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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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In situ characterization of particle formation in spray flame synthesis using wide-angle light scattering

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Particuology 2024年第3期86卷 304-312页

作者： simon Aβmann Franz j.T.Huber Stefan Will Lehrstuhl für Technische Thermodynamik(LTT) Friedrich-Alexander-Universitat Erlangen-Nürnberg(FAU)Erlangen91058Germany Erlangen Graduate Schoolin Advanced Optical Technologies(SAOT) Friedrich-Alexander-Universitat Erlangen-Nurnberg(FAU)Erlangen91052Germany Competence Unit Engineering of Advanced Materials(EAM) Friedrich-Alexander-Universitat Erlangen-Nürnberg(FAU)Erlangen91052Germany

Wide-angle light scattering(WALS)was used for in situ measurements of droplet and nanoparticle size distributions during the synthesis of titania and iron oxide particles from liquid precursor solutions in the standardized SpraySyn burner for spray flame *** was synthesized from titanium tetraisopropoxide(TTIP)and iron oxide from iron(II)nitrate nonahydrate(INN)using ethanol(EtOH)as *** images were taken at heights up to 120 mm above the burner surface and classified into droplet and particle *** size distributions were derived from a sequential analysis of scattering data containing the oscillating Mie pattern,the lognormal size distribution parameters for spherical and fractal particle fractions from a multivariate approach on averaged particle scattering *** results show that the precursor addition leads to altered evaporation behavior and even droplet disruption probably induced by puffing or micro-explosions compared to pure *** the case of TTIP(a hygroscopic alkoxide),the synthesis of a large fraction of spheres was observed,while the nitrate INN leads to the formation of mostly fractal aggregates.

关键词： Spray flame synthesis Metal oxide particles Elastic light scattering Droplet size distribution Nanoparticle morphology Particle size distribution

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Stable diffusion gradients in microfluidic conduits bounded by fluid walls

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Microsystems & Nanoengineering 2024年第3期10卷 357-367页

作者： Federico Nebuloni Cyril Deroy Peter R.cook Edmond j.Walsh Department of Engineering Science Osney Thermo-Fluids InstituteUniversity of OxfordOxford OX20ESUK Sir William Dunn School of Pathology University of OxfordOxford OX13REUK

Assays mimicking in vitro the concentration gradients triggering biological responses like those involved in fighting infections and blood clotting are essential for biomedical *** assays prove especially attractive as they allow precise control of gradient shape allied to a reduction in *** microfluidic devices are fabricated using solid plastics that prevent direct access to responding ***-walled microfluidics allows the manufacture of circuits on standard Petri dishes in seconds,coupled to simple operating methods;cell-culture medium sitting in a standard dish is confined to circuits by fluid walls made of an immiscible *** develop and experimentally validate an analytical model of diffusion between two or more aqueous streams flowing at different rates into a fluid-walled conduit with the cross-section of a circular *** solid walls,fluid walls morph during flows as pressures fall,with wall shape changing down the *** model is validated experimentally for Fourier numbers<0.1 using fluorescein diffusing between laminar *** enables a priori prediction of concentration gradients throughout a conduit,so allowing rapid circuit design as well as providing bioscientists with an accurate way of predicting local concentrations of bioactive molecules around responsive and nonresponsive cells.

关键词： walls diffusion attractive

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Effects of a school-based karate intervention on academic achievement,psychosocial functioning,and physical fitness:A multi-country cluster randomized controlled trial

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journal of Sport and Health Science 2024年第1期13卷 90-98页

作者： Tania Pinto-Escalona Erica Gobbi Pedro L.Valenzuela simon j.Bennett Pierluigi Aschieri Manuel Martin-Loeches Antonio Paoli Oscar Martinez-de-Quel Faculty of Education Complutense University of MadridMadrid 28040Spain Department of Biomolecular Sciences University of Urbino“Carlo Bo”Urbino 61029Italy Department of Systems Biology University of AlcaláMadrid 28805Spain Research Institute for Sport and Exercise Sciences Faculty of ScienceLiverpool John Moores UniversityLiverpoolL33AFUK Italian judo WrestlingKarate and Martial Arts FederationRome 00122Italy Psychobiology&Methods for the Behavioural Sciences Department Complutense University of MadridMadrid 28040Spain Department of Biomedical Sciences University of PaduaPadua 35122Italy

Purpose:To examine the effects of a school-based karate intervention on academic achievement,psychosocial functioning,and physical fitness in children aged 7-8 ***:Twenty schools in 5 different European countries(2 second-grade classrooms per school)participated in a cluster randomized controlled trial(Sport at School trial).Participants were assigned to either a control group,which continued with their habitual physical education lessons,or to an intervention group,which replaced these lessons with a 1-year karate intervention(Karate Mind and Movement program).A total of 721 children(344 girls and 377 boys,7.4±0.5 years old,mean±SD)completed the study,of which 333 and 388 were assigned to the control group and intervention group,*** included academic performance(average grade),psychosocial functioning(Strengths and Difficulties Questionnaire for parents),and different markers of physical fitness(cardiorespiratory fitness,balance,and flexibility).Results:The intervention provided small but significant benefits compared to the control group for academic achievement(d=0.16;p=0.003),conduct problems(d=-0.28;p=0.003),cardiorespiratory fitness(d=0.36;p0.05).Conclusion:A 1-year school-based karate intervention was effective in improving academic achievement,conduct problems,and physical fitness in primary school *** results support the inclusion of karate during physical education lessons.

关键词： Academic performance Cardiorespiratory fitness Conduct problems Karate Physical fitness

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Machine learning ensemble model prediction of northward shift in potato cyst nematodes(Globodera rostochiensis and G. pallida)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 and MedicineQingdao Agricultural University Harry Butler Institute Murdoch University School of Information Technology Murdoch University Hebei Dahaituo National Nature Reserve Management Centre

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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Estimates for Lyme borreliosis infections based on models using sentinel canine and human seroprevalence data

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Infectious Disease Modelling 2020年第1期5卷 871-888页

作者： Michael j.cook Basant K.Puri Vis a Vis Symposiums Bury St EdmundsUK CAR CambridgeUK

Two models were developed to estimate Lyme borreliosis(LB)*** was based on the seroprevalence of Borrelia infections in human *** model used corrections for false negative and false positive results from published test sensitivity and specificity measures.A second model based on Borrelia infections in sentinel dogs was used to quantify the prevalence of Lyme disease Borrelia infections in humans;the reference baseline for this model was human and canine infections in Germany.A comparison of the two models is shown and differences *** relationships between incidence,prevalence and total infection burden for LB were derived from published data and these were used in both models to calculate annual incidence,prevalence and total LB *** modelling was conservative and based on medical insurance records coded for erythema *** model growth rates were used in place of the commonly adopted exponential *** mean of the two models was used to create estimates for various countries and *** from the analyses for LB estimated for 2018 include:incidence e USA 473,000/year,Germany 471,000/year,France 434,000/year and UK 132,000/year;prevalence e USA 2.4 million,Germany 2.4 million,France 2.2 million and UK 667,000;total infections e USA 10.1 million,Germany 10.0 million,France 9.3 million and UK 2.8 *** for the world for 2018 are:incidence 12.3 million/year;prevalence 62.1 million;and total infection burden 262.0 *** figures are far higher than officially published data and reflect not only the underestimation of diagnosed cases,which is acknowledged by health agencies,but also undiagnosed and misdiagnosed cases.

关键词： Lyme disease Borreliosis Linear regression models Seropositive Companion animals Sentinel animals

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Detecting subtle yet fast skeletal muscle contractions with ultrasoft and durable graphene-based cellular materials

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National Science Review 2022年第4期9卷 105-115页

作者： Zijun He Zheng Qi Huichao Liu Kangyan Wang Leslie Roberts jefferson Z.Liu Yilun Liu Stephen j.Wang Mark j.cook George P.simon Ling Qiu Dan Li Department of Chemical Engineering The University of Melbourne Department of Materials Science and Engineering Monash University Department of Chemical Engineering Monash University State Key Laboratory for Strength and Vibration of Mechanical Structures School of Aerospace EngineeringXi'an Jiaotong University Neurophysiology Department Department of Neurology and Neurological ResearchSt Vincent's Hospital Department of Medicine St.Vincent's HospitalUniversity of Melbourne Department of Mechanical Engineering University of Melbourne Department of Design Monash University School of Design The Hong Kong Polytechnic University Shenzhen Geim Graphene Center Tsinghua-Berkeley Shenzhen InstituteTsinghua University

Human bodily movements are primarily controlled by the contractions of skeletal muscles. Unlike joint or skeletal movements that are generally performed in the large displacement range, the contractions of the skeletal muscles that underpin these movements are subtle in intensity yet high in frequency. This subtlety of movement makes it a formidable challenge to develop wearable and durable so?t materials to electrically monitor such motions with high fidelity for the purpose of, for example, muscle/neuromuscular disease diagnosis. Here we report that an intrinsically fragile ultralow-density graphene-based cellular monolith sandwiched between silicone rubbers can exhibit a highly effective stress and strain transfer mechanism at its interface with the rubber, with a remarkable improvement in stretchability(>100%). In particular, this hybrid also exhibits a highly sensitive, broadband-frequency electrical response(up to 180 Hz) for a wide range of strains. By correlating the mechanical signal of muscle movements obtained from this hybrid material with electromyography, we demonstrate that the strain sensor based on this hybrid material may provide a new, so?t and wearable mechanomyography approach for real-time monitoring of complex neuromuscular–skeletal interactions in a broad range of healthcare and human–machine interface applications. This work also provides a new architecture-enabled functional so?t material platform for wearable electronics.

关键词： cellular graphene strain sensors high-frequency electromechanical property surface mechanomyography skeletal muscle activity

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Evaluation of an automated spike-and-wave complex detection algorithm in the EEG from a rat model of absence epilepsy

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Neuroscience Bulletin 2015年第5期31卷 601-610页

作者： Sebastien H.Bauquier Alan Lai jonathan L.jiang Yi Sui Mark j.cook Faculty of Veterinary and Agricultural Sciences The University of Melbourne Department of Electrical and Electronic Engineering The University of Melbourne Department of Clinical Neurosciences St Vincent's Hospital Faculty of Medicine The University of Melbourne Department of Neurology Shenyang First People's Hospital

The aim of this prospective blinded study was to evaluate an automated algorithm for spike-andwave discharge（SWD） detection applied to EEGs from genetic absence epilepsy rats from Strasbourg（GAERS）.Five GAERS underwent four sessions of 20-min EEG *** EEG was manually analyzed for SWDs longer than one second by two investigators and automatically using an algorithm developed in MATLAB（？）.The sensitivity,specificity,positive predictive value（PPV）,and negative predictive value（NPV） were calculated for the manual（reference） versus the automatic（test） *** results showed that the algorithm had specificity,sensitivity,PPV and NPV 〉94%,comparable to published methods that are based on analyzing EEG changes in the frequency *** provides a good alternative as a method designed to mimic human manual marking in the time domain.

关键词： GAERS seizure detection epilepsy

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Muscadine or amla extracts standardized to ellagic acid content ameliorate glucolipotoxicity associatedβ-cell dysfunction via inhibition of IL-1βand improved insulin secretion

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食物生产加工与营养(英文) 2020年第1期2卷 91-101页

作者： Srikanth Earpina Karen McDonough Millicent Yeboah-Awudzi Kristina j.cook Sita Aggarwal jack N.Losso Chronic Degenerative Disease Prevention Laboratory School of Nutrition and Food ScienceLouisiana State University AgCenterLouisiana State University SystemBaton RougeLA 70803USA School of Animal Science Louisiana State University AgCenterLouisiana State University SystemBaton RougeLA 70803USA William Hansel Cancer Prevention Pennington Biomedical Research CenterLouisiana State University SystemBaton RougeLA 70808USA Louisiana State University System Baton RougeLA 70803USA

Glucolipotocixity induces IL-1βsecretion which impairs pancreaticβ-cell insulin *** acid and urolithin A have strong anti-inflammatory effect on *** and amla are very good sources of ellagic *** present study examined the effect of ellagic acid,ellagic acid-rich muscadine or amla extract,or urolothin A on inflammation inβcells under glucolipotoxic *** NIT-1βcells were incubated in glucolipotoxic conditions(33.3 mM glucose,250μM palmitic acid or 33.3 mM glucose+250μM palmitic acid with or without ellagic acid,ellagic acid-rich muscadine or amla extracts standardized to its ellagic acid content,or urolithin A).Inflammatory status was evidenced by ELISA analysis of insulin and IL-1β*** acid-rich muscadine or amla extracts dose-dependently stimulated insulin secretion and down-regulated IL-1βbetter than pure ellagic acid,or urolithin *** A did not statistically stimulate insulin secretion and did not inhibit IL-1β.

关键词： Muscadine Amla Ellagic acid NIT-1 pancreaticβ-cells glucose,Palmitic acid Glucolipotoxicity IL-1β Inflammation Inflammasome Insulin secretion

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The Triple Combination of Meropenem,Avibactam,and a Metallo-b-Lactamase Inhibitor Optimizes Antibacterial Coverage Against Different b-Lactamase Producers

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Engineering 2024年第7期38卷 124-132页

作者： Zhuoren Ling Alistair james Macdonald Farley Aditya Lankapalli Yanfang Zhang Shonnette Premchand-Branker Kate cook Andrei Baran Charlotte Gray-Hammerton Claudia Orbegozo Rubio Edgars Suna jordan Mathias jürgen Brem Kirsty Sands Maria Nieto-Rosado Maria Mykolaivna Trush Nadira Naznin Rakhi Willames Martins Yuqing Zhou Christopher joseph Schofield Timothy Walsh Department of Biology&Ineos Oxford Institute for Antimicrobial Research University of OxfordOxford OX13REUK Chemistry Research Laboratory Department of Chemistry and the Ineos Oxford Institute for Antimicrobial ResearchUniversity of OxfordOxford OX13TAUK Latvian Institute of Organic Synthesis Riga LV-1006Latvia Department of Medical Microbiology Division of Infection and ImmunitySchool of MedicineCardiff UniversityCardiff CF144XNUK Enzymology and Applied Biocatalysis Research Center Faculty of Chemistry and Chemical EngineeringBabes-Bolyai UniversityCluj-Napoca 400028Romania

This work explores the potential of a triple combination of meropenem(MEM),a novel metallo-blactamase(MBL)inhibitor(indole-2-carboxylate 58(InC58)),and a serine-b-lactamase(SBL)inhibitor(avibactam(AVI))for broad-spectrum activity against carbapenemase-producing bacteria.A diverse panel comprising MBL-and SBL-producing strains was used for susceptibility testing of the triple combination using the agar dilution *** frequency of resistance(FoR)to MEM combined with InC58 was *** were sequenced and tested for cross resistance,fitness,and the stability of the resistance *** with the double combinations of MEM plus an SBL or MBL inhibitor,the triple combination extended the spectrum of activity to most of the isolates bearing SBLs(oxacillinase-48(OXA-48)and Klebsiella pneumoniae carbapenemase-2(KPC-2))and MBLs(New Delhi metallo-blactamases(NDMs)),although it was not effective against Verona integron-encoded metallo-blactamase(VIM)-carrying Pseudomonas aeruginosa(***)and OXA-23-carrying Acinetobacter baumannii(***).The FoR to MEM plus InC58 ranged from 2.22×10^(-7)to 1.13×10^(-6).The resistance correlated with mutations to ompC and comR,affecting porin C and copper permeability,*** mutants manifested a fitness cost,a decreased level of resistance during passage without antibiotic pressure,and cross resistance to another carbapenem(imipenem)and a b-lactamase inhibitor(taniborbactam).In conclusion,compared with the dual combinations,the triple combination of MEM with InC58 and AVI showed a much wider spectrum of activity against different carbapenemaseproducing bacteria,revealing a new strategy to combat b-lactamase-mediated antimicrobial resistance.

关键词： Carbapenemase Metallo/serine-b-lactamase inhibitor Avibactam Meropenem Antimicrobial resistance

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