Remarkably different results between two studies from North America on genomic mutations and sensitivity to DNA demethylating agents for myelodysplastic syndromes

Sekeres et al. （1） conducted a multicenter randomized, controlled trial to compare whether azacitidine-based combinations with lenalidomide or vorinostat produce superior overall response rates to azacitidine in the treatment of myelodysplastic syndromes （MDS）. In that trial, 224 patients with higher-risk MDS and 53 with chronic myelomonocytic leukemia （CMML） were enrolled and randomly assigned to the ＂azacitidine＂ group, ＂azacitidine plus lenalidomide＂ group or ＂azacitidine plus vorinostat＂ group. The researchers found that patients with MDS treated with azacitidine-based combinations had similar response rate to azacitidine monotherapy. Using genomic mutation analysis, they found that the overall response rate to azacitidine-based treatment was higher for patients with mutations in DNMT3A and lower for those with mutations in SRSF2. Whereas in another study, Welch et al. enrolled 26 patients with MDS and 90 with acute myeloid leukemia （AML） who were treated with decitabine, and they found that patients with TP53 mutations had a higher response rate, but not those with DNMT3A mutations （2）. We propose that this big discrepancy in the conclusions between the two studies might have been caused by the presence of many co-interacting factors, e.g. study aims, DNA demethylating agents, treatment protocols, and patient sources.

Mutation detection and fast identification of switching system based on data-driven method

In the engineering field,switching systems have been extensively studied,where sudden changes of parameter value and structural form have a significant impact on the operational performance of the system.Therefore,it is important to predict the behavior of the switching system,which includes the accurate detection of mutation points and rapid reidentification of the model.However,few efforts have been contributed to accurately locating the mutation points.In this paper,we propose a new measure of mutation detection—the threshold-based switching index by analogy with the Lyapunov exponent.We give the algorithm for selecting the optimal threshold,which greatly reduces the additional data collection and the relative error of mutation detection.In the system identification part,considering the small data amount available and noise in the data,the abrupt sparse Bayesian regression(abrupt-SBR)method is proposed.This method captures the model changes by updating the previously identified model,which requires less data and is more robust to noise than identifying the new model from scratch.With two representative dynamical systems,we illustrate the application and effectiveness of the proposed methods.Our research contributes to the accurate prediction and possible control of switching system behavior.

Sensitivity analysis of pull-in voltage for RF MEMS switch based on modified couple stress theory

An approximate analytical model for calculating the pull-in voltage of a stepped cantilever-type radio frequency （RF） micro electro-mechanical system （MEMS） switch is developed based on the Euler-Bernoulli beam and a modified couple stress theory, and is validated by comparison with the finite element results. The sensitivity functions of the pull-in voltage to the designed parameters are derived based on the proposed model. The sensitivity investigation shows that the pull-in voltage sensitivities increase/decrease nonlinearly with the increases in the designed parameters. For the stepped cantilever beam, there exists a nonzero optimal dimensionless length ratio, where the pull-in voltage is insensitive. The optimal value of the dimensionless length ratio only depends on the dimensionless width ratio, and can be obtained by solving a nonlinear equation. The determination of the designed parameters is discussed, and some recommendations are made for the RF MEMS switch optimization.

Estimation of enhanced low dose rate sensitivity mechanisms using temperature switching irradiation on gate-controlled lateral PNP transistor

The mechanisms occurring when the switched temperature technique is applied,as an accelerated enhanced low dose rate sensitivity(ELDRS)test technique,are investigated in terms of a specially designed gate-controlled lateral PNP transistor(GLPNP)that used to extract the interface traps(Nit)and oxide trapped charges(Not).Electrical characteristics in GLPNP transistors induced by ^(60)Co gamma irradiation are measured in situ as a function of total dose,showing that generation of Nit in the oxide is the primary cause of base current variations for the GLPNP.Based on the analysis of the variations of Nit and Not,with switching the temperature,the properties of accelerated protons release and suppressed protons loss play critical roles in determining the increased Nit formation leading to the base current degradation with dose accumulation.Simultaneously the hydrogen cracking mechanisms responsible for additional protons release are related to the neutralization of Not extending enhanced Nit buildup.In this study the switched temperature irradiation has been employed to conservatively estimate the ELDRS of GLPNP,which provides us with a new insight into the test technique for ELDRS.

Mutation-induced spatial differences in neuraminidase structure and sensitivity to neuraminidase inhibitors

Neuraminidase （NA）, a major surface glycoprotein of influenza virus with well-defined active sites, is an ideal plat- form for the development of antiviral drugs. However, a growing number of NA mutations have drug resistance to today＇s inhibitors. Numerous efforts are made to explore the resistance mechanisms through understanding the structural changes in mutated NA proteins and the associated different binding profiles of inhibitors, via x-ray, nuclear magnetic resonance, electron microscopy, and molecular dynamics methods. This review presents the architectural features of mutated NA proteins, as well as the respective inhibitor sensitivities arising from these spatial differences. Finally, we summarize the resistance mechanisms of today＇s neuraminidase inhibitors and the outlook tbr the development of novel inhibitors.

A COMPLETE SCREEN FOR MUTATIONS OF THE RHODOPSIN GENE IN A PANEL OF CHINESE PATIENTS WITH AUTOSOMAL DOMINANT RETINITIS PIGMENTOSA

Objective To evaluate the prevalence of rhodopsin (RHO) mutations and the genotype-phenotype relationships in Chinese patients with autosomal dominant retinitis pigmentosa (ADRP) by conformation sensitive gel electrophoresis (CSGE) and direct DNA sequencing. Methods We have screened the five coding exons and splice sites of RHO gene in 27 probands who had no relativity from Chinese ADRP families and 100 normal controls to identify disease-associated mutations, using CSGE and direct DNA sequencing. Family members of some probands with disease-associated mutations were also genotyped to determine whether the RHO mutations segregated with retinitis pigmentosa (RP) in their families. Results Two RHO mutations, Pro347Leu and Pro327 (1-bp del), were identified separately in two families, thus the frequency of RHO mutations among this set of Chinese ADRP families is about 7.4% (2/27). Pro347Leu mutation was found in one ADRP proband as well as three her children who also had RP. She had relatively early onset at about 17 years. The only one child without this mutation had no symptom or sign of RP at age of 34. Pro327 (1-bp del) was identified in a late-onset ADRP patient, who appeared night blindness around 30 years old and in her fifties electroretinogram (ERG) has been flat in both scotopic and photopic phases. Family analysis showed that this mutation also existed in her younger dau-ghter and her elder sister, both of them also had RP. Three other family members were genotypically and phenotypically normal. Neither of the two mutations was detected in 100 normal controls.Conclusions The frequency of RHO mutations in Chinese patients was lower than that in Europe and North America. The phenotype of the patients with Pro347Leu corresponded to type 1 ADRP, with severe rod degeneration and some cone preservation later, while the phenotype of the patients carrying Pro327 (1-bp del) corresponded to type 2 ADRP, with a concomitant loss of rod and cone visual function. CSGE was found to be a sensitive, simple, and practical method for the screening of a large number of samples under highly reproducible conditions, and could be utilized in routine molecular diagnostic laboratories.

A low noise charge sensitive preamplifier with switch control feedback resistance

In this paper, the design and analysis of a new low noise charge sensitive preamplifier for silicon strip, Si(Li), CdZnTe and CsI detectors etc. with switch control feedback resistance were described, the entire system to be built using the CMOS transistors. The circuit configuration of the CSP proposed in this paper can be adopted to develop CMOS-based Application Specific Integrated Circuit further for Front End Electronics of read-out system of nuclear physics, particle physics and astrophysics research, etc. This work is an implemented design that we succeed after a simulation to obtain a rise time less than 3ns, the output resistance less than 94? and the linearity almost good.

Mass genetics study of rhodopsin point mutations in retinitis pigmentosa

Objective: To evaluate the incidence and pattern of rhodopsin (RHO) mutations in Chinese patients with retinitis pigmentosa (RP). Methods: Conformation sensitive gel electrophoresis (CSGE) and direct DNA sequencing were applied to detect point mutations that occurred in the five coding exons and splice sites of RHO gene in 98 index patients with RP. Results: Four patients of one ADRP family were found to have a missense mutation at codon 347, Pro347Leu. One late-onset RP patient and her daughter, without clinical expression at present, were discovered to have a novel frameshift mutation at codon 327, Pro327 (1-bp del) . Neither of the two mutations was found in 100 normal controls. Ala299Ser was found in one RP patient. Two control subjects also had Ala299Ser, suggesting its nonpathogenicity and just single nucleotide polymorphism (SNP). Conclusion: Two RP patients had rhodopsin mutations, thus the expected frequency of RHO mutations in RP is about 2.0% (95% confidence interval: 0.3%-4.4%). A highly conserved C-terminal sequence QVS(A) PA was altered due to Pro347Leu and thereby misdirecting rhodopsin to incorrect subcellular location. Loss of all phosphory-lation sites at the C-terminus and a highly conserved sequence QVS(A)PA may occur because of Pro327(1-bp del) . To elucidate the predominant biochemical defects in such mutant, transgenic mice and transfected culture cells carrying Pro327(1-bp del) would be of great value.

A Nonlinear Electrical Resonator as a Simple Touch-Sensitive Switch with Memory

We introduce a novel switching mechanism that relies on the bistability of a simple nonlinear electrical resonator which incorporates a varactor diode as its capacitive element. The switching action can be made fast and is self-contained in that no further circuitry is necessary. Unlike a flip-flop, whose state is flipped by applying a TTL pulse, this nonlinear switch can be engaged external to the circuit via magnetic, inductive or capacitive coupling;in this way, the switch becomes intrinsically touch-sensitive. Alternatively, the switching action can also be accomplished using frequency-shift-keying (FSK) modulation, which holds the promise of fast manipulation of the memory state. We demonstrate the potential application of these ideas by constructing a touch-sensitive LED lattice.

非小细胞肺癌EGFR基因少见突变P733L对第1代和第3代EGFR-TKI敏感性的研究

目的:探讨表皮生长因子受体(EGFR)基因少见突变P733L对第1代和第3代EGFR酪氨酸激酶抑制剂(EGFR-TKI)的敏感性。方法:通过四唑盐比色法和平板克隆实验分析EGFR L858R和P733L肺癌细胞对第1代和第3代EGFR-TKI的敏感性;通过Transwell实验分析第1代和第3代EGFR-TKI对EGFR L858R和P733L肺癌细胞迁移的抑制作用;通过检测凋亡蛋白分析第1代和第3代EGFR-TKI促进EGFR L858R和P733L肺癌细胞凋亡的作用。结果:第1代和第3代EGFR-TKI对EGFR L858R和P733L细胞的增殖、克隆形成和细胞迁移都有抑制作用。与EGFR野生型肺癌细胞相比,第1代和第3代EGFR-TKI处理后,EGFR L858R和P733L细胞的EGFR激酶活性受到抑制,细胞凋亡明显增加。结论:EGFR P733L突变细胞对第1代和第3代EGFR-TKI的敏感性与EGFR L858R突变细胞的敏感性相似,本研究为EGFR基因少见突变从EGFR-TKI治疗中获益提供了实验证据。

基于时间敏感网络的PTP交换机技术研究

基于时间敏感网络设计的高精度时间同步系统是目前工业互联网、大数据科学等领域的硬件基础之一。由于传统交换机在标记报文时间戳时无法避免网络栈内部的延迟和不确定性,为了实现更高的时间同步精度和稳定性,基于EVB-KSZ9477S PTP交换机并借助OK335xS开发板辅助控制,设计实现了PTP时间同步系统。该系统采用硬件辅助标记报文时间戳,计算消除PTP帧在网络栈内的不确定性误差,通过内部修正,从而实现较高的时间同步精度。结果表明,相较于普通交换机,基于TSN的PTP交换机的时间同步系统可实现±20 ns以内的时间同步精度和更低的抖动,具有良好的时间同步性能。

世界卫生组织《结核分枝杆菌耐药相关基因突变目录(第2版)》解读

耐药结核病是2035年实现全球终结结核病流行目标的巨大障碍。世界卫生组织(World Health Organization,WHO)倡导采用快速分子药物敏感性检测技术进行耐药结核病早期诊断,而覆盖全面可靠的耐药检测靶标是提高分子药物敏感性检测技术可靠性的关键。WHO于2023年11月发布《结核分枝杆菌耐药相关基因突变目录(第2版)》,目的是基于更广泛的全球数据汇总形成更为全面准确的耐药相关基因突变目录,为开发与完善基于测序或其他方法的新型分子药物敏感性检测技术提供支持。本文对第2版目录相较于第1版目录在分析流程与耐药突变等内容的更新进行了详细的解读,并对未来目录完善的方向进行了展望。

基于降维粒子群的大电网断面功率极限计算方法

随着电力系统的发展,系统运行方式日益复杂。为了提高电力系统运行安全水平,提出一种基于降维粒子群的大电网断面功率极限计算方法。首先综合考虑大电网静态安全稳定约束和暂态稳定约束,建立断面功率极限计算模型;然后,提出了基于功率灵敏度的降维粒子群算法,根据功率灵敏度和聚合系数对可调节发电机组进行分群处理,利用降维粒子群算法计算得到了极限功率、发电机组功率调节量以及极限功率制约因素,实现了大电网断面功率极限的快速寻优。最后在我国某地区2128节点电网和我国某跨区12643节点联网中验证了该方法的有效性和正确性。

利福平耐药结核分枝杆菌对氟喹诺酮类药物表型耐药与其基因突变的一致性研究

目的:研究利福平耐药结核分枝杆菌(Mycobacterium tuberculosis,MTB)对氟喹诺酮类药物(fluoroquinolones,FQs)耐药基因突变特征与FQs最低抑菌浓度(minimum inhibitory concentration,MIC)的关系。方法:选取2016—2021年北京市结核病防治机构及定点医院收治的利福平耐药结核病(rifampicin resistant tuberculosis,RR-TB)患者分离培养阳性菌株进行微孔板法药物敏感性检测,总结RR-TB患者菌株对左氧氟沙星(levofloxacin,Lfx)和莫西沙星(moxifloxacin,Mfx)的MIC值;同时进行一代测序。分析FQs耐药相关基因gyrA和gyrB突变特征与FQs MIC之间的关系;以表型药物敏感性试验(phenotypic drug susceptibility testing,pDST)结果为参照标准,评价基因型药物敏感性试验(genotypic drug susceptibility testing,gDST)对FQs耐药的检测效能;探讨RR-MTB对FQs表型耐药与基因型耐药差异的原因。结果:303株RR-TB患者菌株中,FQs pDST耐药率为27.7%(84/303),gyrA基因突变检出率为25.1%(76/303),未检测到gyrB基因突变。以pDST结果为参照标准,gDST检测RR-MTB的FQs耐药性的敏感度和特异度分别为84.5%(71/84;95%CI:74.6.1%~91.2%)和97.7%(214/219;95%CI:94.5%~99.1%)。两种方法结果不一致的菌株有25株,不一致率为8.3%(25/303)。FQs耐药菌株的MIC主要为2μg/ml,最常见的突变位点发生在第94位点(53.9%,41/76),gyrA基因在第88和94位点突变与pDST耐药完全一致,而第90和91位点突变的pDST耐药一致率分别为95.8%(23/24)和3/5。第88位点的突变与Lfx pDST耐药相关,与Mfx pDST高浓度耐药相关;第90位点的突变以丙氨酸转变为缬氨酸为主(92.3%,24/26),该突变发生的Lfx和Mfx最低MIC为临界浓度(1μg/ml和0.25μg/ml)。第94位点天冬氨酸突变为天冬酰胺均为Lfx和Mfx高浓度耐药(1/1),该位点天冬氨酸突变为酪氨酸与Lfx耐药(1/1)相关,与Mfx高浓度耐药相关(1/1)。结论:北京地区RR-MTB的FQs耐药的主要机制是gyrA基因突变,不同gyrA基因突变提示FQs耐药水平存在差异。FQs pDST和gDST检测RR-MTB的结果高度一致,可及早应用gDST检测RR-TB患者的FQs的耐药性,以指导临床制定合理治疗方案。

交换机的时间感知整形器的设计

时间敏感网络(TSN)是应用于未来工业网络实时性的一种增强型以太网技术。作为主要关键技术之一,流量调度机制决定了时间敏感网络数据传输的确定性和实时性,对其进行研究是非常具有价值的。在研究了802.1Qbv标准中所定义的时间感知整形器的实现机制和完整的处理流程的基础上,提出了一种时间感知整形器调度机制的设计。将整个设计在自研的TSN交换机平台上进行组网测试,验证了调度器可支持时间敏感业务流的确定性传输。

TSDSIR:机器人系统中多业务并发的消息数据流调度

针对机器人云-边-端协同场景中所面临的多业务并发、多模态消息数据混杂等特点,基于机器人操作系统2(ROS2)中消息分发机理分析,提出了面向时间敏感属性的多消息动态调度方法。首先,根据ROS2中多话题消息流并发属性和网络实时状态,定义了消息数据优先权、最大传输时间和剩余传输时间等流调度参数,进而对待调度的流队列状态进行实时表征。其次,设计了包含时间优先和优先权优先的混杂切换调度模型,并结合流调度参数给出调度切换规则及理论边界条件。最后,提出了ROS2中面向时间敏感属性的多消息动态调度方法,并在其数据分发服务层中集成应用。仿真实验与实际应用验证表明,所提方法能提升ROS2中多消息流并发传输效率,同时保障高优先级的、具有时间敏感属性的消息数据实时可靠传输。

基于时间敏感网络的变电站通信网络低时延控制方法

以降低变电站通信网络时延为目标,基于时间敏感网络设计了一种低时延控制方法。首先,在变电站通信网络的站控层和过程层中,利用时间敏感网络交换机组建时间敏感子网络,再将不同交换机终端辨识为多个线性参数模型。然后,利用模糊控制方法控制交换机同步时钟的误差,根据模糊C均值聚类方法确定低时延控制的模糊规则前件,利用时间敏感网络的参数辨识获取模糊规则后件。最后,依据模糊控制前件与后件,结合模糊控制与广义预测控制,实现时间敏感网络时延的反馈校正。实验结果表明,采用该方法控制变电站通信网络时延量后,网络通信最大时延被控制在100μs以内,最大时延抖动被控制在20μs以内,说明该方法有效实现了设计预期。

起动机电磁开关结构分析与优化研究

电磁开关是汽车起动机的关键部件之一,研究表明电磁开关的电接触结构存在熔焊失效的风险,是限制起动机寿命的重要因素之一。本文利用Simscape平台对电磁开关电接触结构进行参数灵敏度分析,从优化叠簧刚度的角度入手,提出采用波形弹簧的电磁开关结构,通过在LS-Dyna软件上进行有限元分析,波形弹簧结构能够有效缓冲电接触部位的振动,并能有效减少电接触部位电弧的发生,从而提高抗熔焊性。

厄洛替尼联合贝伐珠单抗一线治疗EGFR敏感突变阳性晚期非小细胞肺癌的临床观察

目的观察厄洛替尼联合贝伐珠单抗一线治疗表皮生长因子受体(EGFR)敏感突变阳性晚期非小细胞肺癌的临床效果。方法采用前瞻性随机对照研究,选择EGFR敏感突变阳性晚期非小细胞肺癌患者作为研究对象。采用随机数字表法将患者分为对照组与观察组,对照组采用厄洛替尼治疗,观察组采用厄洛替尼联合贝伐珠单抗治疗。比较2组患者临床疗效、血清肿瘤标志物水平[癌胚抗原(CEA)、细胞角蛋白21-1片段(CYFRA21-1)、血管内皮生长因子(VEGF)]、免疫功能[白细胞分化抗原3(CD3)、白细胞分化抗原4(CD4)、白细胞分化抗原8(CD8)]以及用药不良反应情况。结果治疗3个月后,观察组患者客观缓解率(ORR)、疾病控制率(DCR)均高于对照组,差异有统计学意义(P<0.05)。治疗后,观察组血清CEA、CYFRA21-1、VEGF水平低于对照组,差异有统计学意义(P<0.05);观察组CD3^(+)、CD4^(+)、CD4^(+)/CD8^(+)高于对照组,CD8^(+)低于对照组,差异有统计学意义(P<0.05)。2组患者治疗不良反应发生率比较,差异无统计学意义(P>0.05)。结论厄洛替尼联合贝伐珠单抗一线治疗EGFR敏感突变阳性晚期非小细胞肺癌可以有效提高临床疗效,改善患者免疫功能。

Relationship between Mutation of IR in the mtr System of Neisseria Gonorrhoeae and Multiple Antibiotic Resistance

To study the relationship between mutation of the inverted repeat sequence （IR） in the multiple transferable resistant system （mtr） of Neisseria gonorrhoeae （NG） and its multiple antibiotic resistance, minimal inhibitory concentrations （MICs） for the clinically isolated strains were tested by agar-dilution-method. The mtr system＇s IR gene of NG was sequenced after amplification by polymerase chain reaction （PCR）. Either two susceptive or five penicillin-resistant strains had no base mutation in IR gene, while all of the 13 strains with multiple-antibiotic-resistance had a singlebase deletion （A/T）. The result suggests that a single-base deletion of the thirteen-base IR sequence in mtr system of NG might result in multiple antibiotic resistance but is not associated with single antibiotic resistance.