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"Eines der schwierigsten geschichtlichen Probleme stellt sich mit der Frage, wie der Aufstieg Roms zu erklären ist und wie sein Untergang. Das Verständnis für diese weltgeschichtlichen Vorgänge wird erleichtert, wenn man sich vergegenwärtigt, dass sie nicht eine, sondern viele Ursachen hatten. Der Untergang des Römischen Weltreiches war kein Ereignis, sondern ein Prozess, der sich über 300 Jahre erstreckte. Es gibt Nationen, die nicht so lange existiert haben, wie Rom allein brauchte, um unterzugehen." So die bedeutungsvollen Worte aus dem Off über dem Vorspann des fast dreistündigen Hollywood-Filmes "Der Untergang des Römischen Reiches" (1963) von Anthony Mann – in den Hauptrollen Alec Guinness als Marc Aurel und Sophia Loren als dessen Tochter Lucilla. ...
Electric stimulation of the auditory nerve via cochlear implants has made the treatment of sensory deafness possible. Advanced signal processing and stimulation paradigms have led to continuously improved results in speech understanding. Consequently, indication criteria have been extended to patients with profound and severe-to-profound hearing loss and limited speech understanding with conventional acoustic amplification.
Outside this group, a considerable number of patients presents with rather wellpreserved, low frequency hearing of 30-60 dB up to 1 kHz, but severe loss in the mid to high frequency range of more than 60-70 dB. Monosyllabic word scores in these patients do not generally exceed 35%, due to missing consonant information. But, even increasing the audibility of these high frequencies by acoustic amplification still has very limited efficiency for discriminating speech, and therefore, these patients obtain only minor benefit from conventional hearing aids. On the other hand, standard cochlear implantation would carry a high risk of causing complete hearing loss. This situation has led to considering a combination of both modes of stimulation for these patients who are on the borderline between hearing aids and cochlear implant.
In our present model, the surviving low frequency region of the cochlea could still be stimulated acoustically-combined with additional electrical stimulation of the impaired mid and high frequency region of the cochlea.
Several questions still have to be answered with regard to combined electric and acoustic stimulation (EAS). The possible interaction of electric and acoustic stimuli on the different levels off the auditory system is a major issue. Animal experiments clearly demonstrate that tuning properties of auditory neurons, in response to acute acoustic stimulation, are essentially preserved in the presence of electric stimulation even at high levels of electric stimulation, and that chronic electric stimulation of tie intact inner ear does not have a significant effect on the compound action potentials (CAP) thresholds or inner ear function.
In a previous report, we were able to show that this combined F.A.S of the auditory system is possible in humans, and that it has a synergistic effect on speech understanding. Further major issues regard the surgical feasibility and reproducibility of cochlear implantation with the preservation of residual hearing.
Encouraged by our findings, a clinical study was initiated on the application of EAS. So far, seven adults have been included in this study. In addition, one child has been implanted outside the study.
Letzte Fragen
(2004)
Eine Debatte anzuzetteln ist immer ein Risiko. Wer von den – sorgsam, wenn auch letztlich arbiträr ausgewählten – Angeschriebenen und Angesprochenen wird auf die freundliche Einladung einen freundlichen Absagebrief schreiben oder gar nichts schreiben oder nur telephonieren? Wer aus der weiten Welt der Rechtsgeschichte-Leser wird sich beteiligen, ohne ermuntert worden zu sein? Wer wird sich auf die Sache, und das heißt hier die Frage, einlassen? Und wie? Wird es eine spannende Debatte werden oder eine langweilige Bestandsaufnahme? Phantasie oder Inventur? Fußnoten oder Thesen? ...
The transporter associated with antigen processing (TAP1/2) translocates cytosolic peptides of proteasomal degradation into the endoplasmic reticulum (ER) lumen. A peptide-loading complex of tapasin, major histocompatibility complex class I, and several auxiliary factors is assembled at the transporter to optimize antigen display to cytotoxic T-lymphocytes at the cell surface. The heterodimeric TAP complex has unique N-terminal domains in addition to a 6 + 6-transmembrane segment core common to most ABC transporters. Here we provide direct evidence that this core TAP complex is sufficient for (i) ER targeting, (ii) heterodimeric assembly within the ER membrane, (iii) peptide binding, (iv) peptide transport, and (v) specific inhibition by the herpes simplex virus protein ICP47 and the human cytomegalovirus protein US6. We show for the first time that the translocation pore of the transporter is composed of the predicted TM-(5-10) of TAP1 and TM-(4-9) of TAP2. Moreover, we demonstrate that the N-terminal domains of TAP1 and TAP2 are essential for recruitment of tapasin, consequently mediating assembly of the macromolecular peptide-loading complex.
The article presents a brief overview of research and publication in the history of international law in Europe today. The upsurge of interest in historical studies is traced back to a sense of present transformation, with historical studies seeking to explore both aspects of continuity and change in the international legal system. The article outlines three tasks for the discipline in the future: to begin work for international law’s Ideengeschichte, to focus on the relationship between the West and its "Other", and to undertake studies in the historical sociology of international law.
Intra-arterial (IA) chemotherapy for curative treatment of head and neck cancer experienced a revival in the last decade. Mainly, it was used in concurrent combination with radiation in organ-preserving settings. The modern method of transfemoral approach for catheterisation, superselective perfusion of the tumour-feeding vessel, and high-dose (150 mg m−2) administration of cisplatin with parallel systemic neutralisation with sodium thiosulphate (9 g m−2) made preoperative usage feasible. The present paper presents the results of a pilot study on a population of 52 patients with resectable stage 1–4 carcinomas of the oral cavity and the oropharynx, who were treated with one cycle of preoperative IA chemotherapy executed as mentioned above and radical surgery. There have been no interventional complications of IA chemotherapy, and acute side effects have been low. One tracheotomy had to be carried out due to swelling. The overall clinical local response has been 69%. There was no interference with surgery, which was carried out 3–4 weeks later. Pathological complete remission was assessed in 25%. The mean observation time was 3 years. A 3-year overall and disease-free survival was 82 and 69%, respectively, and at 5 years 77 and 59%, respectively. Survival results were compared to a treatment-dependent prognosis index for the same population. As a conclusion, it can be stated that IA high-dose chemotherapy with cisplatin and systemic neutralisation in a neoadjuvant setting should be considered a feasible, safe, and effective treatment modality for resectable oral and oropharyngeal cancer. The low toxicity of this local chemotherapy recommends usage especially in stage 1–2 patients. The potential of survival benefit as indicated by the comparison to the prognosis index should be controlled in a randomised study.
The ubiquitin (Ub) ligase Cbl plays a critical role in attenuation of receptor tyrosine kinase (RTK) signaling by inducing ubiquitination of RTKs and promoting their sorting for endosomal degradation. Herein, we describe the identification of two novel Cbl-interacting proteins, p70 and Clip4 (recently assigned the names Sts-1 and Sts-2, respectively), that inhibit endocytosis of epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor. Sts-1 and Sts-2 contain SH3 domains that interacted with Cbl, Ub-associated domains, which bound directly to mono-Ub or to the EGFR/Ub chimera as well as phosphoglycerate mutase domains that mediated oligomerization of Sts-1/2. Ligand-induced recruitment of Sts-1/Sts-2 into activated EGFR complexes led to inhibition of receptor internalization, reduction in the number of EGFR-containing endocytic vesicles, and subsequent block of receptor degradation followed by prolonged activation of mitogenic signaling pathways. On the other hand, interference with Sts-1/Sts-2 functions diminished ligand-induced receptor degradation, cell proliferation, and oncogenic transformation in cultured fibroblasts. We suggest that Sts-1 and Sts-2 represent a novel class of Ub-binding proteins that regulate RTK endocytosis and control growth factor-induced cellular functions.
THE FINANCIAL SERVICES INDUSTRY IS OPERATING IN HIGHLY VOLATILE MARKETS.
TO CONSIDER THE IMPACT OF UNCERTAIN MARKET ENVIRONMENTS ON INAND OUTSOURCING DECISIONS, WE INTRODUCE A REAL OPTIONS BASED DECISION SUPPORT MODEL. WE APPLY THE MODEL TO AN IT INFRASTRUCTURE OUTSOURCING DECISION AND DETERMINE - BASED ON COST SAVINGS RESULTING FROM OUTSOURCING AND OPTION VALUES ACCOUNTING FOR UNCERTAINTY - DIFFERENT “TRIGGER” OUTPUT VOLUMES WHICH INDICATE IF IN- OR OUTSOURCING IS PREFERABLE. FINALLY WE SHOW THAT THE MODEL CAN ALSO BE TRANSFERRED TO SOURCING DECISIONS OF TRANSACTION BASED BUSINESS PROCESSES LIKE CLEARING AND SETTLEMENT OF SECURITIES.
Vom Kerbholz zur Konzernbilanz? : Wege und Holzwege zu einem autonomen Recht der global economy
(2004)
Die lex mercatoria, die sich abzeichnende transnationale Rechtsordnung der Weltmärkte, ist in aller Munde. Abgesehen von der vagen Idee eines eigenständigen privaten Rechts der internationalen Handels- und Wirtschaftsbeziehungen, das sich jenseits von nationalem Recht und Völkerrecht entwickeln soll, sind indes selbst die Grundfragen der mercatoristischen Doktrin im Streit: So fechten internationale Wirtschaftsjuristen "einen dreißigjährigen Krieg um die Frage der Unabhängigkeit der lex mercatoria aus, ohne daß Münster und Osnabrück in Sicht wären". Auch die Rechtsgeschichte wurde von den streitenden Parteien in diesen Glaubenskrieg verwickelt, geht die neue lex mercatoria angeblich doch zurück auf "das mittelalterliche universale Kaufmannsgewohnheitsrecht des interregionalen und internationalen Handels- und Wirtschaftsverkehrs, das sich außerhalb des römischen Rechts autonom und in eigenständigen handels- und gesellschaftsrechtlichen Formen entwickelt hatte". Strittig ist, ob die neue lex mercatoria ihren Namen zu Recht trägt oder nur dessen historische Dignität ausbeutet und dadurch eine ihr nicht zukommende Universalität und Autonomie suggeriert; kaum hinterfragt wurde dagegen, ob das immer wieder bemühte historische Vorbild auch tatsächlich die ihm zugeschriebenen Eigenschaften aufweist. ...
Supersilylated tetrachlorodigermane (tBu3Si)Cl2GeGeCl2(SitBu3) and trigermoxetane (tBu3Si)3Ge3Cl3O
(2004)
In contrast to the tetrachlorodigermane (tBu3Si)Cl2Ge-GeCl2(SitBu3), the cis,transcyclotrigermane (tBu3SiGeCl)3 is sensitive to oxygen. Its treatment with O2 at ambient temperature leads to the trigermoxetane (tBu3Si)3Ge3Cl3O. According to an X-ray structure analysis of single crystals consisting of cocrystallized (tBu3Si)3Ge3Cl3O and (tBu3Si)Cl2Ge-GeCl2(SitBu3) the trigermaoxetane contains an almost planar Ge3O-ring while the tetrachlorodigermane (tBu3Si)Cl2Ge- GeCl2(SitBu3) possesses a Si-Ge-Ge-Si chain which is exactly all trans,
Women with thrombophilic defects have been shown to be at increased risk, not only of pregnancy associated thromboembolism but also of other vascular complications of pregnancy, including preeclampsia and fetal loss. First trimester fetal loss is associated with factor V Leiden mutation, activated protein C resistance without factor V Leiden mutation and prothrombin G20210A mutation. Late nonrecurrent fetal loss is associated with factor V Leiden mutation, prothrombin mutation and protein S deficiency. Concerning acquired thrombophilia, recurrent fetal loss is a well-documented finding in patients with antiphospholipid antibodies. Associations between thrombophilia polymorphisms and an increased risk of intrauterine growth restriction have been discussed in small series of cases but could not be confirmed in large scale studies. Frequencies for anticardiolipin antibodies or lupus anticoagulants and antinuclear antibodies were significantly higher in women with infants small for gestational age compared to controls. Concerning preeclampsia, gestational hypertension and thrombophilia, a number of studies have examined these relationships with conflicting results. For factor V Leiden, MTHFR C677T and prothrombin mutation, no association with preeclampsia was observed, when severe cases were excluded. If studies were restricted to those of severe preeclampsia, an association with the factor V Leiden mutation was apparent and, to a lesser extent, with the MTHFR-mutation. For antithrombotic therapy, it was shown that in women with antiphospholipid syndrome and recurrent pregnancy loss, unfractionated heparin plus lowdose aspirin results in significantly better gestational outcome than lowdose aspirin alone. Concerning therapy of women with inherited thrombophilia and pregnancy loss, only small, uncontrolled studies are available, demonstrating improved pregnancy outcome when low molecular weight heparin (LMWH) is used for treatment. In conclusion, heritable thrombophilia and the antiphospholipid-syndrome are major causes of fetal loss after exclusion of other underlying pathologies like chromosomal abnormalities, and screening should be recommended. LMWH with or without aspirin may be used for treatment. There is little value in antenatal screening for prothrombotic polymorphisms to predict the development of small for gestational age infants, preeclampsia or gestational hypertension.
Phosphorylation of the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA1a) was studied with time-resolved Fourier transform infrared spectroscopy. ATP and ATP analogs (ITP, 2'- and 3'-dATP) were used to study the effect of the adenine ring and the ribose hydroxyl groups on ATPase phosphorylation. All modifications of ATP altered conformational changes and phosphorylation kinetics. The differences compared with ATP increased in the following order: 3'-dATP > ITP > 2'-dATP. Enzyme phosphorylation with ITP results in larger absorbance changes in the amide I region, indicating larger conformational changes of the Ca(2+)-ATPase. The respective absorbance changes obtained with 3'-dATP are significantly different from the others with different band positions and amplitudes in the amide I region, indicating different conformational changes of the protein backbone. ATPase phosphorylation with 3'-dATP is also much ( approximately 30 times) slower than with ATP. Our results indicate that modifications to functional groups of ATP (the ribose 2'- and 3'-OH and the amino group in the adenine ring) affect gamma-phosphate transfer to the phosphorylation site of the Ca(2+)-ATPase by changing the extent of conformational change and the phosphorylation rate. ADP binding to the ADP-sensitive phosphoenzyme (Ca(2)E1P) stabilizes the closed conformation of Ca(2)E1P.
Arsenic trioxide is a toxic metalloid and carcinogen that is also used as an anticancer drug, and for this reason it is important to identify the routes of arsenite uptake by cells. In this study the ability of hexose transporters to facilitate arsenic trioxide uptake in Saccharomyces cerevisiae was examined. In the absence of glucose, strains with disruption of the arsenite efflux gene ACR3 accumulated high levels of (73)As(OH)(3). The addition of glucose inhibited uptake by approximately 80%. Disruption of FPS1, the aquaglyceroporin gene, reduced glucose-independent uptake by only about 25%, and the residual uptake was nearly completely inhibited by hexoses, including glucose, galactose, mannose, and fructose but not pentoses or disaccharides. A strain lacking FPS1, ACR3, and all genes for hexose permeases except for HXT3, HXT6, HXT7, and GAL2 exhibited hexose-inhibitable (73)As(OH)(3) uptake, whereas a strain lacking all 18 hexose transport-related genes (HXT1 to HXT17 and GAL2), FPS1 and ACR3, exhibited <10% of wild type (73)As(OH)(3) transport. When HXT1, HXT3, HXT4, HXT5, HXT7, or HXT9 was individually expressed in that strain, hexose-inhibitable (73)As(OH)(3) uptake was restored. In addition, the transport of [(14)C]glucose was inhibited by As(OH)(3). These results clearly demonstrate that hexose permeases catalyze the majority of the transport of the trivalent metalloid arsenic trioxide.
Am anderen Ende derWelt, in einem argentinischen Städtchen im Bundesstaat Buenos Aires, versetzten die epochalen Ereignisse in Europa nach dem Fall des Eisernen Vorhangs den Bürger Dinko Šakić in Entzücken. Fünfzig Jahre nachdem er aus seiner Heimat geflüchtet war, führten die tektonischen Umwälzungen nach dem Ende des Kommunismus und der europäischen Teilung sogar zur staatlichen Verselbständigung seiner einstigen Heimat Kroatien – zu einer jahrzehntelang nicht einmal im Traum denkbaren Entwicklung. Dinko Šakić setzte sich daraufhin öffentlich für seine frühere Heimat ein. Es fiel ihm gar nicht ein, dass ihn seine Vergangenheit einholen könnte. Wahrscheinlich weil er "ein gutes Gewissen" hatte, ein von ihm gern benutzter Ausdruck, oder weil er in der jungen Republik Kroatien eine Art Fortsetzung jenes Staatsgebildes sah, dem er in seiner Jugend "gedient" hatte (auch ein beliebter Ausdruck Šakićs). In der größten lateinamerikanischen Kroatengemeinde in Argentinien gab es wahrscheinlich nichts, was ihn zur Vorsicht hätte mahnen können. Er schien die Öffentlichkeit geradezu gesucht, womöglich sogar eine Anerkennung erwartet zu haben. Bei einem Empfang zu Ehren des kroatischen Präsidenten während dessen Staatsbesuchs in Argentinien wurde Šakić von Journalisten beobachtet, wie er Tudjman nicht von der Seite weichen wollte, was diesen sichtlich irritierte und zu Hause für Empörung sorgte. Šakić, der sich selbst bei mehreren Gelegenheiten als glühenden kroatischen Nationalisten schilderte, weshalb er schon als Jugendlicher Anhänger der Ustascha-Organisation geworden sei, ahnte offensichtlich nicht, dass seine Art der Heimatliebe dort Entsetzen hervorrufen würde. ...
Nitric oxide (NO)-sensitive soluble guanylyl cyclase (sGC) is the major cytosolic receptor for NO, catalyzing the conversion of GTP to cGMP. In a search for proteins specifically interacting with human sGC, we have identified the multidomain protein AGAP1, the prototype of an ArfGAP protein with a GTPase-like domain, Ankyrin repeats, and a pleckstrin homology domain. AGAP1 binds through its carboxyl terminal portion to both the α1 and β1 subunits of sGC. We demonstrate that AGAP1 mRNA and protein are co-expressed with sGC in human, murine, and rat cells and tissues and that the two proteins interact in vitro and in vivo. We also show that AGAP1 is prone to tyrosine phosphorylation by Src-like kinases and that tyrosine phosphorylation potently increases the interaction between AGAP1 and sGC, indicating that complex formation is modulated by reversible phosphorylation. Our findings may hint to a potential role of AGAP1 in integrating signals from Arf, NO/cGMP, and tyrosine kinase signaling pathways.
Epigraphic documents attest that the two neighbouring, inland sites, Idalion and Tamassos, were kingdoms during the Cypro-Archaic period, and that-within an interval of nearly a century - they were both incorporated by the kingdom of Kition during the Cypro-Classical period, thereby losing their independent status. The geographical position of Idalion and Tamassos must have been both a blessing and a curse: while the two polities could thrive on the exploitation of the nearby copper mines, they also had to withstand the economic interest of other Cypriote polities in these natural resources. In addition, we may assume that, because of their inland position, Idalion and Tamassos were forced to seek economic collaboration with polities that had direct access to the sea for the export and exchange of commodities beyond the island. We may further expect that the control of ore-mining and forestry activities must have been a potential source of territorial strife between the two inland kingdoms. Therefore, the geo-economic reality likely induced Idalion and Tamassos to a dualistic relationship of being both allies and competitors. ...
Balloon-borne measurements of CFC-11 (on flights of the DIRAC in situ gas chromatograph and the DESCARTES grab sampler), ClO and O3 were made during the 1999/2000 winter as part of the SOLVE-THESEO 2000 campaign. Here we present the CFC-11 data from nine flights and compare them first with data from other instruments which flew during the campaign and then with the vertical distributions calculated by the SLIMCAT 3-D CTM. We calculate ozone loss inside the Arctic vortex between late January and early March using the relation between CFC-11 and O3 measured on the flights, the peak ozone loss (1200 ppbv) occurs in the 440–470 K region in early March in reasonable agreement with other published empirical estimates. There is also a good agreement between ozone losses derived from three independent balloon tracer data sets used here. The magnitude and vertical distribution of the loss derived from the measurements is in good agreement with the loss calculated from SLIMCAT over Kiruna for the same days.
Vor gut 150 Jahren erschien 1852 der erste Band eines ebenso anspruchsvollen wie bis heute respektierten Buches unter dem Titel "Geist des römischen Rechts auf den verschiedenen Stufen seiner Entwicklung". Geschrieben hatte dieses Buch Rudolf Jhering, damals Professor des römischen Rechts in Gießen. Es sollte sein Lebenswerk bleiben – bis hinein in die große Fortsetzung zum "Zweck des Rechts". Das Buch hat Geschichte gemacht, denn der Autor suchte nicht Geschichten, sondern die Geschichte des Rechts überhaupt. Das Bleibende, die "letzten Gründe" trieben ihn um, so wie seinen Altergenossen Karl Marx, der lebenslang nach der "letzten Instanz" in aller Geschichte suchte. Beide waren fest überzeugt, dieses "Letzte" wissenschaftlich ermitteln zu können. Rechtsgeschichte betrieb Jhering daher zugleich als Universalgeschichte, allgemeine Rechtslehre und Rechtsphilosophie. Was das bedeuten kann und was davon bleibt, geht uns nach wie vor unmittelbar an. Auch wir hängen an den Marionettenfäden historischer und philosophischer Grundhaltungen und Grundbegriffe. Auch wir kommen ohne sie nicht aus. Wissenschaft kann und soll das bewusst machen. Die Unschuld der Naivität ist ihr nicht erlaubt. Dazu muss man zeigen, was dieser Jhering bedeutete, wer er war, welches Problem er mit seinem Hauptwerk aufnahm, und welche Lösungen er dafür anbot. ...
Alix/AIP1 is an adaptor protein involved in regulating the function of receptor and cytoskeleton-associated tyrosine kinases. Here, we investigated its interaction with and regulation by Src. Tyr319 of Alix bound the isolated Src homology-2 (SH2) domain and was necessary for interaction with intact Src. A proline-rich region in the C terminus of Alix bound the Src SH3 domain, but this interaction was dependent on the release of the Src SH2 domain from its Src internal ligand either by interaction with Alix Tyr319 or by mutation of Src Tyr527. Src phosphorylated Alix at a C-terminal region rich in tyrosines, an activity that was stimulated by the presence of the Alix binding partner SETA/CIN85. Phosphorylation of Alix by Src caused it to translocate from the membrane and cytoskeleton to the cytoplasm and reduced its interaction with binding partners SETA/CIN85, epidermal growth factor receptor, and Pyk2. As a consequence of this, Src antagonized the negative regulation of receptor tyrosine kinase internalization and cell adhesion by Alix. We propose a model whereby Src antagonizes the effects of Alix by phosphorylation of its C terminus, leading to the disruption of interactions with target proteins.
Da consideração de que moral e direito implicam uma referência ao ponto de vista do participante, o autor explica que o segundo compensa a fraqueza da primeira nas condições modernas. Apoiando-se na teoria do discurso de Habermas, ele argumenta por uma relação interna entre Estado de direito e democracia. Primeiro, porque direitos humanos e soberania popular se implicam mutuamente. Depois, porque a idéia de Estado de direito envolve agora o conceito de poder comunicativo: a sobreposição e interligação de formas de comunicação baseadas em argumentos. Desta segunda relação, o autor extrai uma concepção de democracia em que a fonte de legitimidade não é mais a vontade pré-determinada dos indivíduos, mas o próprio processo de deliberação.
The development of image-guided neurosurgery represents a substantial improvement in the microsurgical treatment of tumors, vascular malformations and other intracranial lesions. Despite the wide applicability and many fascinating aspects of image-guided navigation systems, a major drawback of this technology is they use images, mainly MRI pictures, acquired preoperatively, on which the planning of the operative procedure as well as its intraoperative performance is based. As dynamic changes of the intracranial contents regularly occur during the surgical procedure, the surgeon is faced with a continuously changing intraoperative field. Only intraoperatively acquired images will provide the neurosurgeon with the information he needs to perform real intraoperative image-guided surgery. A number of tools have been developed in recent years, like intraoperative ultrasound and dedicated moveable intraoperative CT units. Because of its excellent imaging qualities, combined with the avoidance of ionizing radiation, MRI currently is and definitely will be in the future for the superior imaging method for intraoperative image guidance. In this short overview, the development as well as some of the current and possible future applications of MRI-guided neurosurgery is outlined.
"Ein jegliches hat seine Zeit und alles Vornehmen unter dem Himmel hat seine Stunde". Wir wissen das. Wir wussten es vermutlich schon lange bevor der "Prediger" Salomo (3.1), der ein Philosoph war, uns vor nunmehr gut 2200 Jahren darüber belehrte. Aber wir handeln nur selten nach unseren Einsichten. Trennungen fallen schwer und Gewohnheiten verkleiden sich bereitwillig als Notwendigkeit. Verschwendung ist den Reichen keine Kategorie, und wer vom Verschwender lebt, erhebt keine Vorwürfe. Schließlich das Wichtigste: Wer außer Gott hat Kraft und Befugnis "Zeit" und "Stunde" zu bestimmen? ...
Quantitative analysis of the cardiac fibroblast transcriptome implications for NO/cGMP signaling
(2004)
Cardiac fibroblasts regulate tissue repair and remodeling in the heart. To quantify transcript levels in these cells we performed a comprehensive gene expression study using serial analysis of gene expression (SAGE). Among 110,169 sequenced tags we could identify 30,507 unique transcripts. A comparison of SAGE data from cardiac fibroblasts with data derived from total mouse heart revealed a number of fibroblast-specific genes. Cardiac fibroblasts expressed a specific collection of collagens, matrix proteins and metalloproteinases, growth factors, and components of signaling pathways. The NO/cGMP signaling pathway was represented by the mRNAs for α1 and β1 subunits of guanylyl cyclase, cGMP-dependent protein kinase type I (cGK I), and, interestingly, the G-kinase-anchoring protein GKAP42. The expression of cGK I was verified by RT-PCR and Western blot. To establish a functional role for cGK I in cardiac fibroblasts we studied its effect on cell proliferation. Selective activation of cGK I with a cGMP analog inhibited the proliferation of serum-stimulated cardiac fibroblasts, which express cGK I, but not higher passage fibroblasts, which contain no detectable cGK I. Currently, our data suggest that cGK I mediates the inhibitory effects of the NO/cGMP pathway on cardiac fibroblast growth. Furthermore the SAGE library of transcripts expressed in cardiac fibroblasts provides a basis for future investigations into the pathological regulatory mechanisms underlying cardiac fibrosis.
Im Niemandsland
(2004)
Dass die Regierungen westlicher Staaten eine offene oder verdeckte Tendenz haben, die ihnen in einem langen historischen Prozess auferlegten rechtsstaatlichen Bindungen aus politischen Gründen wenn nicht abzustreifen, so doch zu lockern, ist ein Thema, das Juristen, Ökonomen, Politologen und Soziologen gleichermaßen beschäftigt. Giorgio Agamben, italienischer Philosoph und Ästhetiker, spitzt die Thematik mit der These zu, die "Normalität" staatlichen Lebens existiere nicht mehr, es sei das "Niemandsland" des Ausnahmezustandes, "in dem wir leben" ("lo stato di eccezione 'in cui viviamo'"). Er sei die "fundamentale politische Struktur" unserer Zeit; er habe inzwischen die "größte planetarische Entfaltung" erreicht, die Menschen auf die "nuda vita", das nackte Leben, reduziert, das dem Kalkül der Macht unterworfen sei und in eine "beispiellose biopolitische Katastrophe" auszuarten drohe. Seine "Materialisierung" hat der Ausnahmezustand in den nationalsozialistischen Konzentrationslagern wie in allen Lagern gefunden, in denen Menschen von der "normalen Ordnung" ausgeschlossen werden; Guantánamo ist für Agamben ein aktuelles Beispiel. Die "Lager" in allen ihren Erscheinungsformen sind die "verborgene Matrix der Politik". Der Ausnahmezustand ist ein arcanum imperii, dessen "Demaskierung" die einzige Möglichkeit ist, den durch ihn bewirkten "Bann" zu brechen. ...
The major light-harvesting complex (LHC-II) of higher plants plays a crucial role in capturing light energy for photosynthesis and in regulating the flow of energy within the photosynthetic apparatus. Native LHC-II isolated from plant tissue consists of three isoforms, Lhcb1, Lhcb2, and Lhcb3, which form homo- and heterotrimers. All three isoforms are highly conserved among different species, suggesting distinct functional roles. We produced the three LHC-II isoforms by heterologous expression of the polypeptide in Escherichia coli and in vitro refolding with purified pigments. Although Lhcb1 and Lhcb2 are very similar in polypeptide sequence and pigment content, Lhcb3 is clearly different because it lacks an N-terminal phosphorylation site and has a higher chlorophyll a/b ratio, suggesting the absence of one chlorophyll b. Low temperature absorption and fluorescence emission spectra of the pure isoforms revealed small but significant differences in pigment organization. The oligomeric state of the pure isoforms and of their permutations was investigated by native gel electrophoresis, sucrose density gradient centrifugation, and SDS-PAGE. Lhcb1 and Lhcb2 formed trimeric complexes by themselves and with one another, but Lhcb3 was able to do so only in combination with one or both of the other isoforms. We conclude that the main role of Lhcb1 and Lhcb2 is in the adaptation of photosynthesis to different light regimes. The most likely role of Lhcb3 is as an intermediary in light energy transfer from the main Lhcb1/Lhcb2 antenna to the photosystem II core.
"Solidarität" ist ein Wieselwort von gallertartiger Konsistenz. Es ist allgegenwärtig, gibt sich bedeutungsschwer und meist auch etwas vorwurfsvoll. Sein Kontext ist durchweg normativ. Es taucht dort auf, wo es um den Appell an Personen auf der gleichen Ebene geht. Typischerweise rufen Gruppen nach "Solidarität", deren innere Bindungen bröckeln oder die sich in Gefahrenlagen zusammenscharen. Als es noch Standesgenossen gab, erinnerten sie gerne an die Solidarität, wenn es darum ging, den Zusammenhalt derselben Schicht zu wahren. Die alten Zünfte, Gilden, Gaffeln, Einungen und Genossenschaften waren Solidaritätsverbände. Die Arbeiterbewegung übernahm hiervon nicht nur das Wort "Genossen", sondern auch den Appell an die Klassensolidarität. Und selbst wer heutzutage einen Krieg führen will, erinnert an alte Dankesschulden und appelliert an die Solidarität der Bundesgenossen. ...
Stable supercomplexes of bacterial respiratory chain complexes III (ubiquinol:cytochrome c oxidoreductase) and IV (cytochrome c oxidase) have been isolated as early as 1985 (Berry, E. A., and Trumpower, B. L. (1985) J. Biol. Chem. 260, 2458-2467). However, these assemblies did not comprise complex I (NADH:ubiquinone oxidoreductase). Using the mild detergent digitonin for solubilization of Paracoccus denitrificans membranes we could isolate NADH oxidase, assembled from complexes I, III, and IV in a 1:4:4 stoichiometry. This is the first chromatographic isolation of a complete “respirasome.” Inactivation of the gene for tightly bound cytochrome c552 did not prevent formation of this supercomplex, indicating that this electron carrier protein is not essential for structurally linking complexes III and IV. Complex I activity was also found in the membranes of mutant strains lacking complexes III or IV. However, no assembled complex I but only dissociated subunits were observed following the same protocols used for electrophoretic separation or chromatographic isolation of the supercomplex from the wild-type strain. This indicates that the P. denitrificans complex I is stabilized by assembly into the NADH oxidase supercomplex. In addition to substrate channeling, structural stabilization of a membrane protein complex thus appears as one of the major functions of respiratory chain supercomplexes.
Respiratory chain complex I contains 8-9 iron-sulfur clusters. In several cases, the assignment of these clusters to subunits and binding motifs is still ambiguous. To test the proposed ligation of the tetranuclear iron-sulfur cluster N5 of respiratory chain complex I, we replaced the conserved histidine 129 in the 75-kDa subunit from Yarrowia lipolytica with alanine. In the mutant strain, reduced amounts of fully assembled but destabilized complex I could be detected. Deamino-NADH: ubiquinone oxidoreductase activity was abolished completely by the mutation. However, EPR spectroscopic analysis of mutant complex I exhibited an unchanged cluster N5 signal, excluding histidine 129 as a cluster N5 ligand.
The genetic variability of hepatitis B virus (HBV) represents a challenge for the sensitivity of immunodiagnosis, especially for the detection of surface antigen (HBsAg). There are two types of variants of HBV. Naturally occurring variants are the results of random changes selected over years of population pressure. These variants include HBV genotypes and unusual sequences, which may be poorly detected by immunoassays. The selected variants are mutants that arise in individuals under medically (vaccine, hepatitis B immune globulin and antiviral therapy) or naturally (chronic hepatitis B) induced immune pressure. HBV S-gene mutants have been identified in successfully immunized people worldwide. Based on the assumption that current vaccines containing S protein do not cross-protect against S gene mutants, a mathematical model predicts the disappearance of wild-type HBV in areas with HBsAg endemicity and the emergence of S gene mutants in approximately 100 years as a consequence of universal HBV vaccination. Mutant viruses may escape detection by commercial HBsAg kits. There are several reports on HBsAg negative carriers (HBVDNA positive) of S gene mutants with immunosilent infection or ‘‘unusual’’ serologic constellations. Although S gene mutants have been found to be associated with a more severe clinical course of HBV infection and hepatocellular carcinoma, the clinical significance of the genetic variability of HBV genotypes and HBsAg mutants needs to be further investigated. Detection of HBsAg needs to be improved by the introduction of new HBsAg assays able to recognize S gene mutants described so far and with a lower detection threshold than current immunoassays in order to detect smallest amounts of HBsAg in low-level carriers. There is also a need for more complete epidemiological data on the prevalence of HBsAg mutants in Western Europe and assays for the (differential) screening of mutants need to be developed and evaluated.
A small electrostatic storage ring is the central machine of the Frankfurt Ion Storage Experiments (FIRE) which will be built at the new Stern-Gerlach Center of Frankfurt University. As a true multiuser, multipurpose facility with ion energies up to 50 keV, it will allow new methods to analyze complex many-particle systems from atoms to very large biomolecules. With envisaged storage times of some seconds and beam emittances in the order of a few mm mrad, measurements with up to 6 orders of magnitude better resolutions as compared to single-pass experiments become possible. In comparison to earlier designs, the ring lattice was modified in many details: Problems in earlier designs were related to, e.g., the detection of light particles and highly charged ions with different charge states. Therefore, the deflectors were redesigned completely, allowing a more flexible positioning of the diagnostics. Here, after an introduction to the concept of electrostatic machines, an overview of the planned FIRE is given and the ring lattice and elements are described in detail.
Structural and functional characterization of the dimerization region of soluble guanylyl cyclase
(2004)
Soluble guanylyl cyclase (sGC) is a ubiquitous enzyme that functions as a receptor for nitric oxide. Despite the obligate heterodimeric nature of sGC, the sequence segments mediating subunit association have remained elusive. Our initial screening for relevant interaction site(s) in the most common sGC isoenzyme, α1 β1, identified two regions in each subunit, i.e. the regulatory domains and the central regions, contributing to heterodimer formation. To map the relevant segments in the β1 subunit precisely, we constructed multiple N- and C-terminal deletion variants and cotransfected them with full-length α1 in COS cells. Immunoprecipitation revealed that a sequence segment spanning positions 204–408 mediates binding of β1 to α1 The same region of β1[204–408] was found to promote β /β1 homodimerization. Fusion of [204 β1–408] to enhanced green fluorescent protein conferred binding activity to the recipient protein. Coexpression of β1[204–408] with α1 or β1 targeted the sGC subunits for proteasomal degradation, suggesting that β1[204–408] forms structurally deficient complexes with α1 and β1. Analysis of deletion constructs lacking portions of the β1 dimerization region identified two distinct segments contributing to α1 binding, i.e. an N-terminal site covering positions 204–244 and a C-terminal site at 379–408. Both sites are crucial for sGC function because deletion of either site rendered sGC dimerization-deficient and thus functionally inactive. We conclude that the dimerization region of β1 extends over 205 residues of its regulatory and central domains and that two discontinuous sites of 41 and 30 residues, respectively, facilitate binding of β1 to the α1 subunit of sGC.