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Sample records for phys stat sol

  1. Preface: phys. stat. sol. (a) 202/12

    NASA Astrophysics Data System (ADS)

    Neumann, Wolfgang; Stutzmann, Martin; Hildebrandt, Stefan

    2005-09-01

    The present special issue contains a collection of Original Papers dedicated to Professor Johannes Heydenreich on the occasion of his 75th birthday.Johannes Heydenreich, born on 20 June 1930 in Plauen/Vogtland near Dresden, studied physics at the Pädagogische Hochschule Potsdam, where he obtained his first academic degree Dipl. Phys. in 1958. He received his doctoral degree at the Martin Luther University in Halle in 1961 and the Habilitation degree in 1969. Already during his studies in Potsdam, he showed an interest in electron microscopy due to the influence of his teacher and supervisor Prof. Picht, one of the pioneers in electron optics. His interests were strengthened when Johannes Heydenreich did the experimental work for his Diploma degree at the Institute for Experimental Physics of the University of Halle, where he met Prof. Heinz Bethge for the first time. This was the beginning of a fruitful and longstanding collaboration. In 1962 Johannes Heydenreich joined the team of the later Institute for Solid State Physics and Electron Microscopy of the Academy of Sciences of the GDR, in Halle, for which the basis was laid by Prof. Bethge in 1960.Heydenreich has been working as Assistant Director for many years and played a decisive role in introducing and organising the various techniques of electron microscopy in the institute.The research activities of Prof. Heydenreich covered a broad spectrum over the years. At the beginning of his career he made significant contributions in the field of electron mirror microscopy. After that, his main interests were focused on transmission electron microscopy, ranging from diffraction contrast analysis of crystal defects to high-resolution electron microscopy and image processing. His favourite field was studies of defect-induced phenomena in advanced materials. The so-called Bethge-Heydenreich, the book Electron Microscopy in Solid State Physics, published at first in a German edition in 1982 and later in a revised

  2. Preface: phys. stat. sol. (a) 202/7

    NASA Astrophysics Data System (ADS)

    Pollak, Fred H.; Misiewicz, Jan; Sitarek, Piotr

    2005-05-01

    We have recently observed a growing interest in using the powerful technique of optical modulation spectroscopy. These applications are related mostly to the characterization of low dimensional semiconductor structures and devices based on them.The International Workshop on Modulation Spectroscopy of Semiconductor Structures (MS3) at the beginning of July 2004 gathered in Wrocaw (in the southwest part of Poland) almost 40 participants, half of them from abroad. The 8 invited and 16 contributed talks were presented by the leaders of research teams from the USA, Japan, Taiwan, Canada, Germany, France, the Netherlands, Sweden, Ireland, Russia, Lithuania and Poland. Part of the MS3 workshop was held at the Laboratory of Advanced Optical Spectroscopy, Institute of Physics, Wrocaw University of Technology, where discussions on technical matter of the modulation spectroscopy were carried out in a relaxing atmosphere over a cup of coffee.The topics of the MS3 workshop included: advantages of photoreflectance, electroreflectance, contactless electroreflectance, thermoreflectance, differential reflectance and wavelength-modulated surface photovoltage spectroscopy. The applications of the above methods to investigate transistor, diode and laser structures including VCSELs, low dimensional structures of both wings of the spectrum, i.e. wide band gap materials like GaN, AlGaN, ZnO and low band gap materials such as GaInN(Sb)As, InAs, InSb, and FeSi2 were demonstrated.It is our great pleasure to publish the most interesting of the MS3 workshop presentations in this issue of physica status solidi (a).The organizers acknowledge Wrocaw University of Technology, the Center of Exellence CEPHONA from the Institute of Electron Technology in Warsaw and the Polish Committee for Scientific Research for financial support of the workshop.

  3. Preface: phys. stat. sol. (c) 1/7

    NASA Astrophysics Data System (ADS)

    Cheikhrouhou, Abdelwaheb

    2004-05-01

    The Third International Conference on Magnetic and Superconducting Materials (MSM03) belongs to a series of conferences, held biannually, aiming at providing a forum to the scientists in the magnetic and superconducting materials areas over the world.The first conference of the series (MSM99) was held in Iran with the proceedings published by World Scientific in 2000, and the second conference (MSM01) was held in Jordan with the proceedings published in Physica B 321 (2002).MSM03 was organized by the Materials Physics Laboratory, Sfax University (Laboratoire de Physique des Matériaux de la Faculté des Sciences de Sfax), with many domestic and international supporting institutions. It was held in Monastir (Tunisia), 1-4 September 2003, with over 150 participants and keynote lecturers attending from the following countries: Algeria, Austria, China, Czech Republic, Egypt, France, Germany, Hungary, Iran, Italy, Japan, Jordan, Morocco, Netherlands, Pakistan, Poland, Russia, Spain, Sudan, Sultanate of Oman, Taiwan, Tunisia, United Kingdom and United States of America.Altogether, about 170 papers on a variety of subjects relevant to the topic of the conference were presented, out of which 42 were keynote lectures. The submissions were peer-reviewed, and ultimately 115 articles were selected for publication in this journal. However, it must be noted that 13 of 39 keynote speakers did not submit their manuscripts for publication. Invited and other speakers were distinguished members of the international scientific community who are interested in pure sciences and materials research, and involved in the fabrication, characterization and investigation of the physical properties of magnetic and superconducting materials. High-caliber scientists attended the conference contributing to its success and the event resulted in new international relationships in research and cooperation. The Chairman of the Organizing Committee was Professor Abdelwaheb Cheikhrouhou, Materials Physics Laboratory, Sciences Faculty of Sfax (Tunisia) and the Co-Chairmen were Professor Sami Mahmood, Dean of Sciences at Yarmouk University (Jordan) and Professor Mohamed Akhavan from the Sharif University of Technology (Iran). The four-day conference consisted of several oral and poster sessions, followed by social programs in the evenings. The success of the event could be measured during the closing session on the last day, when several delegates emphasized the high-quality science that had been evident at the conference. A post conference three-day tour to the south of Tunisia (Matmata, Douz City: the gate of desert and the mountains oasis: Tamerza, Mides and Chebika) was also arranged. The conference was generously sponsored by: - The Tunisian Ministry of High Education, Scientific Research and Technology - The Tunisian Secretary of State for Scientific Research and Technology - The Tunisian National Office of Tourism - The Abdus Salam International Centre for Theoretical Physics (ICTP) - French Institute for Cooperation in Tunisia - Tunisian-Italian Scientific Partnership - British Gas - Tunisian Society for Electricity and Gas - Imex Olive Oil -Confiserie TRIKI Le Moulin The next MSM conference in 2005 will be held in Morocco.

  4. Preface: phys. stat. sol. (c) 1/9

    NASA Astrophysics Data System (ADS)

    Leitch, Andrew; Botha, Reinhardt

    2004-08-01

    The Conference on Photo-responsive Materials took place at the Kariega Game Reserve in the Eastern Cape, South Africa from 25-29 February 2004. More than 60 delegates from 12 different countries participated in the four-day event.The purpose of the conference was to bring together scientists working on various aspects of photo-responsive materials, so as to stimulate this important field of solid state physics in Southern Africa. As may be seen from the list of papers appearing in these proceedings, there was much interest in copper indium diselenide as a thin film material for photovoltaic applications. Also worth mentioning were the valuable contributions on ZnO, GaN and other materials that are currently attracting attention worldwide.The conference program allowed sufficient time for interaction and exchanging of views. Being in a game reserve in the heart of the beautiful Eastern Cape, delegates were also taken on game drives and had the opportunity of taking a river cruise up the Kariega River to view the majestic fish eagle.The members of the academic program committee were: Vivian Alberts (Rand Afrikaans University), Danie Auret (University of Pretoria), Darrell Comins (University of the Witwatersrand), and Reinhardt Botha and Andrew Leitch (University of Port E All papers appearing in these proceedings underwent a strict reviewing process separate from the conference. We express our appreciation to the referees for their diligence in this important task. The conference was organized by the Department of Physics at the University of Port Elizabeth, under the auspices of the Condensed Matter Physics and Materials Science (CMPMS) subgroup of the South African Institute of Physics. It was sponsored by EMF Limited (UK), Sensors Unlimited Inc. (USA), and Carl Zeiss (Pty) Ltd. Special thanks must go to Dr Eunete van Wyk for her professional assistance in the preparation of these proceedings.

  5. Preface: phys. stat. sol. (b) 241/9

    NASA Astrophysics Data System (ADS)

    Morawetz, Klaus

    2004-07-01

    Modelling and Simulation in Molecular Systems, Mesoscopic Structures, and Material Science was the title of a workshop held at the University of Technology in Chemnitz from 21 to 23 April 2004. This workshop coincided with the 50th birthday of Michael Schreiber. Therefore, the idea to publish a special issue is supported by two good reasons. First, a topical collection is appropriate for giving an overview about a field and to initiate further studies. This is one intention of the present issue. Second, the birthday is a suitable occasion for reflecting on the status of the different fields where Michael Schreiber has been active himself. Motivated by the characteristic name of the workshop (MS4), which expresses the broad range of his activities, the contributions are grouped into three main chapters: Disorder and Interaction, Phase Transitions and Criticality, and Transport Properties.The first part starts with the currently intensively discussed topic of composite Fermions in the paper by B. Kramer et al. This method of rewriting correlations as new quasiparticles has amongst other things the merit of explaining such exciting phenomena as the fractional quantum Hall effect. The methodological questions of Ward identities, causality, and conservation laws are the focus of the systematic investiga-tion in the second article by V. Janis et al. which concentrates on the problem of disorder and configura-tional averaging. The interplay between disorder and correlation is treated in the third contribution by C. Schuster et al., where different theoretical methods are tested on the problem of Friedel oscillations within the one-dimensional Heisenberg and Hubbard model. In the next contribution, M. Berciu et al. focus on localization as one consequence of disorder. The localized and extended electronic states are treated, together with the magnetic degrees of freedom, like spin waves. One of the astonishing consequence of localiza-tion is the observation of resonant Rayleigh backscattering. This is investigated by random matrix theory in the next article by E. Runge et al. and extended to exciton transitions in semiconductor nanostructures. In order to characterize localization, A. Eilmes et al. consider the two-dimensional Anderson model in the following article with special focus on the critical exponents for the localization length. The chapter on disorder ends with a contribution by A. Aldea et al. where the disorder effects are investigated in twodimensional systems with perpendicular magnetic fields such that the interplay between Landau levels and localized states can be considered.The second chapter in the collection is devoted to critical phenomena and phase transitions. It starts with an overview of the most prominent example of critical phenomena, high-Tc superconductivity. A. Sherman presents a review on magnetic and spectral properties of cuprate perovskites within t - J models. The long-range hopping problem and the extraction of critical exponents are the topic of the contribution by E. Cuevas, who calculated the level spacing distribution as well as the correlation dimen-sion in the strong coupling limit. The critical points and the thermodynamics of quenched spatial disordered systems are then treated by T. Vojta et al. Here it is shown that different parts of a system might undergo phase transitions controlled by different parameter values. Different microstructures are important when phenomena like the growth of crystals are considered. Consequently the latter problem is treated in the next contribution by H. Emmrich et al., who develop an analytical solution and compare it to simulations in order to provide insights into the universality of diffusion-limited crystal growth. That the applications of critical phenomena are quite versatile is demonstrated in a short paper by J. Stäring et al. who show how statistical methods can be employed to optimize networks of wireless communication. This chapter on critical phenomena ends with a methodological investigation by U. Grimm. This concerns the often applied random matrix theory, and a method to calculate the level spacing distribution by using coupled differential equations.The third chapter is devoted to transport. It starts with an article about conductance fluctuations by M. Ortuno et al. These quantum fluctuations are considered in localized systems which is directly related to the topics in the first chapter. M. Schröder et al. present in the next article a method to propagate wave functions by approximating them by multi-dimensional wave packets. In contrast to variational methods, this method is based on stochastic calculus. In the case where only a few electrons are transferred, as in the reaction of donor-acceptor complexes and molecular wires, a unified description is presented in the contribution by V. May et al. The transfer rate and the stationary current are calculated and their depend-ence on the length of the molecular system is shown. The method of Green's functions based on local orbitals is used in the next article by M. Albrecht et al. to calculate molecular charge transport. This results into a Landauer theory for the calculation of the transmission coefficient. The special role of elec-tron-electron interaction in the transport properties of disordered wires is considered by H. Mori et al. Here the interplay of interaction and disorder is investigated and the different roles of interaction for the localization phenomena are discussed. We close this chapter on transport by an investigation of electronic transport through nanoparticle arrays. The self-assembled nanoparticle structures are considered within the contri-bution by K. Nicolic whose structures represent very promising nanoelectronic devices.The broad-range approaches and applications selected in these three chapters demonstrate the exciting interplay between structure, disorder, and correlations and suggest the kind of future developments which are to be expected within this field. Finally, in the name of all authors and workshop participants: Happy birthday to Michael Schreiber and all best wishes for exciting future scientific activities!

  6. Preface: phys. stat. sol. (c) 1/6

    NASA Astrophysics Data System (ADS)

    Kavokin, Alexey

    2004-04-01

    This volume contains some of the papers presented at the Third International Conference on Physics of Light-Matter Coupling in Nanostructures (PLMCN3) which took place in Acireale, Sicily, from 1 to 4 October 2003. This meeting was fourth in the series started by PLMCN (St. Nectaire, 2000) and continued by PLMCN1 (Rome, 2001) and PLMCN2 (Rithymnon, 2002). All four conferences had the same format (about 70 participants), similar subject scope (interface between fundamental physics of light-matter coupling phenomena and applied research on new semiconductor materials and low-dimensional structures), and the proceedings of all of them have been published in physica status solidi.During these four years, a huge progress has been achieved in the understanding of exciton-polariton effects in microcavities. From the discovery of stimulated scattering of polaritons in 1999 to the first experimental reports of polariton Bose condensation and lasing, attention to this rapidly developing research area has been increased drastically. It is clear now that realization of a new generation of opto-electronic devices, referred to as polariton devices, is a realistic task for the coming decade. To achieve this target, much work has to be done both in fundamental research on dynamics of exciton-polaritons in microcavities and experimental realization of high-quality microcavities presumably based on wide-band gap semiconductors like GaN, ZnO, ZnSe, suitable for the observation of strong exciton-light coupling at room temperature. Forty nine research teams from twelve European countries have created a Polariton Consortium aimed at integration of the European research effort towards fabrication of polariton devices. PLMCN3 was not only an international conference devoted, in particular, to the research on polariton devices, but also the first scientific meeting of this community.The PLMCN meetings since the very first one have been sponsored by the US Army European Research Office (ERO). This time, with the initiative of Jim Harvey from ERO, a special session has been organized on the devices of 21st century, where a number of intriguing ideas have been proposed on new light sources, polariton lasers, and quantum memory elements based on microcavities. A special prize for the most crazy but realizable idea has been won by Misha Portnoi (Exeter) for the concept of a white diode based on a microcavity.Each PLMCN meeting brings participants from new countries. This time, the traditionally strong participation from Japan, Russia, the European Union and the USA has been enforced by a representative delegation from Israel and two speakers from Mexico. We are looking forward for new-comers from other countries not yet involved in the PLMCN community, to join us for the next meeting to be held in St. Petersburg on 29 June-3 July 2004. Sergey Ivanov from the A. F. Ioffe Institute chairs the local Organizing Committee of this future conference. We are going to keep a unique informal and creative atmosphere being characteristic of the PLMCN meetings. We invite all those who wish to know more about light-matter coupling in solids or to present any new interesting results in this area and at the same time to enjoy the beautiful city of St. Petersburg, to contact Sergey Ivanov (ivan@beam.ioffe.rssi.ru) or myself (kavokin@lasmea.univ-bpclermont.fr). We are looking forward to welcoming you in St. Petersburg!

  7. Preface: phys. stat. sol. (b) 242/1

    NASA Astrophysics Data System (ADS)

    Ginzburg, V. L.; Maksimov, E. G.

    2005-01-01

    We have accepted with great pleasure the suggestion of the Guest Editor Miodrag Kuli to write a short preface to the special issue of this journal, which is devoted to the role played by electron-phonon interaction (EPI) in high-temperature superconductors (HTSC). From the very beginning, it was absolutely clear to us that there is no metal in which the EPI could be ignored, and high-temperature superconducting compounds cannot be an exception in this respect. We expressed this opinion, in particular, in our early Review Article [1] and in the talk [2] given at the Grenoble M2S HTSC Conference in 1994. We would like to emphasize that we were not in isolation. There have been many other researchers, some authors of this issue among them, who have also considered the EPI as an essential part of the physics of high-temperature superconductors. However, a large part of researchers in the field, including a few famous scientists, have considered the EPI to be irrelevant to high-temperature superconductivity. Up to now, we do not understand the scientific basis for such an opinion. Moreover, that point of view has never been shared by some other famous scientists; in this respect mention should be made of J. Friedel and A. A. Abrikosov.Turning back to physics, we would like to point out some features of high-temperature superconducting cuprates, which should lead to the existence of a strong EPI in these materials. First of all, it is the proximity of these compounds, even in the optimally doped case, to the layered ionic crystals. This fact has been emphasized in our early publications as well as in many papers by other authors, and it is discussed in detail in the Review Article by C. Falter published in this issue. There are other approaches to the HTSC compounds, which allow to consider that a strong EPI exists. They are also based on some peculiarities in the crystalline and chemical structure of these compounds, in particular, on their multiphase nanoscale structure. This point is discussed by J. Phillips in this issue.There are also many experimental indications in favor of the existence of a strong EPI in the HTSC cuprates. For example, the behavior of the electron relaxation, the peculiarities of the phonon spectra, the interaction of the Josephson current with phonons, and the electron mass renormalization. All these phenomena have been discussed in the recent Review Articles [3, 4]. Currently, additional evidence was provided which has thrown new light on the role played by the EPI in HTSC systems. These are the ARPES experiments conducted by the Stanford group, which have given an unambiguous proof of the electron mass renormalization due to the EPI. A Review Article of this group by T. Cuk et al. is also presented in this issue. We should also mention the contribution of L. Pintschovius who presented new interesting results on the electron-phonon coupling effects observed by means of inelastic neutron scattering.A comprehensive discussion of a major part of the electron-phonon coupling effects presented in the Review Articles [1, 3] has been based on the traditional approach of the Eliashberg type. Up to now, we consider this approach to be quite suitable for pursuing a number of goals, mainly for describing properties of the normal state. Nevertheless, we do not disclaim the importance of more detailed investigations of the EPI, which take into account the strong anisotropy, the interplay between electron-phonon and electron-electron interaction, and the non-adiabatic effects. Four Review Articles in this issue, by Schneider, by Rösch, Han, Gunnarsson and Crespi, by Kuli and Dolgov, and by Cappelluti and Pietronero are devoted to different aspects of these problems.To conclude, we would like to emphasize that the main problem related to the mechanism of superconductivity in the HTSC cuprates is the interplay between the strong EPI and the electron exchange and correlation. Unfortunately, previous work did not crack this problem and much effort should be made in the future. We hope that the publication of this issue will aid to attract the attention of many researchers to the investigation of unsolved problems of the EPI in HTSC systems.

  8. Editorial: phys. stat. sol. (c) 3/1

    NASA Astrophysics Data System (ADS)

    Stutzmann, Martin

    2006-01-01

    Dear Colleagues and Friends,on behalf of the Publishers, the Editorial Office, and the Editors of physica status solidi we wish you all the best for the coming year 2006! It is our sincere hope that your personal and professional experience with our journal has been a positive one and that you will continue to choose physica status solidi for the publication of your scientific findings in solid state physics also in the future.In doing so, you will be in increasingly good company! As a matter of fact, 2005 has been a year of exceptional growth in the number of manuscripts submitted to physica status solidi . Thus, the number of Original Papers which have reached our Editorial Office in Berlin has increased by as much as 30% compared to the long term average over the last ten years. For the Rapid Research Letter section, the corresponding increase has been even more impressive: more than +100% just in the last two years. We view this development as a confirmation of our longstanding efforts to ensure a timely publication service of high scientific quality. One relevant indicator for the high scientific standards expected from articles which are submitted for publication in physica status solidi is the average acceptance rate, which currently is less than 40%. This rate has continuously decreased from a value of about 60% ten years ago and bears witness to our efforts to strive for quality rather than quantity.Also, physica status solidi has been able to continue its long tradition as a truly international journal, despite of the strong competition in an established field such as solid state physics. In 2005, submitted papers have originated almost equally from the Americas, Europe, and Asia, with a clearly growing contribution from China, India, and Japan. We are actively working together with our international Editorial Boards and the Regional Editors to maintain a reasonable balance among papers from different parts of the world. The increasing international visibility of physica status solidi is impressively documented by the ever rising numbers of article downloads via the internet: on the average, each of the 2000 articles published annually in physica status solidi is presently accessed about 100 times via the www. Finally, let me mention some other recent developments, which are not so directly visible from the outside. Thus, a new all electronic publishing system has become operative in our Berlin Editorial Office in 2005, which allows a more efficient and timely handling of manuscripts from submission to publication (www.manuscriptXpress.com) and is particularly valuable for the editing of conference proceedings (conferences.wiley-vch.de). In addition, the functionality of the journal within the Wiley InterScience website has been enhanced by new features such as Citation Tracking. Together with the ongoing digitization of all physica status solidi issues since the 1960s, which is expected to be complete in 2006, this makes the physica status solidi homepage at Wiley InterScience a very valuable tool for literature search in solid state physics, past and present. Try it out at www.interscience.wiley.com! All of us from physica status solidi would like to convey to you our very best wishes for good health and success in the coming year 2006!

  9. Editorial: phys. stat. sol. (a) 203/1

    NASA Astrophysics Data System (ADS)

    Stutzmann, Martin

    2006-01-01

    Dear Colleagues and Friends,on behalf of the Publishers, the Editorial Office, and the Editors of physica status solidi we wish you all the best for the coming year 2006! It is our sincere hope that your personal and professional experience with our journal has been a positive one and that you will continue to choose physica status solidi for the publication of your scientific findings in solid state physics also in the future.In doing so, you will be in increasingly good company! As a matter of fact, 2005 has been a year of exceptional growth in the number of manuscripts submitted to physica status solidi. Thus, the number of Original Papers which have reached our Editorial Office in Berlin has increased by as much as 30% compared to the long term average over the last ten years. For the Rapid Research Letter section, the corresponding increase has been even more impressive: more than +100% just in the last two years. We view this development as a confirmation of our longstanding efforts to ensure a timely publication service of high scientific quality. One relevant indicator for the high scientific standards expected from articles which are submitted for publication in physica status solidi is the average acceptance rate, which currently is less than 40%. This rate has continuously decreased from a value of about 60% ten years ago and bears witness to our efforts to strive for quality rather than quantity.Also, physica status solidi has been able to continue its long tradition as a truly international journal, despite of the strong competition in an established field such as solid state physics. In 2005, submitted papers have originated almost equally from the Americas, Europe, and Asia, with a clearly growing contribution from China, India, and Japan. We are actively working together with our international Editorial Boards and the Regional Editors to maintain a reasonable balance among papers from different parts of the world. The increasing international visibility of physica status solidi is impressively documented by the ever rising numbers of article downloads via the internet: on the average, each of the 2000 articles published annually in physica status solidi is presently accessed about 100 times via the www.Finally, let me mention some other recent developments, which are not so directly visible from the outside. Thus, a new all electronic publishing system has become operative in our Berlin Editorial Office in 2005, which allows a more efficient and timely handling of manuscripts from submission to publication (www.manuscriptXpress.com) and is particularly valuable for the editing of conference proceedings (conferences.wiley-vch.de). In addition, the functionality of the journal within the Wiley InterScience website has been enhanced by new features such as Citation Tracking. Together with the ongoing digitization of all physica status solidi issues since the 1960s, which is expected to be complete in 2006, this makes the physica status solidi homepage at Wiley InterScience a very valuable tool for literature search in solid state physics, past and present. Try it out at www.interscience.wiley.com!All of us from physica status solidi would like to convey to you our very best wishes for good health and success in the coming year 2006!

  10. Editorial: phys. stat. sol. (b) 243/1

    NASA Astrophysics Data System (ADS)

    Stutzmann, Martin

    2006-01-01

    Dear Colleagues and Friends,on behalf of the Publishers, the Editorial Office, and the Editors of physica status solidi we wish you all the best for the coming year 2006! It is our sincere hope that your personal and professional experience with our journal has been a positive one and that you will continue to choose physica status solidi for the publication of your scientific findings in solid state physics also in the future.In doing so, you will be in increasingly good company! As a matter of fact, 2005 has been a year of exceptional growth in the number of manuscripts submitted to physica status solidi . Thus, the number of Original Papers which have reached our Editorial Office in Berlin has increased by as much as 30% compared to the long term average over the last ten years. For the Rapid Research Letter section, the corresponding increase has been even more impressive: more than +100% just in the last two years. We view this development as a confirmation of our longstanding efforts to ensure a timely publication service of high scientific quality. One relevant indicator for the high scientific standards expected from articles which are submitted for publication in physica status solidi is the average acceptance rate, which currently is less than 40%. This rate has continuously decreased from a value of about 60% ten years ago and bears witness to our efforts to strive for quality rather than quantity.Also, physica status solidi has been able to continue its long tradition as a truly international journal, despite of the strong competition in an established field such as solid state physics. In 2005, submitted papers have originated almost equally from the Americas, Europe, and Asia, with a clearly growing contribution from China, India, and Japan. We are actively working together with our international Editorial Boards and the Regional Editors to maintain a reasonable balance among papers from different parts of the world. The increasing international visibility of physica status solidi is impressively documented by the ever rising numbers of article downloads via the internet: on the average, each of the 2000 articles published annually in physica status solidi is presently accessed about 100 times via the www.Finally, let me mention some other recent developments, which are not so directly visible from the outside. Thus, a new all electronic publishing system has become operative in our Berlin Editorial Office in 2005, which allows a more efficient and timely handling of manuscripts from submission to publication (www.manuscriptXpress.com) and is particularly valuable for the editing of conference proceedings (conferences.wiley-vch.de). In addition, the functionality of the journal within the Wiley InterScience website has been enhanced by new features such as Citation Tracking. Together with the ongoing digitization of all physica status solidi issues since the 1960s, which is expected to be complete in 2006, this makes the physica status solidi homepage at Wiley InterScience a very valuable tool for literature search in solid state physics, past and present. Try it out at www.interscience.wiley.com!All of us from physica status solidi would like to convey to you our very best wishes for good health and success in the coming year 2006!

  11. Preface: phys. stat. sol. (a) 201/11

    NASA Astrophysics Data System (ADS)

    Bergonzo, Philippe; Haenen, Ken; Nebel, Christoph; Nesládek, Milo; Vanek, Milan

    2004-09-01

    The present issue of physica status solidi (a) contains a collection of 24 papers presented at the 9th International Workshop on Surface and Bulk Defects in CVD Diamond Films held in Diepen- beek-Hasselt, Belgium, 18-20 February 2004. The concept of this workshop originated in 1996 with the idea of bringing together scientists who are active and innovative in the field of electronic and optical properties of thin film diamond. Since then, this meeting have grown up to a regular conference devoted to new issues in CVD diamond research and related to diamond as a material for electronics and nanobioelectronics. This year the programme was spread over two and a half days, including 8 invited lectures from a total of 39 talks, and a poster session featuring 15 posters. In addition we were able to connect this meeting with a workshop on Defects and Impurities in Crystalline Boron Nitride Compounds, scientifically organized from the University of Antwerp and leading finally to a joint meeting lasting four days. The papers from the BN workshop are joining this proceeding issue on pages 2559-2598.At SBDD IX, topics ranged from homo- and heteroepitaxial growth, doping, hydrogen induced surface conductivity, defects and their characterization, to devices including bio-sensing applications. As usual, very intense and lively discussions took place among participants, from young students to established scientists, after talks, during breaks and in the evenings while enjoying the hospitality of the Limburgs Universitair Centrum and especially the city of Hasselt. The number of participants reached a record breaking 96 this year, with participants coming from fifteen different countries (Australia, Austria, Belgium, Czech Republic, France, Germany, Israel, Italy, Japan, Mexico, Romania, Russia, Sweden, UK, USA). This yearly increasing number indicates that this workshop is continuing to be very attractive to a large scientific community, as it summarizes the up-to-date research on diamond as a wide band gap semiconductor.The workshop would have not been possible without the support of many people and institutions. For financial aid we are especially indebted to the Scientific Research Community Surface Modification of Materials of the F. W. O.-Vlaanderen (Belgium) and its continuous support since starting this workshop 9 years ago. We also thank the Limburgs Universitair Centrum for offering the lecture hall and infrastructure facilities. Finally we highly appreciate the active approach of the editorial staff of physica status solidi in this conference and would like to thank most notably Stefan Hildebrandt and Katharina Fröhlich, for their excellent and patient work, making this already the sixth successfully published proceedings of SBDD in pss (a).To finish, we would all like to invite you for the 10th anniversary of the SBDD series in February 2005 in Diepenbeek-Hasselt and we look forward to seeing you at:Surface and Bulk Defects in CVD Diamond Films, X23-25 February 2005Limburgs Universitair Centrum, Diepenbeek - Hasselt, Belgiumhttp://www.imo.luc.ac.be/SBDD2005

  12. Preface: phys. stat. sol. (a) 203/12

    NASA Astrophysics Data System (ADS)

    Jackman, Richard B.; Nesládek, Milo; Haenen, Ken

    2006-09-01

    The 30 papers gathered in this issue of physica status solidi (a) give a thorough overview over different topics that were presented during the 11th edition of the International Workshop on Surface and Bulk Defects in CVD Diamond Films (SBDD), which took place from 22 to 24 February 2006, at the Hasselt University in Diepenbeek-Hasselt, Belgium. Since its start more than 10 years ago, the SBDD Workshop has grown into a well-established, yearly early bird meeting place, addressing new emerging science related to the progress in the CVD diamond field. The 10 invited lectures, 29 contributed oral presentations and 26 posters were presented in several sessions during an intense two and a half day long meeting.The number of participants reached 115 this year with participants coming from fifteen countries: Austria, Belgium, Czech Republic, France, Germany, Israel, Italy, Japan, Mexico, Poland, Russia, Singapore, Slovak Republic, Sweden, UK, and USA. The mixture of young and established scientists, including a great proportion of students, made this meeting a hot spot of lively discussions on a wide range of scientific subjects, not only during the meeting itself, but also at several occasions throughout many social events offered by the hospitality of the city of Hasselt.It stands for itself that the workshop would not have been possible without the support of many people and institutions. For financial aid we are especially indebted to the Scientific Research Community Surface Modification of Materials of the F.W.O.-Vlaanderen (Belgium), whose incessant support plays an important role in keeping this meeting going. We also thank the Hasselt University for offering the lecture hall and infrastructure facilities and Seki Technotron Corp. for sponsoring the poster reception and their presence with a table top exhibit. Finally we highly appreciate the active approach of the editorial staff of physica status solidi in this conference and would like to thank most notably Stefan Hildebrandt, Ron Schulz-Rheinländer, Christoph Lellig, and Julia Hübner, for their excellent and patient work, bringing the number of successfully published proceedings of SBDD in pss (a) up to 8 already!To finish, we would all like to invite you to the 12th edition of the SBDD series, newly renamed as Hasselt Diamond Workshop, to be held at its established location of Diepenbeek-Hasselt. We look forward meeting you again at SBDD XII in 2007:Hasselt Diamond Workshop - SBDD XII28 February-2 March 2007Hasselt University, Diepenbeek-Hasselt, Belgiumhttp://www.imo.uhasselt.be/SBDD2007London, Paris, Hasselt, August 2006

  13. Preface: phys. stat. sol. (c) 1/10

    NASA Astrophysics Data System (ADS)

    Suh, Eun-Kyung; Yoon, Euijoon; Lee, Hyung Jae

    2004-09-01

    The Fifth International Symposium on Blue Laser and Light Emitting Diodes (ISBLLED-2004) was held in Gyeongju, Korea from 15-19 March 2004. Gyeongju, the ancient capital of the thousand-year Silla kingdom (57 B.C. to 935 A.D.) provided additional pleasure to the participants as an exceptional open-air museum with antique treasures scattered all around the city.During the last decade we have witnessed remarkable developments in wide-gap semiconductors and light emitting devices in the spectral range from the visible to deep UV. The purpose of the Symposium was to provide a forum for intensive discussion on the issues and main progress especially in optoelectronic devices, material growth and characterization, and quantum structures of wide bandgap semiconductors. A total of 243 papers including 220 contributed and 23 invited ones were presented and discussed by 487 participants from 17 countries world-wide. Among them, 154 manuscripts were submitted and reviewed by the usual evaluation process of physica status solidi. Some were rejected or withdrawn, and finally 139 papers are published in the special issues of physica status solidi (a), (b), and (c). We gratefully acknowledge the referees for their careful review. The papers are grouped into 7 categories. The subheadings and the number of papers in each are as follows: Optoelectronic devices, 43; Growth and characterization, 45; Nano and quantum structures, 21; Contacts, 8; Zinc oxide, 9; Indium nitride and indium rich InGaN, 6; Others, 7. The special session of the Symposium, The LED Highlight, designed partially to meet the challenging targets of the technology, i.e., energy savings and clean environment preservation, drew much attention and is edited as a special coloured section in this issue.The next symposium is scheduled for Montpellier, France, in 2006. We wish the organizers of that symposium the best of luck and hope to see all of the ISBLLED-2004 participants again at ISBLLED-2006.ISBLLED-2004 was sponsored by The Research Society for the Wide-gap Semiconductors, Korean Physical Society, Office of Naval Research, Korea Science and Engineering Foundation, Korea Research Foundation, Korea Association for Photonics Industry Development, Asian Office of Aerospace Research and Development, and Korea Photonics Technology Institute. We would like to thank Ms. E. S. Hwang for her devotion to the preparation and the Proceedings of the symposium including the manuscript handling for publication.

  14. Preface: phys. stat. sol. (a) 201/8

    NASA Astrophysics Data System (ADS)

    Shin, Sung-Chul

    2004-06-01

    The KMS/SOMMA Meeting 2003 was held 3-6 December 2003 at Spapia Hotel, Daejeon, Korea. It was the 5th SOMMA (International Symposium on Magnetic Materials and Applications) organized by ReCAMM (Research Center for Advanced Magnetic Materials) of Chungnam National University. Since 2002, the Korean Magnetics Society (KMS) winter conference has been jointly held with SOMMA. This was the second time to have a KMS/SOMMA joint meeting. The main objective of the meeting was to provide an international forum to discuss up-to-date results on magnetism and magnetic materials. The conference brought together 360 participants from 12 countries. Sessions of the meeting were: Theory and Fundamentals, Magnetic Random Access Memory, Spintronics, Information Storage, Nanostructured Materials, Sensors, and Interdisciplinary. In these seven sessions, 325 papers were presented including 66 oral and 259 poster presentations. Since the symposium was held in Korea, this enabled a large number of Asian scientists to attend: 239 from Korea, 41 from Japan, 7 from Taiwan, and 5 from China.The conference program had 25 invited and plenary speakers. They were Y. Ando (Tohoku U.), M. Inoue (Toyohashi U. Tech), H. Kubota (Tohoku U.), K. Mohri (Nagoya U.), M. Sahashi, M. Takahashi, K. Takanashi, M. Tsunoda (Tohoku U.), and H. Yoda (Toshiba) from Japan; A. J. Freeman (Northwestern U.), A. T. Hanbicki (NRL), F. B. Humphrey (Boston U.), and S. Sun (IBM) from the USA; J. D. Boeck (IMEC, Belgium), B. Dieny (CEA, France), N. Garcia (CSIS, Spain), G. Reiss (Bielefeld U., Germany), T. Stobiecki (U. M. & M. Krakow, Poland), and M. Wolfram (Singulus Tech, Germany) from Europe; C. G. Kim, D. J. Kim (CNU), T. W. Kim (SAIT), S. H. Lim (KIST), Sung-Chul Shin (KAIST), and Yoon Hee Chung (POSTEC) from Korea.For the first time, the SOMMA Proceedings appear in physica status solidi. The Editors hope that the Proceedings could provide chances for deeper and wider understanding of the presentations as well as for enhanced relationship between all participants. We deeply appreciate the help of the editorial staff of physica status solidi for their efficient and kind help during the paper preparations and publications.Finally, we would like to take this opportunity to thank all members of the Advisory Committee, Organizing Committee, referees, and KMS staff for their effort before, during, and after the meeting.

  15. Preface: phys. stat. sol. (b) 241/7

    NASA Astrophysics Data System (ADS)

    Shin, Sung-Chul

    2004-06-01

    The KMS/SOMMA Meeting 2003 was held 3-6 December 2003 at Spapia Hotel, Daejeon, Korea. It was the 5th SOMMA (International Symposium on Magnetic Materials and Applications) organized by ReCAMM (Research Center for Advanced Magnetic Materials) of Chungnam National University. Since 2002, the Korean Magnetics Society (KMS) winter conference has been jointly held with SOMMA. This was the second time to have a KMS/SOMMA joint meeting.The main objective of the meeting was to provide an international forum to discuss up-to-date results on magnetism and magnetic materials. The conference brought together 360 participants from 12 countries. Sessions of the meeting were: Theory and Fundamentals, Magnetic Random Access Memory, Spintronics, Information Storage, Nanostructured Materials, Sensors, and Interdisciplinary. In these seven sessions, 325 papers were presented including 66 oral and 259 poster presentations. Since the symposium was held in Korea, this enabled a large number of Asian scientists to attend: 239 from Korea, 41 from Japan, 7 from Taiwan, and 5 from China.The conference program had 25 invited and plenary speakers. They were Y. Ando (Tohoku U.), M. Inoue (Toyohashi U. Tech), H. Kubota (Tohoku U.), K. Mohri (Nagoya U.), M. Sahashi, M. Takahashi, K. Takanashi, M. Tsunoda (Tohoku U.), and H. Yoda (Toshiba) from Japan; A. J. Freeman (Northwestern U.), A. T. Hanbicki (NRL), F. B. Humphrey (Boston U.), and S. Sun (IBM) from the USA; J. D. Boeck (IMEC, Belgium), B. Dieny (CEA, France), N. Garcia (CSIS, Spain), G. Reiss (Bielefeld U., Germany), T. Stobiecki (U. M. & M. Krakow, Poland), and M. Wolfram (Singulus Tech, Germany) from Europe; C. G. Kim, D. J. Kim (CNU), T. W. Kim (SAIT), S. H. Lim (KIST), Sung-Chul Shin (KAIST), and Yoon Hee Chung (POSTEC) from Korea.For the first time, the SOMMA Proceedings appear in physica status solidi. The Editors hope that the Proceedings could provide chances for deeper and wider understanding of the presentations as well as for enhanced relationship between all participants. We deeply appreciate the help of the editorial staff of physica status solidi for their efficient and kind help during the paper preparations and publications.Finally, we would like to take this opportunity to thank all members of the Advisory Committee, Organizing Committee, referees, and KMS staff for their effort before, during, and after the meeting.

  16. Preface: phys. stat. sol. (b) 242/13

    NASA Astrophysics Data System (ADS)

    Esser, Norbert; Zahn, Dietrich R. T.

    2005-11-01

    Wolfgang Richter celebrated his 65th birthday on 2 January 2005. On such an occasion, usually marking retirement, achievements and breakthroughs in research are reviewed. But Wolfgang Richter is not retiring: he has accepted an offer of a professorship at the University Rome II Tor Vergata. As he explained to us with his famous smile, he plans to concentrate his future efforts even more on his true love in science - the optical diagnostics of interfaces.Wolfgang Richter has been working in the field of optical spectroscopy of solids since his PhD studies at the University of Cologne. Having finished his PhD in 1969 in the field of infrared spectroscopy he decided to reduce the probed volume by increasing the energy of probing photons: Raman spectroscopy! During his postdoctoral and Habilitation periods (1970-1979) at Pennsylvania State University, Max-Planck-Institut für Festkörperforschung, and RWTH Aachen, he pursued his interest in resonance Raman spectroscopy on semiconductors.In 1979 he received his first appointment as full professor at the University of Ulm. He returned to RWTH Aachen in 1981 and discovered his true destiny: semiconductor interfaces. At that time in the Department of Semiconductor Technology, metal-organic vapour phase epitaxy (MOVPE) was under development as a new technique for growing semiconductor layers. The underlying processes in MOVPE were known to be complex and very difficult to analyse with available experimental techniques, due to the unfriendly, reactive gas phase environment. Optical diagnostics turned out to be the key to a better understanding of MOVPE processes. Wolfgang Richter moved from RWTH Aachen to TU Berlin at the end of 1988 and began building a strong research group concentrating on interface analysis from two complementary sides: on the one hand, tracking MOVPE growth processes online by in situ optics and, on the other hand, advancing the fundamental understanding of optical spectra of interfaces by relating the optical response to atomic structures. Combining both aspects has finally led to considerable progress in surface and interface optics, as well as in vapour phase epitaxy and, moreover, the in situ optical tools developed are nowadays available as standard options in commercial MOVPE machines.The advances largely concerned the development of reflectance anisotropy spectroscopy and spectroscopic ellipsometry as in situ optical tools. However, considerable progress in Raman spectroscopy was also made: analysis of surfaces, ultrathin layers down to a single monolayer or even sub-monolayer coverages, and sub-wavelength spatial resolution were demonstrated in recent years. Current challenges concern, in particular, organic materials, molecule-solid interfaces and bio-interfaces, which will help in the development of many new applications and devices. Interfaces will play a crucial role in many of these developments and optical spectroscopy offers promising capabilities for analysing such interfaces. Wolfgang Richter and his group at University of Rome II Tor Vergata are sure to be active in this emerging field for a long time to come.Based on a symposium on Optical Spectroscopy of Interfaces at the Spring Meeting of the German Physical Society in Berlin 2005, we have asked former and present colleagues of Wolfgang Richter to contribute to this special issue of physica status solidi (b) on Advanced Optical Diagnostics of Surfaces, Nanostructures and Ultrathin Films. We think that the collection of 26 papers gives an excellent overview on recent achievements and future developments in the field of linear optics. In addition to a number of Original Papers on experimental work and some Review Articles, the issue includes examples of the current approaches of computational theory to solid state optics and interface optics. We hope that this issue will stimulate the expansion of the growing field of optical analysis of interfaces, nanostructures and ultrathin layers into new areas of basic and applied science. After the success in characterising inorganic materials, it is

  17. Dedication: phys. stat. sol. (a) 202/15

    NASA Astrophysics Data System (ADS)

    Albrecht, Martin

    2005-12-01

    The papers in this issue are dedicated to Professor Horst Paul Strunk on the occasion of his 65th birthday and his retirement from active teaching. This volume honours a scientist who has made a lasting impact on the field in electron microscopic characterisation of growth and relaxation phenomena in epitaxial growth of semiconductors. Born in The Hague, The Netherlands, on 13 June 1940, he studied physics in Stuttgart where he received his degree in Physics in 1968. He joined the group of Prof. Seeger at the Max-Planck-Institut für Metallforschung and defended his Ph.D. on defects in NaCl at Stuttgart University in 1973. He spent one year at Cornell University as a visiting Professor before joining Technische Universität Hamburg-Harburg in 1983. There he created the Zentralbereich Elektronenmikroskopie and was a professor for materials analytics from 1983 till 1989. In 1989 he changed to the University of Erlangen-Nürnberg, where he established the Verbundlabor für hochauflösende Elektronenmikroskopie and directed the Lehrstuhl Mikrocharakterisierung at the Institut für Werkstoffwissenschaften of the same university. He spent two research periods at the Universities of Rennes in France and Campinas in Brazil. Together with his colleague Prof. Jürgen Werner he created the series of conferences on polycrystalline semiconductors POLYSE which he has been supervising together with Jürgen Werner since 1990.The research activities of Horst P. Strunk are focused on microstructure of materials and their relation to macroscopic physical properties. Main topics are dislocations, their formation and interaction mechanisms, strain relaxation as well as fundamental mechanisms of epitaxial growth. The spectrum of materials covers a wide range starting from metals over ionic crystals, e.g. NaCl to elemental and compound semiconductors. From the beginning, the main tool of study has been the transmission electron microscope. However, Horst P. Strunk recognised that a thorough understanding of materials problems would require the combined use of structural characterisation, advanced spectroscopy and modelling. Therefore he complemented electron microscopic approaches by optical methods e.g. Raman spectroscopy and cathodoluminescence. Modelling of strain states by finite elements and of defect structures by ab-initio calculations became an important topic especially in the last years. It is characteristic for the scientific approach of Horst Strunk that methodological developments were not an end in itself but linked to problems in solid state physics and materials sciences. Among the scientific works of Strunk, a few examples should be highlighted which mark important stages in his scientific career. Pioneering work has been done on the influence of dislocations in homoepitaxial growth of Si and GaAs in collaboration with Elisabeth Bauser in Stuttgart. Strunk correlated growth spirals on the surface to dislocations that caused these step sources. Studying the dislocation structure of heteroepitaxial Ge/GaAs layers, Strunk discovered that a new dislocation multiplication source works which, later known as Hagen-Strunk source, had a strong impact on understanding of relaxation processes by dislocations in heteroepitaxial semiconductor systems. Work on electrical and structural properties of grain boundaries in silicon was performed together with Jürgen Werner. This was the starting point of a long lasting research on photovoltaic materials that accompanies Strunk till today. Fundamental studies on heteroepitaxial growth were performed in the system SiGe grown from solution. In this context, finite elements were established for the first time in the study of nanostructured materials. In the last years correlated studies on structural and optical properties on III-nitride heterostructures were done by cathodoluminescence in the transmission electron microscope. The impact of Horst P. Strunk's work is evident from the fact that his lab became part of collaborative international projects based on the unique facilities at the Verbundlabor für Hochauflösende Elektronenmikroskopie and the profound knowledge in the field of crystal growth and solid state physics present in his group. The articles in this issue contain original research results contributed by his friends, collaborators and former students. They are a testimony of the lasting impact of Horst P. Strunk's work and they express the authors' gratefulness for benefiting from his work. This volume gives us a unique opportunity to say thank you to Horst P. Strunk and to wish him a new period in his life that should continue to be scientifically as fruitful as up to now but less affected by the burden of administrative work than during the last years.

  18. Preface: phys. stat. sol. (b) 243/5

    NASA Astrophysics Data System (ADS)

    Artacho, Emilio; Beck, Thomas L.; Hernández, Eduardo

    Between 20 and 24 June 2005 the Centre Européen de Calcul Atomique et Moléculaire - or CECAM, as it is more widely known - hosted a workshop entitled State-of-the-art, developments and perspectives of real-space electronic structure methods in condensed-matter and chemical physics, organized with the support of CECAM itself and the ?k network. The workshop was attended by some forty participants coming from fifteen countries, and about thirty presentations were given. The workshop provided a lively forum for the discussion of recent methodological developments in electronic structure calculations, ranging from linear-scaling methods, mesh techniques, time-dependent density functional methods, and a long etcetera, which had been our ultimate objective when undertaking its organization.The first-principles simulation of solids, liquids and complex matter in general has jumped in the last few years from the relatively confined niches in condensed matter and materials physics and in quantum chemistry, to cover most of the sciences, including nano, bio, geo, environmental sciences and engineering. This effect has been propitiated by the ability of simulation techniques to deal with an ever larger degree of complexity. Although this is partially to be attributed to the steady increase in computer power, the main factor behind this change has been the coming of age of the main theoretical framework for most of the simulations performed today, together with an extremely active development of the basic algorithms for its computer implementation. It is this latter aspect that is the topic of this special issue of physica status solidi.There is a relentless effort in the scientific community seeking to achieve not only higher accuracy, but also more efficient, cost-effective and if possible simpler computational methods in electronic structure calculations [1]. From the early 1990s onwards there has been a keen interest in the computational condensed matter and chemical physics communities in methods that had the potential to overcome the unfavourable scaling of the computational cost with the system size, implicit in the momentum-space formalism familiar to solid-state physicists and the quantum chemistry approaches more common in chemical physics and physical chemistry. This interest was sparkled by the famous paper in which Weitao Yang [2] introduced the Divide and Conquer method. Soon afterwards several practical schemes aiming to achieve linear-scaling calculations, by exploiting what Walter Kohn called most aptly the near-sightedness of quantum mechanics [3], were proposed and explored (for a review on linear-scaling methods, see [4]). This search for novel, more efficient and better scaling algorithms proved to be fruitful in more than one way. Not only was it the start of several packages which are well-known today (such as Siesta, Conquest, etc.), but it also leads to new ways of representing electronic states and orbitals, such as grids [5, 6], wavelets [7], finite elements, etc. Also, the drive to exploit near-sightedness attracted computational solid state physicists to the type of atomic-like basis functions traditionally used in the quantum chemistry community. At the same time computational chemists learnt about plane waves and density functional theory, and thus a fruitful dialogue was started between two communities that hitherto had not had much contact.Another interesting development that has begun to take place over the last decade or so is the convergence of several branches of science, notably physics, chemistry and biology, at the nanoscale. Experimentalists in all these different fields are now performing highly sophisticated measurements on systems of nanometer size, the kind of systems that us theoreticians can address with our computational methods, and this convergence of experiment and theory at this scale has also been very fruitful, particularly in the fields of electronic transport and STM image simulation. It is now quite common to find papers at the cutting edge of nanoscience and nanotechnology co-authored by experimentalists and theorists, and it can only be expected that this fruitful interplay between theory and experiment will increase in the future.It was considerations such as these that moved us to propose to CECAM and ?k the celebration of a workshop devoted to the discussion of recent developments in electronic structure techniques, a proposal that was enthusiastically received, not just by CECAM and ?k, but also by our invited speakers and participants. Interest in novel electronic structure methods is now as high as ever, and we are therefore very happy that physica status solidi has given us the opportunity to devote a special issue to the topics covered in the workshop. This special issue of physica status solidi gathers invited contributions from several attendants to the workshop, contributions that are representative of the range of topics and issues discussed then, including progress in linear scaling methods, electronic transport, simulation of STM images, time-dependent DFT methods, etc. It rests for us to thank all the contributors to this special issue for their efforts, CECAM and ?k for funding the workshop, physica status solidi for agreeing to devote this special issue to the workshop, and last but not least Emmanuelle and Emilie, the CECAM secretaries, for their invaluable practical help in putting this workshop together

  19. Preface: phys. stat. sol. (a) 203/4

    NASA Astrophysics Data System (ADS)

    Kittler, Martin; Yang, Deren

    2006-03-01

    This issue of physica status solidi (a) contains the majority of papers presented at the 2nd Sino-German Symposium The Silicon Age which was held at the Lindner Hotel Cottbus, Germany, 19-24 September 2005. This meeting followed the 1st Symposium Progress in Silicon Materials held in June 2002 in Hangzhou, P.R. China. 8 Chinese and 14 German scientists from universities, research institutes and industry were invited to present their views about different aspects of silicon.There was a continuous progress in silicon materials development during the last 40-50 years, driven by the need of the IC industry for better and larger monocrystalline silicon wafers. Moreover, low-cost crystalline silicon now dominates the world's production of solar cells in the photovoltaics industry. Furthermore, there are intensive research activities worldwide for on-chip integration of Si-based photonics in CMOS technology. In addition, new areas being connected with silicon are starting to appear, namely Si-based biochips and nanoelectronics. Silicon, one can reasonably argue, is already the most investigated of all materials. However, there is still a need for continuation of research and development regarding numerous aspects of Si and also SiGe, including related technologies, advanced diagnostics or the role of crystal defects, which are the working fields of many laboratories all over the world. This was also shown by the presentations at the symposium and can be found in the contributions contained in this issue.The organizers would like to thank the participants for their high level contributions and discussions during the symposium. This intensive and open communication allowed the participants to create synergies between the different fields of silicon research and also to build up relationships for cooperation between Chinese and German research groups.Finally, we would like to thank the Sino-German Science Center for the financial support of the symposium.

  20. Preface: phys. stat. sol. (b) 242/9

    NASA Astrophysics Data System (ADS)

    Sánchez, Maria

    2005-07-01

    The XVII Latin American Symposium on Solid State Physics took place in the conference rooms of the Convent San Francisco de Asis, in the heart of the Old Havana. The sixteen previous editions were organized in eight different countries; the last two were in Colombia (Cartagena, 1999) and Venezuela (Merida, 2002). After eighteen years the meeting came back to Havana in 2004.The program topics included: Surfaces and interfaces analysis; Spintronics; Magnetism; Materials and energy; Ab-initio methods, simulations and modeling in solids; Nanophysics, nanomaterials and nanotechnology; New materials, properties and applications; Preparation of materials, thin films and characterization; High temperature superconductivity; Techniques of structural analysis in solids. The program included 6 plenary talks, 13 invited talks, 58 oral presentations (in eight sessions) and 200 poster contributions (in four poster sessions).The meeting attracted more than 200 participants from 14 countries. The physica status solidi Young Researcher Award sponsored by Wiley-VCH was conferred at the meeting. This prize was divided between two participants: Clara Calderón (Study of electrical transport properties of ZnO thin films used as front contact of solar cells) from Colombia and Aim?? Pelaiz Barranco (AC behavior in lanthanum modified PZT ferroelectric ceramics) from Cuba. Special Mentions went to Val??rie Halté (Femtosec-ond dynamics of transmission of gold arrays of sub-wavelength holes) from France, Erick Larramendi Cancio (Cd desorption induced by Zn exposure during atomic layer epitaxy of CdxZn1-xTe) and Julio Cesar Rimada Herrera (Quantum and conversion efficiency calculation of AlGaAs/GaAs multiple quantum well solar cells) from Cuba.Nanostructures and in general low dimensional physics related to different systems was a very hot topic during the meeting. Some talks and presentations were devoted to optoelectronic materials and devices. Characterization of solids by different structural and optical techniques together with modeling and simulations were also important subjects of the symposium.The XVIII Symposium will be held in Mexico in 2006.The editors wish to thank all the participants who contributed to the success of the meeting and hope that it helped to develop close links between researchers and institutions of Latin America.

  1. Well-Defined SiO2@P(EtOx-stat-EI) Core-Shell Hybrid Nanoparticles via Sol-Gel Processes.

    PubMed

    Eckardt, Oliver; Pietsch, Christian; Zumann, Oliver; von der Lühe, Moritz; Brauer, Delia S; Schacher, Felix H

    2016-02-01

    Positively charged nanoparticles (NPs) are very interesting for biomedical and pharmaceutical applications, such as nonviral gene delivery. Here, the synthesis of SiO2 nanoparticles with a covalently grafted poly(2-ethyl-2-oxazoline) (PEtOx) shell (SiO2@PEtOx) is presented. PEtOx with a degree of polymerization of 20 and 38 is synthesized via microwave supported cationic ring-opening polymerization and subsequently end-functionalized with a triethoxysilyl linker for subsequent grafting to silica particles with hydrodynamic radii of 7, 31, and 152 nm. The resulting SiO2@PEtOx particles are characterized by using dynamic light scattering (DLS), transmission electron microscopy (TEM, cryoTEM), and scanning electron microscopy (SEM) to determine changes in particle size. Thermal gravimetrical analysis is used to quantify the amount of polymer on the silica surface. Subsequent in situ transformation of SiO2@PEtOx particles into SiO2@P(EtOx-stat-EI) (poly(2-ethyl-2-oxazoline-stat-ethylene imine) grafted silica particles) under acidic conditions inverts the surface charge from negative to positive according to ζ-potential measurements. The P(EtOx-stat-EI) shell could be used for the deposition of Au NP afterward. PMID:26676077

  2. Acanthamoeba castellanii STAT protein.

    PubMed

    Kicinska, Anna; Leluk, Jacek; Jarmuszkiewicz, Wieslawa

    2014-01-01

    STAT (signal transducers and activators of transcription) proteins are one of the important mediators of phosphotyrosine-regulated signaling in metazoan cells. We described the presence of STAT protein in a unicellular, free-living amoebae with a simple life cycle, Acanthamoeba castellanii. A. castellanii is the only, studied to date, Amoebozoan that does not belong to Mycetozoa but possesses STATs. A sequence of the A. castellanii STAT protein includes domains similar to those of the Dictyostelium STAT proteins: a coiled coil (characteristic for Dictyostelium STAT coiled coil), a STAT DNA-binding domain and a Src-homology domain. The search for protein sequences homologous to A. castellanii STAT revealed 17 additional sequences from lower eukaryotes. Interestingly, all of these sequences come from Amoebozoa organisms that belong to either Mycetozoa (slime molds) or Centramoebida. We showed that there are four separated clades within the slime mold STAT proteins. The A. castellanii STAT protein branches next to a group of STATc proteins from Mycetozoa. We also demonstrate that Amoebozoa form a distinct monophyletic lineage within the STAT protein world that is well separated from the other groups. PMID:25338074

  3. Summary of PhysPAG Activity

    NASA Astrophysics Data System (ADS)

    Nousek, John A.

    2014-01-01

    The Physics of the Cosmos Program Analysis Group (PhysPAG) is responsible for solicitiing and coordinating community input for the development and execution of NASA's Physics of the Cosmos (PCOS) program. In this session I will report on the activity of the PhysPAG, and solicit community involvement in the process of defining PCOS objectives, planning SMD architecture, and prioritizing PCOS activities. I will also report on the activities of the PhysPAG Executive Committee, which include the chairs of the Science Analysis Groups/ Science Interest Groups which fall under the PhysPAG sphere of interest. Time at the end of the presentation willl be reserved for questions and discussion from the community.

  4. Summary of PhysPAG Activities

    NASA Astrophysics Data System (ADS)

    Ritz, Steven M.

    2013-01-01

    The Physics of the Cosmos (PCOS) Program Analysis Group (PhysPAG) provides an important interface between the scientific community and NASA in matters related to PCOS objectives, and also provides opportunities for community discussions. An Executive Committee facilitates the work of several subgroups, including an Inflation Probe Science Analysis Group (IPSAG), an X-ray group (XRSAG) , a gamma-ray,group (GRSAG), a gravitational wave group (GWSAG), and a cosmic-ray group (CRSAG). In addition to identifying opportunities and issues, these groups also help articulate technology needs. Membership in all the SAGs is completely open, with information and newsletter signups available on the PhysPAG pages at the PCOS program website. The PhysPAG reports to the Astrophysics Subcommittee of the NASA Advisory Council. A summary of PhysPAG activities will be given, along with time for questions and discussion.

  5. STAT inhibitors for cancer therapy

    PubMed Central

    2013-01-01

    Signal Transducer and Activator of Transcription (STAT) proteins are a family of cytoplasmic transcription factors consisting of 7 members, STAT1 to STAT6, including STAT5a and STAT5b. STAT proteins are thought to be ideal targets for anti-cancer therapy since cancer cells are more dependent on the STAT activity than their normal counterparts. Inhibitors targeting STAT3 and STAT5 have been developed. These included peptidomimetics, small molecule inhibitors and oligonucleotides. This review summarized advances in preclinical and clinical development of these compounds. PMID:24308725

  6. Summary of PhysPAG Activities

    NASA Astrophysics Data System (ADS)

    Ritz, Steven M.

    2012-01-01

    The Physics of the Cosmos (PCOS) Program Analysis Group (PhysPAG) provides an important interface between the scientific community and NASA in matters related to PCOS objectives. An Executive Committee facilitates the work of several subgroups, including a Technology Science Analysis Group and an Inflation Probe Science Analysis Group. Work is also starting in areas of X-ray, gamma-ray, and gravitational wave astrophysics. The PAG reports to the Astrophysics Subcommittee of the NASA Advisory Council. A summary of PhysPAG activities will be given, along with time for questions and discussion.

  7. CPR Facts and Stats

    MedlinePlus

    ... CPR About CPR & First Aid CPR Facts & Stats History of CPR Cardiac Arrest vs. Heart Attack International ... Training Kits RQI AHA Instructors ECC Educational Conferences Programs CPR In Schools Hands-Only CPR ...

  8. Fast wave power flow along SOL field lines in NSTX

    NASA Astrophysics Data System (ADS)

    Perkins, R. J.; Bell, R. E.; Diallo, A.; Gerhardt, S.; Hosea, J. C.; Jaworski, M. A.; Leblanc, B. P.; Kramer, G. J.; Phillips, C. K.; Roquemore, L.; Taylor, G.; Wilson, J. R.; Ahn, J.-W.; Gray, T. K.; Green, D. L.; McLean, A.; Maingi, R.; Ryan, P. M.; Jaeger, E. F.; Sabbagh, S.

    2012-10-01

    On NSTX, a major loss of high-harmonic fast wave (HHFW) power can occur along open field lines passing in front of the antenna over the width of the scrape-off layer (SOL). Up to 60% of the RF power can be lost and at least partially deposited in bright spirals on the divertor floor and ceiling [1,2]. The flow of HHFW power from the antenna region to the divertor is mostly aligned along the SOL magnetic field [3], which explains the pattern of heat deposition as measured with infrared (IR) cameras. By tracing field lines from the divertor back to the midplane, the IR data can be used to estimate the profile of HHFW power coupled to SOL field lines. We hypothesize that surface waves are being excited in the SOL, and these results should benchmark advanced simulations of the RF power deposition in the SOL (e.g., [4]). Minimizing this loss is critical optimal high-power long-pulse ICRF heating on ITER while guarding against excessive divertor erosion.[4pt] [1] J.C. Hosea et al., AIP Conf Proceedings 1187 (2009) 105. [0pt] [2] G. Taylor et al., Phys. Plasmas 17 (2010) 056114. [0pt] [3] R.J. Perkins et al., to appear in Phys. Rev. Lett. [0pt] [4] D.L. Green et al., Phys. Rev. Lett. 107 (2011) 145001.

  9. [STAT3 inhibitor].

    PubMed

    Kitamura, Toshio

    2011-01-01

    Clinical efficacies of various molecular-targeted drugs have been recently demonstrated. Most of these drugs are kinase inhibitors. A most successful drug Glivec is an inhibitor of Bcr-Abl fusion kinase, derived from a well-known causative chromosome translocation of chronic myeloid leukemia(CML). Although other kinase inhibitors have also proved to be useful in the therapy of malignant diseases including an ALK inhibitor for lung carcinomas, a general problem of kinase inhibitors is their lowspecificities. Therefore, the complication of these drugs must be overcome. Recently, trials to develop moleculartargeted therapy whose targets are molecules other than kinases have also been promising. Among molecular targets, STAT3 has attracted a great deal of researchers' attention because it is constitutively activated in most malignant tumors and plays important roles in carcinogenesis. This article summarizes the current situation and problems to be solved with STAT3 inhibitors as well as our recent findings on the molecular mechanisms of STAT3 activation. PMID:21368456

  10. Students' Attitudes toward Statistics (STATS).

    ERIC Educational Resources Information Center

    Sutarso, Toto

    The purposes of this study were to develop an instrument to measure students' attitude toward statistics (STATS), and to define the underlying dimensions that comprise the STATS. The instrument consists of 24 items. The sample included 79 male and 97 female students from the statistics classes at the College of Education and the College of…

  11. The new PhysTEC program at Boston University

    NASA Astrophysics Data System (ADS)

    Jenkins, Juliet; Duffy, Andrew

    2011-11-01

    The Boston University Physics Department was recently awarded a three-year grant from the Physics Teacher Education Coalition (PhysTEC). PhysTEC's main aims are to improve the education of future physics teachers, and to increase the number of qualified physics teachers in the school system. Although there have been over 20 PhysTEC-funded sites across the country, BU is the first PhysTEC site in New England. Our goals with this poster are to raise awareness about PhysTEC, and to talk about what we are doing and what we plan to do at BU with our PhysTEC funding. A key part of the PhysTEC program is the teacher-in-residence (TIR), an experienced physics teacher who comes to campus for a year to promote physics teaching as a profession and to lend their experience to education-related efforts. Our first TIR is Juliet Jenkins. The poster will discuss Ms. Jenkins' role in the Department of Physics and in the School of Education as we move forward with new efforts to promote teaching, including a Learning Assistant program, a pilot studio section of one of our introductory physics courses, and a new education course that allows undergraduate students to observe teachers in the classroom.

  12. MAC-bridging for multi-PHYs communication in BAN.

    PubMed

    Ullah, Sana; Khan, Pervez; Ullah, Niamat; Kwak, Kyung Sup

    2010-01-01

    Body Area Network (BAN) is a collection of low-power, miniaturised, and intelligent sensor nodes that are used for unobtrusive and ambulatory health monitoring of a patient without any additional constraints. These nodes operate on different frequency bands or Multiple Physical Layers (Multi-PHYs). Additionally, some BAN applications demand a logical connection between different nodes working on different Multi-PHYs. In this paper, the idea of controlling Multi-PHYs using one MAC protocol is introduced. Unlike existing procedures where different nodes working on different channels are connected at the link layer bridging/switching, the proposed procedure called bridging logically connects them at the MAC layer. In other words, the bridge is used to relay or filter packets between different PHYs in the same BAN. Numerical approximations are presented to analyze the stochastic behaviour of the bridges, all of them having Multi-PHYs interfaces. The MICS and the ISM bands are regarded as PHY1 and PHY2, respectively. The performance results are presented for PHY2 (given that data is already received from PHY1) in terms of probability of successful transmission, number of failed requests, power consumption, and delay. Simulations are conducted to validate the analytical results. It can be seen that the deployment of multiple bridges along with the corresponding nodes allows Multi-PHYs communication with high transmission probability, low power consumption, and tolerable delay. PMID:22163447

  13. Eriocalyxin B Inhibits STAT3 Signaling by Covalently Targeting STAT3 and Blocking Phosphorylation and Activation of STAT3.

    PubMed

    Yu, Xiaokui; He, Li; Cao, Peng; Yu, Qiang

    2015-01-01

    Activated STAT3 plays an important role in oncogenesis by stimulating cell proliferation and resisting apoptosis. STAT3 therefore is an attractive target for cancer therapy. We have screened a traditional Chinese herb medicine compound library and found Eriocalyxin B (EB), a diterpenoid from Isodon eriocalyx, as a specific inhibitor of STAT3. EB selectively inhibited constitutive as well as IL-6-induced phosphorylation of STAT3 and induced apoptosis of STAT3-dependent tumor cells. EB did not affect the upstream protein tyrosine kinases or the phosphatase (PTPase) of STAT3, but rather interacted directly with STAT3. The effects of EB could be abolished by DTT or GSH, suggesting a thiol-mediated covalent linkage between EB and STAT3. Site mutagenesis of cysteine in and near the SH2 domain of STAT3 identified Cys712 to be the critical amino acid for the EB-induced inactivation of STAT3. Furthermore, LC/MS/MS analyses demonstrated that an α, β-unsaturated carbonyl of EB covalently interacted with the Cys712 of STAT3. Computational modeling analyses also supported a direct interaction between EB and the Cys712 of STAT3. These data strongly suggest that EB directly targets STAT3 through a covalent linkage to inhibit the phosphorylation and activation of STAT3 and induces apoptosis of STAT3-dependent tumor cells. PMID:26010889

  14. Eriocalyxin B Inhibits STAT3 Signaling by Covalently Targeting STAT3 and Blocking Phosphorylation and Activation of STAT3

    PubMed Central

    Yu, Xiaokui; He, Li; Cao, Peng; Yu, Qiang

    2015-01-01

    Activated STAT3 plays an important role in oncogenesis by stimulating cell proliferation and resisting apoptosis. STAT3 therefore is an attractive target for cancer therapy. We have screened a traditional Chinese herb medicine compound library and found Eriocalyxin B (EB), a diterpenoid from Isodon eriocalyx, as a specific inhibitor of STAT3. EB selectively inhibited constitutive as well as IL-6-induced phosphorylation of STAT3 and induced apoptosis of STAT3-dependent tumor cells. EB did not affect the upstream protein tyrosine kinases or the phosphatase (PTPase) of STAT3, but rather interacted directly with STAT3. The effects of EB could be abolished by DTT or GSH, suggesting a thiol-mediated covalent linkage between EB and STAT3. Site mutagenesis of cysteine in and near the SH2 domain of STAT3 identified Cys712 to be the critical amino acid for the EB-induced inactivation of STAT3. Furthermore, LC/MS/MS analyses demonstrated that an α, β-unsaturated carbonyl of EB covalently interacted with the Cys712 of STAT3. Computational modeling analyses also supported a direct interaction between EB and the Cys712 of STAT3. These data strongly suggest that EB directly targets STAT3 through a covalent linkage to inhibit the phosphorylation and activation of STAT3 and induces apoptosis of STAT3-dependent tumor cells. PMID:26010889

  15. STAT1 and STAT3 do not participate in FGF-mediated growth arrest in chondrocytes.

    PubMed

    Krejci, Pavel; Salazar, Lisa; Goodridge, Helen S; Kashiwada, Tamara A; Schibler, Matthew J; Jelinkova, Petra; Thompson, Leslie Michels; Wilcox, William R

    2008-02-01

    Activating mutations in fibroblast growth factor receptor 3 (FGFR3) cause several human skeletal dysplasias as a result of attenuation of cartilage growth. It is believed that FGFR3 inhibits chondrocyte proliferation via activation of signal transducers and activators of transcription (STAT) proteins, although the exact mechanism of both STAT activation and STAT-mediated inhibition of chondrocyte growth is unclear. We show that FGFR3 interacts with STAT1 in cells and is capable of activating phosphorylation of STAT1 in a kinase assay, thus potentially serving as a STAT1 kinase in chondrocytes. However, as demonstrated by western blotting with phosphorylation-specific antibodies, imaging of STAT nuclear translocation, STAT transcription factor assays and STAT luciferase reporter assays, FGF does not activate STAT1 or STAT3 in RCS chondrocytes, which nevertheless respond to a FGF stimulus with potent growth arrest. Moreover, addition of active STAT1 and STAT3 to the FGF signal, by means of cytokine treatment, SRC-mediated STAT activation or expression of constitutively active STAT mutants does not sensitize RCS chondrocytes to FGF-mediated growth arrest. Since FGF-mediated growth arrest is rescued by siRNA-mediated downregulation of the MAP kinase ERK1/2 but not STAT1 or STAT3, our data support a model whereby the ERK arm but not STAT arm of FGF signaling in chondrocytes accounts for the growth arrest phenotype. PMID:18198189

  16. STAT3 the oncogene - still eluding therapy?

    PubMed

    Wake, Matthew S; Watson, Christine J

    2015-07-01

    The STAT family of transcription factors (signal transducers and activators of transcription) transduce signals from cytokine receptors to the nucleus, where STAT dimers bind to DNA and regulate transcription. STAT3 is the most ubiquitous of the STATs, being activated by a wide variety of cytokines and growth factors. STAT3 has many roles in physiological processes such as inflammatory signalling, aerobic glycolysis and immune suppression, and was also the first family member shown to be aberrantly activated in a wide range of both solid and liquid tumours. STAT3 promotes tumorigenesis by regulating the expression of various target genes, including cell-cycle regulators, angiogenic factors and anti-apoptosis genes. Paradoxically, in some circumstances, STAT3 signalling induces cell death. The best known example is the involuting mammary gland, where STAT3 is essential for induction of a lysosomal pathway of cell death. Nevertheless, direct silencing or inhibition of STAT3 diminishes tumour growth and survival in both animal and human studies. This suggests that abolishing STAT3 activity may be an effective cancer therapeutic strategy. However, despite this potential as a therapeutic target, and the extensive attempts by many laboratories and pharmaceutical companies to develop an effective STAT3 inhibitor for use in the clinic, no direct STAT3 inhibitor has been approved for clinical use. In this review, we focus on the role of STAT3 in tumorigenesis, and discuss its potential as a therapeutic target for cancer treatment. PMID:25825152

  17. PeriStats: Perinatal Statistics

    MedlinePlus

    ... is developed by the March of Dimes Perinatal Data Center and provides access to maternal and infant health ... on PeriStats sometimes different from my health department's data? What should I do if pop-up blocker ... We acknowledge the Centers for Disease Control and Prevention for its support ...

  18. The role of stat1b in zebrafish hematopoiesis

    PubMed Central

    Song, Hao; Yan, Yi-lin; Titus, Tom; He, Xinjun; Postlethwait, John H.

    2011-01-01

    STAT1 mediates response to interferons and regulates immunity, cell proliferation, apoptosis, and sensitivity of Fanconi Anemia cells to apoptosis after interferon signaling; the roles of STAT1 in embryos, however, are not understood. To explore embryonic functions of STAT1, we investigated stat1b, an unstudied zebrafish co-ortholog of human STAT1. Zebrafish stat1a encodes all five domains of the human STAT1-alpha splice form but, like the human STAT1-beta splice variant, stat1b lacks a complete transactivation domain; thus, two unlinked zebrafish paralogs encode protein forms translated from two splice variants of a single human gene, as expected by subfunctionalization after genome duplication. Phylogenetic and conserved synteny studies showed that stat1b and stat1a arose as duplicates in the teleost genome duplication (TGD) and clarified the evolutionary origin of STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B and STAT6 by tandem and genome duplication. RT-PCR revealed maternal expression of stat1a and stat1b. In situ hybridization detected stat1b but not stat1a expression in embryonic hematopoietic tissues. Morpholino knockdown of stat1b, but not stat1a, decreased expression of the myeloid and granulocyte markers spi and mpo and increased expression of the hematopoietic progenitor marker scl, the erythrocyte marker gata1, and hemoglobin. These results suggest that zebrafish Stat1b promotes myeloid development at the expense of erythroid development. PMID:21914475

  19. Activating STAT6 mutations in follicular lymphoma

    PubMed Central

    Yildiz, Mehmet; Li, Hongxiu; Bernard, Denzil; Amin, Nisar A.; Ouillette, Peter; Jones, Siân; Saiya-Cork, Kamlai; Parkin, Brian; Jacobi, Kathryn; Shedden, Kerby; Wang, Shaomeng; Chang, Alfred E.; Kaminski, Mark S.

    2015-01-01

    Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma in the Western world. FL cell-intrinsic and cell-extrinsic factors influence FL biology and clinical outcome. To further our understanding of the genetic basis of FL, we performed whole-exome sequencing of 23 highly purified FL cases and 1 transformed FL case and expanded findings to a combined total of 114 FLs. We report recurrent mutations in the transcription factor STAT6 in 11% of FLs and identified the STAT6 amino acid residue 419 as a novel STAT6 mutation hotspot (p.419D/G, p.419D/A, and p.419D/H). FL-associated STAT6 mutations were activating, as evidenced by increased transactivation in HEK293T cell–based transfection/luciferase reporter assays, heightened interleukin-4 (IL-4) –induced activation of target genes in stable STAT6 transfected lymphoma cell lines, and elevated baseline expression levels of STAT6 target genes in primary FL B cells harboring mutant STAT6. Mechanistically, FL-associated STAT6 mutations facilitated nuclear residency of STAT6, independent of IL-4–induced STAT6-Y641 phosphorylation. Structural modeling of STAT6 based on the structure of the STAT1-DNA complex revealed that most FL-associated STAT6 mutants locate to the STAT6-DNA interface, potentially facilitating heightened interactions. The genetic and functional data combined strengthen the recognition of the IL-4/JAK/STAT6 axis as a driver of FL pathogenesis. PMID:25428220

  20. Stat3 inhibition in neural lineage cells.

    PubMed

    Chiba, Tomohiro; Mack, Laura; Delis, Natalia; Brill, Boris; Groner, Bernd

    2012-06-01

    Abstract Deregulation of signal transducer and activator of transcription 3 (Stat3) is attracting attentions in neurological disorders of elderly populations, e.g., Stat3 is inactivated in hippocampal neurons of Alzheimer's disease (AD) brains, whereas it is often constitutively activated in glioblastoma multiforme (GBM), correlating with poor prognosis. Stat3-inhibiting drugs have been intensively developed for chemotherapy based on the fact that GBM, in many cases, are "addicted" to Stat3 activation. Stat3 inhibitors, however, potentially have unfavorable side effects on postmitotic neurons, normal permanent residents in the central nervous system. It is, therefore, of great importance to address detailed cellular responses of neural lineage cells including normal neurons, astrocytes, and neuronal/glial cancer cell lines to several classes of Stat3 inhibitors focusing on their effective concentrations. Here, we picked up five human and mouse cancer cell lines (Neuro-2a and SH-SY5Y neuroblastoma cell lines and Tu-9648, U-87MG, and U-373MG glioblastoma cell lines) and treated with various Stat3 inhibitors. Among them, Stattic, FLLL31, and resveratrol potently suppressed P-Stat3 and cell viability in all the tested cell lines. Stat3 knockdown or expression of dominant-negative Stat3 further sensitized cells to the inhibitors. Expression of familial AD-related mutant amyloid precursor protein sensitized neuronal cells, not glial cells, to Stat3 inhibitors by reducing P-Stat3 levels. Primary neurons and astrocytes also responded to Stat3 inhibitors with similar sensitivities to those observed in cancer cell lines. Thus, Stat3 inhibitors should be carefully targeted to GBM cells to avoid potential neurotoxicity leading to AD-like neuropsychiatric dysfunctions. PMID:25436682

  1. Identification of STAT1 and STAT3 Specific Inhibitors Using Comparative Virtual Screening and Docking Validation

    PubMed Central

    Szelag, Malgorzata; Czerwoniec, Anna; Wesoly, Joanna; Bluyssen, Hans A. R.

    2015-01-01

    Signal transducers and activators of transcription (STATs) facilitate action of cytokines, growth factors and pathogens. STAT activation is mediated by a highly conserved SH2 domain, which interacts with phosphotyrosine motifs for specific STAT-receptor contacts and STAT dimerization. The active dimers induce gene transcription in the nucleus by binding to a specific DNA-response element in the promoter of target genes. Abnormal activation of STAT signaling pathways is implicated in many human diseases, like cancer, inflammation and auto-immunity. Searches for STAT-targeting compounds, exploring the phosphotyrosine (pTyr)-SH2 interaction site, yielded many small molecules for STAT3 but sparsely for other STATs. However, many of these inhibitors seem not STAT3-specific, thereby questioning the present modeling and selection strategies of SH2 domain-based STAT inhibitors. We generated new 3D structure models for all human (h)STATs and developed a comparative in silico docking strategy to obtain further insight into STAT-SH2 cross-binding specificity of a selection of previously identified STAT3 inhibitors. Indeed, by primarily targeting the highly conserved pTyr-SH2 binding pocket the majority of these compounds exhibited similar binding affinity and tendency scores for all STATs. By comparative screening of a natural product library we provided initial proof for the possibility to identify STAT1 as well as STAT3-specific inhibitors, introducing the ‘STAT-comparative binding affinity value’ and ‘ligand binding pose variation’ as selection criteria. In silico screening of a multi-million clean leads (CL) compound library for binding of all STATs, likewise identified potential specific inhibitors for STAT1 and STAT3 after docking validation. Based on comparative virtual screening and docking validation, we developed a novel STAT inhibitor screening tool that allows identification of specific STAT1 and STAT3 inhibitory compounds. This could increase our

  2. STAT5 Outcompetes STAT3 To Regulate the Expression of the Oncogenic Transcriptional Modulator BCL6

    PubMed Central

    Walker, Sarah R.; Nelson, Erik A.; Yeh, Jennifer E.; Pinello, Luca; Yuan, Guo-Cheng

    2013-01-01

    Inappropriate activation of the transcription factors STAT3 and STAT5 has been shown to drive cancer pathogenesis through dysregulation of genes involved in cell survival, growth, and differentiation. Although STAT3 and STAT5 are structurally related, they can have opposite effects on key genes, including BCL6. BCL6, a transcriptional repressor, has been shown to be oncogenic in diffuse large B cell lymphoma. BCL6 also plays an important role in breast cancer pathogenesis, a disease in which STAT3 and STAT5 can be activated individually or concomitantly. To determine the mechanism by which these oncogenic transcription factors regulate BCL6 transcription, we analyzed their effects at the levels of chromatin and gene expression. We found that STAT3 increases expression of BCL6 and enhances recruitment of RNA polymerase II phosphorylated at a site associated with transcriptional initiation. STAT5, in contrast, represses BCL6 expression below basal levels and decreases the association of RNA polymerase II at the gene. Furthermore, the repression mediated by STAT5 is dominant over STAT3-mediated induction. STAT5 exerts this effect by displacing STAT3 from one of the two regulatory regions to which it binds. These findings may underlie the divergent biology of breast cancers containing activated STAT3 alone or in conjunction with activated STAT5. PMID:23716595

  3. STAT3 Impairs STAT5 Activation in the Development of IL-9-Secreting T Cells.

    PubMed

    Olson, Matthew R; Verdan, Felipe Fortino; Hufford, Matthew M; Dent, Alexander L; Kaplan, Mark H

    2016-04-15

    Th cell subsets develop in response to multiple activating signals, including the cytokine environment. IL-9-secreting T cells develop in response to the combination of IL-4 and TGF-β, although they clearly require other cytokine signals, leading to the activation of transcription factors including STAT5. In Th17 cells, there is a molecular antagonism of STAT5 with STAT3 signaling, although whether this paradigm exists in other Th subsets is not clear. In this paper, we demonstrate that STAT3 attenuates the ability of STAT5 to promote the development of IL-9-secreting T cells. We demonstrate that production of IL-9 is increased in the absence of STAT3 and cytokines that result in a sustained activation of STAT3, including IL-6, have the greatest potency in repressing IL-9 production in a STAT3-dependent manner. Increased IL-9 production in the absence of STAT3 correlates with increased endogenous IL-2 production and STAT5 activation, and blocking IL-2 responses eliminates the difference in IL-9 production between wild-type and STAT3-deficient T cells. Moreover, transduction of developing Th9 cells with a constitutively active STAT5 eliminates the ability of IL-6 to reduce IL-9 production. Thus, STAT3 functions as a negative regulator of IL-9 production through attenuation of STAT5 activation and function. PMID:26976954

  4. Function of shrimp STAT during WSSV infection.

    PubMed

    Wen, Rong; Li, Fuhua; Li, Shihao; Xiang, Jianhai

    2014-06-01

    JAK/STAT signaling pathway plays key roles in the antiviral immunity of mammals, fish and insect. However, limited knowledge is known about the function of JAK/STAT signaling pathway in the antiviral immunity of shrimp although virus disease has caused severe mortality in shrimp aquaculture. In order to understand the function of JAK/STAT signaling pathway in the antiviral immunity of shrimp, dsRNA interfering technique was used to silence the expression of STAT gene in Litopenaeus vannamei, and the mortality of shrimp was detected after WSSV infection. Furthermore, the expressions of some potential target genes regulated by STAT or genes related to RNA interfering pathway were detected in STAT silenced shrimp during WSSV infection. The WSSV copy number in STAT silenced shrimp was 10(2)-10(3) copies/ng DNA which was much lower than that in the control. The mortality in STAT silenced shrimp caused by WSSV infection decreased very significantly compared to their controls. The function of STAT was verified in vitro cultured cells of hematopoietic tissue of crayfish Cherax quadricarinatus by adding specific inhibitor of STAT3(S3I-201), and the cultured cells treated with S3I-201 showed much less WSSV copy number than their controls, which further suggested that STAT might be helpful for the replication of WSSV. Expression analysis on the potential STAT target genes and genes in RNA interfering pathway provide important information for understanding the functional mechanism of STAT in antiviral immunity of shrimp. PMID:24727196

  5. Role of STAT3 in lung cancer

    PubMed Central

    Dutta, Pranabananda; Sabri, Nafiseh; Li, Jinghong; Li, Willis X

    2014-01-01

    Lung cancer remains a challenging disease. It is responsible for the high cancer mortality rates in the US and worldwide. Elucidation of the molecular mechanisms operative in lung cancer is an important first step in developing effective therapies. Accumulating evidence over the last 2 decades suggests a critical role for Signal Transducer and Activator of Transcription 3 (STAT3) as a point of convergence for various signaling pathways that are dysregulated in the disease. In this review, we discuss possible molecular mechanisms involving STAT3 in lung tumorigenesis based on recent literature. We consider possible roles of STAT3 in cancer cell proliferation and survival, in the tumor immune environment, and in epigenetic regulation and interaction of STAT3 with other transcription factors. We also discuss the potential role of STAT3 in tumor suppression, which complicates strategies of targeting STAT3 in cancer therapy. PMID:26413424

  6. STAT3 Signaling in Polycystic Kidney Disease

    PubMed Central

    Weimbs, Thomas; Talbot, Jeffrey J.

    2015-01-01

    Mutations in the gene coding for the integral membrane protein polycystin-1 (PC1) are the cause of most cases of autosomal-dominant polycystic kidney disease (ADPKD), a very common disease that leads to kidney failure and currently lacks approved treatment. Recent work has revealed that PC1 can regulate the transcription factor STAT3, and that STAT3 is aberrantly activated in the kidneys of ADPKD patients and PKD mouse models. Recent approaches to directly inhibit STAT3 in PKD mouse models have been promising. Numerous signaling pathways are known to activate STAT3 and many have long been implicated in the pathogenesis of PKD - such as EGF/EGFR, HGF/c-Met, Src. However, a role of STAT3 in the pathogenesis of PKD had never been considered until now. Here, we review the current findings that suggest that STAT3 is a promising target for the treatment of PKD. PMID:26523147

  7. Screening approaches to generating STAT inhibitors

    PubMed Central

    Walker, Sarah R.; Frank, David A.

    2012-01-01

    STAT transcription factors are regulators of critical cellular processes such as proliferation, survival, and self-renewal. While the activity of these proteins is tightly regulated under physiological conditions, they can become constitutively activated in a broad range of human cancers. This inappropriate STAT activation leads to enhanced transcription of genes that can directly lead to the malignant phenotype. Since STATs are largely dispensable for normal cell function, this has raised the possibility that STATs might be key targets for cancer therapy. Although a number of structure-based strategies have been used to develop STAT inhibitors, an alternate approach is to use cell-based assays that make use of the transcriptional function of STATs. Employing these systems, one can screen large chemical libraries to identify compounds that specifically block the function of a given STAT. This approach can lead to the identification of compounds that inhibit STATs by a variety of mechanisms, and can suggest novel targets for therapy. This type of functional screening strategy has already identified a drug that potently inhibits STAT3, and which is now being evaluated in a clinical trial for patients with chronic lymphocytic leukemia. PMID:24058786

  8. Impact of the N-Terminal Domain of STAT3 in STAT3-Dependent Transcriptional Activity.

    PubMed

    Hu, Tiancen; Yeh, Jennifer E; Pinello, Luca; Jacob, Jaison; Chakravarthy, Srinivas; Yuan, Guo-Cheng; Chopra, Rajiv; Frank, David A

    2015-10-01

    The transcription factor STAT3 is constitutively active in many cancers, where it mediates important biological effects, including cell proliferation, differentiation, survival, and angiogenesis. The N-terminal domain (NTD) of STAT3 performs multiple functions, such as cooperative DNA binding, nuclear translocation, and protein-protein interactions. However, it is unclear which subsets of STAT3 target genes depend on the NTD for transcriptional regulation. To identify such genes, we compared gene expression in STAT3-null mouse embryonic fibroblasts (MEFs) stably expressing wild-type STAT3 or STAT3 from which NTD was deleted. NTD deletion reduced the cytokine-induced expression of specific STAT3 target genes by decreasing STAT3 binding to their regulatory regions. To better understand the potential mechanisms of this effect, we determined the crystal structure of the STAT3 NTD and identified a dimer interface responsible for cooperative DNA binding in vitro. We also observed an Ni(2+)-mediated oligomer with an as yet unknown biological function. Mutations on both dimer and Ni(2+)-mediated interfaces affected the cytokine induction of STAT3 target genes. These studies shed light on the role of the NTD in transcriptional regulation by STAT3 and provide a structural template with which to design STAT3 NTD inhibitors with potential therapeutic value. PMID:26169829

  9. Telltale Animation (Sol 9)

    NASA Technical Reports Server (NTRS)

    2008-01-01

    This animation of the NASA's Phoenix Mars Lander's telltale was made from five images taken by Phoenix's Stereo Surface Imager (SSI) near 3:00 PM local Mars time on the ninth Martian day of the mission, or Sol 9 (June 3, 2008). The images were taken with a blue filter (450 nanometer, R6) that focuses at items on the deck rather than the workspace or horizon.

    The Phoenix Mission is led by the University of Arizona, Tucson, on behalf of NASA. Project management of the mission is by NASA's Jet Propulsion Laboratory, Pasadena, Calif. Spacecraft development is by Lockheed Martin Space Systems, Denver.

  10. Telltale Animation (Sol 8)

    NASA Technical Reports Server (NTRS)

    2008-01-01

    This animation of the NASA's Phoenix Mars Lander's telltale was made from five images taken by Phoenix's Stereo Surface Imager (SSI) just after 1:10 PM local Mars time on the eighth Martian day of the mission, or Sol 8 (June 2, 2008). The images were taken with a blue filter (450 nanometer, R6) that focuses at items on the deck rather than the workspace or horizon.

    The Phoenix Mission is led by the University of Arizona, Tucson, on behalf of NASA. Project management of the mission is by NASA's Jet Propulsion Laboratory, Pasadena, Calif. Spacecraft development is by Lockheed Martin Space Systems, Denver.

  11. Telltale Animation (Sol 9)

    NASA Technical Reports Server (NTRS)

    2008-01-01

    This animation of the NASA's Phoenix Mars Lander's telltale was made from five images taken by Phoenix's Stereo Surface Imager (SSI) just after 4:37 PM local Mars time on the ninth Martian day of the mission, or Sol 9 (June 3, 2008). The images were taken with a blue filter (450 nanometer, R6) that focuses at items on the deck rather than the workspace or horizon.

    The Phoenix Mission is led by the University of Arizona, Tucson, on behalf of NASA. Project management of the mission is by NASA's Jet Propulsion Laboratory, Pasadena, Calif. Spacecraft development is by Lockheed Martin Space Systems, Denver.

  12. Opposing roles of STAT1 and STAT3 in IL-21 function in CD4+ T cells.

    PubMed

    Wan, Chi-Keung; Andraski, Allison B; Spolski, Rosanne; Li, Peng; Kazemian, Majid; Oh, Jangsuk; Samsel, Leigh; Swanson, Phillip A; McGavern, Dorian B; Sampaio, Elizabeth P; Freeman, Alexandra F; Milner, Joshua D; Holland, Steven M; Leonard, Warren J

    2015-07-28

    IL-21 is a type I cytokine essential for immune cell differentiation and function. Although IL-21 can activate several STAT family transcription factors, previous studies focused mainly on the role of STAT3 in IL-21 signaling. Here, we investigated the role of STAT1 and show that STAT1 and STAT3 have at least partially opposing roles in IL-21 signaling in CD4(+) T cells. IL-21 induced STAT1 phosphorylation, and this was augmented in Stat3-deficient CD4(+) T cells. RNA-Seq analysis of CD4(+) T cells from Stat1- and Stat3-deficient mice revealed that both STAT1 and STAT3 are critical for IL-21-mediated gene regulation. Expression of some genes, including Tbx21 and Ifng, was differentially regulated by STAT1 and STAT3. Moreover, opposing actions of STAT1 and STAT3 on IFN-γ expression in CD4(+) T cells were demonstrated in vivo during chronic lymphocytic choriomeningitis infection. Finally, IL-21-mediated induction of STAT1 phosphorylation, as well as IFNG and TBX21 expression, were higher in CD4(+) T cells from patients with autosomal dominant hyper-IgE syndrome, which is caused by STAT3 deficiency, as well as in cells from STAT1 gain-of-function patients. These data indicate an interplay between STAT1 and STAT3 in fine-tuning IL-21 actions. PMID:26170288

  13. Nanocrystal/sol-gel nanocomposites

    DOEpatents

    Petruska, Melissa A.; Klimov, Victor L.

    2012-06-12

    The present invention is directed to solid composites including colloidal nanocrystals within a sol-gel host or matrix and to processes of forming such solid composites. The present invention is further directed to alcohol soluble colloidal nanocrystals useful in formation of sol-gel based solid composites

  14. Nanocrystal/sol-gel nanocomposites

    DOEpatents

    Petruska, Melissa A.; Klimov, Victor L.

    2007-06-05

    The present invention is directed to solid composites including colloidal nanocrystals within a sol-gel host or matrix and to processes of forming such solid composites. The present invention is further directed to alcohol soluble colloidal nanocrystals useful in formation of sol-gel based solid composites.

  15. Thermosensitive periodontal sol of ciprofloxacin hydrochloride and serratiopeptidase: Pharmaceutical and mechanical analysis

    PubMed Central

    Singh, Kushal Pal; Chhabra, Gulshan; Sharma, Vijay; Pathak, Kamla

    2014-01-01

    Aim: The aim of the present work was to explore the development of a dual-controlled release periodontal system of a potent broad spectrum first-generation fluoroquinolone, ciprofloxacin, and the anti-inflammatory enzyme serratiopeptidase (STP). Materials and Methods: Based on 32 full factorial design, thermoreversible periodontal sols capable of controlled dual delivery of ciprofloxacin hydrochloride and STP were designed using pluronic F127 and carbopol 934P as thermosensitive gelling polymers. Sol gel transition characteristics, %cumulative drug release at 48th h and exvivo mucoadhesive strength were designated as dependent responses. The sols were mucoadhesive, syringeable, and inverted into gels at simulated periodontal cavity temperature. Results: F9 with optimal drug release was identified as the best formulation. Extra design check point generated using Design Expert software 8.02 (Stat-Ease, USA) validated the experimental design. Textural analysis revealed that the developed sols were syringeable and spreadable enough for periodontal treatment so it can be expected that hardness and compressibility of sols would pose no problem during clinical application. The in vitro release behavior exhibited controlled release of both cipro HCl and STP (>90% release). Conclusion: A dual-controlled release thermoreversible periodontal sol of ciproflaxin and STP was successfully developed. Incorporation of STP as anti-inflammatory agent has the potential of developing a therapeutically efficacious system of cipro HCl for treatment of periodontal inflammatory anaerobic infections. PMID:24678456

  16. STATs in cancer inflammation and immunity: a leading role for STAT3

    PubMed Central

    Yu, Hua; Pardoll, Drew; Jove, Richard

    2016-01-01

    Commensurate with their roles in regulating cytokine-dependent inflammation and immunity, signal transducer and activator of transcription (STAT) proteins are central in determining whether immune responses in the tumour microenvironment promote or inhibit cancer. Persistently activated STAT3 and, to some extent, STAT5 increase tumour cell proliferation, survival and invasion while suppressing anti-tumour immunity. The persistent activation of STAT3 also mediates tumour-promoting inflammation. STAT3 has this dual role in tumour inflammation and immunity by promoting pro-oncogenic inflammatory pathways, including nuclear factor-κB (NF-κB) and interleukin-6 (IL-6)–GP130–Janus kinase (JAK) pathways, and by opposing STAT1- and NF-κB-mediated T helper 1 anti-tumour immune responses. Consequently, STAT3 is a promising target to redirect inflammation for cancer therapy. PMID:19851315

  17. STAT signaling in the pathogenesis and treatment of myeloid malignancies

    PubMed Central

    Bar-Natan, Michal; Nelson, Erik A.; Xiang, Michael; Frank, David A.

    2012-01-01

    STAT transcription factors play a critical role in mediating the effects of cytokines on myeloid cells. As STAT target genes control key processes such as survival, proliferation and self-renewal, it is not surprising that constitutive activation of STATs, particularly STAT3 and STAT5, are common events in many myeloid tumors. STATs are activated both by mutant tyrosine kinases as well as other pathogenic events, and continued activation of STATs is common in the setting of resistance to kinase inhibitors. Thus, the targeting of STATs, alone or in combination with other drugs, will likely have increasing importance for cancer therapy. PMID:24058751

  18. Histone deacetylase inhibitors block IFNγ-induced STAT1 phosphorylation.

    PubMed

    Ginter, Torsten; Bier, Carolin; Knauer, Shirley K; Sughra, Kalsoom; Hildebrand, Dagmar; Münz, Tobias; Liebe, Theresa; Heller, Regine; Henke, Andreas; Stauber, Roland H; Reichardt, Werner; Schmid, Johannes A; Kubatzky, Katharina F; Heinzel, Thorsten; Krämer, Oliver H

    2012-07-01

    Signal transducer and activator of transcription 1 (STAT1) is important for innate and adaptive immunity. Histone deacetylase inhibitors (HDACi) antagonize unbalanced immune functions causing chronic inflammation and cancer. Phosphorylation and acetylation regulate STAT1 and different IFNs induce phosphorylated STAT1 homo-/heterodimers, e.g. IFNα activates several STATs whereas IFNγ only induces phosphorylated STAT1 homodimers. In transformed cells HDACi trigger STAT1 acetylation linked to dephosphorylation by the phosphatase TCP45. It is unclear whether acetylation differentially affects STAT1 activated by IFNα or IFNγ, and if cellular responses to both cytokines depend on a phosphatase-dependent inactivation of acetylated STAT1. Here, we report that HDACi counteract IFN-induced phosphorylation of a critical tyrosine residue in the STAT1 C-terminus in primary cells and hematopoietic cells. STAT1 mutants mimicking a functionally inactive DNA binding domain (DBD) reveal that the number of acetylation-mimicking sites in STAT1 determines whether STAT1 is recruited to response elements after stimulation with IFNγ. Furthermore, we show that IFNα-induced STAT1 heterodimers carrying STAT1 molecules mimicking acetylation bind cognate DNA and provide innate anti-viral immunity. IFNγ-induced acetylated STAT1 homodimers are though inactive, suggesting that heterodimerization and complex formation can rescue STAT1 lacking a functional DBD. Apparently, the type of cytokine determines how acetylation affects the nuclear entry and DNA binding of STAT1. Our data contribute to a better understanding of STAT1 regulation by acetylation. PMID:22425562

  19. PREFACE: Prospects in Neutrino Physics 2013 - NuPhys2013

    NASA Astrophysics Data System (ADS)

    2015-04-01

    The first "Prospects in Neutrino Physics 2013 - NuPhys2013" conference was held at the Institute of Physics, IoP, London, 19-20 December 2013 and was attended by about 130 delegates from institutions worldwide. Lunch and coffee breaks allowed discussions among delegates and speakers to take place in an informal setting. This conference is unique in discussing the worldwide strategy to address unresolved issues in neutrino physics, and shape the future directions of particle physics. We discussed the current status and focussed especially on the prospects of future experiments, their performance and physics reach. It is particularly timely due to the recent measurements in neutrino physics and planned worldwide experiments. The following topics were addressed: • Theory and Phenomenology Perspectives • Future Long and Short Baseline Neutrino Oscillation Experiments • Reactor neutrino and flux • Neutrinoless double beta decays • Solar, atmospheric, supernova neutrinos • Neutrino cosmology in which both the phenomenological and experimental aspects were equally addressed. World-leading experts in the different neutrino areas were invited to give review talks. To encourage and facilitate the participation of early-career researchers and PhD students, a poster session formed a key aspect of this meeting. The conference was organized by Francesca Di Lodovico and Silvia Pascoli. It was sponsored by the IoP through their Topic Research Meeting Grant, and also supported by Durham IPPP, ERC-207282, FP7 invisibles project, Queen Mary University of London.

  20. STATs: An Old Story, Yet Mesmerizing

    PubMed Central

    Abroun, Saeid; Saki, Najmaldin; Ahmadvand, Mohammad; Asghari, Farahnaz; Salari, Fatemeh; Rahim, Fakher

    2015-01-01

    Signal transducers and activators of transcription (STATs) are cytoplasmic transcription factors that have a key role in cell fate. STATs, a protein family comprised of seven members, are proteins which are latent cytoplasmic transcription factors that convey signals from the cell surface to the nucleus through activation by cytokines and growth factors. The signaling pathways have diverse biological functions that include roles in cell differentiation, proliferation, development, apoptosis, and inflammation which place them at the center of a very active area of research. In this review we explain Janus kinase (JAK)/STAT signaling and focus on STAT3, which is transient from cytoplasm to nucleus after phosphorylation. This procedure controls fundamental biological processes by regulating nuclear genes controlling cell proliferation, survival, and development. In some hematopoietic disorders and cancers, overexpression and activation of STAT3 result in high proliferation, suppression of cell differentiation and inhibition of cell maturation. This article focuses on STAT3 and its role in malignancy, in addition to the role of microRNAs (miRNAs) on STAT3 activation in certain cancers. PMID:26464811

  1. The role of STAT3 in autophagy

    PubMed Central

    You, Liangkun; Wang, Zhanggui; Li, Hongsen; Shou, Jiawei; Jing, Zhao; Xie, Jiansheng; Sui, Xinbing; Pan, Hongming; Han, Weidong

    2015-01-01

    Autophagy is an evolutionarily conserved process in eukaryotes that eliminates harmful components and maintains cellular homeostasis in response to a series of extracellular insults. However, these insults may trigger the downstream signaling of another prominent stress responsive pathway, the STAT3 signaling pathway, which has been implicated in multiple aspects of the autophagic process. Recent reports further indicate that different subcellular localization patterns of STAT3 affect autophagy in various ways. For example, nuclear STAT3 fine-tunes autophagy via the transcriptional regulation of several autophagy-related genes such as BCL2 family members, BECN1, PIK3C3, CTSB, CTSL, PIK3R1, HIF1A, BNIP3, and microRNAs with targets of autophagy modulators. Cytoplasmic STAT3 constitutively inhibits autophagy by sequestering EIF2AK2 as well as by interacting with other autophagy-related signaling molecules such as FOXO1 and FOXO3. Additionally, the mitochondrial translocation of STAT3 suppresses autophagy induced by oxidative stress and may effectively preserve mitochondria from being degraded by mitophagy. Understanding the role of STAT3 signaling in the regulation of autophagy may provide insight into the classic autophagy model and also into cancer therapy, especially for the emerging targeted therapy, because a series of targeted agents execute antitumor activities via blocking STAT3 signaling, which inevitably affects the autophagy pathway. Here, we review several of the representative studies and the current understanding in this particular field. PMID:25951043

  2. The role of STAT3 in autophagy.

    PubMed

    You, Liangkun; Wang, Zhanggui; Li, Hongsen; Shou, Jiawei; Jing, Zhao; Xie, Jiansheng; Sui, Xinbing; Pan, Hongming; Han, Weidong

    2015-01-01

    Autophagy is an evolutionarily conserved process in eukaryotes that eliminates harmful components and maintains cellular homeostasis in response to a series of extracellular insults. However, these insults may trigger the downstream signaling of another prominent stress responsive pathway, the STAT3 signaling pathway, which has been implicated in multiple aspects of the autophagic process. Recent reports further indicate that different subcellular localization patterns of STAT3 affect autophagy in various ways. For example, nuclear STAT3 fine-tunes autophagy via the transcriptional regulation of several autophagy-related genes such as BCL2 family members, BECN1, PIK3C3, CTSB, CTSL, PIK3R1, HIF1A, BNIP3, and microRNAs with targets of autophagy modulators. Cytoplasmic STAT3 constitutively inhibits autophagy by sequestering EIF2AK2 as well as by interacting with other autophagy-related signaling molecules such as FOXO1 and FOXO3. Additionally, the mitochondrial translocation of STAT3 suppresses autophagy induced by oxidative stress and may effectively preserve mitochondria from being degraded by mitophagy. Understanding the role of STAT3 signaling in the regulation of autophagy may provide insight into the classic autophagy model and also into cancer therapy, especially for the emerging targeted therapy, because a series of targeted agents execute antitumor activities via blocking STAT3 signaling, which inevitably affects the autophagy pathway. Here, we review several of the representative studies and the current understanding in this particular field. PMID:25951043

  3. Targeting constitutively-activated STAT3 in hypoxic ovarian cancer, using a novel STAT3 inhibitor

    PubMed Central

    McCann, Georgia A.; Naidu, Shan; Rath, Kellie S.; Bid, Hemant K.; Tierney, Brent J.; Suarez, Adrian; Varadharaj, Saradhadevi; Zhang, Jianying; Hideg, Kálmán; Houghton, Peter; Kuppusamy, Periannan; Cohn, David E.; Selvendiran, Karuppaiyah

    2014-01-01

    Tumor hypoxia, a feature of many solid tumors including ovarian cancer, is associated with resistance to therapies. We previously demonstrated that hypoxic exposure results in increased expression of phosphorylated signal transducer and activator of transcription 3 (pSTAT3). We hypothesized the activation of STAT3 could lead to chemotherapeutic resistance in ovarian cancer cells in hypoxic conditions. In this study, we demonstrate the level of pSTAT3 Tyr705 is increased in the hypoxic regions of human epithelial ovarian cancer (EOC) specimens, as determined by HIF-1α and CD-31 staining. In vitro mutagenesis studies proved that pSTAT3 Tyr705 is necessary for cell survival and proliferation under hypoxic conditions. In addition, we show that S1PR1, a regulator of STAT3 transcription via the JAK/STAT pathway, is highly expressed in hypoxic ovarian cancer cells (HOCCs). Knock down of S1PR1 in HOCCs reduced pSTAT3 Tyr705 levels and was associated with decreased cell survival. Treatment of HOCCs with the STAT3 inhibitor HO-3867 resulted in a rapid and dramatic decrease in pSTAT3 Tyr705 levels as a result of ubiquitin proteasome degradation. STAT3-target proteins Bcl-xL, cyclin D2 and VEGF showed similar decreases in HO-3867 treated cells. Taken together, these findings suggest that activation of STAT3 Tyr705 promotes cell survival and proliferation in HOCCs, and that S1PR1 is involved in the initiation of STAT3 activation. Targeting hypoxia-mediated STAT3 activation represents a therapeutic option for ovarian cancer and other solid tumors. PMID:25594014

  4. Monoclonal Antibodies Specific for STAT3β Reveal Its Contribution to Constitutive STAT3 Phosphorylation in Breast Cancer

    PubMed Central

    Bharadwaj, Uddalak; Kasembeli, Moses M.; Eckols, T. Kris; Kolosov, Mikhail; Lang, Paul; Christensen, Kurt; Edwards, Dean P.; Tweardy, David J.

    2014-01-01

    Since its discovery in mice and humans 19 years ago, the contribution of alternatively spliced Stat3, Stat3β, to the overall functions of Stat3 has been controversial. Tyrosine-phosphorylated (p) Stat3β homodimers are more stable, bind DNA more avidly, are less susceptible to dephosphorylation, and exhibit distinct intracellular dynamics, most notably markedly prolonged nuclear retention, compared to pStat3α homodimers. Overexpression of one or the other isoform in cell lines demonstrated that Stat3β acted as a dominant-negative of Stat3α in transformation assays; however, studies with mouse strains deficient in one or the other isoform indicated distinct contributions of Stat3 isoforms to inflammation. Current immunological reagents cannot differentiate Stat3β proteins derived from alternative splicing vs. proteolytic cleavage of Stat3α. We developed monoclonal antibodies that recognize the 7 C-terminal amino acids unique to Stat3β (CT7) and do not cross-react with Stat3α. Immunoblotting studies revealed that levels of Stat3β protein, but not Stat3α, in breast cancer cell lines positively correlated with overall pStat3 levels, suggesting that Stat3β may contribute to constitutive Stat3 activation in this tumor system. The ability to unambiguously discriminate splice alternative Stat3β from proteolytic Stat3β and Stat3α will provide new insights into the contribution of Stat3β vs. Stat3α to oncogenesis, as well as other biological and pathological processes. PMID:25268166

  5. Employing Introductory Statistics Students at "Stats Dairy"

    ERIC Educational Resources Information Center

    Keeling, Kellie

    2011-01-01

    To combat students' fear of statistics I employ my students at a fictional company, Stats Dairy, run by cows. Almost all examples used in the class notes, exercises, humour and exams use data "collected" from this company.

  6. JAKs and STATs in invertebrate model organisms.

    PubMed

    Dearolf, C R

    1999-09-01

    Invertebrate organisms provide systems to elucidate the developmental roles of Janus kinase (JAK)/signal transducers and activators of transcription (STAT) signaling pathways, thereby complementing research conducted with mammalian cells and animals. Components of the JAK/STAT protein pathway have been identified and characterized in the fruit fly Drosophila melanogaster and the cellular slime mold Dictyostelium discoideum. This review summarizes the molecular and genetic data obtained from these model organisms. In particular, a Drosophila JAK/STAT pathway regulates normal segmentation, cell proliferation, and differentiation, and hyperactivation of the pathway leads to tumor formation and leukemia-like defects. A Dictyostelium STAT regulates the development of stalk cells during the multicellular part of the life cycle. Future research utilizing these organisms should continue to provide insights into the roles and regulation of these proteins and their signaling pathways. PMID:10526575

  7. The JAK-STAT Pathway at Twenty

    PubMed Central

    Stark, George R.; Darnell, James E.

    2014-01-01

    We look back on the discoveries that the tyrosine kinases TYK2 and JAK1 and the transcription factors STAT1, STAT2, and IRF9 are required for the cellular response to type I interferons. This initial description of the JAK-STAT pathway led quickly to additional discoveries that type II interferons and many other cytokines signal through similar mechanisms. This well-understood pathway now serves as a paradigm showing how information from protein-protein contacts at the cell surface can be conveyed directly to genes in the nucleus. We also review recent work on the STAT proteins showing the importance of several different posttranslational modifications, including serine phosphorylation, acetylation, methylation, and sumoylation. These remarkably proficient proteins also provide noncanonical functions in transcriptional regulation and they also function in mitochondrial respiration and chromatin organization in ways that may not involve transcription at all. PMID:22520844

  8. Nanomolar-Potency Small Molecule Inhibitor of STAT5 Protein

    PubMed Central

    2014-01-01

    We herein report the design and synthesis of the first nanomolar binding inhibitor of STAT5 protein. Lead compound 13a, possessing a phosphotyrosyl-mimicking salicylic acid group, potently and selectively binds to STAT5 over STAT3, inhibits STAT5–SH2 domain complexation events in vitro, silences activated STAT5 in leukemic cells, as well as STAT5′s downstream transcriptional targets, including MYC and MCL1, and, as a result, leads to apoptosis. We believe 13a represents a useful probe for interrogating STAT5 function in cells as well as being a potential candidate for advanced preclinical trials. PMID:25419444

  9. Distinct roles of STAT3 and STAT5 in the pathogenesis and targeted therapy of breast cancer

    PubMed Central

    Walker, Sarah R.; Xiang, Michael; Frank, David A.

    2013-01-01

    The transcription factors STAT3 and STAT5 play important roles in the regulation of mammary gland function during pregnancy, lactation, and involution. Given that STAT3 and STAT5 regulate genes involved in proliferation and survival, it is not surprising that inappropriate activation of STAT3 and STAT5 occurs commonly in breast cancer. Although these proteins are structurally similar, they have divergent and opposing effects on gene expression and cellular phenotype. Notably, when STAT5 and STAT3 are activated simultaneously, STAT5 has a dominant effect, and leads to decreased proliferation and increased sensitivity to cell death. Similarly, in breast cancer, activation of both STAT5 and STAT3 is associated with longer patient survival than activation of STAT3 alone. Pharmacological inhibitors of STAT3 and STAT5 are being developed for cancer therapy, though understanding the activation state and functional interaction of STAT3 and STAT5 in a patient's tumor may be critical for the optimal use of this strategy. PMID:23531638

  10. Methylsulfonylmethane suppresses breast cancer growth by down-regulating STAT3 and STAT5b pathways.

    PubMed

    Lim, Eun Joung; Hong, Dae Young; Park, Jin Hee; Joung, Youn Hee; Darvin, Pramod; Kim, Sang Yoon; Na, Yoon Mi; Hwang, Tae Sook; Ye, Sang-Kyu; Moon, Eon-Soo; Cho, Byung Wook; Do Park, Kyung; Lee, Hak Kyo; Park, Taekyu; Yang, Young Mok

    2012-01-01

    Breast cancer is the most aggressive form of all cancers, with high incidence and mortality rates. The purpose of the present study was to investigate the molecular mechanism by which methylsulfonylmethane (MSM) inhibits breast cancer growth in mice xenografts. MSM is an organic sulfur-containing natural compound without any toxicity. In this study, we demonstrated that MSM substantially decreased the viability of human breast cancer cells in a dose-dependent manner. MSM also suppressed the phosphorylation of STAT3, STAT5b, expression of IGF-1R, HIF-1α, VEGF, BrK, and p-IGF-1R and inhibited triple-negative receptor expression in receptor-positive cell lines. Moreover, MSM decreased the DNA-binding activities of STAT5b and STAT3, to the target gene promoters in MDA-MB 231 or co-transfected COS-7 cells. We confirmed that MSM significantly decreased the relative luciferase activities indicating crosstalk between STAT5b/IGF-1R, STAT5b/HSP90α, and STAT3/VEGF. To confirm these findings in vivo, xenografts were established in Balb/c athymic nude mice with MDA-MB 231 cells and MSM was administered for 30 days. Concurring to our in vitro analysis, these xenografts showed decreased expression of STAT3, STAT5b, IGF-1R and VEGF. Through in vitro and in vivo analysis, we confirmed that MSM can effectively regulate multiple targets including STAT3/VEGF and STAT5b/IGF-1R. These are the major molecules involved in tumor development, progression, and metastasis. Thus, we strongly recommend the use of MSM as a trial drug for treating all types of breast cancers including triple-negative cancers. PMID:22485142

  11. JAK/STAT signalling: STAT cannot play with Ken and Barbie.

    PubMed

    Hombría, James Castelli-Gair; Sotillos, Sol

    2006-02-01

    Transcriptional responses to the activation of a signalling pathway are cell-specific. New data show that the sequence-specific transcriptional repressors of the KEN/BCL-6 family play an important role in the selection of STAT targets in vertebrates and invertebrates, indicating that all STAT proteins may share this ancestral mechanism. PMID:16461274

  12. Physics of the Cosmos Program Analysis Group (PhysPAG) Report

    NASA Astrophysics Data System (ADS)

    Nousek, John A.

    2015-01-01

    The Physics of the Cosmos Program Analysis Group (PhysPAG) serves as a forum for soliciting and coordinating input and analysis from the scientific community in support of the PCOS program objectives. I will outline the activities of the PhysPAG over the past year, since the last meeting during the AAS meeting in National Harbor, and mention the activities of the PhysPAG related Scientific Interest Groups.

  13. Weapons of STAT destruction. Interferon evasion by paramyxovirus V protein.

    PubMed

    Horvath, Curt M

    2004-12-01

    The signal transducer and activator of transcription (STAT) family of proteins function to activate gene transcription downstream of myriad cytokine and growth factor signals. The prototype STAT proteins, STAT1 and STAT2, are required for innate and adaptive antimicrobial immune responses that result from interferon signal transduction. While many viruses have evolved the ability to avoid these antiviral cytokines, the Paramyxoviruses are distinct in their abilities to interfere directly with STAT proteins. Individual paramyxovirus species differ greatly in their precise mechanism of STAT signaling evasion, but a virus-encoded protein called V plays a central role in this process. The theme of V-dependent interferon evasion and its variations provide significant insights into virus-host interactions and viral immune evasion that can help define targets for antiviral drug design. Exposure of the viral weapons of STAT destruction may also be instructive for application to STAT-directed therapeutics for diseases characterized by STAT hyperactivity. PMID:15606749

  14. A time- and dose-dependent STAT1 expression system

    PubMed Central

    Leitner, Nicole R; Strobl, Birgit; Bokor, Marion; Painz, Ronald; Kolbe, Thomas; Rülicke, Thomas; Müller, Mathias; Karaghiosoff, Marina

    2006-01-01

    Background The signal transducer and activator of transcription (STAT) family of transcription factors mediates a variety of cytokine dependent gene regulations. STAT1 has been mainly characterized by its role in interferon (IFN) type I and II signaling and STAT1 deficiency leads to high susceptibility to several pathogens. For fine-tuned analysis of STAT1 function we established a dimerizer-inducible system for STAT1 expression in vitro and in vivo. Results The functionality of the dimerizer-induced STAT1 system is demonstrated in vitro in mouse embryonic fibroblasts and embryonic stem cells. We show that this two-vector based system is highly inducible and does not show any STAT1 expression in the absence of the inducer. Reconstitution of STAT1 deficient cells with inducible STAT1 restores IFNγ-mediated gene induction, antiviral responses and STAT1 activation remains dependent on cytokine stimulation. STAT1 expression is induced rapidly upon addition of dimerizer and expression levels can be regulated in a dose-dependent manner. Furthermore we show that in transgenic mice STAT1 can be induced upon stimulation with the dimerizer, although only at low levels. Conclusion These results prove that the dimerizer-induced system is a powerful tool for STAT1 analysis in vitro and provide evidence that the system is suitable for the use in transgenic mice. To our knowledge this is the first report for inducible STAT1 expression in a time- and dose-dependent manner. PMID:17184522

  15. Sol-gel derived sorbents

    DOEpatents

    Sigman, Michael E.; Dindal, Amy B.

    2003-11-11

    Described is a method for producing copolymerized sol-gel derived sorbent particles for the production of copolymerized sol-gel derived sorbent material. The method for producing copolymerized sol-gel derived sorbent particles comprises adding a basic solution to an aqueous metal alkoxide mixture for a pH.ltoreq.8 to hydrolyze the metal alkoxides. Then, allowing the mixture to react at room temperature for a precalculated period of time for the mixture to undergo an increased in viscosity to obtain a desired pore size and surface area. The copolymerized mixture is then added to an immiscible, nonpolar solvent that has been heated to a sufficient temperature wherein the copolymerized mixture forms a solid upon the addition. The solid is recovered from the mixture, and is ready for use in an active sampling trap or activated for use in a passive sampling trap.

  16. Opportunity's Surroundings on Sol 1687

    NASA Technical Reports Server (NTRS)

    2009-01-01

    NASA's Mars Exploration Rover Opportunity used its navigation camera to take the images combined into this 360-degree view of the rover's surroundings on the 1,687th Martian day, or sol, of its surface mission (Oct. 22, 2008).

    Opportunity had driven 133 meters (436 feet) that sol, crossing sand ripples up to about 10 centimeters (4 inches) tall. The tracks visible in the foreground are in the east-northeast direction.

    Opportunity's position on Sol 1687 was about 300 meters southwest of Victoria Crater. The rover was beginning a long trek toward a much larger crater, Endeavour, about 12 kilometers (7 miles) to the southeast.

    This view is presented as a cylindrical projection with geometric seam correction.

  17. Opportunity's Surroundings on Sol 1818

    NASA Technical Reports Server (NTRS)

    2009-01-01

    NASA's Mars Exploration Rover Opportunity used its navigation camera to take the images combined into this full-circle view of the rover's surroundings during the 1,818th Martian day, or sol, of Opportunity's surface mission (March 5, 2009). South is at the center; north at both ends.

    The rover had driven 80.3 meters (263 feet) southward earlier on that sol. Tracks from the drive recede northward in this view.

    The terrain in this portion of Mars' Meridiani Planum region includes dark-toned sand ripples and lighter-toned bedrock.

    This view is presented as a cylindrical projection with geometric seam correction.

  18. Granulin, a novel STAT3-interacting protein, enhances STAT3 transcriptional function and correlates with poorer prognosis in breast cancer

    PubMed Central

    Yeh, Jennifer E.; Kreimer, Simion; Walker, Sarah R.; Emori, Megan M.; Krystal, Hannah; Richardson, Andrea; Ivanov, Alexander R.; Frank, David A.

    2015-01-01

    Since the neoplastic phenotype of a cell is largely driven by aberrant gene expression patterns, increasing attention has been focused on transcription factors that regulate critical mediators of tumorigenesis such as signal transducer and activator of transcription 3 (STAT3). As proteins that interact with STAT3 may be key in addressing how STAT3 contributes to cancer pathogenesis, we took a proteomics approach to identify novel STAT3-interacting proteins. We performed mass spectrometry-based profiling of STAT3-containing complexes from breast cancer cells that have constitutively active STAT3 and are dependent on STAT3 function for survival. We identified granulin (GRN) as a novel STAT3-interacting protein that was necessary for both constitutive and maximal leukemia inhibitory factor (LIF)induced STAT3 transcriptional activity. GRN enhanced STAT3 DNA binding and also increased the time-integrated amount of LIF-induced STAT3 activation in breast cancer cells. Furthermore, silencing GRN neutralized STAT3-mediated tumorigenic phenotypes including viability, clonogenesis, and migratory capacity. In primary breast cancer samples, GRN mRNA levels were positively correlated with STAT3 gene expression signatures and with reduced patient survival. These studies identify GRN as a functionally important STAT3-interacting protein that may serve as an important prognostic biomarker and potential therapeutic target in breast cancer. PMID:26000098

  19. Overexpression of STAT3/pSTAT3 was associated with poor prognosis in gastric cancer: a meta-analysis

    PubMed Central

    He, Shaozhong; Liao, Guixiang; Liu, Yungen; Huang, Liling; Kang, Mafei; Chen, Longhua

    2015-01-01

    Signal transducer and activator of transcription 3 (STAT3) and phospho-STAT3 (pSTAT3) play important roles in the development of gastric cancer. STAT3 is often associated with cell survival, proliferation, and transformation. The prognostic value of STAT3/pSTAT3 in patients with gastric cancer remains controversial in numerous published studies. The aim of this study was to summarize recent findings relevant to the prognostic role of STAT3 and pSTAT3 in patients with gastric cancer. A meta-analysis was performed by searching Web of Knowledge, EMBASE, and PubMed to identify studies on the prognostic impact of STAT3/pSTAT3 in gastric cancers in August 2014. In all, 10 studies were included in the analysis. Data were collected for comparing survival rates in patients with high STAT3 levels compared to those with low levels. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. Sensitivity analysis was conducted, and publication bias was evaluated. Eventually, 1667 cases of gastric cancer were subjected to the final analysis. Among patients with gastric cancer, poor survival was predicted by higher expressions of STAT3 (HR=2.30; 95% CI=1.13-4.68; P=0.02) and pSTAT3 (HR=1.75; 95% CI=1.17-2.61; P=0.006). Moreover, overexpression of STAT3 was associated with poor tumor stage. Additionally, our analysis did not show any statistically significant effect of publication bias regarding STAT3 or pSTAT3. The results of this meta-analysis demonstrated that overexpression of STAT3 and pSTAT3 was associated with poor prognosis in gastric cancer. PMID:26884913

  20. Activation of transcription factors STAT1 and STAT5 in the mouse median eminence after systemic ciliary neurotrophic factor administration.

    PubMed

    Severi, Ilenia; Senzacqua, Martina; Mondini, Eleonora; Fazioli, Francesca; Cinti, Saverio; Giordano, Antonio

    2015-10-01

    Exogenously administered ciliary neurotrophic factor (CNTF) causes weight loss in obese rodents and humans through leptin-like activation of the Jak-STAT3 signaling pathway in hypothalamic arcuate neurons. Here we report for the first time that 40min after acute systemic treatment, rat recombinant CNTF (intraperitoneal injection of 0.3mg/kg of body weight) induced nuclear translocation of the tyrosine-phosphorylated forms of STAT1 and STAT5 in the mouse median eminence and other circumventricular organs, including the vascular organ of the lamina terminalis and the subfornical organ. In the tuberal hypothalamus of treated mice, specific nuclear immunostaining for phospo-STAT1 and phospho-STAT5 was detected in ependymal cells bordering the third ventricle floor and lateral recesses, and in median eminence cells. Co-localization studies documented STAT1 and STAT5 activation in median eminence β-tanycytes and underlying radial glia-like cells. A few astrocytes in the arcuate nucleus responded to CNTF by STAT5 activation. The vast majority of median eminence tanycytes and radial glia-like cells showing phospho-STAT1 and phospho-STAT5 immunoreactivity were also positive for phospho-STAT3. In contrast, STAT3 was the sole STAT isoform activated by CNTF in arcuate nucleus and median eminence neurons. Finally, immunohistochemical evaluation of STAT activation 20, 40, 80, and 120min from the injection demonstrated that cell activation was accompanied by c-Fos expression. Collectively, our findings show that CNTF activates STAT3, STAT1, and STAT5 in vivo. The distinctive activation pattern of these STAT isoforms in the median eminence may disclose novel targets and pathways through which CNTF regulates food intake. PMID:26133794

  1. Evolution of the JAK-STAT pathway.

    PubMed

    Liongue, Clifford; Ward, Alister C

    2013-01-01

    The JAK-STAT pathway represents a finely tuned orchestra capable of rapidly facilitating an exquisite symphony of responses from a complex array of extracellular signals. This review explores the evolution of the JAK-STAT pathway: the origins of the individual domains from which it is constructed, the formation of individual components from these basic building blocks, the assembly of the components into a functional pathway, and the subsequent reiteration of this basic template to fulfill a variety of roles downstream of cytokine receptors. PMID:24058787

  2. Evolution of the JAK-STAT pathway

    PubMed Central

    Liongue, Clifford; Ward, Alister C.

    2013-01-01

    The JAK-STAT pathway represents a finely tuned orchestra capable of rapidly facilitating an exquisite symphony of responses from a complex array of extracellular signals. This review explores the evolution of the JAK-STAT pathway: the origins of the individual domains from which it is constructed, the formation of individual components from these basic building blocks, the assembly of the components into a functional pathway, and the subsequent reiteration of this basic template to fulfill a variety of roles downstream of cytokine receptors. PMID:24058787

  3. Structural Tailoring of Advanced Turboprops (STAT)

    NASA Technical Reports Server (NTRS)

    Brown, Kenneth W.

    1988-01-01

    This interim report describes the progress achieved in the structural Tailoring of Advanced Turboprops (STAT) program which was developed to perform numerical optimizations on highly swept propfan blades. The optimization procedure seeks to minimize an objective function, defined as either direct operating cost or aeroelastic differences between a blade and its scaled model, by tuning internal and external geometry variables that must satisfy realistic blade design constraints. This report provides a detailed description of the input, optimization procedures, approximate analyses and refined analyses, as well as validation test cases for the STAT program. In addition, conclusions and recommendations are summarized.

  4. Sol-Gel Derived Hafnia Coatings

    NASA Technical Reports Server (NTRS)

    Feldman, Jay D.; Stackpoole, Mairead; Blum, Yigal; Sacks, Michael; Ellerby, Don; Johnson, Sylvia M.; Venkatapathy, Ethiras (Technical Monitor)

    2002-01-01

    Sol-gel derived hafnia coatings are being developed to provide an oxidation protection layer on ultra-high temperature ceramics for potential use in turbine engines (ultra-efficient engine technology being developed by NASA). Coatings using hafnia sol hafnia filler particles will be discussed along with sol synthesis and characterization.

  5. SOL Tests Create Unfair Pressure.

    ERIC Educational Resources Information Center

    Ernst, Katie

    2000-01-01

    A seventh-grader explains why the Virginia Standards of Learning tests unfairly pressure her and her teachers. She wants her free reading time restored and wishes politicians would worry more about students understanding--not just memorizing--facts. She praises teachers who go beyond the SOL. (MLH)

  6. The SOL: No Easy Answers.

    ERIC Educational Resources Information Center

    Pasi, Raymond

    2000-01-01

    Since the state board adopted the Standards of Learning, Virginia high-school teachers maintain tighter schedules and more often use direct instruction instead of group activities to cover the new curriculum. A two-edged sword, the SOL has engendered an increased interest in professional collaboration. (MLH)

  7. Dataset of STAT5A status in breast cancer

    PubMed Central

    Mukhopadhyay, Utpal K.; Cass, Jamaica; Raptis, Leda; Craig, Andrew W.; Bourdeau, Véronique; Varma, Sonal; Gupta, Sandip Sen; Elliott, Bruce E.; Ferbeyre, Gerardo

    2016-01-01

    We analysed STAT5A gene expression in breast cancer using the Oncomine database. We exemplify four representative studies showing that STAT5A is generally downregulated in breast cancer. PMID:27014737

  8. Mitochondrial Stat3, the Need for Design Thinking

    PubMed Central

    Yang, Rui; Rincon, Mercedes

    2016-01-01

    Stat3 has been studied extensively as a transcription factor, however the finding that Stat3 also localizes to mitochondria has opened a new area to discover non-classical functions. Here we review the current knowledge of mitochondrial Stat3 as a regulator of the electron transport chain (ETC) and its impact on mitochondrial production of ATP and ROS. We also describe recent findings identifying Stat3 as a regulator of mitochondrial Ca2+ homeostasis through its effect on the ETC. It is becoming evident that these non-classical functions of Stat3 can have a major impact on cancer progression, cardiovascular diseases, and inflammatory diseases. Therefore, mitochondrial Stat3 functions challenge the current design of therapies that solely target Stat3 as a transcription factor and suggest the need for “design thinking,” which leads to the development of novel strategies, to intervene the Stat3 pathway. PMID:27019635

  9. Exploring dual inhibitors for STAT1 and STAT5 receptors utilizing virtual screening and dynamics simulation validation.

    PubMed

    Raj, Utkarsh; Kumar, Himansu; Gupta, Saurabh; Varadwaj, Pritish Kumar

    2016-10-01

    Signal transducer and activator of transcription (STAT) proteins are latent cytoplasmic transcription factors that transduce signals from cytokines and growth factors to the nucleus and thereby regulate the expression of a variety of target genes. Although mutations of STATs have not been reported in human tumors but the activity of several members of the family, such as STAT1 and STAT5, is deregulated in a variety of human carcinoma. STAT1 and STAT5 share a structural similarity with a highly conserved SH2 domain which is responsible for the activation of STAT proteins on interaction with phosphotyrosine motifs for specific STAT-receptor contacts and STAT dimerization. The purpose of this study is to identify domain-specific dual inhibitors for both STAT1 and STAT5 proteins from a database of natural products and natural product-like compounds comprising of over 90,000 compounds. Virtual screening-based molecular docking was performed in order to find novel natural dual inhibitors. Further, the study was supported by the 50-ns molecular dynamics simulation for receptor-ligand complexes (STAT1-STOCK-1N-69677 and STAT5-STOCK-1N-69677). Analysis of molecular interactions in the SH2 domains of both STAT1 and STAT5 proteins with the ligand revealed few conserved amino acid residues which are responsible to stabilize the ligands within the binding pocket through bonded and non-bonded interactions. This study suggested that compound STOCK-1N-69677 might putatively act as a dual inhibitor of STAT1 and STAT5 receptors, through its binding to the SH2 domain. PMID:26471877

  10. STAT2 Mediates Innate Immunity to Dengue Virus in the Absence of STAT1 via the Type I Interferon Receptor

    PubMed Central

    Perry, Stuart T.; Buck, Michael D.; Lada, Steven M.; Schindler, Christian; Shresta, Sujan

    2011-01-01

    Dengue virus (DENV) is a mosquito-borne flavivirus, and symptoms of infection range from asymptomatic to the severe dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). High viral loads correlate with disease severity, and both type I & II interferons (IFNs) are crucial for controlling viral replication. We have previously reported that signal transducer and activator of transcription (STAT) 1-deficient mice are resistant to DENV-induced disease, but little is known about this STAT1-independent mechanism of protection. To determine the molecular basis of the STAT1-independent pathway, mice lacking STAT1, STAT2, or both STAT1 and STAT2 were infected with a virulent mouse-adapted strain of DENV2. In the first 72 hours of infection, the single-deficient mice lacking STAT1 or STAT2 possessed 50–100 fold higher levels of viral RNA than wild type mice in the serum, spleen, and other visceral tissues, but remained resistant to DENV-induced death. In contrast, the double-deficient mice exhibited the early death phenotype previously observed in type I and II IFN receptor knockout mice (AG129), indicating that STAT2 is the mediator of the STAT1-independent host defense mechanism. Further studies demonstrated that this STAT2-dependent STAT1-independent mechanism requires the type I IFN receptor, and contributes to the autocrine amplification of type I IFN expression. Examination of gene expression in the spleen and bone marrow-derived macrophages following DENV infection revealed STAT2-dependent pathways can induce the transcription of a subset of interferon stimulated genes even in the absence of STAT1. Collectively, these results help elucidate the nature of the poorly understood STAT1-independent host defense mechanism against viruses by identifying a functional type I IFN/STAT2 signaling pathway following DENV infection in vivo. PMID:21379341

  11. STAT1 deficiency redirects IFN signalling toward suppression of TLR response through a feedback activation of STAT3

    PubMed Central

    Kim, Hun Sik; Kim, Dong Chan; Kim, Hong-Mi; Kwon, Hyung-Joon; Kwon, Soon Jae; Kang, Suk-Jo; Kim, Sun Chang; Choi, Go-Eun

    2015-01-01

    Interferons (IFNs) potentiate macrophage activation typically via a STAT1-dependent pathway. Recent studies suggest a functioning of STAT1-independent pathway in the regulation of gene expression by IFN-γ, thus pointing to the diversity in cellular responses to IFNs. Many functions of IFNs rely on cross-regulation of the responses to exogenous inflammatory mediators such as TLR ligands. Here we investigated the contribution of STAT1-independent pathway to macrophage activation and its underlying mechanism in the context of combined stimulation of IFN and TLR. We found that TLR-induced production of inflammatory cytokines (TNF-α, IL-12) was not simply nullified but was significantly suppressed by signaling common to IFN-γ and IFN-β in STAT1-null macrophages. Such a shift in the suppression of TLR response correlated with a sustained STAT3 activation and attenuation of NF-κB signaling. Using a JAK2/STAT3 pathway inhibitor or STAT3-specific siRNA, blocking STAT3 in that context restored TNF-α production and NF-κB signaling, thus indicating a functional cross-regulation among STAT1, STAT3, and NF-κB. Our results suggest that STAT1 deficiency reprograms IFN signaling from priming toward suppression of TLR response via feedback regulation of STAT3, which may provide a new insight into the host defense response against microbial pathogens in a situation of STAT1 deficiency. PMID:26299368

  12. CANCER CONTROL AND POPULATION SCIENCES FAST STATS

    EPA Science Inventory

    Fast Stats links to tables, charts, and graphs of cancer statistics for all major cancer sites by age, sex, race, and geographic area. The statistics include incidence, mortality, prevalence, and the probability of developing or dying from cancer. A large set of statistics is ava...

  13. FastStats: Older Persons' Health

    MedlinePlus

    ... 2015, table 20 [PDF - 9.8 MB] More data Adult Day Services Centers AgingStats.gov Deaths From Unintentional Injury Among Adults Aged 65 and Over: United States, 2000–2013 Health Characteristics ... 2007 Medicare Data [PDF - 177 KB] Health, United States, trend tables ...

  14. Solar Technical Assistance Team (STAT) (Fact Sheet)

    SciTech Connect

    Not Available

    2014-05-01

    The Solar Technical Assistance Team (STAT) is a team of solar technology and deployment experts who ensure that the best information on policies, regulations, financing, and other issues is getting into the hands of state government decision makers when they need it.

  15. Understanding STAT3 signaling in cardiac ischemia.

    PubMed

    O'Sullivan, K E; Breen, E P; Gallagher, H C; Buggy, D J; Hurley, J P

    2016-05-01

    Cardiovascular disease is the leading cause of death worldwide. It remains one of the greatest challenges to global health and will continue to dominate mortality trends in the future. Acute myocardial infarction results in 7.4 million deaths globally per annum. Current management strategies are centered on restoration of coronary blood flow via percutaneous coronary intervention, coronary artery bypass grafting and administration of anti-platelet agents. Such myocardial reperfusion accounts for 40-50 % of the final infarct size in most cases. Signaling transducer and activator of transcription 3 (STAT3) has been shown to have cardioprotective effects via canonical and non-canonical activation and modulation of mitochondrial and transcriptional responses. A significant body of in vitro and in vivo evidence suggests that activation of the STAT3 signal transduction pathway results in a cardio protective response to ischemia and attempts have been made to modulate this with therapeutic effect. Not only is STAT3 important for cardiomyocyte function, but it also modulates the cardiac microenvironment and communicates with cardiac fibroblasts. To this end, we here review the current evidence supporting the manipulation of STAT3 for therapeutic benefit in cardiac ischemia and identify areas for future research. PMID:27017613

  16. Therapeutic modulators of STAT signalling for human diseases

    PubMed Central

    Miklossy, Gabriella; Hilliard, Tyvette S.; Turkson, James

    2014-01-01

    The signal transducer and activator of transcription (STAT) proteins have important roles in biological processes. The abnormal activation of STAT signalling pathways is also implicated in many human diseases, including cancer, autoimmune diseases, rheumatoid arthritis, asthma and diabetes. Over a decade has passed since the first inhibitor of a STAT protein was reported and efforts to discover modulators of STAT signalling as therapeutics continue. This Review discusses the outcomes of the ongoing drug discovery research endeavours against STAT proteins, provides perspectives on new directions for accelerating the discovery of drug candidates, and highlights the noteworthy candidate therapeutics that have progressed to clinical trials. PMID:23903221

  17. Therapeutic modulators of STAT signalling for human diseases.

    PubMed

    Miklossy, Gabriella; Hilliard, Tyvette S; Turkson, James

    2013-08-01

    The signal transducer and activator of transcription (STAT) proteins have important roles in biological processes. The abnormal activation of STAT signalling pathways is also implicated in many human diseases, including cancer, autoimmune diseases, rheumatoid arthritis, asthma and diabetes. Over a decade has passed since the first inhibitor of a STAT protein was reported and efforts to discover modulators of STAT signalling as therapeutics continue. This Review discusses the outcomes of the ongoing drug discovery research endeavours against STAT proteins, provides perspectives on new directions for accelerating the discovery of drug candidates, and highlights the noteworthy candidate therapeutics that have progressed to clinical trials. PMID:23903221

  18. Nanocrystal/sol-gel nanocomposites

    DOEpatents

    Klimov, Victor L.; Petruska, Melissa A.

    2010-05-25

    The present invention is directed to a process for preparing a solid composite having colloidal nanocrystals dispersed within a sol-gel matrix, the process including admixing colloidal nanocrystals with an amphiphilic polymer including hydrophilic groups selected from the group consisting of --COOH, --OH, --SO.sub.3H, --NH.sub.2, and --PO.sub.3H.sub.2 within a solvent to form an alcohol-soluble colloidal nanocrystal-polymer complex, admixing the alcohol-soluble colloidal nanocrystal-polymer complex and a sol-gel precursor material, and, forming the solid composite from the admixture. The present invention is also directed to the resultant solid composites and to the alcohol-soluble colloidal nanocrystal-polymer complexes.

  19. Opportunity's Surroundings on Sol 1798

    NASA Technical Reports Server (NTRS)

    2009-01-01

    NASA's Mars Exploration Rover Opportunity used its navigation camera to take the images combined into this 180-degree view of the rover's surroundings during the 1,798th Martian day, or sol, of Opportunity's surface mission (Feb. 13, 2009). North is on top.

    The rover had driven 111 meters (364 feet) southward on the preceding sol. Tracks from that drive recede northward in this view. For scale, the distance between the parallel wheel tracks is about 1 meter (about 40 inches).

    The terrain in this portion of Mars' Meridiani Planum region includes dark-toned sand ripples and lighter-toned bedrock.

    This view is presented as a cylindrical projection with geometric seam correction.

  20. Metal-silica sol-gel materials

    NASA Technical Reports Server (NTRS)

    Stiegman, Albert E. (Inventor)

    2002-01-01

    The present invention relates to a single phase metal-silica sol-gel glass formed by the co-condensation of a transition metal with silicon atoms where the metal atoms are uniformly distributed within the sol-gel glass as individual metal centers. Any transition metal may be used in the sol-gel glasses. The present invention also relates to sensor materials where the sensor material is formed using the single phase metal-silica sol-gel glasses. The sensor materials may be in the form of a thin film or may be attached to an optical fiber. The present invention also relates to a method of sensing chemicals using the chemical sensors by monitoring the chromatic change of the metal-silica sol-gel glass when the chemical binds to the sensor. The present invention also relates to oxidation catalysts where a metal-silica sol-gel glass catalyzes the reaction. The present invention also relates to a method of performing oxidation reactions using the metal-silica sol-gel glasses. The present invention also relates to organopolymer metal-silica sol-gel composites where the pores of the metal-silica sol-gel glasses are filled with an organic polymer polymerized by the sol-gel glass.

  1. Response to 'Comment on 'Undamped electrostatic plasma waves''[Phys. Plasmas 20, 034701 (2013)

    SciTech Connect

    Valentini, F.; Perrone, D.; Veltri, P.; Califano, F.; Pegoraro, F.; Morrison, P. J.; O'Neil, T. M.

    2013-03-15

    Numerical and experimental evidence is given for the occurrence of the plateau states and concomitant corner modes proposed in Valentini et al.[Phys. Plasmas 19, 092103 (2012)]. It is argued that these states provide a better description of reality for small amplitude off-dispersion disturbances than the conventional Bernstein-Greene-Kruskal or cnoidal states such as those proposed in Schamel [Phys. Plasmas 20, 034701 (2013)].

  2. Comment on 'Nonlinear gyrokinetic theory with polarization drift' [Phys. Plasmas 17, 082304 (2010)

    SciTech Connect

    Leerink, S.; Parra, F. I.; Heikkinen, J. A.

    2010-12-15

    In this comment, we show that by using the discrete particle distribution function the changes of the phase-space volume of gyrocenter coordinates due to the fluctuating ExB velocity do not explicitly appear in the Poisson equation and the [Sosenko et al., Phys. Scr. 64, 264 (2001)] result is recovered. It is demonstrated that there is no contradiction between the work presented by Sosenko et al. and the work presented by [Wang et al., Phys. Plasmas 17, 082304 (2010)].

  3. Response to ``Comment on `Undamped electrostatic plasma waves''' [Phys. Plasmas 20, 034701 (2013)

    NASA Astrophysics Data System (ADS)

    Valentini, F.; Perrone, D.; Califano, F.; Pegoraro, F.; Veltri, P.; Morrison, P. J.; O'Neil, T. M.

    2013-03-01

    Numerical and experimental evidence is given for the occurrence of the plateau states and concomitant corner modes proposed in Valentini et al. [Phys. Plasmas 19, 092103 (2012)]. It is argued that these states provide a better description of reality for small amplitude off-dispersion disturbances than the conventional Bernstein-Greene-Kruskal or cnoidal states such as those proposed in Schamel [Phys. Plasmas 20, 034701 (2013)].

  4. An autoregulatory enhancer controls mammary-specific STAT5 functions

    PubMed Central

    Metser, Gil; Shin, Ha Youn; Wang, Chaochen; Yoo, Kyung Hyun; Oh, Sumin; Villarino, Alejandro V.; O'Shea, John J.; Kang, Keunsoo; Hennighausen, Lothar

    2016-01-01

    Signal Transducers and Activators of Transcription (STATs) are principal transcription factors downstream of cytokine receptors. Although STAT5A is expressed in most tissues it remains to be understood why its premier, non-redundant functions are restricted to prolactin-induced mammary gland development and function. We report that the ubiquitously expressed Stat5a/b locus is subject to additional lineage-specific transcriptional control in mammary epithelium. Genome-wide surveys of epigenetic status and transcription factor occupancy uncovered a putative mammary-specific enhancer within the intergenic sequences separating the two Stat5 genes. This region exhibited several hallmarks of genomic enhancers, including DNaseI hypersensitivity, H3K27 acetylation and binding by GR, NFIB, ELF5 and MED1. Mammary-specific STAT5 binding was obtained at two canonical STAT5 binding motifs. CRISPR/Cas9-mediated genome editing was used to delete these sites in mice and determine their biological function. Mutant animals exhibited an 80% reduction of Stat5 levels in mammary epithelium and a concomitant reduction of STAT5-dependent gene expression. Transcriptome analysis identified a class of mammary-restricted genes that was particularly dependent on high STAT5 levels as a result of the intergenic enhancer. Taken together, the mammary-specific enhancer enables a positive feedback circuit that contributes to the remarkable abundance of STAT5 and, in turn, to the efficacy of STAT5-dependent mammary physiology. PMID:26446995

  5. Comparative evolutionary genomics of the STAT family of transcription factors

    PubMed Central

    Wang, Yaming; Levy, David E.

    2012-01-01

    The STAT signaling pathway is one of the seven common pathways that govern cell fate decisions during animal development. Comparative genomics revealed multiple incidences of stat gene duplications throughout metazoan evolutionary history. While pseudogenization is a frequent fate of duplicated genes, many of these STAT duplications evolved into novel genes through rapid sequence diversification and neofunctionalization. Additionally, the core of STAT gene regulatory networks, comprising stat1 through 4, stat5 and stat6, arose early in vertebrate evolution, probably through the two whole genome duplication events that occurred after the split of Cephalochordates but before the rise of Chondrichthyes. While another complete genome duplication event took place during the evolution of bony fish after their separation from the tetrapods about 450 million years ago (Mya), modern fish have only one set of these core stats, suggesting the rapid loss of most duplicated stat genes. The two stat5 genes in mammals likely arose from a duplication event in early Eutherian evolution, a period from about 310 Mya at the avian-mammal divergence to the separation of marsupials from other mammals about 130 Mya. These analyses indicate that whole genome duplications and gene duplications by unequal chromosomal crossing over were likely the major mechanisms underlying the evolution of STATs. PMID:24058748

  6. The Complex Role of STAT3 in Viral Infections

    PubMed Central

    Kuchipudi, Suresh V.

    2015-01-01

    Signal transducer and activators of transcription-3 (STAT3) regulates diverse biological functions including cell growth, differentiation, and apoptosis. In addition, STAT3 plays a key role in regulating host immune and inflammatory responses and in the pathogenesis of many cancers. Several studies reported differential regulation of STAT3 in a range of viral infections. Interestingly, STAT3 appears to direct seemingly contradictory responses and both pro- and antiviral roles of STAT3 have been described. This review summarized the currently known functions of STAT3 in the regulation of viral replication and pathogenesis of viral infections. Some of the key unanswered questions and the gap in our current understanding of the role of STAT3 in viral pathogenesis are discussed. PMID:26199948

  7. Nucleic acid-based approaches to STAT inhibition.

    PubMed

    Sen, Malabika; Grandis, Jennifer R

    2012-10-01

    Silencing of abnormally activated genes can be accomplished in a highly specific manner using nucleic acid based approaches. The focus of this review includes the different nucleic acid based inhibition strategies such as antisense oligodeoxynucleotides, small interfering RNA (siRNA), dominant-negative constructs, G-quartet oligonucleotides and decoy oligonucleotides, their mechanism of action and the effectiveness of these approaches to targeting the STAT (signal transducer and activator of transcription) proteins in cancer. Among the STAT proteins, especially STAT3, followed by STAT5, are the most frequently activated oncogenic STATs, which have emerged as plausible therapeutic cancer targets. Both STAT3 and STAT5 have been shown to regulate numerous oncogenic signaling pathways including proliferation, survival, angiogenesis and migration/invasion. PMID:24058785

  8. Interaction of mumps virus V protein variants with STAT1-STAT2 heterodimer: experimental and theoretical studies

    PubMed Central

    2010-01-01

    Background Mumps virus V protein has the ability to inhibit the interferon-mediated antiviral response by inducing degradation of STAT proteins. Two virus variants purified from Urabe AM9 mumps virus vaccine differ in their replication and transcription efficiency in cells primed with interferon. Virus susceptibility to IFN was associated with insertion of a non-coded glycine at position 156 in the V protein (VGly) of one virus variant, whereas resistance to IFN was associated with preservation of wild-type phenotype in the V protein (VWT) of the other variant. Results VWT and VGly variants of mumps virus were cloned and sequenced from Urabe AM9 vaccine strain. VGly differs from VWT protein because it possesses an amino acid change Gln103Pro (Pro103) and the Gly156 insertion. The effect of V protein variants on components of the interferon-stimulated gene factor 3 (ISGF3), STAT1 and STAT2 proteins were experimentally tested in cervical carcinoma cell lines. Expression of VWT protein decreased STAT1 phosphorylation, whereas VGly had no inhibitory effect on either STAT1 or STAT2 phosphorylation. For theoretical analysis of the interaction between V proteins and STAT proteins, 3D structural models of VWT and VGly were predicted by comparing with simian virus 5 (SV5) V protein structure in complex with STAT1-STAT2 heterodimer. In silico analysis showed that VWT-STAT1-STAT2 complex occurs through the V protein Trp-motif (W174, W178, W189) and Glu95 residue close to the Arg409 and Lys415 of the nuclear localization signal (NLS) of STAT2, leaving exposed STAT1 Lys residues (K85, K87, K296, K413, K525, K679, K685), which are susceptible to proteasome degradation. In contrast, the interaction between VGly and STAT1-STAT2 heterodimer occurs in a region far from the NLS of STAT2 without blocking of Lys residues in both STAT1 and STAT2. Conclusions Our results suggest that VWT protein of Urabe AM9 strain of mumps virus may be more efficient than VGly to inactivate both the IFN

  9. Hybrid sol-gel optical materials

    DOEpatents

    Zeigler, J.M.

    1993-04-20

    Hybrid sol-gel materials comprise silicate sols cross-linked with linear polysilane, polygermane, or poly(silane-germane). The sol-gel materials are useful as optical identifiers in tagging and verification applications and, in a different aspect, as stable, visible light transparent non-linear optical materials. Methyl or phenyl silicones, polyaryl sulfides, polyaryl ethers, and rubbery polysilanes may be used in addition to the linear polysilane. The linear polymers cross-link with the sol to form a matrix having high optical transparency, resistance to thermooxidative aging, adherence to a variety of substrates, brittleness, and a resistance to cracking during thermal cycling.

  10. Hybrid sol-gel optical materials

    DOEpatents

    Zeigler, John M.

    1993-01-01

    Hybrid sol-gel materials comprise silicate sols cross-linked with linear polysilane, polygermane, or poly(silane-germane). The sol-gel materials are useful as optical identifiers in tagging and verification applications and, in a different aspect, as stable, visible light transparent non-linear optical materials. Methyl or phenyl silicones, polyaryl sulfides, polyaryl ethers, and rubbery polysilanes may be used in addition to the linear polysilane. The linear polymers cross-link with the sol to form a matrix having high optical transparency, resistance to thermooxidative aging, adherence to a variety of substrates, brittleness, and a resistance to cracking during thermal cycling.

  11. Hybrid sol-gel optical materials

    DOEpatents

    Zeigler, John M.

    1992-01-01

    Hybrid sol-gel materials comprise silicate sols cross-linked with linear polysilane, polygermane, or poly(silane-germane). The sol-gel materials are useful as optical identifiers in tagging and verification applications and, in a different aspect, as stable, visible light transparent non-linear optical materials. Methyl or phenyl silicones, polyaryl sulfides, polyaryl ethers, and rubbery polysilanes may be used in addition to the linear polysilane. The linear polymers cross-link with the sol to form a matrix having high optical transparency, resistance to thermooxidative aging, adherence to a variety of substrates, brittleness, and a resistance to cracking during thermal cycling.

  12. SOL - SIZING AND OPTIMIZATION LANGUAGE COMPILER

    NASA Technical Reports Server (NTRS)

    Scotti, S. J.

    1994-01-01

    SOL is a computer language which is geared to solving design problems. SOL includes the mathematical modeling and logical capabilities of a computer language like FORTRAN but also includes the additional power of non-linear mathematical programming methods (i.e. numerical optimization) at the language level (as opposed to the subroutine level). The language-level use of optimization has several advantages over the traditional, subroutine-calling method of using an optimizer: first, the optimization problem is described in a concise and clear manner which closely parallels the mathematical description of optimization; second, a seamless interface is automatically established between the optimizer subroutines and the mathematical model of the system being optimized; third, the results of an optimization (objective, design variables, constraints, termination criteria, and some or all of the optimization history) are output in a form directly related to the optimization description; and finally, automatic error checking and recovery from an ill-defined system model or optimization description is facilitated by the language-level specification of the optimization problem. Thus, SOL enables rapid generation of models and solutions for optimum design problems with greater confidence that the problem is posed correctly. The SOL compiler takes SOL-language statements and generates the equivalent FORTRAN code and system calls. Because of this approach, the modeling capabilities of SOL are extended by the ability to incorporate existing FORTRAN code into a SOL program. In addition, SOL has a powerful MACRO capability. The MACRO capability of the SOL compiler effectively gives the user the ability to extend the SOL language and can be used to develop easy-to-use shorthand methods of generating complex models and solution strategies. The SOL compiler provides syntactic and semantic error-checking, error recovery, and detailed reports containing cross-references to show where

  13. STAT3 regulated ARF expression suppresses prostate cancer metastasis

    PubMed Central

    Pencik, Jan; Schlederer, Michaela; Gruber, Wolfgang; Unger, Christine; Walker, Steven M.; Chalaris, Athena; Marié, Isabelle J.; Hassler, Melanie R.; Javaheri, Tahereh; Aksoy, Osman; Blayney, Jaine K.; Prutsch, Nicole; Skucha, Anna; Herac, Merima; Krämer, Oliver H.; Mazal, Peter; Grebien, Florian; Egger, Gerda; Poli, Valeria; Mikulits, Wolfgang; Eferl, Robert; Esterbauer, Harald; Kennedy, Richard; Fend, Falko; Scharpf, Marcus; Braun, Martin; Perner, Sven; Levy, David E.; Malcolm, Tim; Turner, Suzanne D.; Haitel, Andrea; Susani, Martin; Moazzami, Ali; Rose-John, Stefan; Aberger, Fritz; Merkel, Olaf; Moriggl, Richard; Culig, Zoran; Dolznig, Helmut; Kenner, Lukas

    2015-01-01

    Prostate cancer (PCa) is the most prevalent cancer in men. Hyperactive STAT3 is thought to be oncogenic in PCa. However, targeting of the IL-6/STAT3 axis in PCa patients has failed to provide therapeutic benefit. Here we show that genetic inactivation of Stat3 or IL-6 signalling in a Pten-deficient PCa mouse model accelerates cancer progression leading to metastasis. Mechanistically, we identify p19ARF as a direct Stat3 target. Loss of Stat3 signalling disrupts the ARF–Mdm2–p53 tumour suppressor axis bypassing senescence. Strikingly, we also identify STAT3 and CDKN2A mutations in primary human PCa. STAT3 and CDKN2A deletions co-occurred with high frequency in PCa metastases. In accordance, loss of STAT3 and p14ARF expression in patient tumours correlates with increased risk of disease recurrence and metastatic PCa. Thus, STAT3 and ARF may be prognostic markers to stratify high from low risk PCa patients. Our findings challenge the current discussion on therapeutic benefit or risk of IL-6/STAT3 inhibition. PMID:26198641

  14. Targeting STAT3 in cancer: how successful are we?

    PubMed Central

    Yue, Peibin; Turkson, James

    2008-01-01

    Background Aberrant activation of the signal transducer and activator of transcription (STAT)3 occurs in many human tumors. Moreover, studies utilizing genetic and pharmacological approaches to modulate constitutive STAT3 activity have provided compelling evidence for the critical role of aberrant STAT3 activity in malignant transformation and tumor progression, and thereby validated STAT3 as a novel cancer drug target. Objective This review is intended to be a full coverage of the efforts to develop direct STAT3 inhibitors and will provide a discussion on the inhibitory modalities developed to date. Methods Review of the literature focused on the modalities and mechanisms that directly target and inhibit the STAT protein or its functions. Results/conclusion While a variety of STAT3 inhibitors have been identified that induce antitumor cell effects in vitro and in vivo, the landscape remains murky. With a few exceptions, most of the STAT3 inhibitors reported to date have not undergone an in vivo efficacy, pharmacology or toxicity testing. Also, there is no evidence, per the published literature of an impending clinical development for the few agents that were reported to exhibit in vivo efficacy. Overall, there is the need for a reassessment of the ongoing strategies to target STAT3 intended not only for refinement, but also for incorporating some new technologies to strengthen our efforts and ensure the success – sooner, rather than later – of identifying suitable anti-STAT3 agents for development into clinically useful anticancer therapeutics. PMID:19053881

  15. e-Phys: a suite of intracellular neurophysiology programs integrating COM (component object model) technologies.

    PubMed

    Nguyen, Quoc-Thang; Miledi, Ricardo

    2003-09-30

    Current computer programs for intracellular recordings often lack advanced data management, are usually incompatible with other applications and are also difficult to adapt to new experiments. We have addressed these shortcomings in e-Phys, a suite of electrophysiology applications for intracellular recordings. The programs in e-Phys use Component Object Model (COM) technologies available in the Microsoft Windows operating system to provide enhanced data storage, increased interoperability between e-Phys and other COM-aware applications, and easy customization of data acquisition and analysis thanks to a script-based integrated programming environment. Data files are extensible, hierarchically organized and integrated in the Windows shell by using the Structured Storage technology. Data transfers to and from other programs are facilitated by implementing the ActiveX Automation standard and distributed COM (DCOM). ActiveX Scripting allows experimenters to write their own event-driven acquisition and analysis programs in the VBScript language from within e-Phys. Scripts can reuse components available from other programs on other machines to create distributed meta-applications. This paper describes the main features of e-Phys and how this package was used to determine the effect of the atypical antipsychotic drug clozapine on synaptic transmission at the neuromuscular junction. PMID:12948545

  16. Opportunity's View, Sol 958 (Stereo)

    NASA Technical Reports Server (NTRS)

    2006-01-01

    [figure removed for brevity, see original site] Left-eye view of a stereo pair for PIA01897

    [figure removed for brevity, see original site] Right-eye view of a stereo pair for PIA01897

    NASA's Mars Exploration Rover Opportunity used its navigation camera to take the images combined into this stereo view of the rover's surroundings on the 958th sol, or Martian day, of its surface mission (Oct. 4, 2006).

    This view is presented as a cylindrical-perspective projection with geometric seam correction. The image appears three-dimensional when viewed through red-green stereo glasses.

  17. Opportunity's View, Sol 959, (Stereo)

    NASA Technical Reports Server (NTRS)

    2006-01-01

    [figure removed for brevity, see original site] Left-eye view of a stereo pair for PIA01893

    [figure removed for brevity, see original site] Right-eye view of a stereo pair for PIA01893

    NASA's Mars Exploration Rover Opportunity used its navigation camera to take the images combined into this stereo view of the rover's surroundings on sol (or Martian day) 959 of its surface mission.

    This view is presented as a cylindrical-perspective projection with geometric seam correction.

  18. Anopheles gambiae Ag-STAT, a new insect member of the STAT family, is activated in response to bacterial infection.

    PubMed

    Barillas-Mury, C; Han, Y S; Seeley, D; Kafatos, F C

    1999-02-15

    A new insect member of the STAT family of transcription factors (Ag-STAT) has been cloned from the human malaria vector Anopheles gambiae. The domain involved in DNA interaction and the SH2 domain are well conserved. Ag-STAT is most similar to Drosophila D-STAT and to vertebrate STATs 5 and 6, constituting a proposed ancient class A of the STAT family. The mRNA is expressed at all developmental stages, and the protein is present in hemocytes, pericardial cells, midgut, skeletal muscle and fat body cells. There is no evidence of transcriptional activation following bacterial challenge. However, bacterial challenge results in nuclear translocation of Ag-STAT protein in fat body cells and induction of DNA-binding activity that recognizes a STAT target site. In vitro treatment with pervanadate (vanadate and H2O2) translocates Ag-STAT to the nucleus in midgut epithelial cells. This is the first evidence of direct participation of the STAT pathway in immune responses in insects. PMID:10022838

  19. The preliminary SOL (Sizing and Optimization Language) reference manual

    NASA Technical Reports Server (NTRS)

    Lucas, Stephen H.; Scotti, Stephen J.

    1989-01-01

    The Sizing and Optimization Language, SOL, a high-level special-purpose computer language has been developed to expedite application of numerical optimization to design problems and to make the process less error-prone. This document is a reference manual for those wishing to write SOL programs. SOL is presently available for DEC VAX/VMS systems. A SOL package is available which includes the SOL compiler and runtime library routines. An overview of SOL appears in NASA TM 100565.

  20. JAK/STAT pathway dysregulation in tumors: A Drosophila perspective

    PubMed Central

    Amoyel, Marc; Anderson, Abigail M.; Bach, Erika A.

    2014-01-01

    Sustained activation of the JAK/STAT pathway is causal to human cancers. This pathway is less complex in Drosophila, and its dysregulation has been linked to several tumor models in this organism. Here, we discuss models of metastatic epithelial and hematopoietic tumors that are causally linked to dysregulation of JAK/STAT signaling in Drosophila. First, we focus on cancer models in imaginal discs where ectopic expression of the JAK/STAT pathway ligand Unpaired downstream of distinct tumor suppressors has emerged as an unexpected mediator of neoplastic transformation. We also discuss the collaboration between STAT and oncogenic Ras in epithelial transformation. Second, we examine hematopoietic tumors, where mutations that cause hyperactive JAK/STAT signaling are necessary and sufficient for “fly leukemia”. We highlight the important contributions that genetic screens in Drosophila have made to understanding the JAK/STAT pathway, its developmental roles, and how its function is co-opted during tumorigenesis. PMID:24685611

  1. Role of STAT3 in Cancer Metastasis and Translational Advances

    PubMed Central

    Patil, Prachi; Gude, Rajiv P.

    2013-01-01

    Signal transducer and activator of transcription 3 (STAT3) is a latent cytoplasmic transcription factor, originally discovered as a transducer of signal from cell surface receptors to the nucleus. It is activated by tyrosine phosphorylation at position 705 leading to its dimerization, nuclear translocation, DNA binding, and activation of gene transcription. Under normal physiological conditions, STAT3 activation is tightly regulated. However, compelling evidence suggests that STAT3 is constitutively activated in many cancers and plays a pivotal role in tumor growth and metastasis. It regulates cellular proliferation, invasion, migration, and angiogenesis that are critical for cancer metastasis. In this paper, we first describe the mechanism of STAT3 regulation followed by how STAT3 is involved in cancer metastasis, then we summarize the various small molecule inhibitors that inhibit STAT3 signaling. PMID:24199193

  2. Structure of the mouse Stat 3/5 locus: evolution from Drosophila to zebrafish to mouse.

    PubMed

    Miyoshi, K; Cui, Y; Riedlinger, G; Robinson, P; Lehoczky, J; Zon, L; Oka, T; Dewar, K; Hennighausen, L

    2001-01-15

    Signal transducers and activators of transcription (Stat) are transcription factors that can be activated by many cytokines. While Drosophila contains only one Stat (d-Stat), mammals contain seven, with STATs 3, 5a, and 5b being the closest functional relatives. To understand the evolutionary relationship between d-Stat and vertebrate STATs 3 and 5, we isolated, sequenced, and analyzed the zebrafish Stat3 (z-Stat3) gene and a 500-kb region spanning mouse chromosome 11, 60.5 cM containing three Stat genes (m-Stats). Within this region we identified the genes encoding m-Stats 3, 5a, and 5b, Cnp1, Hcrt/Orexin, Ptrf, GCN5, mDj11, and four new genes. The 5' ends of the m-Stat5a and m-Stat5b genes are juxtaposed to each other, and the 3' ends of the m-Stat3 and Stat5a genes face each other. While the m-Stat5a and m-Stat3 genes have one promoter each, which are active in many tissues, the m-Stat5b gene acquired two distinct promoters. The distal promoter is expressed ubiquitously, and transcription from the proximal promoter is restricted to liver, muscle, and mammary tissue. Through a comparison of exon-intron boundaries from the m-Stat3, m-Stat5a, and m-Stat5b, z-Stat3, and d-Stat genes, we deduced their evolutionary relationship. We propose that the Stat3 and Stat5 lineages are derived from the duplication of a common primordial gene and that d-Stat is a part of the Stat5 lineage. PMID:11161808

  3. Radiosensitization by Inhibiting STAT1 in Renal Cell Carcinoma

    SciTech Connect

    Hui Zhouguang; Tretiakova, Maria; Zhang Zhongfa; Li Yan; Wang Xiaozhen; Zhu, Julie Xiaohong; Gao Yuanhong; Mai Weiyuan; Furge, Kyle; Qian Chaonan; Amato, Robert; Butler, E. Brian

    2009-01-01

    Purpose: Renal cell carcinoma (RCC) has been historically regarded as a radioresistant malignancy, but the molecular mechanism underlying its radioresistance is not understood. This study investigated the role of signal transducer and activator of transcription 1 (STAT1), a transcription factor downstream of the interferon-signaling pathway, in radioresistant RCC. Methods and Materials: The expressions of STAT1 and STAT3 in 164 human clear cell RCC samples, 47 papillary RCC samples, and 15 normal kidney tissue samples were examined by microarray expression profiling and immunohistochemistry. Western blotting was performed to evaluate the total and phosphorylated STAT1 expression in CRL-1932 (786-O) (human clear cell RCC), SKRC-39 (human papillary RCC), CCL-116 (human fibroblast), and CRL-1441 (G-401) (human Wilms tumor). STAT1 was reduced or inhibited by fludarabine and siRNA, respectively, and the effects on radiation-induced cell death were investigated using clonogenic assays. Results: STAT1 expression, but not STAT3 expression, was significantly greater in human RCC samples (p = 1.5 x 10{sup -8} for clear cell; and p = 3.6 x 10{sup -4} for papillary). Similarly, the expression of STAT1 was relatively greater in the two RCC cell lines. STAT1 expression was reduced by both fludarabine and siRNA, significantly increasing the radiosensitivity in both RCC cell lines. Conclusion: This is the first study reporting the overexpression of STAT1 in human clear cell and papillary RCC tissues. Radiosensitization in RCC cell lines was observed by a reduction or inhibition of STAT1 signaling, using fludarabine or siRNA. Our data suggest that STAT1 may play a key role in RCC radioresistance and manipulation of this pathway may enhance the efficacy of radiotherapy.

  4. Structural Tailoring of Advanced Turboprops (STAT) programmer's manual

    NASA Technical Reports Server (NTRS)

    Brown, K. W.; Harvey, P. R.

    1989-01-01

    The Structural Tailoring of Advanced Turboprops (STAT) computer program was developed to perform numerical optimizations on highly swept propfan blades. This manual describes the functionality of the STAT system from a programmer's viewpoint. It provides a top-down description of module intent and interaction. The purpose of this manual is to familiarize the programmer with the STAT system should he/she wish to enhance or verify the program's function.

  5. STAT3 in Cancer—Friend or Foe?

    PubMed Central

    Zhang, Hai-Feng; Lai, Raymond

    2014-01-01

    The roles and significance of STAT3 in cancer biology have been extensively studied for more than a decade. Mounting evidence has shown that constitutive activation of STAT3 is a frequent biochemical aberrancy in cancer cells, and this abnormality directly contributes to tumorigenesis and shapes many malignant phenotypes in cancer cells. Nevertheless, results from more recent experimental and clinicopathologic studies have suggested that STAT3 also can exert tumor suppressor effects under specific conditions. Importantly, some of these studies have demonstrated that STAT3 can function either as an oncoprotein or a tumor suppressor in the same cell type, depending on the specific genetic background or presence/absence of specific coexisting biochemical defects. Thus, in the context of cancer biology, STAT3 can be a friend or foe. In the first half of this review, we will highlight the “evil” features of STAT3 by summarizing its oncogenic functions and mechanisms. The differences between the canonical and non-canonical pathway will be highlighted. In the second half, we will summarize the evidence supporting that STAT3 can function as a tumor suppressor. To explain how STAT3 may mediate its tumor suppressor effects, we will discuss several possible mechanisms, one of which is linked to the role of STAT3β, one of the two STAT3 splicing isoforms. Taken together, it is clear that the roles of STAT3 in cancer are multi-faceted and far more complicated than one appreciated previously. The new knowledge has provided us with new approaches and strategies when we evaluate STAT3 as a prognostic biomarker or therapeutic target. PMID:24995504

  6. Sol-gel kinetics by NMR

    SciTech Connect

    Assink, R.A.; Kay, B.D.

    1991-01-01

    The chemical synthesis of advanced ceramic and glass materials by the sol-gel process has become an area of increasing activity in the field of material science. The sol-gel process provides a means to prepare homogeneous, high purity materials with tailored chemical and physical properties. This paper surveyed the nuclear magnetic resonance (NMR) studies of silicon-based sol-gel kinetics. A review of the various models which have been used to analyze the chemical kinetics of various sol-gel systems was presented. The utility of NMR spectroscopy was demonstrated in investigating the influence that various reaction conditions have on the reaction pathways by which sol-gel derived materials are synthesized. By observing in a direct fashion the chemical pathway of the sol-gel, it is often possible to relate the final properties of the material to the formulation and reaction conditions of the sol-gel. The study of reaction kinetics by NMR is expected to play an increasingly important role in understanding sol-gel processing and material properties. 15 refs. (DP)

  7. Comment on 'Turbulent equipartition theory of toroidal momentum pinch' [Phys. Plasmas 15, 055902 (2008)

    SciTech Connect

    Peeters, A. G.; Angioni, C.; Strintzi, D.

    2009-03-15

    The comment addresses questions raised on the derivation of the momentum pinch velocity due to the Coriolis drift effect [A. G. Peeters et al., Phys. Rev. Lett. 98, 265003 (2007)]. These concern the definition of the gradient, and the scaling with the density gradient length. It will be shown that the turbulent equipartition mechanism is included within the derivation using the Coriolis drift, with the density gradient scaling being the consequence of drift terms not considered in [T. S. Hahm et al., Phys. Plasmas 15, 055902 (2008)]. Finally the accuracy of the analytic models is assessed through a comparison with the full gyrokinetic solution.

  8. Targeting transcription factor STAT3 for cancer prevention and therapy.

    PubMed

    Chai, Edna Zhi Pei; Shanmugam, Muthu K; Arfuso, Frank; Dharmarajan, Arunasalam; Wang, Chao; Kumar, Alan Prem; Samy, Ramar Perumal; Lim, Lina H K; Wang, Lingzhi; Goh, Boon Cher; Ahn, Kwang Seok; Hui, Kam Man; Sethi, Gautam

    2016-06-01

    Signal Transducers and Activators of Transcription (STATs) comprise an important class of transcription factors that have been implicated in a wide variety of essential cellular functions related to proliferation, survival, and angiogenesis. Among various STAT members, STAT3 is frequently overexpressed in tumor cells as well as tissue samples, and regulates the expression of numerous oncogenic genes controlling the growth and metastasis of tumor cells. The current review briefly discusses the importance of STAT3 as a potential target for cancer therapy and also provides novel insights into various classes of existing pharmacological inhibitors of this transcription factor that can be potentially developed as anti-cancer drugs. PMID:26478441

  9. Mast cell homeostasis and the JAK–STAT pathway

    PubMed Central

    Morales, JK; Falanga, YT; Depcrynski, A; Fernando, J; Ryan, JJ

    2011-01-01

    The Janus kinase/signal transducer and activator of transcription (JAK–STAT) pathway mediates important responses in immune cells. Activation of any of the four JAK family members leads to phosphorylation of one or more of seven STAT family members. Phosphorylation of STAT family members leads to their dimerization and translocation into the nucleus, in which they bind specific DNA sequences to activate gene transcription. Regulation of JAKs and STATs therefore has a significant effect on signal transduction and subsequent cellular responses. Mast cells are important mediators of allergic disease and asthma. These cells have the ability to cause profound inflammation and vasodilation upon the release of preformed mediators, as well as subsequent synthesis of new inflammatory mediators. The regulation of mast cells is therefore of intense interest for the treatment of allergic disease. An important regulator of mast cells, STAT5, is activated downstream of the receptors for immunoglobulin E, interleukin-3 and stem cell factor. STAT5 contributes to mast cell homeostasis, by mediating proliferation, survival, and mediator release. Regulators of the JAK–STAT pathway, such as the suppressors of cytokine signaling (SOCS) and protein inhibitor of activated STAT (PIAS) proteins, are required to fine tune the immune response and maintain homeostasis. A better understanding of the role and regulation of JAKs and STATs in mast cells is vital for the development of new therapeutics. PMID:20535135

  10. STAT3 Inhibitors: Finding a Home in Lymphoma and Leukemia

    PubMed Central

    Munoz, Javier; Dhillon, Navjot; Janku, Filip; Watowich, Stephanie S.

    2014-01-01

    The Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathway is an active mediator of cytokine signaling in the pathogenesis of solid and hematologic malignancies. The seven-member STAT family is composed of latent cytoplasmic transcription factors that are activated by phosphorylation intertwined in a network with activation that ultimately leads to cell proliferation. An activated kinase enzyme phosphorylates one STAT factor or more, which shuttle to the nucleus to regulate gene expression, promoting cell survival. Somatic STAT3 mutations have been recently reported in large granular lymphocytic leukemia, aplastic anemia, and myelodysplastic syndrome. Furthermore, the relationship between BCL6 and STAT3 in diffuse large B-cell lymphomas, particularly on the activated B-cell subtype, needs to be further explored. The search for therapeutic STAT3 inhibitors that abrogate the JAK/STAT pathway is currently under way. Targeting the STAT pathway, which seems to be critical in tumorigenesis, is promising for multiple malignancies including lymphoma and leukemia. In this paper, we review mechanisms of action, failures, and successes of STAT3 inhibitors. PMID:24705981

  11. The role of JAK-STAT signaling within the CNS.

    PubMed

    Nicolas, Celine S; Amici, Mascia; Bortolotto, Zuner A; Doherty, Andrew; Csaba, Zsolt; Fafouri, Assia; Dournaud, Pascal; Gressens, Pierre; Collingridge, Graham L; Peineau, Stephane

    2013-01-01

    JAK-STAT is an efficient and highly regulated system mainly dedicated to the regulation of gene expression. Primarily identified as functioning in hematopoietic cells, its role has been found critical in all cell types, including neurons. This review will focus on JAK-STAT functions in the mature central nervous system. Our recent research suggests the intriguing possibility of a non-nuclear role of STAT3 during synaptic plasticity. Dysregulation of the JAK-STAT pathway in inflammation, cancer and neurodegenerative diseases positions it at the heart of most brain disorders, highlighting the importance to understand how it can influence the fate and functions of brain cells. PMID:24058789

  12. STAT5B deficiency: Impacts on human growth and immunity.

    PubMed

    Hwa, Vivian

    2016-06-01

    Growth hormone (GH) promotes postnatal human growth primarily by regulating insulin-like growth factor (IGF)-I production through activation of the GH receptor (GHR)-signal transducer and activator of transcription (STAT)-5B signaling cascade. The critical importance of STAT5B in human IGF-I production was confirmed with the identification of the first homozygous, autosomal recessive, STAT5B mutation in a young female patient who phenotypically resembled patients with classical growth hormone insensitivity (GHI) syndrome (Laron syndrome) due to mutations in the GHR gene, presenting with severe postnatal growth failure and marked IGF-I deficiency. Of note, the closely related STAT5A, which shares >95% amino acid identity with STAT5B, could not compensate for loss of functional STAT5B. To date, 7 homozygous, inactivating, STAT5B mutations in 10 patients have been reported. STAT5B deficient patients, unlike patients deficient in GHR, can also present with a novel, potentially fatal, primary immunodeficiency, which can manifest as chronic pulmonary disease. STAT5B deficiency may be underestimated in endocrine, immunology and pulmonary clinics. PMID:26703237

  13. Interleukin 2 signaling involves the phosphorylation of Stat proteins.

    PubMed

    Frank, D A; Robertson, M J; Bonni, A; Ritz, J; Greenberg, M E

    1995-08-15

    One of the most important cytokines involved in immune response regulation is interleukin 2 (IL-2), a potent activator of the proliferation and function of T lymphocytes and natural killer cells. The mechanisms by which the effects of IL-2 are propagated within cells are not understood. While the binding of IL-2 to its receptor was recently shown to lead to the activation of two kinases, Jak-1 and Jak-3, subsequent steps in the signaling pathway to the nucleus that lead to the activation of specific genes had not been characterized. Since many cytokines that activate Jak kinases also lead to the tyrosine phosphorylation and activation of members of the Stat family of transcription factors, the ability of IL-2 to trigger Stat phosphorylation was examined. Exposure of activated human T lymphocytes or of a natural killer cell line (NKL) to IL-2 leads to the phosphorylation of Stat1 alpha, Stat1 beta, and Stat3, as well as of two Stat-related proteins, p94 and p95. p94 and p95 share homology with Stat1 at the phosphorylation site and in the Src homology 2 (SH2) domain, but otherwise are immunologically distinct from Stat1. These Stat proteins were found to translocate to the nucleus and to bind to a specific DNA sequence. These findings suggest a mechanism by which IL-2 binding to its receptor may activate specific genes involved in immune cell function. PMID:7544001

  14. Permanent Habitats in Earth-Sol/Mars-Sol Orbit Positions

    NASA Astrophysics Data System (ADS)

    Greenspon, J.

    Project Outpost is a manned Earth-Sol/Mars-Sol platform that enables permanent occupation in deep space. In order to develop the program elements for this complex mission, Project Outpost will rely primarily on existing/nearterm technology and hardware for the construction of its components. For the purposes of this study, four mission requirements are considered: 1. Outpost - Man's 1st purpose-produced effort of space engineering, in which astructure is developed/constructed in an environment completely alien to currentpractices for EVA guidelines. 2. Newton - a concept study developed at StarGate Research, for the development ofa modified Hohmann personnel orbital transport operating between Earth andMars. Newton would serve as the primary crew delivery apparatus throughrepeatable transfer scheduling for all Earth-Lpoint-Mars activities. Thispermanent "transit system" would establish the foundations for Solar systemcolonization. 3. Cruis - a concept study developed at StarGate Research, for the development of amodified Hohmann cargo orbital transport operating between Earth and Mars.Cruis would serve as the primary equipment delivery apparatus throughrepeatable transfer scheduling for all Earth-Lpoint-Mars activities. Thispermanent "transit system" would establish the foundations for Solar systemcolonization, and 4. Ares/Diana - a more conventional space platform configuration for Lunar andMars orbit is included as a construction baseline. The operations of these assetsare supported, and used for the support, of the outpost. Outpost would be constructed over a 27-year period of launch opportunities into Earth-Sol or Mars-Sol Lagrange orbit (E-S/M-S L1, 4 or 5). The outpost consists of an operations core with a self-contained power generation ability, a docking and maintenance structure, a Scientific Research complex and a Habitation Section. After achieving initial activation, the core will provide the support and energy required to operate the outpost in a 365

  15. A New STAT3-binding Partner, ARL3, Enhances the Phosphorylation and Nuclear Accumulation of STAT3.

    PubMed

    Togi, Sumihito; Muromoto, Ryuta; Hirashima, Koki; Kitai, Yuichi; Okayama, Taichiro; Ikeda, Osamu; Matsumoto, Naoki; Kon, Shigeyuki; Sekine, Yuichi; Oritani, Kenji; Matsuda, Tadashi

    2016-05-20

    Signal transducer and activator of transcription 3 (STAT3) is involved in cell proliferation, differentiation, and cell survival during immune responses, hematopoiesis, neurogenesis, and other biological processes. STAT3 activity is regulated by a variety of mechanisms, including phosphorylation and nuclear translocation. To clarify the molecular mechanisms underlying the regulation of STAT3 activity, we performed yeast two-hybrid screening. We identified ARL3 (ADP-ribosylation factor-like 3) as a novel STAT3-binding partner. ARL3 recognizes the DNA-binding domain as well as the C-terminal region of STAT3 in vivo, and their binding was the strongest when both proteins were activated. Importantly, small interfering RNA-mediated reduction of endogenous ARL3 expression decreased IL-6-induced tyrosine phosphorylation, nuclear accumulation, and transcriptional activity of STAT3. These results indicate that ARL3 interacts with STAT3 and regulates the transcriptional activation of STAT3 by influencing its nuclear accumulation of STAT3. PMID:27048653

  16. The non-pathogenic Henipavirus Cedar paramyxovirus phosphoprotein has a compromised ability to target STAT1 and STAT2.

    PubMed

    Lieu, Kim G; Marsh, Glenn A; Wang, Lin-Fa; Netter, Hans J

    2015-12-01

    Immune evasion by the lethal henipaviruses, Hendra (HeV) and Nipah virus, is mediated by its interferon (IFN) antagonist P gene products, phosphoprotein (P), and the related V and W proteins, which can target the signal transducer and activator of transcription 1 (STAT1) and STAT2 proteins to inhibit IFN/STAT signaling. However, it is not clear if the recently identified non-pathogenic Henipavirus, Cedar paramyxovirus (CedPV), is also able to antagonize the STAT proteins. We performed comparative studies between the HeV P gene products (P/V/W) and CedPV-P (CedPV does not encode V or W) and demonstrate that differences exist in their ability to engage the STAT proteins using immunoprecipitation and quantitative confocal microscopic analysis. In contrast to HeV-P gene encoded proteins, the ability of CedPV-P to interact with and relocalize STAT1 or STAT2 is compromised, correlating with a reduced capacity to inhibit the mRNA synthesis of IFN-inducible gene MxA. Furthermore, infection studies with HeV and CedPV demonstrate that HeV is more potent than CedPV in inhibiting the IFN-α-mediated nuclear accumulation of STAT1. These results strongly suggest that the ability of CedPV to counteract the IFN/STAT response is compromised compared to HeV. PMID:26526590

  17. Erratum: Binary neutron stars with arbitrary spins in numerical relativity [Phys. Rev. D 92, 124012 (2015)

    NASA Astrophysics Data System (ADS)

    Tacik, Nick; Foucart, Francois; Pfeiffer, Harald P.; Haas, Roland; Ossokine, Serguei; Kaplan, Jeff; Muhlberger, Curran; Duez, Matt D.; Kidder, Lawrence E.; Scheel, Mark A.; Szilágyi, Béla

    2016-08-01

    The code used in [Phys. Rev. D 92, 124012 (2015)] erroneously computed the enthalpy at the center of the neutron stars. Upon correcting this error, density oscillations in evolutions of rotating neutron stars are significantly reduced (from ˜20 % to ˜0.5 % ). Furthermore, it is possible to construct neutron stars with faster rotation rates.

  18. Comment on ``Quantum key distribution without alternative measurements'' [Phys. Rev. A 61, 052312 (2000)

    NASA Astrophysics Data System (ADS)

    Zhang, Yong-Sheng; Li, Chuan-Feng; Guo, Guang-Can

    2001-03-01

    In a recent paper [A. Cabello, Phys. Rev. A 61, 052312 (2000)], a quantum key distribution protocol based on entanglement swapping was proposed. However, in this Comment, it is shown that this protocol is insecure if Eve uses a special strategy to attack.

  19. Activation of Hepatic STAT3 Maintains Pulmonary Defense during Endotoxemia

    PubMed Central

    Hilliard, Kristie L.; Allen, Eri; Traber, Katrina E.; Kim, Yuri; Wasserman, Gregory A.; Jones, Matthew R.; Mizgerd, Joseph P.

    2015-01-01

    Pneumonia and infection-induced sepsis are worldwide public health concerns. Both pathologies elicit systemic inflammation and induce a robust acute-phase response (APR). Although APR activation is well regarded as a hallmark of infection, the direct contributions of liver activation to pulmonary defense during sepsis remain unclear. By targeting STAT3-dependent acute-phase changes in the liver, we evaluated the role of liver STAT3 activity in promoting host defense in the context of sepsis and pneumonia. We employed a two-hit endotoxemia/pneumonia model, whereby administration of 18 h of intraperitoneal lipopolysaccharide (LPS; 5 mg/kg of body weight) was followed by intratracheal Escherichia coli (106 CFU) in wild-type mice or those lacking hepatocyte STAT3 (hepSTAT3−/−). Pneumonia alone (without endotoxemia) was effectively controlled in the absence of liver STAT3. Following endotoxemia and pneumonia, however, hepSTAT3−/− mice, with significantly reduced levels of circulating and airspace acute-phase proteins, exhibited significantly elevated lung and blood bacterial burdens and mortality. These data suggested that STAT3-dependent liver responses are necessary to promote host defense. While neither recruited airspace neutrophils nor lung injury was altered in endotoxemic hepSTAT3−/− mice, alveolar macrophage reactive oxygen species generation was significantly decreased. Additionally, bronchoalveolar lavage fluid from this group of hepSTAT3−/− mice allowed greater bacterial growth ex vivo. These results suggest that hepatic STAT3 activation promotes both cellular and humoral lung defenses. Taken together, induction of liver STAT3-dependent gene expression programs is essential to countering the deleterious consequences of sepsis on pneumonia susceptibility. PMID:26216424

  20. Activation of Hepatic STAT3 Maintains Pulmonary Defense during Endotoxemia.

    PubMed

    Hilliard, Kristie L; Allen, Eri; Traber, Katrina E; Kim, Yuri; Wasserman, Gregory A; Jones, Matthew R; Mizgerd, Joseph P; Quinton, Lee J

    2015-10-01

    Pneumonia and infection-induced sepsis are worldwide public health concerns. Both pathologies elicit systemic inflammation and induce a robust acute-phase response (APR). Although APR activation is well regarded as a hallmark of infection, the direct contributions of liver activation to pulmonary defense during sepsis remain unclear. By targeting STAT3-dependent acute-phase changes in the liver, we evaluated the role of liver STAT3 activity in promoting host defense in the context of sepsis and pneumonia. We employed a two-hit endotoxemia/pneumonia model, whereby administration of 18 h of intraperitoneal lipopolysaccharide (LPS; 5 mg/kg of body weight) was followed by intratracheal Escherichia coli (10(6) CFU) in wild-type mice or those lacking hepatocyte STAT3 (hepSTAT3(-/-)). Pneumonia alone (without endotoxemia) was effectively controlled in the absence of liver STAT3. Following endotoxemia and pneumonia, however, hepSTAT3(-/-) mice, with significantly reduced levels of circulating and airspace acute-phase proteins, exhibited significantly elevated lung and blood bacterial burdens and mortality. These data suggested that STAT3-dependent liver responses are necessary to promote host defense. While neither recruited airspace neutrophils nor lung injury was altered in endotoxemic hepSTAT3(-/-) mice, alveolar macrophage reactive oxygen species generation was significantly decreased. Additionally, bronchoalveolar lavage fluid from this group of hepSTAT3(-/-) mice allowed greater bacterial growth ex vivo. These results suggest that hepatic STAT3 activation promotes both cellular and humoral lung defenses. Taken together, induction of liver STAT3-dependent gene expression programs is essential to countering the deleterious consequences of sepsis on pneumonia susceptibility. PMID:26216424

  1. Opportunity's View on Sol 354

    NASA Technical Reports Server (NTRS)

    2005-01-01

    NASA's Mars Exploration Rover Opportunity captured this 360-degree panorama with its navigation camera on the rover's 354th martian day, or sol (Jan. 21, 2005). The view is presented as a cylindrical projection with geometric seam correction. Just to the right of center is the divot where Opportunity's heat shield hit the ground after protecting the spacecraft during descent through Mars'atmosphere. The heat shield was jettisoned about 90 seconds before Opportunity landed about 800 meters (half a mile) away. To the left of the divot is the flank portion of the heat shield debris and in the left foreground is the main wreckage of the heat shield. On the far right is a basketball-size rock dubbed 'Heat Shield Rock,' which Opportunity's inspection identified as an iron-nickel meteorite. The rim of 'Endurance Crater' is visible on the horizon on both the left and right ends of this full-circle view.

  2. STAT1-S727 - the license to kill

    PubMed Central

    Putz, Eva M.; Gotthardt, Dagmar; Sexl, Veronika

    2014-01-01

    Serine phosphorylation has generally been considered indispensable for full transcriptional activity of STAT proteins. Recent data indicate that CDK8-mediated phosphorylation of signal transducer and activator of transcription 1 (STAT1) on S727 inhibits natural killer (NK) cell cytotoxicity and restrains tumor surveillance. These findings implicate CDK8 as a promising target for immunotherapy. PMID:25941617

  3. SolTrace Optical Analysis Software

    Energy Science and Technology Software Center (ESTSC)

    2001-12-31

    SolTrace is a software package that models solar power optical systems and analyzes their performance. SolTrace can model parabolic trough collectors, point-focus concentrating systems, and power towers. It rapidly displays and saves data as scatter plots, flux maps, and performance graphs. SolTrace can model optical geometry as a series of stages, composed of optical elements that possess attributes such as shape, contour, and optical quality. It can also model any number of stages containing anymore » number of different elements, and it features an extensive variety of available shapes and contours.« less

  4. An insight into JAK-STAT signalling in dermatology.

    PubMed

    Palanivel, J A; Macbeth, A E; Chetty, N C; Levell, N J

    2014-06-01

    Many emerging studies have implicated the Janus kinase/signal transducer and activator of transcription (JAK-STAT) cytokine signalling mechanism in disease pathogenesis. This signalling pathway is involved in haematopoiesis and immune development. Mutations in genes regulating JAK-STAT signalling can cause common inflammatory disorders and myeloproliferative disorders. JAK and STAT inhibitors are new management tools for disorders such as myelofibrosis and rheumatoid arthritis. Evidence suggests that the cytokine components of the JAK-STAT pathways play a crucial role in common skin disorders, including psoriasis and atopic dermatitis. We present an overview for the clinical dermatologist of the significance of these signalling pathways in various skin disorders, and introduce the potential application of JAK and STAT inhibition as a new therapeutic tool in dermatology. PMID:24825142

  5. Propulsion Study for Small Transport Aircraft Technology (STAT)

    NASA Technical Reports Server (NTRS)

    Gill, J. C.; Earle, R. V.; Staton, D. V.; Stolp, P. C.; Huelster, D. S.; Zolezzi, B. A.

    1980-01-01

    Propulsion requirements were determined for 0.5 and 0.7 Mach aircraft. Sensitivity studies were conducted on both these aircraft to determine parametrically the influence of propulsion characteristics on aircraft size and direct operating cost (DOC). Candidate technology elements and design features were identified and parametric studies conducted to select the STAT advanced engine cycle. Trade off studies were conducted to determine those advanced technologies and design features that would offer a reduction in DOC for operation of the STAT engines. These features were incorporated in the two STAT engines. A benefit assessment was conducted comparing the STAT engines to current technology engines of the same power and to 1985 derivatives of the current technology engines. Research and development programs were recommended as part of an overall technology development plan to ensure that full commercial development of the STAT engines could be initiated in 1988.

  6. STAT3 and STAT6 Signaling Pathways Synergize to Promote Cathepsin Secretion from Macrophages via IRE1α Activation.

    PubMed

    Yan, Dongyao; Wang, Hao-Wei; Bowman, Robert L; Joyce, Johanna A

    2016-09-13

    Tumor-associated macrophages play critical roles during tumor progression by promoting angiogenesis, cancer cell proliferation, invasion, and metastasis. Cysteine cathepsin proteases, produced by macrophages and cancer cells, modulate these processes, but it remains unclear how these typically lysosomal enzymes are regulated and secreted within the tumor microenvironment. Here, we identify a STAT3 and STAT6 synergy that potently upregulates cathepsin secretion by macrophages via engagement of an unfolded protein response (UPR) pathway. Whole-genome expression analyses revealed that the TH2 cytokine interleukin (IL)-4 synergizes with IL-6 or IL-10 to activate UPR via STAT6 and STAT3. Pharmacological inhibition of the UPR sensor IRE1α blocks cathepsin secretion and blunts macrophage-mediated cancer cell invasion. Similarly, genetic deletion of STAT3 and STAT6 signaling components impairs tumor development and invasion in vivo. Together, these findings demonstrate that cytokine-activated STAT3 and STAT6 cooperate in macrophages to promote a secretory phenotype that enhances tumor progression in a cathepsin-dependent manner. PMID:27626662

  7. Different STAT transcription complexes drive early and delayed responses to type I Interferons

    PubMed Central

    Plumlee, Courtney R.; Perry, Stuart; Gu, Ai Di; Lee, Carolyn; Shresta, Sujan; Decker, Thomas; Schindler, Christian

    2015-01-01

    Interferons, which transduce pivotal signals through signal transducer and activator of transcription (Stat)1 and Stat2, effectively suppress the replication of Legionella pneumophila in primary murine macrophages. Whereas the ability of IFN-γ to impede L. pneumophila growth is fully dependent on Stat1, IFN-α/β unexpectedly suppresses L. pneumophila growth in both Stat1 and Stat2 deficient macrophages. New studies demonstrating that the robust response to IFN-α/β is lost in Stat1-Stat2 double knockout macrophages, suggest that Stat1 and Stat2 are functionally redundant in their ability to direct an innate response towards L. pneumophila. Since the ability of IFN-α/β to signal through Stat1-dependent complexes (i.e., Stat1-Stat1 and Stat1-Stat2 dimers) has been well characterized, the current studies focus on how Stat2 is able to direct a potent response to IFN-α/β in the absence of Stat1. These studies reveal that IFN-α/β is able to drive the formation of a Stat2 and IRF9 complex that drives the expression of a subset of IFN stimulated genes (ISGs), but with substantially delayed kinetics. These observations raise the possibility that this pathway evolved in response to microbes that have devised strategies to subvert Stat1 dependent responses. PMID:26019270

  8. So, Why Sol-Mi? American Music Education

    ERIC Educational Resources Information Center

    Bennett, Peggy D.

    2005-01-01

    Walk into any primary grade music class in the U.S., and you will likely hear teacher and students singing a musical greeting, such as "Good morning boys and girls" (sol-mi-mi-sol-sol-mi) and the response "Good morning Miss Purdy" (sol-mi-mi-sol-mi-mi). Since about the 1970s, teachers have been beginning and ending music class for young children…

  9. PMA activates Stat3 in the Jak/Stat pathway and induces SOCS5 in rat brain astrocytes.

    PubMed

    Hwang, Mi-Na; Kim, Kwang Soo; Choi, Yo-Woo; Jou, Ilo; Yoon, Sungpil

    2007-02-28

    Suppressors of cytokine signaling (SOCS) family members are negative feedback regulators of the Jak/Stat pathway, which is an essential inflammatory signaling pathway. We investigated expression of eight members of the SOCS family in rat astrocytes, using two inflammatory stimulants, PMA and IFN-gamma. Only a few SOCS genes were induced by both stimulants, and we detected an increase in SOCS5 protein with PMA. PMA activated the Jnk, Erk, p38, and Jak/Stat signal pathways. In addition, it increased the level of activated-Stat3 resulting from tyrosine phosphorylation. A gel-shift assay showed that a protein in nuclear extracts from PMA-treated cells was able to bind to Stat binding elements. These results suggest that activated Stat3 binds to SOCS promoters and leads to their transcriptional induction. PMID:17464217

  10. Sol-gel antireflective coating on plastics

    DOEpatents

    Ashley, C.S.; Reed, S.T.

    1988-01-26

    An antireflection film made from reliquified sol-gel hydrolyzation, condensation polymeric reaction product of a silicon, alkoxides and/or metal alkoxides, or mixtures thereof. The film is particularly useful for coating plastics.

  11. Sol-gel antireflective coating on plastics

    DOEpatents

    Ashley, Carol S.; Reed, Scott T.

    1990-01-01

    An antireflection film made from a reliquified sol-gel hydrolyzation, condensation polymeric reaction product of a silicon, alkoxides and/or metal alkoxides, or mixtures thereof. The film is particularly useful for coating plastics.

  12. Sol-gel deposited electrochromic coatings

    SciTech Connect

    Ozer, N.; Lampert, C.M.

    1995-06-01

    Electrochromic devices have increasing application in display devices, switchable mirrors and smart windows. A variety of vacuum deposition technologies have been used to make electrochromic devices. The sol- gel process offers an alternative approach to the synthesis of optical quality and low cost electrochromic device layers. This study summarizes the developments in sol-gel deposited electrochromic films. The sol-gel process involves the formation of oxide networks upon hydrolysis-condensation of alkoxide precursors. In this study we cover the sol-gel deposited oxides of WO[sub 3], V[sub 2]O[sub 5], TiO[sub 2], Nb[sub 2]O[sub 5], and NiO[sub x].

  13. Chemistry Teacher Education Coalition: Extending the PhysTEC Model to Chemistry

    NASA Astrophysics Data System (ADS)

    Kirchhoff, Mary

    2012-02-01

    The American Association of Employment in Education reports that chemistry, like physics, faces ``some shortage'' of educators. Inspired by the success of the Physics Teacher Education Coalition (PhysTEC), the American Chemical Society (ACS) is developing the Chemistry Teacher Education Coalition (CTEC) to actively engage chemistry departments in the preparation of future chemistry teachers. Engaging chemistry departments in teacher preparation would increase the number and diversity of well-prepared high school chemistry teachers while catalyzing cultural change within chemistry departments. Many features of PhysTEC, such as a grant competition to create model teacher preparation programs and regular conferences, are directly applicable to chemistry. This presentation will provide an overview of ACS efforts to launch a successful CTEC initiative.

  14. Comment on ``Hydrophobic effects on partial molar volume'' [J. Chem. Phys. 122, 094509 (2005)

    NASA Astrophysics Data System (ADS)

    Graziano, Giuseppe

    2005-10-01

    It is pointed out that the results obtained by Imai and Hirata [ J. Chem. Phys.122, 094509 (2005)] for the partial molar volume of benzene in a detailed model of water and in a hypothetical nonpolar water model should be interpreted with care. By turning off the electrostatic interactions among water molecules, keeping fixed the molar volume and so the liquid number density, in order to produce the hypothetical nonpolar water without H bonds, the size of water molecules increases from about 2.8 to about 3.2Å. This fact is due to the bunching-up effect of H bonds. The consequences of this fact are clarified by means of calculations performed using the analytical expression of the partial molar volume derived by Lee [J. Phys. Chem.87, 112 (1983)] from the scaled particle theory equation of state for hard-sphere mixtures.

  15. Improving Science Teacher Preparation through the APS PhysTEC and NSF Noyce Programs

    NASA Astrophysics Data System (ADS)

    Williams, Tasha; Tyler, Micheal; van Duzor, Andrea; Sabella, Mel

    2013-03-01

    Central to the recruitment of students into science teaching at a school like CSU, is a focus on the professional nature of teaching. The purpose of this focus is twofold: it serves to change student perceptions about teaching and it prepares students to become teachers who value continued professional development and value the science education research literature. The Noyce and PhysTEC programs at CSU place the professional nature of teaching front and center by involving students in education research projects, paid internships, attendance at conferences, and participation in a new Teacher Immersion Institute and a Science Education Journal Reading Class. This poster will focus on specific components of our teacher preparation program that were developed through these two programs. In addition we will describe how these new components provide students with diverse experiences in the teaching of science to students in the urban school district. Supported by the NSF Noyce Program (0833251) and the APS PhysTEC Program.

  16. Crater Rim Path, Sol 1,215

    NASA Technical Reports Server (NTRS)

    2007-01-01

    The route followed by NASA's Mars Exploration Rover Opportunity during its exploration partway around the rim of Victoria Crater is marked on this map. The rover first reached the edge of the crater on it's 951st Martian day, or sol (Sept. 26, 2006). This map shows travels through sol 1,215 (June 24, 2007). The underlying image is from the High Resolution Imaging Science Experiment (HiRISE) camera on NASA's Mars Reconnaissance Orbiter.

  17. Spirit 360-Degree View, Sol 388 (vertical)

    NASA Technical Reports Server (NTRS)

    2005-01-01

    NASA's Mars Exploration Rover Spirit used its navigation camera to take the images combined into this 360-degree view of the rover's surroundings on Spirit's 388th martian day, or sol (Feb. 4, 2005). Spirit had driven about 13 meters (43 feet) uphill toward 'Cumberland Ridge' on this sol. This location is catalogued as Spirit's Site 102, Position 513. The view is presented in a vertical projection with geometric and brightness seam correction.

  18. Spirit 360-Degree View, Sol 388

    NASA Technical Reports Server (NTRS)

    2005-01-01

    NASA's Mars Exploration Rover Spirit used its navigation camera to take the images combined into this 360-degree view of the rover's surroundings on Spirit's 388th martian day, or sol (Feb. 4, 2005). Spirit had driven about 13 meters (43 feet) uphill toward 'Cumberland Ridge' on this sol. This location is catalogued as Spirit's Site 102, Position 513. The view is presented in a cylindrical projection with geometric and brightness seam correction.

  19. Spirit 360-Degree View, Sol 388 (polar)

    NASA Technical Reports Server (NTRS)

    2005-01-01

    NASA's Mars Exploration Rover Spirit used its navigation camera to take the images combined into this 360-degree view of the rover's surroundings on Spirit's 388th martian day, or sol (Feb. 4, 2005). Spirit had driven about 13 meters (43 feet) uphill toward 'Cumberland Ridge' on this sol. This location is catalogued as Spirit's Site 102, Position 513. The view is presented in a cylindrical projection with geometric and brightness seam correction.

  20. Sol-Gels for Optical Sensors

    NASA Astrophysics Data System (ADS)

    Podbielska, Halina; Ulatowska-Jarża, Agnieszka; Müller, Gerhard; Eichler, Hans J.

    Sol-gel process allows for formation of glassy and ceramics materials in temperatures much lower than offered by conventional melting techniques. The first paper on sol-gels was published over 150 years ago by Ebelmen, however, the rapid development of this technology and applications occurred in the last few years. There is a broad range of possible applications of solgel derived materials, what marked this technology as one of the most promising fields of contemporary material sciences

  1. Altered interleukin-12 responsiveness in Th1 and Th2 cells is associated with the differential activation of STAT5 and STAT1.

    PubMed

    Gollob, J A; Murphy, E A; Mahajan, S; Schnipper, C P; Ritz, J; Frank, D A

    1998-02-15

    T-cell activation in response to interleukin-12 (IL-12) is mediated through signaling events that include the tyrosine phosphorylation of STAT4. IL-12 responsiveness and the ability of IL-12 to activate STAT4 is different in T cells induced to differentiate into a Th1 or Th2 phenotype. In this report, we show that STAT5, STAT1alpha, and STAT1beta, in addition to STAT4, are tyrosine phosphorylated in response to IL-12 in phytohemagglutinin (PHA)-activated human T cells. To understand how the activation of these STATs contributes to T-cell IL-12 responsiveness, we analyzed the IL-12-induced activation of STAT5 and STAT1 in T cells stimulated to undergo Th1 or Th2 differentiation. The IL-12-induced tyrosine phosphorylation of STAT5 and STAT1, but not STAT4, is augmented in T cells activated into Th1 cells with PHA + interferon-gamma (IFN-gamma) compared with T cells activated with PHA alone. STAT5 DNA binding induced by IL-12 is also augmented in T cells activated with PHA + IFN-gamma compared with T cells activated with PHA alone, whereas STAT4 DNA binding is not increased. In contrast, the IL-12-induced activation of these STATs is inhibited in T cells activated into Th2 cells with PHA + IL-4. The enhancement of IL-12 signaling by IFN-gamma is not a direct effect of IFN-gamma on T cells, but rather is mediated by IL-12 that is produced by antigen-presenting cells in response to IFN-gamma. This positive autoregulatory effect of IL-12 on the activation of select STATs correlates with an increase in T-cell IFN-gamma production in response to IL-12. These findings suggest that the activation of STAT5 and STAT1 may augment select STAT4-dependent functional responses to IL-12 in Th1 cells. PMID:9454765

  2. JAK/STAT/SOCS-signaling pathway and colon and rectal cancer

    PubMed Central

    Slattery, Martha L.; Lundgreen, Abbie; Kadlubar, Susan A.; Bondurant, Kristina L.; Wolff, Roger K.

    2012-01-01

    The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway is involved in immune function and cell growth. We evaluated the association between genetic variation in JAK1 (10 SNPs), JAK2 (9 SNPs), TYK2 (5 SNPs), SOCS1 (2 SNPs), SOCS2 (2 SNPs), STAT1 (16 SNPs), STAT2 (2 SNPs), STAT3 (6 SNPs), STAT4 (21 SNPs), STAT5A (2 SNPs), STAT5B (3 SNPs), STAT6 (4 SNPs) with risk of colorectal cancer. We used data from population-based case-control studies (colon cancer n=1555 cases, 1956 controls; rectal cancer n=754 cases, 959 controls). JAK2, SOCS2, STAT1, STAT3, STAT5A, STAT5B, and STAT6 were associated with colon cancer; STAT3, STAT4, STAT6, and TYK2 were associated with rectal cancer. Given the biological role of the JAK/STAT-signaling pathway and cytokines, we evaluated interaction with IFNG, TNF, and IL6; numerous statistically significant associations after adjustment for multiple comparisons were observed. The following statistically significant interactions were observed: TYK2 with aspirin/NSAID use; STAT1, STAT4, and TYK2 with estrogen status; and JAK2, STAT2, STAT4, STAT5A, STAT5B, and STAT6 with smoking status and colon cancer risk; JAK2, STAT6, and TYK2 with aspirin/NSAID use; JAK1 with estrogen status; STAT2 with cigarette smoking and rectal cancer. JAK2, SOCS1, STAT3, STAT5, and TYK2 were associated with colon cancer survival (HRR of 3.3 95% CI 2.01, 5.42 for high mutational load). JAK2, SOCS1, STAT1, STAT4, and TYK2 were associated with rectal cancer survival (HRR 2.80 95 %CI 1.63, 4.80). These data support the importance of the JAK/STAT-signaling pathway in colorectal cancer and suggest targets for intervention. PMID:22121102

  3. Sol-gel method for encapsulating molecules

    DOEpatents

    Brinker, C. Jeffrey; Ashley, Carol S.; Bhatia, Rimple; Singh, Anup K.

    2002-01-01

    A method for encapsulating organic molecules, and in particular, biomolecules using sol-gel chemistry. A silica sol is prepared from an aqueous alkali metal silicate solution, such as a mixture of silicon dioxide and sodium or potassium oxide in water. The pH is adjusted to a suitably low value to stabilize the sol by minimizing the rate of siloxane condensation, thereby allowing storage stability of the sol prior to gelation. The organic molecules, generally in solution, is then added with the organic molecules being encapsulated in the sol matrix. After aging, either a thin film can be prepared or a gel can be formed with the encapsulated molecules. Depending upon the acid used, pH, and other processing conditions, the gelation time can be from one minute up to several days. In the method of the present invention, no alcohols are generated as by-products during the sol-gel and encapsulation steps. The organic molecules can be added at any desired pH value, where the pH value is generally chosen to achieve the desired reactivity of the organic molecules. The method of the present invention thereby presents a sufficiently mild encapsulation method to retain a significant portion of the activity of the biomolecules, compared with the activity of the biomolecules in free solution.

  4. Novel sol-gel bioactive fibers.

    PubMed

    Oréfice, R L; Hench, L L; Clark, A E; Brennan, A B

    2001-06-15

    Bioactive fibers were produced using a sol-gel method. The rheological properties of two different sol compositions prepared from a mixture of TEOS, phosphorous alkoxide and calcium nitrate, or calcium chloride in a water-ethanol solution, are reported. The sols were extruded through a spinneret to produce continuous 10 microm-diameter fibers. Discontinuous fibers and fibrous mats were prepared by air-spraying the multicomponent sols. The sol-gel fibers were converted to the bioactive fibers by three different thermal treatments at either 600 degrees, 700 degrees, or 900 degrees C for 3 h. SEM, BET, EDX, and FTIR were used to characterize the morphology and structure of the fibers. The BET measured surface area of the fibers sintered at 900 degrees C was 0 m(2)/gm compared to a value of 200 m(2)/gm for a typical sol-gel-derived particle of similar composition. Both the continuous and discontinuous fibers exhibited in vitro bioactivity in a simulated body fluid. PMID:11288073

  5. Idiopathic pancreatitis in a patient with a STAT3 mutation

    PubMed Central

    Peppers, Brian; Frith, John; Tcheurekdjian, Haig; Hostoffer, Robert

    2016-01-01

    Background: Hyperimmunoglobulin E syndrome (HIES) is a rare primary immunodeficiency characterized by recurrent skin infections with abscesses, recurrent pneumonias with pneumatoceles, and immunoglobulin E levels of >10 times the upper limit of normal. Case: The patient described herein had a classic case of signal transducer and activator of transcription 3 (STAT3) deficiency associated with HIES diagnosed several years before this particular presentation. He demonstrated extraimmune manifestations of the disease as well, including characteristic facies and a history of skeletal fractures. In addition, the patient had several distinct episodes of idiopathic pancreatitis for which a full gastrointestinal workup had been performed. STAT3 mutation was confirmed by genotyping at the time of diagnosis of HIES. Conclusions: STAT3, a mammalian protein that regulates cell growth, survival, and differentiation, has been linked to human pancreatic carcinogenesis as well as the above-mentioned immune deficiency. Mouse studies demonstrated that genetic ablation of STAT3 exacerbates the course of acute pancreatitis, whereas normal pancreatic STAT3 seems to have a protective effect against necrotizing pancreatitis. An association between STAT3 mutations and pancreatitis has not yet been revealed in humans. Here we describe a case of acute pancreatitis that presented in a patient with STAT3 mutation. PMID:27103560

  6. Resveratrol and STAT inhibitor enhance autophagy in ovarian cancer cells

    PubMed Central

    Zhong, L-X; Zhang, Y; Wu, M-L; Liu, Y-N; Zhang, P; Chen, X-Y; Kong, Q-Y; Liu, J; Li, H

    2016-01-01

    Autophagic activity reflects cellular response to drug treatment and can be regulated by STAT3 signaling. Resveratrol inhibits STAT3 activation and causes remarkable growth arrest and cell death of ovarian cancer (OC) cells. However, the autophagic status and its relevance with resveratrol’s anti-OC effects remain unclear. We analyzed the states of autophagic activities, the nature of autophagosomes and the levels of autophagy-related proteins (LC-3, Beclin 1 and STAT3) in resveratrol-treated CAOV-3 and OVCAR-3 OC cells using multiple approaches. We elucidated the correlation of STAT3 inhibition with autophagic activity by treating OC cells with an upstream inhibitor of STAT proteins, AG490. Resveratrol efficiently suppressed growth, induced apoptosis and inactivated STAT3 signaling of the two OC cell lines. We found enhanced autophagic activity accompanied with Beclin-1 upregulation and LC3 enzymatic cleavage in resveratrol-treated OC cells. Immunofluorescent (IF) microscopic and IF-based confocal examinations demonstrated the accumulation of cytoplasmic granules co-labeled with LC3 and cytochrome C in resveratrol- or AG490-treated OC cells. Using electron microscopy, we confirmed an increase in autophagosomes and mitochondrial spheroids in either resveratrol- or AG490-treated OC cells. This study demonstrates the abilities of resveratrol to enhance apoptotic and autophagic activities in OC cells, presumably via inactivating STAT3 signaling. Resveratrol or the selective JAK2 inhibitor also leads to mitochondrial turnover, which would be unfavorable for OC cell survival and sensitize OC cells to resveratrol. PMID:27551495

  7. Inhibition of STAT5: A therapeutic option in BCR-ABL1-driven leukemia

    PubMed Central

    Berger, Angelika; Sexl, Veronika; Valent, Peter; Moriggl, Richard

    2014-01-01

    The two transcription factors STAT5A and STAT5B are central signaling molecules in leukemias driven by Abelson fusion tyrosine kinases and they fulfill all criteria of drug targets. STAT5A and STAT5B display unique nuclear shuttling mechanisms and they have a key role in resistance of leukemic cells against treatment with tyrosine kinase inhibitors (TKI). Moreover, STAT5A and STAT5B promote survival of leukemic stem cells. We here discuss the possibility of targeting up-stream kinases with TKI, direct STAT5 inhibition via SH2 domain obstruction and blocking nuclear translocation of STAT5. All discussed options will result in a stop of STAT5 transport to the nucleus to block STAT5-mediated transcriptional activity. In summary, recently described shuttling functions of STAT5 are discussed as potentially druggable pathways in leukemias. PMID:25333255

  8. Gusev Dust Devil, Sol 543

    NASA Technical Reports Server (NTRS)

    2005-01-01

    One dust devil scoots across the center of the view in this movie clip showing a few dust devils inside Mars' Gusev Crater. The clip consists of frames taken by the navigation camera on NASA's Mars Exploration Rover Spirit during the rover's 543rd martian day, or sol (July 13, 2005).

    Spirit began seeing dust devil activity around the beginning of Mars' spring season. Activity increased as spring continued, but fell off again for about two weeks during a dust storm. As the dust storm faded away, dust devil activity came back. In the mid-afternoons as the summer solstice approached, dust devils were a very common occurrence on the floor of Gusev crater. The early-spring dust devils tended to move southwest-to-northeast, across the dust devil streaks in Gusev seen from orbit. Increasingly as the season progresses, the dust devils are seen moving northwest-to-southeast, in the same direction as the streaks. Scientists are watching for the big dust devils that leave those streaks.

    In this clip, contrast has been enhanced for anything in the images that changes from frame to frame, that is, for the dust moved by wind. The total time elapsed during the taking of these frames was 8 minutes, 21 seconds.

  9. Gusev Dust Devil, sol 532

    NASA Technical Reports Server (NTRS)

    2005-01-01

    This movie clip shows a dust devil seen by NASA's Mars Exploration Rover Spirit during the rover's 532nd martian day, or sol (July 2, 2005). The dust-carrying whirlwind is moving across a plain inside Gusev Crater and viewed from Spirit's vantage point on hills rising from the plain. The clip consists of frames taken by Spirit's navigation camera, processed to enhance contrast for anything in the images that changes from frame to frame. The total elapsed time during the taking of these frames was 8 minutes, 48 seconds.

    Spirit began seeing dust devil activity around the beginning of Mars' spring season. Activity increased as spring continued, but fell off again for about two weeks during a dust storm. As the dust storm faded away, dust devil activity came back. In the mid-afternoons as the summer solstice approached, dust devils were a very common occurrence on the floor of Gusev crater. The early-spring dust devils tended to move southwest-to-northeast, across the dust devil streaks in Gusev seen from orbit. Increasingly as the season progresses, the dust devils are seen moving northwest-to-southeast, in the same direction as the streaks. Scientists are watching for the big dust devils that leave those streaks.

  10. Coherent Structures in the SOL

    NASA Astrophysics Data System (ADS)

    Aydemir, A. Y.

    2004-11-01

    Long-time simulations of density ``blobs'' in the tokamak scrape-off layer show that most cannot be categorized as ``coherent structures.'' Born near the separatrix, blobs are expected to propagate a distance 5-10 times their own linear dimensions before reaching the chamber walls. Using a simple two-field model commonly used in the literature, we find that small, fast-moving blobs go unstable to Kelvin-Helmholtz modes, as also observed by previous workers. Nonlinearly, these modes lead to repeated vortex-shedding, with its accompanying mass loss, leaving behind only a small fraction of the original blob mass. Large, slow-moving blobs, on the other hand, tend to be unstable to Rayleigh-Taylor modes. The ``RT Fingers'' quickly and violently break up the blob into smaller filaments that continue to propagate radially as they spread the mass poloidally. In this case, only a diffuse cloud of particles makes it to the wall. Blobs of the ``correct size'', however, do behave coherently, retaining most of their original mass. These coherent structures exhibit a steepened leading edge that remains KH-stable, and a long tail. Together, these characteristics agree with the experimental observations for ``intermittent-events'' in the SOL with steep rise and slow decay times. Extension of this work to 3D using a more sophisticated physics-model is being contemplated.

  11. Hyperactivated Stat3 boosts axon regeneration in the CNS.

    PubMed

    Mehta, Saloni T; Luo, Xueting; Park, Kevin K; Bixby, John L; Lemmon, Vance P

    2016-06-01

    Axonal regeneration after spinal cord injury (SCI) is intrinsically and extrinsically inhibited by multiple factors. One major factor contributing to intrinsic regeneration failure is the inability of mature neurons in the central nervous system (CNS) to activate regeneration-associated transcription factors (TFs) post-injury. A prior study identified TFs overexpressed in neurons of the peripheral nervous system (PNS) compared to the CNS; some of these could be involved in the ability of PNS neurons to regenerate. Of these, signal transducer and activator of transcription 3 (STAT3), as well its downstream regeneration-associated targets, showed a significant upregulation in PNS neurons relative to CNS neurons, and a constitutively active variant of Stat3 (Stat3CA) promoted neurite growth when expressed in cerebellar neurons (Lerch et al., 2012; Smith et al., 2011). To further enhance STAT3's neurite outgrowth enhancing activity, Stat3CA was fused with a viral activation domain (VP16). VP16 hyperactivates TFs by recruiting transcriptional co-factors to the DNA binding domain (Hirai et al., 2010). Overexpression of this VP16-Stat3CA chimera in primary cortical neurons led to a significant increase of neurite outgrowth as well as Stat3 transcriptional activity in vitro. Furthermore, in vivo transduction of retinal ganglion cells (RGCs) with AAV constructs expressing VP16-Stat3CA resulted in regeneration of optic nerve axons after injury, to a greater degree than for those expressing Stat3CA alone. These findings confirm and extend the concept that overexpression of hyperactivated transcription factors identified as functioning in PNS regeneration can promote axon regeneration in the CNS. PMID:27060489

  12. B lymphocytes from patients with chronic lymphocytic leukemia contain signal transducer and activator of transcription (STAT) 1 and STAT3 constitutively phosphorylated on serine residues.

    PubMed

    Frank, D A; Mahajan, S; Ritz, J

    1997-12-15

    To explore the pathogenesis of chronic lymphocytic leukemia (CLL), we examined whether phosphorylation of one or more signal transducer and activator of transcription (STAT) factors was abnormal in cells from CLL patients. No constitutive tyrosine phosphorylation was detected on any STAT in CLL cells. To assess the phosphorylation of serine residues of STAT1 and STAT3 in CLL cells, we raised antibodies that specifically recognize the form of STAT1 phosphorylated on ser-727 and the form of STAT3 phosphorylated on ser-727. We found that in 100% of patients with CLL (n = 32), STAT1 and STAT3 were constitutively phosphorylated on serine. This was in contrast to normal peripheral blood B lymphocytes or CD5+) B cells isolated from tonsils, in which this phosphorylation was absent. Serine phosphorylation of STAT1 and STAT3 was seen occasionally in other leukemias, but it was a universal finding only in CLL. The serine phosphorylation of these STATs was a continuous process, as incubation of CLL cells with the kinase inhibitor H7 led to the dephosphorylation of these serine residues. The STAT serine kinase in CLL cells has not been identified, and appears to be neither mitogen-activated protein kinase nor pp70(s6k). In summary, the constitutive serine phosphorylation of STAT1 and STAT3 is present in all CLL samples tested to date, although the physiologic significance of this modification remains to be determined. PMID:9399961

  13. A membrane penetrating peptide aptamer inhibits STAT3 function and suppresses the growth of STAT3 addicted tumor cells

    PubMed Central

    Borghouts, Corina; Delis, Natalia; Brill, Boris; Weiss, Astrid; Mack, Laura; Lucks, Peter; Groner, Bernd

    2012-01-01

    Cancer cells are characterized by the aberrant activation of signaling pathways governing proliferation, survival, angiogenesis, migration and immune evasion. These processes are partially regulated by the transcription factor STAT3. This factor is inappropriately activated in diverse tumor types. Since tumor cells can become dependent on its persistent activation, STAT3 is a favorable drug target. Here, we describe the functional characterization of the recombinant STAT3 inhibitor, rS3-PA. This inhibitor is based on a 20 amino acid peptide which specifically interacts with the dimerization domain of STAT3. It is integrated into a thioredoxin scaffold and fused to a protein transduction domain. Protein gel blot and immunofluorescence analyses showed that rS3-PA is efficiently taken up by cells via an endocytosis independent mechanism. Intracellularly, it reduces the phosphorylation of STAT3 and enhances its degradation. This leads to the downregulation of STAT3 target gene expression on the mRNA and protein levels. Subsequently, tumor cell proliferation, survival and migration and the induction of angiogenesis are inhibited. In contrast, normal cells remain unaffected. Systemic administration of rS3-PA at doses of 7.5 mg/kg reduced P-STAT3 levels and significantly inhibited tumor growth up to 35% in a glioblastoma xenograft mouse model. PMID:24058750

  14. FastStats: Health of Mexican American Population

    MedlinePlus

    ... Death Life Expectancy Race and Ethnicity Health of American Indian or Alaska Native Population Health of Asian or ... 1 [PDF - 993 KB] Related FastStats Health of American Indian or Alaska Native Population Health of Asian or ...

  15. IL-6 blockade reverses the abnormal STAT activation of peripheral blood leukocytes from rheumatoid arthritis patients.

    PubMed

    Ortiz, M A; Diaz-Torné, C; Hernández, M V; Reina, D; de la Fuente, D; Castellví, I; Moya, P; Ruiz, J M; Corominas, H; Zamora, C; Cantó, E; Sanmartí, R; Juarez, C; Vidal, S

    2015-06-01

    Considering the interplay of multiple STATs in response to cytokines, we investigated how IL-6 and its blocking affect STAT signaling in rheumatoid arthritis (RA). Leukocytes obtained from RA patients before and after tocilizumab treatment and healthy donors (HDs) were cytokine-stimulated and STAT phosphorylation was analyzed by cytometry. RA patients had significantly fewer pSTAT1+, pSTAT3+, and pSTAT6+ monocytes and pSTAT5+ lymphocytes than HDs. After 24weeks of treatment, percentages of IFNγ-induced pSTAT1+ and IL-10-induced pSTAT3+ monocytes in RA patients increased, reaching levels comparable to HDs. pSTAT1+ and pSTAT3+ cells correlated inversely with RA disease activity index and levels of pSTAT+ cells at baseline were higher in patients with good EULAR response to tocilizumab. IFNγ-induced pSTAT1+ cells correlated inversely with memory T cells and anti-CCP levels. IL-10-induced pSTAT3+ cells correlated with Treg/Teff ratio. Our findings suggest that IL-6 blocking reduces the inflammatory mechanisms through the correction of STAT1 and STAT3 activation status. PMID:25847223

  16. Using the PhysX engine for Physics-based Virtual Surgery with Force Feedback

    PubMed Central

    Maciel, Anderson; Halic, Tansel; Lu, Zhonghua; Nedel, Luciana P.; De, Suvranu

    2010-01-01

    Background The development of modern surgical simulators is highly challenging as they must support complex simulation environments. The demand for higher realism in such simulators has driven researchers to adopt physics-based models which are computationally very demanding. This poses a major problem since real time interactions must permit graphical updates of 30 Hz and a much higher rate of 1 kHz for force feedback (haptics). Recently several physics engines have been developed which offer multi-physics simulation capabilities including rigid and deformable bodies, cloth and fluids. While such physics engines provide unique opportunities for the development of surgical simulators, their higher latencies, compared to what is necessary for real time graphics and haptics, offer significant barriers to their use in interactive simulation environments. Methods In this work, we propose solutions to this problem and demonstrate how a multimodal surgical simulation environment may be developed based on NVIDIA’s PhysX physics library. Hence, models that are undergoing relatively low frequency updates in PhysX can exist in an environment that demands much higher frequency updates for haptics. We use a collision handling layer to interface between the physical response provided by PhysX and the haptic rendering device to provide both real time tissue response and force feedback. Results Our simulator integrates a bimanual haptic interface for force-feedback and per-pixel shaders for graphics realism in real time. To demonstrate the effectiveness of our approach, we present the simulation of the Laparoscopic Adjustable Gastric Banding (LAGB) procedure as a case study. Conclusions To develop complex and realistic surgical trainers with realistic organ geometries and tissue properties demands stable physics-based deformation methods which are not always compatible with the interaction level required for such trainers. We have shown that combining different modeling

  17. Somatic STAT3 Mutations in Large Granular Lymphocytic Leukemia

    PubMed Central

    Koskela, Hanna L.M.; Eldfors, Samuli; Ellonen, Pekka; van Adrichem, Arjan J.; Kuusanmäki, Heikki; Andersson, Emma I.; Lagström, Sonja; Clemente, Michael J.; Olson, Thomas; Jalkanen, Sari E.; Majumder, Muntasir Mamun; Almusa, Henrikki; Edgren, Henrik; Lepistö, Maija; Mattila, Pirkko; Guinta, Kathryn; Koistinen, Pirjo; Kuittinen, Taru; Penttinen, Kati; Parsons, Alun; Knowles, Jonathan; Saarela, Janna; Wennerberg, Krister; Kallioniemi, Olli; Porkka, Kimmo; Loughran, Thomas P.; Heckman, Caroline A.; Maciejewski, Jaroslaw P.; Mustjoki, Satu

    2013-01-01

    BACKGROUND T-cell large granular lymphocytic leukemia is a rare lymphoproliferative disorder characterized by the expansion of clonal CD3+CD8+ cytotoxic T lymphocytes (CTLs) and often associated with autoimmune disorders and immune-mediated cytopenias. METHODS We used next-generation exome sequencing to identify somatic mutations in CTLs from an index patient with large granular lymphocytic leukemia. Targeted resequencing was performed in a well-characterized cohort of 76 patients with this disorder, characterized by clonal T-cell–receptor rearrangements and increased numbers of large granular lymphocytes. RESULTS Mutations in the signal transducer and activator of transcription 3 gene (STAT3) were found in 31 of 77 patients (40%) with large granular lymphocytic leukemia. Among these 31 patients, recurrent mutational hot spots included Y640F in 13 (17%), D661V in 7 (9%), D661Y in 7 (9%), and N647I in 3 (4%). All mutations were located in exon 21, encoding the Src homology 2 (SH2) domain, which mediates the dimerization and activation of STAT protein. The amino acid changes resulted in a more hydrophobic protein surface and were associated with phosphorylation of STAT3 and its localization in the nucleus. In vitro functional studies showed that the Y640F and D661V mutations increased the transcriptional activity of STAT3. In the affected patients, downstream target genes of the STAT3 pathway (IFNGR2, BCL2L1, and JAK2) were up-regulated. Patients with STAT3 mutations presented more often with neutropenia and rheumatoid arthritis than did patients without these mutations. CONCLUSIONS The SH2 dimerization and activation domain of STAT3 is frequently mutated in patients with large granular lymphocytic leukemia; these findings suggest that aberrant STAT3 signaling underlies the pathogenesis of this disease. (Funded by the Academy of Finland and others.) PMID:22591296

  18. Development of T-STAT for Early Autism Screening

    ERIC Educational Resources Information Center

    Chiang, Chung-Hsin; Wu, Chin-Chin; Hou, Yuh-Ming; Chu, Ching-Lin; Liu, Jiun-Horng; Soong, Wei-Tsuen

    2013-01-01

    This study's purpose was to modify the Screening Tool for Autism in Two-Year-Olds (STAT) into a Taiwanese version called T-STAT. Study 1 included 15 children with Autism and 15 children with Developmental Delay (DD) or language impairment (LI) aged between 24 and 35 months. Study 2 had 77 young children with Autism, PDD-NOS, or DD/LI as a…

  19. Comment on 'General nonlocality in quantum fields'[J. Math. Phys. 49, 033513 (2008)

    SciTech Connect

    Wang Haijun

    2010-05-15

    In a recent paper [H.-J. Wang, J. Math. Phys. 49, 033513 (2008)] a complex-geometry model was proposed to interpret the interaction of electromagnetism and the interaction between quarks while the nonlocal effects are involved. In that theoretical frame, from the metric matrix one can obtain a determinant-form condition to describe qualitatively the typical characteristics for the aforementioned interactions. In this comment we attempt to extend this kind of qualitative description to weak interaction by finding out an appropriate metric tensor for it.

  20. Comment on ``Quasirelativistic theory equivalent to fully relativistic theory'' [J. Chem. Phys. 123, 241102 (2005)

    NASA Astrophysics Data System (ADS)

    Filatov, Michael

    2006-09-01

    The connection between the exact quasirelativistic approach developed in the title reference [W. Kutzelnigg and W. Liu, J. Chem. Phys. 123, 241102 (2005)] and the method of elimination of the small component in matrix form developed previously by Dyall is explicitly worked out. An equation that links Hermitian and non-Hermitian formulations of the exact quasirelativistic theory is derived. Besides establishing a kinship between the existing formulations, the proposed equation can be employed for the derivation of new formulations of the exact quasirelativistic theory.

  1. Toward sol-gel-based sensors

    SciTech Connect

    Jordan, J.D.; Ingersoll, C.M.; Dunbar, R.A.

    1995-12-31

    Advances in biotechnology have produced a variety of antibodies and other biomolecules that possess selective recognition capabilities. Current techniques for the immobilization of these biomolecules typically involve multistep derivatization of a primary substrate, which is labor intensive and often requires large volumes of costly reagents. Further, these immobilization chemistries often adversely affect the characteristic properties of the protein (e.g., the binding affinity). As a result, the need for fast, accurate, inexpensive, and simple to operate diagnostic assays escalates. Because of their room temperature processing, transparency, inertness, and tunable pore structure, sol-gel-derived composites represent promising chemical and biosensing platforms. To date, many researchers have entrapped proteins and enzymes in sol-gel monoliths, and found that they retain some of their native properties. Our group first reported on the affinity of a sol-gel entrapped antibody. However, although these biogel monoliths were promising, analyte diffusion through the monolith matrix is slow, resulting in long response times. Thus, it is clear that the next level of sol-gel-derived biosensor must depend on thin film technology. In the current work, the affinity of fluorescein entrapped within a sol-gel derived thin film for the anti fluorescent hapten, 5- (and 6-)-carboxy 4{prime}, 5{prime}-dimethylfluorescein, is investigated. A novel film preparation technique will be introduced, and the response and response times of these films as a function of processing and storage conditions will be discussed.

  2. Digging Movie from Phoenix's Sol 18

    NASA Technical Reports Server (NTRS)

    2008-01-01

    The Surface Stereo Imager on NASA's Phoenix Mars Lander recorded the images combined into this movie of the lander's Robotic Arm enlarging and combining the two trenches informally named 'Dodo' (left) and 'Goldilocks.'

    The 21 images in this sequence were taken over a period of about 2 hours during Phoenix's Sol 18 (June 13, 2008), or the 18th Martian day since landing.

    The main purpose of the Sol 18 dig was to dig deeper for learning the depth of a hard underlying layer. A bright layer, possibly ice, was increasingly exposed as the digging progressed. Further digging and scraping in the combined Dodo-Goldilocks trench was planned for subsequent sols.

    The combined trench is about 20 centimeters (about 8 inches) wide. The depth at the end of the Sol 18 digging is 5 to 6 centimeters (about 2 inches).

    The Goldilocks trench was the source of soil samples 'Baby Bear' and 'Mama Bear,' which were collected on earlier sols and delivered to instruments on the lander deck. The Dodo trench was originally dug for practice in collecting and depositing soil samples.

    The Phoenix Mission is led by the University of Arizona, Tucson, on behalf of NASA. Project management of the mission is by NASA's Jet Propulsion Laboratory, Pasadena, Calif. Spacecraft development is by Lockheed Martin Space Systems, Denver.

  3. Deletion of Intestinal Epithelial Cell STAT3 Promotes T Lymphocyte STAT3 Activation and Chronic Colitis Following Acute Dextran Sodium Sulfate Injury in Mice

    PubMed Central

    Willson, Tara A.; Jurickova, Ingrid; Collins, Margaret; Denson, Lee A.

    2015-01-01

    BACKGROUND Intestinal epithelial cell (IEC) Stat3 is required for wound healing following acute Dextran Sodium Sulfate (DSS) injury. We hypothesized that loss of IEC STAT3 would promote the development of chronic colitis following acute DSS injury. METHODS Colitis was induced in IEC-specific Stat3 deficient mice (Stat3ΔIEC) and littermate controls (Stat3Flx/Flx) with 4%DSS for 7 days, followed by water consumption for 21 days. Epithelial and immune mediators and severity of colitis were determined. RESULTS Survival, colon length, and histologic injury were significantly worse at day 28 in Stat3ΔIEC mice. IEC proliferation and apoptosis did not vary by genotype at day 14 or day 28. The colonic lamina propria frequency of pSTAT3+ cells was increased at day 28 and correlated with histologic injury in Stat3ΔIEC mice. The frequency of colonic F480+pSTAT3+ macrophages and CD3+pSTAT3+ T-lymphocytes were increased in Stat3ΔIEC mice as compared to Stat3Flx/Flx controls. In Stat3ΔIEC mice, colonic expression of Stat3 target genes Reg3β and Reg3γ which mediate epithelial restitution were significantly decreased, while expression of IL-17a, IFNγ, CXCL2, CXCL10, and CCL2 were significantly increased and correlated with the increase in histologic severity at Day 28(p<.05). IL-17a expression also correlated with the increased lamina propria frequency of CD3+pSTAT3+ T-lymphocytes. CONCLUSIONS Loss of intestinal epithelial Stat3 leads to more severe chronic inflammation following acute injury which is not accounted for by a sustained defect in epithelial proliferation or apoptosis 7 or 21 days after one cycle of DSS but rather defective REG3 expression and expansion of pSTAT3+ lymphocytes and IL-17a expression. PMID:23429443

  4. Cooperative DNA Binding and Sequence-Selective Recognition Conferred by the STAT Amino-Terminal Domain

    NASA Astrophysics Data System (ADS)

    Xu, Xiang; Sun, Ya-Lin; Hoey, Timothy

    1996-08-01

    STAT proteins (signal transducers and activators of transcription) activate distinct target genes despite having similar DNA binding preferences. The transcriptional specificity of STAT proteins was investigated on natural STAT binding sites near the interferon-gamma gene. These sites are arranged in multiple copies and required cooperative interactions for STAT binding. The conserved amino-terminal domain of STAT proteins was required for cooperative DNA binding, although this domain was not essential for dimerization or binding to a single site. Cooperative binding interactions enabled the STAT proteins to recognize variations of the consensus site. These sites can be specific for the different STAT proteins and may function to direct selective transcriptional activation.

  5. STAT Signaling in Different Breast Cancer Sub-types

    PubMed Central

    Furth, Priscilla A.

    2013-01-01

    This review summarizes information on expression of Signal Transducer and Activator of Transcription (STAT)s 1, 2, 3, 4, 5a/b and 6 in cancer cells from different human breast cancer sub-types. STAT proteins, especially STATs 1,3 and 5a/b are expressed in some but not all cancers from all of the different major breast cancer sub-types. However, well-designed studies comparing expression patterns at the protein level in cancer and surrounding stromal cells are still needed to fully examine links with prognosis and therapeutic response. Moreover, it is not yet known if distinct expression patterns of STAT proteins could have dissimilar impacts in different sub-types, especially between the luminal A and B ER+ sub-types and the different TNBC sub-types. Recent data indicating that STAT5 can be activated secondary to a therapeutic intervention and mediate resistance suggests that expression patterns should not only be examined in pre-treatment but also post-treatment samples from different sub-types. PMID:23562422

  6. Stat1 Nuclear Translocation by Nucleolin upon Monocyte Differentiation

    PubMed Central

    Jerke, Uwe; Tkachuk, Sergey; Kiyan, Julia; Stepanova, Victoria; Kusch, Angelika; Hinz, Michael; Dietz, Rainer; Haller, Hermann; Fuhrman, Bianca; Dumler, Inna

    2009-01-01

    Background Members of the signal transducer and activator of transcription (Stat) family of transcription factors traverse the nuclear membrane through a specialized structure, called the nuclear pore complex (NPC), which represents a selective filter for the import of proteins. Karyophilic molecules can bind directly to a subset of proteins of the NPC, collectively called nucleoporins. Alternatively, the transport is mediated via a carrier molecule belonging to the importin/karyopherin superfamily, which transmits the import into the nucleus through the NPC. Methodology/Principal Findings In this study, we provide evidence for an alternative Stat1 nuclear import mechanism, which is mediated by the shuttle protein nucleolin. We observed Stat1-nucleolin association, nuclear translocation and specific binding to the regulatory DNA element GAS. Using expression of nucleolin transgenes, we found that the nuclear localization signal (NLS) of nucleolin is responsible for Stat1 nuclear translocation. We show that this mechanism is utilized upon differentiation of myeloid cells and is specific for the differentiation step from monocytes to macrophages. Conclusions/Significance Our data add the nucleolin-Stat1 complex as a novel functional partner for the cell differentiation program, which is uniquely poised to regulate the transcription machinery via Stat1 and nuclear metabolism via nucleolin. PMID:20011528

  7. STAT signaling in mammary gland differentiation, cell survival and tumorigenesis

    PubMed Central

    Haricharan, S; Li, Y

    2013-01-01

    The mammary gland is a unique organ that undergoes extensive and profound changes during puberty, menstruation, pregnancy, lactation and involution. The changes that take place during puberty involve large-scale proliferation and invasion of the fat-pad. During pregnancy and lactation, the mammary cells are exposed to signaling pathways that inhibit apoptosis, induce proliferation and invoke terminal differentiation. Finally, during involution the mammary gland is exposed to milk stasis, programed cell death and stromal reorganization to clear the differentiated milk-producing cells. Not surprisingly, the signaling pathways responsible for bringing about these changes in breast cells are often subverted during the process of tumorigenesis. The STAT family of proteins is involved in every stage of mammary gland development, and is also frequently implicated in breast tumorigenesis. While the roles of STAT3 and STAT5 during mammary gland development and tumorigenesis are well studied, others members, e.g. STAT1 and STAT6, have only recently been observed to play a role in mammary gland biology. Continued investigation into the STAT protein network in the mammary gland will likely yield new biomarkers and risk factors for breast cancer, and may also lead to novel prophylactic or therapeutic strategies against breast cancer. PMID:23541951

  8. STAT3 in the systemic inflammation of cancer cachexia.

    PubMed

    Zimmers, Teresa A; Fishel, Melissa L; Bonetto, Andrea

    2016-06-01

    Weight loss is diagnostic of cachexia, a debilitating syndrome contributing mightily to morbidity and mortality in cancer. Most research has probed mechanisms leading to muscle atrophy and adipose wasting in cachexia; however cachexia is a truly systemic phenomenon. Presence of the tumor elicits an inflammatory response and profound metabolic derangements involving not only muscle and fat, but also the hypothalamus, liver, heart, blood, spleen and likely other organs. This global response is orchestrated in part through circulating cytokines that rise in conditions of cachexia. Exogenous Interleukin-6 (IL6) and related cytokines can induce most cachexia symptomatology, including muscle and fat wasting, the acute phase response and anemia, while IL-6 inhibition reduces muscle loss in cancer. Although mechanistic studies are ongoing, certain of these cachexia phenotypes have been causally linked to the cytokine-activated transcription factor, STAT3, including skeletal muscle wasting, cardiac dysfunction and hypothalamic inflammation. Correlative studies implicate STAT3 in fat wasting and the acute phase response in cancer cachexia. Parallel data in non-cancer models and disease states suggest both pathological and protective functions for STAT3 in other organs during cachexia. STAT3 also contributes to cancer cachexia through enhancing tumorigenesis, metastasis and immune suppression, particularly in tumors associated with high prevalence of cachexia. This review examines the evidence linking STAT3 to multi-organ manifestations of cachexia and the potential and perils for targeting STAT3 to reduce cachexia and prolong survival in cancer patients. PMID:26860754

  9. Differential Contribution of IL-4 and STAT6 vs STAT4 to the Development of Lupus Nephritis1

    PubMed Central

    Singh, Ram Raj; Saxena, Vijay; Zang, Song; Li, Lily; Finkelman, Fred D.; Witte, David P.; Jacob, Chaim O.

    2008-01-01

    Mechanisms that initiate lupus nephritis and cause progression to end-stage renal disease remain poorly understood. In this study, we show that lupus-prone New Zealand Mixed 2410 mice that develop a severe glomerulosclerosis and rapidly progressive renal disease overexpress IL-4 in vivo. In these mice, STAT6 deficiency or anti-IL-4 Ab treatment decreases type 2 cytokine responses and ameliorates kidney disease, particularly glomerulosclerosis, despite the presence of high levels of IgG anti-dsDNA Abs. STAT4 deficiency, however, decreases type 1 and increases type 2 cytokine responses, and accelerates nephritis, in the absence of high levels of IgG anti-dsDNA Abs. Thus, STAT6 and IL-4 may selectively contribute to the development of glomerulosclerosis, whereas STAT4 may play a role in autoantibody production. PMID:12707364

  10. Upgrades for TwinSol facility

    NASA Astrophysics Data System (ADS)

    O'Malley, P. D.; Bardayan, D. W.; Kolata, J. J.; Hall, M. R.; Hall, O.; Allen, J.; Becchetti, F. D.

    2016-06-01

    TwinSol, a pair of coupled, superconducting solenoids, was one of the first devices capable of producing beams of radioactive nuclei at energies near the Coulomb barrier. A primary beam from University of Notre Dame (UND) tandem accelerator is used to bombard a primary target producing a secondary beam in flight. TwinSol is used to gather, separate, and focus the recoils. Since it was commissioned at the UND in 1997, at least 58 publications have reported data from its use and there have been hundreds of collaborators from many different countries that use this device. Currently, plans are in place at the UND to provide several upgrades to TwinSol, including a multi-cell gas production target and the possible addition of a third solenoid. Upgrades currently in progress will be discussed along with future plans.

  11. Opportunity's Surroundings on Sol 1687 (Polar)

    NASA Technical Reports Server (NTRS)

    2009-01-01

    NASA's Mars Exploration Rover Opportunity used its navigation camera to take the images combined into this 360-degree view of the rover's surroundings on the 1,687th Martian day, or sol, of its surface mission (Oct. 22, 2008).

    Opportunity had driven 133 meters (436 feet) that sol, crossing sand ripples up to about 10 centimeters (4 inches) tall. The tracks visible in the foreground are in the east-northeast direction.

    Opportunity's position on Sol 1687 was about 300 meters southwest of Victoria Crater. The rover was beginning a long trek toward a much larger crater, Endeavour, about 12 kilometers (7 miles) to the southeast.

    This view is presented as a polar projection with geometric seam correction.

  12. Before & After of Rasping on Sol 56

    NASA Technical Reports Server (NTRS)

    2008-01-01

    This animation combines two images of the trench informally named 'Snow White' taken by the Surface Stereo Imager on NASA's Phoenix Mars Lander on July 21, 2008, during the lander's 56th Martian day, or sol, since landing.

    The earlier Sol 56 image is the one without a shadow falling across the lower right corner of the image. It was taken after Phoenix had used its motorized rasp to get some material from the trench into the scoop on the lander's robotic arm. The later Sol 56 image was taken after the arm had scraped clean an area that includes the rasping site.

    The trench is about 23 centimeters (9 inches) wide. These images were taken through the camera's red filter.

    The Phoenix Mission is led by the University of Arizona, Tucson, on behalf of NASA. Project management of the mission is led by NASA's Jet Propulsion Laboratory, Pasadena, Calif. Spacecraft development is by Lockheed Martin Space Systems, Denver.

  13. Opportunity's Surroundings on Sol 1687 (Vertical)

    NASA Technical Reports Server (NTRS)

    2009-01-01

    NASA's Mars Exploration Rover Opportunity used its navigation camera to take the images combined into this 360-degree view of the rover's surroundings on the 1,687th Martian day, or sol, of its surface mission (Oct. 22, 2008).

    Opportunity had driven 133 meters (436 feet) that sol, crossing sand ripples up to about 10 centimeters (4 inches) tall. The tracks visible in the foreground are in the east-northeast direction.

    Opportunity's position on Sol 1687 was about 300 meters southwest of Victoria Crater. The rover was beginning a long trek toward a much larger crater, Endeavour, about 12 kilometers (7 miles) to the southeast.

    This view is presented as a vertical projection with geometric seam correction.

  14. Comment on ``Undamped electrostatic plasma waves'' [Phys. Plasmas 19, 092103 (2012)

    NASA Astrophysics Data System (ADS)

    Schamel, Hans

    2013-03-01

    The relevance of linear "corner modes" for the description of coherent electrostatic structures, as proposed by Valentini et al. [Phys. Plasmas 19, 092103 (2012)], is questioned. Coherency in their on-dispersion simulation is instead found to be caused by particle trapping in agreement with Schamel's nonlinear wave model [Phys. Plasmas 19, 020501 (2012)]. The revealed small amplitude structures are hence of cnoidal electron hole type exhibiting vortices in phase space. They are ruled by trapping nonlinearity rather than by linearity or quasi-linear effects, as commonly assumed. Arguments are presented, which give preference to these cnoidal hole modes over Bernstein-Greene-Kruskal modes. To fully account for a realistic theoretical scenario, however, at least four ingredients are mandatory. Several corrections of the conventional body of thought about the proper kinetic wave description are proposed. They may prove useful for the general acceptance of this "new" nonlinear wave concept concerning structure formation, updating several prevailing concepts such as the general validity of a linear wave Ansatz for small amplitudes, as assumed in their paper. It is conjectured that this nonlinear trapping model can be generalized to the vortex structures of similar type found in the more general setting of driven turbulence of magnetized plasmas. They appear as eddies in both, the phase and the position spaces, embedded intermittently on the Debye length scale.

  15. Structural basis for recruitment of CBP/p300 coactivators by STAT1 and STAT2 transactivation domains

    PubMed Central

    Wojciak, Jonathan M; Martinez-Yamout, Maria A; Dyson, H Jane; Wright, Peter E

    2009-01-01

    CBP/p300 transcriptional coactivators mediate gene expression by integrating cellular signals through interactions with multiple transcription factors. To elucidate the molecular and structural basis for CBP-dependent gene expression, we determined structures of the CBP TAZ1 and TAZ2 domains in complex with the transactivation domains (TADs) of signal transducer and activator of transcription 2 (STAT2) and STAT1, respectively. Despite the topological similarity of the TAZ1 and TAZ2 domains, subtle differences in helix packing and surface grooves constitute major determinants of target selectivity. Our results suggest that TAZ1 preferentially binds long TADs capable of contacting multiple surface grooves simultaneously, whereas smaller TADs that are restricted to a single contiguous binding surface form complexes with TAZ2. Complex formation for both STAT TADs involves coupled folding and binding, driven by intermolecular hydrophobic and electrostatic interactions. Phosphorylation of S727, required for maximal transcriptional activity of STAT1, does not enhance binding to any of the CBP domains. Because the different STAT TADs recognize different regions of CBP/p300, there is a potential for multivalent binding by STAT heterodimers that could enhance the recruitment of the coactivators to promoters. PMID:19214187

  16. Neutron detector using sol-gel absorber

    SciTech Connect

    Hiller, J.M.; Wallace, S.A.; Dai, S.

    1999-10-26

    An neutron detector composed of fissionable material having ions of lithium, uranium, thorium, plutonium, or neptunium, contained within a glass film fabricated using a sol-gel method combined with a particle detector is disclosed. When the glass film is bombarded with neutrons, the fissionable material emits fission particles and electrons. Prompt emitting activated elements yielding a high energy electron contained within a sol-gel glass film in combination with a particle detector is also disclosed. The emissions resulting from neutron bombardment can then be detected using standard UV and particle detection methods well known in the art, such as microchannel plates, channeltrons, and silicon avalanche photodiodes.

  17. Neutron detector using sol-gel absorber

    DOEpatents

    Hiller, John M.; Wallace, Steven A.; Dai, Sheng

    1999-01-01

    An neutron detector composed of fissionable material having ions of lithium, uranium, thorium, plutonium, or neptunium, contained within a glass film fabricated using a sol-gel method combined with a particle detector is disclosed. When the glass film is bombarded with neutrons, the fissionable material emits fission particles and electrons. Prompt emitting activated elements yielding a high energy electron contained within a sol-gel glass film in combination with a particle detector is also disclosed. The emissions resulting from neutron bombardment can then be detected using standard UV and particle detection methods well known in the art, such as microchannel plates, channeltrons, and silicon avalanche photodiodes.

  18. Spirit 360-Degree View on Sol 409

    NASA Technical Reports Server (NTRS)

    2005-01-01

    NASA's Mars Exploration Rover Spirit used its navigation camera to take the images combined into this 360-degree view of the rover's surroundings on Spirit's 409th martian day, or sol (Feb. 26, 2005). Spirit had driven 2 meters (7 feet) on this sol to get in position on 'Cumberland Ridge' for looking into 'Tennessee Valley' to the east. This location is catalogued as Spirit's Site 108. Rover-wheel tracks from climbing the ridge are visible on the right. The summit of 'Husband Hill' is at the center, to the south. This view is presented in a cylindrical projection with geometric and brightness seam correction.

  19. Spirit Beside 'Home Plate,' Sol 1809

    NASA Technical Reports Server (NTRS)

    2009-01-01

    NASA Mars Exploration Rover Spirit used its navigation camera to take the images assembled into this 120-degree view southward after a short drive during the 1,809th Martian day, or sol, of Spirit's mission on the surface of Mars (February 3, 2009).

    Spirit had driven about 2.6 meters (8.5 feet) that sol, continuing a clockwise route around a low plateau called 'Home Plate.' In this image, the rocks visible above the rovers' solar panels are on the slope at the northern edge of Home Plate.

    This view is presented as a cylindrical projection with geometric seam correction.

  20. Tagging of Genomic STAT3 and STAT1 with Fluorescent Proteins and Insertion of a Luciferase Reporter in the Cyclin D1 Gene Provides a Modified A549 Cell Line to Screen for Selective STAT3 Inhibitors

    PubMed Central

    Samsonov, Andrey; Zenser, Nathan; Zhang, Fan; Zhang, Hongyi; Fetter, John; Malkov, Dmitry

    2013-01-01

    Signal transducer and activator of transcription 3 (STAT3) is an oncogenic protein that is constitutively activated in numerous cancer cell lines and human cancers. Another STAT family member, STAT1, possesses cancer-inhibitory properties and can promote apoptosis in tumor cells upon activation. To better characterize these important cancer related genes, we tagged STAT3 and STAT1 loci with fluorescent protein (FP) sequences (RFP and GFP respectively) by targeted integration via zinc finger nuclease (ZFN) - mediated homologous recombination in A549 cells that express aberrantly activated STAT3. We inserted the FP transgenes at the N-terminus of the STAT3 locus and at the C-terminus of the STAT1 locus. The integration resulted in endogenous expression of fluorescent STAT3 and STAT1 chimeric fusion proteins. When stimulated with IL-6 or IFN-γ, the cells showed robust nuclear translocation of RFP-STAT3 or STAT1-GFP, respectively. Pre-incubation of cells with a known specific STAT3 inhibitor showed that IFN-γ-induced translocation of STAT1-GFP was not impaired. STAT3 activates multiple downstream targets such as genes involved in cell cycle progression - e.g. cyclin D1. To detect changes in expression of endogenous cyclin D1, we used ZFN technology to insert a secreted luciferase reporter behind the cyclin D1 promoter and separated the luciferase and cyclin D1 coding regions by a 2A sequence to induce a translational skip. The luciferase insertion was made in the RFP-STAT3/STAT1-GFP cell line to have all three reporters in a single cell line. Addition of a STAT3 inhibitor led to suppression of cyclin D1 promoter activity and cell growth arrest. The triple-modified cell line provides a simple and convenient method for high-content screening and pre-clinical testing of potential STAT3 inhibitors in live cells while ensuring that the STAT1 pathway is not affected. This approach of reporting endogenous gene activities using ZFN technology could be applied to other cancer

  1. Comment on: ``The hindered rotor density-of-states interpolation function'' [J. Chem. Phys. 106, 6675 (1997)] and ``The hindered rotor density- of-states'' [J. Chem. Phys. 108, 2314 (1998)

    NASA Astrophysics Data System (ADS)

    McClurg, Richard B.

    1999-10-01

    There has been some confusion regarding the various approximations for the hindered rotor partition function and its associated thermodynamic functions and density of states. This comment seeks to clarify the situation by comparing and contrasting the various functions, particularly with regard to the consistent use of reference energies. Only the tabular data of Pitzer and Gwinn [J. Chem. Phys. 10, 428 (1942)] and our analytic function [J. Chem. Phys. 106, 6675 (1997)] have consistent reference energies. The main contribution of our publication is the set of simple, asymptotically correct expressions for the thermodynamic functions. There are similar, but different approximations to the density of states given by Knyazev and co-workers [J. Phys. Chem. A 102, 3916 (1998)] and by me [J. Chem. Phys. 108, 1748 (1998)].

  2. Erratum to “Comment on “Geometry effect on the magnetic ordering of geometrically frustrated rectangular and triangular magnets” [Phys. Lett. A 375 (13) (2011) 1548]” [Phys. Lett. A 375 (27) (2011) 2680-2681

    NASA Astrophysics Data System (ADS)

    Nascimento, F. S.; Mól, L. A. S.; Pereira, A. R.; Moura-Melo, W. A.

    2012-10-01

    In a recent comment [Phys. Lett. A 375 (2011) 2680] some of us argued that a misleading evaluation of dipolar interactions in spin ice systems studied by Li et al. [Phys. Lett. A 375 (2011) 1548], does not lead to the ground-state transitions that they observed. However, a bug found in our computational code showed that there is indeed the predicted transitions even for a proper evaluation of dipolar interactions.

  3. Leptin-Induced JAK/STAT Signaling and Cancer Growth.

    PubMed

    Mullen, McKay; Gonzalez-Perez, Ruben Rene

    2016-01-01

    Growth factor and cytokine signaling can influence the development of several cancer types. One of the key players in the development of cancer is the Janus kinas (JAK) signal transducer of activators of transcription (STAT) signaling pathway. The majority of growth factors and cytokine interactions with their membrane-bound receptors trigger JAK-STAT activation. The influential relationship between obesity and cancer is a fact. However, there is a complex sequence of events contributing to the regulation of this mechanism to promote tumor growth, yet to be fully elucidated. The JAK-STAT pathway is influenced by obesity-associated changes that have been shown to impact cancer growth and progression. This intricate process is highly regulated by a vast array of adipokines and cytokines that exert their pleiotropic effects on cancer cells to enhance metastasis to distant target sites. Leptin is a cytokine, or more precise, an adipokine secreted mainly by adipose tissue that requires JAK-STAT activation to exert its biological functions. Leptin is the central regulator of energy balance and appetite. Leptin binding to its receptor OB-R in turn activates JAK-STAT, which induces proliferation, angiogenesis, and anti-apoptotic events in normal cells and malignant cells expressing the receptor. Leptin also induces crosstalk with Notch and IL-1 (NILCO), which involves other angiogenic factors promoting tumor growth. Therefore, the existence of multiple novel classes of therapeutics that target the JAK/STAT pathway has significant clinical implications. Then, the identification of the signaling networks and factors that regulate the obesity-cancer link to which potential pharmacologic interventions can be implemented to inhibit tumor growth and metastasis. In this review, we will discuss the specific relationship between leptin-JAK-STAT signaling and cancer. PMID:27472371

  4. Activation of oligodendroglial Stat3 is required for efficient remyelination

    PubMed Central

    Steelman, Andrew J.; Zhou, Yun; Koit, Hisami; Kim, SunJa; Payne, H. Ross; Lu, Q. Richard; Li, Jianrong

    2016-01-01

    Multiple sclerosis is the most prevalent demyelinating disease of the central nervous system (CNS) and is histologically characterized by perivascular demyelination as well as neurodegeneration. While the degree of axonal damage is correlated with clinical disability, it is believed that remyelination can protect axons from degeneration and slow disease progression. Therefore, understanding the intricacies associated with myelination and remyelination may lead to therapeutics that can enhance the remyelination process and slow axon degeneration and loss of function. Ciliary neurotrophic factor (CNTF) family cytokines such as leukemia inhibitory factor (LIF) and interleukin11(IL-11) are known to promote oligodendrocyte maturation and remyelination in experimental models of demyelination. Because CNTF family member binding to the gp 130 receptor results in activation of the JAK2/Stat3 pathway we investigated the necessity of oligodendroglial Stat3 in transducing the signal required for myelination and remyelination. We found that Stat3 activation in the CNS coincides with myelination during development. Stimulation of oligodendrocyte precursor cells (OPCs) with CNTF or LIF promoted OPC survival and final differentiation, which was completely abolished by pharmacologic blockade of Stat3 activation with JAK2 inhibitor. Similarly, genetic ablation of Stat3 in oligodendrocyte lineage cells prevented CNTF-induced OPC differentiation in culture. In vivo, while oligodendroglial Stat3 signaling appears to be dispensable for developmental CNS myelination, it is required for oligodendrocyte regeneration and efficient remyelination after toxin-induced focal demyelination in the adult brain. Our data suggest a critical function for oligodendroglial Stat3 signaling in myelin repair. PMID:27060559

  5. Activation of oligodendroglial Stat3 is required for efficient remyelination.

    PubMed

    Steelman, Andrew J; Zhou, Yun; Koito, Hisami; Kim, SunJa; Payne, H Ross; Lu, Q Richard; Li, Jianrong

    2016-07-01

    Multiple sclerosis is the most prevalent demyelinating disease of the central nervous system (CNS) and is histologically characterized by perivascular demyelination as well as neurodegeneration. While the degree of axonal damage is correlated with clinical disability, it is believed that remyelination can protect axons from degeneration and slow disease progression. Therefore, understanding the intricacies associated with myelination and remyelination may lead to therapeutics that can enhance the remyelination process and slow axon degeneration and loss of function. Ciliary neurotrophic factor (CNTF) family cytokines such as leukemia inhibitory factor (LIF) and interleukin 11 (IL-11) are known to promote oligodendrocyte maturation and remyelination in experimental models of demyelination. Because CNTF family member binding to the gp130 receptor results in activation of the JAK2/Stat3 pathway we investigated the necessity of oligodendroglial Stat3 in transducing the signal required for myelination and remyelination. We found that Stat3 activation in the CNS coincides with myelination during development. Stimulation of oligodendrocyte precursor cells (OPCs) with CNTF or LIF promoted OPC survival and final differentiation, which was completely abolished by pharmacologic blockade of Stat3 activation with JAK2 inhibitor. Similarly, genetic ablation of Stat3 in oligodendrocyte lineage cells prevented CNTF-induced OPC differentiation in culture. In vivo, while oligodendroglial Stat3 signaling appears to be dispensable for developmental CNS myelination, it is required for oligodendrocyte regeneration and efficient remyelination after toxin-induced focal demyelination in the adult brain. Our data suggest a critical function for oligodendroglial Stat3 signaling in myelin repair. PMID:27060559

  6. Rac1 promotes chondrogenesis by regulating STAT3 signaling pathway.

    PubMed

    Kim, Hyoin; Sonn, Jong Kyung

    2016-09-01

    The small GTPase protein Rac1 is involved in a wide range of biological processes including cell differentiation. Previously, Rac1 was shown to promote chondrogenesis in micromass cultures of limb mesenchyme. However, the pathways mediating Rac1's role in chondrogenesis are not fully understood. This study aimed to explore the molecular mechanisms by which Rac1 regulates chondrogenic differentiation. Phosphorylation of signal transducer and activator of transcription 3 (STAT3) was increased as chondrogenesis proceeded in micromass cultures of chick wing bud mesenchyme. Inhibition of Rac1 with NSC23766, janus kinase 2 (JAK2) with AG490, or STAT3 with stattic inhibited chondrogenesis and reduced phosphorylation of STAT3. Conversely, overexpression of constitutively active Rac1 (Rac L61) increased phosphorylation of STAT3. Rac L61 expression resulted in increased expression of interleukin 6 (IL-6), and treatment with IL-6 increased phosphorylation of STAT3. NSC23766, AG490, and stattic prohibited cell aggregation, whereas expression of Rac L61 increased cell aggregation, which was reduced by stattic treatment. Our studies indicate that Rac1 induces STAT3 activation through expression and action of IL-6. Overexpression of Rac L61 increased expression of bone morphogenic protein 4 (BMP4). BMP4 promoted chondrogenesis, which was inhibited by K02288, an activin receptor-like kinase-2 inhibitor, and increased phosphorylation of p38 MAP kinase. Overexpression of Rac L61 also increased phosphorylation of p38 MAPK, which was reduced by K02288. These results suggest that Rac1 activates STAT3 by expression of IL-6, which in turn increases expression and activity of BMP4, leading to the promotion of chondrogenesis. PMID:27306109

  7. Comment on "Effects of damping solitary wave in a viscosity bounded plasma" [Phys. Plasmas 21, 022118 (2014)

    NASA Astrophysics Data System (ADS)

    Ghosh, Uday Narayan; Chatterjee, Prasanta; Roychoudhury, Rajkumar

    2015-07-01

    Recently Gun Li et al. discussed "Effects of damping solitary wave in a viscosity bounded plasma" [Phys. Plasmas 21, 022118 (2014)]. The paper contains some serious errors which have been pointed out in this Comment.

  8. Comment on “Effects of damping solitary wave in a viscosity bounded plasma” [Phys. Plasmas 21, 022118 (2014)

    SciTech Connect

    Ghosh, Uday Narayan Chatterjee, Prasanta; Roychoudhury, Rajkumar

    2015-07-15

    Recently Gun Li et al. discussed “Effects of damping solitary wave in a viscosity bounded plasma” [Phys. Plasmas 21, 022118 (2014)]. The paper contains some serious errors which have been pointed out in this Comment.

  9. Comment on 'Mathematical and physical aspects of Kappa velocity distribution' [Phys. Plasmas 14, 110702 (2007)

    SciTech Connect

    Hellberg, M. A.; Mace, R. L.; Baluku, T. K.; Kourakis, I.; Saini, N. S.

    2009-09-15

    A recent paper [L.-N. Hau and W.-Z. Fu, Phys. Plasmas 14, 110702 (2007)] deals with certain mathematical and physical properties of the kappa distribution. We comment on the authors' use of a form of distribution function that is different from the 'standard' form of the kappa distribution, and hence their results, inter alia for an expansion of the distribution function and for the associated number density in an electrostatic potential, do not fully reflect the dependence on {kappa} that would be associated with the conventional kappa distribution. We note that their definition of the kappa distribution function is also different from a modified distribution based on the notion of nonextensive entropy.

  10. Comment on ``Mathematical and physical aspects of Kappa velocity distribution'' [Phys. Plasmas 14, 110702 (2007)

    NASA Astrophysics Data System (ADS)

    Hellberg, M. A.; Mace, R. L.; Baluku, T. K.; Kourakis, I.; Saini, N. S.

    2009-09-01

    A recent paper [L.-N. Hau and W.-Z. Fu, Phys. Plasmas 14, 110702 (2007)] deals with certain mathematical and physical properties of the kappa distribution. We comment on the authors' use of a form of distribution function that is different from the "standard" form of the kappa distribution, and hence their results, inter alia for an expansion of the distribution function and for the associated number density in an electrostatic potential, do not fully reflect the dependence on κ that would be associated with the conventional kappa distribution. We note that their definition of the kappa distribution function is also different from a modified distribution based on the notion of nonextensive entropy.

  11. Sol-Gel Synthesis Of Aluminoborosilicate Powders

    NASA Technical Reports Server (NTRS)

    Bull, Jeffrey; Leiser, Daniel; Selvaduray, Guna

    1992-01-01

    Application of sol-gel process to synthesis of aluminoborosilicate powders shows potential for control of microstructures of materials. Development of materials having enhanced processing characteristics prove advantageous in extending high-temperature endurance of fibrous refractory composite insulation made from ceramic fibers.

  12. Opportunity's View After Drive on Sol 1806

    NASA Technical Reports Server (NTRS)

    2009-01-01

    NASA's Mars Exploration Rover Opportunity used its navigation camera to take the images combined into this full-circle view of the rover's surroundings just after driving 60.86 meters (200 feet) on the 1,806th Martian day, or sol, of Opportunity's surface mission (Feb. 21, 2009). North is at the center; south at both ends.

    Tracks from the drive extend northward across dark-toned sand ripples and light-toned patches of exposed bedrock in the Meridiani Planum region of Mars. For scale, the distance between the parallel wheel tracks is about 1 meter (about 40 inches).

    Engineers designed the Sol 1806 drive to be driven backwards as a strategy to redistribute lubricant in the rovers wheels. The right-front wheel had been showing signs of increased friction.

    The rover's position after the Sol 1806 drive was about 2 kilometer (1.2 miles) south southwest of Victoria Crater. Cumulative odometry was 14.74 kilometers (9.16 miles) since landing in January 2004, including 2.96 kilometers (1.84 miles) since climbing out of Victoria Crater on the west side of the crater on Sol 1634 (August 28, 2008).

    This view is presented as a cylindrical projection with geometric seam correction.

  13. Volume Changes of a Thixotropic, Sodium Bentonite Suspension during Sol-Gel-Sol Transition.

    PubMed

    Anderson, D M; Leaming, G F; Sposito, G

    1963-09-13

    Dilatometric measurements during the sol-gel-sol transition of an air-free, thixotropic, sodium bentonite suspension revealed a reversible change in volume of about 2.4 X 10(-4) percent. The volume of the suspension increased during gelation and decreased when the gel was subsequently liquified. This is taken as evidence of a progressive building up, during gelation, of a water structure less dense than normal. PMID:17739493

  14. Human Cytomegalovirus IE1 Protein Disrupts Interleukin-6 Signaling by Sequestering STAT3 in the Nucleus

    PubMed Central

    Reitsma, Justin M.; Sato, Hiromi; Nevels, Michael

    2013-01-01

    In the canonical STAT3 signaling pathway, binding of agonist to receptors activates Janus kinases that phosphorylate cytoplasmic STAT3 at tyrosine 705 (Y705). Phosphorylated STAT3 dimers accumulate in the nucleus and drive the expression of genes involved in inflammation, angiogenesis, invasion, and proliferation. Here, we demonstrate that human cytomegalovirus (HCMV) infection rapidly promotes nuclear localization of STAT3 in the absence of robust phosphorylation at Y705. Furthermore, infection disrupts interleukin-6 (IL-6)-induced phosphorylation of STAT3 and expression of a subset of IL-6-induced STAT3-regulated genes, including SOCS3. We show that the HCMV 72-kDa immediate-early 1 (IE1) protein associates with STAT3 and is necessary to localize STAT3 to the nucleus during infection. Furthermore, expression of IE1 is sufficient to disrupt IL-6-induced phosphorylation of STAT3, binding of STAT3 to the SOCS3 promoter, and SOCS3 gene expression. Finally, inhibition of STAT3 nuclear localization or STAT3 expression during infection is linked to diminished HCMV genome replication. Viral gene expression is also disrupted, with the greatest impact seen following viral DNA synthesis. Our study identifies IE1 as a new regulator of STAT3 intracellular localization and IL-6 signaling and points to an unanticipated role of STAT3 in HCMV infection. PMID:23903834

  15. Structural Tailoring of Advanced Turboprops (STAT). Theoretical manual

    NASA Technical Reports Server (NTRS)

    Brown, K. W.

    1992-01-01

    This manual describes the theories in the Structural Tailoring of Advanced Turboprops (STAT) computer program, which was developed to perform numerical optimizations on highly swept propfan blades. The optimization procedure seeks to minimize an objective function, defined as either direct operating cost or aeroelastic differences between a blade and its scaled model, by tuning internal and external geometry variables that must satisfy realistic blade design constraints. The STAT analyses include an aerodynamic efficiency evaluation, a finite element stress and vibration analysis, an acoustic analysis, a flutter analysis, and a once-per-revolution (1-p) forced response life prediction capability. The STAT constraints include blade stresses, blade resonances, flutter, tip displacements, and a 1-P forced response life fraction. The STAT variables include all blade internal and external geometry parameters needed to define a composite material blade. The STAT objective function is dependent upon a blade baseline definition which the user supplies to describe a current blade design for cost optimization or for the tailoring of an aeroelastic scale model.

  16. Mechanisms of Jak/STAT signaling in immunity and disease

    PubMed Central

    Villarino, Alejandro V.; Kanno, Yuka; O’Shea, John J.

    2015-01-01

    More than 2 decades ago, experiments on the antiviral mechanisms of interferons led to the discovery of Janus kinases (JAK) and their downstream effectors, the signal transducer of activation (STAT) proteins. This pathway has since become a paradigm for membrane to nucleus signaling and has come to explain how a broad range of soluble factors, including cytokines and hormones, mediate their diverse functions. Jak/STAT research has not only impacted basic science, particularly in the context of intercellular communication and cell-extrinsic control of gene expression, but has also become a prototype for transition from bench to bedside, culminating in the development and clinical implementation of pathway-specific therapeutics. This brief review will synthesize current understanding of Jak/STAT biology while taking stock of the lessons learned and the challenges that lie ahead. PMID:25527793

  17. Mycoplasma pneumoniae Modulates STAT3-STAT6/EGFR-FOXA2 Signaling To Induce Overexpression of Airway Mucins

    PubMed Central

    Hao, Yonghua; Kuang, Zhizhou; Jing, Jia; Miao, Jinfeng; Mei, Li Yu; Lee, Ryan J.; Kim, Susie; Choe, Shawn; Krause, Duncan C.

    2014-01-01

    Aberrant mucin secretion and accumulation in the airway lumen are clinical hallmarks associated with various lung diseases such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis. Mycoplasma pneumoniae, long appreciated as one of the triggers of acute exacerbations of chronic pulmonary diseases, has recently been reported to promote excessive mucus secretion. However, the mechanism of mucin overproduction induced by M. pneumoniae remains unclear. This study aimed to determine the mechanism by which M. pneumoniae induces mucus hypersecretion by using M. pneumoniae infection of mouse lungs, human primary bronchial epithelial (NHBE) cells cultured at the air-liquid interface, and the conventionally cultured airway epithelial NCI-H292 cell line. We demonstrated that M. pneumoniae induced the expression of mucins MUC5AC and MUC5B by activating the STAT6-STAT3 and epidermal growth factor receptor (EGFR) signal pathways, which in turn downregulated FOXA2, a transcriptional repressor of mucin biosynthesis. The upstream stimuli of these pathways, including interleukin-4 (IL-4), IL-6, and IL-13, increased dramatically upon exposure to M. pneumoniae. Inhibition of the STAT6, STAT3, and EGFR signaling pathways significantly restored the expression of FOXA2 and attenuated the expression of airway mucins MUC5AC and MUC5B. Collectively, these studies demonstrated that M. pneumoniae induces airway mucus hypersecretion by modulating the STAT/EGFR-FOXA2 signaling pathways. PMID:25287927

  18. Evaluation of STAT medication ordering process in a community hospital

    PubMed Central

    Walsh., Kim; Schwartz., Barbara

    Background: In most health care facilities, problems related to delays in STAT medication order processing time are of common concern. Objective: The purpose of this study was to evaluate processing time for STAT orders at Kimball Medical Center. Methods: All STAT orders were reviewed to determine processing time; order processing time was also stratified by physician order entry (physician entered (PE) orders vs. non-physician entered (NPE) orders). Collected data included medication ordered, indication, time ordered, time verified by pharmacist, time sent from pharmacy, and time charted as given to the patient. Results: A total of 502 STAT orders were reviewed and 389 orders were included for analysis. Overall, median time was 29 minutes, IQR 16–63; p<0.0001.). The time needed to process NPE orders was significantly less than that needed for PE orders (median 27 vs. 34 minutes; p=0.026). In terms of NPE orders, the median total time required to process STAT orders for medications available in the Automated Dispensing Devices (ADM) was within 30 minutes, while that required to process orders for medications not available in the ADM was significantly greater than 30 minutes. For PE orders, the median total time required to process orders for medications available in the ADM (i.e., not requiring pharmacy involvement) was significantly greater than 30 minutes. [Median time = 34 minutes (p<0.001)]. Conclusion: We conclude that STAT order processing time may be improved by increasing the availability of medications in ADM, and pharmacy involvement in the verification process. PMID:27382418

  19. Ethanolamine is a novel STAT-3 dependent cardioprotective agent.

    PubMed

    Kelly, Roisin F; Lamont, Kim T; Somers, Sarin; Hacking, Damian; Lacerda, Lydia; Thomas, Paul; Opie, Lionel H; Lecour, Sandrine

    2010-11-01

    Ethanolamine is a biogenic amine found naturally in the body as part of membrane lipids and as a metabolite of the cardioprotective substances, sphingosine-1-phosphate (S1P) and anandamide. In the brain, ethanolamine, formed from the breakdown of anandamide protects against ischaemic apoptosis. However, the effects of ethanolamine in the heart are unknown. Signal transducer and activator of transcription 3 (STAT-3) is a critical prosurvival factor in ischaemia/reperfusion (I/R) injury. Therefore, we investigated whether ethanolamine protects the heart via activation of STAT-3. Isolated hearts from wildtype or cardiomyocyte specific STAT-3 knockout (K/O) mice were pre-treated with ethanolamine (Etn) (0.3 mmol/L) before I/R insult. In vivo rat hearts were subjected to 30 min ischaemia/2 h reperfusion in the presence or absence of 5 mg/kg S1P and/or the FAAH inhibitor, URB597. Infarct size was measured at the end of each protocol by triphenyltetrazolium chloride staining. Pre-treatment with ethanolamine decreased infarct size in isolated mouse or rat hearts subjected to I/R but this infarct sparing effect was lost in cardiomyocyte specific STAT-3 deficient mice. Pre-treatment with ethanolamine increased nuclear phosphorylated STAT-3 [control 0.75 ± 0.08 vs. Etn 1.50 ± 0.09 arbitrary units; P < 0.05]. Our findings suggest a novel cardioprotective role for ethanolamine against I/R injury via activation of STAT-3. PMID:20938668

  20. Bcl6 promotes osteoblastogenesis through Stat1 inhibition

    SciTech Connect

    Fujie, Atsuhiro; Funayama, Atsushi; Miyauchi, Yoshiteru; Sato, Yuiko; Kobayashi, Tami; Kanagawa, Hiroya; Katsuyama, Eri; Hao, Wu; Tando, Toshimi; Watanabe, Ryuichi; Morita, Mayu; Miyamoto, Kana; Kanaji, Arihiko; Morioka, Hideo; Matsumoto, Morio; Toyama, Yoshiaki; Miyamoto, Takeshi

    2015-02-13

    Bone mass is tightly controlled by a balance between osteoclast and osteoblast activities. Although these cell types mature via different pathways, some factors reportedly regulate differentiation of both. Here, in a search for factors governing osteoblastogenesis but also expressed in osteoclasts to control both cell types by one molecule, we identified B cell lymphoma 6 (Bcl6) as one of those factors and show that it promotes osteoblast differentiation. Bcl6 was previously shown to negatively regulate osteoclastogenesis. We report that lack of Bcl6 results in significant inhibition of osteoblastogensis in vivo and in vitro and in defects in secondary ossification center formation in vivo. Signal transducer and activator of transcription 1 (Stat1) reportedly attenuates osteoblast differentiation by inhibiting nuclear translocation of runt-related transcription factor 2 (Runx2), which is essential for osteoblast differentiation. We found that lack of Bcl6 resulted in significant elevation of Stat1 mRNA and protein expression in osteoblasts and showed that Stat1 is a direct target of Bcl6 using a chromatin immune-precipitation assay. Mice lacking both Bcl6 and Stat1 (DKO) exhibited significant rescue of bone mass and osteoblastic parameters as well as partial rescue of secondary ossification center formation compared with Bcl6-deficient mice in vivo. Altered osteoblastogenesis in Bcl6-deficient cells was also restored in DKO in vitro. Thus, Bcl6 plays crucial roles in regulating both osteoblast activation and osteoclast inhibition. - Highlights: • Bcl6 is required for osteoblast differentiation. • Bcl6{sup −/−} mice exhibited altered osteoblastogenesis and reduced bone mass in vivo and in vitro. • We identified Stat1 as a direct target of Bcl6 in osteoblasts. • Bcl6 and Stat1 doubly deficient mice exhibited rescued bone phenotypes compared with Bcl6{sup −/−} mice.

  1. SOL Properties of HHFW Electron Heating Generated H-modes in NSTX

    NASA Astrophysics Data System (ADS)

    Hosea, Joel; Bell, R. E.; Diallo, A.; Gerhardt, S.; Jaworski, M. A.; Kramer, G. J.; Leblanc, B. P.; Perkins, R. J.; Phillips, C. K.; Roquemore, L.; Taylor, G.; Wilson, J. R.; Ahn, J.-W.; Gray, T. K.; Maingi, R.; McLean, A.; Ryan, P. M.; Sabbagh, S.

    2012-10-01

    In neutral beam generated H-modes, it has been shown that high harmonic fast wave power lost to the divertor regions flows along the magnetic field lines passing in front of the antenna [1]. Here we extend this power flow study to the case of HHFW generated H-modes [2]. Using the field strike point spiral from the Spiral code as a guide (Langmuir probe characteristics near the outer vessel strike radius are used to specify the best equilibrium for the code), it is found that for comparable launched RF powers the power loss in the outer scrape off layer (SOL) is generally much less for the HHFW generated H-mode case. Also, much of the heating in the lower divertor region is at/near the outer vessel strike radius as expected for low RF power loss in the SOL. The dependence of the loss at the outer vessel strike radius on the possible presence of ETG turbulence will be discussed.[4pt] [1] R. Perkins et al., to be published in Phys Rev Letters.[0pt] [2] J. Hosea et al, EPS Conf. Proc. (Strasbourg 2011) paper P2-098.

  2. Distribution of the mammalian Stat gene family in mouse chromosomes

    SciTech Connect

    Copeland, N.G.; Gilbert, D.J.; Jenkins, N.A.

    1995-09-01

    Studies of transcriptional activation by interferons and a variety of cytokines have led to the identification of a family of proteins that serve as signal transducers and activators of transcription, Stats. Here, we report that the seven mouse Stat loci map in three clusters, with each cluster located on a different mouse autosome. The data suggest that the family has arisen via a tandem duplication of the ancestral locus, followed by dispersion of the linked loci to different mouse chromosomes. 28 refs., 1 fig., 1 tab.

  3. STAT1β Is Not Dominant Negative and Is Capable of Contributing to Gamma Interferon-Dependent Innate Immunity

    PubMed Central

    Semper, Christian; Leitner, Nicole R.; Lassnig, Caroline; Parrini, Matthias; Mahlakõiv, Tanel; Rammerstorfer, Michael; Lorenz, Karin; Rigler, Doris; Müller, Simone; Kolbe, Thomas; Vogl, Claus; Rülicke, Thomas; Staeheli, Peter; Decker, Thomas; Müller, Mathias

    2014-01-01

    The transcription factor STAT1 is essential for interferon (IFN)-mediated immunity in humans and mice. STAT1 function is tightly regulated, and both loss- and gain-of-function mutations result in severe immune diseases. The two alternatively spliced isoforms, STAT1α and STAT1β, differ with regard to a C-terminal transactivation domain, which is absent in STAT1β. STAT1β is considered to be transcriptionally inactive and to be a competitive inhibitor of STAT1α. To investigate the functions of the STAT1 isoforms in vivo, we generated mice deficient for either STAT1α or STAT1β. As expected, the functions of STAT1α and STAT1β in IFN-α/β- and IFN-λ-dependent antiviral activity are largely redundant. In contrast to the current dogma, however, we found that STAT1β is transcriptionally active in response to IFN-γ. In the absence of STAT1α, STAT1β shows more prolonged IFN-γ-induced phosphorylation and promoter binding. Both isoforms mediate protective, IFN-γ-dependent immunity against the bacterium Listeria monocytogenes, although with remarkably different efficiencies. Our data shed new light on the potential contributions of the individual STAT1 isoforms to STAT1-dependent immune responses. Knowledge of STAT1β's function will help fine-tune diagnostic approaches and help design more specific strategies to interfere with STAT1 activity. PMID:24710278

  4. Inducible, Dose-Adjustable and Time-Restricted Reconstitution of Stat1 Deficiency In Vivo

    PubMed Central

    Leitner, Nicole R.; Lassnig, Caroline; Rom, Rita; Heider, Susanne; Bago-Horvath, Zsuzsanna; Eferl, Robert; Müller, Simone; Kolbe, Thomas; Kenner, Lukas; Rülicke, Thomas; Strobl, Birgit; Müller, Mathias

    2014-01-01

    Signal transducer and activator of transcription (STAT) 1 is a key player in interferon (IFN) signaling, essential in mediating host defense against viruses and other pathogens. STAT1 levels are tightly regulated and loss- or gain-of-function mutations in mice and men lead to severe diseases. We have generated a doxycycline (dox) -inducible, FLAG-tagged Stat1 expression system in mice lacking endogenous STAT1 (i.e. Stat1ind mice). We show that STAT1 expression depends on the time and dose of dox treatment in primary cells and a variety of organs isolated from Stat1ind mice. In bone marrow-derived macrophages, a fraction of the amount of STAT1 present in WT cells is sufficient for full expression of IFN-induced genes. Dox-induced STAT1 established protection against virus infections in primary cells and mice. The availability of the Stat1ind mouse model will enable an examination of the consequences of variable amounts of STAT1. The model will also permit the study of STAT1 dose-dependent and reversible functions as well as of STAT1's contributions to the development, progression and resolution of disease. PMID:24489749

  5. Sol-gel processing of metal sulfides

    NASA Astrophysics Data System (ADS)

    Stanic, Vesha

    Metal sulfides were synthesised via a sol-gel process using various metal alkoxides and hydrogen sulfide in toluene. Colloidal gels were prepared from germanium ethoxide, germanium isopropoxide, zinc tert-butoxide and tungsten (VI) ethoxide, whereas colloidal powder was produced from tungsten (V) dichloride ethoxide. Special precautions were necessary to protect the reaction mixture from water contamination which produced metal oxides. Results indicated that the main source of water is the hydrogen sulfide gas. In addition, synthesis of metal sulfides from a mixture of metal oxide and sulfide was demonstrated by the example of monoclinic germanium disulfide. It was produced by reaction of the sol-gel product with sulfur. Heat treatment of the sol-gel product and sulfur yielded single phase GeSsb2. The sol-gel prepared materials and their heat treated products were characterized by various methods. A chemical kinetics study of the functional groups -OR, -SH and Ssp{2-} was carried out for the sol-gel processing of GeSsb2 from of hydrogen sulfide and two different alkoxides, germanium ethoxide and germanium isopropoxide. The study was performed for different concentrations of precursors at different molar ratios and temperatures. The results indicate that the proposed reaction mechanism was simplified under appropriate reaction conditions. Experimentally determined rate constants of thiolysis and condensations demonstrate that thiolysis is slow and that condensations are fast steps, regardless of the studied reaction conditions. A study of the temperature effect on the reaction rate constant shows that it increases with temperature in accord with both Arrhenius law and transition-state theory. Activation energies, Esba, and activation parameters DeltaSsp{ddagger}, DeltaHsp{ddagger} and DeltaGsp{ddagger}, were determined for thiolysis and condensation reactions. The potentiometric tiration method was used for quantitative determination of germanium sulfide and

  6. PREFACE: International Symposium "Nanoscience and Quantum Physics 2011" (nanoPHYS'11)

    NASA Astrophysics Data System (ADS)

    Saito, Susumu; Tanaka, Hidekazu; Nakamura, Takashi; Nakamura, Masaaki

    2011-07-01

    Quantum physics has developed modern views of nature for more than a century. In addition to this traditional role, quantum physics has acquired new significance in the 21st century as the field responsible for driving and supporting nanoscience research, which will have even greater importance in the future because nanoscience will be the academic foundation for new technologies. The Department of Physics, Tokyo Institute of Technology, are now conducting a "Nanoscience and Quantum Physics" project (Physics G-COE project) supported by the Global Center of Excellence Program of the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT) in order to promote research and education in these important academic fields. The International Symposium on Nanoscience and Quantum Physics, held in Tokyo, Japan, 26-28 January 2011 (nanoPHYS'11) was organized by the Physics G-COE project of the Tokyo Institute of Technology to provide an international forum for the open exchange of topical information and for stimulating discussion on novel concepts and future prospects of nanoscience and quantum physics. There were a total of 118 papers including 34 invited papers. This nanoPHYS'11 is the fourth symposium of this kind organized by the Tokyo Institute of Technology. Topics focused on in the symposium included: Category 1: Novel nanostructure (Nanowires, Nanotubes, Spin-related structure, etc) Category 2: Novel transport and electronic properties (Graphene, Topological insulators, Coherent control, etc) Category 3: Electronic and optical properties of nanostructure Category 4: Fundamental physics and new concept in quantum physics Category 5: Quantum Physics - Quantum information Category 6: Quantum Physics - Nuclear and Hadron Physics Category 7: Quantum Physics - Astrophysics, etc All the papers submitted to this issue have been reviewed under a stringent refereeing process, according to the normal rules of this Journal. The editors are grateful to all the

  7. Erratum: Measurement of Branching Fractions and Mass Spectra of B→Kππγ [Phys. Rev. Lett. 98, 211804 (2007)

    NASA Astrophysics Data System (ADS)

    Aubert, B.; Barate, R.; Boutigny, D.; Couderc, F.; Karyotakis, Y.; Lees, J. P.; Poireau, V.; Tisserand, V.; Zghiche, A.; Grauges, E.; Palano, A.; Pappagallo, M.; Pompili, A.; Chen, J. C.; Qi, N. D.; Rong, G.; Wang, P.; Zhu, Y. S.; Eigen, G.; Ofte, I.; Stugu, B.; Abrams, G. S.; Battaglia, M.; Breon, A. B.; Brown, D. N.; Button-Shafer, J.; Cahn, R. N.; Charles, E.; Day, C. T.; Gill, M. S.; Gritsan, A. V.; Groysman, Y.; Jacobsen, R. G.; Kadel, R. W.; Kadyk, J.; Kerth, L. T.; Kolomensky, Yu. G.; Kukartsev, G.; Lynch, G.; Mir, L. M.; Oddone, P. J.; Orimoto, T. J.; Pripstein, M.; Roe, N. A.; Ronan, M. T.; Wenzel, W. A.; Barrett, M.; Ford, K. E.; Harrison, T. J.; Hart, A. J.; Hawkes, C. M.; Morgan, S. E.; Watson, A. T.; Fritsch, M.; Goetzen, K.; Held, T.; Koch, H.; Lewandowski, B.; Pelizaeus, M.; Peters, K.; Schroeder, T.; Steinke, M.; Boyd, J. T.; Burke, J. P.; Chevalier, N.; Cottingham, W. N.; Kelly, M. P.; Cuhadar-Donszelmann, T.; Fulsom, B. G.; Hearty, C.; Knecht, N. S.; Mattison, T. S.; McKenna, J. A.; Khan, A.; Kyberd, P.; Saleem, M.; Teodorescu, L.; Blinov, A. E.; Blinov, V. E.; Bukin, A. D.; Druzhinin, V. P.; Golubev, V. B.; Kravchenko, E. A.; Onuchin, A. P.; Serednyakov, S. I.; Skovpen, Yu. I.; Solodov, E. P.; Yushkov, A. N.; Best, D.; Bondioli, M.; Bruinsma, M.; Chao, M.; Eschrich, I.; Kirkby, D.; Lankford, A. J.; Mandelkern, M.; Mommsen, R. K.; Roethel, W.; Stoker, D. P.; Buchanan, C.; Hartfiel, B. L.; Foulkes, S. D.; Gary, J. W.; Long, O.; Shen, B. C.; Wang, K.; Zhang, L.; Del Re, D.; Hadavand, H. K.; Hill, E. J.; Macfarlane, D. B.; Paar, H. P.; Rahatlou, S.; Sharma, V.; Berryhill, J. W.; Campagnari, C.; Cunha, A.; Dahmes, B.; Hong, T. M.; Mazur, M. A.; Richman, J. D.; Verkerke, W.; Beck, T. W.; Eisner, A. M.; Flacco, C. J.; Heusch, C. A.; Kroseberg, J.; Lockman, W. S.; Nesom, G.; Schalk, T.; Schumm, B. A.; Seiden, A.; Spradlin, P.; Williams, D. C.; Wilson, M. G.; Albert, J.; Chen, E.; Dubois-Felsmann, G. P.; Dvoretskii, A.; Hitlin, D. G.; Narsky, I.; Piatenko, T.; Porter, F. C.; Ryd, A.; Samuel, A.; Andreassen, R.; Jayatilleke, S.; Mancinelli, G.; Meadows, B. T.; Sokoloff, M. D.; Blanc, F.; Bloom, P.; Chen, S.; Ford, W. T.; Nauenberg, U.; Olivas, A.; Rankin, P.; Ruddick, W. O.; Smith, J. G.; Ulmer, K. A.; Wagner, S. R.; Zhang, J.; Chen, A.; Eckhart, E. A.; Soffer, A.; Toki, W. H.; Wilson, R. J.; Zeng, Q.; Altenburg, D.; Feltresi, E.; Hauke, A.; Spaan, B.; Brandt, T.; Brose, J.; Dickopp, M.; Klose, V.; Lacker, H. M.; Nogowski, R.; Otto, S.; Petzold, A.; Schott, G.; Schubert, J.; Schubert, K. R.; Schwierz, R.; Sundermann, J. E.; Bernard, D.; Bonneaud, G. R.; Grenier, P.; Schrenk, S.; Thiebaux, Ch.; Vasileiadis, G.; Verderi, M.; Bard, D. J.; Clark, P. J.; Gradl, W.; Muheim, F.; Playfer, S.; Xie, Y.; Andreotti, M.; Azzolini, V.; Bettoni, D.; Bozzi, C.; Calabrese, R.; Cibinetto, G.; Luppi, E.; Negrini, M.; Piemontese, L.; Anulli, F.; Baldini-Ferroli, R.; Calcaterra, A.; de Sangro, R.; Finocchiaro, G.; Patteri, P.; Peruzzi, I. M.; Piccolo, M.; Zallo, A.; Buzzo, A.; Capra, R.; Contri, R.; Vetere, M. Lo; Macri, M.; Monge, M. R.; Passaggio, S.; Patrignani, C.; Robutti, E.; Santroni, A.; Tosi, S.; Bailey, S.; Brandenburg, G.; Chaisanguanthum, K. S.; Morii, M.; Won, E.; Wu, J.; Dubitzky, R. S.; Langenegger, U.; Marks, J.; Schenk, S.; Uwer, U.; Bhimji, W.; Bowerman, D. A.; Dauncey, P. D.; Egede, U.; Flack, R. L.; Gaillard, J. R.; Morton, G. W.; Nash, J. A.; Nikolich, M. B.; Taylor, G. P.; Vazquez, W. P.; Charles, M. J.; Mader, W. F.; Mallik, U.; Mohapata, A. K.; Cochran, J.; Crawley, H. B.; Eyges, V.; Meyer, W. T.; Prell, S.; Rosenberg, E. I.; Rubin, A. E.; Yi, J.; Arnaud, N.; Davier, M.; Giroux, X.; Grosdidier, G.; Hocker, A.; Diberder, F. Le; Lepeltier, V.; Lutz, A. M.; Oyanguren, A.; Petersen, T. C.; Pierini, M.; Plaszcynski, S.; Rodier, S.; Roudeau, P.; Schune, M. H.; Stocchi, A.; Wormser, G.; Cheng, C. H.; Lange, D. J.; Simani, M. C.; Wright, D. M.; Bevan, A. J.; Chavez, C. A.; Coleman, J. P.; Forster, I. J.; Fry, J. R.; Gabathuler, E.; Gamet, R.; George, K. A.; Hutchcroft, D. E.; Parry, R. J.; Payne, D. J.; Schofield, K. C.; Touramanis, C.; Cormack, C. M.; Lodovico, F. Di; Sacco, R.; Brown, C. L.; Cowan, G.; Flaecher, H. U.; Green, M. G.; Hopkins, D. A.; Jackson, P. S.; McMahon, T. R.; Ricciardi, S.; Salvatore, F.; Brown, D.; Davis, C. L.; Allison, J.; Barlow, N. R.; Barlow, R. J.; Hodgkinson, M. C.; Lafferty, G. D.; Naisbit, M. T.; Williams, J. C.; Chen, C.; Farbin, A.; Hulsbergen, W. D.; Jawahery, A.; Kovalskyi, D.; Lae, C. K.; Lillard, V.; Roberts, D. A.; Simi, G.; Blaylock, G.; Dallapiccola, C.; Hertzbach, S. S.; Kofler, R.; Koptchev, V. B.; Li, X.; Moore, T. B.; Saremi, S.; Staengle, H.; Willocq, S.; Cowan, R.; Koeneke, K.; Sciolla, G.; Sekula, S. J.; Spitznagel, M.; Taylor, F.; Yamamoto, R. K.; Kim, H.; Patel, P. M.; Robertson, S. H.; Lazzaro, A.; Lombardo, V.; Palombo, F.; Bauer, J. M.; Cremaldi, L.; Eschenburg, V.; Godang, R.; Kroeger, R.; Reidy, J.; Sanders, D. A.; Summers, D. J.; Zhao, H. W.; Brunet, S.; Cote, D.; Taras, P.; Viaud, B.; Nicholson, H.; Cavallo, N.; Nardo, G. De; Fabozzi, F.; Gatto, C.; Lista, L.; Monorchio, D.; Paolucci, P.; Piccolo, D.; Sciacca, C.; Baak, M.; Bulten, H.; Raven, G.; Snoek, H. L.; Wilden, L.; Jessop, C. P.; Losecco, J. M.; Allmendinger, T.; Benelli, G.; Gan, K. K.; Honscheid, K.; Hufnagel, D.; Jackson, P. D.; Kagan, H.; Kass, R.; Pulliam, T.; Rahimi, A. M.; Ter-Antonyan, R.; Wong, Q. K.; Brau, J.; Frey, R.; Igonkina, O.; Lu, M.; Potter, C. T.; Sinev, N. B.; Strom, D.; Strube, J.; Torrence, E.; Dorigo, A.; Galeazzi, F.; Margoni, M.; Morandin, M.; Posocco, M.; Rotondo, M.; Simonetto, F.; Stroili, R.; Voci, C.; Benayoun, M.; Briand, H.; Chauveau, J.; David, P.; Buono, L. Del; de La Vaissiere, Ch.; Hamon, O.; John, M. J. J.; Leruste, Ph.; Malcles, J.; Ocariz, J.; Roos, L.; Therin, G.; Behera, P. K.; Gladney, L.; Guo, Q. H.; Panetta, J.; Biasini, M.; Covarelli, R.; Pacetti, S.; Pioppi, M.; Angelini, C.; Batignani, G.; Bettarini, S.; Bucci, F.; Calderini, G.; Carpinelli, M.; Cenci, R.; Forti, F.; Giorgi, M. A.; Lusiani, A.; Marchiori, G.; Morganti, M.; Neri, N.; Paoloni, E.; Rama, M.; Rizzo, G.; Walsh, J.; Haire, M.; Judd, D.; Wagoner, D. E.; Biesiada, J.; Danielson, N.; Elmer, P.; Lau, Y. P.; Lu, C.; Olsen, J.; Smith, A. J. S.; Telnov, A. V.; Bellini, F.; Cavoto, G.; D'Orazio, A.; Marco, E. Di; Faccini, R.; Ferrarotto, F.; Ferroni, F.; Gaspero, M.; Gioi, L. Li; Mazzoni, M. A.; Morganti, S.; Piredda, G.; Polci, F.; Tehrani, F. Safai; Voena, C.; Schroder, H.; Wagner, G.; Waldi, R.; Adye, T.; Groot, N. De; Franek, B.; Gopal, G. P.; Olaiya, E. O.; Wilson, F. F.; Aleksan, R.; Emery, S.; Gaidot, A.; Ganzhur, S. F.; Giraud, P.-F.; Graziani, G.; de Monchenault, G. Hamel; Kozanecki, W.; Legendre, M.; London, G. W.; Mayer, B.; Vasseur, G.; Yeche, Ch.; Zito, M.; Purohit, M. V.; Weidemann, W.; Wilson, J. R.; Yumiceva, F. X.; Abe, T.; Allen, M. T.; Aston, D.; Bartoldus, R.; Berger, N.; Boyarski, A. M.; Buchmueller, O. L.; Claus, R.; Convery, M. R.; Cristinziani, M.; Dingfelder, J. C.; Dong, D.; Dorfan, J.; Dujmic, D.; Dunwoodie, W.; Fan, S.; Field, R. C.; Glanzman, T.; Gowdy, S. J.; Hadig, T.; Halyo, V.; Hast, C.; Hryn'Ova, T.; Innes, W. R.; Kelsey, M. H.; Kim, P.; Kocian, M. L.; Leith, D. W. G. S.; Libby, J.; Luitz, S.; Luth, V.; Lynch, H. L.; Marsiske, H.; Messner, R.; Muller, D. R.; O'Grady, C. P.; Ozcan, V. E.; Perazzo, A.; Perl, M.; Ratcliff, B. N.; Roodman, A.; Salnikov, A. A.; Schindler, R. H.; Schwiening, J.; Snyder, A.; Stelzer, J.; Su, D.; Sullivan, M. K.; Suzuki, K.; Swain, S.; Thompson, J. M.; Va'Vra, J.; Weaver, M.; Weinstein, A. J. R.; Wisniewski, W. J.; Wittgen, M.; Wright, D. H.; Yarritu, A. K.; Yi, K.; Young, C. C.; Burchat, P. R.; Edwards, A. J.; Majewski, S. A.; Petersen, B. A.; Roat, C.; Ahmed, M.; Ahmed, S.; Alam, M. S.; Ernst, J. A.; Saeed, M. A.; Wappler, F. R.; Zain, S. B.; Bugg, W.; Krishnamurthy, M.; Spanier, S. M.; Eckmann, R.; Ritchie, J. L.; Satpathy, A.; Schwitters, R. F.; Izen, J. M.; Kitayama, I.; Lou, X. C.; Ye, S.; Bianchi, F.; Bona, M.; Gallo, F.; Gamba, D.; Bomben, M.; Bosisio, L.; Cartaro, C.; Cossutti, F.; Ricca, G. Della; Dittongo, S.; Grancagnolo, S.; Lanceri, L.; Vitale, L.; Martinez-Vidal, F.; Pavini, R. S.; Banerjee, Sw.; Bhuyan, B.; Brown, C. M.; Fortin, D.; Hamano, K.; Kowalewski, R.; Roney, J. M.; Sobie, R. J.; Back, J. J.; Harrison, P. F.; Latham, T. E.; Mohanty, G. B.; Band, H. R.; Chen, X.; Cheng, B.; Dasu, S.; Datta, M.; Eichenbaum, A. M.; Flood, K. T.; Hollar, J. J.; Johnson, J. R.; Kutter, P. E.; Li, H.; Liu, R.; Mellado, B.; Mihalyi, A.; Pan, Y.; Prepost, R.; Tan, P.; von Wimmersperg-Toeller, J. H.; Wu, S. L.; Yu, Z.; Neal, H.

    2008-05-01

    We present a measurement of the partial branching fractions and mass spectra of the exclusive radiative penguin processes B -> K pi pi gamma in the range m_Kpipi < 1.8 GeV/c^2. We reconstruct four final states: K+ pi- pi+ gamma, K+ pi- pi0 gamma, Ks pi- pi+ gamma, and Ks pi+ pi- gamma, where Ks -> pi+ pi-. Using 232 million e+ e- -> B Bbar events recorded by the BaBar experiment at the PEP-II asymmetric-energy storage ring, we measure the branching fractions BR(B+ -> K+ pi- pi+ gamma) = (2.95 +- 0.13 (stat.) +- 0.20 (syst.)) x 10^-5, BR(B0 -> K+ pi- pi0 gamma) = (4.07 +- 0.22 (stat.) +- 0.31 (syst.)) x 10^-5, BR(B0 -> K0 pi+ pi- gamma) = (1.85 +- 0.21 (stat.) +- 0.12 (syst.)) x 10^-5, and BR(B+ -> K0 pi+ pi0 gamma) = (4.56 +- 0.42 (stat.) +- 0.31 (syst.)) x 10^-5.

  8. Two Domains of the V Protein of Virulent Canine Distemper Virus Selectively Inhibit STAT1 and STAT2 Nuclear Import▿

    PubMed Central

    Röthlisberger, Anne; Wiener, Dominique; Schweizer, Matthias; Peterhans, Ernst; Zurbriggen, Andreas; Plattet, Philippe

    2010-01-01

    Canine distemper virus (CDV) causes in dogs a severe systemic infection, with a high frequency of demyelinating encephalitis. Among the six genes transcribed by CDV, the P gene encodes the polymerase cofactor protein (P) as well as two additional nonstructural proteins, C and V; of these V was shown to act as a virulence factor. We investigated the molecular mechanisms by which the P gene products of the neurovirulent CDV A75/17 strain disrupt type I interferon (IFN-α/β)-induced signaling that results in the establishment of the antiviral state. Using recombinant knockout A75/17 viruses, the V protein was identified as the main antagonist of IFN-α/β-mediated signaling. Importantly, immunofluorescence analysis illustrated that the inhibition of IFN-α/β-mediated signaling correlated with impaired STAT1/STAT2 nuclear import, whereas the phosphorylation state of these proteins was not affected. Coimmunoprecipitation assays identified the N-terminal region of V (VNT) responsible for STAT1 targeting, which correlated with its ability to inhibit the activity of the IFN-α/β-mediated antiviral state. Conversely, while the C-terminal domain of V (VCT) could not function autonomously, when fused to VNT it optimally interacted with STAT2 and subsequently efficiently suppressed the IFN-α/β-mediated signaling pathway. The latter result was further supported by a single mutation at position 110 within the VNT domain of CDV V protein, resulting in a mutant that lost STAT1 binding while retaining a partial STAT2 association. Taken together, our results identified the CDV VNT and VCT as two essential modules that complement each other to interfere with the antiviral state induced by IFN-α/β-mediated signaling. Hence, our experiments reveal a novel mechanism of IFN-α/β evasion among the morbilliviruses. PMID:20427537

  9. Elevated interleukin-27 levels in human neonatal macrophages regulate indoleamine dioxygenase in a STAT-1 and STAT-3-dependent manner.

    PubMed

    Jung, Joo-Yong; Gleave Parson, Madeline; Kraft, Jennifer D; Lyda, Logan; Kobe, Brianna; Davis, Celestia; Robinson, Jembber; Peña, Maria Marjorette O; Robinson, Cory M

    2016-09-01

    Microbial infections are a major cause of infant mortality as a result of limitations in immune defences. Interleukin-27 (IL-27) is a heterodimeric cytokine produced primarily by leucocytes and is immunosuppressive toward lymphocytes and leucocytes. Our laboratory demonstrated that human neonatal macrophages express IL-27 more abundantly than adult macrophages. Similarly in mice, IL-27 expression is elevated early in life and maintained through infancy. To determine IL-27-regulated mechanisms that may limit immunity, we evaluated the expression of a number of genes in response to this cytokine in primary human neonatal macrophages. Indoleamine 2,3-dioxygenase (IDO) gene expression was increased dose-responsively by IL-27. We have previously demonstrated inhibition of T-cell proliferation and cytokine production by neonatal macrophage-generated IL-27, and IDO is often implicated in this negative regulation. An increase in IDO protein was demonstrated by immunofluorescence microscopy and was consistent with increased enzyme activity following treatment with IL-27. Inclusion of a soluble receptor to neutralize endogenous IL-27, decreased IDO expression and activity compared with untreated macrophages. In response to IL-27, neonatal macrophages phosphorylate signal transdcuer and activator of transcription 1 (STAT-1) and STAT-3. Both transcription factors are recruited to the IDO regulatory region. STAT-3 dominates during steady-state regulation by lower levels of endogenous IL-27 production. A shift to enhanced STAT-1 recruitment occurs during increased levels of exogenously supplied IL-27. These data suggest an interesting interplay of STAT-1 and STAT-3 to regulate IDO activity and immunosuppression in response to different levels of IL-27 in the microenvironment of the immune response that may further our understanding of this interesting cytokine. PMID:27238498

  10. PyDecay/GraphPhys: A Unified Language and Storage System for Particle Decay Process Descriptions

    SciTech Connect

    Dunietz, Jesse N.; /MIT /SLAC

    2011-06-22

    To ease the tasks of Monte Carlo (MC) simulation and event reconstruction (i.e. inferring particle-decay events from experimental data) for long-term BaBar data preservation and analysis, the following software components have been designed: a language ('GraphPhys') for specifying decay processes, common to both simulation and data analysis, allowing arbitrary parameters on particles, decays, and entire processes; an automated visualization tool to show graphically what decays have been specified; and a searchable database storage mechanism for decay specifications. Unlike HepML, a proposed XML standard for HEP metadata, the specification language is designed not for data interchange between computer systems, but rather for direct manipulation by human beings as well as computers. The components are interoperable: the information parsed from files in the specification language can easily be rendered as an image by the visualization package, and conversion between decay representations was implemented. Several proof-of-concept command-line tools were built based on this framework. Applications include building easier and more efficient interfaces to existing analysis tools for current projects (e.g. BaBar/BESII), providing a framework for analyses in future experimental settings (e.g. LHC/SuperB), and outreach programs that involve giving students access to BaBar data and analysis tools to give them a hands-on feel for scientific analysis.

  11. Comment on "Diffusion of n-type dopants in germanium" [Appl. Phys. Rev. 1, 011301 (2014)

    NASA Astrophysics Data System (ADS)

    Cowern, N. E. B.; Simdyankin, S.; Goss, J. P.; Napolitani, E.; De Salvador, D.; Bruno, E.; Mirabella, S.; Ahn, C.; Bennett, N. S.

    2015-09-01

    The authors of the above paper call into question recent evidence on the properties of self-interstitials, I, in Ge [Cowern et al., Phys. Rev. Lett. 110, 155501 (2013)]. We show that this judgment stems from invalid model assumptions during analysis of data on B marker-layer diffusion during proton irradiation, and that a corrected analysis fully supports the reported evidence. As previously stated, I-mediated self-diffusion in Ge exhibits two distinct regimes of temperature, T: high-T, dominated by amorphous-like mono-interstitial clusters—i-morphs—with self-diffusion entropy ≈30 k, and low-T, where transport is dominated by simple self-interstitials. In a transitional range centered on 475 °C both mechanisms contribute. The experimental I migration energy of 1.84 ± 0.26 eV reported by the Münster group based on measurements of self-diffusion during irradiation at 550 °C < T < 680 °C further establishes our proposed i-morph mechanism.

  12. Droplet Spreading with Sol-Gel Transition

    NASA Astrophysics Data System (ADS)

    Jalaal, Maziyar; Stoeber, Boris; Balmforth, Neil J.

    2014-11-01

    The impact and spreading of liquid droplets on a smooth solid substrate is a classical subject with several industrial applications such as ink-jet printing, spray cooling, coating, and many others. For many of these deposition processes, controlling the final shape of the drop is critical. In the current research, a new technique for controlling the spreading of droplets impacting a substrate is presented. This technique exploits the rheology of a thermo-responsive polymer solution that undergoes a reversible sol/gel transition above a critical temperature. Experiments are conducted using a combination of shadowgraphy and micro-PIV to observe spreading drops. It is shown that the final diameter of a droplet can be controlled through the temperature of the substrate and the tunable sol/gel transition temperature of the fluid.A mathematical model is provided to further elucidate the flow dynamics.

  13. Novel carboxy functionalized sol-gel precursors

    SciTech Connect

    Wolter, H.; Storch, W.; Gellermann, C.

    1996-12-31

    A novel family of inorganic-organic copolymers (ORMOCER`s) derived from urethane- and thioether(meth)acrylate alkoxysilanes has been successfully exploited for a variety of diverse applications. In order to widen the range of applications an additional functionality (carboxy group) has been incorporated int his silane type. Conventional sol-gel processing facilitates the formation of an inorganic Si-O-Si-network via hydrolysis and polycondensation reactions of alkoxysilyl moieties and in addition, the (meth)acrylate groups are available for radically induced polymerization to obtain a complementary organic polymer structure. The presence of a carboxy group would appear to have great potential for a range of diverse areas of application, such as an internal catalyst for the sol-gel process, complexation of elements such as Zr and Ti, increasing the adhesion to various substrates and modification of solubility. A number of novel silanes and their syntheses will be described in this paper.

  14. Phoenix Robotic Arm's Workspace After 90 Sols

    NASA Technical Reports Server (NTRS)

    2008-01-01

    During the first 90 Martian days, or sols, after its May 25, 2008, landing on an arctic plain of Mars, NASA's Phoenix Mars Lander dug several trenches in the workspace reachable with the lander's robotic arm.

    The lander's Surface Stereo Imager camera recorded this view of the workspace on Sol 90, early afternoon local Mars time (overnight Aug. 25 to Aug. 26, 2008). The shadow of the the camera itself, atop its mast, is just left of the center of the image and roughly a third of a meter (one foot) wide.

    The workspace is on the north side of the lander. The trench just to the right of center is called 'Neverland.'

    The Phoenix Mission is led by the University of Arizona, Tucson, on behalf of NASA. Project management of the mission is by NASA's Jet Propulsion Laboratory, Pasadena, Calif. Spacecraft development is by Lockheed Martin Space Systems, Denver.

  15. Opportunity's View on Sols 1803 and 1804

    NASA Technical Reports Server (NTRS)

    2009-01-01

    NASA's Mars Exploration Rover Opportunity used its navigation camera to take the images combined into this full-circle view of the rover's surroundings during the 1,803rd and 1,804th Martian days, or sols, of Opportunity's surface mission (Feb. 18 and 19, 2009). South is at the center; north at both ends.

    The rover had driven 55 meters on Sol 1803 before beginning to take the frames in this view. Tracks from that drive recede northward. For scale, the distance between the parallel wheel tracks is about 1 meter (about 40 inches).

    The terrain in this portion of Mars' Meridiani Planum region includes dark-toned sand ripples and lighter-toned bedrock.

    This view is presented as a cylindrical projection with geometric seam correction.

  16. Opportunity's Surroundings After Sol 1820 Drive

    NASA Technical Reports Server (NTRS)

    2009-01-01

    NASA's Mars Exploration Rover Opportunity used its navigation camera to take the images combined into this full-circle view of the rover's surroundings during the 1,820th to 1,822nd Martian days, or sols, of Opportunity's surface mission (March 7 to 9, 2009). South is at the center; north at both ends.

    The rover had driven 20.6 meters toward the northwest on Sol 1820 before beginning to take the frames in this view. Tracks from that drive recede southwestward. For scale, the distance between the parallel wheel tracks is about 1 meter (about 40 inches).

    The terrain in this portion of Mars' Meridiani Planum region includes dark-toned sand ripples and small exposures of lighter-toned bedrock.

    This view is presented as a cylindrical projection with geometric seam correction.

  17. Opportunity's Surroundings After Sol 1820 Drive (Polar)

    NASA Technical Reports Server (NTRS)

    2009-01-01

    NASA's Mars Exploration Rover Opportunity used its navigation camera to take the images combined into this full-circle view of the rover's surroundings during the 1,820th to 1,822nd Martian days, or sols, of Opportunity's surface mission (March 7 to 9, 2009).

    This view is presented as a polar projection with geometric seam correction. North is at the top.

    The rover had driven 20.6 meters toward the northwest on Sol 1820 before beginning to take the frames in this view. Tracks from that drive recede southwestward. For scale, the distance between the parallel wheel tracks is about 1 meter (about 40 inches).

    The terrain in this portion of Mars' Meridiani Planum region includes dark-toned sand ripples and small exposures of lighter-toned bedrock.

  18. Opportunity's Surroundings on Sol 1818 (Polar)

    NASA Technical Reports Server (NTRS)

    2009-01-01

    NASA's Mars Exploration Rover Opportunity used its navigation camera to take the images combined into this full-circle view of the rover's surroundings during the 1,818th Martian day, or sol, of Opportunity's surface mission (March 5, 2009). South is at the center; north at both ends.

    This view is presented as a polar projection with geometric seam correction. North is at the top.

    The rover had driven 80.3 meters (263 feet) southward earlier on that sol. Tracks from the drive recede northward in this view.

    The terrain in this portion of Mars' Meridiani Planum region includes dark-toned sand ripples and lighter-toned bedrock.

  19. Opportunity's Surroundings After Sol 1820 Drive (Vertical)

    NASA Technical Reports Server (NTRS)

    2009-01-01

    NASA's Mars Exploration Rover Opportunity used its navigation camera to take the images combined into this full-circle view of the rover's surroundings during the 1,820th to 1,822nd Martian days, or sols, of Opportunity's surface mission (March 7 to 9, 2009).

    This view is presented as a vertical projection with geometric seam correction. North is at the top.

    The rover had driven 20.6 meters toward the northwest on Sol 1820 before beginning to take the frames in this view. Tracks from that drive recede southwestward. For scale, the distance between the parallel wheel tracks is about 1 meter (about 40 inches).

    The terrain in this portion of Mars' Meridiani Planum region includes dark-toned sand ripples and small exposures of lighter-toned bedrock.

  20. Opportunity's Surroundings on Sol 1818 (Vertical)

    NASA Technical Reports Server (NTRS)

    2009-01-01

    NASA's Mars Exploration Rover Opportunity used its navigation camera to take the images combined into this full-circle view of the rover's surroundings during the 1,818th Martian day, or sol, of Opportunity's surface mission (March 5, 2009). South is at the center; north at both ends.

    This view is presented as a vertical projection with geometric seam correction. North is at the top.

    The rover had driven 80.3 meters (263 feet) southward earlier on that sol. Tracks from the drive recede northward in this view.

    The terrain in this portion of Mars' Meridiani Planum region includes dark-toned sand ripples and lighter-toned bedrock.

  1. Opportunity's Surroundings on Sol 1798 (Vertical)

    NASA Technical Reports Server (NTRS)

    2009-01-01

    NASA's Mars Exploration Rover Opportunity used its navigation camera to take the images combined into this 180-degree view of the rover's surroundings during the 1,798th Martian day, or sol, of Opportunity's surface mission (Feb. 13, 2009). North is on top.

    This view is presented as a vertical projection with geometric seam correction.

    The rover had driven 111 meters (364 feet) southward on the preceding sol. Tracks from that drive recede northward in this view. For scale, the distance between the parallel wheel tracks is about 1 meter (about 40 inches).

    The terrain in this portion of Mars' Meridiani Planum region includes dark-toned sand ripples and lighter-toned bedrock.

  2. Opportunity's Surroundings on Sol 1798 (Polar)

    NASA Technical Reports Server (NTRS)

    2009-01-01

    NASA's Mars Exploration Rover Opportunity used its navigation camera to take the images combined into this 180-degree view of the rover's surroundings during the 1,798th Martian day, or sol, of Opportunity's surface mission (Feb. 13, 2009). North is on top.

    This view is presented as a polar projection with geometric seam correction.

    The rover had driven 111 meters (364 feet) southward on the preceding sol. Tracks from that drive recede northward in this view. For scale, the distance between the parallel wheel tracks is about 1 meter (about 40 inches).

    The terrain in this portion of Mars' Meridiani Planum region includes dark-toned sand ripples and lighter-toned bedrock.

  3. Impediment to Spirit Drive on Sol 1806

    NASA Technical Reports Server (NTRS)

    2009-01-01

    The hazard avoidance camera on the front of NASA's Mars Exploration Rover Spirit took this image after a drive by Spirit on the 1,806th Martian day, or sol, (January 31, 2009) of Spirit's mission on the surface of Mars.

    The wheel at the bottom right of the image is Spirit's right-front wheel. Because that wheel no longer turns, Spirit drives backwards dragging that wheel. The drive on Sol 1806 covered about 30 centimeters (1 foot). The rover team had planned a longer drive, but Spirit stopped short, apparently from the right front wheel encountering the partially buried rock visible next to that wheel.

    The hazard avoidance cameras on the front and back of the rover provide wide-angle views. The hill on the horizon in the right half of this image is Husband Hill. Spirit reached the summit of Husband Hill in 2005.

  4. Innovative materials based on sol gel technology

    NASA Astrophysics Data System (ADS)

    Reisfeld, Renata; Saraidarov, Tsiala

    2006-01-01

    We review the sol-gel based new materials which were prepared in our laboratory including: tunable lasers, active waveguides, luminescent solar concentrators, electrochromic, photochromic and gasochromic plates for smart windows, chemical and biological sensors, semiconductor quantum dots and complexes of rare earth ions. In this paper we present the firstly obtained results of the Eu sulfide nanocrystalline (NCs) powder material and doped in the sol-gel based zirconia films. The powder and films were studied by high resolution transmittance electron microscopy (HRTEM), energy dispersive X-ray spectroscopy analysis (EDS) and luminescence spectroscopy. Eu sulfide nanocrystals (NCs) ranging between 8 and 10 nm were obtained as powder and 3-4 nm incorporated in zirconia film.

  5. The JAK2 inhibitor AZD1480 potently blocks Stat3 signaling and oncogenesis in solid tumors.

    PubMed

    Hedvat, Michael; Huszar, Dennis; Herrmann, Andreas; Gozgit, Joseph M; Schroeder, Anne; Sheehy, Adam; Buettner, Ralf; Proia, David; Kowolik, Claudia M; Xin, Hong; Armstrong, Brian; Bebernitz, Geraldine; Weng, Shaobu; Wang, Lin; Ye, Minwei; McEachern, Kristen; Chen, Huawei; Morosini, Deborah; Bell, Kirsten; Alimzhanov, Marat; Ioannidis, Stephanos; McCoon, Patricia; Cao, Zhu A; Yu, Hua; Jove, Richard; Zinda, Michael

    2009-12-01

    Persistent activation of Stat3 is oncogenic and is prevalent in a wide variety of human cancers. Chronic cytokine stimulation is associated with Stat3 activation in some tumors, implicating cytokine receptor-associated Jak family kinases. Using Jak2 inhibitors, we demonstrate a central role of Jaks in modulating basal and cytokine-induced Stat3 activation in human solid tumor cell lines. Inhibition of Jak2 activity is associated with abrogation of Stat3 nuclear translocation and tumorigenesis. The Jak2 inhibitor AZD1480 suppresses the growth of human solid tumor xenografts harboring persistent Stat3 activity. We demonstrate the essential role of Stat3 downstream of Jaks by inhibition of tumor growth using short hairpin RNA targeting Stat3. Our data support a key role of Jak kinase activity in Stat3-dependent tumorigenesis. PMID:19962667

  6. Analysis of STAT1 expression and biological activity reveals interferon-tau-dependent STAT1-regulated SOCS genes in the bovine endometrium.

    PubMed

    Vitorino Carvalho, A; Eozenou, C; Healey, G D; Forde, N; Reinaud, P; Chebrout, M; Gall, L; Rodde, N; Padilla, A Lesage; Delville, C Giraud; Leveugle, M; Richard, C; Sheldon, I M; Lonergan, P; Jolivet, G; Sandra, O

    2016-03-01

    Signal transducer and activator of transcription (STAT) proteins are critical for the regulation of numerous biological processes. In cattle, microarray analyses identified STAT1 as a differentially expressed gene in the endometrium during the peri-implantation period. To gain new insights about STAT1 during the oestrous cycle and early pregnancy, we investigated STAT1 transcript and protein expression, as well as its biological activity in bovine tissue and cells of endometrial origin. Pregnancy increased STAT1 expression on Day 16, and protein and phosphorylation levels on Day 20. In cyclic and pregnant females, STAT1 was located in endometrial cells but not in the luminal epithelium at Day 20 of pregnancy. The expression of STAT1 during the oestrous cycle was not affected by progesterone supplementation. In vivo and in vitro, interferon-tau (IFNT) stimulated STAT1 mRNA expression, protein tyrosine phosphorylation and nuclear translocation. Using chromatin immunoprecipitation in IFNT-stimulated endometrial cells, we demonstrated an increase of STAT1 binding on interferon regulatory factor 1 (IRF1), cytokine-inducible SH2-containing protein (CISH), suppressor of cytokine signaling 1 and 3 (SOCS1, SOCS3) gene promoters consistent with the induction of their transcripts. Our data provide novel molecular insights into the biological functions of STAT1 in the various cells composing the endometrium during maternal pregnancy recognition and implantation. PMID:25116692

  7. Ring-Resonator/Sol-Gel Interferometric Immunosensor

    NASA Technical Reports Server (NTRS)

    Bearman, Gregory; Cohen, David

    2007-01-01

    A proposed biosensing system would be based on a combination of (1) a sensing volume containing antibodies immobilized in a sol-gel matrix and (2) an optical interferometer having a ring resonator configuration. The antibodies would be specific to an antigen species that one seeks to detect. In the ring resonator of the proposed system, light would make multiple passes through the sensing volume, affording greater interaction length and, hence, greater antibody- detection sensitivity.

  8. Spirit Near 'Stapledon' on Sol 1802 (Polar)

    NASA Technical Reports Server (NTRS)

    2009-01-01

    NASA Mars Exploration Rover Spirit used its navigation camera for the images assembled into this full-circle view of the rover's surroundings during the 1,802nd Martian day, or sol, (January 26, 2009) of Spirit's mission on the surface of Mars. North is at the top.

    This view is presented as a polar projection with geometric seam correction.

    Spirit had driven down off the low plateau called 'Home Plate' on Sol 1782 (January 6, 2009) after spending 12 months on a north-facing slope on the northern edge of Home Plate. The position on the slope (at about the 9-o'clock position in this view) tilted Spirit's solar panels toward the sun, enabling the rover to generate enough electricity to survive its third Martian winter. Tracks at about the 11-o'clock position of this panorama can be seen leading back to that 'Winter Haven 3' site from the Sol 1802 position about 10 meters (33 feet) away. For scale, the distance between the parallel wheel tracks is about one meter (40 inches).

    Where the receding tracks bend to the left, a circular pattern resulted from Spirit turning in place at a soil target informally named 'Stapledon' after William Olaf Stapledon, a British philosopher and science-fiction author who lived from 1886 to 1950. Scientists on the rover team suspected that the soil in that area might have a high concentration of silica, resembling a high-silica soil patch discovered east of Home Plate in 2007. Bright material visible in the track furthest to the right was examined with Spirit's alpha partical X-ray spectrometer and found, indeed, to be rich in silica.

    The team laid plans to drive Spirit from this Sol 1802 location back up onto Home Plate, then southward for the rover's summer field season.

  9. Spirit Near 'Stapledon' on Sol 1802

    NASA Technical Reports Server (NTRS)

    2009-01-01

    NASA Mars Exploration Rover Spirit used its navigation camera for the images assembled into this full-circle view of the rover's surroundings during the 1,802nd Martian day, or sol, (January 26, 2009) of Spirit's mission on the surface of Mars. South is at the center; north is at both ends.

    Spirit had driven down off the low plateau called 'Home Plate' on Sol 1782 (January 6, 2009) after spending 12 months on a north-facing slope on the northern edge of Home Plate. The position on the slope (at about the 9-o'clock position in this view) tilted Spirit's solar panels toward the sun, enabling the rover to generate enough electricity to survive its third Martian winter. Tracks at about the 11-o'clock position of this panorama can be seen leading back to that 'Winter Haven 3' site from the Sol 1802 position about 10 meters (33 feet) away. For scale, the distance between the parallel wheel tracks is about one meter (40 inches).

    Where the receding tracks bend to the left, a circular pattern resulted from Spirit turning in place at a soil target informally named 'Stapledon' after William Olaf Stapledon, a British philosopher and science-fiction author who lived from 1886 to 1950. Scientists on the rover team suspected that the soil in that area might have a high concentration of silica, resembling a high-silica soil patch discovered east of Home Plate in 2007. Bright material visible in the track furthest to the right was examined with Spirit's alpha partical X-ray spectrometer and found, indeed, to be rich in silica.

    The team laid plans to drive Spirit from this Sol 1802 location back up onto Home Plate, then southward for the rover's summer field season.

    This view is presented as a cylindrical projection with geometric seam correction.

  10. Spirit Near 'Stapledon' on Sol 1802 (Vertical)

    NASA Technical Reports Server (NTRS)

    2009-01-01

    NASA Mars Exploration Rover Spirit used its navigation camera for the images assembled into this full-circle view of the rover's surroundings during the 1,802nd Martian day, or sol, (January 26, 2009) of Spirit's mission on the surface of Mars. North is at the top.

    This view is presented as a vertical projection with geometric seam correction.

    Spirit had driven down off the low plateau called 'Home Plate' on Sol 1782 (January 6, 2009) after spending 12 months on a north-facing slope on the northern edge of Home Plate. The position on the slope (at about the 9-o'clock position in this view) tilted Spirit's solar panels toward the sun, enabling the rover to generate enough electricity to survive its third Martian winter. Tracks at about the 11-o'clock position of this panorama can be seen leading back to that 'Winter Haven 3' site from the Sol 1802 position about 10 meters (33 feet) away. For scale, the distance between the parallel wheel tracks is about one meter (40 inches).

    Where the receding tracks bend to the left, a circular pattern resulted from Spirit turning in place at a soil target informally named 'Stapledon' after William Olaf Stapledon, a British philosopher and science-fiction author who lived from 1886 to 1950. Scientists on the rover team suspected that the soil in that area might have a high concentration of silica, resembling a high-silica soil patch discovered east of Home Plate in 2007. Bright material visible in the track furthest to the right was examined with Spirit's alpha partical X-ray spectrometer and found, indeed, to be rich in silica.

    The team laid plans to drive Spirit from this Sol 1802 location back up onto Home Plate, then southward for the rover's summer field season.

  11. JAK1 Activates STAT3 Activity in Non-Small-Cell Lung Cancer cells and IL-6 Neutralizing Antibodies can Suppress JAK1-STAT3 Signaling

    PubMed Central

    Song, Lanxi; Rawal, Bhupendra; Nemeth, Jeffrey A.; Haura, Eric B.

    2014-01-01

    Members of the signal transducer and activator of transcription (STAT) family of transcription factors are potential targets for the treatment and prevention of cancers including non-small-cell lung cancer. STAT proteins can be phosphorylated and activated by diverse upstream kinases including cytokine receptors and tyrosine kinases. We examined STAT protein activation in lung cancer cell lines including those with activating mutations in the EGFR and examined upstream kinases responsible for STAT3 phosphorylation and activation using small molecules, antibodies, and RNA interference. We found more pronounced STAT3 activation in cells with activating EGFR mutations yet inhibition of EGFR activity had no effect on STAT3 activation. Inhibition of JAK1 with small molecules or RNA interference resulted in loss of STAT3 tyrosine phosphorylation and inhibition of cell growth. An interleukin-6 neutralizing antibody, siltuximab (CNTO 328) could inhibit STAT3 tyrosine phosphorylation in a cell-dependent manner. Siltuximab could completely inhibit STAT3 tyrosine phosphorylation in H1650 cells and this resulted in inhibition of lung cancer cell growth in vivo. Combined EGFR inhibition with erlotinib and siltuximab resulted in dual inhibition of both tyrosine and serine STAT3 phosphorylation, more pronounced inhibition of STAT3 transcriptional activity, and translated into combined effects on lung cancer growth in a mouse model. Our results suggest that JAK1 is responsible for STAT3 activation in lung cancer cells, and that indirect attacks on JAK1-STAT3 using an IL-6 neutralizing antibody with or without EGFR inhibition can inhibit lung cancer growth in lung cancer subsets. PMID:21216930

  12. SOL Width Scaling in the MAST Tokamak

    NASA Astrophysics Data System (ADS)

    Ahn, Joon-Wook; Counsell, Glenn; Connor, Jack; Kirk, Andrew

    2002-11-01

    Target heat loads are determined in large part by the upstream SOL heat flux width, Δ_h. Considerable effort has been made in the past to develop analytical and empirical scalings for Δh to allow reliable estimates to be made for the next-step device. The development of scalings for a large spherical tokamak (ST) such as MAST is particularly important both for development of the ST concept and for improving the robustness of scalings derived for conventional tokamaks. A first such scaling has been developed in MAST DND plasmas. The scaling was developed by flux-mapping data from the target Langmuir probe arrays to the mid-plane and fitting to key upstream parameters such as P_SOL, bar ne and q_95. In order to minimise the effects of co-linearity, dedicated campaigns were undertaken to explore the widest possible range of each parameter while keeping the remainder as fixed as possible. Initial results indicate a weak inverse dependence on P_SOL and approximately linear dependence on bar n_e. Scalings derived from consideration of theoretical edge transport models and integration with data from conventional devices is under way. The established scaling laws could be used for the extrapolations to the future machine such as Spherical Tokamak Power Plant (STPP). This work is jointly funded by Euratom and UK Department of Trade and Industry. J-W. Ahn would like to recognise the support of a grant from the British Foreign & Commonwealth Office.

  13. Sol-Gel Manufactured Energetic Materials

    DOEpatents

    Simpson, Randall L.; Lee, Ronald S.; Tillotson, Thomas M.; Hrubesh, Lawrence W.; Swansiger, Rosalind W.; Fox, Glenn A.

    2005-05-17

    Sol-gel chemistry is used for the preparation of energetic materials (explosives, propellants and pyrotechnics) with improved homogeneity, and/or which can be cast to near-net shape, and/or made into precision molding powders. The sol-gel method is a synthetic chemical process where reactive monomers are mixed into a solution, polymerization occurs leading to a highly cross-linked three dimensional solid network resulting in a gel. The energetic materials can be incorporated during the formation of the solution or during the gel stage of the process. The composition, pore, and primary particle sizes, gel time, surface areas, and density may be tailored and controlled by the solution chemistry. The gel is then dried using supercritical extraction to produce a highly porous low density aerogel or by controlled slow evaporation to produce a xerogel. Applying stress during the extraction phase can result in high density materials. Thus, the sol-gel method can be used for precision detonator explosive manufacturing as well as producing precision explosives, propellants, and pyrotechnics, along with high power composite energetic materials.

  14. Sol-gel manufactured energetic materials

    DOEpatents

    Simpson, Randall L.; Lee, Ronald S.; Tillotson, Thomas M.; Hrubesh, Lawrence W.; Swansiger, Rosalind W.; Fox, Glenn A.

    2003-12-23

    Sol-gel chemistry is used for the preparation of energetic materials (explosives, propellants and pyrotechnics) with improved homogeneity, and/or which can be cast to near-net shape, and/or made into precision molding powders. The sol-gel method is a synthetic chemical process where reactive monomers are mixed into a solution, polymerization occurs leading to a highly cross-linked three dimensional solid network resulting in a gel. The energetic materials can be incorporated during the formation of the solution or during the gel stage of the process. The composition, pore, and primary particle sizes, gel time, surface areas, and density may be tailored and controlled by the solution chemistry. The gel is then dried using supercritical extraction to produce a highly porous low density aerogel or by controlled slow evaporation to produce a xerogel. Applying stress during the extraction phase can result in high density materials. Thus, the sol-gel method can be used for precision detonator explosive manufacturing as well as producing precision explosives, propellants, and pyrotechnics, along with high power composite energetic materials.

  15. Opportunity's Surroundings on Sol 1687 (Stereo)

    NASA Technical Reports Server (NTRS)

    2009-01-01

    [figure removed for brevity, see original site] Left-eye view of a color stereo pair for PIA11739 [figure removed for brevity, see original site] Right-eye view of a color stereo pair for PIA11739

    NASA's Mars Exploration Rover Opportunity used its navigation camera to take the images combined into this stereo, 360-degree view of the rover's surroundings on the 1,687th Martian day, or sol, of its surface mission (Oct. 22, 2008). The view appears three-dimensional when viewed through red-blue glasses.

    Opportunity had driven 133 meters (436 feet) that sol, crossing sand ripples up to about 10 centimeters (4 inches) tall. The tracks visible in the foreground are in the east-northeast direction.

    Opportunity's position on Sol 1687 was about 300 meters southwest of Victoria Crater. The rover was beginning a long trek toward a much larger crater, Endeavour, about 12 kilometers (7 miles) to the southeast.

    This panorama combines right-eye and left-eye views presented as cylindrical-perspective projections with geometric seam correction.

  16. 2-Guanidinoquinazolines as new inhibitors of the STAT3 pathway

    PubMed Central

    LaPorte, Matthew G.; da Paz Lima, Dimas José; Zhang, Feng; Sen, Malabika; Grandis, Jennifer R.; Camarco, Daniel; Hua, Yun; Johnston, Paul A.; Lazo, John S.; Resnick, Lynn O.; Wipf, Peter; Huryn, Donna M.

    2014-01-01

    Synthesis and SAR investigation of 2-guanidinoquinazolines, initially identified in a high content screen for selective STAT3 pathway inhibitors, led to a more potent analog (11c) that demonstrated improved anti-proliferative activity against a panel of HNSCC cell lines. PMID:25288188

  17. STAT6-dependent and -independent mechanisms in Th2 polarization

    PubMed Central

    Maier, Elisabeth; Duschl, Albert; Horejs-Hoeck, Jutta

    2012-01-01

    Th2 cells play a key role in directing immune responses against helminths. Additionally, Th2 cells are crucial for many types of allergic reactions. Whereas the molecular mechanisms underlying the differentiation of other types of Th cells are well understood, Th2 differentiation is still a controversial topic. IL-4 and its downstream transcription factor signal transducer and activator of transcription (STAT)6 are well-known key mediators in Th2 differentiation. The fact that Th2 cells themselves are the most potent source of IL-4 suggests that additional mechanisms promoting the initiation of Th2 differentiation exist. This article gives an overview on STAT6-dependent and -independent mechanisms involved in the process of Th2 polarization, including Notch, mTORC2, IL-2/STAT5, and Wnt. Furthermore, we emphasize the role of STAT6 not only as a transcriptional activator promoting Th2 development, but also in fine-tuning alternative signaling pathways which are involved in the initiation of Th2 polarization. PMID:23041833

  18. Fun with SFX and stat_object_offline.

    SciTech Connect

    Ou, Carol

    2012-04-01

    SFX's built-in statistical reports can be handy, but sometimes you might want to slice and dice SFX statistics a little more closely than those reports allow. This session will discuss some preliminary efforts to use the data in SFX's stat{_}object{_}offline table to learn more about our users and how they use SFX.

  19. Stat3 Is Important for Follicular Regulatory T Cell Differentiation

    PubMed Central

    Wu, Hao; Xie, Markus M.; Liu, Hong; Dent, Alexander L.

    2016-01-01

    The production of antibody is precisely controlled during the germinal center (GC) reaction. This process is dependent on the help from follicular T helper (Tfh) cells to germinal center (GC) B cells and is regulated by regulatory follicular T helper (Tfr) cells. How Tfr cells develop and how their suppressive activity functions are not well understood. Here, we found that Stat3 is indispensible for Tfr cell differentiation. After immunization with Sheep Red Blood Cells (SRBC), the loss of Tfr cells caused by deletion of Stat3 in Treg cells does not affect the size of Tfh or GC B cell population, but rather leads to strongly enhanced production of antigen-specific IgG1 and IgG2b. In Peyer’s patches (PPs) in the gut, we found that Stat3 expression in Treg cells is also required for Tfr cell formation to commensal organisms. However, loss of Tfr cells in the gut did not affect the numbers of Tfh cells and GC B cells, nor affect IgG1 or IgA switching by GC B cells. Overall, our study has uncovered unique roles of Stat3 in Tfr cell differentiation and the regulation of the antibody response. PMID:27148746

  20. Nuclear unphosphorylated STAT3 correlates with a worse prognosis in human glioblastoma.

    PubMed

    Rodrigues, Bruna R; Queiroz-Hazarbassanov, Nicolle; Lopes, Marilene H; Bleggi-Torres, Luis F; Suzuki, Sérgio; Cunha, Isabela W; Sanematsu, Paulo; Martins, Vilma R

    2016-06-01

    Glioblastoma (GBM) is currently the most aggressive form of brain tumor identified, and STAT3 is known to play an important role in gliomagenesis. Moreover, while several studies have used pharmacological approaches to modulate STAT3 activity, the results have been contradictory. In this study, expressions of STAT3, pSTAT3 (Y705), and pSTAT3 (S727) were evaluated using immunohistochemistry assays of tissue microarrays containing non-neoplastic tissue (NN, n=12), grade II astrocytomas (n=33), grade III astrocytomas (n=12), and GBM (n=85) specimens. In GBM specimens, STAT3 was overexpressed and exhibited greater nuclear localization compared with lower grade astrocytomas and NN. Conversely, nuclear localization of pSTAT3 (Y705) and pSTAT3 (S727) exhibited a similar phenotype in both GBMs and NNs. MET was also detected as a non-canonical pathway marker for STAT3. For tumors with higher levels of STAT3 nuclear localization, and not pSTAT3 (Y705) and pSTAT3 (S727), these specimens exhibited increased levels of MET expression. Thus, a non-canonical pathway may mediate a proportion of the STAT3 that translocates to the nucleus. Moreover, tumors which exhibited greater nuclear localization of STAT3 corresponded with patients that presented with lower rates of recurrence-free survival and overall survival. In contrast, the phosphorylated forms of STAT3 did not correlate with patient survival. These findings suggest that phosphorylation-independent mechanisms may mediate the nuclear translocation and activation of STAT3. Further studies are needed to identify the mechanisms involved, especially those that provide targets to achieve efficient inhibition and control of GBM progression. PMID:27013058

  1. Methotrexate Is a JAK/STAT Pathway Inhibitor

    PubMed Central

    Thomas, Sally; Fisher, Katherine H.; Snowden, John A.; Danson, Sarah J.; Brown, Stephen; Zeidler, Martin P.

    2015-01-01

    Background The JAK/STAT pathway transduces signals from multiple cytokines and controls haematopoiesis, immunity and inflammation. In addition, pathological activation is seen in multiple malignancies including the myeloproliferative neoplasms (MPNs). Given this, drug development efforts have targeted the pathway with JAK inhibitors such as ruxolitinib. Although effective, high costs and side effects have limited its adoption. Thus, a need for effective low cost treatments remains. Methods & Findings We used the low-complexity Drosophila melanogaster pathway to screen for small molecules that modulate JAK/STAT signalling. This screen identified methotrexate and the closely related aminopterin as potent suppressors of STAT activation. We show that methotrexate suppresses human JAK/STAT signalling without affecting other phosphorylation-dependent pathways. Furthermore, methotrexate significantly reduces STAT5 phosphorylation in cells expressing JAK2 V617F, a mutation associated with most human MPNs. Methotrexate acts independently of dihydrofolate reductase (DHFR) and is comparable to the JAK1/2 inhibitor ruxolitinib. However, cells treated with methotrexate still retain their ability to respond to physiological levels of the ligand erythropoietin. Conclusions Aminopterin and methotrexate represent the first chemotherapy agents developed and act as competitive inhibitors of DHFR. Methotrexate is also widely used at low doses to treat inflammatory and immune-mediated conditions including rheumatoid arthritis. In this low-dose regime, folate supplements are given to mitigate side effects by bypassing the biochemical requirement for DHFR. Although independent of DHFR, the mechanism-of-action underlying the low-dose effects of methotrexate is unknown. Given that multiple pro-inflammatory cytokines signal through the pathway, we suggest that suppression of the JAK/STAT pathway is likely to be the principal anti-inflammatory and immunosuppressive mechanism-of-action of low

  2. Erratum: Studying the precision of ray tracing techniques with Szekeres models [Phys. Rev. D 92, 023532 (2015)

    NASA Astrophysics Data System (ADS)

    Koksbang, S. M.; Hannestad, S.

    2015-09-01

    This erratum serves to give corrections of two errors made in Koksbang and Hannestad [Phys. Rev. D, 92, 023532 (2015)]. One error consists of having used the expression for the Doppler convergence for a flat background to study the convergence on curved backgrounds. The other error which was made, is a typo in the numerical code used to study the convergence in onion models with curved backgrounds. After correcting this typo, the results of Sec. VI A in Koksbang and Hannestad [Phys. Rev. D, 92, 023532 (2015)] were recomputed. Contrary to the original results, the new results show that the ray-tracing scheme studied in Koksbang and Hannestad [Phys. Rev. D, 92, 023532 (2015)] can reproduce the exact results in LTB onion models very well. The corrections and new results are described more elaborately below.

  3. Sol-gel processing to form doped sol-gel monoliths inside hollow core optical fiber and sol-gel core fiber devices made thereby

    NASA Technical Reports Server (NTRS)

    Shaw, Harry C. (Inventor); Ott, Melanie N. (Inventor); Manuel, Michele V. (Inventor)

    2002-01-01

    A process of fabricating a fiber device includes providing a hollow core fiber, and forming a sol-gel material inside the hollow core fiber. The hollow core fiber is preferably an optical fiber, and the sol-gel material is doped with a dopant. Devices made in this manner includes a wide variety of sensors.

  4. Profibrogenic phenotype in caveolin-1 deficiency via differential regulation of STAT-1/3 proteins.

    PubMed

    Ryter, Stefan W; Choi, Augustine M K; Kim, Hong Pyo

    2014-10-01

    Fibrosis underlies the pathogenesis of several human diseases, which can lead to severe injury of vital organs. We previously demonstrated that caveolin-1 expression is reduced in experimental fibrosis and that caveolin-1 exerts antiproliferative and antifibrotic effects in lung fibrosis models. The signal transducers and activators of transcription (STAT) proteins, STAT1 and STAT3, can be activated simultaneously. STAT1 can inhibit cell growth and promote apoptosis while STAT3 inhibits apoptosis. Here, we show that caveolin-1-deficient (cav-1(-/-)) lung fibroblasts display dramatically upregulated STAT3 activation in response to platelet-derived growth factor-BB and transforming growth factor-β stimuli, whereas STAT1 activation is undetectable. Downregulation of protein tyrosine phosphatase-1B played a role in the preferential activation of STAT3 in cav-1(-/-) fibroblasts. Genetic deletion of STAT3 by siRNA modulated the expression of genes involved in cell proliferation and fibrogenesis. Basal expression of α-smooth muscle actin was prominent in cav-1(-/-) liver and kidney, consistent with deposition of collagen in these organs. Collectively, we demonstrate that the antiproliferative and antifibrogenic properties of caveolin-1 in vitro are mediated by the balance between STAT1 and STAT3 activation. Deregulated STAT signaling associated with caveolin-1 deficiency may be relevant to proliferative disorders such as tissue fibrosis. PMID:25263949

  5. Truncated pStat5B is associated with the Idd4 locus in NOD mice

    SciTech Connect

    Davoodi-Semiromi, Abdoreza . E-mail: semiromi@pathology.ufl.edu; McDuffie, Marcia; Litherland, Sally; Clare-Salzler, Michael

    2007-05-11

    We investigate JAK-STAT5 activation and its relationship to full-length Stat5B (FL-Stat5) and constitutive phosphorylated carboxy-truncated Stat5B (ct-pStat5) in four different strains of mouse. Our electrophoresis mobility shift assays data indicate constitutive phosphorylation of full-length-Stat5 (p < 0.001) and DNA binding in NOD but not in B6 mice. Our data suggest that the relative ratio of FL-Stat5: ct-Stat5 in NOD is 5- to 8-fold lower (p < 0.0001) when compared with normal B6 mice. Additionally, EMSAs data from B6.NOD/c11 suggest contribution of Idd4 susceptibility locus on chromosome 11 in constitutive phosphorylation of Stat5 in NOD mice. The presence of ct-pStat5 in regulatory T cells of NOD mice suggests this form of Stat5 is associated with impaired function of Tregs in NOD mouse. In agreement with our previous report the JAK-Stat5B defective pathway in NOD mice along with other defective factors is associated with the pathogenesis of autoimmune type 1 diabetes in NOD mice.

  6. Mutational analysis of acute-phase response factor/Stat3 activation and dimerization.

    PubMed Central

    Sasse, J; Hemmann, U; Schwartz, C; Schniertshauer, U; Heesel, B; Landgraf, C; Schneider-Mergener, J; Heinrich, P C; Horn, F

    1997-01-01

    Signal transducer and transcription (STAT) factors are activated by tyrosine phosphorylation in response to a variety of cytokines, growth factors, and hormones. Tyrosine phosphorylation triggers dimerization and nuclear translocation of these transcription factors. In this study, the functional role of carboxy-terminal portions of the STAT family member acute-phase response factor/Stat3 in activation, dimerization, and transactivating potential was analyzed. We demonstrate that truncation of 55 carboxy-terminal amino acids causes constitutive activation of Stat3 in COS-7 cells, as is known for the Stat3 isoform Stat3beta. By the use of deletion and point mutants, it is shown that both carboxy- and amino-terminal portions of Stat3 are involved in this phenomenon. Dimerization of Stat3 was blocked by point mutations affecting residues both in the vicinity of the tyrosine phosphorylation site (Y705) and more distant from this site, suggesting that multiple interactions are involved in dimer formation. Furthermore, by reporter gene assays we demonstrate that carboxy-terminally truncated Stat3 proteins are incapable of transactivating an interleukin-6-responsive promoter in COS-7 cells. In HepG2 hepatoma cells, however, these truncated Stat3 forms transmit signals from the interleukin-6 signal transducer gp130 equally well as does full-length Stat3. We conclude that, dependent on the cell type, different mechanisms allow Stat3 to regulate target gene transcription either with or without involvement of its putative carboxy-terminal transactivation domain. PMID:9234724

  7. Differences in antiproliferative effect of STAT3 inhibition in HCC cells with versus without HBV expression

    SciTech Connect

    Hong, Yun; Zhou, Lin; Xie, Haiyang; Wang, Weilin; Zheng, Shusen

    2015-06-05

    Chronic infection with hepatitis B virus (HBV) plays an important role in the etiology of hepatocellular carcinoma (HCC). Signal transducer and activator of transcription 3 (STAT3) inactivation could inhibit the tumor growth of HCC. In this study, differential antiproliferative effect of STAT3 inhibition was observed with HBV-related HCC cells being more resistant than non-HBV-related HCC cells. Resistance of HBV-related HCC cells to STAT3 inhibition was positively correlated to the expression of HBV. Enhanced ERK activation after STAT3 blockade was detected in HBV-related HCC cells but not in non-HBV-related HCC cells. Combined ERK and STAT3 inhibition eliminates the discrepancy between the two types of HCC cells. Moderate reduced HBV expression was found after STAT3 inhibition. These findings disclose a discrepancy in cellular response to STAT3 inhibition between non-HBV-related and HBV-related HCC cells and underscore the complexity of antiproliferative effect of STAT3 inactivation in HBV-related HCC cells. - Highlights: • HBV endows HCC cells with resistance to STAT3 inactivation on proliferation. • Abnormal ERK activation after STAT3 inhibition in HBV-related HCC cells. • Combined ERK and STAT3 inhibition eliminates the discrepancy. • STAT3 inhibition moderately reduces HBV expression.

  8. STAT3 Serine 727 Phosphorylation: A Relevant Target to Radiosensitize Human Glioblastoma.

    PubMed

    Ouédraogo, Zangbéwendé Guy; Müller-Barthélémy, Mélanie; Kemeny, Jean-Louis; Dedieu, Véronique; Biau, Julian; Khalil, Toufic; Raoelfils, Lala Ines; Granzotto, Adeline; Pereira, Bruno; Beaudoin, Claude; Guissou, Innocent Pierre; Berger, Marc; Morel, Laurent; Chautard, Emmanuel; Verrelle, Pierre

    2016-01-01

    Radiotherapy is an essential component of glioma standard treatment. Glioblastomas (GBM), however, display an important radioresistance leading to tumor recurrence. To improve patient prognosis, there is a need to radiosensitize GBM cells and to circumvent the mechanisms of resistance caused by interactions between tumor cells and their microenvironment. STAT3 has been identified as a therapeutic target in glioma because of its involvement in mechanisms sustaining tumor escape to both standard treatment and immune control. Here, we studied the role of STAT3 activation on tyrosine 705 (Y705) and serine 727 (S727) in glioma radioresistance. This study explored STAT3 phosphorylation on Y705 (pSTAT3-Y705) and S727 (pSTAT3-S727) in glioma cell lines and in clinical samples. Radiosensitizing effect of STAT3 activation down-modulation by Gö6976 was explored. In a panel of 15 human glioma cell lines, we found that the level of pSTAT3-S727 was correlated to intrinsic radioresistance. Moreover, treating GBM cells with Gö6976 resulted in a highly significant radiosensitization associated to a concomitant pSTAT3-S727 down-modulation only in GBM cell lines that exhibited no or weak pSTAT3-Y705. We report the constitutive activation of STAT3-S727 in all GBM clinical samples. Targeting pSTAT3-S727 mainly in pSTAT3-Y705-negative GBM could be a relevant approach to improve radiation therapy. PMID:25736961

  9. The JAK/STAT signaling cascade in gastric carcinoma (Review).

    PubMed

    Khanna, Puja; Chua, Pei Jou; Bay, Boon Huat; Baeg, Gyeong Hun

    2015-11-01

    Gastric carcinoma remains one of the most prevalent forms of cancer worldwide, despite the decline in incidence rates, increased awareness of the disease and advancement in treatment strategies. Helicobacter pylori infection, dietary factors, lifestyle influences and various genetic aberrations have been shown to contribute to the development and progression of gastric cancer. Recent studies on the genomic landscape of gastric adenocarcinoma have identified several key signaling molecules, including epidermal growth factor receptor family (ErbB) members, vascular endothelial growth factor receptor family (VEGFR) members and PI3K/Akt/mTOR pathway components, that have been implicated in the molecular pathogenesis of gastric cancers. However, clinical trials with compounds that target these molecules have failed to show a significant improvement in overall survival rates when supplemented with conventional therapies. Therefore, it is essential to identify effective prognostic and/or diagnostic biomarkers and develop molecular targeted therapies. The JAK/STAT cascade is a principal signal transduction pathway in cytokine and growth factor signaling, regulating various cellular processes such as cell proliferation, differentiation, migration and survival. Numerous in vivo and in vitro studies have shown that dysregulated JAK/STAT signaling is a driving force in the pathogenesis of various solid cancers as well as hematopoietic malignancies. Hence, a large number of preclinical and clinical studies of drugs targeting this pathway are currently underway. Notably, aberrant JAK/STAT signaling has also been implicated in gastric cancers. In this review, we focus on the ongoing research on the JAK/STAT cascade in gastric carcinoma and discuss the therapeutic potential of targeting JAK/STAT signaling for the treatment of gastric cancer. PMID:26398764

  10. The reliability of the i-STAT clinical portable analyser.

    PubMed

    Dascombe, B J; Reaburn, P R J; Sirotic, A C; Coutts, A J

    2007-06-01

    The purpose of this investigation was to assess the reliability of the i-STAT clinical portable analyser and CG(4)(+) cartridge measures of blood pH, partial pressures of O(2) (pO(2)) and CO(2) (pCO(2)), bicarbonate ([HCO(3)(-)]), base excess (BE), total carbon dioxide (TCO(2)), oxygen saturation (sO(2)) and blood lactate ([BLa(-)]) at various exercise intensities. A comparison between [BLa(-)] measured by the i-STAT and the Accusport lactate analysers during an intermittent treadmill run was also undertaken. The technical error of measurement (TEM%) at rest, at moderate (200W) and maximal exercise (V O(2)max) was acceptable (<15%) for all parameters. The intra-class correlation coefficients for each analyte ranged from weak-to-strong across resting (ICC=0.19-0.96) and moderate (ICC=0.30-0.96) exercise intensities. The ICC for all analytes were observed to be strong following maximal intensity exercise (ICC=0.77-0.95). The comparison of the [BLa(-)] measures between the i-STAT and Accusport showed that the difference between measures was acceptable at both low (<4mmolL(-1)) (-0.39+/-0.27mmolL(-1)), moderate to high concentrations (>4mmolL(-1)) (0.58+/-1.22mmolL(-1)), and across all [BLa(-)] data (0.36+/-1.13mmolL(-1)). In conclusion, the i-STAT clinical analyser and CG(4)(+) cartridge provides reliable measures of a number of blood parameters across exercise intensities. The [BLa(-)] measures from the i-STAT analyser are consistent with that of the Accusport lactate analyser. PMID:16846754

  11. A Streamflow Statistics (StreamStats) Web Application for Ohio

    USGS Publications Warehouse

    Koltun, G.F.; Kula, Stephanie P.; Puskas, Barry M.

    2006-01-01

    A StreamStats Web application was developed for Ohio that implements equations for estimating a variety of streamflow statistics including the 2-, 5-, 10-, 25-, 50-, 100-, and 500-year peak streamflows, mean annual streamflow, mean monthly streamflows, harmonic mean streamflow, and 25th-, 50th-, and 75th-percentile streamflows. StreamStats is a Web-based geographic information system application designed to facilitate the estimation of streamflow statistics at ungaged locations on streams. StreamStats can also serve precomputed streamflow statistics determined from streamflow-gaging station data. The basic structure, use, and limitations of StreamStats are described in this report. To facilitate the level of automation required for Ohio's StreamStats application, the technique used by Koltun (2003)1 for computing main-channel slope was replaced with a new computationally robust technique. The new channel-slope characteristic, referred to as SL10-85, differed from the National Hydrography Data based channel slope values (SL) reported by Koltun (2003)1 by an average of -28.3 percent, with the median change being -13.2 percent. In spite of the differences, the two slope measures are strongly correlated. The change in channel slope values resulting from the change in computational method necessitated revision of the full-model equations for flood-peak discharges originally presented by Koltun (2003)1. Average standard errors of prediction for the revised full-model equations presented in this report increased by a small amount over those reported by Koltun (2003)1, with increases ranging from 0.7 to 0.9 percent. Mean percentage changes in the revised regression and weighted flood-frequency estimates relative to regression and weighted estimates reported by Koltun (2003)1 were small, ranging from -0.72 to -0.25 percent and -0.22 to 0.07 percent, respectively.

  12. Ionogel Electrolytes through Sol-Gel Processing

    NASA Astrophysics Data System (ADS)

    Horowitz, Ariel I.

    Electrical energy needs have intensified due to the ubiquity of personal electronics, the decarbonization of energy services through electrification, and the use of intermittent renewable energy sources. Despite developments in mechanical and thermal methods, electrochemical technologies are the most convenient and effective means of storing electrical energy. These technologies include both electrochemical cells, commonly called batteries, and electrochemical double-layer capacitors, or "supercapacitors", which store energy electrostatically. Both device types require an ion-conducting electrolyte. Current devices use solutions of complex salts in organic solvents, leading to both toxicity and flammability concerns. These drawbacks can be avoided by replacing conventional electrolytes with room-temperature molten salts, known as ionic liquids (ILs). ILs are non-volatile, non-flammable, and offer high conductivity and good electrochemical stability. Device mass can be reduced by combining ILs with a solid scaffold material to form an "ionogel," further improving performance metrics. In this work, sol-gel chemistry is explored as a means of forming ionogel electrolytes. Sol-gel chemistry is a solution-based, industrially-relevant, well-studied technique by which solids such as silica can be formed in situ. Previous works used a simple acid-catalyzed sol-gel reaction to create brittle, glassy ionogels. Here, both the range of products that can be accomplished through sol-gel processing and the understanding of interactions between ILs and the sol-gel reaction network are greatly expanded. This work introduces novel ionogel materials, including soft and compliant silica-supported ionogels and PDMS-supported ionogels. The impacts of the reactive formulation, IL identity, and casting time are detailed. It is demonstrated that variations in formulation can lead to rapid gelation and open pore structures in the silica scaffold or slow gelation and more dense silica

  13. Comment on ``The application of the thermodynamic perturbation theory to study the hydrophobic hydration'' [J. Chem. Phys. 139, 024101 (2013)

    NASA Astrophysics Data System (ADS)

    Graziano, Giuseppe

    2013-09-01

    It is shown that the behaviour of the hydration thermodynamic functions obtained in the 3D Mercedes-Benz model of water by Mohoric et al. [J. Chem. Phys. 139, 024101 (2013)] is not qualitatively correct with respect to experimental data for a solute whose diameter is 1.5-fold larger than that of a water molecule. It is also pointed out that the failure is due to the fact that the used 3D Mercedes-Benz model of water [A. Bizjak, T. Urbic, V. Vlachy, and K. A. Dill, J. Chem. Phys. 131, 194504 (2009)] does not reproduce in a quantitatively correct manner the peculiar temperature dependence of water density.

  14. Erratum: Diffusive quantum criticality in three-dimensional disordered Dirac semimetals [Phys. Rev. B 90, 241112(R) (2014)

    NASA Astrophysics Data System (ADS)

    Roy, Bitan; Das Sarma, S.

    2016-03-01

    We correct erroneous conclusions from our previous article [Phys. Rev. B 90, 241112(R) (2014), 10.1103/PhysRevB.90.241112] regarding the values of various critical exponents, calculated to two-loop order. Furthermore, from a three-loop renormalization group flow equation, we argue, that ɛ -expansion near two spatial dimensions, with ɛ =d -2 , may not be reliable to address the critical properties of the disorder-driven Dirac semimetal-metal quantum phase transition in d =3 .

  15. 'Papillary' solitary fibrous tumor/hemangiopericytoma with nuclear STAT6 expression and NAB2-STAT6 fusion.

    PubMed

    Ishizawa, Keisuke; Tsukamoto, Yoshitane; Ikeda, Shunsuke; Suzuki, Tomonari; Homma, Taku; Mishima, Kazuhiko; Nishikawa, Ryo; Sasaki, Atsushi

    2016-04-01

    This report describes clinicopathological findings, including genetic data of STAT6, in a solitary fibrous tumor (SFT)/hemangiopericytoma (HPC) of the central nervous system in an 83-year-old woman with a bulge in the left forehead. She noticed it about 5 months before, and it had grown rapidly for the past 1 month. Neuroradiological studies disclosed a well-demarcated tumor that accompanied the destruction of the skull. The excised tumor showed a prominent papillary structure, where atypical cells were compactly arranged along the fibrovascular core ('pseudopapillary'). There was rich vasculature, some of which resembled 'staghorn' vessels. Mitotic figures were occasionally found. Whorls, psammoma bodies, or intra-nuclear pseudoinclusions were not identified. By immunohistochemistry, CD34 was strongly positive in the tumor cells, and STAT6 was localized in their nuclei. By reverse transcription-polymerase chain reaction (RT-PCR), an NAB2-STAT6 fusion gene, NAB2 exon6-STAT6 exon17, was detected, establishing a definite diagnosis of SFT/HPC. 'Papillary' SFT/HPC needs to be recognized as a possible morphological variant of SFT/HPC, and should be borne in mind in its diagnostic practice. PMID:26746203

  16. Method of making particles from an aqueous sol

    DOEpatents

    Rankin, G.W.; Hooker, J.R.

    1973-07-24

    A process for preparing gel particles from an aqueous sol by forming the sol into droplets in a liquid system wherein the liquid phase contains a liquid organic solvent and a barrier agent. The barrier agent prevents dehydration from occurring too rapidly and permits surface tension effects to form sol droplets into the desired spheroidal shape. A preferred barrier agent is mineral oil. (Official Gazette)

  17. Global changes in STAT target selection and transcription regulation upon interferon treatments

    PubMed Central

    Hartman, Stephen E.; Bertone, Paul; Nath, Anjali K.; Royce, Thomas E.; Gerstein, Mark; Weissman, Sherman; Snyder, Michael

    2005-01-01

    The STAT (signal transducer and activator of transcription) proteins play a crucial role in the regulation of gene expression, but their targets and the manner in which they select them remain largely unknown. Using chromatin immunoprecipitation and DNA microarray analysis (ChIP-chip), we have identified the regions of human chromosome 22 bound by STAT1 and STAT2 in interferon-treated cells. Analysis of the genomic loci proximal to these binding sites introduced new candidate STAT1 and STAT2 target genes, several of which are affiliated with proliferation and apoptosis. The genes on chromosome 22 that exhibited interferon-induced up- or down-regulated expression were determined and correlated with the STAT-binding site information, revealing the potential regulatory effects of STAT1 and STAT2 on their target genes. Importantly, the comparison of STAT1-binding sites upon interferon (IFN)-γ and IFN-α treatments revealed dramatic changes in binding locations between the two treatments. The IFN-α induction revealed nonconserved STAT1 occupancy at IFN-γ-induced sites, as well as novel sites of STAT1 binding not evident in IFN-γ-treated cells. Many of these correlated with binding by STAT2, but others were STAT2 independent, suggesting that multiple mechanisms direct STAT1 binding to its targets under different activation conditions. Overall, our results reveal a wealth of new information regarding IFN/STAT-binding targets and also fundamental insights into mechanisms of regulation of gene expression in different cell states. PMID:16319195

  18. Molecular cloning and expression analysis of the STAT1 gene from olive flounder, Paralichthys olivaceus

    PubMed Central

    Park, Eun-Mi; Kang, Jung-Ha; Seo, Jung Soo; Kim, GunDo; Chung, Jongkyeong; Choi, Tae-Jin

    2008-01-01

    Background Signal transducer and activator of transcription 1 (STAT1) is a critical component of interferon (IFN)-alpha/beta and IFN-gamma signaling. Although seven isoforms of STAT proteins have been reported from mammals, limited information is available for the STAT genes in fish. We isolated complementary DNA with high similarity to mammalian STAT1 from the olive flounder, Paralichthys olivaceus. Results A DNA fragment containing the conserved SH2 domain was amplified by RT-PCR using degenerate primers designed based on the highly conserved sequences in the SH2 domains of the zebrafish and mammalian STAT1. The complete cDNA sequence was obtained by 5' and 3' RACE. The flounder STAT1 transcript consisted of 2,909 bp that encoded a polypeptide of 749 amino acids. The overall similarity between flounder STAT1 and other STATs was very high, with the highest amino acid sequence identity to snakehead (89%). Phylogenetic analyses reveal that flounder STAT1 is in the same monophyletic group with snakehead STAT1. Quantitative real time RT-PCR and in situ hybridization revealed that STAT1 was expressed in almost all examined organs and tissues, with high expression in gill, spleen, kidney, and heart. The accumulation of STAT1 mRNA in different developmental stages, as determined by real time RT-PCR, increased with development. Conclusion Recent cloning of various cytokine genes and the STAT1 gene of olive flounder here suggest that fish also use the highly specialized JAK-STAT pathway for cytokine signaling. Identification of other STAT genes will elucidate in detail the signal transduction system in this fish. PMID:18578892

  19. Live-Cell Imaging of the Association of STAT6-GFP with Mitochondria

    PubMed Central

    Khan, Rasel; Lee, Jason E.; Yang, Yang-Ming; Liang, Feng-Xia; Sehgal, Pravin B.

    2013-01-01

    The transcription factor STAT3 has been previously reported to be associated with mitochondria. However, we have been unable to visualize an association of STAT3-GFP, STAT3-DsRed or STAT3-Flag with mitochondria in human Hep3B hepatocytes thus far even though an association of these molecules with other cytoplasmic organelles (endosomes) was readily demonstrable. We then addressed the broader question of a possible association of other STAT-family of proteins with mitochondria by first using immunolocalization assays in Hep3B and human pulmonary arterial endothelial and smooth muscle cells. Strong anti-STAT6-immunolocalization with mitochondria was apparent in fluorescence and electron microscopy assays of cells first washed with a digitonin-sucrose buffer to remove bulk soluble STAT proteins. In live-cell imaging studies, STAT6-GFP, but not N1-GFP, was observed to constitutively colocalize with MitoTracker- and tetramethylrhodamine ethyl ester (TMRE)-positive mitochondria, and with mitochondrial F1-ATPase when assayed by immunofluorescence after fixation. This association was Tyr-phosphorylation independent in that a STAT6 truncated protein (STAT61-459-GFP) which lacked the SH2 domain (517–632) and the cytokine-activated Y641 phosphorylation site also accumulated in MitoTracker-positive mitochondria. This was consistent with the unexpected discovery that anti-STAT6-immunofluoresence also associated with mitochondria in mouse embryo fibroblasts (MEFs) from both wild-type and the STAT6SH2-/SH2- mouse. MEFs from the latter mouse, which had been engineered in 1996 to be deleted in the STAT6 SH2 domain (amino acids 505–584) expressed an immune-specific ∼50 kDa protein detectable in whole cell and mitochondria-enriched fractions. Taken together, the present data provide the first definitive evidence of the association of any STAT-protein family member with mitochondria - that of STAT6. PMID:23383189

  20. Salidroside attenuates inflammatory response via suppressing JAK2-STAT3 pathway activation and preventing STAT3 transfer into nucleus.

    PubMed

    Qi, Zhilin; Qi, Shimei; Ling, Liefeng; Lv, Jun; Feng, Zunyong

    2016-06-01

    Salidroside (SAL) is an active ingredient isolated from the Rhodiola rosea, has potent anti-inflammatory effect, but the mechanism is still elusive. The purpose of this study is to verify the effects of SAL on LPS-induced inflammatory response and investigate the possible underlying molecular mechanism. RAW264.7 cells were pre-incubated with SAL for 2h, then stimulated with or without LPS for another 16h. The levels of TNF-α, MCP-1, IL-6, and PGE2 were detected by ELISA, and the production of NO was determined by nitrite analysis. The expression levels of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were detected by Western blotting. In RAW264.7 cells and murine peritoneal macrophages, the activation of signal molecules was also measured by Western blot. The nuclear translocation of STAT3 was determined by Laser confocal and nucleocytoplasmic separation experiments. Our results showed that SAL attenuated the productions of TNF-α, IL-6, MCP-1, PGE2 and NO dose dependently. SAL also suppressed LPS-induced expressions of iNOS and COX-2 significantly. Further studies revealed that SAL down-regulated the phosphorylation of JAK2-STAT3 signaling pathway and reduced the nuclear translocation of STAT3 induced by LPS in RAW264.7 cells and primary peritoneal macrophages. In addition, consistent with the results in vitro, in the model of mice acute lung injury (ALI) induced by LPS, SAL reduced the infiltration of inflammatory cells and decreased the levels of serum TNF-α and IL-6 obviously. Taken together, these data indicated that SAL exerted anti-inflammatory action via down-regulating LPS-induced activation of JAK2-STAT3 pathway and suppressing STAT3 transfer into the nucleus at least in part. PMID:27085677

  1. Sol gels. (Latest citations from Materials Business file). Published Search

    SciTech Connect

    1996-01-01

    The bibliography contains citations concerning sol gel derived materials. The citations examine research conducted by universities, corporations and government agencies for the development of novel sol gel processes, and commercial applications of these techniques. Uses of sol gels in the production of glass, ceramics, composites, protective coatings, and hybrid organic/inorganic materials are described. Other topics include new products, expanding markets for sol gel derived materials, and profit potential. (Contains 50-250 citations and includes a subject term index and title list.) (Copyright NERAC, Inc. 1995)

  2. Sol-gel processing with inorganic metal salt precursors

    DOEpatents

    Hu, Zhong-Cheng

    2004-10-19

    Methods for sol-gel processing that generally involve mixing together an inorganic metal salt, water, and a water miscible alcohol or other organic solvent, at room temperature with a macromolecular dispersant material, such as hydroxypropyl cellulose (HPC) added. The resulting homogenous solution is incubated at a desired temperature and time to result in a desired product. The methods enable production of high quality sols and gels at lower temperatures than standard methods. The methods enable production of nanosize sols from inorganic metal salts. The methods offer sol-gel processing from inorganic metal salts.

  3. Active components with inhibitory activities on IFN-γ/STAT1 and IL-6/STAT3 signaling pathways from Caulis Trachelospermi.

    PubMed

    Liu, Xiao-Ting; Wang, Zhe-Xing; Yang, Yu; Wang, Lin; Sun, Ruo-Feng; Zhao, Yi-Min; Yu, Neng-Jiang

    2014-01-01

    Initial investigation for new active herbal extract with inhibiting activity on JAK/STAT signaling pathway revealed that the extract of Caulis Trachelospermi, which was separated by 80% alcohol extraction and subsequent HP-20 macroporous resin column chromatography, was founded to strongly inhibit IFN-γ-induced STAT1-responsive luciferase activity (IFN-γ/STAT1) with IC50 value of 2.43 μg/mL as well as inhibiting IL-6-induced STAT3-responsive luciferase activity (IL-6/STAT3) with IC50 value of 1.38 μg/mL. Subsequent study on its active components led to the isolation and identification of two new dibenzylbutyrolactone lignans named 4-demethyltraxillaside (1) and nortrachelogenin 4-O-β-D-glucopyranoside (2), together with six known compounds. The lignan compounds 1-4 together with other lignan compounds isolated in previous study were tested the activities on IFN-γ/STAT1 and IL-6/STAT3 pathways. The following result showed that the main components trachelogenin and arctigenin had corresponding activities on IFN-γ/STAT1 pathway with IC50 values of 3.14 μM and 9.46 μM as well as trachelogenin, arctigenin and matairesinol strongly inhibiting IL-6/STAT3 pathway with IC50 values of 3.63 μM, 6.47 μM and 2.92 μM, respectively. PMID:25100250

  4. STAT3 as a target for inducing apoptosis in solid and hematological tumors

    PubMed Central

    Siddiquee, Khandaker Al Zaid; Turkson, James

    2008-01-01

    Studies in the past few years have provided compelling evidence for the critical role of aberrant Signal Transducer and Activator of Transcription 3 (STAT3) in malignant transformation and tumorigenesis. Thus, it is now generally accepted that STAT3 is one of the critical players in human cancer formation and represents a valid target for novel anticancer drug design. This review focuses on aberrant STAT3 and its role in promoting tumor cell survival and supporting the malignant phenotype. A brief evaluation of the current strategies targeting STAT3 for the development of novel anticancer agents against human tumors harboring constitutively active STAT3 will also be presented. PMID:18227858

  5. Crispene E, a cis-clerodane diterpene inhibits STAT3 dimerization in breast cancer cells.

    PubMed

    Mantaj, Julia; Rahman, S M Abdur; Bokshi, Bishwajit; Hasan, Choudhury M; Jackson, Paul J M; Parsons, Richard B; Rahman, Khondaker M

    2015-04-01

    Crispene E, a new clerodane-type diterpene, inhibited STAT3 dimerization in a cell-free fluorescent polarisation assay and was found to have significant toxicity against STAT3-dependent MDA-MB 231 breast cancer cell line and selectively inhibited the expression of STAT3 and STAT3 target genes cyclin D1, Fascin and bcl-2. Molecular docking studies suggest the molecule inhibits STAT3 by interacting with its SH2 domain. The compound has been isolated from Tinospora crispa and characterized using standard spectroscopic techniques. PMID:25721973

  6. Comments on ''theory of dissipative density-gradient-driven turbulence in the tokamak edge'' (Phys. Fluids 28, 1419 (1985))

    SciTech Connect

    Krommes, J.A.

    1985-11-01

    The author critiques the model of tokamak edge turbulence by P.W. Terry and P.H. Diamond (Phys. Fluids 28, 1419, 1985). The critique includes a discussion of the physical basis, consistency and quantitative accuracy of the Terry-Diamond model. 19 refs. (WRF)

  7. Erratum: “Hamiltonian magnetohydrodynamics: Lagrangian, Eulerian, and dynamically accessible stability—Theory” [Phys. Plasmas 20, 092104 (2013)

    SciTech Connect

    Andreussi, T.; Morrison, P. J.; Pegoraro, F.

    2015-03-15

    An algebraic mistake in the rendering of the Energy Casimir stability condition for a symmetric magnetohydrodynamics plasma configuration with flows made in the article Andreussi et al. “Hamiltonian magnetohydrodynamics: Lagrangian, Eulerian, and dynamically accessible stability—Theory,” Phys. Plasmas 20, 092104 (2013) is corrected.

  8. Comment on ``A proposal for in vitro/GFR molecular erythema action spectrum'' [J. Appl. Phys. 104, 034701 (2008)

    NASA Astrophysics Data System (ADS)

    Björn, Lars Olof; de Gruijl, Frank R.; Diffey, Brian; Norval, Mary

    2009-06-01

    The recent article by de Souza, Lorenzini and Rizzatti [J. A. V. de Souza, F. Lorenzini, and M. R. Rizatti, J. Appl. Phys. 104, 034701 (2008)] in this journal needs corrections and clarifications on several points. The model used by them is not suitable for the study of erythema.

  9. Comment on "A new approach to optimum design in thermoelectric cooling systems" [J. Appl. Phys. 80, 5494 (1996)

    NASA Astrophysics Data System (ADS)

    Chen, Jincan; Schouten, Jan A.

    1997-12-01

    It is pointed out that there are some errors existing in a recent investigation in this journal [M. Yamanishi, J. Appl. Phys. 80, 5494 (1996)]. The correct results are given so that one can better understand the performance of real thermoelectric cooler systems.

  10. Comment on "Replica-exchange-with-tunneling for fast exploration of protein landscapes" [J. Chem. Phys. 143, 224102 (2015)

    NASA Astrophysics Data System (ADS)

    Sakuraba, Shun

    2016-08-01

    In "Replica-exchange-with-tunneling for fast exploration of protein landscapes" [F. Yaşar et al., J. Chem. Phys. 143, 224102 (2015)], a novel sampling algorithm called "Replica Exchange with Tunneling" was proposed. However, due to its violation of the detailed balance, the algorithm fails to sample from the correct canonical ensemble.

  11. Response to 'Comment on 'Nonlinear properties of small amplitude dust ion acoustic solitary waves'' [Phys. Plasmas 15, 104703 (2008)

    SciTech Connect

    Gupta, M. R.; Sarkar, S.; Khan, Manoranjan; Ghosh, Samiran

    2008-10-15

    The objections are not justified. It should have been noted that ion charge number z{sub i}=1 throughout the referred paper [Ghosh et al., Phys. Plasmas 7, 3594 (2000)]. There is no inconsistency in the formulation of the referred paper as explained in the text.

  12. Interleukin 2 and erythropoietin activate STAT5/MGF via distinct pathways.

    PubMed Central

    Wakao, H; Harada, N; Kitamura, T; Mui, A L; Miyajima, A

    1995-01-01

    Signal transducers and activators of transcription (STAT) proteins play an important role in cytokine signal transduction in conjunction with Janus kinases (JAKs). MGF/STAT5 is known as prolactin regulated STAT. Here we demonstrate that interleukin 2 (IL-2) as well as erythropoietin (EPO) stimulate STAT5 and induce tyrosine phosphorylation of STAT5. These IL-2- and EPO-induced STATs have an identical DNA binding specificity and immunoreactivity. We also show that IL-4 induces a DNA binding factor which possesses similar, but distinct, DNA binding specificity from that of STAT5 and is immunologically different from STAT5. Analysis of two EPO receptor (EPOR) transfected CTLL-2 cell lines discloses that IL-2 activates JAK1 and JAK3 as well as STAT5, while EPO stimulates STAT5 and JAK2 in EPO-responsive CTLL-2 cells (ERT/E2). On the contrary, EPO activates neither JAK2 nor STAT5 in other cell lines that failed to respond to EPO (ERT cells). EPOR and JAK2 associate with each other regardless of EPO presence in ERT/E2 cells, however, such an interaction is not present in ERT cells. Thus, EPOR and JAK2 association seems to be important for EPO responsiveness in CTLL-2 cells. Images PMID:7781605

  13. IL-4/Stat6 activities correlate with apoptosis and metastasis in colon cancer cells

    SciTech Connect

    Li Benhui; Yang Xianzi; Li Pindong; Yuan Qin; Liu Xiaohong; Yuan Jia; Zhang Wenjie

    2008-05-02

    IL-4-induced Stat6 signaling is active in a variety of cell types and plays a role in cell proliferation/growth and resistance to apoptosis. Using EMSA, we identified differential IL-4/Stat6 activities in colorectal cancer cell lines, HT-29 being active Stat6{sup high} phenotype and Caco-2 being defective Stat6{sup null} phenotype, respectively. Active Stat6{sup high} HT-29 cells exhibited resistance to apoptosis by flowcytometry and aggressive metastasis by Transwell assay compared with defective Stat6{sup null} Caco-2 cells. Comparing one another using RT-PCR, Stat6{sup high} HT-29 cells expressed more mRNA of anti-apoptotic and pro-metastatic genes Survivin, MDM2, and TMPRSS4, while Stat6{sup null} Caco-2 cells expressed more mRNA of pro-apoptotic and anti-metastatic genes BAX, CAV1, and P53, respectively. This is the first study describing correlations of IL-4/Stat6 activities with apoptosis and metastasis in colon cancer. These findings, together with the observation of constitutive Stat6 activation in many human malignancies, suggest that Stat6 activities could be a biomarker for cancer cell's invasive/metastatic capability.

  14. Nifuroxazide inhibits survival of multiple myeloma cells by directly inhibiting STAT3.

    PubMed

    Nelson, Erik A; Walker, Sarah R; Kepich, Alicia; Gashin, Laurie B; Hideshima, Teru; Ikeda, Hiroshi; Chauhan, Dharminder; Anderson, Kenneth C; Frank, David A

    2008-12-15

    Constitutive activation of the transcription factor STAT3 contributes to the pathogenesis of many cancers, including multiple myeloma (MM). Since STAT3 is dispensable in most normal tissue, targeted inhibition of STAT3 is an attractive therapy for patients with these cancers. To identify STAT3 inhibitors, we developed a transcriptionally based assay and screened a library of compounds known to be safe in humans. We found the drug nifuroxazide to be an effective inhibitor of STAT3 function. Nifuroxazide inhibits the constitutive phosphorylation of STAT3 in MM cells by reducing Jak kinase autophosphorylation, and leads to down-regulation of the STAT3 target gene Mcl-1. Nifuroxazide causes a decrease in viability of primary myeloma cells and myeloma cell lines containing STAT3 activation, but not normal peripheral blood mononuclear cells. Although bone marrow stromal cells provide survival signals to myeloma cells, nifuroxazide can overcome this survival advantage. Reflecting the interaction of STAT3 with other cellular pathways, nifuroxazide shows enhanced cytotoxicity when combined with either the histone deacetylase inhibitor depsipeptide or the MEK inhibitor UO126. Therefore, using a mechanistic-based screen, we identified the clinically relevant drug nifuroxazide as a potent inhibitor of STAT signaling that shows cytotoxicity against myeloma cells that depend on STAT3 for survival. PMID:18824601

  15. Nifuroxazide inhibits survival of multiple myeloma cells by directly inhibiting STAT3

    PubMed Central

    Nelson, Erik A.; Walker, Sarah R.; Kepich, Alicia; Gashin, Laurie B.; Hideshima, Teru; Ikeda, Hiroshi; Chauhan, Dharminder; Anderson, Kenneth C.

    2008-01-01

    Constitutive activation of the transcription factor STAT3 contributes to the pathogenesis of many cancers, including multiple myeloma (MM). Since STAT3 is dispensable in most normal tissue, targeted inhibition of STAT3 is an attractive therapy for patients with these cancers. To identify STAT3 inhibitors, we developed a transcriptionally based assay and screened a library of compounds known to be safe in humans. We found the drug nifuroxazide to be an effective inhibitor of STAT3 function. Nifuroxazide inhibits the constitutive phosphorylation of STAT3 in MM cells by reducing Jak kinase autophosphorylation, and leads to down-regulation of the STAT3 target gene Mcl-1. Nifuroxazide causes a decrease in viability of primary myeloma cells and myeloma cell lines containing STAT3 activation, but not normal peripheral blood mononuclear cells. Although bone marrow stromal cells provide survival signals to myeloma cells, nifuroxazide can overcome this survival advantage. Reflecting the interaction of STAT3 with other cellular pathways, nifuroxazide shows enhanced cytotoxicity when combined with either the histone deacetylase inhibitor depsipeptide or the MEK inhibitor UO126. Therefore, using a mechanistic-based screen, we identified the clinically relevant drug nifuroxazide as a potent inhibitor of STAT signaling that shows cytotoxicity against myeloma cells that depend on STAT3 for survival. PMID:18824601

  16. Inborn errors of human STAT1: allelic heterogeneity governs the diversity of immunological and infectious phenotypes

    PubMed Central

    Boisson-Dupuis, Stephanie; Kong, Xiao-Fei; Okada, Satoshi; Cypowyj, Sophie; Puel, Anne; Abel, Laurent; Casanova, Jean-Laurent

    2012-01-01

    The genetic dissection of various human infectious diseases has led to the definition of inborn errors of human STAT1 immunity of four types, including (i) autosomal recessive (AR) complete STAT1 deficiency, (ii) AR partial STAT1 deficiency, (iii) autosomal dominant (AD) STAT1 deficiency, and (iv) AD gain of STAT1 activity. The two types of AR STAT1 defect give rise to a broad infectious phenotype with susceptibility to intramacrophagic bacteria (mostly mycobacteria) and viruses (herpes viruses at least), due principally to the impairment of IFN-γ-mediated and IFN-α/β-mediated immunity, respectively. Clinical outcome depends on the extent to which the STAT1 defect decreases responsiveness to these cytokines. AD STAT1 deficiency selectively predisposes individuals to mycobacterial disease, owing to the impairment of IFN-γ-mediated immunity, as IFN-α/β-mediated immunity is maintained. Finally, AD gain of STAT1 activity is associated with autoimmunity, probably owing to an enhancement of IFN-α/β-mediated immunity. More surprisingly, it is also associated with chronic mucocutaneous candidiasis, through as yet undetermined mechanisms involving an inhibition of the development of IL-17-producing T cells. Thus, germline mutations in human STAT1 define four distinct clinical disorders. Various combinations of viral, mycobacterial and fungal infections are therefore allelic at the human STAT1 locus. These experiments of Nature neatly highlight the clinical and immunological impact of the human genetic dissection of infectious phenotypes. PMID:22651901

  17. The dark and the bright side of Stat3: proto-oncogene and tumor-suppressor.

    PubMed

    Ecker, Andrea; Simma, Olivia; Hoelbl, Andrea; Kenner, Lukas; Beug, Hartmut; Moriggl, Richard; Sexl, Veronika

    2009-01-01

    Stat transcription factors have been implicated in tumorigenesis in mice and men. Stat3 and Stat5 are considered powerful proto-oncogenes, whereas Stat1 has been demonstrated to suppress tumor formation. We demonstrate here for the first time that a constitutive active version of Stat3alpha (Stat3alphaC) may also suppress transformation. Mouse embryonic fibroblasts (MEFs) deficient for p53 can be transformed with either c-myc or with rasV12 alone. Interestingly, transformation by c-myc is efficiently suppressed by co-expression of Stat3alphaC, but Stat3alphaC does not interfere with transformation by the rasV12-oncogene. In contrast, transplantation of bone marrow cells expressing Stat3alphaC induces the formation of a highly aggressive T cell leukemia in mice. The leukemic cells invaded multiple organs including lung, heart, salivary glands, liver and kidney. Interestingly, transplanted mice developed a similar leukemia when the bone marrow cells were transduced with Stat3beta, which is also constitutively active when expressed at significant levels. Our experiments demonstrate that Stat3 has both - tumor suppressing and tumor promoting properties. PMID:19273247

  18. STAT1 Pathway Mediates Amplification of Metastatic Potential and Resistance to Therapy

    PubMed Central

    Pitroda, Sean P.; Golden, Daniel W.; Bhayani, Mihir; Shao, Michael Y.; Darga, Thomas E.; Beveridge, Mara G.; Sood, Ravi F.; Sutton, Harold G.; Beckett, Michael A.; Mauceri, Helena J.; Posner, Mitchell C.; Weichselbaum, Ralph R.

    2009-01-01

    Background Traditionally IFN/STAT1 signaling is connected with an anti-viral response and pro-apoptotic tumor-suppressor functions. Emerging functions of a constitutively activated IFN/STAT1 pathway suggest an association with an aggressive tumor phenotype. We hypothesized that tumor clones that constitutively overexpress this pathway are preferentially selected by the host microenvironment due to a resistance to STAT1-dependent cytotoxicity and demonstrate increased metastatic ability combined with increased resistance to genotoxic stress. Methodology/Principal Findings Here we report that clones of B16F1 tumors grown in the lungs of syngeneic C57BL/6 mice demonstrate variable transcriptional levels of IFN/STAT1 pathway expression. Tumor cells that constitutively overexpress the IFN/STAT1 pathway (STAT1H genotype) are selected by the lung microenvironment. STAT1H tumor cells also demonstrate resistance to IFN-gamma (IFNγ), ionizing radiation (IR), and doxorubicin relative to parental B16F1 and low expressors of the IFN/STAT1 pathway (STAT1L genotype). Stable knockdown of STAT1 reversed the aggressive phenotype and decreased both lung colonization and resistance to genotoxic stress. Conclusions Our results identify a pathway activated by tumor-stromal interactions thereby selecting for pro-metastatic and therapy-resistant tumor clones. New therapies targeted against the IFN/STAT1 signaling pathway may provide an effective strategy to treat or sensitize aggressive tumor clones to conventional cancer therapies and potentially prevent distant organ colonization. PMID:19503789

  19. Transcription Factor STAT3 as a Novel Molecular Target for Cancer Prevention

    PubMed Central

    Xiong, Ailian; Yang, Zhengduo; Shen, Yicheng; Zhou, Jia; Shen, Qiang

    2014-01-01

    Signal Transducers and Activators of Transcription (STATs) are a family of transcription factors that regulate cell proliferation, differentiation, apoptosis, immune and inflammatory responses, and angiogenesis. Cumulative evidence has established that STAT3 has a critical role in the development of multiple cancer types. Because it is constitutively activated during disease progression and metastasis in a variety of cancers, STAT3 has promise as a drug target for cancer therapeutics. Recently, STAT3 was found to have an important role in maintaining cancer stem cells in vitro and in mouse tumor models, suggesting STAT3 is integrally involved in tumor initiation, progression and maintenance. STAT3 has been traditionally considered as nontargetable or undruggable, and the lag in developing effective STAT3 inhibitors contributes to the current lack of FDA-approved STAT3 inhibitors. Recent advances in cancer biology and drug discovery efforts have shed light on targeting STAT3 globally and/or specifically for cancer therapy. In this review, we summarize current literature and discuss the potential importance of STAT3 as a novel target for cancer prevention and of STAT3 inhibitors as effective chemopreventive agents. PMID:24743778

  20. Regulation of STATs by polycystin-1 and their role in polycystic kidney disease

    PubMed Central

    Weimbs, Thomas; Olsan, Erin E.; Talbot, Jeffrey J.

    2013-01-01

    Autosomal-dominant polycystic kidney disease (ADPKD) is a common genetic disease caused by mutations in the gene coding for polycystin-1 (PC1). PC1 can regulate STAT transcription factors by a novel, dual mechanism. STAT3 and STAT6 are aberrantly activated in renal cysts. Genetic and pharmacological approaches to inhibit STAT3 or STAT6 have led to promising results in ADPKD mouse models. Here, we review current findings that lead to a model of PC1 as a key regulator of STAT signaling in renal tubule cells. We discuss how PC1 may orchestrate appropriate epithelial responses to renal injury, and how this system may lead to aberrant STAT activation in ADPKD thereby causing inappropriate activation of tissue repair programs that culminate in renal cyst growth and fibrosis. PMID:24058808

  1. Stat3 is involved in control of MASP2 gene expression

    SciTech Connect

    Unterberger, Claudia; Hanson, Steven; Klingenhoff, Andreas; Oesterle, Daniela; Frankenberger, Marion; Endo, Yuichi; Matsushita, Misao; Fujita, Teizo; Schwaeble, Wilhelm; Weiss, Elisabeth H.; Ziegler-Heitbrock, Loems; Stover, Cordula

    2007-12-28

    Little is known about determinants regulating expression of Mannan-binding lectin associated serine protease-2 (MASP-2), the effector component of the lectin pathway of complement activation. Comparative bioinformatic analysis of the MASP2 promoter regions in human, mouse, and rat, revealed conservation of two putative Stat binding sites, termed StatA and StatB. Site directed mutagenesis specific for these sites was performed. Transcription activity was decreased 5-fold when StatB site was mutated in the wildtype reporter gene construct. Gel retardation and competition assays demonstrated that proteins contained in the nuclear extract prepared from HepG2 specifically bound double-stranded StatB oligonucleotides. Supershift analysis revealed Stat3 to be the major specific binding protein. We conclude that Stat3 binding is important for MASP2 promoter activity.

  2. KAP1 regulates type I interferon/STAT1-mediated IRF-1 gene expression

    SciTech Connect

    Kamitani, Shinya; Ohbayashi, Norihiko; Ikeda, Osamu; Togi, Sumihito; Muromoto, Ryuta; Sekine, Yuichi; Ohta, Kazuhide; Ishiyama, Hironobu; Matsuda, Tadashi

    2008-05-30

    Signal transducers and activators of transcription (STATs) mediate cell proliferation, differentiation, and survival in immune responses, hematopoiesis, neurogenesis, and other biological processes. Recently, we showed that KAP1 is a novel STAT-binding partner that regulates STAT3-mediated transactivation. KAP1 is a universal co-repressor protein for the KRAB zinc finger protein superfamily of transcriptional repressors. In this study, we found KAP1-dependent repression of interferon (IFN)/STAT1-mediated signaling. We also demonstrated that endogenous KAP1 associates with endogenous STAT1 in vivo. Importantly, a small-interfering RNA-mediated reduction in KAP1 expression enhanced IFN-induced STAT1-dependent IRF-1 gene expression. These results indicate that KAP1 may act as an endogenous regulator of the IFN/STAT1 signaling pathway.

  3. Cross-talk between KLF4 and STAT3 regulates axon regeneration

    NASA Astrophysics Data System (ADS)

    Qin, Song; Zou, Yuhua; Zhang, Chun-Li

    2013-10-01

    Cytokine-induced activation of signal transducer and activator of transcription 3 (STAT3) promotes the regrowth of damaged axons in the adult central nervous system (CNS). Here we show that KLF4 physically interacts with STAT3 upon cytokine-induced phosphorylation of tyrosine 705 (Y705) on STAT3. This interaction suppresses STAT3-dependent gene expression by blocking its DNA-binding activity. The deletion of KLF4 in vivo induces axon regeneration of adult retinal ganglion cells (RGCs) via Janus kinase (JAK)-STAT3 signalling. This regeneration can be greatly enhanced by exogenous cytokine treatment, or removal of an endogenous JAK-STAT3 pathway inhibitor called suppressor of cytokine signalling 3 (SOCS3). These findings reveal an unexpected cross-talk between KLF4 and activated STAT3 in the regulation of axon regeneration that might have therapeutic implications in promoting repair of injured adult CNS.

  4. The Role of STAT3 in Non-Small Cell Lung Cancer

    PubMed Central

    Harada, Daijiro; Takigawa, Nagio; Kiura, Katsuyuki

    2014-01-01

    Persistent phosphorylation of signal transducer and activator of transcription 3 (STAT3) has been demonstrated in 22%~65% of non-small cell lung cancers (NSCLC). STAT3 activation is mediated by receptor tyrosine kinases, such as epidermal growth factor receptor (EGFR) and MET, cytokine receptors, such as IL-6, and non-receptor kinases, such as Src. Overexpression of total or phosphorylated STAT3 in resected NSCLC leads to poor prognosis. In a preclinical study, overexpression of STAT3 was correlated with chemoresistance and radioresistance in NSCLC cells. Here, we review the role of STAT3 and the mechanisms of treatment resistance in malignant diseases, especially NSCLC. As STAT3 is a critical mediator of the oncogenic effects of EGFR mutations, we discuss STAT3 pathways in EGFR-mutated NSCLC, referring to mechanisms of EGFR tyrosine kinase inhibitor resistance. PMID:24675568

  5. The Role of STAT3 in Non-Small Cell Lung Cancer.

    PubMed

    Harada, Daijiro; Takigawa, Nagio; Kiura, Katsuyuki

    2014-01-01

    Persistent phosphorylation of signal transducer and activator of transcription 3 (STAT3) has been demonstrated in 22%~65% of non-small cell lung cancers (NSCLC). STAT3 activation is mediated by receptor tyrosine kinases, such as epidermal growth factor receptor (EGFR) and MET, cytokine receptors, such as IL-6, and non-receptor kinases, such as Src. Overexpression of total or phosphorylated STAT3 in resected NSCLC leads to poor prognosis. In a preclinical study, overexpression of STAT3 was correlated with chemoresistance and radioresistance in NSCLC cells. Here, we review the role of STAT3 and the mechanisms of treatment resistance in malignant diseases, especially NSCLC. As STAT3 is a critical mediator of the oncogenic effects of EGFR mutations, we discuss STAT3 pathways in EGFR-mutated NSCLC, referring to mechanisms of EGFR tyrosine kinase inhibitor resistance. PMID:24675568

  6. 'Victoria' After Sol 950 Drive (Stereo)

    NASA Technical Reports Server (NTRS)

    2006-01-01

    [figure removed for brevity, see original site] Left-eye view of a stereo pair for PIA08778

    [figure removed for brevity, see original site] Right-eye view of a stereo pair for PIA08778 [figure removed for brevity, see original site] Cylindrical view for PIA08778

    A drive of about 30 meters (about 100 feet) on the 950th Martian day, or sol, of Opportunity's exploration of Mars' Meridiani Planum region (Sept. 25, 2006) brought the NASA rover to within about 20 meters (about 66 feet) of the rim of 'Victoria Crater.' From that position, the rover's navigation camera took the exposures combined into this stereo anaglyph, which appears three-dimensional when viewed through red-green glasses. The scalloped shape of the crater is visible on the left edge. Due to a small dune or ripple close to the nearest part of the rim, the scientists and engineers on the rover team planned on sol 951 to drive to the right of the ripple, but not quite all the way to the rim, then to proceed to the rim the following sol. The image is presented in cylindrical projection with geometric seam correction.

    Victoria Crater is about 800 meters (one-half mile) in diameter, about five times wider than 'Endurance Crater,' which Opportunity spent six months examining in 2004, and about 40 times wider than 'Eagle Crater,' where Opportunity first landed. The great lure of Victoria is the expectation that a thick stack of geological layers will be exposed in the crater walls, potentially several times the thickness that was previously studied at Endurance and therefore, potentially preserving several times the historical record.

  7. Spirit's Surroundings on 'West Spur,' Sol 305

    NASA Technical Reports Server (NTRS)

    2005-01-01

    This 360-degree panorama shows the terrain surrounding NASA's Mars Exploration Rover Spirit as of the rover's 305th martian day, or sol, (Nov. 11, 2004). At that point, Spirit was climbing the 'West Spur' of the 'Columbia Hills.' The rover had just finished inspecting a rock called 'Lutefisk' and was heading uphill toward an area called 'Machu Picchu.' Spirit used its navigational camera to take the images combined into this mosaic. The rover's location when the images were taken is catalogued as the mission's site 89, position 205. The view is presented here as a cylindrical projection with geometric seam correction.

  8. Fluoride glasses from sol gels. Final report

    SciTech Connect

    Uhlmann, D.R.

    1986-09-15

    The use of sol-gel coatings to strengthen oxide glasses was demonstrated for the case of fused silica. Increases in strength to as much as 2.2 times the strength of uncoated glass were obtained. The strengthening does not involve the annealing of surface microcracks, but rather the filling-in of such flaws. The strengthening does not depend on coating thickness over the range 2000-10000 Angstroms, but does depend significantly upon the state of hydrolysis of the substrate surface.

  9. Spirit Near 'Stapledon' on Sol 1802 (Stereo)

    NASA Technical Reports Server (NTRS)

    2009-01-01

    [figure removed for brevity, see original site] Left-eye view of a color stereo pair for PIA11781 [figure removed for brevity, see original site] Right-eye view of a color stereo pair for PIA11781

    NASA Mars Exploration Rover Spirit used its navigation camera for the images assembled into this stereo, full-circle view of the rover's surroundings during the 1,802nd Martian day, or sol, (January 26, 2009) of Spirit's mission on the surface of Mars. South is at the center; north is at both ends.

    This view combines images from the left-eye and right-eye sides of the navigation camera. It appears three-dimensional when viewed through red-blue glasses with the red lens on the left.

    Spirit had driven down off the low plateau called 'Home Plate' on Sol 1782 (January 6, 2009) after spending 12 months on a north-facing slope on the northern edge of Home Plate. The position on the slope (at about the 9-o'clock position in this view) tilted Spirit's solar panels toward the sun, enabling the rover to generate enough electricity to survive its third Martian winter. Tracks at about the 11-o'clock position of this panorama can be seen leading back to that 'Winter Haven 3' site from the Sol 1802 position about 10 meters (33 feet) away. For scale, the distance between the parallel wheel tracks is about one meter (40 inches).

    Where the receding tracks bend to the left, a circular pattern resulted from Spirit turning in place at a soil target informally named 'Stapledon' after William Olaf Stapledon, a British philosopher and science-fiction author who lived from 1886 to 1950. Scientists on the rover team suspected that the soil in that area might have a high concentration of silica, resembling a high-silica soil patch discovered east of Home Plate in 2007. Bright material visible in the track furthest to the right was examined with Spirit's alpha partical X-ray spectrometer and found, indeed, to be rich in silica.

    The team laid plans to drive Spirit from

  10. Overcoming Chemoresistance of Pediatric Ependymoma by Inhibition of STAT3 Signaling.

    PubMed

    Phi, Ji Hoon; Choi, Seung-Ah; Kim, Seung-Ki; Wang, Kyu-Chang; Lee, Ji Yeoun; Kim, Dong Gyu

    2015-10-01

    The long-term clinical outcome of pediatric intracranial epepdymoma is poor with a high rate of recurrence. One of the main reasons for this poor outcome is the tumor's inherent resistance to chemotherapy. Signal transducer and activator of transcription 3 (STAT3) is overactive in many human cancers, and inhibition of STAT3 signaling is an emerging area of interest in oncology. In this study, the possibility of STAT3 inhibition as a treatment was investigated in pediatric intracranial ependymoma tissues and cell lines. STAT3 activation status was checked in ependymoma tissues. The responses to conventional chemotherapeutic agents and a STAT3 inhibitor WP1066 in primarily cultured ependymoma cells were measured by cell viability assay. Apoptosis assays were conducted to reveal the cytotoxic mechanism of applied agents. Knockdown of STAT3 was tried to confirm the effects of STAT3 inhibition in ependymoma cells. High levels of phospho-STAT3 (p-STAT3) expression were observed in ependymoma tissue, especially in the anaplastic histology group. There was no cytotoxic effect of cisplatin, ifosfamide, and etoposide. Both brain tumor-initiating cells (BTICs) and bulk tumor cells (BCs) showed considerably decreased viability after WP1066 treatment. However, BTICs had fewer responses than BCs. No additive or synergistic effect was observed for combination therapy of WP1066 and cisplatin. WP1066 effectively abrogated p-STAT3 expression. An increased apoptosis and decreased Survivin expression were observed after WP1066 treatment. Knockdown of STAT3 also decreased cell survival, supporting the critical role of STAT3 in sustaining ependymoma cells. In this study, we observed a cytotoxic effect of STAT3 inhibitor on ependymoma BTICs and BCs. There is urgent need to develop new therapeutic agents for pediatric ependymoma. STAT3 inhibitors may be a new group of drugs for clinical application. PMID:26500028

  11. Suppression of autophagy augments the radiosensitizing effects of STAT3 inhibition on human glioma cells

    SciTech Connect

    Yuan, Xiaopeng; Du, Jie; Hua, Song; Zhang, Haowen; Gu, Cheng; Wang, Jie; Yang, Lei; Huang, Jianfeng; Yu, Jiahua Liu, Fenju

    2015-01-15

    Radiotherapy is an essential component of the standard therapy for newly diagnosed glioblastoma. To increase the radiosensitivity of glioma cells is a feasible solution to improve the therapeutic effects. It has been suggested that inhibition of signal transducer and activator of transcription 3 (STAT3) can radiosensitize glioma cells, probably via the activation of mitochondrial apoptotic pathway. In this study, human malignant glioma cells, U251 and A172, were treated with an STAT3 inhibitor, WP1066, or a short hairpin RNA plasmid targeting STAT3 to suppress the activation of STAT3 signaling. The radiosensitizing effects of STAT3 inhibition were confirmed in glioma cells. Intriguingly, combination of ionizing radiation exposure and STAT3 inhibition triggered a pronounced increase of autophagy flux. To explore the role of autophagy, glioma cells were treated with 3-methyladenine or siRNA for autophagy-related gene 5, and it was demonstrated that inhibition of autophagy further strengthened the radiosensitizing effects of STAT3 inhibition. Accordingly, more apoptotic cells were induced by the dual inhibition of autophagy and STAT3 signaling. In conclusion, our data revealed a protective role of autophagy in the radiosensitizing effects of STAT3 inhibition, and inhibition of both autophagy and STAT3 might be a potential therapeutic strategy to increase the radiosensitivity of glioma cells. - Highlights: • Inactivation of STAT3 signaling radiosensitizes malignant glioma cells. • STAT3 inhibition triggers a significant increase of autophagy flux induced by ionizing radiation in glioma cells. • Suppression of autophagy further strengthens the radiosensitizing effects of STAT3 inhibition in glioma cells. • Dual inhibition of autophagy and STAT3 induce massive apoptotic cells upon exposure to ionizing radiation.

  12. STAT2 Is Required for TLR-Induced Murine Dendritic Cell Activation and Cross-Presentation.

    PubMed

    Xu, Jun; Lee, Michael H; Chakhtoura, Marita; Green, Benjamin L; Kotredes, Kevin P; Chain, Robert W; Sriram, Uma; Gamero, Ana M; Gallucci, Stefania

    2016-07-01

    TLR-stimulated cross-presentation by conventional dendritic cells (cDCs) is important in host defense and antitumor immunity. We recently reported that cDCs lacking the type I IFN signaling molecule STAT2 are impaired in cross-presenting tumor Ags to CD8(+) T cells. To investigate how STAT2 affects cross-presentation, we determined its requirements for dendritic cell activation. In this study, we report that STAT2 is essential for the activation of murine female cDCs upon TLR3, -4, -7, and -9 stimulation. In response to various TLR ligands, Stat2(-/-) cDCs displayed reduced expression of costimulatory molecules and type I IFN-stimulated genes. The cDC responses to exogenous IFN-α that we evaluated required STAT2 activation, indicating that the canonical STAT1-STAT2 heterodimers are the primary signaling transducers of type I IFNs in cDCs. Interestingly, LPS-induced production of IL-12 was STAT2 and type I IFN receptor (IFNAR) dependent, whereas LPS-induced production of TNF-α and IL-6 was STAT2 and IFNAR independent, suggesting a specific role of the IFNAR-STAT2 axis in the stimulation of proinflammatory cytokines by LPS in cDCs. In contrast, R848- and CpG-induced cytokine production was less influenced by the IFNAR-STAT2 axis. Short kinetics and IFNAR blockade studies showed that STAT2 main function is to transduce signals triggered by autocrine type I IFNs. Importantly, Stat2(-/-) cDCs were deficient in cross-presenting to CD8(+) T cells in vitro upon IFN-α, CpG, and LPS stimulation, and also in cross-priming and licensing cytotoxic T cell killers in vivo. We conclude that STAT2 plays a critical role in TLR-induced dendritic cell activation and cross-presentation, and thus is vital in host defense. PMID:27233962

  13. Intersection of mTOR and STAT signaling in immunity

    PubMed Central

    Saleiro, Diana; Platanias, Leonidas C.

    2014-01-01

    Optimal regulation of immune networks is essential for generation of effective immune responses, and defects in such networks can lead to immunodeficiency, while uncontrolled responses can result in autoimmune disorders. mTOR and STAT signaling cascades are key regulators of differentiation and function of cells of the immune system. Both pathways act as sensors and transducers of environmental stimuli, and recent evidence has revealed points of crosstalk between these pathways, highlighting synergistic regulation of immune cell differentiation and function. Here we review the current understanding of mTOR and STAT interactions in T cells and innate immune cells, and discuss potential mechanisms underlying these events. We further outline models for the intersection of these pathways in the regulation of immunity, and highlight important areas for future research. PMID:25592035

  14. Activating STAT3 Alpha for Promoting Healing of Neurons

    NASA Technical Reports Server (NTRS)

    Conway, Greg

    2008-01-01

    A method of promoting healing of injured or diseased neurons involves pharmacological activation of the STAT3 alpha protein. Usually, injured or diseased neurons heal incompletely or not at all for two reasons: (1) they are susceptible to apoptosis (cell death); and (2) they fail to engage in axogenesis that is, they fail to re-extend their axons to their original targets (e.g., muscles or other neurons) because of insufficiency of compounds, denoted neurotrophic factors, needed to stimulate such extension. The present method (see figure) of treatment takes advantage of prior research findings to the effect that the STAT3 alpha protein has anti-apoptotic and pro-axogenic properties.

  15. STAT3: A Novel Molecular Mediator of Resistance to Chemoradiotherapy

    PubMed Central

    Spitzner, Melanie; Ebner, Reinhard; Wolff, Hendrik A.; Ghadimi, B. Michael; Wienands, Jürgen; Grade, Marian

    2014-01-01

    Chemoradiotherapy (CRT) represents a standard treatment for many human cancers, frequently combined with radical surgical resection. However, a considerable percentage of primary cancers are at least partially resistant to CRT, which represents a substantial clinical problem, because it exposes cancer patients to the potential side effects of both irradiation and chemotherapy. It is therefore exceedingly important to determine the molecular characteristics underlying CRT-resistance and to identify novel molecular targets that can be manipulated to re-sensitize resistant tumors to CRT. In this review, we highlight much of the recent evidence suggesting that the signal transducer and activator of transcription 3 (STAT3) plays a prominent role in mediating CRT-resistance, and we outline why inhibition of STAT3 holds great promise for future multimodal treatment concepts in oncology. PMID:25268165

  16. Biology and significance of the JAK/STAT signalling pathways

    PubMed Central

    Kiu, Hiu; Nicholson, Sandra E

    2013-01-01

    Since its discovery two decades ago, the activation of the JAK/STAT pathway by numerous cytokines and growth factors has resulted in it becoming one of the most well studied intracellular signalling networks. The field has progressed from the identification of the individual components, to high-resolution crystal structures of both JAK and STAT, and an understanding of the complexities of the molecular activation and deactivation cycle which results in a diverse, yet highly specific and regulated pattern of transcriptional responses. While there is still more to learn, we now appreciate how disruption and de-regulation of this pathway can result in clinical disease and look forward to adoption of the next generation of JAK inhibitors in routine clinical treatment. PMID:22339650

  17. Constitutive STAT5 Activation Correlates With Better Survival in Cervical Cancer Patients Treated With Radiation Therapy

    SciTech Connect

    Chen, Helen H.W.; Chou, Cheng-Yang; Wu, Yuan-Hua; Hsueh, Wei-Ting; Hsu, Chiung-Hui; Guo, How-Ran; Lee, Wen-Ying; Su, Wu-Chou

    2012-02-01

    Purpose: Constitutively activated signal transducers and activators of transcription (STAT) factors, in particular STAT1, STAT3, and STAT5, have been detected in a wide variety of human primary tumors and have been demonstrated to directly contribute to oncogenesis. However, the expression pattern of these STATs in cervical carcinoma is still unknown, as is whether or not they have prognostic significance. This study investigated the expression patterns of STAT1, STAT3, and STAT5 in cervical cancer and their associations with clinical outcomes in patients treated with radical radiation therapy. Methods and Materials: A total of 165 consecutive patients with International Federation of Gynecology and Obstetrics (FIGO) Stages IB to IVA cervical cancer underwent radical radiation therapy, including external beam and/or high-dose-rate brachytherapy between 1989 and 2002. Immunohistochemical studies of their formalin-fixed, paraffin-embedded tissues were performed. Univariate and multivariate analyses were performed to identify and to evaluate the effects of these factors affecting patient survival. Results: Constitutive activations of STAT1, STAT3, and STAT5 were observed in 11%, 22%, and 61% of the participants, respectively. While STAT5 activation was associated with significantly better metastasis-free survival (p < 0.01) and overall survival (p = 0.04), STAT1 and STAT3 activation were not. Multivariate analyses showed that STAT5 activation, bulky tumor ({>=}4 cm), advanced stage (FIGO Stages III and IV), and brachytherapy (yes vs. no) were independent prognostic factors for cause-specific overall survival. None of the STATs was associated with local relapse. STAT5 activation (odds ratio = 0.29, 95% confidence interval = 0.13-0.63) and advanced stage (odds ratio = 2.54; 95% confidence interval = 1.03-6.26) were independent predictors of distant metastasis. Conclusions: This is the first report to provide the overall expression patterns and prognostic significance of

  18. Interleukin-4-induced transcriptional activation by stat6 involves multiple serine/threonine kinase pathways and serine phosphorylation of stat6.

    PubMed

    Pesu, M; Takaluoma, K; Aittomäki, S; Lagerstedt, A; Saksela, K; Kovanen, P E; Silvennoinen, O

    2000-01-15

    Stat6 transcription factor is a critical mediator of IL-4-specific gene responses. Tyrosine phosphorylation is required for nuclear localization and DNA binding of Stat6. The authors investigated whether Stat6-dependent transcriptional responses are regulated through IL-4-induced serine/threonine phosphorylation. In Ramos B cells, the serine/threonine kinase inhibitor H7 inhibited IL-4-induced expression of CD23. Treatment with H7 did not affect IL-4R-mediated immediate signaling events such as tyrosine phosphorylation of Jak1, Jak3, insulin receptor substrate (IRS)-1 and IRS-2, or tyrosine phosphorylation and DNA binding of Stat6. To analyze whether the H7-sensitive pathway was regulating Stat6-activated transcription, we used reporter constructs containing different IL-4 responsive elements. H7 abrogated Stat6-, as well as Stat5-, mediated reporter gene activation and partially reduced C/EBP-dependent reporter activity. By contrast, IL-4-induced transcription was not affected by wortmannin, an inhibitor of the phosphatidyl-inositol 3'-kinase pathway. Phospho-amino acid analysis and tryptic phosphopeptide maps revealed that IL-4 induced phosphorylation of Stat6 on serine and tyrosine residues in Ramos cells and in 32D cells lacking endogenous IRS proteins. However, H7 treatment did not inhibit the phosphorylation of Stat6. Instead, H7 inhibited the IL-4-induced phosphorylation of RNA polymerase II. These results indicate that Stat6-induced transcription is dependent on phosphorylation events mediated by H7-sensitive kinase(s) but that it also involves serine phosphorylation of Stat6 by an H7-insensitive kinase independent of the IRS pathway. (Blood. 2000;95:494-502) PMID:10627454

  19. IL-6/STAT3 axis initiated CAFs via up-regulating TIMP-1 which was attenuated by acetylation of STAT3 induced by PCAF in HCC microenvironment.

    PubMed

    Zheng, Xin; Xu, Meng; Yao, Bowen; Wang, Cong; Jia, Yuli; Liu, Qingguang

    2016-09-01

    Aberrant tumor microenvironment is involved closely in tumor initiation and progression, in which cancer associated fibroblasts (CAFs) play a pivotal role. Both IL-6/STAT3 signaling and TIMP-1 have been found to modulate the crosstalk between tumor cells and CAFs in tumor microenvironment, however, the underlying mechanism remains unclear. Here, we showed that IL-6/STAT3 signaling was activated aberrantly in HCC tissues and correlated with poor post-surgical outcome. The in vitro experiments confirmed that activation of IL-6/STAT3 pathway enhanced TIMP-1 expression directly via phosphorylated STATs (p-STAT3)-binding with TIMP-1 promoter in Huh7 cells. Furthermore, activation of IL-6/STAT3 pathway in HCC cells was shown to induce the transformation from normal liver fibroblasts (LFs) to CAFs via up-regulating TIMP-1 expression. Co-culture with CAFs promoted the growth of Huh7 cells both in vitro and in vivo. Finally, by co-Immunoprecipitation and immunoblotting assessments, PCAF, a well-known acetyltransferase, was revealed to acetylate cytoplasmic STAT3 protein directly and regulate TIMP-1 expression negatively in Huh7 cells. In summary, this investigation indicated that there was a positive IL-6/TIMP-1 feedback loop controlling the crosstalk between HCC cells and its neighbouring fibroblasts. The data here also identified that PCAF repressed TIMP-1 expression via acetylation of STAT3. In conclusion, this investigation demonstrated that CAFs promoted HCC growth via IL-6/STAT3/AKT pathway and TIMP-1 over-expression driven by IL-6/STAT3 pathway in HCC cells brought in more CAFs through activating LFs. Finally, PCAF could block this positive feedback by acetylating STAT3 in HCC cells. PMID:27297362

  20. Automatic electrochemical micro-pH-stat for biomicrosystems.

    PubMed

    Morimoto, Katsuya; Toya, Mariko; Fukuda, Junji; Suzuki, Hiroaki

    2008-02-15

    A microelectrochemical pH-stat with an automatic feedback function was fabricated. The operation of the device is based on the nonstandard use of an electrochemical three-electrode system with a pH-sensitive reference electrode, a Ag/AgCl working electrode, and an iridium auxiliary electrode that functions as an actuator to adjust the solution pH. The combination of the electrodes caused a negative feedback in response to a pH change. The shift of the potential of the pH-sensitive reference electrode caused an overpotential on the Ag/AgCl working electrode, which then caused a significant current increase. This led to the electrolysis of water on the auxiliary electrode and the rapid recovery of the pH. The negative feedback function to stabilize the initial state could be confirmed for changes to both the acidic and basic directions. The performance of the pH-stat was characterized in the titration of acetic acid or ammonia. The charge generated in the feedback process changed linearly with respect to the concentration. The pH-stat was also used in the determination of urea by urease and that of the activities of trypsin and pepsin while maintaining the optimum pH for the enzymes. The pH to be fixed could be changed by changing the working electrode potential. Moreover, the two pH-stats could be used to form a pH gradient in a microflow channel by fixing the pH values at two positions. PMID:18186613

  1. Deubiquitinase USP2a Sustains Interferons Antiviral Activity by Restricting Ubiquitination of Activated STAT1 in the Nucleus

    PubMed Central

    Liu, Jin; Yuan, Yukang; Cheng, Qiao; Zuo, Yibo; Qian, Liping; Guo, Tingting; Qian, Guanghui; Li, Lemin; Ge, Jun; Dai, Jianfeng; Xiong, Sidong; Zheng, Hui

    2016-01-01

    STAT1 is a critical transcription factor for regulating host antiviral defenses. STAT1 activation is largely dependent on phosphorylation at tyrosine 701 site of STAT1 (pY701-STAT1). Understanding how pY701-STAT1 is regulated by intracellular signaling remains a major challenge. Here we find that pY701-STAT1 is the major form of ubiquitinated-STAT1 induced by interferons (IFNs). While total STAT1 remains relatively stable during the early stages of IFNs signaling, pY701-STAT1 can be rapidly downregulated by the ubiquitin-proteasome system. Moreover, ubiquitinated pY701-STAT1 is located predominantly in the nucleus, and inhibiting nuclear import of pY701-STAT1 significantly blocks ubiquitination and downregulation of pY701-STAT1. Furthermore, we reveal that the deubiquitinase USP2a translocates into the nucleus and binds to pY701-STAT1, and inhibits K48-linked ubiquitination and degradation of pY701-STAT1. Importantly, USP2a sustains IFNs-induced pY701-STAT1 levels, and enhances all three classes of IFNs- mediated signaling and antiviral activity. To our knowledge, this is the first identified deubiquitinase that targets activated pY701-STAT1. These findings uncover a positive mechanism by which IFNs execute efficient antiviral signaling and function, and may provide potential targets for improving IFNs-based antiviral therapy. PMID:27434509

  2. A new biocatalyst: Penicillin G acylase immobilized in sol-gel micro-particles with magnetic properties.

    PubMed

    Bernardino, Susana M S A; Fernandes, Pedro; Fonseca, Luís P

    2009-05-01

    The present work focuses on the development and basic characterization of a new magnetic biocatalyst, namely penicillin G acylase (PGA), immobilized in sol-gel matrices with magnetic properties, ultimately aimed for application in cephalexin (CEX) synthesis. A mechanically stable carrier, based on porous xerogels silica matrixes starting from tetramethoxysilane (TMOS), was prepared leading to micro-carriers with medium sized particles of 30 microm, as determined by scanning electron microscopy. An immobilization yield of 95-100% and a recovered activity of 50-65% at 37 degrees C, as determined by penicillin G (PG) hydrolysis (pH STAT method), were observed. These results clearly exceed those reported in a previous work on PGA immobilization in sol-gel, where only 10% of activity was recovered. The values of activity were kept constant for 6 months. Immobilized PGA (682 U/g(dry weight)) retained high specific activity throughout ten consecutive runs for PG hydrolysis, suggesting adequate biocatalyst stability. The CEX synthesis was performed at 14 degrees C, using the free and immobilized PGA in aqueous medium. Phenylglycine methyl ester was used as acyl donor at 90 mM and 7-aminodeacetoxycephalosporanic acid was the limiting substrate at 30 mM. The CEX stoichiometric yield after 1-h reaction was close to 68% (23 mM CEX/h) and 65% (19 mM CEX/h), respectively. PMID:19418472

  3. StatsCasts: screencasts for complementing lectures in statistics classes

    NASA Astrophysics Data System (ADS)

    Dunn, Peter K.; McDonald, Christine; Loch, Birgit

    2015-05-01

    Students who are studying introductory statistics units but are enrolled in non-statistics majors often struggle with the content, and do not stay engaged. Support structures are in place at many Australian universities to help these students. Most of these are face-to-face support centres that the students can visit during opening hours. To provide additional assistance to these students any time, and from anywhere, online media are increasingly used by students - either provided by support centres, or sought independently by students. Little research has been undertaken on the effectiveness of such resources to support student learning. This paper investigates whether students will embrace StatsCasts - short screen-capture videos on key statistical topics that students have struggled with in the past, with narrator explanation provided by the lecturer - as part of their learning strategy and if they will actively engage with the videos. Students enrolled in a large first-year statistics class at an Australian university who had been provided with StatsCasts responded to a survey at the end of the semester. Volunteering students also participated in a focus group to probe deeper into students' perceptions of and motivations for watching the videos. Analysis of the data shows that students do actively engage with the StatsCasts and they appear to become an important component of their study and revision strategy.

  4. IL-17 induces EMT via Stat3 in lung adenocarcinoma

    PubMed Central

    Huang, Qi; Han, Jieli; Fan, Jinshuo; Duan, Limin; Guo, Mengfei; Lv, Zhilei; Hu, Guorong; Chen, Lian; Wu, Feng; Tao, Xiaonan; Xu, Juanjuan; Jin, Yang

    2016-01-01

    Epithelial-mesenchymal transition (EMT) plays a vital role in lung inflammatory diseases, including lung cancer. However, the role and mechanism of action of the proinflammatory cytokine IL-17 in EMT in lung adenocarcinoma remain unresolved. In our study, we discovered that the expression of N-cadherin, Vimentin, Snail1, Snail2, and Twist1 was positively correlated with IL-17 expression, while E-cadherin expression was negatively correlated with IL-17 expression in human lung adenocarcinoma tissues. Moreover, we confirmed that IL-17 promoted EMT in A549 and Lewis lung carcinoma (LLC) cells in vitro by upregulating N-cadherin, Vimentin, Snail1, Snail2, and Twist1 expression and downregulating E-cadherin expression. Stat3 was activated in IL-17-treated A549 and LLC cells, and Stat3 inhibition or siRNA knockdown notably reduced IL-17-induced EMT in A549 and LLC cells. Thus, IL-17 promotes EMT in lung adenocarcinoma via Stat3 signaling; these observations suggest that targeting IL-17 and EMT are potential novel therapeutic strategies for lung cancer. PMID:27186414

  5. Reagentless pH-stat for microliter fluid specimens.

    PubMed

    Kao, Linus T-H; Hsu, Hung-Yi; Gratzl, Miklós

    2008-06-01

    pH-stating is a common technique for monitoring kinetics of various biochemical reactions that involve the generation of hydrogen or hydroxyl ions. In this work, we describe a reagentless electrochemical micro-pH-stat where the titrant of acid or base is produced by water electrolysis on the rotating sample system (RSS) platform. RSS originated from the authors' laboratory as a convective platform to support different analytical techniques in microliter-sized samples. As water electrolysis induces no volume change and the current that generates the reagent can be precisely measured even at low levels, very small samples in the microliter range become accessible for pH-stating: a reduction of more than an order of magnitude in specimen size relative to the most sensitive conventional methods. Nearly 100% current efficiency has been achieved with this system using a 250 microm Pt minidisc working electrode for electrolysis. The developed micro-pH-stat has been validated by the determination of the activity of erythrocyte acetylcholinesterase as a function of substrate concentration and pH. The optimal pH and activity profile obtained are in good agreement with those determined with standard techniques. The micro-pH-stat has the potential for applications for enzyme assays, reagentless pH control, acidity/alkalinity, and buffer capacity measurements in very small samples of biomedical and environmental origin. PMID:18442265

  6. The Rabies Virus Interferon Antagonist P Protein Interacts with Activated STAT3 and Inhibits Gp130 Receptor Signaling

    PubMed Central

    Lieu, Kim G.; Brice, Aaron; Wiltzer, Linda; Hirst, Bevan; Jans, David A.; Blondel, Danielle

    2013-01-01

    Immune evasion by rabies virus depends on targeting of the signal transducers and activator of transcription 1 (STAT1) and STAT2 proteins by the viral interferon antagonist P protein, but targeting of other STAT proteins has not been investigated. Here, we find that P protein associates with activated STAT3 and inhibits STAT3 nuclear accumulation and Gp130-dependent signaling. This is the first report of STAT3 targeting by the interferon antagonist of a virus other than a paramyxovirus, indicating that STAT3 antagonism is important to a range of human-pathogenic viruses. PMID:23698294

  7. Involvement of transcription factor Oct-1 in the regulation of JAK-STAT signaling pathway in cells of Burkitt lymphoma.

    PubMed

    Pankratova, E V; Stepchenko, A G; Krylova, I D; Portseva, T N; Georgieva, S G

    2016-05-01

    We studied the role of transcription factor Oct-1 in the regulation of expression of genes of the JAK-STAT signaling pathway in the Namalwa Burkitt's lymphoma cell line. Overexpression of Oct-1 isoforms (Oct-1A, Oct-1L, and Oct-1X) causes a decrease in the activity of four genes involved in the JAK-STAT signaling pathway-IFNAR2, STAT1, STAT2, and STAT4. As a result of our research, it was found that genes STAT2 and STAT4 are direct targets for Oct-1 protein. PMID:27417729

  8. Biocatalysis with Sol-Gel Encapsulated Acid Phosphatase

    ERIC Educational Resources Information Center

    Kulkarni, Suhasini; Tran, Vu; Ho, Maggie K.-M.; Phan, Chieu; Chin, Elizabeth; Wemmer, Zeke; Sommerhalter, Monika

    2010-01-01

    This experiment was performed in an upper-level undergraduate biochemistry laboratory course. Students learned how to immobilize an enzyme in a sol-gel matrix and how to perform and evaluate enzyme-activity measurements. The enzyme acid phosphatase (APase) from wheat germ was encapsulated in sol-gel beads that were prepared from the precursor…

  9. Spirit View of Phobos Eclipse, Sol 675

    NASA Technical Reports Server (NTRS)

    2005-01-01

    [figure removed for brevity, see original site] Annotated Spirit View of Phobos Eclipse, Sol 675

    NASA's Mars Exploration Rover Spirit observed the Martian moon Phobos entering the shadow of Mars during the night of the rover's 675th sol (Nov. 27, 2005). The panoramic camera captured 16 images, spaced 10 seconds apart, covering the period from when Phobos was in full sunlight to when it was entirely in shadow. As with our own Moon during lunar eclipses on Earth, even when in the planet's shadow, Phobos was not entirely dark. The small amount of light still visible from Phobos is a kind of 'Mars-shine' -- sunlight reflected through Mars' atmosphere and into the shadowed region.

    This view is a time-lapse composite of images taken 20 seconds apart, showing the movement of Phobos from left to right. (At 10 seconds apart, the images of the moon overlap each other.) Scientists are using information about the precise timing of Martian moon eclipses gained from observations such as these to refine calculations about the orbital path of Phobos. The precise position of Phobos will be important to any future spacecraft taking detailed pictures of the moon or landing on its surface.

  10. SOL Reflectometer for Alcator C-Mod

    SciTech Connect

    Hanson, Gregory R; Wilgen, John B; Wukitch, Dr. Steve; Lin, Dr. Yijun; Lau, Cornwall H; Wallace, Gregory M

    2008-01-01

    A two-frequency x-mode reflectometer operating from 100 146 GHz is being deployed on Alcator C-Mod to measure the density profile and fluctuations in the scrape-off layer (SOL) immediately in-front of the new J-port ICRF antenna and the new B-port Lower Hybrid launcher. The reflectometer will cover densities from 1016 to 1020 m-3 at 5 5.4 T. To provide the greatest flexibility and capability to deal with density fluctuations approaching 100% peak to peak in the SOL, both full-phase and differential-phase measurement capabilities with sweep speeds of ~10 s to >1 ms are being implemented. The differential-phase measurement will use a difference-frequency of 500 MHz, corresponding to cutoff layer separations ranging from about 0.1 mm to 1 mm. The reflectometer will have 6 sets of launchers: 3 on the J-port ICRF antenna and 3 on the B-port LHRF launcher. The ICRF and LHRF antennas will incorporate reflectometer antennas at their top, bottom and mid-plane locations.

  11. Opportunity's Sol 446 Position, with Relative Heights

    NASA Technical Reports Server (NTRS)

    2005-01-01

    [figure removed for brevity, see original site] Figure 1: Coding for Information About Relative Elevations This mosaic of navigation-camera frames from NASA's Mars Exploration Rover Opportunity, presented in a vertical projection, shows the rover's position after it dug itself to wheel-hub depth in a small dune during its 446th martian day, or sol (April 26, 2005). In figure 1, the colors are coding for information about relative elevations in the surrounding area. Red areas are the highest in the image, green areas the lowest. The difference between red and green is about 70 centimeters (28 inches).

    The elongated dune, or ripple, is about one-third of a meter (one foot) tall and 2.5 meters (8 feet) wide.

    Opportunity had completed nearly 40 meters (131 feet) of a planned 90-meter (295-foot) drive that sol when its wheels began slipping. The rover was driving backwards at the time. The rover team frequently alternates between backwards and forwards driving to keep wheel lubrication well distributed. The wheels kept rotating enough times to have covered the rest of the distance if they hadn't been slipping, but the rover eventually barely inched forward. After a turn at the end of the planned drive, Opportunity sensed that it had not turned properly and stopped moving.

    The rover team spent more than a week designing and conducting tests under simulated Mars conditions on Earth before choosing the best way for Opportunity to drive out of the dune.

  12. Opportunity's Surroundings After Sol 1820 Drive (Stereo)

    NASA Technical Reports Server (NTRS)

    2009-01-01

    [figure removed for brevity, see original site] Left-eye view of a color stereo pair for PIA11841 [figure removed for brevity, see original site] Right-eye view of a color stereo pair for PIA11841

    NASA's Mars Exploration Rover Opportunity used its navigation camera to take the images combined into this full-circle view of the rover's surroundings during the 1,820th to 1,822nd Martian days, or sols, of Opportunity's surface mission (March 7 to 9, 2009).

    This view combines images from the left-eye and right-eye sides of the navigation camera. It appears three-dimensional when viewed through red-blue glasses with the red lens on the left.

    The rover had driven 20.6 meters toward the northwest on Sol 1820 before beginning to take the frames in this view. Tracks from that drive recede southwestward. For scale, the distance between the parallel wheel tracks is about 1 meter (about 40 inches).

    The terrain in this portion of Mars' Meridiani Planum region includes dark-toned sand ripples and small exposures of lighter-toned bedrock.

    This view is presented as a cylindrical-perspective projection with geometric seam correction.

  13. After Sample-Delivery Attempt, Sol 62

    NASA Technical Reports Server (NTRS)

    2008-01-01

    NASA's Phoenix Mars Lander collected a soil sample and attempted to deliver some of it to a laboratory oven on the deck during the mission's 62nd Martian day, or sol, (July 28, 2008). The sample came from a hard layer at the bottom of the 'Snow White' trench and might have contained water ice mixed with the soil. This image taken after the attempt to deliver the sample through the open doors to cell number zero on the Thermal and Evolved-Gas Analyzer shows that very little of the soil fell onto the screened opening.

    Not enough material reached the oven, through a funnel under the screen, to proceed with analysis of the sample material.

    Phoenix's Robotic Arm Camera took this image at 7:54 a.m. local solar time on Sol 62. The size of the screened opening is about 10 centimeters (4 inches) long by 4 centimeters (1.5 inches) wide.

    The Phoenix Mission is led by the University of Arizona, Tucson, on behalf of NASA. Project management of the mission is by NASA's Jet Propulsion Laboratory, Pasadena, Calif. Spacecraft development is by Lockheed Martin Space Systems, Denver.

  14. Opportunity's Surroundings on Sol 1798 (Stereo)

    NASA Technical Reports Server (NTRS)

    2009-01-01

    [figure removed for brevity, see original site] Left-eye view of a color stereo pair for PIA11850 [figure removed for brevity, see original site] Right-eye view of a color stereo pair for PIA11850

    NASA's Mars Exploration Rover Opportunity used its navigation camera to take the images combined into this stereo 180-degree view of the rover's surroundings during the 1,798th Martian day, or sol, of Opportunity's surface mission (Feb. 13, 2009). North is on top.

    This view combines images from the left-eye and right-eye sides of the navigation camera. It appears three-dimensional when viewed through red-blue glasses with the red lens on the left.

    The rover had driven 111 meters (364 feet) southward on the preceding sol. Tracks from that drive recede northward in this view. For scale, the distance between the parallel wheel tracks is about 1 meter (about 40 inches).

    The terrain in this portion of Mars' Meridiani Planum region includes dark-toned sand ripples and lighter-toned bedrock.

    This view is presented as a cylindrical-perspective projection with geometric seam correction.

  15. View Ahead After Spirit's Sol 1861 Drive

    NASA Technical Reports Server (NTRS)

    2009-01-01

    NASA's Mars Exploration Rover Spirit used its navigation camera to take the images combined into this 210-degree view of the rover's surroundings during the 1,861st to 1,863rd Martian days, or sols, of Spirit's surface mission (March 28 to 30, 2009).

    The center of the scene is toward the south-southwest. East is on the left. West-northwest is on the right.

    The rover had driven 22.7 meters (74 feet) southwestward on Sol 1861 before beginning to take the frames in this view. The drive brought Spirit past the northwestern corner of Home Plate.

    In this view, the western edge of Home Plate is on the portion of the horizon farthest to the left. A mound in middle distance near the center of the view is called 'Tsiolkovsky' and is about 40 meters (about 130 feet) from the rover's position.

    This view is presented as a cylindrical projection with geometric seam correction.

  16. Spirit Beside 'Home Plate,' Sol 1809 (Stereo)

    NASA Technical Reports Server (NTRS)

    2009-01-01

    [figure removed for brevity, see original site] Left-eye view of a color stereo pair for PIA11803 [figure removed for brevity, see original site] Right-eye view of a color stereo pair for PIA11803

    NASA Mars Exploration Rover Spirit used its navigation camera to take the images assembled into this stereo, 120-degree view southward after a short drive during the 1,809th Martian day, or sol, of Spirit's mission on the surface of Mars (February 3, 2009).

    By combining images from the left-eye and right-eye sides of the navigation camera, the view appears three-dimensional when viewed through red-blue glasses with the red lens on the left.

    Spirit had driven about 2.6 meters (8.5 feet) that sol, continuing a clockwise route around a low plateau called 'Home Plate.' In this image, the rocks visible above the rovers' solar panels are on the slope at the northern edge of Home Plate.

    This view is presented as a cylindrical-perspective projection with geometric seam correction.

  17. Opportunity's Surroundings on Sol 1818 (Stereo)

    NASA Technical Reports Server (NTRS)

    2009-01-01

    [figure removed for brevity, see original site] Left-eye view of a color stereo pair for PIA11846 [figure removed for brevity, see original site] Right-eye view of a color stereo pair for PIA11846

    NASA's Mars Exploration Rover Opportunity used its navigation camera to take the images combined into this full-circle view of the rover's surroundings during the 1,818th Martian day, or sol, of Opportunity's surface mission (March 5, 2009). South is at the center; north at both ends.

    This view combines images from the left-eye and right-eye sides of the navigation camera. It appears three-dimensional when viewed through red-blue glasses with the red lens on the left.

    The rover had driven 80.3 meters (263 feet) southward earlier on that sol. Tracks from the drive recede northward in this view.

    The terrain in this portion of Mars' Meridiani Planum region includes dark-toned sand ripples and lighter-toned bedrock.

    This view is presented as a cylindrical-perspective projection with geometric seam correction.

  18. STAT3 inhibition suppresses proliferation of retinoblastoma through down-regulation of positive feedback loop of STAT3/miR-17-92 clusters

    PubMed Central

    Jo, Dong Hyun; Kim, Jin Hyoung; Cho, Chang Sik; Cho, Young-Lai; Jun, Hyoung Oh; Yu, Young Suk; Min, Jeong-Ki; Kim, Jeong Hun

    2014-01-01

    Retinoblastoma, the most common intraocular malignant tumor in children, is characterized by the loss of both functional alleles of RB1 gene, which however alone cannot maintain malignant characteristics of retinoblastoma cells. Nevertheless, the investigation of other molecular aberrations such as matrix metalloproteinases (MMPs) and miRNAs is still lacking. In this study, we demonstrate that STAT3 is activated in retinoblastoma cells, Ki67-positive areas of in vivo orthotopic tumors in BALB/c nude mice, and human retinoblastoma tissues of the advanced stage. Furthermore, target genes of STAT3 including BCL2, BCL2L1, BIRC5, and MMP9 are up-regulated in retinoblastoma cells compared to other retinal constituent cells. Interestingly, STAT3 inhibition by targeted siRNA suppresses the proliferation of retinoblastoma cells and the formation of in vivo orthotopic tumors. In line with these results, STAT3 siRNA effectively induces down-regulation of target genes of STAT3. In addition, miRNA microarray analysis and further real-time PCR experiments with STAT3 siRNA treatment show that STAT3 activation is related to the up-regulation of miR-17-92 clusters in retinoblastoma cells via positive feedback loop between them. In conclusion, we suggest that STAT3 inhibition could be a potential therapeutic approach in retinoblastoma through the suppression of tumor proliferation. PMID:25359779

  19. STAT3 inhibition suppresses proliferation of retinoblastoma through down-regulation of positive feedback loop of STAT3/miR-17-92 clusters.

    PubMed

    Jo, Dong Hyun; Kim, Jin Hyoung; Cho, Chang Sik; Cho, Young-Lai; Jun, Hyoung Oh; Yu, Young Suk; Min, Jeong-Ki; Kim, Jeong Hun

    2014-11-30

    Retinoblastoma, the most common intraocular malignant tumor in children, is characterized by the loss of both functional alleles of RB1 gene, which however alone cannot maintain malignant characteristics of retinoblastoma cells. Nevertheless, the investigation of other molecular aberrations such as matrix metalloproteinases (MMPs) and miRNAs is still lacking. In this study, we demonstrate that STAT3 is activated in retinoblastoma cells, Ki67-positive areas of in vivo orthotopic tumors in BALB/c nude mice, and human retinoblastoma tissues of the advanced stage. Furthermore, target genes of STAT3 including BCL2, BCL2L1, BIRC5, and MMP9 are up-regulated in retinoblastoma cells compared to other retinal constituent cells. Interestingly, STAT3 inhibition by targeted siRNA suppresses the proliferation of retinoblastoma cells and the formation of in vivo orthotopic tumors. In line with these results, STAT3 siRNA effectively induces down-regulation of target genes of STAT3. In addition, miRNA microarray analysis and further real-time PCR experiments with STAT3 siRNA treatment show that STAT3 activation is related to the up-regulation of miR-17-92 clusters in retinoblastoma cells via positive feedback loop between them. In conclusion, we suggest that STAT3 inhibition could be a potential therapeutic approach in retinoblastoma through the suppression of tumor proliferation. PMID:25359779

  20. Human Cytomegalovirus Immediate-Early 1 Protein Rewires Upstream STAT3 to Downstream STAT1 Signaling Switching an IL6-Type to an IFNγ-Like Response

    PubMed Central

    Lukas, Simone; Zenger, Marion; Reitberger, Tobias; Danzer, Daniela; Übner, Theresa; Munday, Diane C.; Paulus, Christina

    2016-01-01

    The human cytomegalovirus (hCMV) major immediate-early 1 protein (IE1) is best known for activating transcription to facilitate viral replication. Here we present transcriptome data indicating that IE1 is as significant a repressor as it is an activator of host gene expression. Human cells induced to express IE1 exhibit global repression of IL6- and oncostatin M-responsive STAT3 target genes. This repression is followed by STAT1 phosphorylation and activation of STAT1 target genes normally induced by IFNγ. The observed repression and subsequent activation are both mediated through the same region (amino acids 410 to 445) in the C-terminal domain of IE1, and this region serves as a binding site for STAT3. Depletion of STAT3 phenocopies the STAT1-dependent IFNγ-like response to IE1. In contrast, depletion of the IL6 receptor (IL6ST) or the STAT kinase JAK1 prevents this response. Accordingly, treatment with IL6 leads to prolonged STAT1 instead of STAT3 activation in wild-type IE1 expressing cells, but not in cells expressing a mutant protein (IE1dl410-420) deficient for STAT3 binding. A very similar STAT1-directed response to IL6 is also present in cells infected with a wild-type or revertant hCMV, but not an IE1dl410-420 mutant virus, and this response results in restricted viral replication. We conclude that IE1 is sufficient and necessary to rewire upstream IL6-type to downstream IFNγ-like signaling, two pathways linked to opposing actions, resulting in repressed STAT3- and activated STAT1-responsive genes. These findings relate transcriptional repressor and activator functions of IE1 and suggest unexpected outcomes relevant to viral pathogenesis in response to cytokines or growth factors that signal through the IL6ST-JAK1-STAT3 axis in hCMV-infected cells. Our results also reveal that IE1, a protein considered to be a key activator of the hCMV productive cycle, has an unanticipated role in tempering viral replication. PMID:27387064

  1. Human Cytomegalovirus Immediate-Early 1 Protein Rewires Upstream STAT3 to Downstream STAT1 Signaling Switching an IL6-Type to an IFNγ-Like Response.

    PubMed

    Harwardt, Thomas; Lukas, Simone; Zenger, Marion; Reitberger, Tobias; Danzer, Daniela; Übner, Theresa; Munday, Diane C; Nevels, Michael; Paulus, Christina

    2016-07-01

    The human cytomegalovirus (hCMV) major immediate-early 1 protein (IE1) is best known for activating transcription to facilitate viral replication. Here we present transcriptome data indicating that IE1 is as significant a repressor as it is an activator of host gene expression. Human cells induced to express IE1 exhibit global repression of IL6- and oncostatin M-responsive STAT3 target genes. This repression is followed by STAT1 phosphorylation and activation of STAT1 target genes normally induced by IFNγ. The observed repression and subsequent activation are both mediated through the same region (amino acids 410 to 445) in the C-terminal domain of IE1, and this region serves as a binding site for STAT3. Depletion of STAT3 phenocopies the STAT1-dependent IFNγ-like response to IE1. In contrast, depletion of the IL6 receptor (IL6ST) or the STAT kinase JAK1 prevents this response. Accordingly, treatment with IL6 leads to prolonged STAT1 instead of STAT3 activation in wild-type IE1 expressing cells, but not in cells expressing a mutant protein (IE1dl410-420) deficient for STAT3 binding. A very similar STAT1-directed response to IL6 is also present in cells infected with a wild-type or revertant hCMV, but not an IE1dl410-420 mutant virus, and this response results in restricted viral replication. We conclude that IE1 is sufficient and necessary to rewire upstream IL6-type to downstream IFNγ-like signaling, two pathways linked to opposing actions, resulting in repressed STAT3- and activated STAT1-responsive genes. These findings relate transcriptional repressor and activator functions of IE1 and suggest unexpected outcomes relevant to viral pathogenesis in response to cytokines or growth factors that signal through the IL6ST-JAK1-STAT3 axis in hCMV-infected cells. Our results also reveal that IE1, a protein considered to be a key activator of the hCMV productive cycle, has an unanticipated role in tempering viral replication. PMID:27387064

  2. STAT3 selectively interacts with Smad3 to antagonize TGF-β.

    PubMed

    Wang, G; Yu, Y; Sun, C; Liu, T; Liang, T; Zhan, L; Lin, X; Feng, X-H

    2016-08-18

    Smad and STAT proteins are critical signal transducers and transcription factors in controlling cell growth and tumorigenesis. Here we report that the STAT3 signaling pathway attenuates transforming growth factor-β (TGF-β)-induced responses through a direct Smad3-STAT3 interplay. Activated STAT3 blunts TGF-β-mediated signaling. Depletion of STAT3 promotes TGF-β-mediated transcriptional and physiological responses, including cell cycle arrest, apoptosis and epithelial-to-mesenchymal transition. STAT3 directly interacts with Smad3 in vivo and in vitro, resulting in attenuation of the Smad3-Smad4 complex formation and suppression of DNA-binding ability of Smad3. The N-terminal region of DNA-binding domain of STAT3 is responsible for the STAT3-Smad3 interaction and also indispensable for STAT3-mediated inhibition of TGF-β signaling. Thus, our finding illustrates a direct crosstalk between the STAT3 and Smad3 signaling pathways that may contribute to tumor development and inflammation. PMID:26616859

  3. Mechanisms of STAT3 activation in the liver of FXR knockout mice.

    PubMed

    Li, Guodong; Zhu, Yan; Tawfik, Ossama; Kong, Bo; Williams, Jessica A; Zhan, Le; Kassel, Karen M; Luyendyk, James P; Wang, Li; Guo, Grace L

    2013-12-01

    Farnesoid X receptor (FXR, Nr1h4) is a ligand-activated transcription factor belonging to the nuclear receptor superfamily. FXR is essential in maintaining bile acid (BA) homeostasis, and FXR(-/-) mice develop cholestasis, inflammation, and spontaneous liver tumors. The signal transducer and activator of transcription 3 (STAT3) is well known to regulate liver growth, and STAT3 is feedback inhibited by its target gene, the suppressor of cytokine signaling 3 (SOCS3). Strong activation of STAT3 was detected in FXR(-/-) mouse livers. However, the mechanism of STAT3 activation with FXR deficiency remains elusive. Wild-type (WT) and FXR(-/-) mice were used to detect STAT3 pathway activation in the liver. In vivo BA feeding or deprivation was used to determine the role of BAs in STAT3 activation, and in vitro molecular approaches were used to determine the direct transcriptional regulation of SOCS3 by FXR. STAT3 was activated in FXR(-/-) but not WT mice. BA feeding increased, but deprivation by cholestyramine reduced, serum inflammatory markers and STAT3 activation. Furthermore, the Socs3 gene was determined as a direct FXR target gene. The elevated BAs and inflammation, along with reduced SOCS3, collectively contribute to the activation of the STAT3 signaling pathway in the liver of FXR(-/-) mice. This study suggests that the constitutive activation of STAT3 may be a mechanism of liver carcinogenesis in FXR(-/-) mice. PMID:24091600

  4. Mechanisms of STAT3 activation in the liver of FXR knockout mice

    PubMed Central

    Li, Guodong; Zhu, Yan; Tawfik, Ossama; Kong, Bo; Williams, Jessica A.; Zhan, Le; Kassel, Karen M.; Luyendyk, James P.; Wang, Li

    2013-01-01

    Farnesoid X receptor (FXR, Nr1h4) is a ligand-activated transcription factor belonging to the nuclear receptor superfamily. FXR is essential in maintaining bile acid (BA) homeostasis, and FXR−/− mice develop cholestasis, inflammation, and spontaneous liver tumors. The signal transducer and activator of transcription 3 (STAT3) is well known to regulate liver growth, and STAT3 is feedback inhibited by its target gene, the suppressor of cytokine signaling 3 (SOCS3). Strong activation of STAT3 was detected in FXR−/− mouse livers. However, the mechanism of STAT3 activation with FXR deficiency remains elusive. Wild-type (WT) and FXR−/− mice were used to detect STAT3 pathway activation in the liver. In vivo BA feeding or deprivation was used to determine the role of BAs in STAT3 activation, and in vitro molecular approaches were used to determine the direct transcriptional regulation of SOCS3 by FXR. STAT3 was activated in FXR−/− but not WT mice. BA feeding increased, but deprivation by cholestyramine reduced, serum inflammatory markers and STAT3 activation. Furthermore, the Socs3 gene was determined as a direct FXR target gene. The elevated BAs and inflammation, along with reduced SOCS3, collectively contribute to the activation of the STAT3 signaling pathway in the liver of FXR−/− mice. This study suggests that the constitutive activation of STAT3 may be a mechanism of liver carcinogenesis in FXR−/− mice. PMID:24091600

  5. Glia maturation factor regulation of STAT expression: a novel mechanism in experimental autoimmune encephalomyelitis.

    PubMed

    Zaheer, Smita; Wu, Yanghong; Bassett, Jon; Yang, Baoli; Zaheer, Asgar

    2007-12-01

    Inflammatory cytokines are implemented in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. We previously demonstrated that glia maturation factor (GMF), a brain protein, isolated, sequenced and cloned in our laboratory, induce expression of proinflammatory cytokine/chemokine in the central nervous system (CNS). We found GMF-deficient (knockout) mice relatively resistant to EAE development after immunization with encephalitogenic MOG peptide 35-55. Consistent with these findings, the expression of proinflammatory cytokines in CNS of mice with EAE differed profoundly between wild type and GMF-knockout mice. In the present study we examined the expressions of six murine signal transducers and activators of transcription (STATs) genes, which are known to regulate the cytokine-dependent signal transduction pathways in autoimmune inflammation. The expressions of STATs genes were evaluated in the brains and spinal cords of wild type and GMF-knockout mice at the peak of EAE by quantitative real-time RT-PCR. Compared to GMF-knockout mice, the expressions of STAT1, STAT2, STAT3, STAT4, STAT5, and STAT6 genes were significantly (P < 0.001) upregulated in the wild type mice exhibiting EAE symptoms. The results are consistent with the diminished development of EAE in the GMF-knockout mice. A significant suppression of STATs expression in GMF-knockout mice suggests GMF as an upstream effector of JAK/STAT signaling. PMID:17551829

  6. Modulation of STAT3 Folding and Function by TRiC/CCT Chaperonin

    PubMed Central

    Kasembeli, Moses; Lau, Wilson Chun Yu; Roh, Soung-Hun; Eckols, T. Kris; Frydman, Judith; Chiu, Wah; Tweardy, David J.

    2014-01-01

    Signal transducer and activator of transcription 3 (Stat3) transduces signals of many peptide hormones from the cell surface to the nucleus and functions as an oncoprotein in many types of cancers, yet little is known about how it achieves its native folded state within the cell. Here we show that Stat3 is a novel substrate of the ring-shaped hetero-oligomeric eukaryotic chaperonin, TRiC/CCT, which contributes to its biosynthesis and activity in vitro and in vivo. TRiC binding to Stat3 was mediated, at least in part, by TRiC subunit CCT3. Stat3 binding to TRiC mapped predominantly to the β-strand rich, DNA-binding domain of Stat3. Notably, enhancing Stat3 binding to TRiC by engineering an additional TRiC-binding domain from the von Hippel-Lindau protein (vTBD), at the N-terminus of Stat3, further increased its affinity for TRiC as well as its function, as determined by Stat3's ability to bind to its phosphotyrosyl-peptide ligand, an interaction critical for Stat3 activation. Thus, Stat3 levels and function are regulated by TRiC and can be modulated by manipulating its interaction with TRiC. PMID:24756126

  7. The measles virus phosphoprotein interacts with the linker domain of STAT1

    SciTech Connect

    Devaux, Patricia Priniski, Lauren; Cattaneo, Roberto

    2013-09-15

    The measles virus (MV) phosphoprotein (P) and V proteins block the interferon (IFN) response by impeding phosphorylation of the signal transducer and activator of transcription 1 (STAT1) by the Janus kinase 1 (JAK1). We characterized how STAT1 mutants interact with P and JAK1 phosphorylation. Certain mutants of the linker, the Src-homology 2 domain (SH2), or the transactivation domain had reduced or abolished phosphorylation through JAK1 after IFN treatment. Other mutants, mainly localized in the linker, failed to interact with P as documented by the lack of interference with nuclear translocation. Thus the functional footprint of P on STAT1 localizes mainly to the linker domain; there is also some overlap with the STAT1 phosphorylation functional footprint on the SH2 domain. Based on these observations, we discuss how the MV-P might operate to inhibit the JAK/STAT pathway. - Highlights: • Residue in the linker and SH2 domains of STAT1 are important for MV-P interaction. • Residue in the linker and SH2 domains of STAT1 are important for STAT1 phosphorylation. • Residues interferring with both functions have similar location on STAT1. • The viral P and V proteins may operate in concert to inhibit the JAK/STAT pathway.

  8. The STAT pathway mediates late phase immunity against Plasmodium in the mosquito Anopheles gambiae

    PubMed Central

    Gupta, Lalita; Molina-Cruz, Alvaro; Kumar, Sanjeev; Rodrigues, Janneth; Dixit, Rajnikant; Zamora, Rodolfo E.; Barillas-Mury, Carolina

    2009-01-01

    The STAT family of transcription factors activate expression of immune system genes in vertebrates. The ancestral STAT gene (AgSTAT-A) appears to have duplicated in the mosquito Anopheles gambiae, giving rise to a second intronless STAT gene (AgSTAT-B), which we show regulates AgSTAT-A expression in adult females. AgSTAT-A participates in the transcriptional activation of nitric oxide synthase (NOS) in response to bacterial and plasmodial infection. Activation of this pathway, however, is not essential for mosquitoes to survive a bacterial challenge. AgSTAT-A silencing reduces the number of early Plasmodium oocysts in the midgut, but nevertheless enhances the overall infection by increasing oocyst survival. Silencing of SOCS, a STAT suppressor, has the opposite effect, reducing Plasmodium infection by increasing NOS expression. Chemical inhibition of mosquito NOS activity after oocyte formation increases oocyte survival. Thus, the AgSTAT-A pathway mediates a late phase anti-plasmodial response that reduces oocyst survival in An. gambiae. PMID:19454353

  9. The STAT pathway mediates late-phase immunity against Plasmodium in the mosquito Anopheles gambiae.

    PubMed

    Gupta, Lalita; Molina-Cruz, Alvaro; Kumar, Sanjeev; Rodrigues, Janneth; Dixit, Rajnikant; Zamora, Rodolfo E; Barillas-Mury, Carolina

    2009-05-01

    The STAT family of transcription factors activates expression of immune system genes in vertebrates. The ancestral STAT gene (AgSTAT-A) appears to have duplicated in the mosquito Anopheles gambiae, giving rise to a second intronless STAT gene (AgSTAT-B), which we show regulates AgSTAT-A expression in adult females. AgSTAT-A participates in the transcriptional activation of nitric oxide synthase (NOS) in response to bacterial and plasmodial infection. Activation of this pathway, however, is not essential for mosquitoes to survive a bacterial challenge. AgSTAT-A silencing reduces the number of early Plasmodium oocysts in the midgut, but nevertheless enhances the overall infection by increasing oocyst survival. Silencing of SOCS, a STAT suppressor, has the opposite effect, reducing Plasmodium infection by increasing NOS expression. Chemical inhibition of mosquito NOS activity after oocyte formation increases oocyte survival. Thus, the AgSTAT-A pathway mediates a late-phase antiplasmodial response that reduces oocyst survival in A. gambiae. PMID:19454353

  10. Myeloid STAT3 promotes formation of colitis-associated colorectal cancer in mice

    PubMed Central

    Pathria, Paulina; Gotthardt, Dagmar; Prchal-Murphy, Michaela; Putz, Eva-Maria; Holcmann, Martin; Schlederer, Michaela; Grabner, Beatrice; Crncec, Ilija; Svinka, Jasmin; Musteanu, Monica; Hoffmann, Thomas; Filipits, Martin; Berger, Walter; Poli, Valeria; Kenner, Lukas; Bilban, Martin; Casanova, Emilio; Müller, Mathias; Strobl, Birgit; Bayer, Editha; Mohr, Thomas; Sexl, Veronika; Eferl, Robert

    2015-01-01

    Myeloid cells lacking STAT3 promote antitumor responses of NK and T cells but it is unknown if this crosstalk affects development of autochthonous tumors. We deleted STAT3 in murine myeloid cells (STAT3Δm) and examined the effect on the development of autochthonous colorectal cancers (CRCs). Formation of Azoxymethane/Dextransulfate (AOM/DSS)-induced CRCs was strongly suppressed in STAT3Δm mice. Gene expression profiling showed strong activation of T cells in the stroma of STAT3Δm CRCs. Moreover, STAT3Δm host mice were better able to control the growth of transplanted MC38 colorectal tumor cells which are known to be killed in a T cell-dependent manner. These data suggest that myeloid cells lacking STAT3 control formation of CRCs mainly via cross activation of T cells. Interestingly, the few CRCs that formed in STAT3Δm mice displayed enhanced stromalization but appeared normal in size indicating that they have acquired ways to escape enhanced tumor surveillance. We found that CRCs in STAT3Δm mice consistently activate STAT3 signaling which is implicated in immune evasion and might be a target to prevent tumor relapse. PMID:26137415

  11. Withaferin A Inhibits STAT3 and Induces Tumor Cell Death in Neuroblastoma and Multiple Myeloma

    PubMed Central

    Yco, Lisette P; Mocz, Gabor; Opoku-Ansah, John; Bachmann, André S

    2014-01-01

    Signal transducer and activator of transcription 3 (STAT3) is an oncogenic transcription factor that has been implicated in many human cancers and has emerged as an ideal target for cancer therapy. Withaferin A (WFA) is a natural product with promising antiproliferative properties through its association with a number of molecular targets including STAT3. However, the effect of WFA in pediatric neuroblastoma (NB) and its interaction with STAT3 have not been reported. In this study, we found that WFA effectively induces dose-dependent cell death in high-risk and drug-resistant NB as well as multiple myeloma (MM) tumor cells, prevented interleukin-6 (IL-6)–mediated and persistently activated STAT3 phosphorylation at Y705, and blocked the transcriptional activity of STAT3. We further provide computational models that show that WFA binds STAT3 near the Y705 phospho-tyrosine residue of the STAT3 Src homology 2 (SH2) domain, suggesting that WFA prevents STAT3 dimer formation similar to BP-1-102, a well-established STAT3 inhibitor. Our findings propose that the antitumor activity of WFA is mediated at least in part through inhibition of STAT3 and provide a rationale for further drug development and clinical use in NB and MM. PMID:25452693

  12. ALA-PDT inhibits proliferation and promotes apoptosis of SCC cells through STAT3 signal pathway.

    PubMed

    Qiao, Li; Mei, Zhusong; Yang, Zhiyong; Li, Xinji; Cai, Hong; Liu, Wei

    2016-06-01

    Previous studies suggest that apoptosis of carcinoma cells led by photodynamics is mainly intrinsic apoptosis, but whether the extrinsic pathway is involved in the treatment of carcinoma by photodynamic therapy is not confirmed. This research investigated the effect of ALA-PDT on the proliferation and apoptosis of SCC cell A431 and COLO-16, and discussed the role played by JAK/STAT3 signal pathway in this process. Our data showed that the expression levels STAT3 and p-STAT3 protein in the cancer tissue are higher than the corresponding adjacent tissue to carcinoma. The expression level of p-STAT3 in cancerous tissue has a correlation with the tumor size and tissue histopathological differentiation. ALA-PDT could inhibit proliferation of A431 and COLO-16 cells, STAT3 knock down could enhance ALA-PDT's inhibition of cell proliferation, and promote apoptosis induced by ALA-PDT. On the other hand, overexpression of STAT3 has the opposite effect. In addition, ALA-PDT can weaken the protein expression of STAT3 and its target gene Bcl-2 mRNA, and ALA-PDT can strengthen the protein expression of STAT3's target gene Bax mRNA. Overexpression of STAT3 can offset the effect on Bcl-2 and Bax by ALA-PDT; on the other hand, STAT3 knocking down can strengthen ALA-PDT's effect on Bcl-2 and Bax. PMID:26805005

  13. Activation of different Stat5 isoforms contributes to cell-type-restricted signaling in response to interferons.

    PubMed Central

    Meinke, A; Barahmand-Pour, F; Wöhrl, S; Stoiber, D; Decker, T

    1996-01-01

    Tyrosine phosphorylation and activation of the transcription factor Stat5 occur in response to stimuli like granulocyte-macrophage colony-stimulating factor, interleukin-3, or erythropoietin that stimulate both proliferation and differentiation of hematopoietic cells. It is unclear whether Stat5 is part of a proliferative response or part of the events leading to cellular differentiation. Here we report that agents promoting differentiation but not proliferation of hematopoietic cells, like phorbol ester or both types of interferons (IFNs), activate Stat5 in promonocytic U937 cells. Both IFN types caused tyrosine phosphorylation and DNA binding of predominantly one Stat5 isoform (Stat5a) despite expression of both Stat5a and Stat5b proteins. Monocytic differentiation of U937 cells led to a strong decrease in IFN-gamma-mediated activation of Stat5 but not of Stat1. Transactivation of Stat5-target genes occurred in response to IFN-gamma, which activates both Stat5 and Stat1, but not in response to granulocyte-macrophage colony-stimulating factor, which activates only Stat5. Tyrosine phosphorylation of Stat5 is not generally part of the IFN response. IFN-gamma did not cause Stat5 activation in HeLa cells, despite the expression of both Stat5 isoforms at similar levels. By contrast, IFN-alpha caused tyrosine phosphorylation and DNA binding of exclusively the b isoform of Stat5, and activated Stat5b formed a DNA binding activity previously found in HeLa cells and designated IFN-alpha activation factor 2. Taken together, our results demonstrate that ligand binding of IFN receptors leads to an isoform-specific activation of Stat5 in a restricted number of cell lineages. Moreover, they suggest that Stat5 might be part of the differentiation response of myeloid cells. PMID:8943349

  14. Fetal anemia and apoptosis of red cell progenitors in Stat5a-/-5b-/- mice: a direct role for Stat5 in Bcl-X(L) induction.

    PubMed

    Socolovsky, M; Fallon, A E; Wang, S; Brugnara, C; Lodish, H F

    1999-07-23

    The erythropoietin receptor (EpoR) is essential for production of red blood cells; a principal function of EpoR is to rescue committed erythroid progenitors from apoptosis. Stat5 is rapidly activated following EpoR stimulation, but its function in erythropoiesis has been unclear since adult Stat5a-/-5b-/- mice have normal steady-state hematocrit. Here we show that Stat5 is essential for the high erythropoietic rate during fetal development. Stat5a-/-5b-/- embryos are severely anemic; erythroid progenitors are present in low numbers, show higher levels of apoptosis, and are less responsive to Epo. These findings are explained by a crucial role for Stat5 in EpoR's antiapoptotic signaling: it mediates the immediate-early induction of Bcl-X(L) in erythroid cells through direct binding to the Bcl-X promoter. PMID:10428030

  15. AURKA regulates JAK2-STAT3 activity in human gastric and esophageal cancers.

    PubMed

    Katsha, Ahmed; Arras, Janet; Soutto, Mohammed; Belkhiri, Abbes; El-Rifai, Wael

    2014-12-01

    Aurora kinase A is a frequently amplified and overexpressed gene in upper gastrointestinal adenocarcinomas (UGCs). Using in vitro cell models of UGCs, we investigated whether AURKA can regulate Signal Transducer and Activator of Transcription 3 (STAT3). Our data indicate that overexpression of AURKA in FLO-1 and AGS cells increase STAT3 phosphorylation at the Tyr705 site, whereas AURKA genetic depletion by siRNA results in decreased phosphorylation levels of STAT3 in FLO-1 and MKN45 cells. Immunofluorescence analysis showed that AURKA overexpression enhanced STAT3 nuclear translocation while AURKA genetic knockdown reduced the nuclear translocation of STAT3 in AGS and FLO-1 cells, respectively. Using a luciferase reporter assay, we demonstrated that AURKA expression induces transcriptional activity of STAT3. Pharmacological inhibition of AURKA by MLN8237 reduced STAT3 phosphorylation along with down-regulation of STAT3 pro-survival targets, BCL2 and MCL1. Moreover, by using clonogenic cells survival assay, we showed that MLN8237 single dose treatment reduced the ability of FLO-1 and AGS cells to form colonies. Additional experiments utilizing cell models of overexpression and knockdown of AURKA indicated that STAT3 upstream non-receptor tyrosine kinase Janus kinase 2 (JAK2) is mediating the effect of AURKA on STAT3. The inhibition of JAK2 using JAK2-specific inhibitor AZD1480 or siRNA knockdown, in presence of AURKA overexpression, abrogated the AURKA-mediated STAT3 activation. These results confirm that the AURKA-JAK2 axis is the main mechanism by which AURKA regulates STAT3 activity. In conclusion, we report, for the first time, that AURKA promotes STAT3 activity through regulating the expression and phosphorylation levels of JAK2. This highlights the importance of targeting AURKA as a therapeutic approach to treat gastric and esophageal cancers. PMID:24953013

  16. STAT3 Inhibition by Microtubule-Targeted Drugs: Dual Molecular Effects of Chemotherapeutic Agents

    PubMed Central

    Walker, Sarah R.; Chaudhury, Mousumi; Frank, David A.

    2011-01-01

    To improve the effectiveness of anti-cancer therapies, it is necessary to identify molecular targets that are essential to a tumor cell but dispensable in a normal cell. Increasing evidence indicates that the transcription factor STAT3, which regulates the expression of genes controlling proliferation, survival, and self-renewal, constitutes such a target. Recently it has been found that STAT3 can associate with the cytoskeleton. Since many of the tumors in which STAT3 is activated, such as breast cancer and ovarian cancer, are responsive to drugs that target microtubules, we examined the effect of these compounds on STAT3. We found that microtubule stabilizers, such as paclitaxel, or microtubule inhibitors, such as vinorelbine, decrease the activating tyrosine phosphorylation of STAT3 in tumor cells and inhibit the expression of STAT3 target genes. Paclitaxel decreases the association between STAT3 and microtubules, and appears to decrease STAT3 phosphorylation through induction of a negative feedback regulator. The cytotoxic activity of paclitaxel in breast cancer cell lines correlates with its ability to decrease STAT3 phosphorylation. However, consistent with the necessity for expression of a negative regulator, treatment of resistant MDA-MB-231 cells with the DNA demethylating agent 5-azacytidine restores the ability of paclitaxel to block STAT3-dependent gene expression. Finally, the combination of paclitaxel and agents that directly target STAT3 has beneficial effects in killing STAT3-dependent cell lines. Thus, microtubule-targeted agents may exert some of their effects by inhibiting STAT3, and understanding this interaction may be important for optimizing rational targeted cancer therapies. PMID:21949561

  17. STAT5 regulation of BCL10 parallels constitutive NFκB activation in lymphoid tumor cells

    PubMed Central

    Nagy, Zsuzsanna S; LeBaron, Matthew J; Ross, Jeremy A; Mitra, Abhisek; Rui, Hallgeir; Kirken, Robert A

    2009-01-01

    Background Signal Transducer and Activator of Transcription 5 A and B (STAT5) are key survival factors in cells of the lymphoid lineage. Identification of novel, tissue-specific STAT5 regulated genes would advance the ability to combat diseases due to aberrant STAT5 signaling. In the present work a library of human STAT5 bound genomic elements was created and validated. Results Of several STAT5 responsive genomic regulatory elements identified, one was located within the first intron of the human BCL10 gene. Chromatin immuno-precipitation reactions confirmed constitutive in vivo STAT5 binding to this intronic fragment in various human lymphoid tumor cell lines. Interestingly, non-phosphorylated STAT5 was found in the nuclei of Kit225 and YT cells in the absence of cytokine stimulation that paralleled constitutive NFκB activation. Inhibition of the hyperactive JAK3/STAT5 pathway in MT-2 cells via the Mannich-base, NC1153, diminished the constitutive in vivo occupancy of BCL10-SBR by STAT5, reduced NFκB activity and BCL10 protein expression in a dose dependent manner. Moreover, depletion of STAT5 via selective antisense oligonucleotide treatment similarly resulted in decreased BCL10 mRNA and protein expression, cellular viability and impaired NFκB activity independent of IL-2. Conclusion These results suggest that the NFκB regulator BCL10 is an IL-2-independent STAT5 target gene. These findings proffer a model in which un-activated STAT5 can regulate pathways critical for lymphoid cell survival and inhibitors that disrupt STAT5 function independent of tyrosine phosphorylation may be therapeutically effective in treating certain leukemias/lymphomas. PMID:19709433

  18. Comment on ``Equation of state of aluminum nitride and its shock response'' [J. Appl. Phys. 76, 4077 (1994)

    NASA Astrophysics Data System (ADS)

    Rosenberg, Z.; Brar, N. S.

    1995-11-01

    A recent article by Dandekar, Abbate, and Frankel [J. Appl. Phys. 76, 4077 (1994)] reviews existing data on high-pressure properties of aluminum nitride (AlN) in an effort to build an equation of state for this material. A rather large portion of that article is devoted to the shear strength of AlN and, in particular, to our data of 1991 with longitudinal and lateral stress gauges [Z. Rosenberg, N. S. Brar, and S. J. Bless, J. Appl. Phys. 70, 167 (1991)]. Since our highest data point has an error of 1 GPa, much of the discussion and conclusions of Dandekar and co-workers are not relevant once this error in data reduction is corrected. We also discuss the relevance of our shear strength data for various issues, such as the phase transformation of AlN at 20 GPa and the general shape of Hugoniot curves for brittle solids.

  19. Comment on “Maxwell's equations and electromagnetic Lagrangian density in fractional form” [J. Math. Phys. 53, 033505 (2012)

    SciTech Connect

    Rabei, Eqab M.; Al-Jamel, A.; Widyan, H.; Baleanu, D.

    2014-03-15

    In a recent paper, Jaradat et al. [J. Math. Phys. 53, 033505 (2012)] have presented the fractional form of the electromagnetic Lagrangian density within the Riemann-Liouville fractional derivative. They claimed that the Agrawal procedure [O. P. Agrawal, J. Math. Anal. Appl. 272, 368 (2002)] is used to obtain Maxwell's equations in the fractional form, and the Hamilton's equations of motion together with the conserved quantities obtained from fractional Noether's theorem are reported. In this comment, we draw the attention that there are some serious steps of the procedure used in their work are not applicable even though their final results are correct. Their work should have been done based on a formulation as reported by Baleanu and Muslih [Phys. Scr. 72, 119 (2005)].

  20. Comment on ``Model of saturated lithium ammonia as a single-component liquid metal'' [J. Chem. Phys. 124, 074702 (2006)

    NASA Astrophysics Data System (ADS)

    Chuev, Gennady N.; Quémerais, Pascal

    2008-01-01

    We demonstrate in this Comment that the theory of simple metals applied to the saturated Li -NH3 solution in the titled paper [U. Pinsook and S. Hannongbua, J. Chem. Phys.124, 074702 (2006)] should account for the peculiarities of the solution, namely, the high solvent polarizability and different energy scales for ion-ion and electron-electron interactions. Calculations not taking into account these peculiarities contradict the experimental phase diagram of the Li -NH3 solution.

  1. Comments on ``Gazeau-Klauder coherent states for trigonometric Rosen-Morse potential'' [J. Math. Phys. 49, 022104 (2008)

    NASA Astrophysics Data System (ADS)

    Fakhri, H.; Dehghani, A.

    2008-05-01

    In a recently published paper in this journal [A. Cheaghlou and O. Faizy, J. Math. Phys. 49, 022104 (2008)], the authors introduce the Gazeau-Klauder coherent states for the trigonometric Rosen-Morse potential as an infinite superposition of the wavefunctions. It is shown that their proposed measure to realize the resolution of the identity condition is not positive definite. Consequently, the claimed coherencies for the trigonometric Rosen-Morse wavefunctions cannot actually exist.

  2. Corrigendum to “Robust limits on Lorentz violation from gamma-ray bursts” [Astropart. Phys. 25 (2006) 402

    NASA Astrophysics Data System (ADS)

    Ellis, John; Mavromatos, N. E.; Nanopoulos, D. V.; Sakharov, A. S.; Sarkisyan, E. K. G.

    2008-03-01

    We correct the fitting formula used [J.R. Ellis, N.E. Mavromatos, D.V. Nanopoulos, A.S. Sakharov, E.K.G. Sarkisyan, Astropart. Phys. 25 (2006) 402. Available from: arxiv:] to obtain a robust limit on a violation of Lorentz invariance that depends linearly on the photon energy. The correction leads to a slight increase of the limit on the scale of the violation, to M > 1.4 ×1016GeV .

  3. Comment on "Non-thermal mechanism of weak microwave fields influence on neurons" [J. Appl. Phys. 114, 104701 (2013)

    NASA Astrophysics Data System (ADS)

    Pekker, M.; Shneider, M. N.

    2016-02-01

    This comment is directly related to previously published work [M. N. Shneider and M. Pekker, J. Appl. Phys. 114, 104701 (2013)], in which we outlined the effect of a non-thermal mechanism of microwave radiation on the activity of neural tissue. In this note, we provide more realistic estimates of the longitudinal sound velocity in the lipid membranes and the corresponding estimates of the microwave resonance frequencies.

  4. Comment on ``Unified explanation of the anomalous dynamic properties of highly asymmetric polymer blends'' [J. Chem. Phys. 138, 054903 (2013)

    NASA Astrophysics Data System (ADS)

    Colmenero, J.

    2013-05-01

    In a recent paper by Ngai and Capaccioli ["Unified explanation of the anomalous dynamic properties of highly asymmetric polymer blends," J. Chem. Phys. 138, 054903 (2013), 10.1063/1.4789585] the authors claimed that the so-called coupling model (CM) provides a unified explanation of all dynamical anomalies that have been reported for dynamically asymmetric blends over last ten years. Approximately half of the paper is devoted to chain-dynamic properties involving un-entangled polymers. According to the authors, the application of the CM to these results is based on the existence of a crossover at a time tc ≈ 1-2 ns of the magnitudes describing chain-dynamics. Ngai and Capaccioli claimed that the existence of such a crossover is supported by the neutron scattering and MD-simulation results, corresponding to the blend poly(methyl methacrylate)/poly(ethylene oxide), by Niedzwiedz et al. [Phys. Rev. Lett. 98, 168301 (2007), 10.1103/PhysRevLett.98.168301] and Brodeck et al. [Macromolecules 43, 3036 (2010), 10.1021/ma902820a], respectively. Being one of the authors of these two papers, I will demonstrate here that there is no evidence supporting such a crossover in the data reported in these papers.

  5. Comment on 'Power loss in open cavity diodes and a modified Child-Langmuir law' [Phys. Plasmas 12, 093102 (2005)

    SciTech Connect

    Swanekamp, S. B.; Ottinger, P. F.

    2007-09-15

    In this Comment, it is shown that no modification of the Child-Langmuir law [Phys. Rev.32, 492 (1911); Phys. Rev. 2, 450 (1913)] is necessary to treat the space-charge-limited flow from a diode with an open boundary as reported in Phys. Plasmas 12, 093102 (2005). The open boundary condition in their simulations can be represented by a voltage source and a resistor whose value is the vacuum-wave impedance of the opening. The diode can be represented as a variable resistor whose value depends on the voltage drop across the diode (as measured by the line integral of E across the diode gap). This is a simple voltage-divider circuit whose analysis shows that the real diode voltage drops as the vacuum-wave impedance increases. Furthermore, it is shown that in equilibrium, the voltage drop between the anode and cathode is independent of the path chosen for the line integral of the electric field so that E=-{nabla}{phi} is valid. In this case, the equations of electrostatics are applicable. This clearly demonstrates that the electric field is electrostatic and static fields DO NOT RADIATE. It is shown that the diode voltage drops as the vacuum wave impedance increases and the current drops according to the Child-Langmuir law. Therefore, the observed drop in circuit current can be explained by a real drop in voltage across the diode and not an effective drop as claimed by the authors.

  6. STAT3 Represses Nitric Oxide Synthesis in Human Macrophages upon Mycobacterium tuberculosis Infection

    PubMed Central

    Queval, Christophe J.; Song, Ok-Ryul; Deboosère, Nathalie; Delorme, Vincent; Debrie, Anne-Sophie; Iantomasi, Raffaella; Veyron-Churlet, Romain; Jouny, Samuel; Redhage, Keely; Deloison, Gaspard; Baulard, Alain; Chamaillard, Mathias; Locht, Camille; Brodin, Priscille

    2016-01-01

    Mycobacterium tuberculosis is a successful intracellular pathogen. Numerous host innate immune responses signaling pathways are induced upon mycobacterium invasion, however their impact on M. tuberculosis replication is not fully understood. Here we reinvestigate the role of STAT3 specifically inside human macrophages shortly after M. tuberculosis uptake. We first show that STAT3 activation is mediated by IL-10 and occurs in M. tuberculosis infected cells as well as in bystander non-colonized cells. STAT3 activation results in the inhibition of IL-6, TNF-α, IFN-γ and MIP-1β. We further demonstrate that STAT3 represses iNOS expression and NO synthesis. Accordingly, the inhibition of STAT3 is detrimental for M. tuberculosis intracellular replication. Our study thus points out STAT3 as a key host factor for M. tuberculosis intracellular establishment in the early stages of macrophage infection. PMID:27384401

  7. EGFR-STAT3 signaling promotes formation of malignant peripheral nerve sheath tumors

    PubMed Central

    Wu, Jianqiang; Patmore, Deanna M.; Jousma, Edwin; Eaves, David W.; Breving, Kimberly; Patel, Ami V.; Schwartz, Eric B.; Fuchs, James R.; Cripe, Timothy P.; Stemmer-Rachamimov, Anat O.; Ratner, Nancy

    2014-01-01

    Malignant peripheral nerve sheath tumors (MPNSTs) develop sporadically or in the context of neurofibromatosis type 1 (NF1). EGFR overexpression has been implicated in MPNST formation, but its precise role and relevant signaling pathways remain unknown. We found that EGFR overexpression promotes mouse neurofibroma transformation to aggressive MPNST (GEM-PNST). Immunohistochemistry demonstrated phosphorylated STAT3 (Tyr705) in both human MPNST and mouse GEM-PNST. A specific JAK2/STAT3 inhibitor FLLL32 delayed MPNST formation in an MPNST xenograft nude mouse model. STAT3 knockdown by shRNA prevented MPNST formation in vivo. Finally, reducing EGFR activity strongly reduced pSTAT3 in vivo. Thus, an EGFR-STAT3 pathway is necessary for MPNST transformation and establishment of MPNST xenografts growth but not for tumor maintenance. Efficacy of the FLLL32 pharmacological inhibitor in delaying MPNST growth suggests that combination therapies targeting JAK/STAT3 might be useful therapeutics. PMID:23318430

  8. EGFR-STAT3 signaling promotes formation of malignant peripheral nerve sheath tumors.

    PubMed

    Wu, J; Patmore, D M; Jousma, E; Eaves, D W; Breving, K; Patel, A V; Schwartz, E B; Fuchs, J R; Cripe, T P; Stemmer-Rachamimov, A O; Ratner, N

    2014-01-01

    Malignant peripheral nerve sheath tumors (MPNSTs) develop sporadically or in the context of neurofibromatosis type 1. Epidermal growth factor receptor (EGFR) overexpression has been implicated in MPNST formation, but its precise role and relevant signaling pathways remain unknown. We found that EGFR overexpression promotes mouse neurofibroma transformation to aggressive MPNST (GEM-PNST). Immunohistochemistry demonstrated phosphorylated STAT3 (Tyr705) in both human MPNST and mouse GEM-PNST. A specific JAK2/STAT3 inhibitor FLLL32 delayed MPNST formation in an MPNST xenograft nude mouse model. STAT3 knockdown by shRNA prevented MPNST formation in vivo. Finally, reducing EGFR activity strongly reduced pSTAT3 in vivo. Thus, an EGFR-STAT3 pathway is necessary for MPNST transformation and establishment of MPNST xenografts growth but not for tumor maintenance. Efficacy of the FLLL32 pharmacological inhibitor in delaying MPNST growth suggests that combination therapies targeting JAK/STAT3 might be useful therapeutics. PMID:23318430

  9. Identification of Lead Compounds as Inhibitors of STAT3: Design, Synthesis and Bioactivity.

    PubMed

    Botta, Antonio; Sirignano, Esther; Popolo, Ada; Saturnino, Carmela; Terracciano, Stefania; Foglia, Antonio; Sinicropi, Maria Stefania; Longo, Pasquale; Di Micco, Simone

    2015-10-01

    STAT3 belongs to the signal transducers and activators of transcription (STAT) family. It has been demonstrated that STAT3 is constitutively activated in many tumors, playing a role in carcinogenesis and tumor progression. For this reason, it has being considered a potential target for cancer therapy. In this context, we have designed, synthesized and evaluated 1,4-dimethyl-carbazole derivatives, targeting the STAT3 protein. Moreover, MTT assay performed on A375 and HeLa, showed significant antiproliferative activity of some of synthesized compounds (3-5). The same compounds (3-5) considerably reduced STAT3 expression, as demonstrated by Western blot analysis. Our multidisciplinary approach shows that 1,4-dimethyl-carbazoles are potential building blocks to develop more affinity ligands of STAT3. PMID:27490969

  10. STAT3 and sphingosine-1-phosphate in inflammation-associated colorectal cancer

    PubMed Central

    Nguyen, Andrew V; Wu, Yuan-Yuan; Lin, Elaine Y

    2014-01-01

    Accumulated evidences have demonstrated that signal transducer and activator of transcription 3 (STAT3) is a critical link between inflammation and cancer. Multiple studies have indicated that persistent activation of STAT3 in epithelial/tumor cells in inflammation-associated colorectal cancer (CRC) is associated with sphingosine-1-phosphate (S1P) receptor signaling. In inflammatory response whereby interleukin (IL)-6 production is abundant, STAT3-mediated pathways were found to promote the activation of sphingosine kinases (SphK1 and SphK2) leading to the production of S1P. Reciprocally, S1P encourages the activation of STAT3 through a positive autocrine-loop signaling. The crosstalk between IL-6, STAT3 and sphingolipid regulated pathways may play an essential role in tumorigenesis and tumor progression in inflamed intestines. Therapeutics targeting both STAT3 and sphingolipid are therefore likely to contribute novel and more effective therapeutic strategies against inflammation-associated CRC. PMID:25132744

  11. Phoenix Telltale Movie with Clouds, Sol 103

    NASA Technical Reports Server (NTRS)

    2008-01-01

    NASA's Phoenix Mars Lander's telltale catches a breeze as clouds move over the landing site on Sol 103 (Sept. 7, 2008), the 103rd Martian day since landing.

    Phoenix's Surface Stereo Imager took this series of images during daily telltale monitoring around 3 p.m. local solar time and captured the clouds moving over the landing site.

    Phoenix can measure wind speed and direction by imaging the telltale, which is about about 10 centimeters (4 inches) tall. The telltale was built by the University of Aarhus, Denmark.

    The Phoenix Mission is led by the University of Arizona, Tucson, on behalf of NASA. Project management of the mission is by NASA's Jet Propulsion Laboratory, Pasadena, Calif. Spacecraft development is by Lockheed Martin Space Systems, Denver.

  12. Martian Arctic Dust Devil, Phoenix Sol 104

    NASA Technical Reports Server (NTRS)

    2008-01-01

    The Surface Stereo Imager on NASA's Phoenix Mars Lander caught this dust devil in action west-southwest of the lander at 11:16 a.m. local Mars time on Sol 104, or the 104th Martian day of the mission, Sept. 9, 2008.

    Dust devils have not been detected in any Phoenix images from earlier in the mission, but at least six were observed in a dozen images taken on Sol 104.

    Dust devils are whirlwinds that often occur when the Sun heats the surface of Mars, or some areas on Earth. The warmed surface heats the layer of atmosphere closest to it, and the warm air rises in a whirling motion, stirring dust up from the surface like a miniature tornado.

    The dust devil visible in the center of this image just below the horizon is estimated to be about 400 meters (about 1,300 feet) from Phoenix, and 4 meters (13 feet) in diameter. It is much smaller than dust devils that have been observed by NASA's Mars Exploration Rover Spirit much closer to the equator. It is closer in size to dust devils seen from orbit in the Phoenix landing region, though still smaller than those.

    The image has been enhanced to make the dust devil easier to see.

    The Phoenix Mission is led by the University of Arizona, Tucson, on behalf of NASA. Project management of the mission is by NASA's Jet Propulsion Laboratory, Pasadena, Calif. Spacecraft development is by Lockheed Martin Space Systems, Denver.

  13. A Central Role for STAT3 in Gammaherpesvirus-Life Cycle and -Diseases.

    PubMed

    Li, Xiaofan; Bhaduri-McIntosh, Sumita

    2016-01-01

    Having co-evolved with humans, herpesviruses have adapted to exploit the host molecular machinery to ensure viral persistence. The cellular protein Signal Transducer and Activator of Transcription 3 (STAT3) is a leading example. STAT3 is a prominent transcription factor that functions in a variety of physiologic processes including embryonic development, inflammation, immunity, and wound healing. Generally activated via growth factor and cytokine signaling, STAT3 can transcriptionally drive oncoproteins, pro-survival and pro-proliferative proteins as well as angiogenic factors, thereby contributing to cancer. As in most non-viral cancers, STAT3 is constitutively active in EBV-related B and epithelial cell cancers and in animal models of KSHV-cancers. Again, similar to non-viral cancers, STAT3 contributes to gammaherpesvirus (EBV and KSHV)-mediated cancers by driving cell proliferation, invasion and angiogenesis. Being herpesviruses, EBV and KSHV establish latency in humans with episodic lytic activation. Importantly, both viruses activate STAT3 almost immediately upon infection of primary cells. In the setting of infection of primary B cells by EBV, this rapidly activated STAT3 plays a key role in suppressing the DNA damage response (DDR) to EBV-oncogene triggered replication stress, thereby facilitating B cell proliferation and ultimately establishment of latency. STAT3 also contributes to maintenance of latency by curbing lytic activation of EBV and KSHV in latent cells that express high levels of STAT3. In this way, gammaherpesviruses exploit STAT3 to overcome cellular anti-proliferative and anti-lytic barriers to promote viral persistence. These investigations into gammaherpesviruses and STAT3 have simultaneously revealed a novel function for STAT3 in suppression of the DDR, a process fundamental to physiologic cell proliferation as well as development of cancer. PMID:27458446

  14. Cardioprotective function of mitochondrial-targeted and transcriptionally inactive STAT3 against ischemia and reperfusion injury.

    PubMed

    Szczepanek, Karol; Xu, Aijun; Hu, Ying; Thompson, Jeremy; He, Jun; Larner, Andrew C; Salloum, Fadi N; Chen, Qun; Lesnefsky, Edward J

    2015-11-01

    Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that contributes a crucial role in protection against ischemia (ISC)-reperfusion (REP) injury by driving expression of anti-apoptotic and anti-oxidant genes. STAT3 is also present in the mitochondria, where it modulates the activity of the electron transport chain (ETC) and the permeability transition pore. Transgenic mice that overexpress a mitochondrial-targeted, transcriptionally inactive STAT3 in cardiomyocytes (MLS-STAT3E mice) exhibit a persistent, partial blockade of electron transfer through complex I that uniquely did not lead to tissue dysfunction at baseline, yet increased mitochondrial ischemic tolerance. The direct contribution of non-transcriptional, mitochondria-localized STAT3 to protection during ISC-REP remains to be established. We hypothesized that the enhanced mitochondrial tolerance to ischemia present in MLS-STAT3E mice would decrease cardiac injury during ISC-REP. In the isolated buffer-perfused heart model, MLS-STAT3E hearts exhibit a decreased infarct size compared to non-transgenic littermate hearts. Contractile recovery, expressed as a percent of LV developed pressure before ISC, is improved in MLS-STAT3E mice. Mitochondria isolated at the end of 60 min. of REP from MLS-STAT3E hearts show attenuated ROS release. The partial and persistent blockade of complex I present in MLS-STAT3E mice decreases cardiac injury during REP, in part via a persistent decrease in ROS production and attenuation of mitochondrial permeability transition pore opening at the onset of REP. In vivo, MLS-STAT3E hearts exhibit substantially higher postoperative survival rate and a substantial decrease in myocardial infarct size. STAT3 mediates cardioprotection not only via canonical action as a transcription factor, but also as a modulator of ETC activity directly in the mitochondria. PMID:26358226

  15. Differential effects of STAT proteins on growth hormone-mediated IGF-I gene expression.

    PubMed

    Varco-Merth, Ben; Rotwein, Peter

    2014-11-01

    Growth hormone (GH) plays a key role regulating somatic growth and in controlling metabolism and other physiological processes in humans and other animal species. GH acts by binding to the extracellular part of its transmembrane receptor, leading to induction of multiple intracellular signal transduction pathways that culminate in changes in gene and protein expression. A key agent in GH-stimulated growth is the latent transcription factor signal transducer and activator of transcription (STAT) 5B, one of four STAT proteins induced by the GH receptor in cultured cells and in vivo. As shown by genetic and biochemical studies, GH-activated STAT5B promotes transcription of the gene encoding the critical growth peptide, insulin-like growth factor-I (IGF-I), and natural null mutations of STAT5B in humans lead to growth failure accompanied by diminished IGF-I expression. Here we have examined the possibility that other GH-activated STATs can enhance IGF-I gene transcription, and thus potentially contribute to GH-regulated somatic growth. We find that human STAT5A is nearly identical to STAT5B in its biochemical and functional responses to GH but that STAT1 and STAT3 show a weaker profile of in vitro binding to STAT DNA elements from the IGF-I gene than STAT5B, and are less potent inducers of gene transcription through these elements. Taken together, our results offer a molecular explanation for why STAT5B is a key in vivo mediator of GH-activated IGF-I gene transcription and thus of GH-regulated somatic growth. PMID:25205818

  16. Association of STAT3 with Cx26 and Cx43 in human uterine endometrioid adenocarcinoma

    PubMed Central

    SULKOWSKA, URSZULA; FEBP, ANDRZEJ WINCEWICZ; SULKOWSKI, STANISLAW

    2016-01-01

    Signal transducer and activator of transcription-3 (STAT3) drives endometrial carcinogenesis, while signaling via gap junctions gets weakened during cancer progression. Connexin 26 (Cx26), Cx43 and STAT3 were immunohistochemically evaluated in 78 endometrioid adenocarcinomas: Nuclear expression of STAT3 positively correlated with cytoplasmic immunoreactivity to Cx43 (P=0.004, r=0.318) and Cx26 (P=0.006, r=0.309). STAT3 correlated with Cx43 (P=0.022, r=0.411) and Cx26 (P=0.008 r=0.466) in G1 tumors. A statistically significant linkage remained in G2 cancers between STAT3 and Cx43 (P=0.061, r=0.262) and Cx26 (P=0.016, r=0.331); however, no correlations were observed in G3 tumors. STAT3 was significantly associated with Cx 43 (p=0.003, r=0.684) and Cx26 (p=0.049, r=0.500) in estrogen receptor (ER) negative adenocarcinomas. STAT3 did not correlate with Cx43 in ER positive adenocarcinomas; however, STAT3 expression remained correlated with Cx26 expression (P=0.035, r=0.268). In progesterone receptor negative tumors STAT3 was significantly associated with Cx43 (P=0.035, r=0.451) and Cx26 (P<0.0001, r=0.707). However, in PgR positive adenocarcinomas STAT3 correlated with Cx43 (P=0.03, r=0.290) but not with Cx26. Thus, it appears that hormone dependent acceleration of cancer growth breaks the association between STAT3 and Cx expression. These associations become weaker as the tumors dedifferentiate from G1 to G3 endometrioid adenocarcinomas. The present study provides evidence that the loss of correlation between STAT3 and selected Cx proteins occurs in tumors with more aggressive behavior. PMID:27313754

  17. Advances in peptidic and peptidomimetic-based approaches to inhibit STAT signaling in human diseases.

    PubMed

    Szelag, Malgorzata; Wesoly, Joanna; Bluyssen, Hans A R

    2016-01-01

    STATs promote fundamental cellular processes, marking them as convergence points of many oncogenic and inflammatory pathways. Therefore, aberrant activation of STAT signaling is implicated in a plethora of human diseases, like cancer, inflammation and auto-immunity. Identification of STAT-specific inhibitors is the topic of great practical importance, and various inhibitory strategies are being pursued. An interesting approach includes peptides and peptide-like biopolymers, because they allow the manipulation of STAT signaling without the transfer of genetic material. Phosphopeptides and peptidomimetics directly target STATs by inhibiting dimerization. Despite that a large number of efficient peptide- based STAT3-specific inhibitors have been reported to date, none of them was able to meet the pharmacological requirements to serve as a potent anti-cancer drug. The existing limitations, like metabolic instability and poor cell permeability during in vivo tests, excluded these macromolecules from further clinical development. To overcome these liabilities, in the last five years many advances have been made to develop next generation STAT-specific inhibitors. Here we discuss the pitfalls of current STAT inhibitory strategies and review the progress on the development of peptide-like prodrugs directly targeting STATs. Novel strategies involve screening of high-complexity libraries of random peptides, as specific STAT3 or STAT5 DNA-binding inhibitors, to construct cell permeable peptide aptamers and aptides for cancer therapy. Another new direction is synthesis of negative dominant α-helical mimetics of the STAT3 N-domain, preventing oligomerization on DNA. Moreover, construction of phosphopeptide conjugates with molecules mediating cellular uptake offers new therapeutic possibilities in treatment of cancer, asthma and allergy. PMID:26521960

  18. Early Activation of STAT3 Regulates Reactive Astrogliosis Induced by Diverse Forms of Neurotoxicity

    PubMed Central

    O'Callaghan, James P.; Kelly, Kimberly A.; VanGilder, Reyna L.; Sofroniew, Michael V.; Miller, Diane B.

    2014-01-01

    Astrogliosis, a cellular response characterized by astrocytic hypertrophy and accumulation of GFAP, is a hallmark of all types of central nervous system (CNS) injuries. Potential signaling mechanisms driving the conversion of astrocytes into “reactive” phenotypes differ with respect to the injury models employed and can be complicated by factors such as disruption of the blood-brain barrier (BBB). As denervation tools, neurotoxicants have the advantage of selective targeting of brain regions and cell types, often with sparing of the BBB. Previously, we found that neuroinflammation and activation of the JAK2-STAT3 pathway in astrocytes precedes up regulation of GFAP in the MPTP mouse model of dopaminergic neurotoxicity. Here we show that multiple mechanistically distinct mouse models of neurotoxicity (MPTP, AMP, METH, MDA, MDMA, KA, TMT) engender the same neuroinflammatory and STAT3 activation responses in specific regions of the brain targeted by each neurotoxicant. The STAT3 effects seen for TMT in the mouse could be generalized to the rat, demonstrating cross-species validity for STAT3 activation. Pharmacological antagonists of the neurotoxic effects blocked neuroinflammatory responses, pSTAT3tyr705 and GFAP induction, indicating that damage to neuronal targets instigated astrogliosis. Selective deletion of STAT3 from astrocytes in STAT3 conditional knockout mice markedly attenuated MPTP-induced astrogliosis. Monitoring STAT3 translocation in GFAP-positive cells indicated that effects of MPTP, METH and KA on pSTAT3tyr705 were localized to astrocytes. These findings strongly implicate the STAT3 pathway in astrocytes as a broadly triggered signaling pathway for astrogliosis. We also observed, however, that the acute neuroinflammatory response to the known inflammogen, LPS, can activate STAT3 in CNS tissue without inducing classical signs of astrogliosis. Thus, acute phase neuroinflammatory responses and neurotoxicity-induced astrogliosis both signal through

  19. Breaking a paradigm: IL-6/STAT3 signaling suppresses metastatic prostate cancer upon ARF expression.

    PubMed

    Culig, Zoran; Pencik, Jan; Merkel, Olaf; Kenner, Lukas

    2016-03-01

    Interleukin 6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) signaling is considered to have important oncogenic functions in prostate cancer (PCa). However, a recent study highlighted the central role of IL-6/STAT3 signaling in regulation of the ARF-MDM2-p53 senescence axis. This reversal of the postulated oncogenic properties of IL-6/STAT3 signaling in PCa has important therapeutic implications. PMID:27308625

  20. A Central Role for STAT3 in Gammaherpesvirus-Life Cycle and -Diseases

    PubMed Central

    Li, Xiaofan; Bhaduri-McIntosh, Sumita

    2016-01-01

    Having co-evolved with humans, herpesviruses have adapted to exploit the host molecular machinery to ensure viral persistence. The cellular protein Signal Transducer and Activator of Transcription 3 (STAT3) is a leading example. STAT3 is a prominent transcription factor that functions in a variety of physiologic processes including embryonic development, inflammation, immunity, and wound healing. Generally activated via growth factor and cytokine signaling, STAT3 can transcriptionally drive oncoproteins, pro-survival and pro-proliferative proteins as well as angiogenic factors, thereby contributing to cancer. As in most non-viral cancers, STAT3 is constitutively active in EBV-related B and epithelial cell cancers and in animal models of KSHV-cancers. Again, similar to non-viral cancers, STAT3 contributes to gammaherpesvirus (EBV and KSHV)-mediated cancers by driving cell proliferation, invasion and angiogenesis. Being herpesviruses, EBV and KSHV establish latency in humans with episodic lytic activation. Importantly, both viruses activate STAT3 almost immediately upon infection of primary cells. In the setting of infection of primary B cells by EBV, this rapidly activated STAT3 plays a key role in suppressing the DNA damage response (DDR) to EBV-oncogene triggered replication stress, thereby facilitating B cell proliferation and ultimately establishment of latency. STAT3 also contributes to maintenance of latency by curbing lytic activation of EBV and KSHV in latent cells that express high levels of STAT3. In this way, gammaherpesviruses exploit STAT3 to overcome cellular anti-proliferative and anti-lytic barriers to promote viral persistence. These investigations into gammaherpesviruses and STAT3 have simultaneously revealed a novel function for STAT3 in suppression of the DDR, a process fundamental to physiologic cell proliferation as well as development of cancer. PMID:27458446

  1. Regulation of Natural Killer Cell Function by STAT3.

    PubMed

    Cacalano, Nicholas A

    2016-01-01

    Natural killer (NK) cells, key members of a distinct hematopoietic lineage, innate lymphoid cells, are not only critical effectors that mediate cytotoxicity toward tumor and virally infected cells but also regulate inflammation, antigen presentation, and the adaptive immune response. It has been shown that NK cells can regulate the development and activation of many other components of the immune response, such as dendritic cells, which in turn, modulate the function of NK cells in multiple synergistic feed back loops driven by cell-cell contact, and the secretion of cytokines and chemokines that control effector function and migration of cells to sites of immune activation. The signal transducer and activator of transcription (STAT)-3 is involved in driving almost all of the pathways that control NK cytolytic activity as well as the reciprocal regulatory interactions between NK cells and other components of the immune system. In the context of tumor immunology, NK cells are a first line of defense that eliminates pre-cancerous and transformed cells early in the process of carcinogenesis, through a mechanism of "immune surveillance." Even after tumors become established, NK cells are critical components of anticancer immunity: dysfunctional NK cells are often found in the peripheral blood of cancer patients, and the lack of NK cells in the tumor microenvironment often correlates to poor prognosis. The pathways and soluble factors activated in tumor-associated NK cells, cancer cells, and regulatory myeloid cells, which determine the outcome of cancer immunity, are all critically regulated by STAT3. Using the tumor microenvironment as a paradigm, we present here an overview of the research that has revealed fundamental mechanisms through which STAT3 regulates all aspects of NK cell biology, including NK development, activation, target cell killing, and fine tuning of the innate and adaptive immune responses. PMID:27148255

  2. Regulation of Natural Killer Cell Function by STAT3

    PubMed Central

    Cacalano, Nicholas A.

    2016-01-01

    Natural killer (NK) cells, key members of a distinct hematopoietic lineage, innate lymphoid cells, are not only critical effectors that mediate cytotoxicity toward tumor and virally infected cells but also regulate inflammation, antigen presentation, and the adaptive immune response. It has been shown that NK cells can regulate the development and activation of many other components of the immune response, such as dendritic cells, which in turn, modulate the function of NK cells in multiple synergistic feed back loops driven by cell–cell contact, and the secretion of cytokines and chemokines that control effector function and migration of cells to sites of immune activation. The signal transducer and activator of transcription (STAT)-3 is involved in driving almost all of the pathways that control NK cytolytic activity as well as the reciprocal regulatory interactions between NK cells and other components of the immune system. In the context of tumor immunology, NK cells are a first line of defense that eliminates pre-cancerous and transformed cells early in the process of carcinogenesis, through a mechanism of “immune surveillance.” Even after tumors become established, NK cells are critical components of anticancer immunity: dysfunctional NK cells are often found in the peripheral blood of cancer patients, and the lack of NK cells in the tumor microenvironment often correlates to poor prognosis. The pathways and soluble factors activated in tumor-associated NK cells, cancer cells, and regulatory myeloid cells, which determine the outcome of cancer immunity, are all critically regulated by STAT3. Using the tumor microenvironment as a paradigm, we present here an overview of the research that has revealed fundamental mechanisms through which STAT3 regulates all aspects of NK cell biology, including NK development, activation, target cell killing, and fine tuning of the innate and adaptive immune responses. PMID:27148255

  3. STAT1, STAT3 and p38MAPK are involved in the apoptotic effect induced by a chimeric cyclic interferon-{alpha}2b peptide

    SciTech Connect

    Blank, Viviana C.; Pena, Clara; Roguin, Leonor P.

    2010-02-15

    In the search of mimetic peptides of the interferon-{alpha}2b molecule (IFN-{alpha}2b), we have previously designed and synthesized a chimeric cyclic peptide of the IFN-{alpha}2b that inhibits WISH cell proliferation by inducing an apoptotic response. Here, we first studied the ability of this peptide to activate intracellular signaling pathways and then evaluated the participation of some signals in the induction of apoptosis. Stimulation of WISH cells with the cyclic peptide showed tyrosine phosphorylation of Jak1 and Tyk2 kinases, tyrosine and serine phosphorylation of STAT1 and STAT3 transcription factors and activation of p38 MAPK pathway, although phosphorylation levels or kinetics were in some conditions different to those obtained under IFN-{alpha}2b stimulus. JNK and p44/42 pathways were not activated by the peptide in WISH cells. We also showed that STAT1 and STAT3 downregulation by RNA interference decreased the antiproliferative activity and the amount of apoptotic cells induced by the peptide. Pharmacological inhibition of p38 MAPK also reduced the peptide growth inhibitory activity and the apoptotic effect. Thus, we demonstrated that the cyclic peptide regulates WISH cell proliferation through the activation of Jak/STAT signaling pathway. In addition, our results indicate that p38 MAPK may also be involved in cell growth regulation. This study suggests that STAT1, STAT3 and p38 MAPK would be mediating the antitumor and apoptotic response triggered by the cyclic peptide in WISH cells.

  4. Dihydroartemisinin as a Putative STAT3 Inhibitor, Suppresses the Growth of Head and Neck Squamous Cell Carcinoma by Targeting Jak2/STAT3 Signaling.

    PubMed

    Jia, Lifeng; Song, Qi; Zhou, Chenyang; Li, Xiaoming; Pi, Lihong; Ma, Xiuru; Li, Hui; Lu, Xiuying; Shen, Yupeng

    2016-01-01

    Developing drugs that can effectively block STAT3 activation may serve as one of the most promising strategy for cancer treatment. Currently, there is no putative STAT3 inhibitor that can be safely and effectively used in clinic. In the present study, we investigated the potential of dihydroartemisinin (DHA) as a putative STAT3 inhibitor and its antitumor activities in head and neck squamous cell carcinoma (HNSCC). The inhibitory effects of DHA on STAT3 activation along with its underlying mechanisms were studied in HNSCC cells. The antitumor effects of DHA against HNSCC cells were explored both in vitro and in vivo. An investigation on cooperative effects of DHA with cisplatin in killing HNSCC cells was also implemented. DHA exhibited remarkable and specific inhibitory effects on STAT3 activation via selectively blocking Jak2/STAT3 signaling. Besides, DHA significantly inhibited HNSCC growth both in vitro and in vivo possibly through induction of apoptosis and attenuation of cell migration. DHA also synergized with cisplatin in tumor inhibition in HNSCC cells. Our findings demonstrate that DHA is a putative STAT3 inhibitor that may represent a new and effective drug for cancer treatment and therapeutic sensitization in HNSCC patients. PMID:26784960

  5. Dihydroartemisinin as a Putative STAT3 Inhibitor, Suppresses the Growth of Head and Neck Squamous Cell Carcinoma by Targeting Jak2/STAT3 Signaling

    PubMed Central

    Jia, Lifeng; Song, Qi; Zhou, Chenyang; Li, Xiaoming; Pi, Lihong; Ma, Xiuru; Li, Hui; Lu, Xiuying; Shen, Yupeng

    2016-01-01

    Developing drugs that can effectively block STAT3 activation may serve as one of the most promising strategy for cancer treatment. Currently, there is no putative STAT3 inhibitor that can be safely and effectively used in clinic. In the present study, we investigated the potential of dihydroartemisinin (DHA) as a putative STAT3 inhibitor and its antitumor activities in head and neck squamous cell carcinoma (HNSCC). The inhibitory effects of DHA on STAT3 activation along with its underlying mechanisms were studied in HNSCC cells. The antitumor effects of DHA against HNSCC cells were explored both in vitro and in vivo. An investigation on cooperative effects of DHA with cisplatin in killing HNSCC cells was also implemented. DHA exhibited remarkable and specific inhibitory effects on STAT3 activation via selectively blocking Jak2/STAT3 signaling. Besides, DHA significantly inhibited HNSCC growth both in vitro and in vivo possibly through induction of apoptosis and attenuation of cell migration. DHA also synergized with cisplatin in tumor inhibition in HNSCC cells. Our findings demonstrate that DHA is a putative STAT3 inhibitor that may represent a new and effective drug for cancer treatment and therapeutic sensitization in HNSCC patients. PMID:26784960

  6. High glucose enhances progression of cholangiocarcinoma cells via STAT3 activation

    PubMed Central

    Saengboonmee, Charupong; Seubwai, Wunchana; Pairojkul, Chawalit; Wongkham, Sopit

    2016-01-01

    Epidemiological studies have indicated diabetes mellitus (DM) as a risk of cholangiocarcinoma (CCA), however, the effects and mechanisms of high glucose on progression of CCA remain unclear. This study reports for the first time of the enhancing effects of high glucose on aggressive phenotypes of CCA cells via STAT3 activation. CCA cells cultured in high glucose media exerted significantly higher rates of cell proliferation, adhesion, migration and invasion than those cultured in normal glucose. The phosphokinase array revealed STAT3 as the dominant signal activated in response to high glucose. Increased nuclear STAT3, p-STAT3 and its downstream target proteins, cyclin D1, vimentin and MMP2, were shown to be underling mechanisms of high glucose stimulation. The link of high glucose and STAT3 activation was confirmed in tumor tissues from CCA patients with DM that exhibited higher STAT3 activation than those without DM. Moreover, the levels of STAT3 activation were correlated with the levels of blood glucose. Finally, decreasing the level of glucose or using a STAT3 inhibitor could reduce the effects of high glucose. These findings suggest that controlling blood glucose or using a STAT3 inhibitor as an alternative approach may improve the therapeutic outcome of CCA patients with DM. PMID:26743134

  7. Sorafenib induces apoptosis in HL60 cells by inhibiting Src kinase-mediated STAT3 phosphorylation.

    PubMed

    Zhao, Wei; Zhang, Tao; Qu, Bingqian; Wu, Xingxin; Zhu, Xu; Meng, Fanyu; Gu, Yanhong; Shu, Yongqian; Shen, Yan; Sun, Yang; Xu, Qiang

    2011-01-01

    Signal transducer and activator of transcription 3 (STAT3) is constitutively active in approximately 50% of acute myeloid leukemia (AML) cases and mediates multiple cellular processes including cell resistance to apoptosis. Inhibition of constitutively active STAT3 has been shown to induce AML cell apoptosis. Our aim was to ascertain if sorafenib, a multikinase inhibitor, may also inhibit STAT3 signaling and, therefore, be efficacious for AML. We found that sorafenib inhibited proliferation and induced apoptosis in human AML cell line (HL60) cells. In addition, sorafenib exposure reduced constitutive STAT3 phosphorylation in HL60 cells and repressed STAT3 DNA-binding activity and Mcl-1 and Bcl-2 expression. Similar results were obtained with the Src kinase inhibitor I, suggesting that sorafenib suppresses STAT3 phosphorylation by inhibiting Src-kinase activity. Furthermore, significant inhibition of Src kinase activity by sorafenib was observed in the kinase assay. In addition, Src could be co-immunoprecipitated with STAT3, and the phosphorylation of STAT3 was significantly inhibited by sorafenib only in cell lines in which phosphorylated Src is highly expressed. Taken together, our study indicates that sorafenib blocks Src kinase-mediated STAT3 phosphorylation and decreases the expression of apoptosis regulatory proteins Mcl-1 and Bcl-2, which are associated with increased apoptosis in HL60 cells. These findings provide a rationale for the treatment of human AML. PMID:20881478

  8. Phosphorylated STAT5 represents a new possible prognostic marker in Hodgkin lymphoma.

    PubMed

    Martini, Maurizio; Hohaus, Stefan; Petrucci, Giovanna; Cenci, Tonia; Pierconti, Francesco; Massini, Giuseppina; Teofili, Luciana; Leone, Giuseppe; Larocca, Luigi M

    2008-03-01

    An important pathogenetic mechanism in Hodgkin lymphoma (HL) is the interaction between the neoplastic and reactive cells mediated by a complex network of cytokines with activation of cytokine signal transduction (STAT) pathways. We studied the prognostic impact of the phosphorylation status of STAT5 in HL. By using immunohistochemical analysis, we found phosphorylated STAT5 (pSTAT5) in 35 (38%) of 93 lymph node biopsy specimens of patients with HL. The detection of pSTAT5 in Hodgkin and Reed-Sternberg (HRS) cells in classical HL (cHL) was not associated with any clinical and biologic features evaluated, including Epstein-Barr virus status. The primary end point for analysis of clinical outcome was freedom from treatment failure (FFTF). At a median follow-up of 5 years, pSTAT5+ patients with cHL had a better FFTF than pSTAT5-patients (77% vs 56%; P = .03), which translated into a reduced risk for failure for pSTAT5+ patients with a hazard ratio of 0.2 (95% confidence interval, 0.06-0.73; P = .015). Our data suggest that the phosphorylation status of STAT5 of HRS cells in cHL could be a prognostic marker in HL. PMID:18285272

  9. Interferon alpha antagonizes STAT3 and SOCS3 signaling triggered by hepatitis C virus.

    PubMed

    Zhao, Lan-Juan; He, Sheng-Fei; Wang, Wen; Ren, Hao; Qi, Zhong-Tian

    2016-04-01

    We aimed to investigate regulation of signal transducer and activator of transcription 3 (STAT3) and suppressor of cytokine signaling 3 (SOCS3) by interferon alpha (IFN-α) and to analyze the relationship between STAT3 and SOCS3 during hepatitis C virus (HCV) infection. Changes in STAT3 and SOCS3 were analyzed at both mRNA and protein levels in human hepatoma cells infected with HCV (J6/JFH1). At 72h of HCV infection, STAT3 expression was decreased with sustained phosphorylation, and IFN-α increased such decrease and phosphorylation. HCV increased SOCS3 expression, while IFN-α impaired such increase, indicating different regulation of STAT3 and SOCS3 by IFN-α. IFN-α-induced expression and phosphorylation of upstream kinases of the JAK/STAT pathway, Tyk2 and Jak1, were suppressed by HCV. Moreover, knockdown of STAT3 by RNA interference led to decreases in HCV RNA replication and viral protein expression, without affecting either the expression of Tyk2 and Jak1 or the SOCS3 induction in response to IFN-α. These results show that IFN-α antagonizes STAT3 and SOCS3 signaling triggered by HCV and that STAT3 regulation correlates inversely with SOCS3 induction by IFN-α, which may be important in better understanding the complex interplay between IFN-α and signal molecules during HCV infection. PMID:26945996

  10. Loss of STAT3 in murine NK cells enhances NK cell-dependent tumor surveillance.

    PubMed

    Gotthardt, Dagmar; Putz, Eva M; Straka, Elisabeth; Kudweis, Petra; Biaggio, Mario; Poli, Valeria; Strobl, Birgit; Müller, Mathias; Sexl, Veronika

    2014-10-01

    The members of the signal transducer and activator of transcription (STAT) family of transcription factors modulate the development and function of natural killer (NK) cells. NK cell-mediated tumor surveillance is particularly important in the body's defense against hematological malignancies such as leukemia. STAT3 inhibitors are currently being developed, although their potential effects on NK cells are not clear. We have investigated the function of STAT3 in NK cells with Stat3(Δ/Δ)Ncr1-iCreTg mice, whose NK cells lack STAT3. In the absence of STAT3, NK cells develop normally and in normal numbers, but display alterations in the kinetics of interferon-γ (IFN-γ) production. We report that STAT3 directly binds the IFN-γ promoter. In various in vivo models of hematological diseases, loss of STAT3 in NK cells enhances tumor surveillance. The reduced tumor burden is paralleled by increased expression of the activating receptor DNAM-1 and the lytic enzymes perforin and granzyme B. Our findings imply that STAT3 inhibitors will stimulate the cytolytic activity of NK cells against leukemia, thereby providing an additional therapeutic benefit. PMID:25185262

  11. Disruption of STAT3 signalling promotes KRAS-induced lung tumorigenesis

    PubMed Central

    Grabner, Beatrice; Schramek, Daniel; Mueller, Kristina M.; Moll, Herwig P.; Svinka, Jasmin; Hoffmann, Thomas; Bauer, Eva; Blaas, Leander; Hruschka, Natascha; Zboray, Katalin; Stiedl, Patricia; Nivarthi, Harini; Bogner, Edith; Gruber, Wolfgang; Mohr, Thomas; Zwick, Ralf Harun; Kenner, Lukas; Poli, Valeria; Aberger, Fritz; Stoiber, Dagmar; Egger, Gerda; Esterbauer, Harald; Zuber, Johannes; Moriggl, Richard; Eferl, Robert; Győrffy, Balázs; Penninger, Josef M.; Popper, Helmut; Casanova, Emilio

    2015-01-01

    STAT3 is considered to play an oncogenic role in several malignancies including lung cancer; consequently, targeting STAT3 is currently proposed as therapeutic intervention. Here we demonstrate that STAT3 plays an unexpected tumour-suppressive role in KRAS mutant lung adenocarcinoma (AC). Indeed, lung tissue-specific inactivation of Stat3 in mice results in increased KrasG12D-driven AC initiation and malignant progression leading to markedly reduced survival. Knockdown of STAT3 in xenografted human AC cells increases tumour growth. Clinically, low STAT3 expression levels correlate with poor survival and advanced malignancy in human lung AC patients with smoking history, which are prone to KRAS mutations. Consistently, KRAS mutant lung tumours exhibit reduced STAT3 levels. Mechanistically, we demonstrate that STAT3 controls NF-κB-induced IL-8 expression by sequestering NF-κB within the cytoplasm, thereby inhibiting IL-8-mediated myeloid tumour infiltration and tumour vascularization and hence tumour progression. These results elucidate a novel STAT3–NF-κB–IL-8 axis in KRAS mutant AC with therapeutic and prognostic relevance. PMID:25734337

  12. A Chemical Biology Approach to Developing STAT Inhibitors: Molecular Strategies for Accelerating Clinical Translation

    PubMed Central

    Nelson, Erik A.; Sharma, Sreenath V.; Settleman, Jeffrey; Frank, David A.

    2011-01-01

    STAT transcription factors transduce signals from the cell surface to the nucleus, where they regulate the expression of genes that control proliferation, survival, self-renewal, and other critical cellular functions. Under normal physiological conditions, the activation of STATs is tightly regulated. In cancer, by contrast, STAT proteins, particularly STAT3 and STAT5, become activated constitutively, thereby driving the malignant phenotype of cancer cells. Since these proteins are largely dispensable in the function of normal adult cells, STATs represent a potentially important target for cancer therapy. Although transcription factors have traditionally been viewed as suboptimal targets for pharmacological inhibition, chemical biology approaches have been particularly fruitful in identifying compounds that can modulate this pathway through a variety of mechanisms. STAT inhibitors have notable anti-cancer effects in many tumor systems, show synergy with other therapeutic modalities, and have the potential to eradicate tumor stem cells. Furthermore, STAT inhibitors identified through the screening of chemical libraries can then be employed in large scale analyses such as gene expression profiling, RNA interference screens, or large-scale tumor cell line profiling. Data derived from these studies can then provide key insights into mechanisms of STAT signal transduction, as well as inform the rational design of targeted therapeutic strategies for cancer patients. PMID:21680956

  13. The STAT5 inhibitor pimozide decreases survival of chronic myelogenous leukemia cells resistant to kinase inhibitors

    PubMed Central

    Nelson, Erik A.; Walker, Sarah R.; Weisberg, Ellen; Bar-Natan, Michal; Barrett, Rosemary; Gashin, Laurie B.; Terrell, Shariya; Klitgaard, Josephine L.; Santo, Loredana; Addorio, Martha R.; Ebert, Benjamin L.; Griffin, James D.

    2011-01-01

    The transcription factor STAT5 is an essential mediator of the pathogenesis of chronic myelogenous leukemia (CML). In CML, the BCR/ABL fusion kinase causes the constitutive activation of STAT5, thereby driving the expression of genes promoting survival. BCR/ABL kinase inhibitors have become the mainstay of therapy for CML, although CML cells can develop resistance through mutations in BCR/ABL. To overcome this problem, we used a cell-based screen to identify drugs that inhibit STAT-dependent gene expression. Using this approach, we identified the psychotropic drug pimozide as a STAT5 inhibitor. Pimozide decreases STAT5 tyrosine phosphorylation, although it does not inhibit BCR/ABL or other tyrosine kinases. Furthermore, pimozide decreases the expression of STAT5 target genes and induces cell cycle arrest and apoptosis in CML cell lines. Pimozide also selectively inhibits colony formation of CD34+ bone marrow cells from CML patients. Importantly, pimozide induces similar effects in the presence of the T315I BCR/ABL mutation that renders the kinase resistant to presently available inhibitors. Simultaneously inhibiting STAT5 with pimozide and the kinase inhibitors imatinib or nilotinib shows enhanced effects in inhibiting STAT5 phosphorylation and in inducing apoptosis. Thus, targeting STAT5 may be an effective strategy for the treatment of CML and other myeloproliferative diseases. PMID:21233313

  14. STAT3 Expression, Molecular Features, Inflammation Patterns and Prognosis in a Database of 724 Colorectal Cancers

    PubMed Central

    Morikawa, Teppei; Baba, Yoshifumi; Yamauchi, Mai; Kuchiba, Aya; Nosho, Katsuhiko; Shima, Kaori; Tanaka, Noriko; Huttenhower, Curtis; Frank, David A.; Fuchs, Charles S.; Ogino, Shuji

    2010-01-01

    Purpose STAT3 (signal transducer and activator of transcription 3) is a transcription factor that is constitutively activated in some cancers. STAT3 appears to play crucial roles in cell proliferation and survival, angiogenesis, tumor-promoting inflammation and suppression of anti-tumor host immune response in the tumor microenvironment. Although the STAT3 signaling pathway is a potential drug target, clinical, pathologic, molecular or prognostic features of STAT3-activated colorectal cancer remain uncertain. Experimental Design Utilizing a database of 724 colon and rectal cancer cases, we evaluated phosphorylated STAT3 (p-STAT3) expression by immunohistochemistry. Cox proportional hazards model was used to compute mortality hazard ratio (HR), adjusting for clinical, pathologic and molecular features, including microsatellite instability (MSI), the CpG island methylator phenotype (CIMP), LINE-1 methylation, 18q loss of heterozygosity, TP53 (p53), CTNNB1 (β-catenin), JC virus T-antigen, and KRAS, BRAF, and PIK3CA mutations. Results Among the 724 tumors, 131 (18%) showed high-level p-STAT3 expression (p-STAT3-high), 244 (34%) showed low-level expression (p-STAT3-low), and the remaining 349 (48%) were negative for p-STAT3. p-STAT3 overexpression was associated with significantly higher colorectal cancer-specific mortality [log-rank p=0.0020; univariate HR (p-STAT3-high vs. p-STAT3-negative) 1.85, 95% confidence interval (CI) 1.30–2.63, Ptrend =0.0005; multivariate HR, 1.61, 95% CI 1.11–2.34, Ptrend =0.015). p-STAT3 expression was positively associated with peritumoral lymphocytic reaction (multivariate odds ratio 3.23; 95% CI, 1.89–5.53; p<0.0001). p-STAT3 expression was not associated with MSI, CIMP, or LINE-1 hypomethylation. Conclusions STAT3 activation in colorectal cancer is associated with adverse clinical outcome, supporting its potential roles as a prognostic biomarker and a chemoprevention and/or therapeutic target. PMID:21310826

  15. Revealing the cellular localization of STAT1 during the cell cycle by super-resolution imaging

    NASA Astrophysics Data System (ADS)

    Gao, Jing; Wang, Feng; Liu, Yanhou; Cai, Mingjun; Xu, Haijiao; Jiang, Junguang; Wang, Hongda

    2015-03-01

    Signal transducers and activators of transcription (STATs) can transduce cytokine signals and regulate gene expression. The cellular localization and nuclear trafficking of STAT1, a representative of the STAT family with multiple transcriptional functions, is tightly related with transcription process, which usually happens in the interphase of the cell cycle. However, these priority questions regarding STAT1 distribution and localization at the different cell-cycle stages remain unclear. By using direct stochastic optical reconstruction microscopy (dSTORM), we found that the nuclear expression level of STAT1 increased gradually as the cell cycle carried out, especially after EGF stimulation. Furthermore, STAT1 formed clusters in the whole cell during the cell cycle, with the size and the number of clusters also increasing significantly from G1 to G2 phase, suggesting that transcription and other cell-cycle related activities can promote STAT1 to form more and larger clusters for fast response to signals. Our work reveals that the cellular localization and clustering distribution of STAT1 are associated with the cell cycle, and further provides an insight into the mechanism of cell-cycle regulated STAT1 signal transduction.

  16. Stat3 induces oncogenic Skp2 expression in human cervical carcinoma cells

    SciTech Connect

    Huang, Hanhui; Zhao, Wenrong; Yang, Dan

    2012-02-03

    Highlights: Black-Right-Pointing-Pointer Upregulation of Skp2 by IL-6 or Stat3 activation. Black-Right-Pointing-Pointer Stat3 activates Skp2 expression through bound to its promoter region. Black-Right-Pointing-Pointer Stat3 activates Skp2 expression through recruitment of P300. Black-Right-Pointing-Pointer Stat3 activation decreases the P27 stability. -- Abstract: Dysregulated Skp2 function promotes cell proliferation, which is consistent with observations of Skp2 over-expression in many types of human cancers, including cervical carcinoma (CC). However, the molecular mechanisms underlying elevated Skp2 expression have not been fully explored. Interleukin-6 (IL-6) induced Stat3 activation is viewed as crucial for multiple tumor growth and metastasis. Here, we demonstrate that Skp2 is a direct transcriptional target of Stat3 in the human cervical carcinoma cells. Our data show that IL-6 administration or transfection of a constitutively activated Stat3 in HeLa cells activates Skp2 mRNA transcription. Using luciferase reporter and ChIP assays, we show that Stat3 binds to the promoter region of Skp2 and promotes its activity through recruiting P300. As a result of the increase of Skp2 expression, endogenous p27 protein levels are markedly decreased. Thus, our results suggest a previously unknown Stat3-Skp2 molecular network controlling cervical carcinoma development.

  17. Cucurbitacin B and cucurbitacin I suppress adipocyte differentiation through inhibition of STAT3 signaling.

    PubMed

    Seo, Cho-Rong; Yang, Dong Kwon; Song, No-Joon; Yun, Ui Jeong; Gwon, A-Ryeong; Jo, Dong-Gyu; Cho, Jae Youl; Yoon, Keejung; Ahn, Jee-Yin; Nho, Chu Won; Park, Woo Jin; Yang, Seung Yul; Park, Kye Won

    2014-02-01

    Cucurbitacin B, a member of the cucurbitaceae family, can act as a STAT3 signaling inhibitor to regulate the growth of hepatocellular carcinoma. STAT3 signaling has been shown to inhibit adipocyte differentiation through C/EBPα and PPARγ. Based on these studies, we hypothesized that cucurbitacin B would prevent PPARγ mediated adipocyte differentiation through STAT3 signaling. To test this hypothesis, mesenchymal C3H10T1/2 and 3T3-L1 preadipocyte cells were treated with a sub-cytotoxic concentration of cucurbitacin B. Cucurbitacin B treatment inhibits lipid accumulation and expression of adipocyte markers including PPARγ and its target genes in a dose-dependent manner. Cucurbitacin B treatment impairs STAT3 signaling as manifested by reduced phosphorylation of STAT3 and suppression of STAT3 target gene expression in preadipocytes. The anti-adipogenic effects of cucurbitacin B are significantly blunted in cells with STAT3 silenced by introducing small interfering RNA. Finally, our data show that cucurbitacin I, another cucurbitacin family member, also inhibits adipocyte differentiation by suppressing STAT3 signaling. Together, our data suggest the possibility of utilizing cucurbitacins as a new strategy to treat metabolic diseases and implicate STAT3 as a new target for the development of functional foods and drugs. PMID:24316209

  18. Novel high-throughput screening system for identifying STAT3-SH2 antagonists

    SciTech Connect

    Uehara, Yutaka; Mochizuki, Masato; Matsuno, Kenji; Haino, Takeharu; Asai, Akira

    2009-03-13

    Constitutive activation of the oncogenic transcription factor STAT3 frequently occurs in various human malignancies. STAT3 activation involves dimerization via intermolecular pTyr-SH2 interaction. Thus, antagonizing this interaction is a feasible approach to inhibit STAT3 activation for cancer therapy. In order to identify selective STAT3 inhibitors, we developed a biochemical HTS system based on AlphaScreen technology, which measures the abilities of test compounds to antagonize pTyr-SH2 interactions. We screened our chemical libraries using this system and identified 5,15-diphenylporphyrin (5,15-DPP) as a selective STAT3-SH2 antagonist. Selective inhibition of STAT3 nuclear translocation and DNA biding activity was observed in cells treated with 5,15-DPP. IL-6-dependent dimerization of STAT3, c-myc promoter binding and c-myc protein expression were all suppressed by 5,15-DPP, whereas no decrement in either expression or phosphorylation level of STAT3 was observed. Thus, the HTS assay system represented herein may be useful for identifying novel STAT3-SH2 antagonists.

  19. Luteolin Induces Carcinoma Cell Apoptosis through Binding Hsp90 to Suppress Constitutive Activation of STAT3

    PubMed Central

    Zhao, Bo; Zhao, Zhihui; Zhou, Jiahong; Xu, Yimiao; Xin, Yinqiang; Liu, Chang; Luo, Lan; Yin, Zhimin

    2012-01-01

    Background Abnormal activity of STAT3 is associated with a number of human malignancies. Hsp90 plays a central role in stabilizing newly synthesized proteins and participates in maintaining the functional competency of a number of signaling transducers involved in cell growth, survival and oncogenesis, such as STAT3. Hsp90 interacts with STAT3 and stabilizes Tyr-phosphorylated STAT3. It has been reported that luteolin possesses anticancer activity through degradation of Tyr705-phosphorylated STAT3. Methodology/Principal Findings We found that overexpression of Hsp90 inhibited luteolin-induced degradation of Tyr705-phosphorylated STAT3 and luteolin also reduced the levels of some other Hsp90 interacting proteins. Results from co-immunoprecipitation and immunoblot analysis demonstrated that luteolin prevented the association between Hsp90 and STAT3 and induced both Tyr705- and Ser727-phosphorylated STAT3 degradation through proteasome-dependent pathway. The molecular modeling analysis with CHARMm–Discovery Studio 2.1(DS 2.1) indicated that luteolin could bind to the ATP-binding pocket of Hsp90. SPR technology-based binding assay confirmed the association between luteolin and Hsp90. ATP-sepharose binding assay displayed that luteolin inhibited Hsp90-ATP binding. Conclusions/Significance Luteolin promoted the degradation of Tyr705- and Ser727-phosphorylated STAT3 through interacting with Hsp90 and induced apoptosis of cancer cells. This study indicated that luteolin may act as a potent HSP90 inhibitor in antitumor strategies. PMID:23145121

  20. Constitutive and IFN-gamma-induced nuclear import of STAT1 proceed through independent pathways.

    PubMed

    Meyer, Thomas; Begitt, Andreas; Lödige, Inga; van Rossum, Marleen; Vinkemeier, Uwe

    2002-02-01

    STAT1 functions as both a constitutive transcriptional regulator and, in response to cytokine stimulation of cells, as an inducible tyrosine-phosphorylated transcription factor. Here, we identify and characterize a non-transferable nuclear targeting sequence in the STAT1 DNA-binding domain. This conserved signal is critical for the interferon-gamma (IFN-gamma)-induced nuclear import of phosphorylated STAT1 dimers and requires adjacent positively charged and hydrophobic residues for functioning. Additionally, the constitutive nucleocytoplasmic shuttling of STAT1 in the absence of IFN-gamma stimulation is revealed. Nuclear import and export of unphosphorylated STAT1 are demonstrated to be sensitive towards wheat germ agglutinin and to occur independently of the import receptor p97. Loss-of-function mutations of the dimer-specific import signal block nuclear entry of tyrosine-phosphorylated STAT1, which in turn also prevents induction of cytokine-inducible target genes. Nevertheless, nuclear import of unphosphorylated STAT1 continues and the STAT1-dependent constitutive expression of caspases and the tumor necrosis factor-alpha-mediated induction of apoptosis proceed unaltered. Thus, tyrosine-phosphorylated and unphosphorylated STAT1 molecules shuttle via independent pathways to distinct sets of target genes. PMID:11823427

  1. STAT3 paradoxically stimulates β-catenin expression but inhibits β-catenin function

    PubMed Central

    Ibrahem, Salih; Al-Ghamdi, Saleh; Baloch, Kanwal; Muhammad, Belal; Fadhil, Wakkas; Jackson, Darryl; Nateri, Abdolrahman S; Ilyas, Mohammad

    2014-01-01

    Wnt signalling and the signal transducer and activator of transcription 3 (STAT3) are oncogenic signalling pathways which are deregulated in colorectal cancer (CRC). Here we investigated the interaction of these two pathways. Firstly, we investigated biochemical interaction by inhibiting STAT3 and β-catenin (through gene knock-down and dominant-negative TCF4 expression) in nine CRC cell lines. β-catenin inhibition did not affect STAT3 levels, whereas STAT3 knock-down resulted in reduced β-catenin mRNA and protein levels. The reduction in β-catenin protein was not prevented by proteasome inhibition, and IL6-induced STAT3 activation resulted in increased β-catenin mRNA. This suggests that STAT3 positively regulates β-catenin (at a transcriptional level) and evaluation of 44 CRCs by immunostaining supported this by showing an association between nuclear STAT3 expression and nuclear β-catenin (P = 0.022). We tested the functional interaction between STAT3 and Wnt signalling by knocking down STAT3 and β-catenin individually and in combination. Knock-down of β-catenin and STAT3 individually inhibited cell proliferation (P < 0. 001 for each) through G1 arrest. However, simultaneous knock-down of STAT3 and β-catenin had a significantly weaker effect than knock-down of β-catenin alone (P < 0.01). Knock-down of STAT3 and β-catenin, individually and together, inhibited cell motility (P < 0.001) without evidence of interaction. We conclude that STAT3 regulates β-catenin but β-catenin does not regulate STAT3. The STAT3/β-catenin interaction is complex but may reduce the proliferative activity of β-catenin possibly by taking β-catenin protein beyond the optimal level. This may indicate biological differences in tumours where both STAT3 and β-catenin are activated compared to those where only one is activated. PMID:25348333

  2. Epstein-Barr virus-derived EBNA2 regulates STAT3 activation

    SciTech Connect

    Muromoto, Ryuta; Ikeda, Osamu; Okabe, Kanako; Togi, Sumihito; Kamitani, Shinya; Fujimuro, Masahiro; Harada, Shizuko; Oritani, Kenji; Matsuda, Tadashi

    2009-01-16

    The Epstein-Barr virus (EBV)-encoded latency protein EBNA2 is a nuclear transcriptional activator that is essential for EBV-induced cellular transformation. Here, we show that EBNA2 interacts with STAT3, a signal transducer for an interleukin-6 family cytokine, and enhances the transcriptional activity of STAT3 by influencing its DNA-binding activity. Furthermore, EBNA2 cooperatively acts on STAT3 activation with LMP1. These data demonstrate that EBNA2 acts as a transcriptional coactivator of STAT3.

  3. Revealing the cellular localization of STAT1 during the cell cycle by super-resolution imaging.

    PubMed

    Gao, Jing; Wang, Feng; Liu, Yanhou; Cai, Mingjun; Xu, Haijiao; Jiang, Junguang; Wang, Hongda

    2015-01-01

    Signal transducers and activators of transcription (STATs) can transduce cytokine signals and regulate gene expression. The cellular localization and nuclear trafficking of STAT1, a representative of the STAT family with multiple transcriptional functions, is tightly related with transcription process, which usually happens in the interphase of the cell cycle. However, these priority questions regarding STAT1 distribution and localization at the different cell-cycle stages remain unclear. By using direct stochastic optical reconstruction microscopy (dSTORM), we found that the nuclear expression level of STAT1 increased gradually as the cell cycle carried out, especially after EGF stimulation. Furthermore, STAT1 formed clusters in the whole cell during the cell cycle, with the size and the number of clusters also increasing significantly from G1 to G2 phase, suggesting that transcription and other cell-cycle related activities can promote STAT1 to form more and larger clusters for fast response to signals. Our work reveals that the cellular localization and clustering distribution of STAT1 are associated with the cell cycle, and further provides an insight into the mechanism of cell-cycle regulated STAT1 signal transduction. PMID:25762114

  4. Revealing the cellular localization of STAT1 during the cell cycle by super-resolution imaging

    PubMed Central

    Gao, Jing; Wang, Feng; Liu, Yanhou; Cai, Mingjun; Xu, Haijiao; Jiang, Junguang; Wang, Hongda

    2015-01-01

    Signal transducers and activators of transcription (STATs) can transduce cytokine signals and regulate gene expression. The cellular localization and nuclear trafficking of STAT1, a representative of the STAT family with multiple transcriptional functions, is tightly related with transcription process, which usually happens in the interphase of the cell cycle. However, these priority questions regarding STAT1 distribution and localization at the different cell-cycle stages remain unclear. By using direct stochastic optical reconstruction microscopy (dSTORM), we found that the nuclear expression level of STAT1 increased gradually as the cell cycle carried out, especially after EGF stimulation. Furthermore, STAT1 formed clusters in the whole cell during the cell cycle, with the size and the number of clusters also increasing significantly from G1 to G2 phase, suggesting that transcription and other cell-cycle related activities can promote STAT1 to form more and larger clusters for fast response to signals. Our work reveals that the cellular localization and clustering distribution of STAT1 are associated with the cell cycle, and further provides an insight into the mechanism of cell-cycle regulated STAT1 signal transduction. PMID:25762114

  5. Nuclear protein I{kappa}B-{zeta} inhibits the activity of STAT3

    SciTech Connect

    Wu, Zhihao; Zhang, Xiaoai; Yang, Juntao; Wu, Guangzhou; Zhang, Ying; Yuan, Yanzhi; Jin, Chaozhi; Chang, Zhijie; Wang, Jian; Yang, Xiaoming; He, Fuchu; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032

    2009-09-18

    STAT3 (Signal transducer and activator of transcription 3) is a key transcription factor of the JAK-STAT (Janus kinase/signal transducer and activator of transcription) pathway that regulates cell proliferation and apoptosis. Activation of STAT3 is under tight regulation, and yet the different signaling pathways and the mechanisms that regulate its activity remain to be elucidated. Using a yeast two-hybrid screening, we have identified a nuclear protein I{kappa}B-{zeta} that interacts in a novel way with STAT3. This physical interaction was further confirmed by co-immunoprecipitation assays. The interaction regions were mapped to the coiled-coil domain of STAT3 and the C-terminal of I{kappa}B-{zeta}. Overexpression of I{kappa}B-{zeta} inhibited the transcriptional activity of STAT3. It also suppressed cell growth and induced cell apoptosis in SRC-simulated cells, which is partially mediated by down-regulation of expression of a known STAT3 target gene, MCL1. Our results suggest that I{kappa}B-{zeta} is a negative regulator of STAT3, and demonstrate a novel mechanism in which a component of the NF-{kappa}B signaling pathway inhibits the activation of STAT3.

  6. Silica scintillating materials prepared by sol-gel methods

    SciTech Connect

    Werst, D.W.; Sauer, M.C. Jr.; Cromack, K.R.; Lin, Y.; Tartakovsky, E.A.; Trifunac, A.D.

    1993-12-31

    Silica was investigated as a rad-hard alternative to organic polymer hosts for organic scintillators. Silica sol-gels were prepared by hydrolysis of tetramethoxysilane in alcohol solutions. organic dyes were incorporated into the gels by dissolving in methanol at the sol stage of gel formation. The silica sol-gel matrix is very rad-hard. The radiation stability of silica scintillators prepared by this method is dye-limited. Transient radioluminescence was measured following excitation with 30 ps pulses of 20 MeV electrons.

  7. Molecular host sol-gel films for chemical sensing applications

    SciTech Connect

    Shi, J.; Johnson, S.; Yang, X.; Swanson, B.

    1997-12-31

    Sol-gel cyclodextrin coatings on surface acoustic wave (SAW) device as VOC sensors have been studied. The sol-gel approach to thin films efficiently yields uniform coatings on SAW devices. The films were characterized by ATR-FT-IR, ellipsometry and SEM. The incorporation of molecular host reagents (cyclodextins and their derivatives) into thin films greatly enhance the sensitivity and selectivity of SAW sensors. It is believed that molecular recognition (selective sorption) occurs at the gas-solid interface. From the SAW data, it is possible to calculate the binding constants of sol-gel films towards a variety VOCs. The identification of VOCs based on SAW sensor arrays is discussed.

  8. Sol-gel derived PZT films doped with vanadium pentoxide

    SciTech Connect

    Shen Hongfang; Guo Qing; Zhao Zhiman; Cao Guozhong

    2009-11-15

    The present research investigated the sol-gel preparation, dielectric and ferroelectric properties of PZT films doped with 5 mol% vanadium oxide. Stable PZTV sols can be readily formed, and homogeneous, micrometer thick and pinhole-free PZTV films were obtained by using spin coating followed with rapid annealing. The X-ray diffraction patterns revealed that no parasitic or secondary phases were formed in the sol-gel PZT films with the addition of vanadium oxide. The material doped with vanadium pentoxide showed enhanced dielectric constant and remanent polarization with reduced loss tangent and coercive field.

  9. NAB2-STAT6 gene fusion and STAT6 immunoexpression in extrathoracic solitary fibrous tumors: the association between fusion variants and locations.

    PubMed

    Chuang, I-Chieh; Liao, Kuan-Cho; Huang, Hsuan-Ying; Kao, Yu-Chien; Li, Chien-Feng; Huang, Shih-Chiang; Tsai, Jen-Wei; Chen, Ko-Chin; Lan, Jui; Lin, Po-Chun

    2016-05-01

    Solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm harboring NAB2-STAT6 fusion, which drives STAT6 nuclear relocation. For extrathoracic SFTs, the clinical relevance of this molecular hallmark remains obscure. We assessed STAT6 immunoexpression for 61 extrathoracic SFTs exclusive of the meninges and head and neck, and 25 had analyzable RNAs to distinguish fusion variants by RT-PCR. The immunohistochemical and molecular findings were correlated with clincopathological features and disease-free survival (DFS). Twenty-eight males and 33 females had SFTs in the body cavities (n = 31), extremities (n = 17), and trunk (n = 13), categorized into 53 non-malignant and 8 malignant tumors. The vast majority (n = 57, 93%) exhibited distinctive STAT6 nuclear expression, including malignant ones. The common fusion variants were NAB2ex6-STAT6ex16/17 in 13 SFTs and NAB2ex4-STAT6ex2 in 8, while miscellaneous variants were detected only in 4 SFTs in the limbs and trunk but not in any body cavity-based cases (P = 0.026). The worse DFS was univariately associated with malignant histology (P = 0.04) but unrelated to tumor size, location, or fusion variant. Conclusively, extrathoracic SFTs mostly harbor NAB2ex6-STAT6ex16/17, followed by NAB2ex4-STAT6ex2. Miscellaneous variants are significantly rare in SFTs within the body cavities. The clinical aggressiveness of extrathoraic SFTs is associated with malignant histology but unrelated to the NAB2-STAT6 fusion variants. PMID:27039712

  10. STAT3 supports experimental K-RasG12D–induced murine myeloproliferative neoplasms dependent on serine phosphorylation

    PubMed Central

    Gough, Daniel J.; Marié, Isabelle J.; Lobry, Camille; Aifantis, Iannis

    2014-01-01

    Juvenile myelomonocytic leukemia, acute myeloid leukemia (AML), and other myeloproliferative neoplasms (MPNs) are genetically heterogeneous but frequently display activating mutations in Ras GTPases and activation of signal transducer and activator of transcription 3 (STAT3). Altered STAT3 activity is observed in up to 50% of AML correlating with poor prognosis. Activated STAT proteins, classically associated with tyrosine phosphorylation, support tumor development as transcription factors, but alternative STAT functions independent of tyrosine phosphorylation have been documented, including roles for serine-phosphorylated STAT3 in mitochondria supporting transformation by oncogenic Ras. We examined requirements for STAT3 in experimental murine K-Ras–dependent hematopoietic neoplasia. We show that STAT3 is phosphorylated on S727 but not Y705 in diseased animals. Moreover, a mouse with a point mutation abrogating STAT3 S727 phosphorylation displayed delayed onset and decreased disease severity with significantly extended survival. Activated K-Ras required STAT3 for cytokine-independent growth of myeloid progenitors in vitro, and mitochondrially restricted STAT3 and STAT3-Y705F, both transcriptionally inert mutants, supported factor-independent growth. STAT3 was dispensable for growth of normal or K-Ras–mutant myeloid progenitors in response to cytokines. However, abrogation of STAT3-S727 phosphorylation impaired factor-independent malignant growth. These data document that serine-phosphorylated mitochondrial STAT3 supports neoplastic hematopoietic cell growth induced by K-Ras. PMID:25150294

  11. Effect of Chelating Agents on the Stability of Nano-TiO2 Sol Particles for Sol-Gel Coating.

    PubMed

    Maeng, Wan Young; Yoo, Mi

    2015-11-01

    Agglomeration of sol particles in a titanium alkoxide (tetrabutyl orthotitanate (TBOT), > 97%) solution during the hydrolysis and condensation steps makes the sol solution difficult to use for synthesizing homogeneous sol-gel coating. Here, we have investigated the effect of stabilizing agents (acetic acid and ethyl acetoacetate (EAcAc)) on the agglomeration of Ti alkoxide particles during hydrolysis and condensation in order to determine the optimized conditions for controlling the precipitation of TiO2 particles. The study was conducted at R(AC) ([acetic acid]/[TBOT]) = 0.1-5 and R(EAcAc)([EAcAc]/[TBOT]) = 0.05-0.65. We also studied the effects of a basic catalyst ethanolamine (ETA), water, and HCl on sol stability. The chelating ligands in the precursor sol were analyzed with FT-IR. The coating properties were examined by focused ion beam. The stabilizing agents (acetic acid and EAcAc) significantly influenced the agglomeration and precipitation of TBOT precursor particles during hydrolysis. As R(AC) and R(EAcAc) increased, the agglomeration remarkably decreased. The stability of the sol with acetic acid and EAcAc arises from the coordination of the chelating ligand to TBOT that hinders hydrolysis and condensation. A uniform fine coating (thickness: 30 nm) on stainless steel was obtained by using an optimized sol with R(AC) = 0.5 and R(EAcAc) = 0.65. PMID:26726529

  12. Reply to 'Comment on 'All quantum observables in a hidden-variable model must commute simultaneously'' [Phys. Rev. A 73, 066101 (2006)

    SciTech Connect

    Malley, J. D.; Fine, A.

    2006-06-15

    Nagata [Phys. Rev. A 73, 066101 (2006)] questions whether a general no-go theorem of Malley [Phys. Rev. A 69, 022118 (2004)] applies to local hidden variables and outlines a 'counterexample.' In fact this is not a counterexample at all, but in seeing why it fails we clarify the significance of Malley's result and its relation to other no-go theorems.

  13. MOLECULAR PATHWAYS: JAK/STAT PATHWAY: MUTATIONS, INHIBITORS, AND RESISTANCE

    PubMed Central

    Quintás-Cardama, Alfonso; Verstovsek, Srdan

    2016-01-01

    Aberrant activation of the JAK/STAT pathway has been reported in a variety of disease states, including inflammatory conditions, hematologic malignancies, and solid tumors. For instance, a large proportion of patients with myeloproliferative neoplasms (MPNs) carry the acquired gain-of-function JAK2 V617F somatic mutation. This knowledge has dramatically improved our understanding of the pathogenesis of MPNs and it has facilitated the development of therapeutics capable of suppressing the constitutive activation of the JAK/STAT pathway, now recognized as a common underlying biological abnormality in MPNs. Ruxolitinib is an oral JAK1 and JAK2 inhibitor that has recently been approved for the treatment of myelofibrosis and has been tested against other hematologic malignancies. A series of agents with different specificities against different members of the JAK family of proteins is currently undergoing evaluation in clinical trials for patients with MPNs, lymphoma, and solid tumors such as breast or pancreatic cancer. Despite their significant clinical activity exhibited in myelofibrosis, some patients fail to respond or progress during JAK kinase inhibitor therapy. Recent reports have shed light into the mechanisms of resistance to JAK kinase inhibitor therapy. Several approaches hold promise to overcome such resistance. PMID:23406773

  14. Pharmacologic inhibition of JAK-STAT signaling promotes hair growth

    PubMed Central

    Harel, Sivan; Higgins, Claire A.; Cerise, Jane E.; Dai, Zhenpeng; Chen, James C.; Clynes, Raphael; Christiano, Angela M.

    2015-01-01

    Several forms of hair loss in humans are characterized by the inability of hair follicles to enter the growth phase (anagen) of the hair cycle after being arrested in the resting phase (telogen). Current pharmacologic therapies have been largely unsuccessful in targeting pathways that can be selectively modulated to induce entry into anagen. We show that topical treatment of mouse and human skin with small-molecule inhibitors of the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway results in rapid onset of anagen and subsequent hair growth. We show that JAK inhibition regulates the activation of key hair follicle populations such as the hair germ and improves the inductivity of cultured human dermal papilla cells by controlling a molecular signature enriched in intact, fully inductive dermal papillae. Our findings open new avenues for exploration of JAK-STAT inhibition for promotion of hair growth and highlight the role of this pathway in regulating the activation of hair follicle stem cells. PMID:26601320

  15. Protein inhibitor of activated STAT3 inhibits adipogenic gene expression

    SciTech Connect

    Deng Jianbei; Hua Kunjie; Caveney, Erica J.; Takahashi, Nobuyuki; Harp, Joyce B. . E-mail: jharp@unc.edu

    2006-01-20

    Protein inhibitor of activated STAT3 (PIAS3), a cytokine-induced repressor of signal transducer and activator of transcription 3 (STAT3) and a modulator of a broad array of nuclear proteins, is expressed in white adipose tissue, but its role in adipogenesis is not known. Here, we determined that PIAS3 was constitutively expressed in 3T3-L1 cells at all stages of adipogenesis. However, it translocated from the nucleus to the cytoplasm 4 days after induction of differentiation by isobutylmethylxanthine, dexamethasone, and insulin (MDI). In ob/ob mice, PIAS3 expression was increased in white adipose tissue depots compared to lean mice and was found in the cytoplasm of adipocytes. Overexpression of PIAS3 in differentiating preadipocytes, which localized primarily to the nucleus, inhibited mRNA level gene expression of adipogenic transcription factors C/EBP{alpha} and PPAR{gamma}, as well as their downstream target genes aP2 and adiponectin. PIAS3 also inhibited C/EBP{alpha} promoter activation mediated specifically by insulin, but not dexamethasone or isobutylmethylxanthine. Taken together, these data suggest that PIAS3 may play an inhibitory role in adipogenesis by modulating insulin-activated transcriptional activation events. Increased PIAS3 expression in adipose tissue may play a role in the metabolic disturbances of obesity.

  16. Pharmacologic inhibition of JAK-STAT signaling promotes hair growth.

    PubMed

    Harel, Sivan; Higgins, Claire A; Cerise, Jane E; Dai, Zhenpeng; Chen, James C; Clynes, Raphael; Christiano, Angela M

    2015-10-01

    Several forms of hair loss in humans are characterized by the inability of hair follicles to enter the growth phase (anagen) of the hair cycle after being arrested in the resting phase (telogen). Current pharmacologic therapies have been largely unsuccessful in targeting pathways that can be selectively modulated to induce entry into anagen. We show that topical treatment of mouse and human skin with small-molecule inhibitors of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway results in rapid onset of anagen and subsequent hair growth. We show that JAK inhibition regulates the activation of key hair follicle populations such as the hair germ and improves the inductivity of cultured human dermal papilla cells by controlling a molecular signature enriched in intact, fully inductive dermal papillae. Our findings open new avenues for exploration of JAK-STAT inhibition for promotion of hair growth and highlight the role of this pathway in regulating the activation of hair follicle stem cells. PMID:26601320

  17. Glucose-stat, a glucose-controlled continuous culture.

    PubMed Central

    Kleman, G L; Chalmers, J J; Luli, G W; Strohl, W R

    1991-01-01

    A predictive and feedback proportional control algorithm, developed for fed-batch fermentations and described in a companion paper (G. L. Kleman, J. J. Chalmers, G. W. Luli, and W. R. Strohl, Appl. Environ. Microbiol. 57:910-917, 1991), was used in this work to control a continuous culture on the basis of the soluble-glucose concentration (called the glucose-stat). This glucose-controlled continuous-culture system was found to reach and maintain steady state for 11 to 24 residence times when four different background glucose concentrations (0.27, 0.50, 0.7, and 1.5 g/liter) were used. The predictive-plus-feedback control system yielded very tight control of the continuous nutristat cultures; glucose concentrations were maintained at the set points with less than 0.003 standard error. Acetate production by Escherichia coli B in glucose-stats was found not to be correlated with the level of steady-state soluble-glucose concentration. PMID:2059050

  18. Glucose-stat, a glucose-controlled continuous culture.

    PubMed

    Kleman, G L; Chalmers, J J; Luli, G W; Strohl, W R

    1991-04-01

    A predictive and feedback proportional control algorithm, developed for fed-batch fermentations and described in a companion paper (G. L. Kleman, J. J. Chalmers, G. W. Luli, and W. R. Strohl, Appl. Environ. Microbiol. 57:910-917, 1991), was used in this work to control a continuous culture on the basis of the soluble-glucose concentration (called the glucose-stat). This glucose-controlled continuous-culture system was found to reach and maintain steady state for 11 to 24 residence times when four different background glucose concentrations (0.27, 0.50, 0.7, and 1.5 g/liter) were used. The predictive-plus-feedback control system yielded very tight control of the continuous nutristat cultures; glucose concentrations were maintained at the set points with less than 0.003 standard error. Acetate production by Escherichia coli B in glucose-stats was found not to be correlated with the level of steady-state soluble-glucose concentration. PMID:2059050

  19. Innate Immune Regulation by STAT-mediated Transcriptional Mechanisms

    PubMed Central

    Li, Haiyan S.; Watowich, Stephanie S.

    2014-01-01

    Summary The term innate immunity typically refers to a quick but nonspecific host defense response against invading pathogens. The innate immune system comprises particular immune cell populations, epithelial barriers, and numerous secretory mediators including cytokines, chemokines, and defense peptides. Innate immune cells are also now recognized to play important contributing roles in cancer and pathological inflammatory conditions. Innate immunity relies on rapid signal transduction elicited upon pathogen recognition via pattern recognition receptors (PRRs) and cell:cell communication conducted by soluble mediators, including cytokines. A majority of cytokines involved in innate immune signaling use a molecular cascade encompassing receptor-associated Jak protein tyrosine kinases and STAT (signal transducer and activator of transcription) transcriptional regulators. Here, we focus on roles for STAT proteins in three major innate immune subsets: neutrophils, macrophages, and dendritic cells (DCs). While knowledge in this area is only now emerging, understanding the molecular regulation of these cell types is necessary for developing new approaches to treat human disorders such as inflammatory conditions, autoimmunity, and cancer. PMID:25123278

  20. Sol gel processes. (Latest citations from the NTIS bibliographic database). Published Search

    SciTech Connect

    Not Available

    1993-09-01

    The bibliography contains citations concerning the development and utilization of sol-gel processes and techniques. Topics include antireflective coatings, studies of sol-gel transitions, sol-gel synthesis and polymerization, sol-gel derived thin films and glasses, and sol-gel production of microspheres. Applications in nuclear waste management, nuclear fuel manufacturing, glass optical waveguide development, and solar energy collection are presented. (Contains 250 citations and includes a subject term index and title list.)

  1. Effects of Cell Windows on TwinSol Beams

    NASA Astrophysics Data System (ADS)

    Cushman, Kimmy

    2016-04-01

    In order to study reactions with unstable nuclei, radioactive-ion beams must be used. One method for producing radioactive beams is the TwinSol experimental setup at the University of Notre Dame. At TwinSol, stable and unstable isotope beams bombard a gas target, where one atmosphere of gas must be confined from the surrounding vacuum. Thin foil windows are used to contain the gas in the cell. In order to optimize the quality of secondary beams from TwinSol, it is necessary to understand and minimize the effects of energy loss and straggling in the windows. This work is the beginning of a process to improve the TwinSol design so that secondary beams produced with heavier ions such as Oxygen, Fluorine, and Neon can be pursued.

  2. Production of continuous mullite fiber via sol-gel processing

    NASA Technical Reports Server (NTRS)

    Tucker, Dennis S.; Sparks, J. Scott; Esker, David C.

    1990-01-01

    The development of a continuous ceramic fiber which could be used in rocket engine and rocket boosters applications was investigated at the Marshall Space Flight Center. Methods of ceramic fiber production such as melt spinning, chemical vapor deposition, and precursor polymeric fiber decomposition are discussed and compared with sol-gel processing. The production of ceramics via the sol-gel method consists of two steps, hydrolysis and polycondensation, to form the preceramic, followed by consolidation into the glass or ceramic structure. The advantages of the sol-gel method include better homogeneity and purity, lower preparation temperature, and the ability to form unique compositions. The disadvantages are the high cost of raw materials, large shrinkage during drying and firing which can lead to cracks, and long processing times. Preparation procedures for aluminosilicate sol-gel and for continuous mullite fibers are described.

  3. Organofunctional Sol-Gel Materials for Toxic Metal Separation

    SciTech Connect

    Im, Hee-Jung; Yost, Terry L.; Yang, Yihui; Bramlett, J. Morris; Yu, Xiang-Hua; Fagan, Bryan C.; Allain, Leonardo R.; Chen, Tianniu; Xue, Ziling; Barnes, Craig E.; Dai, Sheng; Rocker, Lee E.; Sepaniak, Michael J.

    2003-09-10

    Inorganic-organic silica sol-gels grafted or encapsulated with organic ligands were prepared and found to selectively and reversibly remove target metal ions such as Cu2+, Cd2+, and Sr2+. These organofunctional sol-gel materials, which were easily prepared from off-the-shelf chemicals, were hydrophilic and showed fast kinetics of metal uptake. The sol-gels were easily regenerated and used in multi-cycle metal removal. In our search for new ligands for metal removal, we found that the reactions of thioacetal ligands with Hg2+ gave Hg(SCH2COOH)2. Our studies of organofunctional sol-gel materials for metal separation will be discussed.

  4. NAB2-STAT6 fusion types account for clinicopathological variations in solitary fibrous tumors.

    PubMed

    Tai, Hui-Chun; Chuang, I-Chieh; Chen, Tse-Ching; Li, Chien-Feng; Huang, Shih-Chiang; Kao, Yu-Chien; Lin, Po-Chun; Tsai, Jen-Wei; Lan, Jui; Yu, Shih-Chen; Yen, Shao-Lun; Jung, Shih-Ming; Liao, Kuan-Cho; Fang, Fu-Min; Huang, Hsuan-Ying

    2015-10-01

    Solitary fibrous tumor (SFT) is characterized by the inv12(q13q13)-derived NAB2-STAT6 fusion, which exhibits variable breakpoints and drives STAT6 nuclear expression. The implications of NAB2-STAT6 fusion variants in pathological features and clinical behavior remain to be characterized in a large cohort of SFTs. We investigated the clinicopathological correlates of this genetic hallmark and analyzed STAT6 immunoexpression in 28 intrathoracic, 37 extrathoracic, and 23 meningeal SFTs. These 88 tumors were designated as histologically nonmalignant in 75 cases and malignant in 13, including 1 dedifferentiated SFT. Eighty cases had formalin-fixed and/or fresh samples to extract assessable RNAs for RT-PCR assay, which revealed NAB2-STAT6 fusion variants comprising 12 types of junction breakpoints in 73 fusion-positive cases, with 65 (89%) falling into 3 major types. The predominant NAB2ex4-STAT6ex2 (n=33) showed constant breakpoints at the ends of involved exons, whereas the NAB2ex6-STAT6ex16 (n=16) and NAB2ex6-STAT6ex17 (n=16) might exhibit variable breakpoints and incorporate NAB2 or STAT6 intronic sequence. Including 73 fusion-positive and 7 CD34-negative SFTs, STAT6 distinctively labeled 87 (99%) SFTs in nuclei, exhibited diffuse reactivity in 73, but did not decorate 98 mimics tested. In seven fusion-negative cases, 6 were STAT6-positive, suggesting rare fusion variants not covered by RT-PCR assay. Regardless of histological subtypes, intrathoracic SFTs affected older patients (P=0.035) and tended to be larger in size (P=0.073). Compared with other variants, NAB2ex4-STAT6ex2/4 fusions were significantly predominant in the SFTs characterised by intrathoracic location (P<0.001), older age (P=0.005), decreased mitoses (P=0.0028), and multifocal or diffuse STAT6 staining (P=0.013), but not found to correlate with disease-free survival. Conclusively, STAT6 nuclear expression was distinctive in the vast majority of SFTs, including all fusion-positive tumors, and

  5. Stat5 signaling specifies basal versus stress erythropoietic responses through distinct binary and graded dynamic modalities.

    PubMed

    Porpiglia, Ermelinda; Hidalgo, Daniel; Koulnis, Miroslav; Tzafriri, Abraham R; Socolovsky, Merav

    2012-08-01

    Erythropoietin (Epo)-induced Stat5 phosphorylation (p-Stat5) is essential for both basal erythropoiesis and for its acceleration during hypoxic stress. A key challenge lies in understanding how Stat5 signaling elicits distinct functions during basal and stress erythropoiesis. Here we asked whether these distinct functions might be specified by the dynamic behavior of the Stat5 signal. We used flow cytometry to analyze Stat5 phosphorylation dynamics in primary erythropoietic tissue in vivo and in vitro, identifying two signaling modalities. In later (basophilic) erythroblasts, Epo stimulation triggers a low intensity but decisive, binary (digital) p-Stat5 signal. In early erythroblasts the binary signal is superseded by a high-intensity graded (analog) p-Stat5 response. We elucidated the biological functions of binary and graded Stat5 signaling using the EpoR-HM mice, which express a "knocked-in" EpoR mutant lacking cytoplasmic phosphotyrosines. Strikingly, EpoR-HM mice are restricted to the binary signaling mode, which rescues these mice from fatal perinatal anemia by promoting binary survival decisions in erythroblasts. However, the absence of the graded p-Stat5 response in the EpoR-HM mice prevents them from accelerating red cell production in response to stress, including a failure to upregulate the transferrin receptor, which we show is a novel stress target. We found that Stat5 protein levels decline with erythroblast differentiation, governing the transition from high-intensity graded signaling in early erythroblasts to low-intensity binary signaling in later erythroblasts. Thus, using exogenous Stat5, we converted later erythroblasts into high-intensity graded signal transducers capable of eliciting a downstream stress response. Unlike the Stat5 protein, EpoR expression in erythroblasts does not limit the Stat5 signaling response, a non-Michaelian paradigm with therapeutic implications in myeloproliferative disease. Our findings show how the binary and

  6. The Chemopreventive Phytochemical Moringin Isolated from Moringa oleifera Seeds Inhibits JAK/STAT Signaling

    PubMed Central

    Weigl, Julia; De Nicola, Gina Rosalinda; Canistro, Donatella; Paolini, Moreno; Iori, Renato; Rascle, Anne

    2016-01-01

    Sulforaphane (SFN) and moringin (GMG-ITC) are edible isothiocyanates present as glucosinolate precursors in cruciferous vegetables and in the plant Moringa oleifera respectively, and recognized for their chemopreventive and medicinal properties. In contrast to the well-studied SFN, little is known about the molecular pathways targeted by GMG-ITC. We investigated the ability of GMG-ITC to inhibit essential signaling pathways that are frequently upregulated in cancer and immune disorders, such as JAK/STAT and NF-κB. We report for the first time that, similarly to SFN, GMG-ITC in the nanomolar range suppresses IL-3-induced expression of STAT5 target genes. GMG-ITC, like SFN, does not inhibit STAT5 phosphorylation, suggesting a downstream inhibitory event. Interestingly, treatment with GMG-ITC or SFN had a limited inhibitory effect on IFNα-induced STAT1 and STAT2 activity, indicating that both isothiocyanates differentially target JAK/STAT signaling pathways. Furthermore, we showed that GMG-ITC in the micromolar range is a more potent inhibitor of TNF-induced NF-κB activity than SFN. Finally, using a cellular system mimicking constitutive active STAT5-induced cell transformation, we demonstrated that SFN can reverse the survival and growth advantage mediated by oncogenic STAT5 and triggers cell death, therefore providing experimental evidence of a cancer chemopreventive activity of SFN. This work thus identified STAT5, and to a lesser extent STAT1/STAT2, as novel targets of moringin. It also contributes to a better understanding of the biological activities of the dietary isothiocyanates GMG-ITC and SFN and further supports their apparent beneficial role in the prevention of chronic illnesses such as cancer, inflammatory diseases and immune disorders. PMID:27304884

  7. The cleaved cytoplasmic tail of polycystin-1 regulates Src-dependent STAT3 activation.

    PubMed

    Talbot, Jeffrey J; Song, Xuewen; Wang, Xiaofang; Rinschen, Markus M; Doerr, Nicholas; LaRiviere, Wells B; Schermer, Bernhard; Pei, York P; Torres, Vicente E; Weimbs, Thomas

    2014-08-01

    Polycystin-1 (PC1) mutations result in proliferative renal cyst growth and progression to renal failure in autosomal dominant polycystic kidney disease (ADPKD). The transcription factor STAT3 (signal transducer and activator of transcription 3) was shown to be activated in cyst-lining cells in ADPKD and PKD mouse models and may drive renal cyst growth, but the mechanisms leading to persistent STAT3 activation are unknown. A proteolytic fragment of PC1 corresponding to the cytoplasmic tail, PC1-p30, is overexpressed in ADPKD. Here, we show that PC1-p30 interacts with the nonreceptor tyrosine kinase Src, resulting in Src-dependent activation of STAT3 by tyrosine phosphorylation. The PC1-p30-mediated activation of Src/STAT3 was independent of JAK family kinases and insensitive to the STAT3 inhibitor suppressor of cytokine signaling 3. Signaling by the EGF receptor (EGFR) or cAMP amplified the activation of Src/STAT3 by PC1-p30. Expression of PC1-p30 changed the cellular response to cAMP signaling. In the absence of PC1-p30, cAMP dampened EGFR- or IL-6-dependent activation of STAT3; in the presence of PC1-p30, cAMP amplified Src-dependent activation of STAT3. In the polycystic kidney (PCK) rat model, activation of STAT3 in renal cystic cells depended on vasopressin receptor 2 (V2R) signaling, which increased cAMP levels. Genetic inhibition of vasopressin expression or treatment with a pharmacologic V2R inhibitor strongly suppressed STAT3 activation and reduced renal cyst growth. These results suggest that PC1, via its cleaved cytoplasmic tail, integrates signaling inputs from EGFR and cAMP, resulting in Src-dependent activation of STAT3 and a proliferative response. PMID:24578126

  8. S-Glutathionylation at Cys328 and Cys542 impairs STAT3 phosphorylation.

    PubMed

    Butturini, Elena; Darra, Elena; Chiavegato, Giulia; Cellini, Barbara; Cozzolino, Flora; Monti, Maria; Pucci, Piero; Dell'Orco, Daniele; Mariotto, Sofia

    2014-08-15

    STAT3 is a latent transcription factor that promotes cell survival and proliferation and is often constitutively active in cancers. Although many reports provide evidence that STAT3 is a direct target of oxidative stress, its redox regulation is poorly understood. Under oxidative conditions STAT3 activity can be modulated by S-glutathionylation, a reversible redox modification of cysteine residues. This suggests the possible cross-talk between phosphorylation and glutathionylation and points out that STAT3 is susceptible to redox regulation. Recently, we reported that decreasing the GSH content in different cell lines induces inhibition of STAT3 activity through the reversible oxidation of thiol groups. In the present work, we demonstrate that GSH/diamide treatment induces S-glutathionylation of STAT3 in the recombinant purified form. This effect was completely reversed by treatment with the reducing agent dithiothreitol, indicating that S-glutathionylation of STAT3 was related to formation of protein-mixed disulfides. Moreover, addition of the bulky negatively charged GSH moiety impairs JAK2-mediated STAT3 phosphorylation, very likely interfering with tyrosine accessibility and thus affecting protein structure and function. Mass mapping analysis identifies two glutathionylated cysteine residues, Cys328 and Cys542, within the DNA-binding domain and the linker domain, respectively. Site direct mutagenesis and in vitro kinase assay confirm the importance of both cysteine residues in the complex redox regulatory mechanism of STAT3. Cells expressing mutant were resistant in this regard. The data presented herein confirmed the occurrence of a redox-dependent regulation of STAT3, identified the more redox-sensitive cysteines within STAT3 structure, and may have important implications for development of new drugs. PMID:24941337

  9. STAT3 is Overactivated in Gastric Cancer Stem-Like Cells

    PubMed Central

    Hajimoradi, Monireh; Mohammad Hassan, Zuhair; Ebrahimi, Marzieh; Soleimani, Masoud; Bakhshi, Mahdieh; Firouzi, Javad; Samani, Fazel Sahraneshin

    2016-01-01

    Objective Gastric cancer (GC) is widely associated with chronic inflammation. The pro inflammatory microenvironment provides conditions that disrupt stem/progenitor cell proliferation and differentiation. The signal transducer and activator of transcrip- tion-3 (STAT3) signaling pathway is involved in inflammation and also contributes to the maintenance of embryonic stem cell (ESCs) pluripotency. Here, we have investi- gated the activation status of STAT3 in GC stem-like cells (GCSLCs). Materials and Methods In this experimental research, CSLCs derived from the human GC cell line MKN-45 and patient specimens, through spheroid body formation, character- ized and then assayed for the STAT3 transcription factor expression in mRNA and protein level further to its activation. Results Spheroid cells showed higher potential for spheroid formation than the pa- rental cells. Furthemore, stemness genes NANOG, c-MYC and SOX-2 were over expressed in spheroids of MKN-45 and in patient samples. In MKN-45 spheroid cells, epithelial mesenchymal transition (EMT) related markers CDH2, SNAIL2, TWIST and VIMENTIN were upregulated (P<0.05), but we observed no change in expression of the E-cadherin epithelial marker. These cells exhibited more resistance to docetaxel (DTX) when compared with parental cells (P<0.05) according to the MTS assay. Al- though immunostaining and Western blotting showed expression of the STAT3 pro- tein in both spheroids and parents, the mRNA level of STAT3 in spheroids was higher than the parents. Nuclear translocation of STAT3 was accompanied by more intensive phospho-STAT3 (p-STAT3) in spheroid structures relative to the parent cells accord- ing to flow cytometry analysis (P<0.05). Conclusion The present findings point to STAT3 over activation in GCSLCs. Com- plementary experiments are required to extend the role of STAT3 in stemness fea- tures and invasion properties of GCSCs and to consider the STAT3 pathway for CSC targeted therapy. PMID:26862521

  10. The Chemopreventive Phytochemical Moringin Isolated from Moringa oleifera Seeds Inhibits JAK/STAT Signaling.

    PubMed

    Michl, Carina; Vivarelli, Fabio; Weigl, Julia; De Nicola, Gina Rosalinda; Canistro, Donatella; Paolini, Moreno; Iori, Renato; Rascle, Anne

    2016-01-01

    Sulforaphane (SFN) and moringin (GMG-ITC) are edible isothiocyanates present as glucosinolate precursors in cruciferous vegetables and in the plant Moringa oleifera respectively, and recognized for their chemopreventive and medicinal properties. In contrast to the well-studied SFN, little is known about the molecular pathways targeted by GMG-ITC. We investigated the ability of GMG-ITC to inhibit essential signaling pathways that are frequently upregulated in cancer and immune disorders, such as JAK/STAT and NF-κB. We report for the first time that, similarly to SFN, GMG-ITC in the nanomolar range suppresses IL-3-induced expression of STAT5 target genes. GMG-ITC, like SFN, does not inhibit STAT5 phosphorylation, suggesting a downstream inhibitory event. Interestingly, treatment with GMG-ITC or SFN had a limited inhibitory effect on IFNα-induced STAT1 and STAT2 activity, indicating that both isothiocyanates differentially target JAK/STAT signaling pathways. Furthermore, we showed that GMG-ITC in the micromolar range is a more potent inhibitor of TNF-induced NF-κB activity than SFN. Finally, using a cellular system mimicking constitutive active STAT5-induced cell transformation, we demonstrated that SFN can reverse the survival and growth advantage mediated by oncogenic STAT5 and triggers cell death, therefore providing experimental evidence of a cancer chemopreventive activity of SFN. This work thus identified STAT5, and to a lesser extent STAT1/STAT2, as novel targets of moringin. It also contributes to a better understanding of the biological activities of the dietary isothiocyanates GMG-ITC and SFN and further supports their apparent beneficial role in the prevention of chronic illnesses such as cancer, inflammatory diseases and immune disorders. PMID:27304884

  11. Comment on ``Free energy simulations of single and double ion occupancy in gramicidin A'' [J. Chem. Phys. 126, 105103 (2007)

    NASA Astrophysics Data System (ADS)

    Roux, Benoît; Andersen, Olaf S.; Allen, Toby W.

    2008-06-01

    In a recent article published by Bastug and Kuyucak [J. Chem. Phys.126, 105103 (2007)] investigated the microscopic factors affecting double ion occupancy in the gramicidin channel. The analysis relied largely on the one-dimensional potential of mean force of ions along the axis of the channel (the so-called free energy profile of the ion along the channel axis), as well as on the calculation of the equilibrium association constant of the ions in the channel binding sites. It is the purpose of this communication to clarify this issue.

  12. Comment on ``Experimental observation of carbon dioxide reduction in exhaust gas from hydrocarbon fuel burning'' [Phys. Plasmas 16, 114502 (2009)

    NASA Astrophysics Data System (ADS)

    Byun, Youngchul; Shin, Dong Nam

    2010-01-01

    The following comments are intended to clarify whether it is possible to convert CO2 into C+O2 by supplying just one-twentieth of energy required thermodynamically, only under the condition that the negative high voltage of dc is applied to the gas stream perpendicularly, in a recent article by Uhm and Kim [H. S. Uhm and C. H. Kim, Phys. Plasmas 16, 114502 (2009)]. Of particular concern is the disobedience of the first and second laws of thermodynamics together with the indistinct measurement of experimental data.

  13. Comment on "Surface electromagnetic wave equations in a warm magnetized quantum plasma" [Phys. Plasmas 21, 072114 (2014)

    NASA Astrophysics Data System (ADS)

    Moradi, Afshin

    2016-07-01

    In a recent article [C. Li et al., Phys. Plasmas 21, 072114 (2014)], Li et al. studied the propagation of surface waves on a magnetized quantum plasma half-space in the Voigt configuration (in this case, the magnetic field is parallel to the surface but is perpendicular to the direction of propagation). Here, we present a fresh look at the problem and obtain a new form of dispersion relation of surface waves of the system. We find that our new dispersion relation does not agree with the result obtained by Li et al.

  14. Comment on 'Dynamics of an electron driven by relativistically intense laser radiation' [Phys. Plasmas 15, 023104 (2008)

    SciTech Connect

    Tian Youwei; Bao Gang; Zheng Ying; Yang Jianping; Yu Wei; Wang Xin

    2010-06-15

    Galkin et al. [Phys. Plasmas 15, 023104 (2008)] presented the comparison of the electron dynamics in the cases of the linear and circular polarizations of the optical fields. They assume that the longitudinal component of the laser field can be neglected in the case of longitudinal displacement less than the Rayleigh range. In this comment, we point out that the longitudinal component must be considered for the minimum spot size less than 10 times wavelength for linearly polarized laser pulse and for the minimum spot size less than 15 times wavelength for circularly polarized laser pulse.

  15. Comment on ``Dynamics of glass-forming liquids. XIII. Microwave heating in slow motion'' [J. Chem. Phys. 130, 194509 (2009)

    NASA Astrophysics Data System (ADS)

    Johari, G. P.

    2012-07-01

    Critical reading of the dielectric method and data in the paper [W. Huang and R. Richert, J. Chem. Phys. 130, 194509 (2009)], 10.1063/1.3139519 showed that (i) the large inter-electrode area of the Teflon spacer used in the dielectric cell affected the spectral data and (ii) the measured Δɛ of propylene carbonate after making the spacer area correction is 1.8-times the known value, indicating errors from unknown sources. This puts into question their support for the dynamic heterogeneity view, and their inference on the magnitude of configurational heat capacity.

  16. Comment on "Frequency-domain stimulated and spontaneous light emission signals at molecular junctions" [J. Chem. Phys. 141, 074107 (2014)

    NASA Astrophysics Data System (ADS)

    Galperin, Michael; Ratner, Mark A.; Nitzan, Abraham

    2015-04-01

    We discuss the derivation of the optical response in molecular junctions presented by U. Harbola et al. [J. Chem. Phys. 141, 074107 (2014)], which questions some terms in the theory of Raman scattering in molecular junctions developed in our earlier publications. We show that the terms considered in our theory represent the correct contribution to calculated Raman scattering and are in fact identical to those considered by Harbola et al. We also indicate drawbacks of the presented approach in treating the quantum transport part of the problem.

  17. Comment on 'Experimental observation of carbon dioxide reduction in exhaust gas from hydrocarbon fuel burning' [Phys. Plasmas 16, 114502 (2009)

    SciTech Connect

    Byun, Youngchul; Shin, Dong Nam

    2010-01-15

    The following comments are intended to clarify whether it is possible to convert CO{sub 2} into C+O{sub 2} by supplying just one-twentieth of energy required thermodynamically, only under the condition that the negative high voltage of dc is applied to the gas stream perpendicularly, in a recent article by Uhm and Kim [H. S. Uhm and C. H. Kim, Phys. Plasmas 16, 114502 (2009)]. Of particular concern is the disobedience of the first and second laws of thermodynamics together with the indistinct measurement of experimental data.

  18. Comment on "Size-efficient metamaterial absorber at low frequencies: Design, fabrication, and characterization" [J. Appl. Phys. 117, 243105 (2015)

    NASA Astrophysics Data System (ADS)

    Liu, Lulu; Liu, Shaobin; Zhang, HaiFeng; Kong, Xiangkun; Yang, Hua; Ding, Guowen; Xu, Ce; Wang, Lingling; Shi, Wei

    2016-06-01

    In a recent article, Khuyen et al. [J. Appl. Phys. 117, 243105 (2015)] proposed a metamaterial perfect absorber (MPA) with a self-asymmetric structure and claimed that it could produce dual-band "perfect absorption." In this report, we demonstrate that the self-asymmetric structure is not a true MPA. The cross-polarization reflection, which is induced by coupling between the induced magnetic field and the incident electric field, is ignored in calculation of absorptivity of that structure. The real absorption rate of this structure is below 60%, which indicates that the structure cannot be called a perfect absorber.

  19. New developments for sol-gel film and fiber processing

    SciTech Connect

    Hurd, A.J.

    1995-03-01

    New insights into the development of microstructure in sol-gel films have recently been revealed by several diagnostic techniques, including imaging ellipsometry, {open_quotes}chemical imaging{close_quotes} by fluorescent tracers, light scattering from capillary waves, and finite-element modeling. The evolution of porosity during the continuous transition from dilute sol to porous solid in restricted geometries such as films and fibers is becoming clearer through fundamental understanding of evaporation dynamics and capillarity.

  20. Martian Dust Devil Movie, Phoenix Sol 104

    NASA Technical Reports Server (NTRS)

    2008-01-01

    The Surface Stereo Imager on NASA's Phoenix Mars Lander caught this dust devil in action west of the lander in four frames shot about 50 seconds apart from each other between 11:53 a.m. and 11:56 a.m. local Mars time on Sol 104, or the 104th Martian day of the mission, Sept. 9, 2008.

    Dust devils have not been detected in any Phoenix images from earlier in the mission, but at least six were observed in a dozen images taken on Sol 104.

    Dust devils are whirlwinds that often occur when the Sun heats the surface of Mars, or some areas on Earth. The warmed surface heats the layer of atmosphere closest to it, and the warm air rises in a whirling motion, stirring dust up from the surface like a miniature tornado.

    The dust devil visible in this sequence was about 1,000 meters (about 3,300 feet) from the lander when the first frame was taken, and had moved to about 1,700 meters (about 5,600 feet) away by the time the last frame was taken about two and a half minutes later. The dust devil was moving westward at an estimated speed of 5 meters per second (11 miles per hour), which is similar to typical late-morning wind speed and direction indicated by the telltale wind gauge on Phoenix.

    This dust devil is about 5 meters (16 feet) in diameter. This is much smaller than dust devils that have been observed by NASA's Mars Exploration Rover Spirit much closer to the equator. It is closer in size to dust devils seen from orbit in the Phoenix landing region, though still smaller than those..

    The image has been enhanced to make the dust devil easier to see. Some of the frame-to-frame differences in the appearance of foreground rocks is because each frame was taken through a different color filter.

    The Phoenix Mission is led by the University of Arizona, Tucson, on behalf of NASA. Project management of the mission is by NASA's Jet Propulsion Laboratory, Pasadena, Calif. Spacecraft development is by Lockheed Martin Space Systems, Denver.

  1. New Record Five-Wheel Drive, Spirit's Sol 1856

    NASA Technical Reports Server (NTRS)

    2009-01-01

    NASA's Mars Exploration Rover Spirit used its navigation camera to take the images that have been combined into this stereo, 180-degree view of the rover's surroundings during the 1,856th Martian day, or sol, of Spirit's surface mission (March 23, 2009). The center of the view is toward the west-southwest.

    The rover had driven 25.82 meters (84.7 feet) west-northwestward earlier on Sol 1856. This is the longest drive on Mars so far by a rover using only five wheels. Spirit lost the use of its right-front wheel in March 2006. Before Sol 1856, the farthest Spirit had covered in a single sol's five-wheel drive was 24.83 meters (81.5 feet), on Sol 1363 (Nov. 3, 2007).

    The Sol 1856 drive made progress on a route planned for taking Spirit around the western side of the low plateau called 'Home Plate.' A portion of the northwestern edge of Home Plate is prominent in the left quarter of this image, toward the south.

    This view is presented as a cylindrical projection with geometric seam correction.

  2. Carbon Monoxide Induces Heme Oxygenase-1 to Modulate STAT3 Activation in Endothelial Cells via S-Glutathionylation

    PubMed Central

    Yang, Yan-Chang; Huang, Yu-Ting; Hsieh, Chia-Wen; Yang, Po-Min; Wung, Being-Sun

    2014-01-01

    IL-6/STAT3 pathway is involved in a variety of biological responses, including cell proliferation, differentiation, apoptosis, and inflammation. In our present study, we found that CO releasing molecules (CORMs) suppress IL-6-induced STAT3 phosphorylation, nuclear translocation and transactivity in endothelial cells (ECs). CO is a byproduct of heme degradation mediated by heme oxygenase (HO-1). However, CORMs can induce HO-1 expression and then inhibit STAT3 phosphorylation. CO has been found to increase a low level ROS and which may induce protein glutathionylation. We hypothesized that CORMs increases protein glutathionylation and inhibits STAT3 activation. We found that CORMs increase the intracellular GSSG level and induce the glutathionylation of multiple proteins including STAT3. GSSG can inhibit STAT3 phosphorylation and increase STAT3 glutathionylation whereas the antioxidant enzyme catalase can suppress the glutathionylation. Furthermore, catalase blocks the inhibition of STAT3 phosphorylation by CORMs treatment. The inhibition of glutathione synthesis by BSO was also found to attenuate STAT3 glutathionylation and its inhibition of STAT3 phosphorylation. We further found that HO-1 increases STAT3 glutathionylation and that HO-1 siRNA attenuates CORM-induced STAT3 glutathionylation. Hence, the inhibition of STAT3 activation is likely to occur via a CO-mediated increase in the GSSG level, which augments protein glutathionylation, and CO-induced HO-1 expression, which may enhance and maintain its effects in IL-6-treated ECs. PMID:25072782

  3. Sodium orthovanadate suppresses palmitate-induced cardiomyocyte apoptosis by regulation of the JAK2/STAT3 signaling pathway.

    PubMed

    Liu, Jing; Fu, Hui; Chang, Fen; Wang, Jinlan; Zhang, Shangli; Caudle, Yi; Zhao, Jing; Yin, Deling

    2016-05-01

    Elevated circulatory free fatty acids (FFAs) especially saturated FFAs, such as palmitate (PA), are detrimental to the heart. However, mechanisms responsible for this phenomenon remain unknown. Here, the role of JAK2/STAT3 in PA-induced cytotoxicity was investigated in cardiomyocytes. We demonstrate that PA suppressed the JAK2/STAT3 pathway by dephosphorylation of JAK2 (Y1007/1008) and STAT3 (Y705), and thus blocked the translocation of STAT3 into the nucleus. Conversely, phosphorylation of S727, another phosphorylated site of STAT3, was increased in response to PA treatment. Pretreatment of JNK inhibitor, but not p38 MAPK inhibitor, inhibited STAT3 (S727) activation induced by PA and rescued the phosphorylation of STAT3 (Y705). The data suggested that JNK may be another upstream factor regulating STAT3, and verified the important function of P-STAT3 (Y705) in PA-induced cardiomyocyte apoptosis. Sodium orthovanadate (SOV), a protein tyrosine phosphatase inhibitor, obviously inhibited PA-induced apoptosis by restoring JAK2/STAT3 pathways. This effect was diminished by STAT3 inhibitor Stattic. Collectively, our data suggested a novel mechanism that the inhibition of JAK2/STAT3 activation was responsible for palmitic lipotoxicity and SOV may act as a potential therapeutic agent by targeting JAK2/STAT3 in lipotoxic cardiomyopathy treatment. PMID:26921179

  4. JAB1 regulates unphosphorylated STAT3 DNA-binding activity through protein–protein interaction in human colon cancer cells

    SciTech Connect

    Nishimoto, Arata; Kugimiya, Naruji; Hosoyama, Toru; Enoki, Tadahiko; Li, Tao-Sheng; Hamano, Kimikazu

    2013-08-30

    Highlights: •JAB1 interacted with unphosphorylated STAT3 in the nucleus. •JAB1 knockdown tended to increase nuclear STAT3 expression. •JAB1 knockdown significantly decreased unphosphorylated STAT3 DNA-binding activity. •JAB1 knockdown significantly decreased MDR1, NANOG, and VEGF expressions. •Nuclear JAB1, but not nuclear STAT3, correlated with STAT3 DNA-binding activity. -- Abstract: Recent studies have revealed that unphosphorylated STAT3 forms a dimer, translocates to the nucleus, binds to the STAT3 binding site, and activates the transcription of STAT3 target genes, thereby playing an important role in oncogenesis in addition to phosphorylated STAT3. Among signaling steps of unphosphorylated STAT3, nuclear translocation and target DNA-binding are the critical steps for its activation. Therefore, elucidating the regulatory mechanism of these signaling steps of unphosphorylated STAT3 is a potential step in the discovery of a novel cancer drug. However, the mechanism of unphosphorylated STAT3 binding to the promoter of target genes remains unclear. In this study, we focused on Jun activation domain-binding protein 1 (JAB1) as a candidate protein that regulates unphosphorylated STAT3 DNA-binding activity. Initially, we observed that both unphosphorylated STAT3 and JAB1 existed in the nucleus of human colon cancer cell line COLO205 at the basal state (no cytokine stimulation). On the other hand, phosphorylated STAT3 did not exist in the nucleus of COLO205 cells at the basal state. Immunoprecipitation using nuclear extract of COLO205 cells revealed that JAB1 interacted with unphosphorylated STAT3. To investigate the effect of JAB1 on unphosphorylated STAT3 activity, RNAi studies were performed. Although JAB1 knockdown tended to increase nuclear STAT3 expression, it significantly decreased unphosphorylated STAT3 DNA-binding activity. Subsequently, JAB1 knockdown significantly decreased the expression levels of MDR1, NANOG, and VEGF, which are STAT3 target

  5. Rotavirus antagonizes cellular antiviral responses by inhibiting the nuclear accumulation of STAT1, STAT2, and NF-kappaB.

    PubMed

    Holloway, Gavan; Truong, Thanhmai T; Coulson, Barbara S

    2009-05-01

    A vital arm of the innate immune response to viral infection is the induction and subsequent antiviral effects of interferon (IFN). Rotavirus reduces type I IFN induction in infected cells by the degradation of IFN regulatory factors. Here, we show that the monkey rotavirus RRV and human rotavirus Wa also block gene expression induced by type I and II IFNs through a mechanism allowing signal transducer and activator of transcription 1 (STAT1) and STAT2 activation but preventing their nuclear accumulation. In infected cells, this may allow rotavirus to block the antiviral actions of IFN produced early in infection or by activated immune cells. As the intracellular expression of rotavirus nonstructural proteins NSP1, NSP3, and NSP4 individually did not inhibit IFN-stimulated gene expression, their involvement in this process is unlikely. RRV and Wa rotaviruses also prevented the tumor necrosis factor alpha-stimulated nuclear accumulation of NF-kappaB and NF-kappaB-driven gene expression. In addition, NF-kappaB was activated by rotavirus infection, confirming earlier findings by others. As NF-kappaB is important for the induction of IFN and other cytokines during viral infection, this suggests that rotavirus prevents cellular transcription as a means to evade host responses. To our knowledge, this is the first report of the use of this strategy by a double-stranded RNA virus. PMID:19244315

  6. Dysregulation of JAK-STAT pathway in hematological malignancies and JAK inhibitors for clinical application.

    PubMed

    Furqan, Muhammad; Mukhi, Nikhil; Lee, Byung; Liu, Delong

    2013-01-01

    JAK-STAT (Janus associated kinase-signal transducer and activator of transcription) pathway plays a critical role in transduction of extracellular signals from cytokines and growth factors involved in hematopoiesis, immune regulation, fertility, lactation, growth and embryogenesis. JAK family contains four cytoplasmic tyrosine kinases, JAK1-3 and Tyk2. Seven STAT proteins have been identified in human cells, STAT1-6, including STAT5a and STAT5b. Negative regulators of JAK-STAT pathways include tyrosine phosphatases (SHP1 and 2, CD45), protein inhibitors of activated STATs (PIAS), suppressors of cytokine signaling (SOCS) proteins, and cytokine-inducible SH2-containing protein (CIS). Dysregulation of JAK-STAT pathway have been found to be key events in a variety of hematological malignancies. JAK inhibitors are among the first successful agents reaching clinical application. Ruxolitinib (Jakafi), a non-selective inhibitor of JAK1 & 2, has been approved by FDA for patients with intermediate to high risk primary or secondary myelofibrosis. This review will also summarize early data on selective JAK inhibitors, including SAR302503 (TG101348), lestaurtinib (CEP701), CYT387, SB1518 (pacritinib), LY2784544, XL019, BMS-911543, NS-018, and AZD1480. PMID:24252238

  7. Stat3 promotes mitochondrial transcription and oxidative respiration during maintenance and induction of naive pluripotency.

    PubMed

    Carbognin, Elena; Betto, Riccardo M; Soriano, Maria E; Smith, Austin G; Martello, Graziano

    2016-03-15

    Transcription factor Stat3 directs self-renewal of pluripotent mouse embryonic stem (ES) cells downstream of the cytokine leukemia inhibitory factor (LIF). Stat3 upregulates pivotal transcription factors in the ES cell gene regulatory network to sustain naïve identity. Stat3 also contributes to the rapid proliferation of ES cells. Here, we show that Stat3 increases the expression of mitochondrial-encoded transcripts and enhances oxidative metabolism. Chromatin immunoprecipitation reveals that Stat3 binds to the mitochondrial genome, consistent with direct transcriptional regulation. An engineered form of Stat3 that localizes predominantly to mitochondria is sufficient to support enhanced proliferation of ES cells, but not to maintain their undifferentiated phenotype. Furthermore, during reprogramming from primed to naïve states of pluripotency, Stat3 similarly upregulates mitochondrial transcripts and facilitates metabolic resetting. These findings suggest that the potent stimulation of naïve pluripotency by LIF/Stat3 is attributable to parallel and synergistic induction of both mitochondrial respiration and nuclear transcription factors. PMID:26903601

  8. The JAK–STAT Pathway Is Critical in Ventilator-Induced Diaphragm Dysfunction

    PubMed Central

    Tang, Huibin; Smith, Ira J; Hussain, Sabah NA; Goldberg, Peter; Lee, Myung; Sugiarto, Sista; Godinez, Guillermo L; Singh, Baljit K; Payan, Donald G; Rando, Thomas A; Kinsella, Todd M; Shrager, Joseph B

    2014-01-01

    Mechanical ventilation (MV) is one of the lynchpins of modern intensive-care medicine and is life saving in many critically ill patients. Continuous ventilator support, however, results in ventilation-induced diaphragm dysfunction (VIDD) that likely prolongs patients’ need for MV and thereby leads to major associated complications and avoidable intensive care unit (ICU) deaths. Oxidative stress is a key pathogenic event in the development of VIDD, but its regulation remains largely undefined. We report here that the JAK–STAT pathway is activated in MV in the human diaphragm, as evidenced by significantly increased phosphorylation of JAK and STAT. Blockage of the JAK–STAT pathway by a JAK inhibitor in a rat MV model prevents diaphragm muscle contractile dysfunction (by ~85%, p < 0.01). We further demonstrate that activated STAT3 compromises mitochondrial function and induces oxidative stress in vivo, and, interestingly, that oxidative stress also activates JAK–STAT. Inhibition of JAK–STAT prevents oxidative stress-induced protein oxidation and polyubiquitination and recovers mitochondrial function in cultured muscle cells. Therefore, in ventilated diaphragm muscle, activation of JAK–STAT is critical in regulating oxidative stress and is thereby central to the downstream pathogenesis of clinical VIDD. These findings establish the molecular basis for the therapeutic promise of JAK–STAT inhibitors in ventilated ICU patients. PMID:25286450

  9. STAT3-survivin signaling mediates a poor response to radiotherapy in HER2-positive breast cancers

    PubMed Central

    Seong, Min-Ki; Seol, Hyesil; Oh, Jeong Su; Kim, Eun-Kyu; Chang, Jong Wook; Hwang, Sang-Gu; Noh, Woo Chul

    2016-01-01

    Although radiotherapy resistance is associated with locoregional recurrence and distant metastasis in breast cancers, clinically relevant molecular markers and critical signaling pathways of radioresistant breast cancer are yet to be defined. Herein, we show that HER2-STAT3-survivin regulation is associated with radiotherapy resistance in HER2-positive breast cancers. Depletion of HER2 by siRNA sensitized HER2-positive breast cancer cells to irradiation by decreasing STAT3 activity and survivin, a STAT3 target gene, expression in HER2-positive breast cancer cells. Furthermore, inhibition of STAT3 activation or depletion of survivin also sensitized HER2-positive breast cancer cells to irradiation, suggesting that the HER2-STAT3-survivin axis is a key pathway in radiotherapy resistance of HER2-positive breast cancer cells. In addition, our clinical analysis demonstrated the association between HER2-positive breast cancers and radiotherapy resistance. Notably, we found that increased expression of phosphorylated STAT3, STAT3, and survivin correlated with a poor response to radiotherapy in HER2-positive breast cancer tissues. These findings suggest that the HER2-STAT3-survivin axis might serve as a predictive marker and therapeutic target to overcome radiotherapy resistance in HER2-positive breast cancers. PMID:26755645

  10. Integrating Immunologic Signaling Networks: The JAK/STAT Pathway in Colitis and Colitis-Associated Cancer

    PubMed Central

    Zundler, Sebastian; Neurath, Markus F.

    2016-01-01

    Cytokines are believed to be crucial mediators of chronic intestinal inflammation in inflammatory bowel diseases (IBD) such as Crohn’s disease (CD) and ulcerative colitis (UC). Many of these cytokines trigger cellular effects and functions through signaling via janus kinase (JAK) and signal transducer and activator of transcription (STAT) molecules. In this way, JAK/STAT signaling controls important events like cell differentiation, secretion of cytokines or proliferation and apoptosis in IBD in both adaptive and innate immune cells. Moreover, JAK/STAT signaling, especially via the IL-6/STAT3 axis, is believed to be involved in the transition of inflammatory lesions to tumors leading to colitis-associated cancer (CAC). In this review, we will introduce the main cellular players and cytokines that contribute to pathogenesis of IBD by JAK/STAT signaling, and will highlight the integrative function that JAK/STATs exert in this context as well as their divergent role in different cells and processes. Moreover, we will explain current concepts of the implication of JAK/STAT signaling in CAC and finally discuss present and future therapies for IBD that interfere with JAK/STAT signaling. PMID:26938566

  11. Activated STAT1 Transcription Factors Conduct Distinct Saltatory Movements in the Cell Nucleus

    PubMed Central

    Speil, Jasmin; Baumgart, Eugen; Siebrasse, Jan-Peter; Veith, Roman; Vinkemeier, Uwe; Kubitscheck, Ulrich

    2011-01-01

    The activation of STAT transcription factors is a critical determinant of their subcellular distribution and their ability to regulate gene expression. Yet, it is not known how activation affects the behavior of individual STAT molecules in the cytoplasm and nucleus. To investigate this issue, we injected fluorescently labeled STAT1 in living HeLa cells and traced them by single-molecule microscopy. We determined that STAT1 moved stochastically in the cytoplasm and nucleus with very short residence times (<0.03 s) before activation. Upon activation, STAT1 mobility in the cytoplasm decreased ∼2.5-fold, indicating reduced movement of STAT1/importinα/β complexes to the nucleus. In the nucleus, activated STAT1 displayed a distinct saltatory mobility, with residence times of up to 5 s and intermittent diffusive motion. In this manner, activated STAT1 factors can occupy their putative chromatin target sites within ∼2 s. These results provide a better understanding of the timescales on which cellular signaling and regulated gene transcription operate at the single-molecule level. PMID:22261046

  12. Autoimmunity, hypogammaglobulinemia, lymphoproliferation, and mycobacterial disease in patients with activating mutations in STAT3.

    PubMed

    Haapaniemi, Emma M; Kaustio, Meri; Rajala, Hanna L M; van Adrichem, Arjan J; Kainulainen, Leena; Glumoff, Virpi; Doffinger, Rainer; Kuusanmäki, Heikki; Heiskanen-Kosma, Tarja; Trotta, Luca; Chiang, Samuel; Kulmala, Petri; Eldfors, Samuli; Katainen, Riku; Siitonen, Sanna; Karjalainen-Lindsberg, Marja-Liisa; Kovanen, Panu E; Otonkoski, Timo; Porkka, Kimmo; Heiskanen, Kaarina; Hänninen, Arno; Bryceson, Yenan T; Uusitalo-Seppälä, Raija; Saarela, Janna; Seppänen, Mikko; Mustjoki, Satu; Kere, Juha

    2015-01-22

    The signal transducer and activator of transcription (STAT) family of transcription factors orchestrate hematopoietic cell differentiation. Recently, mutations in STAT1, STAT5B, and STAT3 have been linked to development of immunodysregulation polyendocrinopathy enteropathy X-linked-like syndrome. Here, we immunologically characterized 3 patients with de novo activating mutations in the DNA binding or dimerization domains of STAT3 (p.K392R, p.M394T, and p.K658N, respectively). The patients displayed multiorgan autoimmunity, lymphoproliferation, and delayed-onset mycobacterial disease. Immunologically, we noted hypogammaglobulinemia with terminal B-cell maturation arrest, dendritic cell deficiency, peripheral eosinopenia, increased double-negative (CD4(-)CD8(-)) T cells, and decreased natural killer, T helper 17, and regulatory T-cell numbers. Notably, the patient harboring the K392R mutation developed T-cell large granular lymphocytic leukemia at age 14 years. Our results broaden the spectrum of phenotypes caused by activating STAT3 mutations, highlight the role of STAT3 in the development and differentiation of multiple immune cell lineages, and strengthen the link between the STAT family of transcription factors and autoimmunity. PMID:25349174

  13. Chemical and Hormonal Effects on STAT5b-Dependent Sexual Dimorphism of the Liver Transcriptome.

    EPA Science Inventory

    The growth hormone (GH)-activated transcription factor signal transducer and activator of transcription 5b (STAT5b) is a key regulator of sexually dimorphic gene expression in the liver. Suppression of hepatic STAT5b signaling is associated with lipid metabolic dysfunction leadi...

  14. Autoimmunity, hypogammaglobulinemia, lymphoproliferation, and mycobacterial disease in patients with activating mutations in STAT3

    PubMed Central

    Haapaniemi, Emma M.; Kaustio, Meri; Rajala, Hanna L. M.; van Adrichem, Arjan J.; Kainulainen, Leena; Glumoff, Virpi; Doffinger, Rainer; Kuusanmäki, Heikki; Heiskanen-Kosma, Tarja; Trotta, Luca; Chiang, Samuel; Kulmala, Petri; Eldfors, Samuli; Katainen, Riku; Siitonen, Sanna; Karjalainen-Lindsberg, Marja-Liisa; Kovanen, Panu E.; Otonkoski, Timo; Porkka, Kimmo; Heiskanen, Kaarina; Hänninen, Arno; Bryceson, Yenan T.; Uusitalo-Seppälä, Raija; Saarela, Janna; Seppänen, Mikko; Kere, Juha

    2015-01-01

    The signal transducer and activator of transcription (STAT) family of transcription factors orchestrate hematopoietic cell differentiation. Recently, mutations in STAT1, STAT5B, and STAT3 have been linked to development of immunodysregulation polyendocrinopathy enteropathy X-linked–like syndrome. Here, we immunologically characterized 3 patients with de novo activating mutations in the DNA binding or dimerization domains of STAT3 (p.K392R, p.M394T, and p.K658N, respectively). The patients displayed multiorgan autoimmunity, lymphoproliferation, and delayed-onset mycobacterial disease. Immunologically, we noted hypogammaglobulinemia with terminal B-cell maturation arrest, dendritic cell deficiency, peripheral eosinopenia, increased double-negative (CD4−CD8−) T cells, and decreased natural killer, T helper 17, and regulatory T-cell numbers. Notably, the patient harboring the K392R mutation developed T-cell large granular lymphocytic leukemia at age 14 years. Our results broaden the spectrum of phenotypes caused by activating STAT3 mutations, highlight the role of STAT3 in the development and differentiation of multiple immune cell lineages, and strengthen the link between the STAT family of transcription factors and autoimmunity. PMID:25349174

  15. Ken & barbie selectively regulates the expression of a subset of Jak/STAT pathway target genes.

    PubMed

    Arbouzova, Natalia I; Bach, Erika A; Zeidler, Martin P

    2006-01-10

    A limited number of evolutionarily conserved signal transduction pathways are repeatedly reused during development to regulate a wide range of processes. Here we describe a new negative regulator of JAK/STAT signaling and identify a potential mechanism by which the pleiotropy of responses resulting from pathway activation is generated in vivo. As part of a genetic interaction screen, we have identified Ken & Barbie (Ken) , which is an ortholog of the mammalian proto-oncogene BCL6 , as a negative regulator of the JAK/STAT pathway. Ken genetically interacts with the pathway in vivo and recognizes a DNA consensus sequence overlapping that of STAT92E in vitro. Tissue culture-based assays demonstrate the existence of Ken-sensitive and Ken-insensitive STAT92E binding sites, while ectopically expressed Ken is sufficient to downregulate a subset of JAK/STAT pathway target genes in vivo. Finally, we show that endogenous Ken specifically represses JAK/STAT-dependent expression of ventral veins lacking (vvl) in the posterior spiracles. Ken therefore represents a novel regulator of JAK/STAT signaling whose dynamic spatial and temporal expression is capable of selectively modulating the transcriptional repertoire elicited by activated STAT92E in vivo. PMID:16401426

  16. Integrating Immunologic Signaling Networks: The JAK/STAT Pathway in Colitis and Colitis-Associated Cancer.

    PubMed

    Zundler, Sebastian; Neurath, Markus F

    2016-01-01

    Cytokines are believed to be crucial mediators of chronic intestinal inflammation in inflammatory bowel diseases (IBD) such as Crohn's disease (CD) and ulcerative colitis (UC). Many of these cytokines trigger cellular effects and functions through signaling via janus kinase (JAK) and signal transducer and activator of transcription (STAT) molecules. In this way, JAK/STAT signaling controls important events like cell differentiation, secretion of cytokines or proliferation and apoptosis in IBD in both adaptive and innate immune cells. Moreover, JAK/STAT signaling, especially via the IL-6/STAT3 axis, is believed to be involved in the transition of inflammatory lesions to tumors leading to colitis-associated cancer (CAC). In this review, we will introduce the main cellular players and cytokines that contribute to pathogenesis of IBD by JAK/STAT signaling, and will highlight the integrative function that JAK/STATs exert in this context as well as their divergent role in different cells and processes. Moreover, we will explain current concepts of the implication of JAK/STAT signaling in CAC and finally discuss present and future therapies for IBD that interfere with JAK/STAT signaling. PMID:26938566

  17. Unexpected oncosuppressive role for STAT3 in KRAS-induced lung tumorigenesis.

    PubMed

    Grabner, Beatrice; Moll, Herwig P; Casanova, Emilio

    2016-05-01

    Signal transducer and activator of transcription 3 (STAT3) plays a critical role in the pathogenesis of several diseases and is considered a therapeutic target in solid cancers, including lung cancer. However, we recently demonstrated a tumor suppressive function of STAT3 in kirsten rat sarcoma oncogene homolog (KRAS)-driven lung cancer. Here, we discuss these findings and their consequences. PMID:27314069

  18. At High Levels, Constitutively Activated STAT3 Induces Apoptosis of Chronic Lymphocytic Leukemia Cells.

    PubMed

    Rozovski, Uri; Harris, David M; Li, Ping; Liu, Zhiming; Wu, Ji Yuan; Grgurevic, Srdana; Faderl, Stefan; Ferrajoli, Alessandra; Wierda, William G; Martinez, Matthew; Verstovsek, Srdan; Keating, Michael J; Estrov, Zeev

    2016-05-15

    In chronic lymphocytic leukemia (CLL), the increment in PBLs is slower than the expected increment calculated from the cells' proliferation rate, suggesting that cellular proliferation and apoptosis are concurrent. Exploring this phenomenon, we found overexpression of caspase-3, higher cleaved poly (ADP-ribose) polymerase levels (p < 0.007), and a higher apoptosis rate in cells from patients with high counts compared with cells from patients with low counts. Although we previously found that STAT3 protects CLL cells from apoptosis, STAT3 levels were significantly higher in cells from patients with high counts than in cells from patients with low counts. Furthermore, overexpression of STAT3 did not protect the cells. Rather, it upregulated caspase-3 and induced apoptosis. Remarkably, putative STAT3 binding sites were identified in the caspase-3 promoter, and a luciferase assay, chromatin immunoprecipitation, and an EMSA revealed that STAT3 activated caspase-3 However, caspase-3 levels increased only when STAT3 levels were sufficiently high. Using chromatin immunoprecipitation and EMSA, we found that STAT3 binds with low affinity to the caspase-3 promoter, suggesting that at high levels, STAT3 activates proapoptotic mechanisms and induces apoptosis in CLL cells. PMID:27076684

  19. STAT3 mediates resistance to MEK inhibitor through microRNA miR-17

    PubMed Central

    Dai, Bingbing; Meng, Jieru; Peyton, Michael; Girard, Luc; Bornmann, William G.; Ji, Lin; Minna, John D.; Fang, Bingliang; Roth, Jack A.

    2012-01-01

    AZD6244 is a small molecule inhibitor of the MEK kinase pathway currently in clinical trials. However, the mechanisms mediating intrinsic resistance to MEK inhibition are not fully characterized. To define molecular mechanisms of MEK inhibitor resistance, we analyzed responses of 38 lung cancer cell lines following AZD6244 treatment and their genome-wide gene expression profiles and identified a panel of genes correlated with sensitivity or resistance to AZD6244 treatment. In particular, Ingenuity pathway analysis revealed that activation of the STAT3 pathway was associated with MEK inhibitor resistance. Inhibition of this pathway by JSI-124, a STAT3-specific small molecule inhibitor, or with STAT3-specific siRNA sensitized lung cancer cells to AZD6244 and induced apoptosis. Moreover, combining a STAT3 inhibitor with AZD6244 induced expression of BIM and polyADP-ribose polymerase (PARP) cleavage, whereas activation of the STAT3 pathway inhibited BIM expression and elicited resistance to MEK inhibitors. We found that the STAT3-regulated microRNA miR-17 played a critical role in MEK inhibitor resistance, such that miR-17 inhibition sensitized resistant cells to AZD6244 by inducing BIM and PARP cleavage. Together, these results indicated that STAT3-mediated overexpression of miR-17 blocked BIM expression and caused resistance to AZD6244. Our findings suggest novel approaches to overcome resistance to MEK inhibitors by combining AZD6244 with STAT3 or miR-17 inhibitors. PMID:21444672

  20. JAK2/STAT3 Inhibition Attenuates Noise-Induced Hearing Loss

    PubMed Central

    Wilson, Teresa; Omelchenko, Irina; Foster, Sarah; Zhang, Yuan; Shi, Xiaorui; Nuttall, Alfred L.

    2014-01-01

    Signal transducers and activators of transcription 3 (STAT3) is a stress responsive transcription factor that plays a key role in oxidative stress-mediated tissue injury. As reactive oxygen species (ROS) are a known source of damage to tissues of the inner ear following loud sound exposure, we examined the role of the Janus kinase 2 (JAK2)/STAT3 signaling pathway in noise induce hearing loss using the pathway specific inhibitor, JSI-124. Mice were exposed to a moderately damaging level of loud sound revealing the phosphorylation of STAT3 tyrosine 705 residues and nuclear localization in many cell types in the inner ear including the marginal cells of the stria vascularis, type II, III, and IV fibrocytes, spiral ganglion cells, and in the inner hair cells. Treatment of the mice with the JAK2/STAT3 inhibitor before noise exposure reduced levels of phosphorylated STAT3 Y705. We performed auditory brain stem response and distortion product otoacoustic emission measurements and found increased recovery of hearing sensitivity at two weeks after noise exposure with JAK2/STAT3 inhibition. Performance of cytocochleograms revealed improved outer hair cell survival in JSI-124 treated mice relative to control. Finally, JAK2/STAT3 inhibition reduced levels of ROS detected in outer hair cells at two hours post noise exposure. Together, these findings demonstrate that inhibiting the JAK2/STAT3 signaling pathway is protective against noise-induced cochlear tissue damage and loss of hearing sensitivity. PMID:25275304

  1. The Multifaceted Roles of STAT3 Signaling in the Progression of Prostate Cancer

    PubMed Central

    Bishop, Jennifer L.; Thaper, Daksh; Zoubeidi, Amina

    2014-01-01

    The signal transducer and activator of transcription (STAT)3 governs essential functions of epithelial and hematopoietic cells that are often dysregulated in cancer. While the role for STAT3 in promoting the progression of many solid and hematopoietic malignancies is well established, this review will focus on the importance of STAT3 in prostate cancer progression to the incurable metastatic castration-resistant prostate cancer (mCRPC). Indeed, STAT3 integrates different signaling pathways involved in the reactivation of androgen receptor pathway, stem like cells and the epithelial to mesenchymal transition that drive progression to mCRPC. As equally important, STAT3 regulates interactions between tumor cells and the microenvironment as well as immune cell activation. This makes it a major factor in facilitating prostate cancer escape from detection of the immune response, promoting an immunosuppressive environment that allows growth and metastasis. Based on the multifaceted nature of STAT3 signaling in the progression to mCRPC, the promise of STAT3 as a therapeutic target to prevent prostate cancer progression and the variety of STAT3 inhibitors used in cancer therapies is discussed. PMID:24722453

  2. Critical Role for Mast Cell Stat5 Activity in Skin Inflammation

    PubMed Central

    Ando, Tomoaki; Xiao, Wenbin; Gao, Peisong; Namiranian, Siavash; Matsumoto, Kenji; Tomimori, Yoshiaki; Hong, Hong; Yamashita, Hirotaka; Kimura, Miho; Kashiwakura, Jun-ichi; Hata, Tissa R.; Izuhara, Kenji; Gurish, Michael F.; Roers, Axel; Rafaels, Nicholas M.; Barnes, Kathleen C.; Jamora, Colin; Kawakami, Yuko; Kawakami, Toshiaki

    2015-01-01

    SUMMARY Atopic dermatitis (AD) is a chronic inflammatory skin disease. Here, we show that phospholipase C-β3 (PLC-β3)-deficient mice spontaneously develop AD-like skin lesions and more severe allergen-induced dermatitis than wild-type mice. Mast cells were required for both AD models and remarkably increased in the skin of Plcb3−/− mice because of the increased Stat5 and reduced SHP-1 activities. Mast cell-specific deletion of Stat5 gene ameliorated allergen-induced dermatitis, whereas that of Shp1 gene encoding Stat5-inactivating SHP-1 exacerbated it. PLC-β3 regulates the expression of periostin in fibroblasts and TSLP in keratinocytes, two proteins critically involved in AD pathogenesis. Furthermore, polymorphisms in PLCB3, SHP1, STAT5A, and STAT5B genes were associated with human AD. Mast cell expression of PLC-β3 was inversely correlated with that of phospho-STAT5, and increased mast cells with high levels of phospho-STAT5 were found in lesional skin of some AD patients. Therefore, STAT5 regulatory mechanisms in mast cells are important for AD pathogenesis. PMID:24412367

  3. STAT3 regulates hypoxia-induced epithelial mesenchymal transition in oesophageal squamous cell cancer

    PubMed Central

    CUI, YAO; LI, YUN-YUN; LI, JIAN; ZHANG, HONG-YAN; WANG, FENG; BAI, XUE; LI, SHAN-SHAN

    2016-01-01

    Hypoxia plays a key role in tumour initiation and metastasis; one of the mechanisms is to induce epithelial-mesenchymal transition (EMT). Signal transducer and activator of transcription 3 (STAT3) is involved in EMT by regulating the transcriptional regulators of E-cadherin, the biomarker of EMT. Until now, however, few studies have focused on the effects of STAT3 in hypoxia-induced EMT in tumour cells. The goal of this study was to investigate the roles of STAT3 in hypoxia-induced EMT in oesophageal squamous cell carcinoma (ESCC). The ESCC cells, TE-1 and EC-1, were incubated in normoxia, or in CoCl2, which was used to mimic hypoxia. With CoCl2, the ESCC cells showed increased migration and invasion abilities, accompanied with upregulation of HIF-1α, STAT3, and vimentin, and downregulation of E-cadherin. Knockdown of STAT3 inhibited EMT of ESCC cells and downregulated HIF-1α in vitro and in vivo. In ChIP assays, STAT3 bound to the promoter of HIF-1α, suggesting that STAT3 regulates transcription of HIF-1α. In conclusion, hypoxia induces EMT of ESCC, and STAT3 regulates this process by promoting HIF-1α expression. PMID:27220595

  4. Insertional Mutagenesis Identifies a STAT3/Arid1b/β-catenin Pathway Driving Neurofibroma Initiation.

    PubMed

    Wu, Jianqiang; Keng, Vincent W; Patmore, Deanna M; Kendall, Jed J; Patel, Ami V; Jousma, Edwin; Jessen, Walter J; Choi, Kwangmin; Tschida, Barbara R; Silverstein, Kevin A T; Fan, Danhua; Schwartz, Eric B; Fuchs, James R; Zou, Yuanshu; Kim, Mi-Ok; Dombi, Eva; Levy, David E; Huang, Gang; Cancelas, Jose A; Stemmer-Rachamimov, Anat O; Spinner, Robert J; Largaespada, David A; Ratner, Nancy

    2016-03-01

    To identify genes and signaling pathways that initiate Neurofibromatosis type 1 (NF1) neurofibromas, we used unbiased insertional mutagenesis screening, mouse models, and molecular analyses. We mapped an Nf1-Stat3-Arid1b/β-catenin pathway that becomes active in the context of Nf1 loss. Genetic deletion of Stat3 in Schwann cell progenitors (SCPs) and Schwann cells (SCs) prevents neurofibroma formation, decreasing SCP self-renewal and β-catenin activity. β-catenin expression rescues effects of Stat3 loss in SCPs. Importantly, P-STAT3 and β-catenin expression correlate in human neurofibromas. Mechanistically, P-Stat3 represses Gsk3β and the SWI/SNF gene Arid1b to increase β-catenin. Knockdown of Arid1b or Gsk3β in Stat3(fl/fl);Nf1(fl/fl);DhhCre SCPs rescues neurofibroma formation after in vivo transplantation. Stat3 represses Arid1b through histone modification in a Brg1-dependent manner, indicating that epigenetic modification plays a role in early tumorigenesis. Our data map a neural tumorigenesis pathway and support testing JAK/STAT and Wnt/β-catenin pathway inhibitors in neurofibroma therapeutic trials. PMID:26904939

  5. An Assessment Blueprint for EncStat: A Statistics Anxiety Intervention Program.

    ERIC Educational Resources Information Center

    Watson, Freda S.; Lang, Thomas R.; Kromrey, Jeffrey D.; Ferron, John M.; Hess, Melinda R.; Hogarty, Kristine Y.

    EncStat (Encouraged about Statistics) is a multimedia program being developed to identify and assist students with statistics anxiety or negative attitudes about statistics. This study explored the validity of the assessment instruments included in EncStat with respect to their diagnostic value for statistics anxiety and negative attitudes about…

  6. Unexpected oncosuppressive role for STAT3 in KRAS-induced lung tumorigenesis

    PubMed Central

    Grabner, Beatrice; Moll, Herwig P.; Casanova, Emilio

    2016-01-01

    ABSTRACT Signal transducer and activator of transcription 3 (STAT3) plays a critical role in the pathogenesis of several diseases and is considered a therapeutic target in solid cancers, including lung cancer. However, we recently demonstrated a tumor suppressive function of STAT3 in kirsten rat sarcoma oncogene homolog (KRAS)-driven lung cancer. Here, we discuss these findings and their consequences. PMID:27314069

  7. Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia

    PubMed Central

    Rajala, Hanna L. M.; Eldfors, Samuli; Kuusanmäki, Heikki; van Adrichem, Arjan J.; Olson, Thomas; Lagström, Sonja; Andersson, Emma I.; Jerez, Andres; Clemente, Michael J.; Yan, Yiyi; Zhang, Dan; Awwad, Andy; Ellonen, Pekka; Kallioniemi, Olli; Wennerberg, Krister; Porkka, Kimmo; Maciejewski, Jaroslaw P.; Loughran, Thomas P.; Heckman, Caroline

    2013-01-01

    Large granular lymphocytic (LGL) leukemia is characterized by clonal expansion of cytotoxic T cells or natural killer cells. Recently, somatic mutations in the signal transducer and activator of transcription 3 (STAT3) gene were discovered in 28% to 40% of LGL leukemia patients. By exome and transcriptome sequencing of 2 STAT3 mutation-negative LGL leukemia patients, we identified a recurrent, somatic missense mutation (Y665F) in the Src-like homology 2 domain of the STAT5b gene. Targeted amplicon sequencing of 211 LGL leukemia patients revealed 2 additional patients with STAT5b mutations (N642H), resulting in a total frequency of 2% (4 of 211) of STAT5b mutations across all patients. The Y665F and N642H mutant constructs increased the transcriptional activity of STAT5 and tyrosine (Y694) phosphorylation, which was also observed in patient samples. The clinical course of the disease in patients with the N642H mutation was aggressive and fatal, clearly different from typical LGL leukemia with a relatively favorable outcome. This is the first time somatic STAT5 mutations are discovered in human cancer and further emphasizes the role of STAT family genes in the pathogenesis of LGL leukemia. PMID:23596048

  8. Fludarabine-induced immunosuppression is associated with inhibition of STAT1 signaling.

    PubMed

    Frank, D A; Mahajan, S; Ritz, J

    1999-04-01

    Fludarabine is a nucleoside analog used in the treatment of hematologic malignancies that can induce severe and prolonged immunosuppression. Although it can be incorporated into the DNA of dividing cells, fludarabine is also a potent inhibitor of cells with a low growth fraction, thus it must have other mechanisms of action. STAT1, which is activated in response to many lymphocyte-activating cytokines including the interferons, is essential for cell-mediated immunity, as the absence of this protein is associated with prominent defects in the ability to control viral infections. Here we show that fludarabine, but not the immunosuppressant cyclosporine A, inhibits the cytokine-induced activation of STAT1 and STAT1-dependent gene transcription in normal resting or activated lymphocytes. Fludarabine caused a specific depletion of STAT1 protein (and mRNA) but not of other STATs. This loss of STAT1 was also seen in cells from patients treated with fludarabine in vivo. Brief exposure to fludarabine led to a sustained loss of STAT1, analogous to the prolonged period of immunosuppression induced by exposure to the drug in vivo. Thus, STAT1 may be a useful target in the development of new immunosuppressive and antineoplastic agents. PMID:10202937

  9. Spirit Movie of Phobos Eclipse, Sol 675

    NASA Technical Reports Server (NTRS)

    2005-01-01

    [figure removed for brevity, see original site] Spirit Phobos Eclipse Animation

    NASA's Mars Exploration Rover Spirit observed the Martian moon Phobos entering the shadow of Mars during the night of the rover's 675th sol (Nov. 27, 2005). The panoramic camera captured 16 images, spaced 10 seconds apart, covering the period from when Phobos was in full sunlight to when it was entirely in shadow. As with our own Moon during lunar eclipses on Earth, even when in the planet's shadow, Phobos was not entirely dark. The small amount of light still visible from Phobos is a kind of 'Mars-shine' -- sunlight reflected through Mars' atmosphere and into the shadowed region.

    This clip is a sequence of the 16 images showing the eclipse at about 10 times normal speed. It shows the movement of Phobos from left to right as the moon enters the shadow. Scientists are using information about the precise timing of Martian moon eclipses gained from observations such as these to refine calculations about the orbital path of Phobos. The precise position of Phobos will be important to any future spacecraft taking detailed pictures of the moon or landing on its surface.

  10. Dust Devils at Gusev, Sol 525

    NASA Technical Reports Server (NTRS)

    2005-01-01

    This movie clip shows several dust devils moving across the plain inside Mars' Gusev Crater. It consists of frames taken by the navigation camera on NASA's Mars Exploration Rover Spirit during the rover's 525th martian day, or sol (June 25, 2005).

    Spirit began seeing dust devil activity around the beginning of Mars' spring season. Activity increased as spring continued, but fell off again for about two weeks during a dust storm. As the dust storm faded away, dust devil activity came back. In the mid-afternoons as the summer solstice approached, dust devils were a very common occurrence on the floor of Gusev crater. The early-spring dust devils tended to move southwest-to-northeast, across the dust devil streaks in Gusev seen from orbit. Increasingly as the season progresses, the dust devils are seen moving northwest-to-southeast, in the same direction as the streaks. Scientists are watching for the big dust devils that leave those streaks. In this clip, contrast has been enhanced for anything in the images that changes from frame to frame, that is, for the dust moved by wind. The total time elapsed during the taking of these frames was 12 minutes, 25 seconds.

  11. Dust Devils at Gusev, Sol 537

    NASA Technical Reports Server (NTRS)

    2005-01-01

    This movie clip shows some distant dust devils and one closer one blowing across the floor of Mars' Gusev Crater. It consists of frames taken by the navigation camera on NASA's Mars Exploration Rover Spirit during the rover's 537th martian day, or sol (July 7, 2005).

    Spirit began seeing dust devil activity around the beginning of Mars' spring season. Activity increased as spring continued, but fell off again for about two weeks during a dust storm. As the dust storm faded away, dust devil activity came back. In the mid-afternoons as the summer solstice approached, dust devils were a very common occurrence on the floor of Gusev crater. The early-spring dust devils tended to move southwest-to-northeast, across the dust devil streaks in Gusev seen from orbit. Increasingly as the season progresses, the dust devils are seen moving northwest-to-southeast, in the same direction as the streaks. Scientists are watching for the big dust devils that leave those streaks.

    In this clip, contrast has been enhanced for anything in the images that changes from frame to frame, that is, for the dust moved by wind. The total time elapsed during the taking of these frames was 13 minutes, 46 seconds.

  12. Sol 568 Dust Devil in Gusev, Unenhanced

    NASA Technical Reports Server (NTRS)

    2005-01-01

    This movie clip shows several dust devils moving from right to left across a plain inside Mars' Gusev Crater, as seen from the vantage point of NASA's Mars Exploration Rover Spirit in hills rising from the plain. The clip consists of frames taken by Spirit's navigation camera during the rover's 543rd martian day, or sol (July 13, 2005). Unlike some other movie clips of dust devils seen by Spirit, the images in this clip have not been processed to enhance contrast of the dust devils. The total time elapsed during the taking of these frames was 12 minutes, 17 seconds.

    Spirit began seeing dust devil activity around the beginning of Mars' spring season. Activity increased as spring continued, but fell off again for about two weeks during a dust storm. As the dust storm faded away, dust devil activity came back. In the mid-afternoons as the summer solstice approached, dust devils were a very common occurrence on the floor of Gusev crater. The early-spring dust devils tended to move southwest-to-northeast, across the dust devil streaks in Gusev seen from orbit. Increasingly as the season progresses, the dust devils are seen moving northwest-to-southeast, in the same direction as the streaks. Scientists are watching for the big dust devils that leave those streaks.

  13. Sol Duc Hot Springs feasibility study

    SciTech Connect

    Not Available

    1981-12-01

    Sol Duc Springs is located in the Olympic National Park in western Washington state. Since the turn of the century, the area has served as a resort, offering hot mineral baths, lodge and overnight cabin accommodations. The Park Service, in conjunction with the concessionaire, is in the process of renovating the existing facilities, most of which are approximately 50 years old. The present renovation work consists of removing all of the existing cabins and replacing them with 36 new units. In addition, a new hot pool is planned to replace the existing one. This report explores the possibility of a more efficient use of the geothermal resource to accompany other planned improvements. It is important to note that the system outlined is based upon the resource development as it exists currently. That is, the geothermal source is considered to be: the two existing wells and the hot springs currently in use. In addition, every effort has been made to accommodate the priorities for utilization as set forth by the Park Service.

  14. Dust Devils in Gusev Crater, Sol 463

    NASA Technical Reports Server (NTRS)

    2005-01-01

    This movie clip shows a several dust devils -- whirlwinds that loft dust into the air -- moving across a plain below the hillside vantage point of NASA's Mars Exploration Rover Spirit. Several of the dust devils are visible at once in some of the frames in this sequence. The local solar time was about 2 p.m., when the ground temperature was high enough to cause turbulence that kicks up dust devils as the wind blows across the plain. The number of seconds elapsed since the first frame is indicated at lower left of the images, typically 20 seconds between frames. Spirit's navigation camera took these images on the rover's 463rd martian day, or sol (April 22, 2005.) Contrast has been enhanced for anything in the images that changes from frame to frame, that is, for the dust devil.

    Scientists expected dust devils since before Spirit landed. The landing area inside Gusev Crater is filled with dark streaks left behind when dust devils pick dust up from an area. It is also filled with bright 'hollows,' which are dust-filled miniature craters. Dust covers most of the terrain. Winds flow into and out of Gusev crater every day. The Sun heats the surface so that the surface is warm to the touch even though the atmosphere at 2 meters (6 feet) above the surface would be chilly. That temperature contrast causes convection. Mixing the dust, winds, and convection can trigger dust devils.

  15. Dust Devil in Gusev Crater, Sol 445

    NASA Technical Reports Server (NTRS)

    2005-01-01

    This movie clip shows a single dust devil -- a whirlwind that lofts dust into the air -- about 2 kilometers (1 mile) away, moving across a plain inside Mars' Gusev Crater for several minutes. The dust devil appears in 21 frames. The number of seconds elapsed since the first frame is indicated at lower left of the images, typically 20 seconds between frames. The navigation camera on NASA's Mars Exploration Rover Spirit took these images on the rover's 445th martian day, or sol (April 14, 2005.) Contrast has been enhanced for anything in the images that changes from frame to frame, that is, for the dust devil.

    Scientists expected dust devils since before Spirit landed. The landing area inside Gusev Crater is filled with dark streaks left behind when dust devils pick dust up from an area. It is also filled with bright 'hollows,' which are dust-filled miniature craters. Dust covers most of the terrain. Winds flow into and out of Gusev crater every day. The Sun heats the surface so that the surface is warm to the touch even though the atmosphere at 2 meters (6 feet) above the surface would be chilly. That temperature contrast causes convection. Mixing the dust, winds, and convection can trigger dust devils.

  16. Large Dust Devil on Horizon, Sol 468

    NASA Technical Reports Server (NTRS)

    2005-01-01

    This movie clip shows a large, distant dust devil -- a whirlwind that lofts dust into the air -- as a dark shape on the horizon near the right side of the images. This dust devil was about 5 kilometers (3 miles) away from NASA's Mars Exploration Rover Spirit, and may have been up to 200 meters or yards in diameter. Smaller dust devils closer to the rover appear bright against the dark ground. Spirit's navigation camera took these images on the rover's 468th martian day, or sol (April 27, 2005.) Contrast has been enhanced for anything in the images that changes from frame to frame, that is, for the dust devil. The number of seconds elapsed since the first frame is indicated at lower left of the images, typically 20 seconds between frames.

    Scientists expected dust devils since before Spirit landed. The landing area inside Gusev Crater is filled with dark streaks left behind when dust devils pick dust up from an area. It is also filled with bright 'hollows,' which are dust-filled miniature craters. Dust covers most of the terrain. Winds flow into and out of Gusev crater every day. The Sun heats the surface so that the surface is warm to the touch even though the atmosphere at 2 meters (6 feet) above the surface would be chilly. That temperature contrast causes convection. Mixing the dust, winds, and convection can trigger dust devils.

  17. Electrophoretic Porosimetry of Sol-Gels

    NASA Technical Reports Server (NTRS)

    Snow, L. A.; Smith, D. D.; Sibille, L.; Hunt, A. J.; Ng, J.; Rose, M. Franklin (Technical Monitor)

    2000-01-01

    It has been hypothesized that gravity has an effect on the formation and resulting microstructure of sol-gels. In order to more clearly resolve the effect of gravity, pores may be non-destructively analyzed in the wet gel, circumventing the shrinkage and coarsening associated with the drying procedure. We discuss the development of an electrophoretic technique, analogous to affinity chromatography, for the determination of pore size distribution and its application to silica gels. Specifically a monodisperse charged dye is monitored by an optical densitometer as it moves through the wet gel under the influence of an electric field. The transmittance data (output) represents the convolution of the dye concentration profile at the beginning of the run (input) with the pore size distribution (transfer function), i.e. linear systems theory applies. Because of the practical difficulty in producing a delta function input dye profile we prefer instead to use a step function. Average pore size is then related to the velocity of this dye front, while the pore size distribution is related to the spreading of the front. Preliminary results of this electrophoretic porosimetry and its application to ground and space-grown samples will be discussed.

  18. PhysBinder: Improving the prediction of transcription factor binding sites by flexible inclusion of biophysical properties.

    PubMed

    Broos, Stefan; Soete, Arne; Hooghe, Bart; Moran, Raymond; van Roy, Frans; De Bleser, Pieter

    2013-07-01

    The most important mechanism in the regulation of transcription is the binding of a transcription factor (TF) to a DNA sequence called the TF binding site (TFBS). Most binding sites are short and degenerate, which makes predictions based on their primary sequence alone somewhat unreliable. We present a new web tool that implements a flexible and extensible algorithm for predicting TFBS. The algorithm makes use of both direct (the sequence) and several indirect readout features of protein-DNA complexes (biophysical properties such as bendability or the solvent-excluded surface of the DNA). This algorithm significantly outperforms state-of-the-art approaches for in silico identification of TFBS. Users can submit FASTA sequences for analysis in the PhysBinder integrative algorithm and choose from >60 different TF-binding models. The results of this analysis can be used to plan and steer wet-lab experiments. The PhysBinder web tool is freely available at http://bioit.dmbr.ugent.be/physbinder/index.php. PMID:23620286

  19. Comment on ``Study of dielectric relaxations of anhydrous trehalose and maltose glasses'' [J. Chem. Phys. 134, 014508 (2011)

    NASA Astrophysics Data System (ADS)

    Kaminski, K.; Wlodarczyk, P.; Paluch, M.

    2011-10-01

    Very recently Kwon et al. [H.-J. Kwon, J.-A. Seo, H. K. Kim, and Y. H. Hwang, J. Chem. Phys. 134, 014508 (2011)] published an article on the study of dielectric relaxation in trehalose and maltose glasses. They carried out broadband dielectric measurements at very wide range of temperatures covering supercooled liquid as well as glassy state of both saccharides. It is worth to mention that authors have also applied a new method for obtaining anhydrous glasses of trehalose and maltose that enables avoiding their caramelization. Four relaxation processes were identified in dielectric spectra of both saccharides. The slower one was identified as structural relaxation process the next one, not observed by the others, was assigned as Johari-Goldstein (JG) β-relaxation, while the last two secondary modes were of the same nature as found by Kaminski et al. [K. Kaminski, E. Kaminska, P. Wlodarczyk, S. Pawlus, D. Kimla, A. Kasprzycka, M. Paluch, J. Ziolo, W. Szeja, and K. L. Ngai, J. Phys. Chem. B 112, 12816 (2008)]. In this comment we show that the authors mistakenly assigned the slowest relaxation process as structural mode of disaccharides. We have proven that this relaxation process is an effect of formation of thin layer of air or water between plate of capacitor and sample. The same effect can be observed if plates of capacitor are oxidized. Thus, we concluded that their slowest mode is connected to the dc conduction process while their β JG process is primary relaxation of trehalose and maltose.

  20. Bell-shaped sol-gel-sol conversions in pH-responsive worm-based nanostructured fluid.

    PubMed

    Zhang, Yongmin; An, Pengyun; Liu, Xuefeng

    2015-03-21

    A pH-switchable worm system was fabricated by simply mixing two non-surface-active compounds, N-(3-(dimethylamino)propyl)palmitamide (PMA) and citric acid (HCA), at a molar ratio of 3 : 1. Such a nanostructured fluid exhibits bell-shaped sol-gel-sol transitions with sequential pH variation, reflecting continuous structural transformations from sphere to worm to no aggregates. PMID:25675411

  1. The Inflammatory Transcription Factors NFκB, STAT1 and STAT3 Drive Age-Associated Transcriptional Changes in the Human Kidney

    PubMed Central

    O’Brown, Zach K.; Van Nostrand, Eric L.; Higgins, John P.; Kim, Stuart K.

    2015-01-01

    Human kidney function declines with age, accompanied by stereotyped changes in gene expression and histopathology, but the mechanisms underlying these changes are largely unknown. To identify potential regulators of kidney aging, we compared age-associated transcriptional changes in the human kidney with genome-wide maps of transcription factor occupancy from ChIP-seq datasets in human cells. The strongest candidates were the inflammation-associated transcription factors NFκB, STAT1 and STAT3, the activities of which increase with age in epithelial compartments of the renal cortex. Stimulation of renal tubular epithelial cells with the inflammatory cytokines IL-6 (a STAT3 activator), IFNγ (a STAT1 activator), or TNFα (an NFκB activator) recapitulated age-associated gene expression changes. We show that common DNA variants in RELA and NFKB1, the two genes encoding subunits of the NFκB transcription factor, associate with kidney function and chronic kidney disease in gene association studies, providing the first evidence that genetic variation in NFκB contributes to renal aging phenotypes. Our results suggest that NFκB, STAT1 and STAT3 underlie transcriptional changes and chronic inflammation in the aging human kidney. PMID:26678048

  2. La Piedad Michoacán Mexico Virus V protein antagonizes type I interferon response by binding STAT2 protein and preventing STATs nuclear translocation.

    PubMed

    Pisanelli, Giuseppe; Laurent-Rolle, Maudry; Manicassamy, Balaji; Belicha-Villanueva, Alan; Morrison, Juliet; Lozano-Dubernard, Bernardo; Castro-Peralta, Felipa; Iovane, Giuseppe; García-Sastre, Adolfo

    2016-02-01

    La Piedad Michoacán Mexico Virus (LPMV) is a member of the Rubulavirus genus within the Paramyxoviridae family. LPMV is the etiologic agent of "blue eye disease", causing a significant disease burden in swine in Mexico with long-term implications for the agricultural industry. This virus mainly affects piglets and is characterized by meningoencephalitis and respiratory distress. It also affects adult pigs, causing reduced fertility and abortions in females, and orchitis and epididymitis in males. Viruses of the Paramyxoviridae family evade the innate immune response by targeting components of the interferon (IFN) signaling pathway. The V protein, expressed by most paramyxoviruses, is a well-characterized IFN signaling antagonist. Until now, there were no reports on the role of the LPMV-V protein in inhibiting the IFN response. In this study we demonstrate that LPMV-V protein antagonizes type I but not type II IFN signaling by binding STAT2, a component of the type I IFN cascade. Our results indicate that the last 18 amino acids of LPMV-V protein are required for binding to STAT2 in human and swine cells. While LPMV-V protein does not affect the protein levels of STAT1 or STAT2, it does prevent the IFN-induced phosphorylation and nuclear translocation of STAT1 and STAT2 thereby inhibiting cellular responses to IFN α/β. PMID:26546155

  3. Feedback Activation of STAT3 as a Cancer Drug-Resistance Mechanism.

    PubMed

    Zhao, Chengguang; Li, Huameng; Lin, Huey-Jen; Yang, Shulin; Lin, Jiayuh; Liang, Guang

    2016-01-01

    Signal transducer and activator of transcription 3 (STAT3) plays crucial roles in several cellular processes such as cell proliferation and survival, and has been found to be aberrantly activated in many cancers. Much research has explored the leading mechanisms for regulating the STAT3 pathway and its role in promoting tumorigenesis. We focus here on recent evidence suggesting that feedback activation of STAT3 plays a prominent role in mediating drug resistance to a broad spectrum of targeted cancer therapies and chemotherapies. We highlight the potential of co-targeting STAT3 and its primary target to overcome drug resistance, and provide perspective on repurposing clinically approved drugs as STAT3 pathway inhibitors, in combination with the FDA-approved receptor tyrosine kinase (RTK) inhibitors, to improve clinical outcome of cancer treatment. PMID:26576830

  4. Targeting STAT3 signaling reduces immunosuppressive myeloid cells in head and neck squamous cell carcinoma.

    PubMed

    Bu, Lin-Lin; Yu, Guang-Tao; Deng, Wei-Wei; Mao, Liang; Liu, Jian-Feng; Ma, Si-Rui; Fan, Teng-Fei; Hall, Bradford; Kulkarni, Ashok B; Zhang, Wen-Feng; Sun, Zhi-Jun

    2016-05-01

    Cumulative evidence suggests that constitutively activated signal transducer and activator of transcription (STAT3) may contribute to sustaining immunosuppressive status, and that inhibiting STAT3 signaling represents a potential strategy to improve antitumor immunity. In the present study, we observed that high levels phosphorylated of STAT3 are significantly associated with the markers for both myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) in human head and neck squamous cell carcinoma (HNSCC). Additionally, we showed that targeting STAT3 signaling with a tolerable selective inhibitor S3I-201 significantly decreased immature myeloid cells such as MDSCs, TAMs and iDCs in genetically defined mice HNSCC model. These findings highlight that targeting STAT3 signaling may be effective to enhance antitumor immunity via myeloid suppressor cells in HNSCC. PMID:27467947

  5. STAT3/IRF1 Pathway Activation Sensitizes Cervical Cancer Cells to Chemotherapeutic Drugs.

    PubMed

    Walch-Rückheim, Barbara; Pahne-Zeppenfeld, Jennifer; Fischbach, Jil; Wickenhauser, Claudia; Horn, Lars Christian; Tharun, Lars; Büttner, Reinhard; Mallmann, Peter; Stern, Peter; Kim, Yoo-Jin; Bohle, Rainer Maria; Rübe, Christian; Ströder, Russalina; Juhasz-Böss, Ingolf; Solomayer, Erich-Franz; Smola, Sigrun

    2016-07-01

    Neoadjuvant radio/chemotherapy regimens can markedly improve cervical cancer outcome in a subset of patients, while other patients show poor responses, but may encounter severe adverse effects. Thus, there is a strong need for predictive biomarkers to improve clinical management of cervical cancer patients. STAT3 is considered as a critical antiapoptotic factor in various malignancies. We therefore investigated STAT3 activation during cervical carcinogenesis and its impact on the response of cervical cancer cells to chemotherapeutic drugs. Tyr705-phosphorylated STAT3 increased from low-grade cervical intraepithelial neoplasia (CIN1) to precancerous CIN3 lesions. Notably, pTyr705-STAT3 activation significantly declined from CIN3 to invasive cancer, also when compared in the same clinical biopsy. pTyr705-STAT3 was also low or absent in cultured human cervical cancer cell lines, consistent with the in vivo expression data. Unexpectedly, IL6-type cytokine signaling inducing STAT3 activation rendered cervical cancer cells significantly more susceptible to chemotherapeutic drugs, that is, cisplatin or etoposide. This chemosensitization was STAT3-dependent and we identified IFN regulatory factor-1 (IRF1) as the STAT3-inducible mediator required for cell death enhancement. In line with these data, pTyr705-STAT3 significantly correlated with nuclear IRF1 expression in cervical cancer in vivo Importantly, high IRF1 expression in pretreatment cervical cancer biopsy cells was associated with a significantly better response to neoadjuvant radio/chemotherapy of the patients. In summary, our study has identified a key role of the STAT3/IRF1 pathway for chemosensitization in cervical cancer. Our results suggest that pretherapeutic IRF1 expression should be evaluated as a novel predictive biomarker for neoadjuvant radio/chemotherapy responses. Cancer Res; 76(13); 3872-83. ©2016 AACR. PMID:27216197

  6. Nongenomic STAT5-dependent effects on Golgi apparatus and endoplasmic reticulum structure and function.

    PubMed

    Lee, Jason E; Yang, Yang-Ming; Liang, Feng-Xia; Gough, Daniel J; Levy, David E; Sehgal, Pravin B

    2012-03-01

    We report unexpected nongenomic functions of signal transducer and activator of transcription (STAT) 5 species in the cytoplasm aimed at preserving the structure and function of the Golgi apparatus and rough endoplasmic reticulum (ER) in vascular cells. Immunoimaging and green fluorescent protein-tagged-STAT5a protein localization studies showed the constitutive association of nonphosphorylated STAT5a, and to a lesser extent STAT5b, with the Golgi apparatus and of STAT5a with centrosomes in human pulmonary arterial endothelial and smooth muscle cells. Acute knockdown of STAT5a/b species using small interfering RNAs (siRNAs), including in the presence of an mRNA synthesis inhibitor (5,6-dichloro-1-β-d-ribofuranosylbenzimidazole), produced a dramatic phenotype within 1 day, consisting of dilatation and fragmentation of Golgi cisternae, a marked tubule-to-cyst change in the ER, increased accumulation of reticulon-4 (RTN4)/Nogo-B and atlastin-3 (ATL3) at cyst-zone boundaries, cystic separation of the outer and inner nuclear membranes, accompanied by scalloped/lunate distortion of the nucleus, with accumulation of RTN4 on convex sides of distorted nuclei. These cells showed inhibition of vesicular stomatitis virus G protein glycoprotein trafficking, mitochondrial fragmentation, and reduced mitochondrial function. STAT5a/b(-/-) mouse embryo fibroblasts also showed altered ER/Golgi dynamics. RTN4 knockdown using siRNA did not affect development of the cystic phenotype; ATL3 siRNA led to effacement of cyst-zone boundaries. In magnetic-bead cross-immunopanning assays, ATL3 bound both STAT5a and STAT5b. Remarkably, this novel cystic ER/lunate nucleus phenotype was characteristic of vascular cells in arterial lesions of idiopathic pulmonary hypertension, an unrelentingly fatal human disease. These data provide evidence of a STAT-family protein regulating the structure of a cytoplasmic organelle and implicate this mechanism in the pathogenesis of a human disease. PMID

  7. STAT3 Regulates ABCA3 Expression and Influences Lamellar Body Formation in Alveolar Type II Cells

    PubMed Central

    Matsuzaki, Yohei; Besnard, Valérie; Clark, Jean C.; Xu, Yan; Wert, Susan E.; Ikegami, Machiko; Whitsett, Jeffrey A.

    2008-01-01

    ATP-Binding Cassette A3 (ABCA3) is a lamellar body associated lipid transport protein required for normal synthesis and storage of pulmonary surfactant in type II cells in the alveoli. In this study, we demonstrate that STAT3, activated by IL-6, regulates ABCA3 expression in vivo and in vitro. ABCA3 mRNA and immunostaining were decreased in adult mouse lungs in which STAT3 was deleted from the respiratory epithelium (Stat3Δ/Δ mice). Consistent with the role of STAT3, intratracheal IL-6 induced ABCA3 expression in vivo. Decreased ABCA3 and abnormalities in the formation of lamellar bodies, the intracellular site of surfactant lipid storage, were observed in Stat3Δ/Δ mice. Expression of SREBP1a and 1c, SCAP, ABCA3, and AKT mRNAs was inhibited by deletion of Stat3 in type II cells isolated from Stat3Δ/Δ mice. The activities of PI3K and AKT were required for normal Abca3 gene expression in vitro. AKT activation induced SREBP expression and increased the activity of the Abca3 promoter in vitro, consistent with the role of STAT3 signaling, at least in part via SREBP, in the regulation of ABCA3. ABCA3 expression is regulated by IL-6 in a pathway that includes STAT3, PI3K, AKT, SCAP, and SREBP. Activation of STAT3 after exposure to IL-6 enhances ABCA3 expression, which, in turn, influences pulmonary surfactant homeostasis. PMID:18096869

  8. Constitutive activation of STAT3 in breast cancer cells: A review.

    PubMed

    Banerjee, Kasturi; Resat, Haluk

    2016-06-01

    Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in numerous cancer types, including more than 40% of breast cancers. In contrast to tight regulation of STAT3 as a latent transcription factor in normal cells, its signaling in breast cancer oncogenesis is multifaceted. Signaling through the IL-6/JAK/STAT3 pathway initiated by the binding of IL-6 family of cytokines (i.e., IL-6 and IL-11) to their receptors have been implicated in breast cancer development. Receptors with intrinsic kinase activity such as EGFR and VEGFR directly or indirectly induce STAT3 activation in various breast cancer types. Aberrant STAT3 signaling promotes breast tumor progression through deregulation of the expression of downstream target genes which control proliferation (Bcl-2, Bcl-xL, Survivin, Cyclin D1, c-Myc and Mcl-1), angiogenesis (Hif1α and VEGF) and epithelial-mesenchymal transition (Vimentin, TWIST, MMP-9 and MMP-7). These multiple modes of STAT3 regulation therefore make it a central linking point for a multitude of signaling processes. Extensive efforts to target STAT3 activation in breast cancer had no remarkable success in the past because the highly interconnected nature of STAT3 signaling introduces lack of selectivity in pathway identification for STAT3 targeted molecular therapies or because its role in tumorigenesis may not be as critical as it was thought. This review provides a full spectrum of STAT3's involvement in breast cancer by consolidating the knowledge about its role in breast cancer development at multiple levels: its differential regulation by different receptor signaling pathways, its downstream target genes, and modification of its transcriptional activity by its coregulatory transcription factors. PMID:26559373

  9. Simple diagnosis of STAT1 gain-of-function alleles in patients with chronic mucocutaneous candidiasis

    PubMed Central

    Mizoguchi, Yoko; Tsumura, Miyuki; Okada, Satoshi; Hirata, Osamu; Minegishi, Shizuko; Imai, Kohsuke; Hyakuna, Nobuyuki; Muramatsu, Hideki; Kojima, Seiji; Ozaki, Yusuke; Imai, Takehide; Takeda, Sachiyo; Okazaki, Tetsuya; Ito, Tsuyoshi; Yasunaga, Shin'ichiro; Takihara, Yoshihiro; Bryant, Vanessa L.; Kong, Xiao-Fei; Cypowyj, Sophie; Boisson-Dupuis, Stéphanie; Puel, Anne; Casanova, Jean-Laurent; Morio, Tomohiro; Kobayashi, Masao

    2014-01-01

    CMCD is a rare congenital disorder characterized by persistent or recurrent skin, nail, and mucosal membrane infections caused by Candida albicans. Heterozygous GOF STAT1 mutations have been shown to confer AD CMCD as a result of impaired dephosphorylation of STAT1. We aimed to identify and characterize STAT1 mutations in CMCD patients and to develop a simple diagnostic assay of CMCD. Genetic analysis of STAT1 was performed in patients and their relatives. The mutations identified were characterized by immunoblot and reporter assay using transient gene expression experiments. Patients' leukocytes are investigated by flow cytometry and immunoblot. Six GOF mutations were identified, three of which are reported for the first time, that affect the CCD and DBD of STAT1 in two sporadic and four multiplex cases in 10 CMCD patients from Japan. Two of the 10 patients presented with clinical symptoms atypical to CMCD, including other fungal and viral infections, and three patients developed bronchiectasis. Immunoblot analyses of patients' leukocytes showed abnormally high levels of pSTAT1 following IFN-γ stimulation. Based on this finding, we performed a flow cytometry-based functional analysis of STAT1 GOF alleles using IFN-γ stimulation and the tyrosine kinase inhibitor, staurosporine. The higher levels of pSTAT1 observed in primary CD14+ cells from patients compared with control cells persisted and were amplified by the presence of staurosporine. We developed a flow cytometry-based STAT1 functional screening method that would greatly facilitate the diagnosis of CMCD patients with GOF STAT1 mutations. PMID:24343863

  10. Activated Rac1 requires gp130 for Stat3 activation, cell proliferation and migration

    SciTech Connect

    Arulanandam, Rozanne; Geletu, Mulu; Feracci, Helene; Raptis, Leda

    2010-03-10

    Rac1 (Rac) is a member of the Rho family of small GTPases which controls cell migration by regulating the organization of actin filaments. Previous results suggested that mutationally activated forms of the Rho GTPases can activate the Signal Transducer and Activator of Transcription-3 (Stat3), but the exact mechanism is a matter of controversy. We recently demonstrated that Stat3 activity of cultured cells increases dramatically following E-cadherin engagement. To better understand this pathway, we now compared Stat3 activity levels in mouse HC11 cells before and after expression of the mutationally activated Rac1 (Rac{sup V12}), at different cell densities. The results revealed for the first time a dramatic increase in protein levels and activity of both the endogenous Rac and Rac{sup V12} with cell density, which was due to inhibition of proteasomal degradation. In addition, Rac{sup V12}-expressing cells had higher Stat3, tyrosine-705 phosphorylation and activity levels at all densities, indicating that Rac{sup V12} is able to activate Stat3. Further examination of the mechanism of Stat3 activation showed that Rac{sup V12} expression caused a surge in mRNA of Interleukin-6 (IL6) family cytokines, known potent Stat3 activators. Knockdown of gp130, the common subunit of this family reduced Stat3 activity, indicating that these cytokines may be responsible for the Stat3 activation by Rac{sup V12}. The upregulation of IL6 family cytokines was required for cell migration and proliferation induced by Rac{sup V12}, as shown by gp130 knockdown experiments, thus demonstrating that the gp130/Stat3 axis represents an essential effector of activated Rac for the regulation of key cellular functions.

  11. MicroRNA-124 suppresses growth of human hepatocellular carcinoma by targeting STAT3

    SciTech Connect

    Lu, Yanxin; Yue, Xupeng; Cui, Yuanyuan; Zhang, Jufeng; Wang, KeWei

    2013-11-29

    Highlights: •miR-124 is down-regulated in hepatocellular carcinoma HepG2 cells. •Over-expression of miR-124 suppresses proliferation and induces apoptosis in HepG2 cells. •miR-124 inhibits xenograft tumor growth in nude mice implanted with HepG2 cells by reducing STAT3 expression. •STATs function as a novel target of miR-124 in HCC HepG2 cells. -- Abstract: The aberrant expression of microRNAs is associated with development and progression of cancers. Down-regulation of miR-124 has been demonstrated in the hepatocellular carcinoma (HCC), but the underlying mechanism by which miR-124 suppresses tumorigenesis in HCC remains elusive. In this study, we found that miR-124 suppresses the tumor growth of HCC through targeting the signal transducers and activators of transcription 3 (STAT3). Overexpression of miR-124 suppressed proliferation and induced apoptosis in HepG-2 cells. Luciferase assay confirmed that miR-124 binding to the 3′-UTR region of STAT3 inhibited the expression of STAT3 and phosphorylated STAT3 proteins in HepG-2 cells. Knockdown of STAT3 by siRNA in HepG-2 cells mimicked the effect induced by miR-124. Overexpression of STAT3 in miR-124-transfected HepG-2 cells effectively rescued the inhibition of cell proliferation caused by miR-124. Furthermore, miR-124 suppressed xenograft tumor growth in nude mice implanted with HepG-2 cells by reducing STAT3 expression. Taken together, our findings show that miR-124 functions as tumor suppressor in HCC by targeting STAT3, and miR-124 may therefore serve as a biomarker for diagnosis and therapeutics in HCC.

  12. Identification, gene expression and immune function of the novel Bm-STAT gene in virus-infected Bombyx mori.

    PubMed

    Zhang, Xiaoli; Guo, Rui; Kumar, Dhiraj; Ma, Huanyan; Liu, Jiabin; Hu, Xiaolong; Cao, Guangli; Xue, Renyu; Gong, Chengliang

    2016-02-10

    Genes in the signal transducer and activator of transcription (STAT) family are vital for activities including gene expression and immune response. To investigate the functions of the silkworm Bombyx mori STAT (Bm-STAT) gene in antiviral immunity, two Bm-STAT gene isoforms, Bm-STAT-L for long form and Bm-STAT-S for short form, were cloned. Sequencing showed that the open reading frames were 2313 bp encoding 770 amino acid residues for Bm-STAT-L and 2202 bp encoding 734 amino acid residues for Bm-STAT-S. The C-terminal 42 amino acid residues of Bm-STAT-L were different from the last 7 amino acid residues of Bm-STAT-S. Immunofluorescence showed that Bm-STAT was primarily distributed in the nucleus. Transcription levels of Bm-STAT in different tissues were determined by quantitative PCR, and the results revealed Bm-STAT was mainly expressed in testes. Western blots showed two bands with molecular weights of 70 kDa and 130 kDa in testes, but no bands were detected in ovaries by using anti-Bm-STAT antibody as the primary antibody. Expression of Bm-STAT in hemolymph at 48 h post infection with B. mori macula-like virus (BmMLV) was slightly enhanced compared with controls, suggesting a weak response induced by infection with BmMLV. Hemocyte immunofluorescence showed that Bm-STAT expression was elevated in B. mori nucleopolyhedrovirus (BmNPV)-infected cells. Moreover, resistance of BmN cells to BmNPV was reduced by downregulation of Bm-STAT expression and increased by upregulation. Resistance of BmN cells to BmCPV was not significantly improved by upregulating Bm-STAT expression. Therefore, we concluded that Bm-STAT is a newly identified insect gene of the STAT family. The JAK-STAT pathway has a more specialized role in antiviral defense in silkworms, but JAK-STAT pathway is not triggered in response to all viruses. PMID:26592694

  13. Comment on “Stationary self-focusing of Gaussian laser beam in relativistic thermal quantum plasma” [Phys. Plasmas 20, 072703 (2013)

    SciTech Connect

    Habibi, M.; Ghamari, F.

    2014-06-15

    Patil and Takale in their recent article [Phys. Plasmas 20, 072703 (2013)], by evaluating the quantum dielectric response in thermal quantum plasma, have modeled the relativistic self-focusing of Gaussian laser beam in a plasma. We have found that there are some important shortcomings and fundamental mistakes in Patil and Takale [Phys. Plasmas 20, 072703 (2013)] that we give a brief description about them and refer readers to important misconception about the use of the Fermi temperature in quantum plasmas, appearing in Patil and Takale [Phys. Plasmas 20, 072703 (2013)].

  14. Comment on ``On the role of dissipation on the Casimir-Polder potential between molecules in dielectric media'' [J. Chem. Phys. 133, 164501 (2010)

    NASA Astrophysics Data System (ADS)

    Dalvit, D. A. R.; Milonni, P. W.

    2011-07-01

    J. J. Rodriguez and A. Salam [J. Chem. Phys. 133, 164501 (2010)], 10.1063/1.3495954 find discrepancies between their calculation and a previously published one [S. Spagnolo, D. A. R. Dalvit, and P. W. Milonni, Phys. Rev. A 75, 052117 (2007)], 10.1103/PhysRevA.75.052117 for the van der Waals interaction of two guest molecules in a host dielectric medium. We trace these discrepancies to what we regard as fundamental errors in the calculation by Rodriguez and Salam.

  15. Inducible STAT3 NH2 Terminal Mono-ubiquitination Promotes BRD4 Complex Formation to Regulate Apoptosis

    PubMed Central

    Ray, Sutapa; Zhao, Yingxin; Jamaluddin, Mohammad; Edeh, Chukwudi B.; Lee, Chang; Brasier, Allan R.

    2014-01-01

    Signal Transducers and Activator of Transcription-3 (STAT3) are latent transcription factors that are regulated by post-translational modifications (PTMs) in response to cellular activation by the IL-6 superfamily of cytokines to regulate cell cycle progression and/or apoptosis. Here we observe that STAT3 is inducibly mono-ubiquitinated and investigate its consequences. Using domain mapping and highly specific selected reaction monitoring- mass spectrometric assays, we identify lysine (K) 97 in its NH2-terminal domain as the major mono-ubiquitin conjugation site. We constructed a mono-ubiquitinated mimic consisting of a deubiquitinase-resistant monomeric ubiquitin fused to the NH2 terminus of STAT3 (ubiquitinated-STAT3 FP). In complex assays of ectopically expressed ubi-STAT3-FP, we observed enhanced complex formation with bromodomain -containing protein 4 (BRD4), a component of the activated positive transcriptional elongation factor (P-TEFb) complex. Chromatin immunoprecipitation experiments in STAT3+/− and STAT3−/− MEFs showed BRD4 recruitment to STAT3-dependent suppressor of cytokine signaling-3 gene (SOCS3). The effect of a selective small molecule inhibitor of BRD4, JQ1, to inhibit SOCS3 expression demonstrated the functional role of BRD4 for STAT3-dependent transcription. Additionally, ectopic ubiquitinated-STAT3 FP expression upregulated BCL2, BCL2L1, APEX1, SOD2, CCND1 and MYC expression indicating the role of ubiquitinated STAT3 in anti-apoptosis and cellular proliferation. Finally we observed that ubiquitinated-STAT3 FP suppressed TNFα-induced apoptotic cell death, indicating the functional importance of mono-ubiquitinated STAT3 in antiapoptotic gene expression. We conclude that STAT3 mono-ubiquitination is a key trigger in BRD4-dependent antiapoptotic and pro-proliferative gene expression programs. Thus, inhibiting the STAT3 mono-ubiquitination - BRD4 pathway may be a novel therapeutic target for the treatment of STAT3-dependent proliferative