bluuebunny/crossref_metadata_2025 huggingface dataset:
Morphology, evolution and stratigraphic distribution in the Middle Ordovician conodont genus Microzarkodina
Authors: Löfgren Anita , Tolmacheva Tatiana
Published: December 2008

Microzarkodina is a genus of mainly Middle Ordovician conodonts that has its centre of distribution in Baltoscandia, and much less commonly occurs in southern China, Australia, Argentina and Laurentia. In Baltica a series of species, Microzarkodina russica n. sp., M. flabellum, M. parva, M. bella, M. hagetiana and M. ozarkodella, established themselves successfully. The succession of species ranges from just below the base of the Middle Ordovician (M. russica) to the upper part of the Middle Ordovician (M. ozarkodella). The species are frequently used for biostratigraphical purposes. The largely contemporaneous species Microzarkodina bella and M. hagetiana probably both evolved from M. parva and mostly occurred in separate areas. Microzarkodina ozarkodella probably evolved from M. hagetiana. This present investigation is based on a total of 94,208 elements, collected from 20 sections and one drill-core site in Sweden, one drill-core site and one outcrop in Estonia and two sections in the St Petersburg area in Russia. The Microzarkodina apparatus probably consisted of 15 or 17 elements: four P, two or four M and nine S elements. The S elements include different Sa, Sb1, Sb2, and Sc element types.
Fremdkörpergeschichten
Authors: Stenz Volker , Thurnheer Robert , Widmer Fritz , Krause Martin
Published: December 2008

Fremdkörper, welche mit oder ohne Absicht in den Körper eingeführt, geschluckt oder aspiriert werden, können beträchtliche Komplikationen verursachen. Nach Diagnosestellung und Lokalisation besteht die Hauptaufgabe darin, den Fremdkörper möglichst schadlos und mit geringem Aufwand zu entfernen. Es werden die Geschichten von einem verschluckten Kugelschreiber, einem anal eingeführten Maiskolben, einer aspirierten Zahnbrücke und verpackten Kokainpäckchen im Enddarm erzählt. Die Hintergründe, die Komplikationen und die Bergung der Objekte werden besprochen.
Erfolgreiche Behandlung einer Thrombotisch Thrombozytopenischen Purpura mit Rituximab
Authors: Arici Birsen , Trendelenburg Marten
Published: December 2008

Eine 15-jährige Patientin mit Thrombotisch Thrombozytopenischer Purpura (TTP) wurde uns zur weiteren Abklärung und Therapie bei fehlendem Ansprechen auf Steroide und IVIG zugewiesen. Aufgrund des Nachweises von Antikörpern gegen ADAMTS13 wurde die Diagnose einer erworbenen TTP gestellt. Komorbiditäten wie zum Beispiel ein Systemischer Lupus erythematodes wurden nicht gefunden. Trotz Plasmaaustausches und hochdosierter Steroidtherapie blieb ein anhaltender Therapieerfolg zunächst aus, weshalb wir uns zur Gabe von Rituximab entschlossen. Bereits nach der ersten von zwei Gaben von Rituximab kam es innerhalb einer Woche zu einer Normalisierung der Thrombozytenzahl. Nebenwirkungen auf Rituximab wurden nicht beobachtet und der Therapieerfolg hielt auch nach Ausschleichen der Plasmaaustausche und der Steroide an.
Swiss Research Agenda for Nursing (SRAN): Die Entwicklung einer Agenda für die klinische Pflegeforschung in der Schweiz
Authors: Imhof Lorenz , Abderhalden Christoph , Cignacco Eva , Eicher Manuela , Mahrer-Imhof Romy , Schubert Maria , Shaha Maya
Published: December 2008

In den angelsächsischen und nordeuropäischen Ländern wurden Agenden für die Pflegeforschung entwickelt, um die Forschung auf gesundheitspolitische Zielsetzungen der Länder auszurichten. In der Schweiz erschwerte das Fehlen einer landesweiten gesundheitspolitischen Zielsetzung eine gemeinsame Ausrichtung der Pflegeforschung. Im Projekt «Swiss Research Agenda for Nursing (SRAN)» wurde deshalb zwischen 2005 und 2007 die erste nationale Agenda entwickelt. Basierend auf Literaturreviews, Expertenbefragungen und einer nationalen Umfrage entwickelte ein Projektteam die Agenda, die an einer Konsensuskonferenz verabschiedet wurde. Die Agenda beschreibt allgemeine forschungsleitende Grundsätze und definiert sieben inhaltliche Schwerpunkte für die Jahre 2007 bis 2017. Priorisiert werden soll Forschung 1) zur Wirkung pflegerischer Maßnahmen, 2) zur Anpassung von Dienstleistungen an ein sich veränderndes Gesundheitssystem, 3) zur Identifizierung pflegerelevanter Phänomene, 4) zum Einfluss der Arbeitsumgebung auf die Pflegequalität, 5) zum Funktionieren familialer Systeme und sozialer Netzwerke, 6) zur Integration der Vielfalt individueller Lebensumstände und 7) zur Umsetzung von ethischen Prinzipien in der Pflege. Mit der Swiss Research Agenda for Nursing liegt erstmals eine nationale Agenda in deutscher und französischer Sprache vor. Sie kann als Orientierung für die strategische Ausrichtung genutzt werden und dient zur Entwicklung eines Aktionsplans zur Förderung der Pflegeforschung in der Schweiz.
Der Beitrag der Onkologiepflege zur Swiss Research Agenda for Nursing – SRAN
Authors: Shaha Maya , Schmid-Büchi Silvia , Abt Judith , Mathis-Jäggi Franziska , Holdener Eveline , Riederer Evelyn , Stoll Hans Ruedi , Fliedner Monica , Imhof Lorenz
Published: December 2008

Krebs gilt weltweit als zweithäufigste Todesursache bei Erwachsenen und Kindern. Eine Krebsdiagnose bedeutet den Beginn einer sich oft über mehrere Monate und Jahre erstreckenden Behandlung, die oft chirurgische Eingriffe in Kombination mit Chemotherapien und Radiotherapien beinhaltet. Auch für die beteiligten Fachpersonen, inklusive der Pflege, bedeutet eine Krebserkrankung eine komplexe Krankheitssituation mit hohen Anforderungen. Um diesen mannigfaltigen Bedürfnissen gerecht zu werden, ist es sinnvoll, Schwerpunkte für die Forschung herauszuarbeiten und Prioritäten zu setzen. Zur Erarbeitung der Forschungsprioritäten in der Onkologiepflege in der Schweiz wurde eine systematische Literaturübersicht durchgeführt. Insgesamt wurden 30 Forschungsschwerpunkte herausgearbeitet. Gemäß den durch die SRAN vorgegebenen Richtlinien wurden 25 Onkologiepflegeschwerpunkte weitergeleitet. Die systematische Erarbeitung der Forschungsschwerpunkte in der Onkologiepflege hat in der Schweiz erstmals zu einer Liste von zu bearbeitenden Themen geführt. Sie ist in der SRAN aufgenommen und in die dortigen Themen integriert worden. Bei einer Überarbeitung der SRAN ist es sinnvoll, die onkologischen Forschungsschwerpunkte mithilfe einer aktualisierten systematischen Literaturübersicht zu ergänzen und einer größeren, repräsentativen Gruppe von Onkologiepflegenden, -expertinnen und -experten sowie Pflegewissenschaftlerinnen mit Onkologieerfahrung zur Bewertung zu unterbereiten. In Zukunft ist der Einbezug der betroffenen Patientinnen und Patienten sowie ihrer Angehörige unabdingbar.
Die Entwicklung einer Pflegeforschungsagenda für die Pädiatrie für die Jahre 2007 bis 2017 als Teil der nationalen «Swiss Research Agenda for Nursing»
Authors: Cignacco Eva
Published: December 2008

Im deutschsprachigen Raum ist der pädiatrische Gesundheitsversorgungsbereich von Forschung gekennzeichnet, die sich mehrheitlich am biomedizinischen Modell orientiert. Pflegewissenschaftliche Erkenntnisse, die Behandlung- und Betreuungsprozesse im pädiatrischen Bereich untersuchen, evaluieren und im Sinne pflegesensitiver Outcomekriterien weiterentwickeln, fehlen nahezu vollständig. Dieser Sachverhalt ist um so problematischer, als ein linearer Transfer bisher gesicherter Erkenntnisse aus der Pflegeforschung im Erwachsenenbereich auf die Pädiatrie nicht zulässig ist. Bei einem schweizerischen Bevölkerungsanteil von Kindern und Jugendlichen bis zu 19 Jahren von 22,3% sind in Zukunft interdisziplinär ausgerichtete pflegewissenschaftliche Forschungsprojekte zu fördern, die sich am bio-psychosozialen Modell orientieren und das Wohlergehen dieser Patientenpopulation samt ihren Eltern in Situationen akuter oder chronischer Erkrankungen durch evidenzbasierte Versorgungsangebote entsprechend zu unterstützen und zu fördern. Weil eine literaturbasierte und auf Expertenmeinung abgestützte Agenda für die pädiatrische Pflegeforschung im gesamten deutschsprachigen Raum bis anhin fehlte, war es das Ziel dieser Arbeit, diese Lücke zu schließen. Vorliegende Arbeit präsentiert für die Schweiz zum ersten Mal eine Ausrichtung für die Pflegeforschung im Bereich der pädiatrischen Pflege für die Jahre 2007 bis 2017. Das mehrstufige Priorisierungsverfahren generierte drei Forschungsschwerpunkte, die für die Pflegeforschung in der Pädiatrie der nächsten zehn Jahre als relevant eingestuft werden: 1) Evaluation der Wirkung pflegerischer Maßnahmen, 2) Konzeptualisierung und Evaluation der praktischen Implikationen familialer Systeme im Behandlungsprozess, 3) Forschungsgestützte Entwicklung neuer pflegerischer Dienstleistungen in einem sich verändernden Gesundheitssystem. Dieser Bericht ist im Kontext des nationalen Projektes «Swiss Research Agenda for Nursing» entstanden. Die Agenda kann als Diskussionsgrundlage für die strategische Ausrichtung genutzt werden und wird zur Entwicklung eines Aktionsplans zur Förderung der pädiatrischen Pflegeforschung in der Schweiz dienen.
Forschungsprioritäten der gerontologischen Pflege
Authors: Imhof Lorenz , Naef Rahel , Mahrer-Imhof Romy
Published: December 2008

In der Schweiz liegt die durchschnittliche Lebenserwartung für Frauen bei 84 Jahren und für Männer bei 79 Jahren. Bis ins Jahr 2030 wird die Zahl der über 80-jährigen Personen um 83% auf 625 000 zunehmen. Es wird angenommen, dass sich damit die Zahl der pflegebedürftigen Personen verdoppeln wird. Damit die Pflege ihre Aufgaben in Zukunft kompetent erfüllen kann, ist sie dringend auch auf Erkenntnisse aus der Pflegeforschung angewiesen. Im Rahmen eines nationalen Projekts wurde eine Agenda formuliert, die mittels Literaturrecherche, Expertenbefragung, einer nationalen Umfrage und einer Konsensuskonferenz die Schwerpunkte für die Pflegeforschung für die Jahre von 2007–2017 festlegt. Einundzwanzig Themen wurden für die gerontologische Pflegeforschung identifiziert. Diese Themen betreffen unter anderem Forschung zur Förderung der Selbstständigkeit und Unabhängigkeit zu Hause, zum Einfluss neuer Technologien auf die Versorgung älterer Menschen, zu Entlastungsangeboten für pflegende Angehörige von Demenzkranken. Im Altersbereich werden pflegewissenschaftliche Forschungen zu mobilitätsfördernden Maßnahmen, zu Delir-Management, zu Interventionen gegen Mangelernährung und zum Umgang mit Depression benötigt. Pflegewissenschaftliche Forschung soll die Kontinuität von Dienstleistungen über Institutions- und professionelle Grenzen hinweg sowie den Einfluss von alterspolitischen Entscheiden untersuchen, um Grundlagen zur Qualitätssicherung im stationären und ambulanten Bereich zu liefern. Mit diesem Artikel liegt erstmals eine Forschungsagenda für die gerontologische Pflege vor, die auf den sieben Schwerpunkten der Swiss Research Agenda for Nursing (SRAN) aufbaut und als Diskussionsgrundlage für strategische Ausrichtungen genutzt werden kann.
Self-Report Imagery Questionnaire Scores and Subtypes of Social-Desirable Responding
Authors: Allbutt John , Ling Jonathan , Heffernan Thomas M. , Shafiullah Mohammed
Published: December 2008

Allbutt, Ling, and Shafiullah (2006) and Allbutt, Shafiullah, and Ling (2006) found that scores on self-report measures of visual imagery experience correlate primarily with the egoistic form of social-desirable responding. Here, three studies are reported which investigated whether this pattern of findings generalized to the ratings of imagery vividness in the auditory modality, a new version of the Vividness of Visual Imagery Questionnaire ( Marks, 1995 ), and reports of visual thinking style. The measure of social-desirable responding used was the Balanced Inventory of Desirable Responding (BIDR; Paulhus, 2002 ). Correlational analysis replicated the pattern seen in our earlier work and of the correlations with the egoistic bias, the correlation with vividness of visual imagery was largest and significant, the correlation with visual thinking style next largest and approached significance, and the correlation with vividness of auditory imagery was the smallest and not significant. The size of these correlations mirrored the extent to which the three aspects of imagery were valued by participants.
Distinguishing Impulsive, Unsocialized Sensation Seeking
Authors: Herrero Óscar , Colom Roberto
Published: December 2008

In 1994 Zuckerman proposed an impulsive and unsocialized form of sensation seeking. Studies considering physical risk seekers (prosocial and antisocial) associate this dimension with Eysenck’s psychoticism (P) and neuroticism (N), as well as with the following subtraits from Zuckerman’s model of sensation seeking: experience seeking (ES), disinhibition (Dis), and boredom susceptibility (BS). The present study explores the structure of sensation seeking in representative samples of males taken from the general population (N = 397) and male prison inmates (N = 183). The results focus on three main points of interest. First, prison inmates score significantly higher in all dimensions (except on E, as measured by the EPQ-R). Second, factor analysis findings show a two factor solution. Dis, ES, and thrill and adventure seeking (TAS) load on the first factor, and this happens for both samples. P, BS, and Dis load on the second factor. These factors are correlated. Finally, a stepwise discriminant analysis shows a 75% rate of correct classifications regarding the distinction between offenders and nonoffenders.
Gender Differences in the Coopersmith Self-Esteem Inventory
Authors: Ponsoda Vicente , Abad Francisco J. , Francis Leslie J. , Hills Peter R.
Published: December 2008

In a study of 802 16-year-old pupils, Francis (1998) found that males scored significantly higher than females on the school short-form of the Coopersmith Self-Esteem Inventory. He concluded that this instrument may be biased in favor of males. The original data employed by Francis have now been re-examined for the incidence of differential item functioning (DIF) by the Mantel-Haenszel, logistic regression, and SIBTEST statistical procedures. The present study has confirmed that 11 items exhibit DIF, on six of which females outperform males and on five of which males outperform females, but no statistically significant collective DIF was found for the set of the 11 items that exhibited DIF. It has been concluded, therefore, that the differences in levels of self-esteem reported by Francis (1998) are the result of genuine gender differences in self-esteem and not to any artifact of test construction. Individual examination of the items that show DIF supports the widely held view that, in general, among males self-esteem tends to be generated personally, whereas among females self-esteem is more dependent on interactions with others.
Jan Hosper's Key Contributions to Geomagnetism
Authors: Irving Ted
Published: December 2008

Although Bernard Brunhes in 1904 presented the first evidence that the geomagnetic field had once reversed in polarity [Laj et al., 2002], modern studies of reversals only began in the late 1940s with the work of Jan Hospers and Alexandre Roche [Opdyke and Channel, 1996]. Hospers also initiated modern studies of the time‐averaged form of the geomagnetic field [Frankel, 1987]. His empirically based notion—that over several thousand years the geomagnetic field averaged to a geocentric axial dipole (GAD) that, as he and others showed, had recurrently reversed its polarity—allowed Creer et al. [1954] to trace the movement of the geographic pole (apparent polar wander path) relative to Britain and by geological extension, to Europe as well. This was the first such path based on paleomagnetic evidence, and it led in turn to the first successful physical test of continental drift [Irving, 1988].
Anniversaries in Solar‐Terrestrial Physics: 2008–2010
Authors: Rishbeth Henry
Published: December 2008

Several notable solar‐terrestrial anniversaries occur between 2008 and 2010. The oldest is the 400‐year anniversary of Galileo Galilei's study of sunspots in 1610. Very large sunspots had been seen without telescopes centuries before Galileo, but his observations started a line of solar research that, among other things, led to the discovery of the Maunder Minimum, a period of extremely low solar activity, from 1645 to 1715, in which sunspots became very rare.
Young Africans Tackle Their Continent's Environmental Issues: Young African Scientists Session at the Fourth International Geosphere‐Biosphere Programme Congress; Cape Town, South Africa, 7 May 2008
Authors: Olwoch Jane Mukarugwiza
Published: December 2008

Africa is often described as a unique and diverse continent. This is reflected in its biodiversity, economic and social circumstances, and diversity in culture and environment. The Young African Scientists (YAS) session at the International Geosphere‐ Biosphere Programme Congress was one of the congress's highlights. Global environmental change research in Africa was presented to an audience that included visiting international and national scientists, policy makers, and a group of schoolchildren. From the uniqueness of Africa's paleoclimate to the diversity and complexity of current and future impacts of environmental change on Africa, the session not only provided an overview of current projects but also highlighted the problems that are intertwined with poverty. This session was sponsored by the Global Change System for Analysis, Research, and Training (START).
Integrating Science and Practice: Adopting the Pasteurian Model
Authors: Reich John W.
Published: December 2008

The field of psychology has a long history of attempting to make its basic science relevant to the analysis and solution of social problems. Some psychologists claim that it has been successful at this goal, but others are not convinced. Historically, the field has followed a linear model in its attempts at being relevant: Basic science is somehow developed first, and later someone comes along to apply it to solve problems in real-world settings. This model is now undergoing serious reconsideration in the physical and biological sciences. An alternative model in which science and practice develop seamlessly is represented in the remarkable career of Louis Pasteur. This article discusses both of these models in the context of psychological science and practice. Three fundamental principles underlying Pasteur's way of doing science and practice are presented. Adopting a Pasteurian framework should help resolve at least some of the debates about our science and practice linkage, but this will require a change in how professionals function and how future generations of professionals are trained. Suggestions are presented for making psychology more Pasteurian to help it achieve its stated goal “as a science, as a profession, and as a means of promoting human welfare.”
Transactive Memory Systems
Authors: Peltokorpi Vesa
Published: December 2008

The literature on transactive memory (TM) continues to grow in several interrelated scholarly fields. Although this increased interest in TM systems has been beneficial, it has also led to a plurality and confusing interpretation of TM theory. To identify gaps and ambiguities in TM literature, this article provides a comprehensive overview of TM theory, distinguishes TM systems from related cognitive concepts, and reviews theory extensions and research in dyads, groups, and teams. Suggested areas for future research and theory extensions are face-to-face communication influencing TM systems, social interaction processes related to expert inferences, task context and levels of analysis, and extension of research to work teams.
Beauty as an Emotion: The Exhilarating Prospect of Mastering a Challenging World
Authors: Armstrong Thomas , Detweiler-Bedell Brian
Published: December 2008

Beauty has received sparse attention from emotion theorists, some of whom have argued that aesthetic pleasure is cognitive in nature and too “disinterested” to be emotional. This view is supported by research suggesting that aesthetic pleasure is based on processing fluency. The authors review recent findings in the psychology of aesthetics and present two arguments. First, processing fluency explains the mild pleasure associated with simple or familiar objects, but it cannot account for the more intense pleasure associated with complex or novel objects. Immediately recognizing an object tends to be mildly pleasant, whereas sensing the prospect of successfully representing a complex object can be exhilarating. Second, to explain how these forms of aesthetic pleasures differ, a theory must go beyond cognitive dynamics. The authors’ affect-based model of emotion differentiates aesthetic pleasures in terms of epistemic goals. Pretty, fluently processed stimuli implicate prevention goals that maintain and protect knowledge. Beautiful, novel stimuli implicate promotion goals that reshape and expand knowledge. The emotional nature of interest and awe are also discussed.
Re‐entry of mature T cells to the thymus: an epiphenomenon?
Authors: Sprent Jonathan , Surh Charles D
Published: December 2008

In certain situations mature post‐thymic T cells are able to leave their residence in the secondary lymphoid tissues and re‐enter the thymus. The physiological significance of this phenomenon is discussed.
TLR9‐independent effects of inhibitory oligonucleotides on macrophage responses to S. typhimurium
Authors: Trieu Angela , Bokil Nilesh , Dunn Jasmyn A , Roberts Tara L , Xu Damo , Liew Foo Y , Hume David A , Stacey Katryn J , Sweet Matthew J
Published: December 2008

Detection of bacterial CpG‐containing DNA (CpG DNA) by innate immune cells is dependent on toll‐like receptor 9 (TLR9). Here we show that the expression of tlr9 mRNA was induced in mouse bone marrow‐derived macrophages (BMMs) upon infection with the facultative Gram‐negative intracellular bacterium Salmonella enterica serovar Typhimurium (S. typhimurium). Treatment of BMM with the inhibitory oligonucleotide (ODN) 2114, an antagonist of TLR9 signalling, enhanced intracellular S. typhimurium numbers approximately fivefold, whereas a control ODN (2310) had no significant effect. Surprisingly, 2114 also amplified S. typhimurium bacterial loads in TLR9‐deficient BMM. Indeed, 2114 suppressed responses (nuclear factor‐κB‐dependent reporter gene expression and interleukin‐12p40 secretion) to not only CpG DNA, but also the TLR2 ligand Pam3Cys, in BMM and RAW264 cells in a sequence‐specific manner. Inhibitory ODNs, which have been proposed as therapeutic agents for the treatment of systemic lupus erythematosus because of their inhibitory effects on TLR9 signalling, may thus compromise the host response to bacterial pathogens through TLR9‐independent mechanisms.
On the opposing views of the self–nonself discrimination by the immune system
Authors: Cohn Melvin
Published: December 2008

Today's generally accepted view of the self–nonself discrimination was voiced by Miller1 in 2004 in a thought‐provoking essay. In spite of its popularity, this position has its limitations, which are analyzed here with a view toward establishing an interactive discussion that hopefully will culminate in agreed upon decisive experiments. The inadequacies of Miller's view of the self–nonself discrimination and their resolution under the associative recognition of antigen model are analyzed.
Isoform-specific differences in the nitrite reductase activity of nitric oxide synthases under hypoxia
Authors: Mikula Ivan , Durocher Suzanne , Martasek Pavel , Mutus Bulent , Slama-Schwok Anny
Published: December 2008

Nitrite (NO2−) recycling to nitric oxide (NO) is catalysed by a number of enzymes and induces a protective vasodilation effect under hypoxia/ischaemia. In the present work, we tested the in vitro ability of the three NOS (nitric oxide synthase) isoforms to release NO from nitrite under anoxia using electrochemical detection, chemiluminescence and absorption spectroscopy. The release of free NO from anoxic nitrite solutions at 15 μM was specific to the endothelial NOS isoform (eNOS) and did not occur with the neuronal (nNOS) or inducible (iNOS) isoforms. Unlike xanthine oxidase, the eNOS reductase domain did not recycle nitrite to NO, and wild-type eNOS did not reduce nitrate. Our data suggest that structural and, by inference, dynamic differences between nNOS and eNOS in the distal haem side account for eNOS being the only isoform capable of converting nitrite into NO at pH 7.6. In human dermal microvascular endothelial cells under careful control of oxygen tension, the rates of NO formation determined by chemiluminescence were enhanced ∼3.6- and ∼8.3-fold under hypoxia (2 p.p.m. O2) and anoxia (argon) respectively compared with normoxia (∼22 p.p.m. O2) using 10 μM extracellular nitrite. NOS inhibitors inhibited this hypoxic NO release. Our data show that eNOS is unique in that it releases NO under all oxygen levels from normoxia to complete anoxia at physiological micromolar nitrite concentrations. The magnitude of the hypoxic NO release by the endothelial cells suggest that the endothelium could provide an appropriate response to acute episodic ischaemia and may explain the observed eNOS-expression-specific protective effect as a short-term response in animal models of acute hypoxia.
Structural and functional studies of Bacillus stearothermophilus serine hydroxymethyltransferase: the role of Asn341, Tyr60 and Phe351 in tetrahydrofolate binding
Authors: Pai Vinitha R. , Rajaram V. , Bisht Shveta , Bhavani B. S. , Rao N. Appaji , Murthy M. R. N. , Savithri H. S.
Published: December 2008

SHMT (serine hydoxymethyltransferase), a type I pyridoxal 5′-phosphate-dependent enzyme, catalyses the conversion of L-serine and THF (tetrahydrofolate) into glycine and 5,10-methylene THF. SHMT also catalyses several THF-independent side reactions such as cleavage of β-hydroxy amino acids, transamination, racemization and decarboxylation. In the present study, the residues Asn341, Tyr60 and Phe351, which are likely to influence THF binding, were mutated to alanine, alanine and glycine respectively, to elucidate the role of these residues in THF-dependent and -independent reactions catalysed by SHMT. The N341A and Y60A bsSHMT (Bacillus stearothermophilus SHMT) mutants were inactive for the THF-dependent activity, while the mutations had no effect on THF-independent activity. However, mutation of Phe351 to glycine did not have any effect on either of the activities. The crystal structures of the glycine binary complexes of the mutants showed that N341A bsSHMT forms an external aldimine as in bsSHMT, whereas Y60A and F351G bsSHMTs exist as a mixture of internal/external aldimine and gem-diamine forms. Crystal structures of all of the three mutants obtained in the presence of L-allo-threonine were similar to the respective glycine binary complexes. The structure of the ternary complex of F351G bsSHMT with glycine and FTHF (5-formyl THF) showed that the monoglutamate side chain of FTHF is ordered in both the subunits of the asymmetric unit, unlike in the wild-type bsSHMT. The present studies demonstrate that the residues Asn341 and Tyr60 are pivotal for the binding of THF/FTHF, whereas Phe351 is responsible for the asymmetric binding of FTHF in the two subunits of the dimer.
Avoidance of the cytochrome c biogenesis system by periplasmic CXXCH motifs
Authors: Mavridou Despoina A.I. , Braun Martin , Thöny-Meyer Linda , Stevens Julie M. , Ferguson Stuart J.
Published: December 2008

The CXXCH motif is usually recognized in the bacterial periplasm as a haem attachment site in apocytochromes c. There is evidence that the Escherichia coli Ccm (cytochrome c maturation) system recognizes little more than the CXXCH sequence. A limited number of periplasmic proteins have this motif and yet are not c-type cytochromes. To explore how unwanted haem attachment to CXXCH might be avoided, and to determine whether haem attachment to the surface of a non-cytochrome protein would be possible, we converted the active-site CXXCK motif of a thioredoxin-like protein into CXXCH, the C-terminal domain of the transmembrane oxidoreductase DsbD (cDsbD). The E. coli Ccm system was found to catalyse haem attachment to a very small percentage of the resultant protein (∼0.2%). We argue that cDsbD folds sufficiently rapidly that only a small fraction fails to avoid the Ccm system, in contrast with bona fide c-type cytochromes that only adopt their tertiary structure following haem attachment. We also demonstrate covalent haem attachment at a low level in vivo to the periplasmic disulfide isomerase DsbC, which contains a native CXXCH motif. These observations provide insight into substrate recognition by the Ccm system and expand our understanding of the requirements for covalent haem attachment to proteins. The possible evolutionary relationship between thioredoxins and c-type cytochromes is discussed.
Signal perception by FNR: the role of the iron–sulfur cluster1
Authors: Crack Jason C. , Jervis Adrian J. , Gaskell Alisa A. , White Gaye F. , Green Jeffrey , Thomson Andrew J. , Le Brun Nick E.
Published: December 2008

The metabolic flexibility of bacteria is key to their ability to survive and thrive in a wide range of environments. Optimal switching from one metabolic pathway to another is a key requirement for this flexibility. Respiration is a good example: many bacteria utilize O2 as the terminal electron acceptor, but can switch to a range of other acceptors, such as nitrate, when O2 becomes limiting. Sensing environmental levels of O2 is the key step in switching from aerobic to anaerobic respiration. In Escherichia coli, the fumarate and nitrate reduction transcriptional regulator (FNR) controls this switch. Under O2-limiting conditions, FNR binds a [4Fe–4S]2+ cluster, generating a transcriptionally active dimeric form. Exposure to O2 results in conversion of the cluster into a [2Fe–2S]2+ form, leading to dissociation of the protein into inactive monomers. The mechanism of cluster conversion, together with the nature of the reaction products, is of considerable current interest, and a near-complete description of the process has now emerged. The [4Fe–4S]2+ into [2Fe–2S]2+ cluster conversion proceeds via a two-step mechanism. In step 1, a one-electron oxidation of the cluster takes place, resulting in the release of a Fe2+ ion, the formation of an intermediate [3Fe–4S]1+ cluster, together with the generation of a superoxide anion. In step 2, the intermediate [3Fe–4S]1+ cluster rearranges spontaneously to form the [2Fe–2S]2+ cluster, releasing two sulfide ions and an Fe3+ ion in the process. The one-electron activation of the cluster, coupled to catalytic recycling of the superoxide anion back to oxygen via superoxide dismutase and catalase, provides a novel means of amplifying the sensitivity of [4Fe–4S]2+ FNR to its signal molecule.
The enzymology of nitric oxide in bacterial pathogenesis and resistance
Authors: Crane Brian R.
Published: December 2008

Mammalian NOSs (nitric oxide synthases) are haem-based monoxygenases that oxidize the amino acid arginine to the intracellular signal and protective cytotoxin nitric oxide (NO). Certain strains of mostly Gram-positive bacteria contain homologues of the mammalian NOS catalytic domain that can act as NOSs when suitable reductants are supplied. Crystallographic analyses of bacterial NOSs, with substrates and haem-ligands, have disclosed important features of assembly and active-centre chemistry, both general to the NOS family and specific to the bacterial proteins. The slow reaction profiles and especially stable haem-oxygen species of NOSs derived from bacterial thermophiles have facilitated the study of NOS reaction intermediates. Functionally, bacterial NOSs are distinct from their mammalian counterparts. In certain strains of Streptomyces, they participate in the biosynthetic nitration of plant toxins. In the radiation-resistant bacterium Deinococcus radiodurans, NOSs are also likely to be involved in biosynthetic nitration reactions, but, furthermore, appear to play an important role in the recovery from damage induced by UV radiation.
New insights into the activity of Pseudomonas aeruginosa cd1 nitrite reductase
Authors: Rinaldo Serena , Arcovito Alessandro , Giardina Giorgio , Castiglione Nicoletta , Brunori Maurizio , Cutruzzolà Francesca
Published: December 2008

The cytochrome cd1 nitrite reductases are enzymes that catalyse the reduction of nitrite to nitric oxide (NO) in the bacterial energy conversion denitrification process. These enzymes contain two different redox centres: one covalently bound c-haem, which is reduced by external donors, and one peculiar d1-haem, where catalysis occurs. In the present paper, we summarize the current understanding of the reaction of nitrite reduction in the light of the most recent results on the enzyme from Pseudomonas aeruginosa and discuss the differences between enzymes from different organisms. We have evidence that release of NO from the ferrous d1-haem occurs rapidly enough to be fully compatible with the turnover, in contrast with previous hypotheses, and that the substrate nitrite is able to displace NO from the d1-haem iron. These results shed light on the mechanistic details of the activity of cd1 nitrite reductases and on the biological role of the d1-haem, whose presence in this class of enzymes has to date been unexplained.
Targeting of microRNAs for therapeutics
Authors: Stenvang Jan , Lindow Morten , Kauppinen Sakari
Published: December 2008

miRNAs (microRNAs) comprise a class of small endogenous non-coding RNAs that post-transcriptionally repress gene expression by base-pairing with their target mRNAs. Recent evidence has shown that miRNAs play important roles in a wide variety of human diseases, such as viral infections, cancer and cardiovascular diseases, and thus miRNAs have rapidly emerged as potential targets for therapeutics. LNAs (locked nucleic acids) comprise a class of bicyclic conformational analogues of RNA, which exhibit high binding affinity to complementary RNA molecules and high stability in blood and tissues in vivo. Recent reports on LNA-mediated miRNA silencing in rodents and primates support the potential of LNA-modified oligonucleotides in studying miRNA functions in vivo and in the future development of miRNA-based therapeutics.
Role of microRNAs in myeloid differentiation
Authors: Fatica Alessandro , Rosa Alessandro , Ballarino Monica , Marchis Maria Laura De , Rasmussen Kasper D. , Bozzoni Irene
Published: December 2008

All types of blood cell of the body are continuously produced by rare pluripotent self-renewing HSCs (haemopoietic stem cells) by a process known as haemopoiesis. This process provides a valuable model for examining how genetic programmes involved in cell differentiation are established, and also how cell-fate specification is altered in leukaemia. Here, we describe examples of how miRNAs (microRNAs) can influence myelopoiesis and how the identification of their target mRNAs has contributed to the understanding of the molecular networks involved in the alternative control between cell growth and differentiation. Ectopic expression and knockdown of specific miRNAs have provided powerful molecular tools able to control the switch between proliferation and differentiation, therefore providing new therapeutic tools for interfering with tumorigenesis.
Role of microRNAs in haemopoiesis, heart hypertrophy and cancer
Authors: Fontana Laura , Sorrentino Antonio , Condorelli Gianluigi , Peschle Cesare
Published: December 2008

miRNAs (microRNAs) are important regulatory molecules that control gene expression in all eukaryotes. miRNAs play an essential role in basic cellular activities such as proliferation, differentiation, morphogenesis and apoptosis. In haemopoiesis, several miRNA-based pathways have been identified. Importantly, miRNA mutations or mis-expression correlate with various human diseases. In cancer, deregulated miRNAs can function as tumour suppressors or oncogenes. The present review focuses on the recent literature concerning the role of miRNAs in three different research areas: haematology, cardiology and oncology, with particular focus on the results obtained by our group.
Regulation of hepatitis C virus by microRNA-122
Authors: Jopling Catherine L.
Published: December 2008

Most metazoan miRNAs (microRNAs) bind to sites in the 3′-UTRs (untranslated regions) of mRNA targets and negatively regulate protein synthesis. The liver-specific miR-122, however, exerts a positive effect on HCV (hepatitis C virus) RNA levels by binding directly to a site in the 5′-UTR of the viral RNA. HCV translation and RNA stability are unaffected, and therefore miR-122 is likely to act at the level of viral replication. The miR-122-binding site in HCV RNA was examined to determine whether the nature of the site is responsible for the unusual mode of action for a miRNA. When the site was placed in the 3′-UTR of a reporter mRNA, miR-122 repressed translation, and therefore the location of the miR-122-binding site dictates its effect on gene expression. Additionally, a second binding site for miR-122 was identified in the HCV 5′-UTR, and miR-122 binding to both sites in the same viral RNA was found to be necessary for viral replication. The two sites are adjacent and are separated by a short spacer, which is largely conserved between HCV genotypes. The binding site requirements for miR-122 to positively regulate HCV replication provide an insight into this unusual mode of miRNA action.
How do microRNAs regulate gene expression?
Authors: Cannell Ian G. , Kong Yi Wen , Bushell Martin
Published: December 2008

miRNAs (microRNAs) are short non-coding RNAs that regulate gene expression post-transcriptionally. They generally bind to the 3′-UTR (untranslated region) of their target mRNAs and repress protein production by destabilizing the mRNA and translational silencing. The exact mechanism of miRNA-mediated translational repression is yet to be fully determined, but recent data from our laboratory have shown that the stage of translation which is inhibited by miRNAs is dependent upon the promoter used for transcribing the target mRNA. This review focuses on understanding how miRNA repression is operating in light of these findings and the questions that still remain.
Atp7b
−/− mice as a model for studies of Wilson's disease
Authors: Lutsenko Svetlana
Published: December 2008

Wilson's disease is a severe human disorder of copper homoeostasis. The disease is associated with various mutations in the ATP7B gene that encodes a copper-transporting ATPase, and a massive accumulation of copper in the liver and several other tissues. The most frequent disease manifestations include a wide spectrum of liver pathologies as well as neurological and psychiatric abnormalities. A combination of copper chelators and zinc therapy has been used to prevent disease progression; however, accurate and timely diagnosis of the disease remains challenging. Similarly, side effects of treatments are common. To understand better the biochemical and cellular basis of Wilson's disease, several animal models have been developed. This review focuses on genetically engineered Atp7b−/− mice and describes the properties of these knockout animals, insights into the disease progression generated using Atp7b−/− mice, as well as advantages and limitations of Atp7b−/− mice as an experimental model for Wilson's disease.
A distinct role in breast cancer for two LIV-1 family zinc transporters
Authors: Taylor Kathryn M.
Published: December 2008

Zinc, essential for normal cell growth, is tightly controlled in cells by two families of zinc transporters. The aberrant expression of zinc transporters from the LIV-1 family of ZIP (Zrt/Irt-like protein) transporters is increasingly being implicated in a variety of disease states. In the present paper, I describe a mechanism for the role of ZIP7 in the progression of breast cancer, identifying it as a new target in breast cancer. Furthermore, I document a link between another zinc transporter, LIV-1, and breast cancer metastasis, identifying it as a potential new prognostic indicator of breast cancer spread.
The role of iron in neurodevelopment: fetal iron deficiency and the developing hippocampus
Authors: Georgieff Michael K.
Published: December 2008

Iron is a ubiquitous nutrient that is necessary for normal neurodevelopment. Gestational conditions that compromise fetal iron status include maternal iron deficiency, smoking, diabetes mellitus and hypertension. The iron-deficient neonate has altered recognition memory function and temperament while iron-deficient. The memory deficits persist even after iron repletion. Animal models demonstrate that early iron deficiency affects neuronal and glial energy metabolism, monoamine metabolism and myelination, consistent with behavioural findings in human infants. Of particular recent interest are genomic changes in transcripts coding for signal transduction, dendritic structure and energy metabolism induced by early iron deficiency that last well into adulthood in spite of iron treatment. Early iron sufficiency is critical for long-term neurological health.
Iron chelation as a potential therapy for neurodegenerative disease
Authors: Hider Robert C. , Ma Yongmin , Molina-Holgado Francisco , Gaeta Alessandra , Roy Sourav
Published: December 2008

Neurodegenerative disorders include a variety of pathological conditions, which share similar critical metabolic processes such as protein aggregation and oxidative stress, both of which are associated with the involvement of metal ions. Chelation therapy could provide a valuable therapeutic approach to such disease states, since metals, particularly iron, are realistic pharmacological targets for the rational design of new therapeutic agents.
Genetic screening for novel Drosophila mutants with discrepancies in iron metabolism
Authors: Mehta Anuja , Deshpande Abhyuday , Missirlis Fanis
Published: December 2008

Ferritin, a symmetrical 24-subunit heteropolymer composed of heavy and light chains, is the primary iron-storage molecule in bacteria, plants and animals. We used a genetically engineered strain of the model organism Drosophila melanogaster which expresses a GFP (green fluorescent protein)-tagged ferritin 1 heavy chain homologue from its native chromosomal locus and incorporated it into endogenous functional ferritin, enabling in vivo visualization of the protein and permitting easy assessment of ferritin status following environmental or genetic perturbations. Random mutagenesis was induced, and individual mutagenized chromosomes were recovered by classic crossing schemes involving phenotypical markers and balancer chromosomes. In wild-type larvae, ferritin is predominantly localized in the brain, in regions of the intestine, in wreath cells and in pericardial cells. A pilot genetic screen revealed a mutant fruitfly strain expressing GFP–ferritin in the anal pads, a pair of organs located ventrally in the posterior end of the fruitfly larva, possibly involved in ion absorption and osmoregulation, which are normally devoid of ferritin. Our continuing genetic screen could reveal transcription factors involved in ferritin regulation and novel proteins important in iron metabolism, hopefully with conserved functions in evolution.
Does satellite cell dysfunction contribute to disease progression in Emery–Dreifuss muscular dystrophy?
Authors: Gnocchi Viola F. , Ellis Juliet A. , Zammit Peter S.
Published: December 2008

Muscular dystrophies comprise at least 34 conditions, characterized by progressive skeletal muscle weakness and degeneration. The loci affected include mutations in both muscle-specific genes and genes that are more widely expressed such as LMNA and EMD, responsible for EDMD (Emery–Dreifuss muscular dystrophy). LMNA encodes A-type lamins, whereas EMD encodes emerin, both located in the nuclear envelope. Mutation or loss of A-type lamins or emerin in the terminally differentiated myonuclei of muscle fibres results in muscle damage. Importantly, since LMNA and EMD are also expressed by the resident skeletal muscle stem cells, the satellite cells, the mutations that cause muscle damage may also directly compromise the regenerative response. Thus EDMD is different from dystrophic conditions such as Duchenne muscular dystrophy, where the mutated gene is only expressed in the muscle fibres. In this brief review, we examine the evidence that myoblasts carrying EDMD-causing mutations are compromised, and discuss the possibility that such dysfunction results in reduced efficiency of muscle regeneration, so actively contributes to disease progression.
Molecular signatures of Emery–Dreifuss muscular dystrophy
Authors: Wheeler Matthew A. , Ellis Juliet A.
Published: December 2008

Mutations in genes encoding the nuclear envelope proteins emerin and lamin A/C lead to a range of tissue-specific degenerative diseases. These include dilated cardiomyopathy, limb-girdle muscular dystrophy and X-linked and autosomal dominant EDMD (Emery–Dreifuss muscular dystrophy). The molecular mechanisms underlying these disorders are poorly understood; however, recent work using animal models has identified a number of signalling pathways that are altered in response to the deletion of either emerin or lamin A/C or expression of Lmna mutants found in patients with laminopathies. A distinguishing feature of patients with EDMD is the association of a dilated cardiomyopathy with conduction defects. In the present article, we describe several of the pathways altered in response to an EDMD phenotype, which are known to be key mediators of hypertrophic growth, and focus on a possible role of an emerin–β-catenin interaction in the pathogenesis of this disease.
Exploring the effects of a dysfunctional nuclear matrix
Authors: Elcock Lauren S. , Bridger Joanna M.
Published: December 2008

The nuclear matrix has remained a contentious structure for decades; many believe that it is an artefact of harsh non-physiological procedures. However, its visualization using milder experimental techniques is leading to its general acceptance by the scientific community. It is a permanent network of core filaments underlying thicker fibres which is proposed to be a platform for numerous important nuclear activities such as transcription and DNA repair. Interestingly, A- and B-type lamin proteins and emerin are components of this nuclear structure; however, they are often referred to only as nuclear envelope proteins. The present mini-review intends to provide an overview of the nuclear matrix, mentioning both its constituents and functional significance. The impact of disease-causing mutations in both emerin and lamin proteins on the structure's ability to regulate and mediate nuclear processes is then discussed.
α-Helix mimetics as inhibitors of protein–protein interactions
Authors: Saraogi Ishu , Hamilton Andrew D.
Published: December 2008

The inhibition of protein–protein interactions using small molecules is a viable approach for the treatment of a range of pathological conditions that result from a malfunctioning of these interactions. Our strategy for the design of such agents involves the mimicry of side-chain residues on one face of the α-helix; these residues frequently play a key role in mediating protein–protein interactions. The first-generation terphenyl scaffold, with a 3,2′,2″-substitution pattern, is able to successfully mimic key helix residues and disrupt therapeutically relevant interactions, including the Bcl-XL–Bak and the p53–hDM2 (human double minute 2) interactions that are implicated in cancer. The second- and third-generation scaffolds have resulted in greater synthetic accessibility and more drug-like character in these molecules.