Glia-to-neuron reprogramming to the rescue?

Over the last two decades,the dogma that cell fate is immutable has been increasingly challenged,with important implications for regenerative medicine.The brea kth rough discovery that induced pluripotent stem cells could be generated from adult mouse fibroblasts is powerful proof that cell fate can be changed.An exciting extension of the discovery of cell fate impermanence is the direct cellular reprogram ming hypothesis-that terminally differentiated cells can be reprogrammed into other adult cell fates without first passing through a stem cell state.

Neurocircuit regeneration by extracellular matrix reprogramming

The brain's extracellular matrix(ECM),which is comprised of protein and glycosaminoglycan(GAG)scaffolds,constitutes 20%-40% of the human brain and is considered one of the largest influencers on brain cell functioning(Soles et al.,2023).Synthesized by neural and glial cells,the brain's ECM regulates a myriad of homeostatic cellular processes,including neuronal plasticity and firing(Miyata et al.,2012),cation buffering(Moraws ki et al.,2015),and glia-neuron interactions(Anderson et al.,2016).Considering the diversity of functions,dynamic remodeling of the brain's ECM indicates that this understudied medium is an active participant in both normal physiology and neurological diseases.

Analysis of Epidemiological Characteristics of Varicella Before and After the Implementation of the Two-dose Varicella Vaccine Immunization Program in Banan District of Chongqing City

Objective:To explore the changes in the epidemiological characteristics of varicella before and after implementing the two-dose varicella vaccine(VarV)immunization program in the Banan District of Chongqing and to provide a reference for future epidemic prevention and control.Methods:The data of reported varicella cases in Banan District from 2014 to 2023 were collected and analyzed using the China Disease Prevention and Control Information System.Descriptive epidemiological methods were employed to assess the changes in the reported incidence of varicella before(2014-2018)and after(2019-2023)the implementation of the two-dose VarV immunization program.Results:The average annual reported incidence rate of varicella in Banan District from 2014 to 2023 was 81.53 per 100,000.From 2014 to 2018,the reported incidence rate showed an upward trend year by year(trend x2=223.96,P<0.05).However,the reported incidence rate decreased from 2019 to 2023(trend x?=189.51,P<0.05).Before and after the adjustment of the immunization program,the reported incidence rate for the 5-9 years old group was 774.62 per 100,000 and 476.98 per 100,000,respectively,with a statistically significant difference(x2=161.26,P<0.05).The onset of varicella showed a bimodal distribution,with peak incidence periods in May-June and October-December.From 2014 to 2023,a total of 155,181 doses of VarV were administered in Banan District.The estimated annual vaccination rate for the first varicella vaccine(VarV1)from 2019 to 2023 was 86.28%,and for the second dose(VarV2)was 59.18%.The primary vaccination targets were the 5-9-year-old group,accounting for 64.21%.Conclusion:After implementing the two-dose VarV immunization program in Banan District,the vaccination rate increased yearly,and the reported incidence of varicella showed a downward trend.The incidence rate of varicella in children aged 5-9 years reduced significantly,but the overall downward trend for the entire population was not as pronounced.Therefore,it is necessary to increase the vaccination rate of VarV2.

Programmed cell death 1 inhibitor sintilimab plus S-1 and gemcitabine for liver metastatic pancreatic ductal adenocarcinoma

BACKGROUND Pancreatic ductal adenocarcinoma(PDAC)is a highly aggressive cancer with poor prognosis.When it metastasizes to the liver,treatment options become particularly limited and challenging.Current treatment options for liver metastatic PDAC are limited,and chemotherapy alone often proves insufficient.Immunotherapy,particularly programmed cell death 1(PD-1)inhibitors like sintilimab,shows potential efficacy for various cancers but has limited reports on PDAC.This study compares the efficacy and safety of sintilimab plus S-1 and gemcitabine vs S-1 and gemcitabine alone in liver metastatic PDAC.AIM To explore the feasibility and effectiveness of combined PD-1 inhibitor sintilimab and S-1 and gemcitabine(combination group)vs S-1 and gemcitabine used alone(chemotherapy group)for treating liver metastatic pancreatic adenocarcinoma.METHODS Eligible patients were those with only liver metastatic PDAC,an Eastern Cooperative Oncology Group performance status of 0-1,adequate organ and marrow functions,and no prior anticancer therapy.Participants in the combination group received intravenous sintilimab 200 mg every 3 weeks,oral S-140 mg/m²twice daily on days 1-14 of a 21-day cycle,and intravenous gemcitabine 1000 mg/m²on days 1 and 8 of the same cycle for up to eight cycles or until disease progression,death,or unacceptable toxicity.Participants in the chemotherapy group received oral S-140 mg/m²twice daily on days 1-14 of a 21-day cycle and intravenous gemcitabine 1000 mg/m²on days 1 and 8 of the same cycle for up to eight cycles.Between June 2020 and December 2021,66 participants were enrolled,with 32 receiving the combination treatment and 34 receiving chemotherapy alone.RESULTS The group receiving the combined therapy exhibited a markedly prolonged median overall survival(18.8 months compared to 10.3 months,P<0.05)and progression-free survival(9.6 months vs 5.4 months,P<0.05).compared to the chemotherapy group.The incidence of severe adverse events did not differ significantly between the two groups(P>0.05).CONCLUSION The combination of PD-1 inhibitor sintilimab with S-1 and gemcitabine demonstrated effectiveness and safety for treating liver metastatic PDAC,meriting further investigation.

Interleukin-17A facilitates tumor progression via upregulating programmed death ligand-1 expression in hepatocellular carcinoma

BACKGROUND Hepatocellular carcinoma(HCC)is an inflammation-associated tumor with a dismal prognosis.Immunotherapy has become an important treatment strategy for HCC,as immunity is closely related to inflammation in the tumor microenvir-onment.Inflammation regulates the expression of programmed death ligand-1(PD-L1)in the immunosuppressive tumor microenvironment and affects im-munotherapy efficacy.Interleukin-17A(IL-17A)is involved in the remodeling of the tumor microenvironment and plays a protumor or antitumor role in different tumors.We hypothesized that IL-17A participates in tumor progression by affe-cting the level of immune checkpoint molecules in HCC.The upregulation of PD-L1 expression in HCC cells by IL-17A was assessed by reverse transcription PCR,western blotting,and flow cytometry.Mechanistic studies were conducted with gene knockout models and pathway inhibitors.The function of IL-17A in immune evasion was explored through coculture of T cells and HCC cells.The effects of IL-17A on the malignant biological behaviors of HCC cells were evaluated in vitro,and the antitumor effects of an IL-17A inhibitor and its synergistic effects with a PD-L1 inhibitor were studied in vivo.RESULTS IL-17A upregulated PD-L1 expression in HCC cells in a dose-dependent manner,whereas IL-17A receptor knockout or treatment with a small mothers against decapentaplegic 2 inhibitor diminished the PD-L1 expression induced by IL-17A.IL-17A enhanced the survival of HCC cells in the coculture system.IL-17A increased the viability,G2/M ratio,and migration of HCC cells and decreased the apoptotic index.Cyclin D1,VEGF,MMP9,and Bcl-1 expression increased after IL-17A treatment,whereas BAX expression decreased.The combination of IL-17A and PD-L1 inhibitors showed synergistic antitumor efficacy and increased cluster of differentiation 8+T lymphocyte infiltration in an HCC mouse model.CONCLUSION IL-17A upregulates PD-L1 expression via the IL-17A receptor/phosphorylation-small mothers against decapenta-plegic 2 signaling pathway in HCC cells.Blocking IL-17A enhances the therapeutic efficacy of PD-L1 antibodies in HCC in vivo.

Ultrastructural Features of Nucleus Degradation During Programmed Cell Death of Starchy Endosperm Cells in Rice

Ultrastructural features of nucleus degradation during programmed cell death (PCD) of starchy endosperm cells in rice ( Oryza sativa L.) were observed using transmission electron microscopy. Several distinct morphological features of PCD have been found in the developing starchy endosperm cells, e.g. nucleus deformation, chromatin condensation, nuclear envelope disruption, and nuclear matrix leakage. DNA ladder displayed a smear of large DNA fragments from nucleus and evident bands of small DNA fragments (140-180 bp) from both nucleus and cytoplasm. In contrast with the rapid nucleus degradation, cell organelles in cytoplasm, such as rough endoplasmic reticulum, amyloplast, and mitochondrion, maintained their metabolic functions for a longer time. Seed reserves were continually synthesized and accumulated in the starchy endosperm cells despite the nucleus degradation during the PCD process. These results suggest that starchy endosperm cells remain active during reserve material synthesis and accumulation in the PCD process. The specific relationships between nucleus and cytoplasm in the developing endosperm cells and the morphological changes of nucleus in the endosperm PCD process were also discussed.

计及DoS攻击和通信时滞的电力系统负荷频率控制

针对电力系统通信网络中存在的时滞和DoS攻击现象,本文提出了基于采样特性的电力系统离散负荷频率控制方案。首先,计及电力系统负荷波动的情况,在多区域电力系统负荷频率控制系统(LFC)模型的基础上,将通信网络中DoS攻击的危害量化为采样信号连续丢失数,并分别考虑通信网络中通信时滞和输出信号采样特性,建立包含输出状态反馈控制器的电力系统LFC模型。其次,基于此模型,利用含有控制命令更新周期、DoS攻击导致的最大采样信号连续丢失数、通信时滞、H_(∞)稳定指标的双边闭环Lyapunov泛函、LMI技术,提出LFC系统满足一定H_(∞)指标的稳定准则,并给出离散状态输出反馈LFC控制器的设计及求解方法。最后,本文以单区域和双区域LFC系统为例进行了仿真验证。结果表明:与已有文献方法相比,本文方法在保持系统H_(∞)渐近稳定前提下,能够容忍更大的通信时滞,且结果的保守性更低;同时可以看出本文所设计的控制器在保证H_(∞)稳定性能的基础上,对一定能量限制的DoS攻击具有弹性的防御性能。因此本文方案的有效性和优越性得到了验证。

外部干扰和随机DoS攻击下的网联车安全H∞队列控制

针对网联车队列系统易受到干扰和拒绝服务(Denial of service, DoS)攻击问题,提出一种外部干扰和随机DoS攻击作用下的网联车安全H∞队列控制方法.首先,采用马尔科夫随机过程,将网联车随机DoS攻击特性建模为一个随机通信拓扑切换模型,据此设计网联车安全队列控制协议.然后,采用线性矩阵不等式(Linear matrix inequality, LMI)技术计算安全队列控制器参数,并应用Lyapunov-Krasovskii稳定性理论,建立在外部扰动和随机DoS攻击下队列系统稳定性充分条件.在此基础上,分析得到该队列闭环系统的弦稳定性充分条件.最后,通过7辆车组成的队列系统对比仿真实验,验证该方法的优越性.

增塑剂DOS在EPDM绝热层中的迁移特性

为了优化丁羟(HTPB)推进剂与三元乙丙橡胶(EPDM)绝热层的应用匹配性,采用浸泡实验、接触实验和复合验证等方法,研究了HTPB推进剂中的增塑剂癸二酸二异辛酯(DOS)向EPDM绝热层迁移的特性及其对绝热层性能的影响规律。结果表明:由于极性相近,DOS容易向EPDM绝热层中发生大量迁移,其初期迁移量较显著且饱和迁移量约为52%;EPDM橡胶的结构参数对绝热层硫化胶的耐DOS迁移特性影响不明显;致密的绝热层交联网络有利于减少DOS在其中的迁移量;绝热层厚度增加时,DOS迁移速率变缓,迁入量减小。HTPB推进剂/HTPB衬层/EPDM绝热层粘接体系复合验证结果表明:在推进剂固化过程中DOS已向绝热层发生迁移,导致绝热层的力学性能和烧蚀性能大幅下降;推进剂固化结束后,绝热层的力学性能下降了55%,线烧蚀率增加了20%;70℃贮存30 d时,力学性能下降超60%,线烧蚀率增加了28%;在EPDM绝热层与HTPB衬层之间设置一层环氧基阻迁移层,可以大幅降低推进剂中的增塑剂DOS在绝热层中的迁移量且能够形成良好粘结。

DoS攻击下多智能体ICPS的最优一致控制

为解决由多个被控对象组成的工业信息物理系统(ICPS)在拒绝服务(DoS)攻击和不确定外界扰动下的一致性控制问题,将多智能体和ICPS相结合,并基于状态观测器和零和博弈方法,设计最优H_(∞)一致控制器。首先,针对多个被控对象组成的ICPS,根据智能体的信息交互特性,构建固定拓扑结构的多智能体ICPS模型。其次,考虑DoS攻击作用在传感器通道和执行器通道时系统通信信道堵塞的影响,采用状态观测器重构被堵塞的状态信息,并构建DoS攻击下基于状态观测器的多智能体ICPS模型。然后,引入干扰抑制水平,并将控制器和干扰者视为零和博弈中的参与者,根据干扰抑制水平的优化目标和H_(∞)性能条件,构建基于零和博弈的最优H_(∞)设计框架。最后,通过对干扰抑制水平的约束,并求解满足H_(∞)一致性的线性矩阵不等式,设计最优一致性控制器。采用4个不间断电源的控制问题作为仿真对象,Matlab仿真结果表明,相比于未对状态重构和未对参数约束的设计方法,本设计方案可使得多智能体ICPS在双通道DoS攻击下达到一致的时间更短,且具有良好的相对稳定性。

Studies on the Programmed Cell Death in Rice During Starchy Endosperm Development

Morphological variations of the nucleus in starchy endosperm cell were observed by theelectron-transmisson microscope during endosperm development in rice. Along with thedevelopment of the starchy endosperm, the nuclei of the cells showed chromatin condensation,the typical feature of programmed cell death (PCD). The nuclei also showed nucleusdeformation, disruption of nuclear envelope, nucleoplasm leaking into the cytoplasm andnucleus disintegration resulting in nuclear residue formation. From the nucleus deformationto the nucleus disintegration, the morphological changes of the nucleus were orderlyprogressive. This indicated that the cell death of starchy endosperm in rice wasprogrammed cell death. Evans Blue staining observation showed that the cell death wasinitially detected in the central part of starchy endosperm in rice, then expandedoutward. The activities of superoxide dismutase (SOD) and catalase (CAT) in rice starchyendosperm both descended continuously as development progressed. The analysis of DNA ofrice starchy endosperm did not show the presence of DNA laddering. The above resultsshowed that the cell death of starchy endosperm in rice was a special form of PCD.

DoS攻击下抛物型多智能体系统的输出反馈领导-跟随一致性

为了解决抛物型多智能体系统(MASs)在拒绝服务(DoS)攻击下的一致性问题,提出了一种基于输出反馈方法的MASs领导-跟随一致性控制协议来应对恶意攻击者发起的DoS攻击,从而实现智能体在无向通信拓扑图上的领导-跟随一致性。对DoS攻击的频率和持续时间进行了分析,利用Lyapunov稳定性定理推导了抛物型偏微分系统的稳定条件,证明了触发时间间隔不为零,避免了芝诺行为的发生,并通过仿真算例验证了理论结果的有效性。

基于联邦学习的无线通信网络DoS攻击检测方法

无线通信网络受到DoS攻击,会使得网络的负载增加,导致延迟增加。而在无线通信网络中,数据通常分散在多个节点上,这会造成数据泄露和被攻击。为此,提出一种基于联邦学习的无线通信网络DoS攻击检测方法。对初始无线通信网络数据进行预处理和归一化,并采用随机森林算法进行降维处理,去除冗余特征,获得最佳网络数据特征集。将特征集输入到以深度卷积神经网络为通用模型的联邦学习训练模型中,独立训练本地模型并进行模型修正,传输至中心服务器进行聚合,收敛后完成训练。利用训练得到的联邦学习模型检测无线通信网络DoS攻击速率,再与接收者接收的容量最大值进行比较,判断是否有DoS攻击。实验结果表明,所提方法在处理大量数据时具有较高的稳定性和可靠性,能够在短时间内准确地检测出DoS攻击。

带DoS攻击补偿的线性离散系统分布式融合滤波器

多传感器网络化线性离散系统的每个传感器基于自己的观测数据可进行局部状态估计。当局部估值被传输给融合中心时,可能遭受DoS(Denial of service)攻击。为了补偿DoS攻击引起的数据丢失,采用丢失数据的预报器进行补偿。应用线性无偏最小方差矩阵加权融合算法获得分布式融合状态滤波器。所提出的分布式融合滤波器改善了局部估计的精度,且比协方差交叉融合算法具有更高的估计精度。仿真例子验证了算法的有效性。

Efficacy and predictive factors of transarterial chemoembolization combined with lenvatinib plus programmed cell death protein-1 inhibition for unresectable hepatocellular carcinoma

BACKGROUND The efficacy and safety of transarterial chemoembolization(TACE)combined with lenvatinib plus programmed cell death protein-1(PD-1)for unresectable hepato-cellular carcinoma(HCC)have rarely been evaluated and it is unknown which factors are related to efficacy.AIM To evaluate the efficacy and independent predictive factors of TACE combined with lenvatinib plus PD-1 inhibitors for unresectable HCC.METHODS This study retrospectively enrolled patients with unresectable HCC who received TACE/lenvatinib/PD-1 treatment between March 2019 and April 2022.Overall survival(OS)and progression-free survival(PFS)were determined.The objective response rate(ORR)and disease control rate(DCR)were evaluated in accordance with the modified Response Evaluation Criteria in Solid Tumors.Additionally,the prognostic factors affecting the clinical outcome were assessed.RESULTS One hundred and two patients were enrolled with a median follow-up duration of 12.63 months.The median OS was 26.43 months(95%CI:17.00-35.87),and the median PFS was 10.07 months(95%CI:8.50-11.65).The ORR and DCR were 61.76%and 81.37%,respectively.The patients with Barcelona Clinic Liver Cancer Classification(BCLC)B stage,early neutrophil-to-lymphocyte ratio(NLR)response(decrease),or early alpha-fetoprotein(AFP)response(decrease>20%)had superior OS and PFS than their counterparts.CONCLUSION This study showed that TACE/lenvatinib/PD-1 treatment was well tolerated with encouraging efficacy in patients with unresectable HCC.The patients with BCLC B-stage disease with early NLR response(decrease)and early AFP response(decrease>20%)may achieve better clinical outcomes with this triple therapy.

Rotational Angiography for 3D Roadmapping of Catheter Interventions in Congenital Heart Disease: Comparison of a Diagnostic and a Low Dose Program

Objectives: To compare the image quality, accuracy and effective dose of the default diagnostic pro-gram with the low dose program. Methods: The diagnostic and low dose programs of three-dimen-sional rotational angiography were compared considering their signal to noise ratio, their carrier to noise ratio and their actual radiation dose in μGy⋅m2/kg. An anthropomorphic phantom underwent both types of scans to evaluate the effective dose. Comparative measurements of vessel diameters were taken in the diagnostic and the low dose program and compared to the angiography as exact basis. The image quality of the scans using the different programs was rated by a specialist physician. Results: The low dose scan does use significantly less radiation and still provides images, which are adequate for 3D navigation of catheter-based interventions. Conclusion: Three-dimensional rotational angiography can be applied with the low dose program and is sufficient for 3D navigation.

Uncertainty quantification of inverse analysis for geomaterials using probabilistic programming

Uncertainty is an essentially challenging for safe construction and long-term stability of geotechnical engineering.The inverse analysis is commonly utilized to determine the physico-mechanical parameters.However,conventional inverse analysis cannot deal with uncertainty in geotechnical and geological systems.In this study,a framework was developed to evaluate and quantify uncertainty in inverse analysis based on the reduced-order model(ROM)and probabilistic programming.The ROM was utilized to capture the mechanical and deformation properties of surrounding rock mass in geomechanical problems.Probabilistic programming was employed to evaluate uncertainty during construction in geotechnical engineering.A circular tunnel was then used to illustrate the proposed framework using analytical and numerical solution.The results show that the geomechanical parameters and associated uncertainty can be properly obtained and the proposed framework can capture the mechanical behaviors under uncertainty.Then,a slope case was employed to demonstrate the performance of the developed framework.The results prove that the proposed framework provides a scientific,feasible,and effective tool to characterize the properties and physical mechanism of geomaterials under uncertainty in geotechnical engineering problems.

Cytokine release syndrome triggered by programmed death 1 blockade(sintilimab)therapy in a psoriasis patient:A case report

BACKGROUND In recent years,immune checkpoint inhibitors(ICIs)have demonstrated remarkable efficacy across diverse malignancies.Notably,in patients with advanced gastric cancer,the use of programmed death 1(PD-1)blockade has significantly prolonged overall survival,marking a pivotal advancement comparable to the impact of Herceptin over the past two decades.While the therapeutic benefits of ICIs are evident,the increasing use of immunotherapy has led to an increase in immune-related adverse events.CASE SUMMARY This article presents the case of a patient with advanced gastric cancer and chronic plaque psoriasis.Following sintilimab therapy,the patient developed severe rashes accompanied by cytokine release syndrome(CRS).Fortunately,effective management was achieved through the administration of glucocorticoid,tocilizumab,and acitretin,which resulted in favorable outcomes.CONCLUSION Glucocorticoid and tocilizumab therapy was effective in managing CRS after PD-1 blockade therapy for gastric cancer in a patient with chronic plaque psoriasis.

Pretreatment can alleviate programmed cell death in mesenchymal stem cells

In this editorial,we delved into the article titled“Cellular preconditioning and mesenchymal stem cell ferroptosis.”This groundbreaking study underscores a pivotal discovery:Ferroptosis,a type of programmed cell death,drastically reduces the viability of donor mesenchymal stem cells(MSCs)after engraftment,thereby undermining the therapeutic value of cell-based therapies.Furthermore,the article proposes that by manipulating ferroptosis mechanisms through preconditioning,we can potentially enhance the survival rate and functionality of MSCs,ultimately amplifying their therapeutic potential.Given the crucial role ferroptosis plays in shaping the therapeutic outcomes of MSCs,we deem it im-perative to further investigate the intricate interplay between programmed cell death and the therapeutic effectiveness of MSCs.

Recent Progress in Reinforcement Learning and Adaptive Dynamic Programming for Advanced Control Applications

Reinforcement learning(RL) has roots in dynamic programming and it is called adaptive/approximate dynamic programming(ADP) within the control community. This paper reviews recent developments in ADP along with RL and its applications to various advanced control fields. First, the background of the development of ADP is described, emphasizing the significance of regulation and tracking control problems. Some effective offline and online algorithms for ADP/adaptive critic control are displayed, where the main results towards discrete-time systems and continuous-time systems are surveyed, respectively.Then, the research progress on adaptive critic control based on the event-triggered framework and under uncertain environment is discussed, respectively, where event-based design, robust stabilization, and game design are reviewed. Moreover, the extensions of ADP for addressing control problems under complex environment attract enormous attention. The ADP architecture is revisited under the perspective of data-driven and RL frameworks,showing how they promote ADP formulation significantly.Finally, several typical control applications with respect to RL and ADP are summarized, particularly in the fields of wastewater treatment processes and power systems, followed by some general prospects for future research. Overall, the comprehensive survey on ADP and RL for advanced control applications has d emonstrated its remarkable potential within the artificial intelligence era. In addition, it also plays a vital role in promoting environmental protection and industrial intelligence.