Enhanced Precision Therapy of Multiple Myeloma Through Engineered Biomimetic Nanoparticles with Dual Targeting

Multiple myeloma(MM)is the second most prevalent hematological malignancy.Current MM treatment strategies are hampered by systemic toxicity and suboptimal therapeutic efficacy.This study addressed these limitations through the development of a potent MM-targeting chemotherapy strategy,which capitalized on the high binding affinity of alendronate for hydroxyapatite in the bone matrix and the homologous targeting of myeloma cell membranes,termed T-PB@M.The results from our investigations highlight the considerable bone affinity of T-PB@M,both in vitro and in vivo.Additionally,this material demonstrated a capability for drug release triggered by low pH conditions.Moreover,T-PB@M induced the generation of reactive oxygen species and triggered cell apoptosis through the poly(ADP-ribose)polymerase 1(PARP1)-Caspase-3-B-cell lymphoma-2(Bcl-2)pathway in MM cells.Notably,T-PB@M preferentially targeted bone-involved sites,thereby circumventing systemic toxic side effects and leading to prolonged survival of MM orthotopic mice.Therefore,this designed target-MM nanocarrier presents a promising and potentially effective platform for the precise treatment of MM.

Preparation and Evaluation of Dual Targeting Nanoparticles for Oral Cancer

A dual-receptor targeting delivery system based on acid-cleavage hydrazone bond was developed in the study. The characters of CMCS-hyd-CUR-EGFR-mAb were identified. The in vitro release studies revealed that this drug delivery system was acid-sensitive, and the self-assembled nanoparticles which were spherical. The in vitro results indicated that the dual-receptor targeting nanoparticles could be faster internalized into the Cal-27 cells via receptor-mediated endocytosis, which exhibited better antitumor activity than the one-receptor nanoparticles. The experimental results clearly reveal that CMCS-hyd-CUR-EGFR mAb provides a novel way for drug delivery in oral cancer treatment.

Research on the Impact of BYD Group’s Green Innovation on Corporate Financial Performance under the Background of“Dual Carbon”

With the increasingly severe global climate change problem,the“dual carbon”goals(peak carbon emissions and carbon neutrality)have become a common focus of international attention.The report of the 20th National Congress of the Communist Party of China clearly emphasizes the need to accelerate the green transformation of development models,implement comprehensive strategies for frugal development,support the growth of green and low-carbon industries,and promote the concept of green consumption.At the same time,“Made in China 2025”also elaborates on the strategic concept of innovation-driven and green development centered,and strives for breakthroughs in key industries such as new energy vehicles.In such a macro environment,adopting green innovation measures by enterprises not only contributes to ecological protection but also has an undeniable impact on their economic performance and overall value.This article takes BYD Group as a case study to explore in detail the positive effects of green innovation on its economic performance.We first systematically organized and analyzed BYD’s specific practices in green innovation;Then,by examining three key financial indicators,BYD’s current financial situation was analyzed in depth;On this basis,combined with research data,the positive impact of green innovation on BYD’s financial performance was revealed;Finally,based on the analysis results,relevant suggestions are proposed to provide reference for the sustainable development of enterprises in the context of“dual carbon.”

Dual Targeting to Mitochondria and Chloroplasts： Characterization of Thr-tRNA Synthetase Targeting Peptide

There is a group of proteins that are encoded by a single gene, expressed as a single precursor protein and dually targeted to both mitochondria and chloroplasts using an ambiguous targeting peptide. Sequence analysis of 43 dual targeted proteins in comparison with 385 mitochondrial proteins and 567 chloroplast proteins ofArabidopsis thaliana revealed an overall significant increase in phenylalanines, leucines, and serines and a decrease in acidic amino acids and glycine in dual targeting peptides （dTPs）. The N-terminal portion of dTPs has significantly more serines than mTPs. The number of arginines is similar to those in mTPs, but almost twice as high as those in cTPs. We have investigated targeting determinants of the dual targeting peptide of Thr-tRNA synthetase （ThrRS-dTP） studying organellar import of N- and C-terminal deletion constructs of ThrRS-dTP coupled to GFR These results show that the 23 amino acid long N-terminal portion of ThrRS-dTP is crucial but not sufficient for the organellar import. The C-terminal deletions revealed that the shortest peptide that was capable of conferring dual targeting was 60 amino acids long. We have purified the ThrRS- dTP（2-60） to homogeneity after its expression as a fusion construct with GST followed by CNBr cleavage and ion exchange chromatography. The purified ThrRS-dTP（2-60） inhibited import of pF1β into mitochondria and of pSSU into chloroplasts at μM concentrations showing that dual and organelle-specific proteins use the same organellar import pathways. Furthermore, the CD spectra of ThrRS-dTP（2-60） indicated that the peptide has the propensity for forming α-helical structure in membrane mimetic environments; however, the membrane charge was not important for the amount of induced helical structure. This is the first study in which a dual targeting peptide has been purified and investigated by biochemical and biophysical means.

Dual Targeting of a Mitochondrial Protein： The Case Study of Cytochrome C1

As a result of the endosymbiotic gene transfer, the majority of proteins of mitochondria and chloroplasts is encoded in the nucleus and synthesized in the cytosol as precursor molecules carrying N-terminal transit peptides for the transport into the respective target organelle. In most instances, transport takes place into either mitochondria or chloroplasts, although a few examples of dual targeting into both organelles have been described. Here, we show by a combination of three different experimental strategies that also cytochrome c1 of potato, a component of the respiratory electron transport chain, is imported not only into mitochondria, but also into plastids. In organello import experiments with isolated mitochondria and chloroplasts, which were analyzed in both single and mixed organelte assays, demonstrate that the processing products accumulating after import within the two endosymbiotic organelles are different in size. Dual targeting of cytochrome c1 is observed also in vivo, after biolistic transformation of leaf epidermal cells with suitable reporter constructions. Finally, Western analyses employing cytochrome c1-specific antiserum provide evidence that the protein accumulates in significant amounts in mitochondria and chloroplasts of both pea and spinach. The possible consequences of our findings on the relevance of the dual targeting phenomenon are discussed.

Engineering a folic acid-decorated ultrasmall gemcitabine nanocarrier for breast cancer therapy: Dual targeting of tumor cells and tumor-associated macrophages

Combination of passive targeting with active targeting is a promising approach to improve the therapeutic efficacy of nanotherapy.However,most reported polymeric systems have sizes above100 nm,which limits effective extravasation into tumors that are poorly vascularized and have dense stroma.This will,in turn,limit the overall effectiveness of the subsequent uptake by tumor cells via active targeting.In this study,we combined the passive targeting via ultra-small-sized gemcitabine(GEM)-based nanoparticles(NPs)with the active targeting provided by folic acid(FA)conjugation for enhanced dual targeted delivery to tumor cells and tumor-associated macrophages(TAMs).We developed an FAmodified prodrug carrier based on GEM(PGEM)to load doxorubicin(DOX),for co-delivery of GEM and DOX to tumors.The co-delivery system showed small particle size of~10 nm in diameter.The ligand-free and FA-targeted micelles showed comparable drug loading efficiency and a sustained DOX release profile.The FA-conjugated micelles effectively increased DOX uptake in cultured KB cancer cells that express a high level of folate receptor(FR),but no obvious increase was observed in 4T1.2 breast cancer cells that have a low-level expression of FR.Interestingly,in vivo,systemic delivery of FAPGEM/DOX led to enhanced accumulation of the NPs in tumor and drastic reduction of tumor growth in a murine 4T1.2 breast cancer model.Mechanistic study showed that 4T1.2 tumor grown in mice expressed a significantly higher level of FOLR2,which was selectively expressed on TAMs.Thus,targeting of TAM may also contribute to the improved in vivo targeted delivery and therapeutic efficacy.

Import Determinants of Organelle-Specific and Dual Targeting Peptides of Mitochondria and Chloroplasts in Arabidopsis thaliana

Most of the mitochondrial and chloroplastic proteins are synthesized in the cytosol as precursor proteins carrying an N-terminal targeting peptide （TP） directing them specifically to a correct organelle. However, there is a group of proteins that are dually targeted to mitochondria and chloroplasts using an ambiguous N-terminal dual targeting peptide （dTP）. Here, we have investigated pattern properties of import determinants of organelle-specific TPs and dTPs combining mathematical multivariate data analysis （MVDA） with in vitro organellar import studies. We have used large datasets of mitochondrial and chloroplastic proteins found in organellar proteomes as well as manually selected data sets of experimentally confirmed organelle-specific TPs and dTPs from Arabidopsis thaliana. Two classes of organelle-specific TPs could be distinguished by MVDA and potential patterns or periodicity in the amino acid sequence contributing to the separation were revealed, dTPs were found to have intermediate sequence features between the organelle-specific TPs. Interestingly, introducing positively charged residues to the dTPs showed clustering towards the mitochondrial TPs in silico and resulted in inhibition of chloroplast, but not mitochondrial import in in vitro organellar import studies. These findings suggest that positive charges in the N-terminal region of TPs may function as an ＇avoidance signal＇ for the chloroplast import.

Dual Targeting of a Processing Peptidase into Both Endosymbiotic Organelles Mediated by a Transport Signal of Unusual Architecture

As a result of the endosymbiotic gene transfer, the majority of proteins of mitochondria and chloroplasts are encoded in the nucleus and synthesized in the cytosol as precursor proteins carrying N-terminal transport signals for the ＇re-import＇ into the respective target organelle. Most of these transport signals are monospecific, although some of them have dual targeting properties, that is, they are recognized both by mitochondria and by chloroplasts as target organelles. We have identified alpha-MPP2, one of the two isoforms of the substrate binding subunit of mitochondrial processing peptidase of Arabidopsis thaliana, as a novel member of this class of nuclear-encoded organelle proteins. As demonstrated by in organello transport experiments with isolated organelles and by in vivo localization studies employing fluorescent chimeric reporter proteins, the N-terminal region of the alpha-MPP2 precursor comprises transport signals for the import into mitochondria as well as into chloroplasts. Both signals are found within the N-terminal 79 residues of the precursor protein, where they occupy partly separated and partly overlapping regions. Deletion mapping combined with in organello and in vivo protein transport studies demonstrate an unusual architecture of this transport signal, suggesting a composition of three functionally separated domains.

Single Source Self-Screen Jamming Elimination and Target Detection for Distributed Dual Antennas Radar System

Detecting target echo in the existence of self-screen jamming is a challenging work for radar system, especially when digital radio frequency memory(DRFM) technique is employed that mixes the jamming and target echo both in spatial and time-frequency domain. The conventional way to solve this problem would suffer from performance degradation when physical target(PT) and false target(FT) are superposed in time. In this paper, we propose a new spatial filter according to the different correlation characteristic between PT and FT. The filter takes the ratio of expected signal power to expected jamming and noise power as the objective function under the constant filter modulus constraint. The optimal filter coefficients are derived with a generalized rayleigh quotient approach. Moreover, we analytically compute the target detection probability and demonstrate the applicability of the proposed method to the correlation coefficient. Monte Carlo simulations are provided to corroborate the proposed studies. Furthermore, the proposed method has simple architecture and low computation complexity, making it easily applied in modern radar system.

Dual-quaternion-based modeling and control for motion tracking of a tumbling target

This paper investigates the problem of controlling a chasing spacecraft(chaser)to track and rendezvous with an uncontrolled target.Based on the actual situation,the torque-free motion of an axisymmetric prolate rigid body is employed to represent the short-term attitude motion of the tumbling target.By taking advantage of the dual quaternion’s compact and efficient description of the general rigid motion,the coupled and integrated model of the 6-degree-of-freedom(6-DOF)relative motion between the chaser and the tumbling target is derived in the chaser’s body fixed frame after taking full consideration of coordinate transformation.Based on the logarithm of dual quaternion,a sliding mode control(SMC)law based on the exponential reaching law and the continuous relay function is brought forward to address the problem of synchronization control of the 6-DOF relative motion.Simulation results illustrate the effectiveness of the proposed method.

Comprehensive Online Management Based on Cloud Platform for Breast Cancer Patients Using Dual-Targeted Therapy with Macromolecular Monoclonal Antibodies

Objective: The purpose of the study was to explore the application effects of the cloud platform-based comprehensive online management for breast cancer patients using dual-targeted therapy with macromolecular monoclonal antibodies. Methods: 120 breast cancer patients treated by dual-targeted therapy with macromolecular monoclonal antibodies were managed by a cloud platform from March to November 2019. Comprehensive online management included consultation about drugs and side effects and frequently asked questions in the dual-targeted therapy with macromolecular monoclonal antibodies. Results: In the consultation about drugs and side effects, there were five patients with fever, neutrophil, cough, and fatigue;24 with diarrhea;25 with nausea;11 with oral mucosal inflammation;10 with rashes and dry skin;8 with insomnia;and 1 with palpitation. Moreover, 110 patients with anxiety about the missed or delayed treatment were properly handled. Conclusion: The comprehensive online management of dual-targeted therapy with macromolecular monoclonal antibodies based on the cloud platform is helpful to satisfy the at-home breast cancer patients’ needs, ensure the continuity of dual-targeted therapy with macromolecular monoclonal antibodies for breast cancer patients, prevent misinformation, alleviate patients’ negative psychological emotions, and reduce patients’ economic losses. The online cloud platform integrated management model is crucial for managing patients with breast cancer treated by dual-targeted therapy.

数字金融对城市碳排放的非线性影响研究

数字金融在经济社会全面绿色转型中发挥政策集成和导向作用,是降碳减排的重要工具。本文基于金融领域的数字化变革现实,以2011—2021年中国284个地级市面板数据为基础,运用固定效应模型、中介效应模型和调节效应模型探究数字金融对碳排放的非线性影响及潜在机制。研究发现:数字金融对碳排放存在先增后减的倒“U”型影响,这一趋势通过一系列稳健性检验得以证实。异质性分析表明,这种倒“U”型影响主要发生在外围城市和资源型城市,在非资源型城市表现为负向线性关系。中介效应分析凸显了技术创新和创业活动作为数字金融影响碳排放的关键途径。调节效应分析强调了地方政府经济增长目标将削弱数字金融对碳排放的倒“U”型影响,环境治理目标则强化两者的倒“U”型关系。地方政府应从数字金融的发展方向、作用方向和配置方向着手,释放碳减排红利。

“双碳”视阈下绿色金融发展影响碳排放的内在机制研究

加快绿色金融发展是我国新发展阶段促进发展方式绿色转型和实现“双碳”目标的战略要求。基于空间Durbin模型和GMM动态分析方法,利用我国2006—2021年30个省(区、市)的面板数据,对绿色金融发展与省际碳排放效果之间的内在关系进行实证研究。研究发现:绿色金融发展能够显著减少区域碳排放,相关结论经过稳健性检验后依然成立;低碳技术创新和融资约束作为中介变量,共同构成了绿色金融发展影响碳排放的传导路径。进一步分析表明,绿色金融发展对碳排放有明显的空间溢出效应,并在我国不同经济发展水平的地区存在区域异质性。研究结论可为新时代我国构建绿色金融发展体系、制定促进“双碳”战略目标实现的相关政策提供支撑。

能耗双控转向碳排放双控的理论逻辑与实践路径

能耗双控向碳排放双控转变是推进碳达峰碳中和的制度保障,系统分析能耗双控转向碳排放双控的理论逻辑及实践路径,对促进企业适应国内国际市场、降低碳排放,保障中国“双碳”目标的实现有重要现实意义。能耗双控通过需求效应、技术效应和要素替代效应影响节能降碳,碳排放双控主要通过技术创新效应、技术溢出效应和产业结构升级效应的综合作用促进节能降碳,碳排放双控节能降碳的作用机制更加完善,更加注重碳排放控制,更能够精准控碳。能耗双控转向碳排放双控有利于企业能源转型、绿电消费的增加,对于“双碳”目标的实现、国际竞争力的提高具有深远的影响。能耗双控转向碳排放双控背景下,中国面临能耗双控转向碳排放双控的识别阶段、分阶段、落实阶段难题,碳市场建设不足,碳排放监管和执法体系不完善的挑战;为顺利推动能耗双控转向碳排放双控,本文提出统筹推进分阶段、差异化考核工作,通过加大碳市场覆盖范围、完善碳交易机制、优化用能权交易市场等加强碳市场建设,加强碳排放监管和法治体系建设等关键举措和推动路径。中国实现绿色低碳发展须注重能耗双控向碳排放双控转变,准确把握能耗双控转向碳排放双控,促进“双碳”目标实现。

基于联邦学习的分布式电采暖互动模式设计与展望

随着“双碳”目标的提出,以及“以电代煤”政策的贯彻落实,大量电采暖设备取代传统燃煤取暖投入运行并接入电网将成为必然趋势。大量电采暖设备可以作为需求侧可调资源进行新能源消纳,但是分布式电采暖所处地理区域较为分散,传统集中式管理的方式又存在隐私泄露、数据孤岛等问题。联邦学习作为一种分布式技术可在保护隐私的前提下支撑电采暖负荷互动,在分布式电采暖互动领域具有较强的适用性。分析了基于联邦学习的分布式电采暖互动需求,以及边缘缓存、隐私防护、通信传输优化和异构资源融合等技术在基于联邦学习的电采暖互动场景中的应用方式,并展望了未来基于联邦学习的分布式电采暖互动前景。

我国海运碳排放市场机制构建的进路统筹

海运碳减排需要统筹运用包括市场机制在内的多种措施。欧盟推进单边海运碳排放交易机制虽然对市场机制在海运领域的运用具有正向推进价值,但基于其制度对共同但有区别责任原则的忽视等原因,与我国的航运利益并不相符。我国应当联合其他非欧盟国家反对欧盟的单边措施,并积极推进国际海事组织(IMO)层面多边海运碳排放市场机制的构建,推动海运碳排放真正实现公正公平的过渡。同时,在国内层面,基于国际国内统筹推进的整体要求,我国需要厘定基于国内立法的海运碳排放市场措施及其实施路径,构建相应的制度保障。

双碳目标下农业机械发展趋势探究

随着我国绿色农业经济的发展,人们对绿色农业机械的发展更加关注。目前绿色农业机械技术仍处于起步阶段,但是农业机械低碳化、智能化依然是未来的发展趋势。该文重点分析了中国农业机械低碳化发展的关键环节,并从中国农机发展历程、农机低碳化发展现状、农机低碳化核心技术创新及农机低碳化应用推广等方面阐述其阶段性特征和发展方向,对未来低碳化农业机械技术发展及市场推广应用提出几点建议。文章指出通过创新驱动、市场驱动、政策驱动促进低碳农业机械快速、高质量发展,推动农业产业结构优化升级,加快落后产能装备快速淘汰,构建绿色农业经济体制,助推中国农业经济绿色转型及国家“双碳”指标顺利达成。

联合疗法在炎症性肠病中的应用进展

炎症性肠病(inflammatory bowel disease,IBD)是一种难治性肠道炎症性疾病,药代动力学的失效及药效学逃逸导致目前以单一靶向治疗为主的方案受到限制,而对于重症及肠外表现的治疗不尽如人意,加速了人们研究联合疗法的进度,既往比较成熟的联合治疗案例进一步推动双靶向治疗方案的研究,该文就IBD联合疗法作一概述。

双靶向新辅助药物联合不同化疗治疗HER-2阳性乳腺癌临床疗效比较

目的探讨双靶向新辅助药物联合不同化学药物治疗(简称化疗)的方案治疗人类表皮生长因子受体-2(HER-2)阳性乳腺癌的临床疗效。方法选取凉山彝族自治州第一人民医院2019年1月至2022年12月收治的HER-2阳性乳腺癌患者110例,按治疗方案的不同分为TcbHP组和AC-THP组,各55例。TcbHP组患者予曲妥珠单抗和帕妥珠单抗联合紫杉类(多西他赛或紫杉醇)和卡铂治疗,以21 d为1个周期,共治疗6个周期;AC-THP组患者予曲妥珠单抗和帕妥珠单抗联合蒽环类药物(吡柔比星或表柔比星)和环磷酰胺治疗,以21 d为1个周期,曲妥珠单抗和帕妥珠单抗及其他药物分别治疗4个周期,共8个周期。结果TcbHP组患者病理完全缓解率为61.80%,稍高于AC-THP组的50.90%(P>0.05)。治疗后,TcbHP组恶心,呕吐,腹泻,心脏毒性及手足综合征程度均显著低于AC-THP组(P<0.05);各肿瘤标志物[糖类抗原(CA19-9,CA125,CA153),癌胚抗原(CEA)]水平均显著低于AC-THP组(P<0.05);左心室射血分数(LVEF)及血清心肌肌钙蛋白I(cTnI)、肌酸激酶同工酶MB(CK-MB)、氨基末端脑钠肽前体(NT-proBNP)水平均无明显变化(P>0.05),且均显著优于AC-THP组(P<0.05)。结论TcbHP方案治疗HER-2阳性乳腺癌的疗效与AC-THP方案相当,但前者降低肿瘤标志物生成的作用更明显,且心脏毒性风险相对更低。

预防与控制:能源市场准入制度因应“双碳”目标的法律机理

能源结构低碳化转型作为“双碳”目标推进的重要战略,需要一系列制度措施来促进“清洁用能”和“能源供给”兼备的能源结构格局之形成。市场机制是能源结构低碳化转型的主要驱动,而能源市场准入制度是发挥市场机制秩序稳定与风险防范作用的重要约束和规制工具。因此,能源结构低碳化转型须构建完善的能源市场准入制度予以落实。传统能源市场准入制度对低碳治理的规制存在局限,革新的能源市场准入制度应当体现出维护能源市场秩序与气候公共利益实现的双重价值追求,功能定位在“预防—控制”的二元结构。“预防—控制”的功能定位呼唤能源市场准入制度明确更为科学的立法导向,该制度的规范建构须分别在“碳源”阶段与“碳流”阶段实施不同的功能分配、资源整合与立法策略:前者聚焦于调适能源开发利用中传统化石能源、清洁能源与可再生能源的比例,促进能源结构的低碳升级;后者注重能源产业的资质准入与行为监督,在保障能源合理供给的基础上强化低碳治理。由此切入,能源市场准入制度的革新应当按照统一性与差异性相结合的原则,从能源供给与低碳控制两个层面归纳所涉制度要素并对之定性,进一步完善准入标准、许可事务、准入审批与后续监管等要素的规范形态,充实规范内容与程序结构,提升制度能力。具言之,一是以协调能源供给与低碳控制为原则,注重不同能源准入情景下需要何种强度的资格准入、规模准入、项目审查等标准的实践性指向,形成具备稳定性与定量性的准入标准;二是以“能源供给的必要性”和“碳风险程度”为划分标准,根据不同能源开采企业与加工转换企业的特性来识别差异化的运营需求与行为要求,进而厘定各类能源产业的许可条件设定与事务分配;三是以准入审批与后续监管并重的结构化联结为理念,构建以“准入事务与标准的履行能力”为中心的专项审查模式与以“能源供给与低碳控制的义务履行实效”为中心的后续监管模式,强化被准入主体的能源服务供给与低碳义务的履行。