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Resistance to ERK1/2 pathway inhibitors;sweet spots,fitness deficits and drug addiction

Cancer Drug Resistance 2019年第2期2卷 365-380页

作者： Matthew j.Sale Kathryn Balmanno simon j.Cook Signalling Programme The Babraham InstituteBabraham Research CampusCambridge CB223ATUK

MEK1/2 inhibitors are clinically approved for the treatment of BRAF-mutant melanoma,where they are used in combination with BRAF inhibitors,and are undergoing evaluation in other *** resistance to MEK1/2 inhibitors,including selumetinib(AZD6244/ARRY-142866),can arise through amplification of BRAF^(V600E) or KRAS^(g13D) to reinstate ERK1/2 *** have found that BRAF^(V600E) amplification and selumetinib resistance are fully reversible following drug *** is because resistant cells with BRAF^(V600E) amplification become addicted to selumetinib to maintain a precise level of ERK1/2 signalling(2%-3%of total ERK1/2 active),that is optimal for cell proliferation and *** withdrawal drives ERK1/2 activation outside of this critical“sweet spot”(~20%-30%of ERK1/2 active)resulting in a p57^(KIP2)-dependent g1 cell cycle arrest and senescence or expression of NOXA and cell death with features of autophagy;these terminal responses select against cells with amplified BRAF^(V600E).ERK1/2-dependent p57^(KIP2) expression is required for loss of BRAF^(V600E) amplification and determines the rate of reversal of selumetinib *** of selumetinib-resistant cells with BRAF^(V600E) amplification as tumour xenografts also requires the presence of selumetinib to“clamp”ERK1/2 activity within the sweet ***,BRAF^(V600E) amplification confers a selective disadvantage or“fitness deficit”during drug withdrawal,providing a rationale for intermittent dosing to forestall ***,selumetinib resistance driven by KRAS^(g13D) amplification/upregulation is not *** these cells ERK1/2 reactivation does not inhibit proliferation but drives a ZEB1-dependent epithelial-to-mesenchymal transition that increases cell motility and promotes resistance to traditional chemotherapy *** results reveal that the emergence of drug-addicted,MEKi-resistant cells,and the opportunity this may afford for intermittent dosing

关键词： BRAF CDKN1C/p57^(KIP2) EMT ERK KRAS MEK MEK inhibitor resistance selumetinib

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Machine learning ensemble model prediction of northward shift in potato cyst nematodes(globodera rostochiensis and ***)distribution under climate change conditions

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journal of Integrative Agriculture 2024年第10期23卷 3576-3591页

作者： Yitong He guanjin Wang Yonglin Ren Shan gao Dong Chu simon j.McKirdy Shandong Engineering Research Centre for Environment-friendly Agricultural Pest Management College of Plant Health andMedicineQingdao Agricultural UniversityQingdao 266109China Harry Butler Institute Murdoch UniversityMurdochWA 6150Australia School of Information Technology Murdoch UniversityPerthWA 6150Australia Hebei Dahaituo National Nature Reserve Management Centre Chicheng 075500China

Potato cyst nematodes(PCNs)are a significant threat to potato production,having caused substantial damage in many *** the future distribution of PCN species is crucial to implementing effective biosecurity strategies,especially given the impact of climate change on pest species invasion and *** learning(ML),specifically ensemble models,has emerged as a powerful tool in predicting species distributions due to its ability to learn and make predictions based on complex data ***,this research utilised advanced machine learning techniques to predict the distribution of PCN species under climate change conditions,providing the initial element for invasion risk *** first used global Climate Models to generate homogeneous climate predictors to mitigate the variation among ***,five machine learning models were employed to build two groups of ensembles,single-algorithm ensembles(ESA)and multi-algorithm ensembles(EMA),and compared their *** this research,the EMA did not always perform better than the ESA,and the ESA of Artificial Neural Network gave the highest performance while being *** results indicated that the distribution range of PCNs would shift northward with a decrease in tropical zones and an increase in northern ***,the total area of suitable regions will not change significantly,occupying 16-20%of the total land surface(18%under current conditions).This research alerts policymakers and practitioners to the risk of PCNs’incursion into new ***,this ML process offers the capability to track changes in the distribution of various species and provides scientifically grounded evidence for formulating long-term biosecurity plans for their control.

关键词： invasive species distribution future climates homogeneous climate predictors single-algorithm ensembles multi-algorithm ensembles artificial neural network

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Deformation correlations,stress field switches and evolution of an orogenic intersection:The Pan-African Kaoko-Damara orogenic junction,Namibia

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geoscience Frontiers 2017年第6期8卷 1187-1232页

作者： ben goscombe David A.Foster David gray ben Wade Antonios Marsellos jason Titus Integrated Terrane Analysis Research(ITAR) 18 Cambridge RdAldgate5154SAAustralia Department of geological Sciences University of FloridaGainesvilleFL32611USA School of Earth Sciences University of TasmaniaHobartTASAustralia Adelaide Microscopy University of AdelaideAdelaide5005SAAustralia Hofstra University HempsteadNYUSA

Age calibrated deformation histories established by detailed mapping and dating of key magmatic time markers are correlated across all tectono-metamorphic provinces in the Damara Orogenic *** across structural belts result in an internally consistent deformation framework with evidence of stress field rotations with similar timing,and switches between different deformation *** principle compressive stress rotated clockwise ~180°in total during Kaoko Belt evolution,and^135° during Damara Belt *** most stages,stress field variation is progressive and can be attributed to events within the Damara Orogenic System,caused by changes in relative trajectories of the interacting Rio De La Plata,Congo,and Kalahari *** orogenesis occurred earliest and evolved from collision and obduction at ~590 Ma,involving E-W directed shortening,progressing through different transpressional states with ~45° rotation of the stress field to strike-slip shear under NW-SE shortening at ~550-530 *** orogenesis evolved from collision at ~555-550 Ma with NW-SE directed shortening in common with the Kaoko Belt,and subsequently evolved through ~90°rotation of the stress field to NE-SW shortening at ~512-508 *** Kaoko and Damara orogenic fronts were operating at the same time,with all three cratons being coaxially convergent during the 550-530 Ma period;Rio De La Plata directed SE against the Congo Craton margin,and both together over-riding the Kalahari Craton margin also towards the *** stress field rotation was punctuated by rapid and significant switches at ~530-525 Ma,~508 Ma and ~505 *** three events included:(1)Culmination of main phase orogenesis in the Damara Belt,coinciding with maximum burial and peak metamorphism at 530-525 *** occurred at the same time as termination of transpression and initiation of transtensional reactivation of shear zones in the Kaoko *** compressive stress switched from NW-

关键词： Damara Orogen Stress fields Orogeny Assembly of gondwana Event geochronology Deformation correlations

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On the Trends of Autonomous Unmanned Systems Research

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Engineering 2022年第5期8卷 20-23页

作者： ben M.Chen Department of Mechanical and Automation Engineering The Chinese University of Hong KongHong Kong 999077China

In recent decades,academia and industry have put increasing attention and investment into the research and development of autonomous unmanned *** autonomous unmanned vehi-cle is a machine equipped with necessary data-processing units,sophisticated sensors,environment perception,automatic control,motion planning,task planning,mission management,and com-munication systems.

关键词： autonomous systems equipped

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Mid/far-infrared photo-detectors based on graphene asymmetric quantum wells

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Chinese Physics B 2016年第9期25卷 573-580页

作者： E ben Salem R Chaabani S jaziri Institut Preparatoire aux Etudes d'Ingenieurs de Tunis 2 Rue Jawaher Lel Nahrou Monfleury 1089 Tunisie Laboratoire de Physique de la Matiere Condensee Departement de Physique Faculte des Sciences de Tunis Campus Universitaire 2092 Tunisie Departement de Physique Faculte des Sciences de Bizerte Jarzouna 7021 Bizerte

We conducted a theoretical study on the electronic properties of a single-layer graphene asymmetric quantum *** of energy levels is limited by electron–hole conversion at the barrier interfaces and free-electron ***–hole conversion at the barrier interfaces can be controlled by introducing an asymmetry between barriers and taking into account the effect of the interactions of the graphene sheet with the *** interaction with the substrate induces an effective mass to carriers,allowing observation of Fabry–P′erot resonances under normal incidence and extinction of Klein *** asymmetry,between barriers creates a transmission gap between confined states and free-electron continuum,allowing the large graphene asymmetric quantum well to be exploited as a photo-detector operating at mid-and far-infrared frequency regimes.

关键词： graphene quantum wells reflection coefficient photo-detector

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Spiral volumetric optoacoustic tomography visualizes multi-scale dynamics in mice

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Light(Science & Applications) 2016年第1期5卷 104-111页

作者： X Luís Deán-ben Thomas F Fehm Steven j Ford Sven gottschalk Daniel Razansky Institute for Biological and Medical Imaging(IBMI) Helmholtz Center Munich85764 NeuherbergGermany School of Medicine and School of Bioengineering Technical University of Munich81675 MunichGermany

Imaging dynamics at different temporal and spatial scales is essential for understanding the biological complexity of living organisms,disease state and *** imaging has been shown to offer exclusive applicability across multiple scales with excellent optical contrast and high resolution in deep-tissue ***,efficient visualization of multi-scale dynamics remained difficult with state-of-the-art systems due to inefficient trade-offs between image acquisition time and effective field of ***,we introduce the spiral volumetric optoacoustic tomography technique that provides spectrally enriched highresolution contrast across multiple spatiotemporal *** vivo experiments in mice demonstrate a wide range of dynamic imaging capabilities,from three-dimensional high-frame-rate visualization of moving organs and contrast agent kinetics in selected areas to whole-body longitudinal studies with unprecedented image *** newly introduced paradigm shift in imaging of multi-scale dynamics adds to the multifarious advantages provided by the optoacoustic technology for structural,functional and molecular imaging.

关键词： multi-scale dynamics multi-spectral imaging optoacoustic tomography real-time imaging whole-body imaging

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Degradation and fate of 2,4-dinitroanisole(DNAN)and its intermediates treated with Mg/Cu bimetal:Surface examination with XAS,DFT,and LDI-MS

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journal of Environmental Sciences 2023年第7期129卷 161-173页

作者： Andrew Mai Emese Hadnagy Qiantao Shi Lotanna Ezeonu jason P.Robbins simon g.Podkolzin Agamemnon Koutsospyros Christos Christodoulatos Center for Environmental Systems Stevens Institute of TechnologyHobokenNJ 07030USA School of Engineering and Technology University of Washington TacomaTacomaWA 98402USA

A novel Mg-based bimetal reagent(Mg/Cu)was used as an enhanced reductive system to degrade insensitivemunition 2,4-dinitroanisole(DNAN),a contaminant found in *** ofDNANwas significantly impacted by dissolved oxygen and studied in anoxic and oxic bimetal systems(i.e.,purging with N2,air,or O_(2) gas).Degradation occurred through sequential nitroreduction:first one nitro group was reduced(ortho or para)to form short-lived intermediates 2-amino-4-nitroanisole or 4-amino-2-nitroanisole(2-ANAN or 4-ANAN),and then subsequent reduction of the other nitro group formed 2,4-diaminoanisole(DAAN).The nitro-amino intermediates demonstrated regioselective reduction in the ortho position to 2-ANAN;Regioselectivity was also impacted by the anoxic/oxic *** O_(2)-purging DNAN degradation rate was slightly enhanced,but most notably O_(2) significantly accelerated DAAN *** also further degraded only in the oxygenated Mg/Cu *** of DNAN byproducts to the reagent occurred regardless of anoxic/oxic condition,resulting in a partition of carbon mass between the adsorbed phase(27%-35%)and dissolved phase(59%-72%).Additional surface techniqueswere applied to investigate contaminant interaction with *** functional theory(DFT)calculations identified preferential adsorption structures for DNAN on Cu with binding through two O atoms of one or both nitro groups.X-ray absorption spectroscopy(XAS)measurements determined the oxidation state of catalyticmetal Cu and formation of a Cu-O-N bond during *** desorption ionization mass spectrometry(LDI-MS)measurements also identified intermediate 2-ANAN adsorbed to the bimetal surface.

关键词： Insensitive munition Magnesium bimetal Reductive degradation Adsorption Surface analysis DFT DNAN Oxic

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An insight into the removal of fluoroquinolones in activated sludge process:Sorption and biodegradation characteristics

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journal of Environmental Sciences 2017年第6期29卷 263-271页

作者： Lu Wang Zhimin Qiang Yangang Li Weiwei ben Key Laboratory of Drinking Water Science and Technology Research Center for Eco-Environmental SciencesChinese Academy of SciencesBeijing 100085China

The detailed sorption steps and biodegradation characteristics of fluoroquinolones （FQs） including ciprofloxacin, enrofloxacin, lomefloxacin, norfloxacin, and ofioxacin were investigated through batch experiments. The results indicate that FQs at a total concentration of 500 μg/L caused little inhibition of sludge bioactivity. Sorption was the primary removal pathway of FQs in the activated sludge process, followed by biodegradation, while hydrolysis and volatilization were negligible. FQ sorption on activated sludge was a reversible process governed by surface reaction, Henry and Freundlich models could describe the FQ sorption isotherms well in the concentration range of 100-300 μg/L. Thermodynamic parameters revealed that FQ sorption on activated sludge is spontaneous, exothermic, and enthalpy-driven. Hydrophobicity-independent mechanisms determined the FQ sorption affinity with activated sludge. The zwitterion of FQs had the strongest sorption affinity, followed by cation and anion, and aerobic condition facilitated FQ sorption. PQs were slowly biodegradable, with long half-lives （〉100 hr）. FQ biodegradation was enhanced with increasing temperature and under aerobic condition, and thus was possibly achieved through co-metabolism during nitrification. This study provides an insight into the removal kinetics and mechanism of FQs in the activated sludge process, but also helps assess the environmental risks of FQs resulting from sludge disposal.

关键词： Fluoroquinolones Sorption Biodegradation Activated sludge

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Dislocation-mediated migration of interphase boundaries

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journal of Materials Science & Technology 2019年第11期35卷 2714-2726页

作者： Zhipeng Sun Fuzhi Dai ben Xu Wenzheng Zhang School of Materials Science and Engineering Tsinghua UniversityBeijing 100084China Science and Technology of Advanced Functional Composite Laboratory Aerospace Research Institute of Materials and Processing TechnologyBeijing 100076China Key Laboratory of Advanced Materials(MOE) State Key Laboratory of New Ceramics and Fine ProcessingChina

Faceted interphase boundaries(IPBs)are commonly observed in lath-shaped precipitates in alloys consisting of simple face-centred cubic(fcc),body centred-cubic(bcc)or hexagonal closed packed(hcp)phases,which normally contain one or two sets of parallel *** influence of these dislocations on interface migration and possible accompanying long-range strain field remain *** elucidate this,we carried out atomistic simulations to investigate the dislocation-mediated migration processes of IPBs in a pure-iron *** results show that the migration of these IPBs is accompanied with the slip of interfacial dislocations,even in high-index slip planes,with two migration modes were observed:the first mode is the uniform migration mode that occurs only when all of the dislocations slip in a common slip plane.A shear-coupled interface migration was observed for this *** other interfaces propagate in the stick-slip migration mode that occurs when the dislocations glide on different slip planes,involving dislocation reaction or tangling.A quantitative relationship was established to link the atomic displacements with the dislocation structure,slip plane,and interface *** macroscopic shear deformation due to the effect of overall atomic displacement shows a good agreement with the results obtained based on the phenomenological theory of martensite *** findings have general implications for the understanding of phase transformations and the surface relief effect at the atomic scale.

关键词： Interphase boundary migration O-line interface Shear-coupled interface migration Dislocation gliding Atomic displacement

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A conceptual framework for characterizing mineralized waste rocks as future resource

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International journal of Mining Science and Technology 2019年第3期29卷 429-435页

作者： Bright Oppong Afum Dylan Caverson Eugene ben-Awuah Mining Optimization Laboratory Bharti School of Engineering Laurentian University

Conventional mining practices do not extract all mineralized rocks due to prevailing *** in mineral prices and processing recovery(technology)could potentially make mineralized waste rocks profitable.A well-integrated mining strategy that focuses on both economic and physical resource depletion is vital to the management of non-renewable mineral *** this paper,a conceptual framework that maximizes the benefits of mining and processing mineralized waste rocks as future resource is *** policy and technical reforms that ensure mining companies incorporate the proposed mineralized waste rocks management framework in their long-term strategic mine plans have been recommended.

关键词： Resource depletion Mineralized waste Conventional mining practices Policy reform Technical reform Future resource

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