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Targeting KRAS in pancreatic cancer

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Oncology Research 2024年第5期32卷 799-805页

作者： SANDRA STICKLER BARBARA RATH gerhard HAMILTON Institute of Pharmacology Medical University of ViennaViennaA-1090Austria

Pancreatic cancer has a dismal prognosis due to late detection and lack of efficient *** Kirsten rat sarcoma virus(KRAS)oncogene is mutated in up to 90%of all pancreatic ductal adenocarcinomas(PDACs)and constitutes an attractive target for ***,the most common KRAS mutations in PDAC are G12D(44%),G12V(34%)and G12R(20%)that are not amenable to treatment by KRAS G12C-directed cysteine-reactive KRAS inhibitors such as Sotorasib and Adagrasib that exhibit clinical efficacy in lung *** G12C mutant pancreatic cancer has been treated with Sotorasib but this mutation is detected only in 2%–3%of ***,the KRAS G12D-directed MRTX1133 inhibitor has entered clinical trials and more of such inhibitors are in *** other KRAS mutations may be targeted indirectly via inhibition of the cognate guanosine exchange factor(GEF)Son of Sevenless 1 that drives *** agents seem to provide the means to target the most frequent KRAS mutations in PDAC and to improve patient outcomes.

关键词： Pancreatic cancer PDAC KRAS SOS1 PROTAC

Electrically tunable third-harmonic generation using intersubband polaritonic metasurfaces

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Light(Science & Applications) 2024年第8期13卷 1666-1674页

作者： Seongjin Park Jaeyeon Yu gerhard Boehm Mikhail A.Belkin Jongwon Lee Department of Electrical Engineering Ulsan National Institute of Science and Technology(UNIST)UlsanRepublic of Korea walter Schottky Institute Technical University of MunichGarchingGermany

Nonlinear intersubband polaritonic metasurfaces,which integrate giant nonlinear responses derived from intersubband transitions of multiple quantum wells(MQws)with plasmonic nanoresonators,not only facilitate efficient frequency conversion at pump intensities on the order of few tens of kw cm^(-2)but also enable electrical modulation of nonlinear responses at the individual meta-atom level and dynamic beam *** electrical modulation characteristics of the magnitude and phase of the nonlinear optical response are realized through Stark tuning of the resonant intersubband *** this study,we report,for the first time,experimental implementations of electrical modulation characteristics of mid-infrared third-harmonic generation(THG)using an intersubband polaritonic metasurface based on MQw with electrically tunable third-order nonlinear ***,we achieved a 450%modulation depth of the THG signal,86%suppression of zero-order THG diffraction tuning based on local phase tuning exceeding 180 degrees,and THG beam steering using phase *** work proposes a new route for electrically tunable flat nonlinear optical elements with versatile functionalities.

关键词： tunable tuning pump

Development of PROTACS degrading KRAS and SOS1

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Oncology Research 2024年第8期32卷 1257-1264页

作者： gerhard HAMILTON MARIE-THERESE EGGERSTORFER SANDRA STICKLER Institute of Pharmacology Medical University of ViennaVienna1090Austria

The Kirsten rat sarcoma virus—son of sevenless 1(KRAS-SOS1)axis drives tumor growth preferentially in pancreatic,colon,and lung ***,KRAS G12C mutated tumors can be successfully treated with inhibitors that covalently block the cysteine of the switch II binding pocket of ***,the range of other KRAS mutations is not amenable to treatment and the G12C-directed agents Sotorasib and Adragrasib show a response rate of only approximately 40%,lasting for a mean period of 8 *** approach to increase the efficacy of inhibitors is their inclusion into proteolysis-targeting chimeras(PROTACs),which degrade the proteins of interest and exhibit much higher antitumor activity through multiple cycles of ***,PROTACs have been developed based on KRAS-or SOS1-directed inhibitors coupled to either von Hippel-Lindau(VHL)or Cereblon(CRBN)ligands that invoke the proteasomal *** of these PROTACs show increased activity in vitro and in vivo compared to their cognate inhibitors but their toxicity in normal tissues is not *** CRBN PROTACs containing thalidomide derivatives cannot be tested in experimental *** to such PROTACS arises through downregulation or inactivation of CRBN or factors of the functional VHL E3 ubiquitin *** highly active KRAS and SOS1 PROTACs have been formulated their clinical application remains difficult.

关键词： Proteolysis-targeting chimeras(PROTACs) Kirsten rat sarcoma virus(KRAS) Son of sevenless 1(SOS1) Von Hippel-Lindau Cereblon

wheat zinc finger protein TaZF interacts with both the powdery mildew AvrPm2 protein and the corresponding wheat Pm2a immune receptor

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Plant Communications 2024年第5期5卷 25-41页

作者： Beatrice Manser Helen Zbinden gerhard Herren Joel Steger Jonatan Isaksson Stephanie Braunlich Thomas wicker Beat Keller Department of Plant and Microbial Biology University of ZurichZollikerstrasse 1078008 ZurichSwitzerland Agroscope Route de Duillier 501260 NyonSwitzerland BIOREBA AG Christoph Merian-Ring 74153 ReinachSwitzerland

Plant defense responses to pathogens are induced after direct or indirect perception of effector proteins or their activity on host *** fungal–plant interactions,relatively little is known about whether,in addi-tion to avirulence effectors and immune receptors,other proteins contribute to specific *** nucleotide-binding leucine-rich repeat(NLR)immune receptor Pm2a in wheat recognizes the fungal pow-dery mildew effector *** found that the predicted wheat zincfinger TaZF interacts with both the fungal avirulence protein AvrPm2 and the wheat NLR *** further demonstrated that the virulent AvrPm2-H2 variant does not interact with *** silencing in wheat resulted in a reduction but not a loss of Pm2a-mediated powdery mildew *** studies showed that the leucine-rich repeat domain of Pm2a is the mediator of the interaction with *** recruits both Pm2a and AvrPm2 from the cytosol to the nucleus,resulting in nuclear localization of Pm2a,TaZF,and AvrPm2 in *** propose that TaZF acts as a facilitator of Pm2a-dependent AvrPm2 effector *** highlight the importance of identifying effector host targets for characterization of NLR-mediated effector recognition.

关键词： plant immunity plant-fungal interactions pathogen effectors nucleotide-binding leucine-rich repeat immune receptor NLR wheat powdery mildew

Translocator protein and neurodegeneration: insights from Alzheimer’s disease

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Neural Regeneration Research 2025年第4期20卷 1090-1091页

作者： Arpit Kumar Pradhan Rainer Rupprecht gerhard Rammes Klinik für Anaesthesiologie und Intensivmedizin der Technischen Universität München Klinikum rechts der IsarMunichGermany Graduate School of Systemic Neurosciences Ludwig-Maximilians-Universität MünchenMartinsriedGermany Department of Psychiatry and Psychotherapy University RegensburgRegensburgGermany

The 18 kDa translocator protein(TSPO)located on the outer mitochondrial membrane regulates several key cellular processes including mitochondrial homeostasis,cholesterol transport,apoptosis,cell proliferation,and maintenance of mitochondrial health(Rupprecht et al.,2022,2023).TSPO is expressed in both peripheral organs and the central nervous system,with a more pronounced expression in tissues that produce *** main reason why TSPO has garnered so much attention is because it plays a key role in neurosteroidogenesis by transferring cholesterol from the outer to the inner mitochondrial membrane,which is the rate-limiting step in neurosteroid synthesis.A cholesterol-recognizing amino acid consensus domain has been identified in the cytosolic C terminus of the TSPO protein by both in vitro and site-directed mutagenesis experiments(Li et al.,2001).However,the role of TSPO in the process of neurosteroid synthesis has been challenged by several studies,particularly TSPO knockout models,which suggest that TSPO removal does not affect the phenotype or the system’s viability(Tu et al.,2014).However,ligands targeting TSPO have been shown to enhance levels of neurosteroids which suggests that neurosteroidogenesis is one of the major functional roles mediated by the TSPO protein.

关键词： cholesterol organs

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Anomalies in the short-range local environment and atomic diffusion in single crystalline equiatomic CrMnFeCoNi highentropy alloy

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Nano Research 2024年第6期17卷 5336-5348页

作者： Alevtina Smekhova Daniel Gaertner Alexei Kuzmin Ana Guilherme Buzanich Goetz Schuck Ivo Zizak gerhard wilde Kirill V.Yusenko Sergiy Divinski Helmholtz-Zentrum Berlin für Materialien und Energie(HZB) D-12489 BerlinGermany Institute of Materials Physics University of MünsterD-48149 MünsterGermany Institute of Solid State Physics University of LatviaLV-1063 RigaLatvia Bundesanstalt für Materialforschung und–prüfung(BAM) D-12489 BerlinGermany

Multi-edge extended X-ray absorption fine structure(EXAFS)spectroscopy combined with reverse Monte Carlo(RMC)simulations was used to probe the details of element-specific local coordinations and component-dependent structure relaxations in single crystalline equiatomic CrMnFeCoNi high-entropy alloy as a function of the annealing *** representative states,namely a high-temperature state,created by annealing at 1373 K,and a low-temperature state,produced by long-term annealing at 993 K,were compared in *** features identified in atomic configurations of particular principal components indicate variations in the local environment distortions connected to different degrees of compositional disorder at the chosen representative *** detected changes provide new atomistic insights and correlate with the existence of kinks previously observed in the Arrhenius dependencies of component diffusion rates in the CrMnFeCoNi high-entropy alloy.

关键词： high-entropy alloys diffusion short-range order extended X-ray absorption fine structure(EXAFS) reverse Monte Carlo

离心力作用下轴承滚道润滑剂流失与定量补油数值模拟

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摩擦学学报 2024年第9期44卷 1184-1191页

作者：高军斌杨萍栗心明高志伟郭峰 Poll gerhard 青岛理工大学机械与汽车工程学院德国莱布尼茨汉诺威大学机械设计与摩擦学研究所

采用自由表面薄膜流动模型，数值模拟了高速轴承壁面润滑剂在离心力作用下的流动过程，并通过外部定量补油对壁面油层厚度和润滑状态进行了调控.结果表明：高速下离心力的作用可使轴承壁面的润滑剂呈现出非线性衰退，使轴承处于乏油润... 详细信息

采用自由表面薄膜流动模型，数值模拟了高速轴承壁面润滑剂在离心力作用下的流动过程，并通过外部定量补油对壁面油层厚度和润滑状态进行了调控.结果表明：高速下离心力的作用可使轴承壁面的润滑剂呈现出非线性衰退，使轴承处于乏油润滑状态；与离心力相比，由表面张力引起的润滑剂回填几乎可以忽略，需依靠外部供油对轴承壁面油层进行增补；通过调整供油时间间隔，可实现轴承壁面润滑剂流动的供失平衡；采用多次微量供油，可将壁面油层厚度和接触区润滑状态调控在一定范围内，进而使轴承处于最佳的润滑状态.

关键词：油层衰退离心力润滑剂补充滚动轴承

来源：博看期刊

限量供油条件下微柱阵列束油表面润滑增效特性研究

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摩擦学学报（中英文） 2024年第2期44卷 117-128页

作者：孙建欣刘成龙郭峰 POLL gerhard 柏林清栗心明青岛理工大学机械与汽车工程学院山东青岛266520 莱布尼兹-汉诺威大学机械设计与摩擦学研究所 Welfengarten130167汉诺威德国

在润滑轨道两侧制备以防指纹油涂层(Anti-fingerprint coating,AFC)修饰的微柱阵列(Micropillar array,MA),形成润湿性梯度束油的润滑增效表面.使用点接触光弹流润滑油膜测量仪测量了该表面在限量供油往复运动条件下的油膜厚度以及油池... 详细信息

在润滑轨道两侧制备以防指纹油涂层(Anti-fingerprint coating,AFC)修饰的微柱阵列(Micropillar array,MA),形成润湿性梯度束油的润滑增效表面.使用点接触光弹流润滑油膜测量仪测量了该表面在限量供油往复运动条件下的油膜厚度以及油池形态,探究了往复频率、束油轨道宽度和载荷对润滑性能的影响,同时与未经AFC修饰的微柱阵列束油表面和仅以AFC形成的束油表面进行了对比.结果表明:制备的经AFC修饰的微柱阵列束油表面比其他2个束油表面有更好的润滑特性,往复运动条件(4 Hz)下明显改善了行程中点及两端点处的润滑状态,相对原始未处理表面行程中点处中心油膜厚度最高提升了51.4%.表面在束油轨道宽度接近Hertz接触区宽度时集油效果最强,随着轨道宽度增加集油效果减弱.载荷对微柱束油阵列表面的集油效果影响显著,随着载荷增大轨道机械分离作用变强、毛细回流作用减弱,造成集油能力和油膜厚度下降.

关键词：微柱阵列润湿性梯度油膜厚度往复运动限量供油

维普期刊数据库博看期刊

Haemorrhage after thrombectomy with adjuvant thrombolysis in unknown onset stroke depends on high early lesion water uptake

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Stroke & Vascular Neurology 2024年第4期9卷 390-398页

作者： Gabriel Broocks Lukas Meyer Uta Hanning Tobias Djamsched Faizy Matthias Bechstein Helge Kniep Noel Van Horn gerhard Schön Ewgenia Barow Götz Thomalla Jens Fiehler Andre Kemmling Department of Diagnostic and Interventional Neuroradiology University Medical Center Hamburg-EppendorfHamburgGermany Department of Medical Biometry and Epidemiology University Medical Center Hamburg EppendorfHamburgGermany Department of Neurology University Medical Center Hamburg-EppendorfHamburgGermany Department of Neuroradiology University MarburgMarburgGermany

Background and purpose In wake-up stroke,CT-based quantitative net water uptake(NwU)might serve as an alternative tool to MRI to guide intravenous thrombolysis with alteplase(IVT).An important complication after IVT is symptomatic intracerebral haemorrhage(sICH).As NwU directly implies ischaemic lesion progression,reflecting blood-brain barrier injury,we hypothesised that NwU predicts sICH in patients who had a ischaemic stroke undergoing thrombectomy with unknown *** Consecutive analysis of all patients who had unknown onset anterior circulation ischaemic stroke who underwent CT at baseline and endovascular treatment between December 2016 and October *** NwU was assessed on baseline *** primary endpoint was *** association of NwU and other baseline parameters to sICH was investigated using inverse-probability weighting(IPw)*** A total of 88 patients were included,of which 46 patients(52.3%)received *** median NwU was 10.7%(IQR:5.1–17.7).The proportion of patients with any haemorrhage and sICH were 35.2%and 13.6%.NwU at baseline was significantly higher in patients with sICH(19.1%vs 9.6%,pwas lower(5 vs 8,pwing IPw,there was no association between IVT and sICH in unadjusted ***,after adjusting for ASPECTS and NwU,there was a significant association between IVT administration and sICH(14.6%,95%CI:3.3%to 25.6%,pwith ischaemic stroke with unknown onset,the combination of high NwU with IVT is directly linked to higher rates of *** ASPECTS for evaluating the extent of the early infarct lesion,quantitative NwU could be used as an imaging biomarker to assess the degree of blood-brain barrier damage in order to predict the risk of sICH in patients with wake up stroke.

关键词： throm thrombolysis high