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The crystal structure of the non-liganded 14-3-3σ protein: insights into determinants of isoform specific ligand binding and dimerization

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Cell Research 2005年第4期15卷 219-227页

作者： Anne BENZINGER, Grzegorz M. POPOWICZ, Joma K. JOY,Sudipta MAJUMDAR,Tad A. HOLAK,Heiko HERMEKING Molecular Oncology Group Max-Planck-Institute for Biochemistry am klopferspitz 18 D-82152 Martinsried Germany NMR Group Max-Planck-Institute for Biochemistry am klopferspitz 18 D-82152 Martinsried Germany NMR Group Max-Planck-Institute for Biochemistry am klopferspitz 18 D-82152 Martinsried Germany NMR Group Max-Planck-Institute for Biochemistry am klopferspitz 18 D-82152 Martinsried Germany NMR Group Max-Planck-Institute for Biochemistry am klopferspitz 18 D-82152 Martinsried Germany Molecular Oncology Group Max-Planck-Institute for Biochemistry am klopferspitz 18 D-82152 Martinsried Germany

Seven different, but highly conserved 14-3-3 proteins are involved in diverse signaling pathways in human cells. It isunclear how the 14-3-3σ isoform, a transcriptional target of p53, exerts its inhibitory effect on the cell cycle in thepresence of other 14-3-3 isoforms, which are constitutively expressed at high levels. In order to identify structuraldifferences between the 14-3-3 isoforms, we solved the crystal structure of the human 14-3-3σ protein at a resolutionof 2.8 ? and compared it to the known structures of 14-3-3ζ and 14-3-3τ. The global architecture of the 14-3-3σ foldis similar to the previously determined structures of 14-3-3ζ and 14-3-3τ: two 14-3-3σ molecules form a cup-shapeddimer. Significant differences between these 14-3-3 isoforms were detected adjacent to the amphipathic groove, whichmediates the binding to phosphorylated consensus motifs in 14-3-3-ligands. Another specificity determining region islocalized between amino-acids 203 to 215. These differences presumably select for the interaction with specific ligands,which may explain the different biological functions of the respective 14-3-3 isoforms. Furthermore, the two 14-3-3σmolecules forming a dimer differ by the spatial position of the ninth helix, which is shifted to the inside of the ligandinteraction surface, thus indicating adaptability of this part of the molecule. In addition, 5 non-conserved residues arelocated at the interface between two 14-3-3σ proteins forming a dimer and represent candidate determinants of homo-and hetero-dimerization specificity. The structural differences among the 14-3-3 isoforms described here presumablycontribute to isoform-specific interactions and functions.

关键词： 14-3-3σ p53 crystal structure tumor suppression 14-3-3 isoform specificity.

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The role of epigenetic inactivation of 14-3-3σ in human cancer

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Cell Research 2005年第4期15卷 237-246页

作者： Dmitri LODYGIN, Heiko HERMEKING Molecular Oncology Max-Planck Institute of Biochemistry am klopferspitz 18 Martinsried/Munich Germany Molecular Oncology Max-Planck Institute of Biochemistry am klopferspitz 18 Martinsried/Munich Germany

Cancer cells show characteristic alterations in DNA methylation patterns. Aberrant CpG methylation of specificpromoters results in inactivation of tumor suppressor genes and therefore plays an important role in carcinogenesis. Thep53-regulated gene 14-3-3σ undergoes frequent epigenetic silencing in several types of cancer, including carcinoma ofthe breast, prostate, and skin, suggesting that the loss of 14-3-3σ expression may be causally involved in tumor *** studies demonstrated that 14-3-3σ is involved in cell-cycle control and prevents the accumulation of chro-mosomal damage. The recent identification of novel 14-3-3σ-associated proteins by a targeted proteomics approachimplies that 14-3-3σ regulates diverse cellular processes, which may become deregulated after silencing of 14-3-3σexpression in cancer cells.

关键词： 14-3-3σ CpG methylation p53 epigenetic silencing cancer cell cycle.

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Rescue of p53 functions by in vitro-transcribed mRNA impedes the growth of high-grade serous ovarian cancer

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Cancer Communications 2024年第1期44卷 101-126页

作者： Monika Raab Izabela Kostova Samuel Peña-Llopis Daniela Fietz Monika Kressin Seyed Mohsen Aberoumandi Evelyn Ullrich Sven Becker Mourad Sanhaji Klaus Strebhardt Department of Gynecology Medical SchoolGoethe-UniversityFrankfurt am MainGermany Translational Genomics in Solid Tumors West German Cancer CenterUniversity HospitalEssenGermany German Cancer Consortium(DKTK) EssenGermany German Cancer Research Center(DKFZ) HeidelbergGermany Histology and Embryology Institute for Veterinary AnatomyGiessenGermany Franfurt Cancer Institute(FCI) Goethe UniversityFrankfurt am MainGermany German Cancer Consortium(DKTK) Partner site Frankfurt/Mainza partnership between DKFZ and University Hospital FrankfurtFrankfurt am MainGermany Experimental Immunology Department for Children and Adolescents MedicineUniversity Hospital FrankfurtGoethe UniversityFrankfurt am MainGermany

Background:The cellular tumor protein p53(TP53)is a tumor suppressor gene that is frequently mutated in human *** various cancer types,the very aggressive high-grade serous ovarian carcinoma(HGSOC)exhibits the high-est prevalence of TP53 mutations,present in>96%of *** intensive efforts to reactivate p53,no clinical drug has been approved to rescue p53 *** this study,our primary objective was to administer in vitro-transcribed(IVT)wild-type(WT)p53-mRNA to HGSOC cell lines,primary cells,and ortho-topic mouse models,with the aim of exploring its impact on inhibiting tumor growth and dissemination,both in vitro and in ***:To restore the activity of p53,WT p53 was exogenously expressed in HGSOC cell lines using a mammalian vector ***,IVT WT p53 mRNA was delivered into different HGSOC model systems(primary cells and patient-derived organoids)using liposomes and studied for proliferation,cell cycle progression,apoptosis,colony formation,and chromosomal *** alterations induced by p53 mRNA were analyzed using RNA sequencing in OVCAR-8 and primary HGSOC cells,followed by ingenuity path-way *** vivo effects on tumor growth and metastasis were studied using orthotopic xenografts and metastatic intraperitoneal mouse ***:Reactivation of the TP53 tumor suppressor gene was explored in differ-ent HGSOC model systems using newly designed IVT mRNA-based *** introduction of WT p53 mRNA triggered dose-dependent apoptosis,cell cycle arrest,and potent long-lasting inhibition of HGSOC cell *** analysis of OVCAR-8 cells upon mRNA-based p53 reactivation revealed significant alterations in gene expression related to p53 signaling,such as apoptosis,cell cycle regulation,and DNA *** p53 function concurrently reduces chromosomal instability within the HGSOC cells,under-scoring its crucial contribution in safeguarding genomic integrity by moderating the baselin

关键词： apoptosis cell cycle chromosomal instability HGSOC metastatic intraperitoneal mouse model HGSOC orthotopic Xenograft model high-grade serous ovarian cancer in vitro-transcribed p53-mRNA liposomal IVT mRNA delivery system patient-derived organoid patient-derived primary cancer cell

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Learning to become addicted,one synapse at a time

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Neural Regeneration Research 2024年第2期19卷 401-402页

作者： Alessio Attardo Sidney B.Cambridge Leibniz Institute for Neurobiology MagdeburgGermany Institute for Anatomy II Dr.Senckenberg AnatomyGoethe-University Frankfurt am MainFrankfurtGermany

Addiction has been extensively studied on many levels:from the molecular level,with various“omics”approaches(Natividad et al.,2018;Grecco et al.,2021),to the clinical level,with psychotherapy and MRI imaging(Ceceli ... 详细信息

关键词： clinical therapy

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EP Aquarii:A New Picture of the Circumstellar Envelope

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Research in Astronomy and Astrophysics 2024年第3期24卷 83-105页

作者： Pham T.Nhung Do T.Hoai Pierre Darriulat Pham Tuan-Anh Pham N.Diep Nguyen B.Ngoc Tran T.Thai Department of Astrophysics Vietnam National Space CenterVietnam Academy of Science and Technology18Hoang Quoc VietNghia DoCau GiayHa Noivietnam

New analyses of earlier ALMA observations of oxygen-rich AGB star EP Aquarii are presented,which complete a previously published analysis and offer a different interpretation of the morpho-kinematics of the circumstellar *** birth of the equatorial density enhancement(EDE)is shown to occur very close to the star where evidence for rotation has been *** to the star and where outflows have been observed:their interaction with the gas of the nascent EDE is seen to play an important role in the development of the wind and the evolution of its radial velocity from 8 to 10 km s^(-1) on the polar symmetry axis to~2 km s^(-1) at the *** implies complex morpho-kinematics:making reliable interpretations with reasonable confidence is *** particular,it questions an earlier interpretation implying the presence of a white dwarf companion orbiting the star at an angular distance of -0″4 from its *** proposes instead an interpretation in terms of a standard mass ejection associated with a shock wave leaving a void of emission in its *** Doppler velocity wings are seen to consist of two components,the upper velocity end of the global wind,reaching above±12 km s^(-1),and an effective line broadening,confined within 200 mas from the center of the star,reaching above±20 km s^(-1) and interpreted as caused by the pattern of shock waves resulting from the interaction between stellar pulsation and convective cell partition.

关键词： stars AGB and post-AGB-(stars) circumstellar matter-radio lines stars

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Litter production and leaf nutrient concentration and remobilization in response to climate seasonality in the central amazon

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Journal of Forestry Research 2024年第3期35卷 131-141页

作者： Ricardo Antonio Marenco Saul Alfredo Antezana-Vera Daniela Pereira Dias Luiz Antonio Candido Instituto Nacional de Pesquisas da amazonia Coordenagao de Uso da Terra e Mudanca ClimaticaAv.Andre Araujo 2936ManausAM69067-375Brazil Programa de pos-Graduagao em Agricultura no Tropico Umido Instituto Nacional de Pesquisas da Amazonia-INPAManausAMBrazil Unidade Academica de Ciencias Agrarias Universidade Federal de JataiBR 364km 195JataiGO 75801-615Brazil

Litterfall is the largest source of nutrients to for-est soils of tropical ***,variability in lit-terfall production,nutrient remobilization,and changes in leaf nutrient concentration with climate seasonality remain largely unknown for the central *** study meas-ured litterfall production,leaf nutrient remobilization,and leaf area index on a forest plateau in the central *** was measured at monthly intervals during 2014,while nitrogen,phosphorus,potassium,calcium and mag-nesium concentrations of leaf litter and canopy leaves were measured in the dry and rainy seasons,and remobilization rates *** area index was also recorded in the dry and rainy *** litterfall varied from 33.2(in the rainy season)to 87.6 g m^(-2) in the dry season,while leaf area index increased slightly in the rainy *** seasonality had no effect on concentrations of nitrogen,calcium,and magnesium,whereas phosphorous and potassium responded to rainfall seasonality *** phosphorous increased,potassium decreased during the dry *** seasons,nitrogen,potassium,and phosphorous decreased in leaf litter;calcium increased in leaf litter,while magnesium remained unaffected with leaf ***,the five nutrients had similar remobilization rates over the *** absence of climate seasonality on nutrient remobilization suggests that the current length of the dry season does not alter nutrient remobilization rates but this may change as dry periods become more prolonged in the future due to climate change.

关键词： Throughfall Nutrient cycling Climatic seasonality Leaf mass per area

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Temperature and structure measurements of heavy-ion-heated diamond using in situ X-ray diagnostics

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Matter and Radiation at Extremes 2024年第4期9卷 80-89页

作者： J.Lutgert P.Hesselbach M.Schorner V.Bagnoud R.Belikov P.Drechsel B.Heuser O.SHumphries P.Katrik B.Lindqvist C.Qu R.Redmer D.Riley G.Schaumann S.Schumacher A.Tauschwitz D.Varentsov K.Weyrich X.Yu B.Zielbauer Zs.Major P.Neumayer D.Kraus Institut fur Physik Universitat RostockAlbert-Einstein-Str.2318059 RostockGermany GSI Helmholtzzentrum fur Schwerionenforschung Planckstr.164291 DarmstadtGermany Institut für Angewandte Physik Goethe-Universität Frankfurt am MainMax-von-Laue-Str.160438 Frankfurt am MainGermany Institut fur Geowissenschaften Goethe-Universitat Frankfurt am MainAltenhoferallee 160438 Frankfurt am MainGermany Helmholtz-Zentrum Dresden-Rossendorf Bautzner Landstr.40001328 DresdenGermany European XFEL GmbH Holzkoppel 422869 SchenefeldGermany Centre for Plasma Physics School of Mathematics and PhysicsQueen’s University BelfastUniversity RoadBelfast BT71NNUnited Kingdom Institut für Kernphysik Technische Universität DarmstadtSchlossgartenstr.964289 DarmstadtGermany State Key Laboratory of Nuclear Physics and Technology Institute of Heavy Ion PhysicsPeking UniversityBeijing 100871China Helmholtz Institut Jena Frobelstieg 307743 JenaGermany

We present in situ measurements of spectrally resolved X-ray scattering and X-ray diffraction from monocrystalline diamond samples heatedwith an intense pulse of heavy *** this way,we determine the samples’heating dynamics and their microscopic and macroscopic structuralintegrity over a timespan of several *** the ratio of elastic to inelastic scattering with state-of-the-art density functionaltheory molecular dynamics simulations allows the inference of average temperatures around 1300 K,in agreement with predictions fromstopping power *** simultaneous diffraction measurements show no hints of any volumetric graphitization of the material,butdo indicate the onset of fracture in the diamond *** experiments pave the way for future studies at the Facility for Antiproton andIon Research,where a substantially increased intensity of the heavy ion beam will be available.

关键词： heated intense structure

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Snapshot imaging of ultrashort electron bunches

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Light(Science & Applications) 2024年第7期13卷 1226-1228页

作者： Andreas Döpp Ludwig-Maximilian-Universität München Am Coulombwall 185748GarchingGermany Max Planck Institut für Quantenoptik Hans-Kopfermann-Strasse 1Garching85748Germany

New measurements combine spatial and temporal information from optical transition radiation to estimate the three-dimensional structure of electron bunches from a laser wakefield accelerator.

关键词： ultrashort Snapshot electron

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Experimental and numerical investigation on alternatives to sandy gravel

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Defence Technology（防务技术） 2024年第1期31卷 130-141页

作者： V.Denefeld H.Aurich Fraunhofer Institute for High-Speed Dynamics Ernst-Mach-Institut(EMI)Ernst-Zermelo-Str.479104FreiburgGermany Fraunhofer Institute for High-Speed Dynamics Ernst-Mach-Institut(EMI)Am Christianswuhr 279400KandernGermany

The NATO agreement STANAG 4569 defines the protection levels for the occupants of logistic and light armored *** Allied Engineering Publication,AEP-55,Volume 2 document outlines the test conditions for underbelly improvised explosive device(IEDs),which must be buried in water-saturated sandy *** use of sandy gravel has some drawbacks,for instance reproducibility,time consumption,and *** paper focuses on the investigation of four alternatives to sandy gravel,which could produce similar specific and cumulative impulses:a concrete pot filled with water,a concrete pot filled with quartz sand,a steel pot without filling and a concrete pot filled with glass spheres(diameter 200μm—300μm)and different water *** impulses are measured with a ring technology developed at the Fraunhofer EMI.A numerical soil model based on the work of Marrs,2014 and Fi serov a,2006 and considering the soil moisture was used to simulate the experiments with glass spheres at different water contents,showing much better agreement with the experiments than the classical Laine&Sandvik model,even for high saturation *** results can be used to create new test conditions at original scale that are more cost-effective,more reproducible and simpler to manage in comparison to the current tests carried out with STANAG sandy gravel.

关键词： Improvised explosive device(IED) Specific impulse Momentum transfer Sandy gravel Glass spheres Numerical model Soil moisture

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RUSAS: Roman Urdu Sentiment Analysis System

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Computers, Materials & Continua 2024年第4期79卷 1463-1480页

作者： Kazim Jawad Muhammad Ahmad Majdah Alvi Muhammad Bux Alvi Faculty of Computer Science and Engineering Frankfurt University of Applied SciencesFrankfurt am Main60318Germany Technical Writer and Researcher Proteus Technologies LLCIslamabad04405Pakistan Faculty of Engineering The Islamia University of BahawalpurBahawalpur63100Pakistan

Sentiment analysis, the meta field of Natural Language Processing (NLP), attempts to analyze and identify thesentiments in the opinionated text data. People share their judgments, reactions, and feedback on the internetusing various languages. Urdu is one of them, and it is frequently used worldwide. Urdu-speaking people prefer tocommunicate on social media in Roman Urdu (RU), an English scripting style with the Urdu language *** have developed versatile lexical resources for features-rich comprehensive languages, but limitedlinguistic resources are available to facilitate the sentiment classification of Roman Urdu. This effort encompassesextracting subjective expressions in Roman Urdu and determining the implied opinionated text polarity. Theprimary sources of the dataset are Daraz (an e-commerce platform), Google Maps, and the manual effort. Thecontributions of this study include a Bilingual Roman Urdu Language Detector (BRULD) and a Roman UrduSpelling Checker (RUSC). These integrated modules accept the user input, detect the text language, correct thespellings, categorize the sentiments, and return the input sentence’s orientation with a sentiment intensity *** developed system gains strength with each input experience gradually. The results show that the languagedetector gives an accuracy of 97.1% on a close domain dataset, with an overall sentiment classification accuracy of94.3%.

关键词： Roman Urdu sentiment analysis Roman Urdu language detector Roman Urdu spelling checker flask

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