bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparatively Evaluating Potential Dissertation and
Thesis Projects
Authors: Rothman Steven B.
Published: March 2008

Graduate students suffer from many pressures when writing a
dissertation. Deadlines loom, jobs are highly competitive,
publishing is always a bonus, and these are often combined with
outside research, teaching fellowships, or other occupations. In
order to finish a quality dissertation without too much wasted time
or effort it is useful for students to begin early and to think hard
about their projects in a variety of ways. Students may have a broad
conceptual interest or field interest without a focused and
tractable project. In addition to the normal practice of discussing
potential projects with advisors and mentors, there are several ways
to evaluate potential projects that may be overlooked. This essay
helps bring a good dissertation project to the front of several
potential ideas a student might have by describing several
characteristics for comparison across topics. In addition, this
essay provides a rubric by which students can develop and discuss a
project with faculty and colleagues. Without a doubt, one of the
most important aspects of preparing a dissertation project is to
discuss that project with faculty mentors and potential committee
members (Banesh 2001). Between these
discussions, or before the first discussion of potential projects,
students can spend considerable time thinking about various ideas
for their thesis or dissertation. Students approaching their project
systematically may have many projects they are considering and wish
to narrow down those projects to a manageable few before discussing
them with advisors. As a first time dissertation writer, however,
most graduate students are unaware of criteria that can be used to
evaluate and compare their ideas objectively so they can compare
several project ideas and narrow down the field. The criteria
described here combine and extend other criteria previously
developed, such as developing questions that are important in the
real world and those that contribute to scholarly literature (King,
Keohane, and Verba 1994). The criteria
described below were developed specifically for dissertation
projects, but are also very useful for students writing theses for
other purposes such as undergraduate senior projects. The guide
provided here should enable students to compare several potential
ideas objectively to begin to find a viable project. Although the
initial development of a thesis project based on a student's
theoretical or empirical interests is mostly idiosyncratic and
personal (See King, Keohane, and Verba 1994; Van Evera 1997), once a
student's interests emerge there are some common ways to objectively
evaluate several dissertation projects. This essay helps students
develop several ways to think about their dissertation projects and
create a rubric so that several projects can be evaluated on
comparable terms. Thanks to the two
anonymous reviewers and Ronald B Mitchell who made instrumental
suggestions on improving the text.
When t = 1 and N = 2:
Creating a Political Science Program at a New Research
University
Authors: Hansford Thomas G. , Nicholson Stephen P.
Published: March 2008

If you could start a political science program from scratch, how
would you do it? Given no institutional history, how would you
design graduate and undergraduate programs? How would you grow your
faculty? How would you attempt to build a reputation in the absence
of a reputation at time t-1? In an
interdisciplinary environment, with which disciplines would you work
most closely? For most political science professors, these might be
interesting hypothetical questions to consider. For the two of us,
these questions are very real and have dominated our recent work
lives as we have just finished our first year as the founding
political science faculty at the brand new University of California
campus, UC Merced. We thank Carissa
Hansford, Shawn Kantor, and Jennifer Nicholson for helpful
comments and suggestions.
Under the Influence? Intellectual Exchange in Political
Science
Authors: Carter David , Spirling Arthur
Published: March 2008

Intellectual exchange is central to progress in any discipline,
including political science. The transfer of knowledge, ideas, and
techniques takes place in many forums (e.g., advisor-student
meetings, conferences, department lounges) and it is no simple task
to systematically identify or quantify this interchange. In general
though, the fruition of a successful or insightful idea is a
published journal article or book. The way in which the author(s) of
a published piece of work acknowledges previous or contemporary work
that contributed to its development is via references or citations.
Thus, while we cannot easily keep track of the
entire process of intellectual exchange that
leads to publication, citations inform us of other (usually
published) work that influenced and contributed to the articles and
books that make up the research output of the field. We thank two anonymous referees for helpful
comments on content and structure.
Comparing Modes of Instruction: The Relative Efficacy of
On-Line and In-Person Teaching for Student Learning
Authors: Dolan Kathleen
Published: March 2008

For many faculty members, the move by universities toward greater
reliance on online and hybrid courses raises questions of course
content and quality. Many faculty, socialized to deliver information
to students in a manner described as “chalk and talk,” wonder
whether moving courses out into the online environment somehow
compromises the education students receive. In fact, there is a
small but growing body of information in political science and other
cognate disciplines that addresses these questions and offers
evidence that online courses, while different from more traditional
face-to-face classes, can offer rich learning opportunities in their
own right. This article seeks to contribute to that body of
knowledge by reporting the results of a quasi-experiment comparing
student success and satisfaction in online and face-to-face
courses. The author gratefully
acknowledges the support of the UWM Center for Instructional and
Professional Development and the assistance of Anthony Ciccone,
Connie Schroeder, and the anonymous reviewers.
Pathways from September 11: Politics, Policy, and State Sovereignty in an Age of Terror
Authors: Messina Anthony M.
Published: March 2008

My nascent book project seeks to identify and assess the effectiveness of European state strategies since September 11, 2001, to navigate the policy contradictions raised by the securitization of immigration. Framing my research is a nearly universal dilemma for politics and policy in a post-September 11 international and domestic security environment: Is the liberal state's traditional role as the guarantor of the physical safety of its citizens reconcilable with its pursuit of expansive immigration policies and inclusive immigrant incorporation policies? While I cannot answer this question definitively, I hope to illuminate the broad parameters of states' policy making freedom under the unfavorable domestic and transnational security conditions within Europe and, by extension, other advanced industrial democracies including the United States.
Blogging Congress: Technological Change and the Politics of the Congressional Press Galleries
Authors: Heaney Michael T.
Published: March 2008

New media historically have had difficulty obtaining access to the U. S. Congress. As technological changes have shifted the competitive balance among news organizations, the more established media have traditionally fought back by attempting to exclude the upstarts from the corridors of power. For example, Associate Senate Historian Donald Ritchie (1991) recounts the struggle by radio to gain a foothold against the opposition of entrenched newspapers in the 1920s and 1930s. The newspaper-controlled Standing Committee of Correspondents, which was responsible for granting credentials to the Capitol Hill Press Gallery, refused to credential radio reporters unless they also worked for newspapers. The dispute was finally settled in 1939 when Congress created a separate Radio Gallery, making Congress “the only national legislature to divide its galleries among different forms of media” (Ritchie 1991, 217). I thank Jeffrey Biggs and Jerry Gallegos for helpful suggestions. Generous financial support for this research was provided by the Congressional Fellowship Program of the American Political Science Association.
Molecular pathogenesis of intrahepatic cholestasis of pregnancy
Authors: Arrese Marco , Macias Rocio I.R. , Briz Oscar , Perez Maria J. , Marin Jose J.G.
Published: March 2008

Intrahepatic cholestasis of pregnancy (ICP) occurs mainly in the third trimester and is characterised by pruritus and elevated serum bile acid levels. ICP is associated with an increased perinatal risk and higher rates of foetal morbidity and mortality. Although the pathogenesis of this disease is unknown, a genetic hypersensitivity to female hormones (oestrogen and/or progesterone) or their metabolites is thought to impair bile secretory function. Recent data suggest that mutations or polymorphisms of genes expressing hepatobiliary transport proteins or their nuclear regulators may contribute to the development and/or severity of ICP. Unidentified environmental factors may also influence pathogenesis of the disease. This review summarises current knowledge on the potential mechanisms involved in ICP at the molecular level.
Adjuvante endokrine Therapie des Mammakarzinoms
Authors: Huober Jens , Thürlimann Beat
Published: March 2008

Standardtherapie bei der prämenopausalen hormonrezeptorpositiven Patientin ist die 5-jährige Tamoxifentherapie, die durch eine hormonablative Therapie ergänzt werden kann. Die Wertigkeit von Aromatasehemmern in Kombination mit GnRH-Analoga wird gegenwärtig im Rahmen von Studien untersucht (TEXT-Studie, ABCSG 12 Studie) und kann bei Kontraindikationen gegen Tamoxifen bei ausgewählten Patientinnen in Betracht gezogen werden. Bei der postmenopausalen hormonrezeptorpositiven Patientin beinhaltet eine optimale adjuvante endokrine Therapie zumeist den Einschluss eines Aromatasehemmers (AI). Der optimale Einsatz der Aromatasehemmer allerdings – entweder schon zu Beginn eingesetzt oder in Sequenz nach 2–3 Jahren Tamoxifen – muss momentan noch offen bleiben. Ob eine Verlängerung der endokrinen Therapie mit einem AI nach dem Einsatz eines AI in den ersten fünf Jahren von Vorteil ist, wie es nach fünf Jahren Tamoxifen beobachtet wurde, ist noch nicht geklärt. Eine 5-jährige Tamoxifentherapie kann immer noch eine sinnvolle Alternative für ausgewählte Patientinnen mit hormonrezeptorpositiver Erkrankung sein.
Der Einsatz von Trastuzumab in der adjuvanten und palliativen Therapie des Mammakarzinoms
Authors: Riemer Angelika B. , Zielinski Christoph C.
Published: March 2008

Trastuzumab ist ein humanisierter monoklonaler Antikörper, der gegen den humanen epidermal growth factor receptor-2 (HER-2/neu) gerichtet ist. Dieser Rezeptor ist in 20–30% von invasivem Brustkrebs überexprimiert, und führt dadurch zu aggressiverem Tumorwachstum. Die Bindung von Trastuzumab an den Rezeptor inhibiert über verschiedene Mechanismen das Wachstum und das Überleben der malignen Zellen. Die Effektivität und Sicherheit einer Therapie mit Trastuzumab, vor allem in Kombination mit verschiedenen Chemotherapien, ist in vielen klinischen Studien gezeigt worden. Die wichtigste Nebenwirkung ist die mögliche Entwicklung einer Kardiomyopathie, welche allerdings selten auftritt. Daher sollte jede Patientin, deren Tumor HER-2/neu überexprimiert oder eine HER-2/neu Genamplifikation aufweist, die Option einer Trastuzumab-Therapie erhalten. Dieser Artikel beleuchtet die wichtigsten Studienergebnisse und diskutiert das aktuelle Wissen über einen optimalen Einsatz des Antikörpers.
Schwangerschaftsassoziiertes Mammakarzinom
Authors: Eisenbrand Marie Christin , Wight Edward , Güth Uwe , Zanetti-Dällenbach Rosanna
Published: March 2008

Die Inzidenz des Mammakarzinoms in der Schwangerschaft beträgt 1:3000. Entgegen früherer Empfehlungen ist dies kein Grund mehr für einen Schwangerschaftsabbruch. Aufgrund schwangerschaftsbedingter Gewebsveränderungen der Brust wird die Diagnose häufig mit Verzögerung gestellt. Prinzipiell gilt, dass ein Knoten in der Brust während der Schwangerschaft genau gleich abgeklärt werden sollte wie außerhalb der Schwangerschaft. Die operative Therapie besteht in der Regel aus der Mastektomie sowie der axillären Lymphonodektomie, wobei im letzten Trimenon auch brusterhaltende Techniken angewandt werden können, gefolgt von einer adjuvanten Radiotherapie postpartum. Eine Chemotherapie kann im zweiten und dritten Trimenon relativ sicher erfolgen. Von einer Radio- sowie einer Hormontherapie sollte in der Schwangerschaft abgesehen werden. Schwangerschaftsbetreuung und Tumorbehandlung sollten in einem Zentrum mit der Möglichkeit der interdisziplinären Zusammenarbeit erfolgen.
Hormontherapie in der Peri- und Postmenopause und Mammakarzinom-Risiko
Authors: Buchholz Stefan , Horn Felicitas , Ortmann Olaf
Published: March 2008

Die Hormontherapie (HT) in Peri- und Postmenopause mit Östrogenen und Gestagenen ist mit einem erhöhten Mammakarzinomrisiko assoziiert. Hormone spielen eine wichtige Rolle im Entstehungsprozess dieser malignen Erkrankung. Für das Risiko, ein Mammakarzinom zu entwickeln, haben reproduktive Faktoren einen relevanten Einfluss. Die Anwendung von Sexualsteroiden im Rahmen einer HT stellt einen potentiellen Risikofaktor dar. Zu der Fragestellung wurden in den letzten Jahren eine Reihe von Beobachtungs- und randomisierten Studien publiziert. Diese Übersicht gibt einen Überblick der derzeitigen Datenlage zu diesem Thema.
Genetische Beratung beim familiären Mammakarzinom
Authors: Pichert Gabriella
Published: March 2008

Er wird zur Zeit geschätzt, dass 25–30% aller Mammakarzinome einen familiären Hintergrund haben. Das Brustkrebslebenszeitrisiko erstgradig Verwandter mit einer Mammakarzinom-Familienanamnese kann je nach genetischem Hintergrund gegenüber dem Bevölkerungsrisiko als leicht, mäßig oder stark erhöht eingeschätzt werden. Individuen aus Familien mit stark erhöhtem Brustkrebsrisiko sollten eine genetische Beratung und Testung angeboten bekommen. In der folgenden Übersicht werden die Elemente der genetischen Beratung und Testung und das Management von Familien mit vererbtem Brust- und Eierstockkrebsrisiko besprochen.
Längsschnittstudie zur Belastung pflegender Angehöriger von demenziell Erkrankten (LEANDER)
Authors: Zank Susanne , Schacke Claudia , Leipold Bernhard
Published: March 2008

Im Rahmen der Längsschnittstudie zur Belastung pflegender Angehöriger demenziell Erkrankter (LEANDER) wurde ein Erhebungsinventar entwickelt, das sich zur Beschreibung differenzieller Belastungsverläufe und zur Evaluation von Interventionen eignet. Das Berliner Inventar zur Angehörigenbelastung (BIZA-D) besteht aus 20 Subskalen mit 88 Items. Hiermit wurde die Wirksamkeit von drei Entlastungsangeboten für die pflegenden Angehörigen demenzkranker Patienten evaluiert. Es konnte gezeigt werden, dass gerontopsychiatrische Tagespflege (1) eine wirksame Entlastung bezüglich ausgewählter Belastungsdimensionen darstellt. Hilfreich war die Intervention in Bezug auf die subjektive Belastung durch Aggressivität und Widerstand, Verwirrtheit und Desorientiertheit des Pflegebedürftigen sowie hinsichtlich der Belastung durch persönliche Einschränkungen. Für die Leistung von ambulanten Pflegediensten (2) konnten signifikante Effekte im Bereich der objektiven Betreuungsaufgaben (basale Pflegeaufgaben und Anleiten und Motivieren) nachgewiesen werden. Für die Nutzung von Gesprächsgruppen (3) ließen sich Effekte weder für objektive Betreuungsaufgaben, noch für die subjektive Belastung belegen.
Demenzservicestellen der M.A.S Alzheimerhilfe Österreich
Authors: Auer Stefanie , Span Edith , Donabauer Yvonne , Reitner Maria , Helm Gerlinde
Published: March 2008

Die Wirksamkeit nicht-pharmakologischer (psychosozialer) Behandlungsmethoden konnten in wissenschaftlichen Untersuchungen gezeigt werden. Methoden der Angehörigenunterstützung können frühzeitige Institutionalisierung verhindern. Förderprogramme für Personen mit Demenz können helfen, Fähigkeiten länger zu erhalten und die Leistungsfähigkeit zu optimieren sowie die Lebensqualität trotz chronischem Verlauf der Krankheit zu erhalten. Flächendeckende Behandlungsstrukturen, welche spezialisiert sind, komplexe nicht-pharmakologische Behandlungen sowohl für Angehörige als auch für Betroffene anzubieten, sind noch selten. Der Vorteil derart spezialisierter Einrichtungen ist es, dass sie Angebote zur Verfügung stellen, die niederschwellig angelegt sind und somit eine frühzeitige Erkennung der Krankheit ermöglichen. Gleichzeitig bieten sie ideale Umgebungen für wissenschaftliche Studien und für die Entwicklung dringend benötigter Praxiskonzepte. Die M.A.S Alzheimerhilfe hat eine Behandlungsstruktur entwickelt, welche psychosoziale Unterstützung sowohl für den Betroffenen als auch für den Angehörigen bietet. Ergebnisse einer ersten Strukturanalyse werden präsentiert.
Demenzkranke Menschen begleiten – pflegende Angehörige entlasten
Authors: Lischka Barbara
Published: March 2008

Im Rahmen des § 45c SGB XI betreuen freiwillige Helferinnen und Helfer stundenweise demenzkranke Menschen, um so deren pflegende Angehörige zu entlasten. Um den Herausforderungen dieser Tätigkeit gewachsen zu sein, benötigen Freiwillige eine gründliche Vorbereitung sowie eine umfassende Begleitung. Am Fallbeispiel einer freiwilligen Helferin, die eine alleinlebende demenzkranke Frau betreut, wird aufgezeigt, dass diese über Wissen über das Krankheitsbild einer Demenz sowie über fachliche und methodische Kompetenz in Bezug auf den Umgang mit demenzkranken Menschen verfügen muss. Kommt hierzu persönliche Kompetenz, in diesem Fall die Fähigkeit, die eigenen Vorstellungen von Sauberkeit und Hygiene hintanzustellen und sich emotional auf die Welt der demenzkranken Frau einzulassen, so kann die soziale Betreuung demenzkranker Menschen durch freiwillige Helferinnen und Helfer gelingen.
Gestörte Kommunikation bei Demenz aus Sicht der pflegenden Angehörigen
Authors: Engel S.
Published: March 2008

Am Gedächtnis-Zentrum Erlangen wurden mit 20 pflegenden Angehörigen von Demenzkranken problemzentrierte Interviews geführt. Das Forschungsthema, zu dem die Befragten um detaillierte Auskunft gebeten wurden, bezog sich auf mögliche Konfliktsituationen zwischen ihnen und ihren demenzkranken Familienangehörigen und mögliche Veränderungen im Umgang miteinander seit Auftreten der demenzielle Erkrankung. Es zeigte sich, dass die Befragten bei der Bearbeitung des Forschungsthemas von einer Vielzahl von gestörten Kommunikationsprozessen berichten. Außerdem wurde deutlich, dass es sich bei diesen gestörten Kommunikationsprozessen nicht nur um Störungen der linguistischen Sprachverarbeitung des Demenzkranken handelt, sondern auch andere Bedingungen gelingender Kommunikation gestört sind. Unter Rückgriff auf Elemente der universalpragmatischen Kommunikationstheorie von Habermas (1976 ) und der sprachphilosophischen Theorie des Symbolischen Interaktionismus ( Mead, 1991 ) konnte – entsprechend des Verfahrens der Grounded Theory – aus den empirischen Daten eine Theorie generiert werden, die die Störungen der Grundvoraussetzungen gelingender Kommunikation im Kontext von Demenz differenziert beschreibt.
Reading About Persons: The Effects of Conjunctions on the Mental Representation of Person Descriptions
Authors: Krolak-Schwerdt Sabine , Wintermantel Margret , Junker Nadine , Kneer Julia
Published: March 2008

Three experiments investigated the processing of person descriptions that consisted of a number of statements about the characteristics of a person. In one condition, each statement referred to a single person attribute and in the other condition, causal and additive conjunctions to verbally link the statements were introduced. Evidence was found that the introduction of verbal links enhanced participants’ memory about the characteristics of the described person. On-line measures of processing showed that the comprehension of person information was strongly facilitated by the introduction of verbal links. Furthermore, the results were due to the introduction of causal connections between person attributes. These findings are discussed in terms of their implications for models of person memory and representation.
Exploring the Multidimensional Facets of Authoritarianism: Authoritarian Aggression and Social Dominance Orientation
Authors: Passini Stefano
Published: March 2008

The relation between authoritarianism and social dominance orientation was analyzed, with authoritarianism measured using a three-dimensional scale. The implicit multidimensional structure (authoritarian submission, conventionalism, authoritarian aggression) of Altemeyer’s (1981, 1988) conceptualization of authoritarianism is inconsistent with its one-dimensional methodological operationalization. The dimensionality of authoritarianism was investigated using confirmatory factor analysis in a sample of 713 university students. As hypothesized, the three-factor model fit the data significantly better than the one-factor model. Regression analyses revealed that only authoritarian aggression was related to social dominance orientation. That is, only intolerance of deviance was related to high social dominance, whereas submissiveness was not.
Diagnostik von Persönlichkeitsstörungen im Jugendalter nach SKID-II
Authors: Salbach-Andrae H. , Bürger A. , Klinkowski N. , Lenz K. , Pfeiffer E. , Fydrich T. , Lehmkuhl U.
Published: March 2008

Zusammenfassung: Fragestellung: Ziel der vorliegenden Untersuchung war eine Überprüfung der Anwendbarkeit des Strukturierten Klinischen Interviews für DSM-IV, Achse II: Persönlichkeitsstörungen (SKID-II) im Jugendalter sowie eine Untersuchung zur Übereinstimmung zwischen SKID-II Diagnosen und klinischem Urteil. Zusätzlich wurde der Frage nachgegangen, welche Faktoren bei Patientinnen einer jugendpsychiatrischen Inanspruchnahmepopulation Persönlichkeitsstörungen (PS) prognostizieren. Methodik: Insgesamt wurden 110 stationär behandelte, jugendpsychiatrische Patienten im Alter von 14-18 Jahren mit dem SKID-II und dem Persönlichkeitsstil- und Störungsinventar (PSSI) untersucht. Ergebnisse: 32.7% der untersuchten Patienten zeigten nach SKID-II die Diagnose einer PS. Die Übereinstimmung zwischen kategorialem Urteil (PS liegt vor versus PS liegt nicht vor) des SKID-II und der klinischen Diagnose erwies sich insgesamt als niedrig. Lediglich für die histrionische PS und für die Borderline-PS ergaben sich annehmbare bis sehr gute Übereinstimmungen. Logistische Regressionsanalysen identifizierten «Anorexia nervosa (bulimisch)», «einfache Aktivitäts- und Aufmerksamkeitsstörung/Störung des Sozialverhaltens (ADHD/SSV)» und «Schicht» als relevante prognostische Faktoren für PS. Schlussfolgerungen: Das SKID-II, das primär für Erwachsene entwickelt wurde, ist für den Gebrauch bei Jugendlichen gut einsetzbar. Im jugendpsychiatrischen Bereich sind die Diagnosen Anorexia nervosa (bulimisch) und ADHD/SSV eng mit der Entwicklung einer PS assoziiert.
Zur Versorgung von Menschen mit Intelligenzminderung und psychischen Störungen in den Kliniken für Kinder- und Jugendpsychiatrie/Psychotherapie in Deutschland - Ergebnisse einer Fragebogenuntersuchung
Authors: Hennicke Klaus
Published: March 2008

Zusammenfassung: Fragestellung: Versorgungssituation geistig behinderter Kindern und Jugendlichen mit psychischen Auffälligkeiten durch die Kliniken der Kinder- und Jugendpsychiatrie in Deutschland im Jahre 2003. Methodik: Postalische Befragung aller Kinder- und Jugendpsychiatrischen Kliniken (N = 136); 68 überwiegend geschlossene Fragen mit Antwortvorgaben; Rücklauf: 54,4%. Ergebnisse: Der durchschnittliche Anteil geistig behinderter Patienten liegt ambulant wie stationär bei 6%. N = 6 (8%) verfügen über ein spezialisiertes ambulantes und stationäres Angebot, N = 4 (5%) haben entweder nur eine entsprechende Station oder eine Spezialambulanz. Die Versorgung erfolgt überwiegend nur im Rahmen der kinder- und jugendpsychiatrischen Grundversorgung. Diagnostik und Therapie erfolgen nach den üblichen Standards des Fachgebietes. Die übermäßige Verwendung von Psychopharmaka ist nicht nachweisbar. Auf einer Schulnotenskala wird die ambulante wie stationäre Versorgung mit etwas schlechter als 4, die psychotherapeutische Versorgung als mangelhaft (Note: 5) bewertet. 83% der Klinikchefs fordern spezialisierte Schwerpunktkliniken in jedem Bundesland. Schlussfolgerungen: Die insgesamt defizitäre Versorgungssituation wurde bestätigt. Mit den wenigen Schwerpunktkliniken und -ambulanzen ist selbst eine annehmbar überregionale Versorgungsstruktur nicht zu leisten. Die versorgungspolitische Forderung der Klinikleitungen ist insofern eindeutig, diesen Mangel durch spezialisierte Kliniken und Ambulanzen aufzuheben. Die Qualität der Diagnostik und Behandlung genügt offensichtlich den fachlichen und ethischen Standards der Kinder- und Jugendpsychiatrie. Umgekehrt sind die oftmals sehr schwierigen diagnostischen und therapeutischen Probleme grundsätzlich mit den Methoden unseres Fachgebiets lösbar.
Langwirksame Medikamente zur Behandlung der hyperkinetischen Störungen 1bearbeitete deutsche Version von Banaschewski et al., Long-acting medications for the hyperkinetic disorders; Eur Child Adolesc Psychiatry (2006); mit freundlicher Genehmigung des Springer-Verlags.
Authors: Banaschewski Tobias , Coghill David , Santosh Paramala , Zuddas Alessandro , Asherson Philip , Buitelaar Jan , Danckaerts Marina , Döpfner Manfred , Faraone Stephen V. , Rothenberger Aribert , Sergeant Joseph , Steinhausen Hans-Christoph , Sonuga-Barke Edmund J.S. , Taylor Eric
Published: March 2008

Zusammenfassung: Ein Expertengremium aus mehreren europäischen Ländern hat sämtliche verfügbaren veröffentlichten und unveröffentlichten Studienergebnisse zum Einsatz von langwirksamen Medikamenten bei ADHS und hyperkinetischer Störung analysiert und auf dieser Grundlage Empfehlungen zur praktischen Anwendung dieser Arzneimittel entwickelt: Auf der Grundlage der Analyse wurde gefolgert: (1) Langwirksame Präparate sollten zugelassen sein und eingesetzt werden; (2) Sie sollen kurzwirksame Arzneimittel (aus Kostengründen und wegen der höheren Flexibilität der Dosierung) nicht vollständig ersetzen. Individuelle Therapieoptionen sind erforderlich. (3) Sowohl ATX als auch Stimulanzien mit retardierter Freisetzung sollten zur Verfügung stehen. Zusätzlich werden ausführliche Empfehlungen gegeben, nach welchen Kriterien ein spezifisches Präparat für den individuellen Patienten ausgewählt werden sollte.
Langwirksame Medikamente zur Behandlung der hyperkinetischen Störungen 1bearbeitete deutsche Version von Banaschewski et al., Long-acting medications for the hyperkinetic disorders; Eur Child Adolesc Psychiatry (2006); mit freundlicher Genehmigung des Springer-Verlags.
Authors: Banaschewski Tobias , Coghill David , Santosh Paramala , Zuddas Alessandro , Asherson Philip , Buitelaar Jan , Danckaerts Marina , Döpfner Manfred , Faraone Stephen V. , Rothenberger Aribert , Sergeant Joseph , Steinhausen Hans-Christoph , Sonuga-Barke Edmund J.S. , Taylor Eric
Published: March 2008

Zusammenfassung: Ein Expertengremium aus mehreren europäischen Ländern hat sämtliche verfügbaren veröffentlichten und unveröffentlichten Studienergebnisse zum Einsatz von langwirksamen Medikamenten bei ADHS und hyperkinetischer Störung analysiert und auf dieser Grundlage praktische Empfehlungen zum Einsatz dieser Arzneimittel entwickelt. Im vorliegenden Artikel werden die Ergebnisse dieser Analyse dargestellt, in der die Wirksamkeit von Stimulanzien mit retardierter Freisetzung und Atomoxetin (ATX) anhand ihrer Effektstärken und der Anzahl der notwendigen Behandlungen (Numbers-Needed-to-Treat) verglichen werden. Auf der Grundlage der Analyse wurde gefolgert, (1) Langwirksame Präparate sollten zugelassen sein und eingesetzt werden; (2) Sie sollten kurzwirksame Arzneimittel (aus Kostengründen und wegen der höheren Flexibilität der Dosierung) nicht vollständig ersetzen. Individuelle Therapieoptionen sind erforderlich. (3) Sowohl ATX als auch Stimulanzien mit retardierter Freisetzung sollten zur Verfügung stehen.
‘Insulator bodies’ are aggregates of proteins but not of insulators
Authors: Golovnin Anton , Melnikova Larisa , Volkov Ilya , Kostuchenko Margarita , Galkin Alexander V , Georgiev Pavel
Published: March 2008

Chromatin insulators are thought to restrict the action of enhancers and silencers. The best‐known insulators in Drosophila require proteins such as Suppressor of Hairy wing (Su(Hw)) and Modifier of mdg4 (Mod(mdg4)) to be functional. The insulator‐related proteins apparently colocalize as nuclear speckles in immunostained cells. It has been asserted that these speckles are ‘insulator bodies’ of many Su(Hw)–insulator DNA sites held together by associated proteins, including Mod(mdg4). As we show here using flies, larvae and S2 cells, a mutant Mod(mdg4) protein devoid of the Q‐rich domain supports the function of Su(Hw)‐dependent insulators and efficiently binds to correct insulator sites on the chromosome, but does not form or enter the Su(Hw)‐marked nuclear speckles; conversely, the latter accumulate another (C‐truncated) Mod(mdg4) mutant that cannot interact with Su(Hw) or with the genuine insulators. Hence, it is not the functional genomic insulators but rather aggregated proteins that make the so‐called ‘insulator bodies’.
NMD resulting from encephalomyocarditis virus IRES‐directed translation initiation seems to be restricted to CBP80/20‐bound mRNA
Authors: Woeller Collynn F , Gaspari Martina , Isken Olaf , Maquat Lynne E
Published: March 2008

Nonsense‐mediated messenger RNA decay (NMD) generally degrades mRNAs that prematurely terminate translation as a means of quality control. NMD in mammalian cells targets newly spliced mRNA that is bound by the cap‐binding protein heterodimer CBP80/20 and one or more post‐splicing exon junction complexes during a pioneer round of translation. NMD targets mRNA that initiates translation using the encephalomyocarditis virus (EMCV) internal ribosome entry site (IRES), therefore NMD might target not only CBP80/20‐bound mRNA but also its remodelled product, eIF4E‐bound mRNA. Here, we provide evidence that NMD triggered by translation initiation at the EMCV IRES, similar to NMD triggered by translation initiation at an mRNA cap, targets CBP80/20‐bound mRNA but does not detectably target eIF4E‐bound mRNA. We show that EMCV IRES‐initiated translation undergoes a CBP80/20‐associated pioneer round of translation that results in CBP80/20‐dependent and Upf factor‐dependent NMD when translation terminates prematurely.
SRP-27 is a novel component of the supramolecular signalling complex involved in skeletal muscle excitation–contraction coupling
Authors: Bleunven Christophe , Treves Susan , Jinyu Xia , Leo Elisa , Ronjat Michel , De Waard Michel , Kern Georg , Flucher Bernhard E. , Zorzato Francesco
Published: March 2008

SRP-27 (sarcoplasmic reticulum protein of 27 kDa) is a newly identified integral membrane protein constituent of the skeletal muscle SR (sarcoplasmic reticulum). We identified its primary structure from cDNA clones isolated from a mouse skeletal muscle cDNA library. ESTs (expressed sequence tags) of SRP-27 were found mainly in cDNA libraries from excitable tissues of mouse. Western blot analysis confirmed the expression of SRP-27 in skeletal muscle and, to a lower extent, in heart and brain. Mild trypsin proteolysis combined with primary-structure prediction analysis suggested that SRP-27 has four transmembrane-spanning alpha helices and its C-terminal domain faces the cytoplasmic side of the endo(sarco)plasmic reticulum. The expression of SRP-27 is higher in fast twitch skeletal muscles compared to slow twitch muscles and peaks during the first month of post-natal development. High-resolution immunohistochemistry and Western blot analysis of subcellular fractions indicated that SRP-27 is distributed in both longitudinal tubules and terminal cisternae of the SR, as well as in the perinuclear membrane systems and the nuclear envelope of myotubes and adult fibres. SRP-27 co-sediments with the RyR (ryanodine receptor) macromolecular complex in high-salt sucrose-gradient centrifugation, and is pulled-down by anti-RyR as well as by maurocalcin, a well characterized RyR modulator. Our results indicate that SRP-27 is part of a SR supramolecular complex, suggesting the involvement of SRP-27 in the structural organization or function of the molecular machinery underlying excitation–contraction coupling.
Identification and function of phosphorylation in the glucose-regulated transcription factor ChREBP
Authors: Tsatsos Nikolas G. , Davies Michael N. , O'callaghan Brennon L. , Towle Howard C.
Published: March 2008

In the liver, induction of genes encoding enzymes involved in de novo lipogenesis occurs in response to increased glucose metabolism. ChREBP (carbohydrate-response-element-binding protein) is a basic helix–loop–helix/leucine zipper transcription factor that regulates expression of these genes. To evaluate the potential role of ChREBP phosphorylation in its regulation, we used MS to identify modified residues. In the present paper, we report the detection of multiple phosphorylation sites of ChREBP expressed in hepatocytes, several of which are only observed under high-glucose conditions. Mutation of each of these serine/threonine residues of ChREBP did not alter its ability to respond to glucose. However, mutation of five N-terminal phosphoacceptor sites resulted in a major decrease in activity under high-glucose conditions. These phosphorylated residues are located within a region of ChREBP (amino acids 1–197) that is critical for glucose regulation. Mutation of Ser56 within this region to an aspartate residue resulted in increased nuclear accumulation and activity under high-glucose conditions. Together, these data suggest that ChREBP activity is regulated by complex multisite phosphorylation patterns involving its N-terminal regulatory region.
Accumulation of 15-deoxy-Δ12,14-prostaglandin J2 adduct formation with Keap1 over time: effects on potency for intracellular antioxidant defence induction
Authors: Oh Joo Yeun , Giles Niroshini , Landar Aimee , Darley-Usmar Victor
Published: March 2008

The COX (cyclo-oxygenase) pathway generates the reactive lipid electrophile 15d-PGJ2 (15-deoxy-Δ12,14-prostaglandin J2), which forms covalent protein adducts that modulate cell signalling pathways. It has been shown that this regulates important biological responses, including protection against oxidative stress, and supports the proposal that 15d-PGJ2 has pharmacological potential. Protective pathways activated by 15d-PGJ2 include those controlling the synthesis of the intracellular antioxidants GSH and the enzyme HO-1 (haem oxygenase-1). The induction of the synthesis of these intracellular antioxidants is, in large part, regulated by covalent modification of Keap1 (Kelch-like erythroid cell-derived protein with cap‘n’collar homology-associated protein 1) by the lipid and the subsequent activation of the EpRE (electrophile-response element). For the first time, we show that the potency of 15d-PGJ2 as a signalling molecule in endothelial cells is significantly enhanced by the accumulation of the covalent adduct with 15d-PGJ2 and endogenous Keap1 over the time of exposure to the prostaglandin. The consequence of this finding is that signalling initiated by electrophilic lipids differs from agonists that do not form covalent adducts with proteins because the constant generation of very low concentrations of 15d-PGJ2 can lead to induction of GSH or HO-1. In the course of these studies we also found that a substantial amount (97–99%) of exogenously added 15d-PGJ2 is inactivated in the medium and does not enter the cells to initiate cell signalling. In summary, we propose that the accumulation of covalent adduct formation with signalling proteins provides a mechanism through which endogenous intracellular formation of electrophilic lipids from COX can exert an anti-inflammatory effect in vivo.
Two interaction sites on mammalian adenylyl cyclase type I and II: modulation by calmodulin and Gβγ
Authors: Diel Susanne , Beyermann Michael , Lloréns Juana María Navarro , Wittig Burghardt , Kleuss Christiane
Published: March 2008

Mammalian ACs (adenylyl cyclases) are integrating effector molecules in signal transduction regulated by a plethora of molecules in either an additive, synergistic or antagonistic manner. Out of nine different isoforms, each AC subtype uses an individual set of regulators. In the present study, we have used chimaeric constructs, point mutations and peptide competition studies with ACs to show a common mechanism of multiple contact sites for the regulatory molecules Gβγ and calmodulin. Despite their chemical, structural and functional variety and different target motifs on AC, Gβγ and calmodulin share a two-site-interaction mechanism with Gαs and forskolin to modulate AC activity. Forskolin and Gαs are known to interact with both cytosolic domains of AC, from inside the catalytic cleft as well as at the periphery. An individual interaction site located at C1 of the specifically regulated AC subtype had been ascribed for both Gβγ and calmodulin. In the present study we now show for these two regulators of AC that a second isoform- and regulator-specific contact site in C2 is necessary to render enzyme activity susceptible to Gβγ or calmodulin modulation. In addition to the PFAHL motif in C1b of ACII, Gβγ contacts the KF loop in C2, whereas calmodulin requires not only the Ca2+-independent AC28 region in C1b but also a Ca2+-dependent domain in C2a of ACI containing the VLG loop to stimulate this AC isoform.
Human PDE4A8, a novel brain-expressed PDE4 cAMP-specific phosphodiesterase that has undergone rapid evolutionary change
Authors: Mackenzie Kirsty F. , Topping Emma C. , Bugaj-Gaweda Bozena , Deng Chengjun , Cheung York-Fong , Olsen Aileen E. , Stockard Cecil R. , High Mitchell Lisa , Baillie George S. , Grizzle William E. , De Vivo Michael , Houslay Miles D. , Wang Daguang , Bolger Graeme B.
Published: March 2008

We have isolated cDNAs encoding PDE4A8 (phosphodiesterase 4 isoform A8), a new human cAMP-specific PDE4 isoform encoded by the PDE4A gene. PDE4A8 has a novel N-terminal region of 85 amino acids that differs from those of the related ‘long’ PDE4A4, PDE4A10 and PDE4A11 isoforms. The human PDE4A8 N-terminal region has diverged substantially from the corresponding isoforms in the rat and other mammals, consistent with rapid evolutionary change in this region of the protein. When expressed in COS-7 cells, PDE4A8 localized predominantly in the cytosol, but approx. 20% of the enzyme was associated with membrane fractions. Cytosolic PDE4A8 was exquisitely sensitive to inhibition by the prototypical PDE4 inhibitor rolipram (IC50 of 11±1 nM compared with 1600 nM for PDE4A4), but was less sensitive to inhibition by cilomilast (IC50 of 101±7 nM compared with 61 nM for PDE4A4). PDE4A8 mRNA was found to be expressed predominantly in skeletal muscle and brain, a pattern that differs from the tissue expression of other human PDE4 isoforms and also from that of rat PDE4A8. Immunohistochemical analysis showed that PDE4A8 could be detected in discrete regions of human brain, including the cerebellum, spinal cord and cerebral cortex. The unique tissue distribution of PDE4A8, combined with the evolutionary divergence of its N-terminus, suggest that this isoform may have a specific function in regulating cAMP levels in human skeletal muscle and brain.
A dominant-negative ESCRT-III protein perturbs cytokinesis and trafficking to lysosomes
Authors: Dukes Joseph D. , Richardson Judith D. , Simmons Ruth , Whitley Paul
Published: March 2008

In eukaryotic cells, the completion of cytokinesis is dependent on membrane trafficking events to deliver membrane to the site of abscission. Golgi and recycling endosomal-derived proteins are required for the terminal stages of cytokinesis. Recently, protein subunits of the ESCRT (endosomal sorting complexes required for transport) that are normally involved in late endosome to lysosome trafficking have also been implicated in abscission. Here, we report that a subunit, CHMP3 (charged multivesicular body protein-3), of ESCRT-III localizes at the midbody. Deletion of the C-terminal autoinhibitory domain of CHMP3 inhibits cytokinesis. At the midbody, CHMP3 does not co-localize with Rab11, suggesting that it is not present on recycling endosomes. These results combined provide compelling evidence that proteins involved in late endosomal function are necessary for the end stages of cytokinesis.
Selective binding of phorbol esters and diacylglycerol by individual C1 domains of the PKD family
Authors: Chen Jun , Deng Fan , Li Jun , Wang Q. Jane
Published: March 2008

The PKD (protein kinase D) family are novel DAG (diacylglycerol) receptors. The twin C1 domains of PKD, designated C1a and C1b, have been shown to bind DAG or phorbol esters. However, their ligand-binding activities and selectivities have not been fully characterized. Here, binding activities of isolated C1a, C1b and intact C1a–C1b domains to DAG and phorbol esters were analysed. The isolated C1b domains of PKD isoforms bind [3H]PDBu ([20-3H]phorbol 12, 13-dibutyrate) with similar high affinities, while they exhibit weaker affinities towards a synthetic DAG analogue, DOG (1,2-dioctanoyl-sn-glycerol), as compared to the control. Mutating a conserved lysine residue at position 22 to tryptophan in C1b of PKD3 fully restores its affinity to DOG, indicating that this residue accounts for its weaker affinity to DOG. In contrast, the non-consensus residues in the isolated C1a domain of PKD mainly contribute to maintaining the protein's structural fold, since converting these residues in C1a of PKD3 to those in PKD1 or PKD2 drastically reduces the maximal number of active receptors, while only minimally impacting ligand-binding activities. Moreover, ligand-binding activities of C1a and C1b are sensitive to the structural context in an intact C1a–C1b domain and exhibit unique patterns of ligand selectivity. C1a and C1b in the intact C1a–C1b of PKD1 are opposite in selectivity for PDBu and DOG. In contrast, C1a of PKD3 exhibits 48-fold higher affinity to DOG as compared to C1b, although both domains bind PDBu with equivalent affinities. Accordingly, mutating C1a of a full-length PKD3–GFP greatly reduces DOG-induced plasma membrane translocation, but does not affect that induced by PMA. In summary, individual C1 domains of PKD isoforms differ in ligand-binding activity and selectivity, implying isoform-selective regulation of PKD by phorbol esters and DAG.
N-terminus-mediated dimerization of ROCK-I is required for RhoE binding and actin reorganization
Authors: Garg Ritu , Riento Kirsi , Keep Nicholas , Morris Jonathan D. H. , Ridley Anne J.
Published: March 2008

ROCK-I (Rho-associated kinase 1) is a serine/threonine kinase that can be activated by RhoA and inhibited by RhoE. ROCK-I has an N-terminal kinase domain, a central coiled-coil region and a RhoA-binding domain near the C-terminus. We have previously shown that RhoE binds to the N-terminal 420 amino acids of ROCK-I, which includes the kinase domain as well as N-terminal and C-terminal extensions. In the present study, we show that N-terminus-mediated dimerization of ROCK-I is required for RhoE binding. The central coiled-coil domain can also dimerize ROCK-I in cells, but this is insufficient in the absence of the N-terminus to allow RhoE binding. The kinase activity of ROCK-I1–420 is required for dimerization and RhoE binding; however, inclusion of part of the coiled-coil domain compensates for lack of kinase activity, allowing RhoE to bind. N-terminus-mediated dimerization is also required for ROCK-I to induce the formation of stellate actin stress fibres in cells. These results indicate that dimerization via the N-terminus is critical for ROCK-I function in cells and for its regulation by RhoE.
Involvement of Egr-1 in HGF-induced elevation of the human 5α-R1 gene in human hepatocellular carcinoma cells
Authors: Rui Caixia , Li Changyan , Xu WangXiang , Zhan Yiqun , Li Yonghui , Yang Xiaoming
Published: March 2008

Steroid 5α-reductase 1 (5α-R1), a key enzyme in the conversion of steroids into their respective 5α-reduced derivatives, plays a key role in some hormone-dependent tumours and is abundant in the liver, although it is also widely distributed throughout the body. HGF (hepatocyte growth factor) is a pleiotropic cytokine/growth factor involved in the progression of hepatocellular carcinoma. In the present paper, we report the stimulatory effect of HGF on human 5α-R1 transcription in hepatocellular carcinoma cells. Pre-treatment with actinomycin D or cycloheximide blocked the up-regulation of 5α-R1 mRNA expression by HGF, indicating that the increased level of 5α-R1 mRNA expression is regulated by transcriptional activation and was dependent on de novo protein synthesis. Functional analysis of the 5′-flanking region of the 5α-R1 gene by transfection analysis showed that the −79 to −50 region functioned as the HGF-responsive region. Mutagenesis and electrophoretic mobility-shift assays demonstrated that induction of 5a-R1 by HGF is mediated by an Egr-1 (early growth-response gene 1)-binding site at −60/−54. In addition, overexpression of Egr-1 was sufficient to transactivate 5α-R1 promoter activity, and knockdown of Egr-1 with gene-specific small interfering RNA resulted in inhibition of HGF-induced up-regulation of endogenous 5α-R1 expression. These data provide the first evidence that HGF stimulates 5α-R1 expression through up-regulation of the transcription factor Egr-1, thus suggesting the possibility that regulation of steroid metabolism by HGF represents a mechanism for high risk of hepatocellular carcinogenesis in males.
The identification and characterization of novel PKCϵ phosphorylation sites provide evidence for functional cross-talk within the PKC superfamily
Authors: Durgan Joanne , Cameron Angus J. , Saurin Adrian T. , Hanrahan Sarah , Totty Nick , Messing Robert O. , Parker Peter J.
Published: March 2008

PKCϵ (protein kinase Cϵ) is a phospholipid-dependent serine/threonine kinase that has been implicated in a broad array of cellular processes, including proliferation, survival, migration, invasion and transformation. Here we demonstrate that, in vitro, PKCϵ undergoes autophosphorylation at three novel sites, Ser234, Ser316 and Ser368, each of which is unique to this PKC isoform and is evolutionarily conserved. We show that these sites are phosphorylated over a range of mammalian cell lines in response to a number of different stimuli. Unexpectedly, we find that, in a cellular context, these phosphorylation events can be mediated in-trans by cPKC (classical PKC) isoforms. The functional significance of this cross-talk is illustrated through the observation that the cPKC-mediated phosphorylation of PKCϵ at residue Ser368 controls an established PKCϵ scaffold interaction. Thus our current findings identify three new phosphorylation sites that contribute to the isoform-specific function of PKCϵ and highlight a novel and direct means of cross-talk between different members of the PKC superfamily.