allow features with high scores to participate in residual operations of all cluster centers.Finally,we get the improved image representation by fusing aggregated feature descriptor and global feature of the input image.To effectively evaluate the proposedmethod,we have carried out a series of experiments on large-scale image datasets and compared them with other state-of-the-art methods.Experiments show that this method greatly improves the precision of image retrieval and computational efficiency.

Spatial relation between fluctuating wall pressure and near-wall streamwise vortices in wall bounded turbulent flow

A new view of the spatial relation between fluctuating wall pressure and near-wall streamwise vortices （NWSV） is proposed for wall bounded turbulent flow by use of the direct numerical simulation （DNS） database. The results show that the wall region with low pressure forms just below the strong NWSV, which is mostly associated with the overhead NWSV. The wall region with high pressure forms downstream of the NWSV, which has a good correspondence with the downwash of the fluids induced by the upstream NWSV. The results provide a significant basis for the detection of NWSV.

Junctional Pacemaker May Replace the Sinoatrial Node

Junctional rhythm is usually seen in the clinic with different causes.We report a case of bicuspid aortic valve accompa-nied by sinoatrial node dysfunction.The junctional escape beat could accelerate with physiological needs and provided for the normal needs of daily life when dysfunction of the sinoatrial node occurred,which provides a new way for the treatment of sinoatrial node dysfunction.Our fi ndings could be potentially signifi cant for identifying causes and choos-ing appropriate treatment strategies by using ECG monitoring in the clinic in the future.