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Mechanism of Na+-dependent citrate transport from the structure of an asymmetrical CitS dimer
(2015)
The common human pathogen Salmonella enterica takes up citrate as a nutrient via the sodium symporter SeCitS. Uniquely, our 2.5 Å x-ray structure of the SeCitS dimer shows three different conformations of the active protomer. One protomer is in the outside-facing state. Two are in different inside-facing states. All three states resolve the substrates in their respective binding environments. Together with comprehensive functional studies on reconstituted proteoliposomes, the structures explain the transport mechanism in detail. Our results indicate a six-step process, with a rigid-body 31° rotation of a helix bundle that translocates the bound substrates by 16 Å across the membrane. Similar transport mechanisms may apply to a wide variety of related and unrelated secondary transporters, including important drug targets.
BACKGROUND: Toxoplasmosis endangers the unborn child if its infectious agent--toxoplasma gondii--is transmitted transplacentally during pregnancy. Although this condition occurs in all parts of the world and represents a major public health burden, no detailed knowledge on the global research architecture of congenital toxoplasmosis is available thus far. Hence, it was the aim of this study to assess the related global research activity over the past 110 years.
METHODS: We employed the NewQIS platform, which combines established scientometric and socioeconomic analysis tools with novel visualizing techniques such as density equalizing mapping projections.
RESULTS: In the Web of Science, 13,044 congenital toxoplasmosis-related items published between 1900 and 2012 were identified. These were issued by 26,483 authors originating from 125 countries. The US was the dominating nation (38.7 % of total scientific output), followed by France (10.9 %) and Great Britain (9.2 %). The US also led the ranking in regards to semi-qualitative parameters (total citations, country-specific h-indices and citation rates). When research activity was related to economic figures, the ratio of total toxoplasmosis publications to the total GDP listed Switzerland first with an average of 589.35 toxoplasmosis-related publications per GDP in 1000 Bio US-$, followed by France (545.16), the UK (486.13) and Brazil (431.84) and the US (311.11). The relation of toxoplasmosis-specific publications to the economic power indicator GDP per capita in 1000 US-$ revealed that the US was ranked first with 97.65 toxoplasmosis-related publications/GDP per capita in 1000 US-$, followed by Brazil (85.95). Subject area analysis indicated a relative shortage of studies that addressed pharmacological or public health aspects of congenital toxoplasmosis.
CONCLUSIONS: This study is the first in-depth approach to sketch a global picture of the congenital toxoplasmosis research architecture. In contrast to other fields of biomedical research, not only high-income countries play a major role regarding congenital toxoplasmosis research but also countries such as Brazil that have a high incidence of congenital toxoplasmosis.
Nachdem Padua dem Proto-Signore Ezzelino III. da Romano entrissen worden war und derselbe wenige Jahre später den Schlachtentod gefunden hatte, verfasste der Paduaner Rolandino eine Chronik, in der er die Ereignisse in der Trevisaner Mark vom späten 12. Jahrhundert bis ins Jahr 1260 schildert. Der vorliegende Aufsatz veranschaulicht, bei weiter Auslegung des Kommunikationsbegriffs, vier Kommunikationsebenen in der und über die Chronik. Anhand ausgewählter Beispiele werden einige Kommunikationskontexte im spätmittelalterlichen Ostoberitalien sowie Darstellungsabsicht, Vorgehensweise und Gegenwartsinteresse des Chronisten und auch die frühe Rezeption des Werkes seitens der paduanischen Bürgerschaft aufgezeigt.
Modern experiments in heavy ion collisions operate with huge data rates that can not be fully stored on the currently available storage devices. Therefore the data flow should be reduced by selecting those collisions that potentially carry the information of the physics interest. The future CBM experiment will have no simple criteria for selecting such collisions and requires the full online reconstruction of the collision topology including reconstruction of short-lived particles.
In this work the KF Particle Finder package for online reconstruction and selection of short-lived particles is proposed and developed. It reconstructs more than 70 decays, covering signals from all the physics cases of the CBM experiment: strange particles, strange resonances, hypernuclei, low mass vector mesons, charmonium, and open-charm particles.
The package is based on the Kalman filter method providing a full set of the particle parameters together with their errors including position, momentum, mass, energy, lifetime, etc. It shows a high quality of the reconstructed particles, high efficiencies, and high signal to background ratios.
The KF Particle Finder is extremely fast for achieving the reconstruction speed of 1.5 ms per minimum-bias AuAu collision at 25 AGeV beam energy on single CPU core. It is fully vectorized and parallelized and shows a strong linear scalability on the many-core architectures of up to 80 cores. It also scales within the First Level Event Selection package on the many-core clusters up to 3200 cores.
The developed KF Particle Finder package is a universal platform for short- lived particle reconstruction, physics analysis and online selection.
Die Relevanz von MSC aus Fettgewebe (ASC) in der regenerativen Medizin überrascht in Anbetracht ihrer breit gefächerten Eigenschaften nicht. Neben antiinflammatorischen Eigenschaften und Hypoxieresistenz können sie in eine Vielzahl von Geweben differenzieren und in geschädigtes Gewebe migrieren, wo sie an Reperaturvorgängen beteiligt sind. Dabei stehen unterschiedliche Quellen zur Isolierung von MSC (und ASC) zur Verfügung. Um ASC therapeutisch einsetzen zu können, ist es essentiell ihre Quellen und ihr Potenzial zu erforschen. Es konnte gezeigt werden, dass perirenales Fettgewebe eine geeignete Quelle für ASC (prASC) darstellt. Der Nachweis der Oberflächenantigene CD73, CD90 und CD105 mittels Durchflusszytometrie sowie die Fähigkeit der prASC an Zellkulturplastik zu adhärieren, erlauben die Schlussfolgerung, dass es sich bei den nach einem bereits etablierten Verfahren isolierten Zellen um MSC handelt. Außerdem konnte durch eine zweiwöchige Kultivierung der prASC in supplementierten Medien die Differenzierung in Adipozyten, Chondrozyten sowie Osteozyten induziert werden. Der Nachweis erfolgte durch cytochemische Färbemethoden. In dieser Arbeit wurde die Differenzierung von prASC in Epithelzellen untersucht. Dafür wurden die Zellen in unterschiedlichen ATRA-haltigen Kulturmedien und konditioniertem Medium aus Tubulusepithelzellen kultiviert. Der Einfluss der Medien wurde mittels Western Blot, qPCR und Immunfluoreszenzfärbung nachgewiesen. Die Kultivierung mit ATRA führte zu einer signifikanten Erhöhung der Expression von CK18 und ZO-1. Dabei handelt es sich um Marker, die charakteristisch für Epithelzellen sind. Es konnte folglich gezeigt werden, dass humane prASC in vitro eindeutig in epithelialer Richtung differenzieren können. Unter dem Einfluss von ATRA-supplementierten Medien exprimierten die kultivierten Zellen Genprodukte, die Epithelzellen zuzuordnen sind.
Welche Bedeutung diese Erkenntnis hat ist noch unklar. Möglicherweise sind prASC, als Stammzellen aus Nischen mit anatomischer Nähe zu den Nieren, potente Kandidaten, um untergegangenes Nierengewebe, wie beispielsweise Tubulusepithelzellen, zu ersetzen.
In der vorliegenden Arbeit wurde das Auftreten einer Fatigue und Depression mit verschiedenen Messinstrumenten in den beiden Vergleichsgruppen Patienten mit einem Prostatakarzinom unter GnRH-Analoga-Therapie im Vergleich zu Patienten mit einem benignen Prostatasyndrom (BPS) untersucht.
Dabei wurde neben der Erhebung des sozioökonomischen Status eine Befragung mittels Brief Fatigue Inventory (BFI), EORTC-QLQ-C30 und dem Beck Depressions-Inventar (BDI) durchgeführt. Die Hypothese war, dass kein Unterschied im Vorhandensein der beiden Merkmale Fatigue und Depression zwischen den beiden Gruppen besteht.
Insgesamt konnten 102 Prostatakarzinom- und 100 BPS-Patienten in die zuvor von der Ethikkommission der Landesärztekammer Hessen genehmigte Studie eingeschlossen werden. Die Datenerhebung erfolgte an ambulanten Patienten in den urologischen Praxisstandorten Prof. Dr. Bickeböller (Frankfurt) und PD Dr. Engl (Oberursel).
In der Auswertung stellte sich ein signifikanter Unterschied hinsichtlich des Durchschnittsalters der Probanden (74,2 Jahre bei den Prostatakarzinompatienten, 70,1 Jahre bei den BPS-Patienten) dar. Bei der Schulbildung und dem Familienstand bestand kein signifikanter Unterschied.
Es konnte gezeigt werden, dass die Fatigue gemessen mittels BFI-Score keinen signifikanten Unterschied zwischen den beiden Gruppen erreichte. Der mittlere BFI-Score bei den Prostatakarzinompatienten lag bei 2,86 und bei den BPS-Patienten bei 2,79 Punkten. Von einer behandlungsbedüftigen, klinisch relevanten Fatigue spricht man nach allgemeinem Konsens bei einem Punktewert > 3. Diese lag bei 36,7% der Prostatakarzinompatienten und bei 33,7% der BPS-Patienten vor (p = 0,321).
Im EORTC-QLQ C30 Fragebogen ergaben sich signifikante Unterschiede für die Funktionscores Rollenfunktion (p = 0,038) und physische Funktion (p = 0,020) sowie für den Symptomscore Fatigue (FA-Score) (p = 0,047) zugunsten der BPS-Patienten, die jeweils bessere Werte erzielten. Dabei lag der durchschnittliche Punktewert der Rollenfunktion bei den Prostatakarzinompatienten mit 70,1 Punkten niedriger als bei den BPS-Patienten mit 77,5 Punkten. Der durchschnittliche Score für die physische Funktion lag bei den Prostatakarzinompatienten bei 71,0 Punkten (BPS-Patienten 78,4 Punkte) und der FA-Score bei 38,3 Punkten (BPS-Patienten 31,4 Punkte), wobei berücksichtigt werden muss, dass beim FA-Score niedrigere Punktewerte ein geringeres Ausmaß an Fatigue repräsentieren.
Der BDI offenbarte signifikante Unterschiede (Angabe in Mittelwerten) bei den Attributen „Selbstkritik“ (Prostatakarzinompatienten 0,23 Punkte, BPS-Patienten 0,44 Punkte, p = 0,015), „Energieverlust“ (Prostatakarzinompatienten 1,01 Punkte, BPS-Patienten 0,71 Punkte, p = 0,020) und „Verlust an sexuellem Interesse“ (Prostatakarzinompatienten 1,65 Punkte, BPS-Patienten 0,69 Punkte, p = 0,000). Von einer milden depressiven Symptomatik spricht man vereinbarungsgemäß ab einem BDI-Gesamt-Mittelwert von ≥ 14 Punkten. Der Mittelwert unserer beiden Vergleichsgruppen lag bei 10,29 (Prostatakarzinompatienten) und 8,6 (Patienten mit BPS) und war mit p = 0,608 nicht signifikant unterschiedlich. Eine Korrelation zwischen Fatigue und Depression konnte nicht erfolgen, da die Anzahl der Patienten mit einer moderaten/schweren Depression aufgrund der kleinen Fallzahl zu gering war.
Insgesamt konnte bei keinem der untersuchten Messinstrumente eine signifikante Korrelation zum Alter oder zum Familienstand festgestellt werden. Es zeigte sich ein signifikanter Unterschied (p = 0,029) im Vergleich der Schulbildung zum Ausmaß der Fatigue im FA-Score bei Prostatakarzinompatienten zuungunsten einer niedrigeren Schulbildung. Bei den BPS-Patienten konnte dieser Sachverhalt nicht gezeigt werden.
Zusammenfassend kann festgestellt werden, dass kein signifikanter Unterschied der beiden Gruppen in Hinblick auf das Ausmaß der Fatigue gemessen mit dem BFI-Score und das Auftreten einer Depression gemessen mit dem BDI besteht. Der signifikante Unterschied der Fatigue gemessen mittels FA-Score des EORTC-QLQ-C30 Fragebogens kann mit einem von Knobel et al. beschriebenen floor/ceiling effect erklärt werden, der bei Karzinompatienten das Ausmaß der Fatigue aufgrund von physischen Einschränkungen überschätzt und bei gesunden Patienten unterschätzt.
Dass Patienten mit einer benignen Grunderkrankung wie dem Prostatasyndrom im gleichen Ausmaß an Fatigue leiden wie Prostatakarzinompatienten wurde in unserer Arbeit erstmalig gezeigt und bedarf der weiteren Forschung, da die bislang bekannten pathophysiologischen Faktoren der Fatigue kein ausreichendes Erklärungsmodell bieten. Eine gestörte Nachtruhe durch die vermehrt im Rahmen des BPS auftretende Nykturie kann als eine der Ursachen angenommen werden, diesbezüglich sollten zukünftig weitere Untersuchungen stattfinden.
In der familienbiographischen Studie „Bürgerliche Lebenswelten im Spiegel eines familiären Briefwechsels“ wird eine bürgerliche, nicht-prominente Familie aus Hamburg über drei Generationen hinweg in der Zeit von 1840 bis 1930 untersucht. Als Quellen wurden knapp 3000 Privatbriefe sowie mehrere Familienchroniken ausgewertet.
Thematisch gehört die Arbeit zum Kontext der deutschsprachigen Bürgertumsforschung und hat eine Schnittmenge mit mehreren thematischen Unterbereichen: Sie legt einen starken Fokus auf geschlechtergeschichtliche Themen und Problemstellungen und weist interdisziplinär Schnittmengen mit der Soziologie auf. Gerade bei der Beschreibung von biographisch hochemotionalen Momenten nähert sie sich bewusst der bislang wenig beachteten ,Gefühlskultur’ bürgerlicher Menschen und ihrer je nach Persönlichkeit sehr individuellen Ausprägung an.
Breast cancer is fast becoming the leading cause of oncologic morbidity and mortality among women worldwide. Demographic changes in Asia, Southeast Asia, and South America will further accelerate this trend. Different specialties are involved in the treatment of breast cancer patients: gynecology, surgery, pathology, hematology/oncology, radiology, radiation oncology, and nuclear medicine. Optimal results are seen in countries providing standardized breast cancer care in certified breast centers. The present article provides an overview of current state-of-the-art treatment strategies and explains the contributions of different specialties to optimal and individualized care for breast cancer patients. Breast cancer will be one of the most important health issues facing physicians involved with women’s health and a basic understanding of current treatment objectives will be essential medical knowledge for everyone taking care of female patients.
Der Pilz Podospora anserina ist seit mehr als fünf Jahrzehnten ein wichtiger Modellorganismus für die Alternsforschung. Insbesondere die Mitochondrien, essentielle eukaryotische Zellorganellen – wegen ihrer Funktion im Energiestoffwechsel häufig auch als „zelluläre Kraftwerke“ bezeichnet, sind Schlüsselfaktoren für den Alterungsprozess dieses Organismus.
Im Rahmen einer vorangegangenen Diplomarbeit wurde daher der Einfluss der mitochondrialen CLPXP-Protease, einem bisher noch wenig erforschten Bestandteil der Proteinqualitätskontrolle in Mitochondrien, auf die Alterung von P. anserina untersucht. Mitochondriale CLPXP-Proteasen sind, wie auch ihre bakteriellen Pendants, aus zwei verschiedenen Untereinheiten aufgebaut: der Protease-Komponente CLPP und der Chaperon-Komponente CLPX. Die Deletion des Gens PaClpP, kodierend für CLPP in P. anserina, führte zu einer überraschenden Verlängerung der gesunden Lebensspanne der Mutante. Darüber hinaus war es möglich, den pilzlichen PaClpP-Deletionsstamm durch Einbringen von CLPP des Menschen zu komplementieren. Dies beweist, dass die Proteasen CLPP des Menschen und von P. anserina funktionell homolog sind. Dadurch eröffnete sich die Perspektive, diesen einfachen Modellorganismus für die Gewinnung potenziell auf den Menschen übertragbarer Erkenntnisse einzusetzen. Bedeutenderweise ist die menschliche CLPXP-Protease wahrscheinlich involviert in die Entstehung verschiedener Krankheiten, darunter das Perrault-Syndrom sowie einige Krebsarten. Die zugrundeliegenden Mechanismen sind jedoch noch weitestgehend unverstanden.
Ziel des in dieser Dissertation beschriebenen Forschungsprojektes war daher die Gewinnung genauerer Einsichten in die molekulare Funktion und die daraus folgende biologische Rolle der mitochondrialen CLPXP-Protease von P. anserina. Der wohl wichtigste Punkt für das detaillierte Verständnis einer Protease ist die Kenntnis ihres Substratspektrums, d. h. der von ihr abgebauten Proteine. Tatsächlich wurde aber bis heute noch in keinem eukaryotischen Organismus eine umfassende Analyse der Substrate einer mitochondrialen CLPXP-Protease vorgenommen. Um diese Wissenslücke zu füllen, wurde in der vorliegenden Arbeit eine ursprünglich in Bakterien entwickelte Verfahrensweise, der sogenannte CLPP „Substrat-trapping Assay“, in P. anserina implementiert. Dafür mussten zunächst die notwendigen handwerklichen Voraussetzungen für den Assay geschaffen werden, insbesondere die effiziente Affinitätsaufreinigung von Proteinen aus isolierten Mitochondrien – einer bisher in P. anserina noch nicht angewandten Technik. Unter Verwendung verschiedener neu hergestellter Varianten der menschlichen Protease-Komponente CLPP, darunter einer proteolytisch inaktiven Variante zum „Einfangen“ von Substraten, konnte der CLPP „Substrat-trapping Assay“ in P. anserina erfolgreich durchgeführt werden. Insgesamt wurden, in Kooperation mit der Arbeitsgruppe von Julian D. Langer (Max-Planck-Institut für Biophysik; Durchführung von massenspektrometrischen Analysen) nahezu 70 spezifische Proteine erstmalig als potenzielle Substrate oder Interaktionspartner einer mitochondrialen CLPXP-Protease identifiziert. Bei einem Großteil dieser Proteine handelt es sich um Enzyme und Komponenten verschiedener Stoffwechselwege – vor allem um solche, die eine zentrale Rolle im mitochondrialen Energiestoffwechsel spielen. Die Ergebnisse der vorliegenden Arbeit legen somit folgende Arbeitsthese als Schlussfazit und gleichzeitig Ausganspunkt für zukünftige Untersuchungen nahe:
Die hauptsächliche molekulare Funktion der mitochondrialen CLPXP-Protease in P. anserina ist die Degradation von Stoffwechselenzymen und ihre biologische Rolle demnach die Kontrolle und Aufrechterhaltung des mitochondrialen und zellulären Energiestoffwechsels.
Insgesamt ist die auf Grundlage des CLPP „Substrat-trapping Assay“ in P. anserina anzunehmende Rolle der mitochondrialen CLPXP-Protease als regulatorische Komponente des mitochondrialen Energiestoffwechsels erstaunlich gut mit Beobachtungen in anderen eukaryotischen Organismen, gerade bezüglich der Relevanz der CLPXP-Protease des Menschen für diverse Krankheiten, zu vereinbaren. Somit erscheint es überaus sinnvoll und vielversprechend, dass in dieser Doktorarbeit erstellte und bisher beispiellose Kompendium potenzieller in vivo Substrate und Interaktionspartner dieser Protease auch als Referenz für zukünftige Untersuchungen außerhalb von P. anserina anzuwenden.
The success stories of design-oriented companies like Apple, Audi or Nike have put design on the agenda in many marketing departments. Consumers cannot elude the effect of aesthetics and therefore design is a major factor for business success. Typically consumers choose the product with the best design, all other aspects being equal. Only when the interplay of product characteristics, brand and design is carefully coordinated can successful products be created. This requires an integrated approach to design, one which is applied right at the beginning of the value chain. Product development, marketing and design need to work in close cooperation, communicate well and frequently, and collect feedback from the market. Superior aesthetics are always important but should be a top priority in cases where efficiency-oriented Asian competitors are able to offer functionally similar products at much lower prices.
The caddisfly subfamily Drusinae BANKS comprises roughly 100 species inhabiting mountain ranges in Europe, Asia Minor and the Caucasus. A 3-gene phylogeny of the subfamily previously identified three major clades that were corroborated by larval morphology and feeding ecologies: scraping grazers, omnivorous shredders and filtering carnivores. Larvae of filtering carnivores exhibit unique head capsule complexities, unknown from other caddisfly larvae. Here we assess the species-level relationships within filtering carnivores, hypothesizing that head capsule complexity is derived from simple shapes observed in the other feeding groups. We summarize the current systematics and taxonomy of the group, clarify the systematic position of Cryptothrix nebulicola, and present a larval key to filtering carnivorous Drusinae. We infer relationships of all known filtering carnivorous Drusinae and 34 additional Drusinae species using Bayesian species tree analysis and concatenated Bayesian phylogenetic analysis of 3805bp of sequence data from six gene regions (mtCOI5-P, mtCOI3-P, 16S mrDNA, CADH, WG, 28S nrDNA), morphological cladistics from 308 characters, and a total evidence analysis. All analyses support monophyly of the three feeding ecology groups but fail to fully resolve internal relationships. Within filtering carnivores, variation in head setation and frontoclypeus structure may be associated with progressive niche adaptation, with less complex species recovered at a basal position. We propose that diversification of complex setation and frontoclypeus shape represents a recent evolutionary development, hypothetically enforcing speciation and niche specificity within filtering carnivorous Drusinae.
An increasing body of evidences from preclinical as well as epidemiological and clinical studies suggest a potential beneficial role of dietary intake of omega-3 fatty acids for cognitive functioning. In this narrative review, we will summarize and discuss recent findings from epidemiological, interventional and experimental studies linking dietary consumption of omega-3 fatty acids to cognitive function in healthy adults. Furthermore, affective disorders and schizophrenia (SZ) are characterized by cognitive dysfunction encompassing several domains. Cognitive dysfunction is closely related to impaired functioning and quality of life across these conditions. Therefore, the current review focues on the potential influence of omega-3 fatty acids on cognition in SZ and affective disorders. In sum, current data predominantly from mechanistic models and animal studies suggest that adjunctive omega-3 fatty acid supplementation could lead to improved cognitive functioning in SZ and affective disorders. However, besides its translational promise, evidence for clinical benefits in humans has been mixed. Notwithstanding evidences indicate that adjunctive omega-3 fatty acids may have benefit for affective symptoms in both unipolar and bipolar depression, to date no randomized controlled trial had evaluated omega-3 as cognitive enhancer for mood disorders, while a single published controlled trial suggested no therapeutic benefit for cognitive improvement in SZ. Considering the pleiotropic mechanisms of action of omega-3 fatty acids, the design of well-designed controlled trials of omega-3 supplementation as a novel, domain-specific, target for cognitive impairment in SZ and affective disorders is warranted.
The current Review article provides a narrative review about the neurobiological underpinnings and treatment of treatment resistant late-life depression (TRLLD). The manuscript focuses on therapeutic targets of late-life depression, which include pharmacological, psychological, biophysical and exercise treatment approaches. Therefore, we summarize available evidences on that kind of therapies for patients suffering from late-life depression. The search for evidences of therapeutic options of late-life depression were done using searching websites as “pubmed”, and using the searching terms “depression”, “late-life depression”, “treatment”, “biophysical therapy”, “exercise therapy”, “pharmacological therapy” and “psychological therapy”. To the end, we summarize and discuss current data, providing some directions for further research.
Treatment recommendations for elderly depressive patients favour a multimodal approach, containing psychological, pharmacological and secondary biophysical therapeutic options. Particularly, a combination of psychotherapy and antidepressant medication reflects the best therapeutic option. However, mostly accepted and used is the pharmacological treatment although evidence suggests that the drug therapy is not as effective as it is in younger depressive patients. Further studies employing larger samples and longer follow-up periods are necessary and may focus on comparability of study designs and involve novel approaches to establish the validity and reliability of multimodal treatment programs.
Understanding how to achieve efficient transduction of hematopoietic stem and progenitor cells (HSPCs), while preserving their long-term ability to self-reproduce, is key for applying lentiviral-based gene engineering methods. SAMHD1 is an HIV-1 restriction factor in myeloid and resting CD4+ T cells that interferes with reverse transcription by decreasing the nucleotide pools or by its RNase activity. Here we show that SAMHD1 is expressed at high levels in HSPCs cultured in a medium enriched with cytokines. Thus, we hypothesized that degrading SAMHD1 in HSPCs would result in more efficient lentiviral transduction rates. We used viral like particles (VLPs) containing Vpx, shRNA against SAMHD1, or provided an excess of dNTPs or dNs to study this question. Regardless of the method applied, we saw no increase in the lentiviral transduction rate. The result was different when we used viruses (HR-GFP-Vpx+) which carry Vpx and encode GFP. These viruses allow assessment of the effects of Vpx specifically in the transduced cells. Using HR-GFP-Vpx+ viruses, we observed a modest but significant increase in the transduction efficiency. These data suggest that SAMHD1 has some limited efficacy in blocking reverse transcription but the major barrier for efficient lentiviral transduction occurs before reverse transcription.
Despite multimodal regimens and diverse treatment options alleviating disease symptoms, morbidity and mortality associated with advanced ischemic heart failure remain high. Recently, technological innovation has led to the development of regenerative therapeutic interventions aimed at halting or reversing the vicious cycle of heart failure progression. Driven by the unmet patient need and fueled by encouraging experimental studies, stem cell-based clinical trials have been launched over the past decade. Collectively, these trials have enrolled several thousand patients and demonstrated the clinical feasibility and safety of cell-based interventions. However, the totality of evidence supporting their efficacy in ischemic heart failure remains limited. Experience from the early randomized stem cell clinical trials underscores the key points in trial design ranging from adequate hypothesis formulation to selection of the optimal patient population, cell type and delivery route. Importantly, to translate the unprecedented promise of regenerative biotherapies into clinical benefit, it is crucial to ensure the appropriate choice of endpoints along the regulatory path. Accordingly, we here provide considerations relevant to the choice of endpoints for regenerative clinical trials in the ischemic heart failure setting.
This dissertation examines the language of politics of leading figures of the ex-Free Aceh Movement or Gerakan Aceh Merdeka‟ (GAM) leading figures in selected Aceh media during the 2012 gubernatorial election campaign. By analyzing their symbolic acts, topic selection, campaign methods, and campaign locations as reported in five selected Aceh media, I demonstrate the process of ex-GAM political rhetoric in the post-conflict election setting. The mixed method approach used in the dissertation includes the following: grounded, content analysis, case study, and rhetorical analysis. Data were collected from three local daily broadsheet newspapers (Serambi Indonesia, Rakyat Aceh and Harian Aceh) and two online news portals (The Atjeh Post and The Globe Journal). The research found that ex-GAM political rhetoric was deeply divided into two opposing political camps: the Irwandi camp as the incumbent independent and the PA camp as the challenger from a newly-established local political party. Both camps highlighted the importance of expressive symbolic acts, such as explaining and making promises in their campaigns. Irwandi introduced more varied, specific, practical, and concrete topics in its rhetoric with diverse and less formal campaign methods that appealed to those who envision a prosperous future in Aceh. By contrast, PA employed general, unrealistic, and abstract topics in its rhetoric with less attractive and more formal campaign methods that appealed to emotional and historical romanticism. In relation to ex-GAM political rhetoric and campaign locations, both focused on the traditional regions in northeast Aceh or in the conflict-sensitive regions where most of their loyalists reside, and on big regencies/cities where the potential voters live. However, during the campaign Irwandi appeared less frequently in ethnically diverse locations, whereas PA appeared more in non-traditional regions such as the previously isolated and less-developed regions in the central highlands and southeast regions of Aceh. In this way they highlighted the rhetoric of economic and infrastructure development and that of unity in diversity taking into account the multi-ethnicity of the voters. In terms of overall media appearances, except in The Atjeh Post, where Muzakir Manaf from PA was dominant, Irwandi Yusuf was the most-reported ex-GAM during the election campaign in the selected media. Finally, the available evidence seems to suggest that Irwandi‘s language of politics was rhetorically more attractive than that of other ex-GAM leaders.
Reading is an essential ability to master everyday life in our society. The ability to read is based on specific connections between brain regions involved in the reading process – so-called cortical networks for reading. These cortical networks for reading allow us to learn the correct identification of visual words. The use of visual words is based on knowledge about the orthography (lexical) and the meaning of words (semantic). This knowledge must be acquired by beginning readers (first grader), i.e. beginning readers learn in a first step to link letters to a whole word and in a second step associate this whole word with meaning. To retrieve this knowledge during visual word recognition (VWR) a cortical network for lexical-semantic process must be activated. However, it is currently unclear whether beginning readers and reading experts activate the same neuronal network during VWR. Therefore, the aim of this thesis was to investigate the question whether beginning readers (first grader, children) and reading experts (adults) use different cortical networks for the lexical-semantic processing in VWR.
To address this question we recorded electroencephalographic (EEG) activity during VWR in children and adults. Children and adults were instructed to read a visualizable word to compare this word with a following picture stimulus. The first part of this thesis is concerned with the analysis of ERPs for visual word recognition in children and adults at sensor level. For both groups we observed the typical ERP components P100 and N170 for visual word recognition. These components differed in amplitude and time course between both groups. The second part of this thesis investigated the neuronal generators (brain areas) of ERPs during VWR and possible differences between children and adults at source level. We observed a high overlap in brain areas involved during VWR in children and adults. However, the brain areas differed in activation and time course between children and adults. Finally, the third and most important part of the thesis investigated the question whether children and adults use different cortical networks for the lexical-semantic processing in VWR over time. To address this question Dynamic Causal Modeling (DCM) and Bayesian model comparison were used. We compared nine biologically plausible cortical network models underlying the ventral lexical-semantic path in VWR. In addition, increasing time intervals were used to consider possible changes of network structure during VWR. The network models included eight brain regions (four bilateral pairs) involved in the lexical-semantic processing in VWR: occipital cortex (OC), temporo-occipital part of inferior temporal gyrus (ITG), temporal pole (TP), and inferior frontal gyrus (IFG). In almost all time intervals we found evidence that children and adults use the same cortical networks for the lexical-semantic processing in VWR. However, we found differences between adults and children in the connection strengths of the favoured model. Interestingly, we found a stronger direct connection from OC to IFG in adults compared to children.
In conclusion, our results suggest that children and adults activate largely the same lexical-semantic networks during VWR over time. This supports the notion that children and adults use the same biological fiber connections for VWR. However in contrast to children, adults showed increased use of the shortcut pathway from OC to IFG. The increased use of the shortcut pathway from OC to IFG in adults can be interpreted as consequence of learning. Learning causes in accordance with the Hebbian learning rule (“neurons that fire together, wire together” (Hebb, 1949)) synaptic change. Consequently the frequent coactivation of the input and output stage of OC and IFG during the lexical-semantic process facilitates the stronger direct connection between both brain areas. The stronger direct connection from OC to IFG most likely allows adult reading experts to speed up the lexical-semantic process during VWR. Accordingly, we conclude that the stronger direct connections from OC to IFG in adults compared to children underlay the different reading capabilities in both groups.
The processing of pain undergoes several changes in aging that affect sensory nociceptive fibers and the endogenous neuronal inhibitory systems. So far, it is not completely clear whether age-induced modifications are associated with an increase or decrease in pain perception. In this study, we assessed the impact of age on inflammatory nociception in mice and the role of the hormonal inhibitory systems in this context. We investigated the nociceptive behavior of 12-month-old versus 6–8-week-old mice in two behavioral models of inflammatory nociception. Levels of TRP channels, and cortisol as well as cortisol targets, were measured by qPCR, ELISA, and Western blot in the differently aged mice. We observed an age-related reduction in nociceptive behavior during inflammation as well as a higher level of cortisol in the spinal cord of aged mice compared to young mice, while TRP channels were not reduced. Among potential cortisol targets, the NF-κB inhibitor protein alpha (IκBα) was increased, which might contribute to inhibition of NF-κB and a decreased expression and activity of the inducible nitric oxide synthase (iNOS). In conclusion, our results reveal a reduced nociceptive response in aged mice, which might be at least partially mediated by an augmented inflammation-induced increase in the hormonal inhibitory system involving cortisol.
The Muskoka Initiative – or the Maternal, Newborn and Child Health (MNCH) Initiative has been a flagship foreign policy strategy of the Harper Conservatives since it was introduced in 2010. However, the maternal health initiative has been met with a number of key criticisms in relation to its failure to address the sexual and reproductive health needs of women in the Global South2. In this article, I examine these criticisms and expose the prevalent and problematic discourse employed in Canadian policy papers and official government speeches pertaining to the MNCH Initiative. I examine the embodiment of the MNCH and how these references to women’s bodies as “walking wombs” facilitate: the objectification and ‘othering’ of women as mothers and childbearers; a discourse of ‘saving mothers’ in a paternalistic and essentialist language; and the purposeful omission of gender equality. Feminist International Relations (IR) and post-colonial literature, as well as critical/feminist Canadian foreign policy scholarship are employed in this paper to frame these critiques.
This paper argues that it is necessary to focus on gender rather than exclusively on women in discussions on global poverty eradication. It argues firstly, that the drivers of poverty are complex and multifaceted leading to a least two different forms of deprivation – transitory and structural poverty – each requiring different forms of analysis and treatment. Transitory poverty can arise as a consequence of an event or shock that would diminish an individual’s capacity to retain or secure employment and where a State lacks an appropriate form of social protection. Structural poverty, on the other hand, arises where groups are excluded from the workforce on a more permanent basis due to a wide variety of factors of discrimination such as sex, race, ethnicity, and age. Focusing on the sex of an individual alone cannot explain why some are more likely to experience different forms of poverty than others. Policies that protect women against transitory poverty, such as care related allowances, are not sufficient to eradicate structural poverty. Secondly, structural poverty prompts an examination of gender roles and relations. Unlike the category of ‘women’, the concept of gender demands consideration of a wider range of intersecting factors that influence life chances. The structure of contemporary gender relations, where women continue to experience higher levels of violence, and carry the greatest burden of responsibility for non-market based production activities, create the social conditions where domination and dependence thrive, and where persistently high rates of poverty seem inevitable. Such circumstances are generated by human agency. Thus, thirdly, it argues that these circumstances can and should be changed through human action. Knowledge of these circumstances gives rise to moral obligations for both men and women to avoid upholding values and practices that lead to domination and dependence as a matter of basic justice.
In this paper, I examine how maternal myths are deployed in popular development literature. Using critical discourse analysis and working within a feminist postcolonial framework I analyse five texts produced by development organizations for popular consumption. I identify how maternal myths are constructed in each text and conduct a contextual analysis of four myths to identify their ideological significance within the development sector. I conclude that that in their construction of maternal myths, these texts, while intended to elicit support for gender and development interventions, reinforce exploitative gender roles and relations and limit women’s experiences of development.
As the lowest in the caste hierarchy, Dalits in Indian society have historically suffered caste-based social exclusion from economic, civil, cultural, and political rights. Women from this community suffer from not only discrimination based on their gender but also caste identity and consequent economic deprivation. Dalit women constituted about 16.60 percent of India’s female population in 2011. Dalit women’s problems encompass not only gender and economic deprivation but also discrimination associated with religion, caste, and untouchability, which in turn results in the denial of their social, economic, cultural, and political rights. They become vulnerable to sexual violence and exploitation due to their gender and caste. Dalit women also become victims of abhorrent social and religious practices such as devadasi/jogini (temple prostitution), resulting in sexual exploitation in the name of religion. The additional discrimination faced by Dalit women on account of their gender and caste is clearly reflected in the differential achievements in human development indicators for this group. In all the indicators of human development, for example, literacy and longevity, Dalit women score worse than Dalit men and non-Dalit women. Thus, the problems of Dalit women are distinct and unique in many ways, and they suffer from the ‘triple burden’ of gender bias, caste discrimination, and economic deprivation. To gain insights into the economic and social status of Dalit women, our paper will delve more closely into their lives and encapsulate the economic and social situations of Dalit women in India. The analyses of human poverty and caste and gender discrimination are based on official data sets as well as a number of primary studies in the labor market and on reproductive health.
Ibegin by providing some background to conceptions of responsibility. I note the extent of disagreement in this area, the diverse and cross-cutting distinctions that are deployed, and the relative neglect of some important problems. These facts make it difficult to attribute responsibility for climate change, but so do some features of climate change itself which I go on to illuminate. Attributions of responsibility are often contested sites because such attributions are fundamentally pragmatic, mobilized in the service of a normative outlook. We should be pluralists about responsibility and shape whatever conceptions can help to explain, guide, and motivate our responses to climate change. I sketch one such notion, ‘intervention-responsibility’, and argue that it should be ascribed to international regimes and organizations, states and other jurisdictions, individuals, and firms. Each has different capacities and thus different intervention-responsibilities responsibilities, but these differences are not always mirrored in public discussion. In particular, the moral responsibility of firms has been greatly neglected.
t is becoming less and less controversial that we ought to aggressively combat climate change. One main reason for doing so is concern for future generations, as it is they who will be the most seriously affected by it. Surprisingly, none of the more prominent deontological theories of intergenerational justice can explain why it is wrong for the present generation to do very little to stop worsening the problem. This paper discusses three such theories, namely indirect reciprocity, common ownership of the earth and human rights. It shows that while indirect reciprocity and common ownership are both too undemanding, the human rights approach misunderstands the nature of our intergenerational relationships, thereby capturing either too much or too little about what is problematic about climate change. The paper finally proposes a way to think about intergenerational justice that avoids the pitfalls of the traditional theories and can explain what is wrong with perpetuating climate change.
This article discusses obstacles to overcoming dangerous climate change. It employs an account of dangerous climate change that takes climate change and climate change policy as dangerous if it imposes avoidable costs of poverty prolongation. It then examines plausible accounts of the collective action problems that seem to explain the lack of ambition to mitigate. After criticizing the merits of two proposals to overcome these problems, it discusses the pledge and review process. It argues that pledge and review possesses the virtues of encouraging broad participation and of providing a procedural safeguard for the right of sustainable development. However, given the perceptions of the marginal short term costs of mitigation, pledge and review is unlikely, at least initially, to issue in an agreement to make deep reductions in greenhouse gas emissions. Because there is no rival approach that seems likely to better instantiate the two virtues, pledge and review may be the best available policy for mitigation. Moreover, recent economic research suggests that the co-benefits of mitigation may be greater than previously assumed and that the costs of renewable energy may be less than previously calculated. This would radically undermine claims that the short term mitigation costs necessarily render mitigation irrational and produce collective action problems. Given the circumstances, pledge and review might be our best hope to avoid dangerous climate change.
In cases in which there is the possibility of massive human losses, the threshold likelihood of their occurrence, and the non-excessive costs of their prevention, we ought to act now. This is all the more definitely the case because it may well be that this is the time-of-last-opportunity to head off one or more potential disasters, all of which may still be preventable by sufficiently rapid reductions in carbon emissions from the combustion of fossil fuel. It is unfair that the present generation should incur as heavy a burden as it does of seizing the last opportunity for prevention of disasters like large sea-level rises, but the unfairness is not sufficient to make the burden unreasonable to bear, especially since it is not in fact as heavy as often believed.
However far we are from either in practice, basic global and intergenerational justice, including climate change mitigation, are taken to be theoretically compatible. If population grows as predicted, this could cease to be the case. This paper asks whether that tragic legacy can now be averted without hard or even tragic choices on population policy. Current generations must navigate between: a high-stakes gamble on undeveloped technology; violating human rights; demanding unbearable sacrifices of the already badly off; institutional unfairness across adults; institutional unfairness across children; failing to protect children’s basic interests; and threatening the autonomy of the family. We are not yet forced to choose between bequeathing a tragic choice and making one, by adopting basically unjust measures. However, even the remaining options present a morally hard choice. The fact we face it is yet another damning indictment on the combined actions and collective failures of the global elite.
Climate justice
(2015)
Perioperative Blutungskomplikationen stellen, insbesondere für neurochirurgisch behandelte Patienten, eine schwerwiegende Komplikation dar und sind mit einer signifikant erhöhten Morbidität und Mortalität assoziiert [1]. Der perioperative Blutverlust ist einer der Hauptgründe für die Transfusion allogener Blutprodukte [2, 3]. Transfusionen von Erythrozytenkonzentraten (EK), Gefrorenem Frischplasma (GFP) und Thrombozytenkonzentraten (TK) sind dabei unabhängige Risikofaktoren für die Entwicklung thromboembolischer, pulmonaler, hämodynamischer oder septischer Komplikationen und selbst mit einer erhöhten perioperativen Morbidität und Mortalität assoziiert [3-10]. In der Literatur wird die Prävalenz von Blutungskomplikationen im Rahmen von intrakraniellen Eingriffen (Raten zwischen 0,8% bis 50%) sehr unterschiedlich beschrieben [1, 11-13]. Gleichwertige Voraussetzungen für die Bildung und Aufrechterhaltung eines stabilen Blutgerinnsels sind, neben einer effizienten primären Hämostase (Thrombozytenzahl und –funktion, Von-Willebrand-Faktor), auch die plasmatische Gerinnung (extrinsische und intrinsische Gerinnungsfaktoren) und der Schutz vor (Hyper)fibrinolyse [14].
Tectonin β-propeller containing protein 2 (TECPR2) was first identified in a mass- spectrometric approach as an interactor of GABARAP, an ATG8-family protein playing a role in autophagy. The mammalian ATG8 protein family consists of seven members, namely MAP1LC3A (LC3A), MAP1LC3B (LC3B), MAP1LC3C (LC3C), GABARAP, GABARAPL1 and GABARAPL2. All share an ubiquitin-like core and possess two additional N-terminal α-helices, which are important for the distinct functions of the proteins. First determined in various organelles the ATG8 proteins are shown to be involved in autophagy, supporting the formation and cargo recruitment of autophagosomes, the vesicles transporting cargo for autophagic degradation.
Autophagy is the process of recycling cytoplasmic contents by degradation of misfolded proteins or damaged organelles in order to supply nutrients. Also clearance of pathogens can be achieved via autophagy. Importantly, LC3B is incorporated into the autophagosomal membrane and is therefore used as the main marker for autophagosomes. Previous studies exhibited that depletion of TECPR2 leads to a loss of LC3B-positive structures in cells, which suggests TECPR2 to positively regulate autophagic processes.
A frame shift deletion in the gene encoding for TECPR2 causes the generation of a premature stop codon and subsequent an unstable version of the protein, which is then degraded. Mutation in the TECPR2 gene triggers a neurodegenerative disorder termed hereditary spastic paraparesis (HSP). HSPs are a diverse group of neurodegenerative diseases that are characterized by spasticity in prevalent lower extremities and were mediated by a loss of axonal integrity of the corticospinal motor neurons. In the context of HSP more than 50 gene loci were identified by now. While TECPR2 is a human ATG8 binding protein and positive regulator of autophagy causing a form of HSP, the exact function of TECPR2 is unknown.
This study primarily focused on the determination of TECPR2’s binding mode to ATG8 proteins in vitro and in cells. The association of TECPR2 to all ATG8-family proteins was confirmed in in vitro pulldown experiments. Following fragment-based binding and peptide array experiments, the LC3-interacting region (LIR) of TECPR2 could be verified with mutants of TECPR2 lacking the LIR motif. Nuclear magnetic resonance (NMR) and isothermal titration calorimetry (ITC) were conducted to gain deeper insights into the binding preference to the different ATG8-family members. Moreover, the crystal structure of TECPR2-LIR was solved. In cells colocalization studies with overexpressed ATG8 proteins unraveled a preferential binding to the LC3-subfamily.
Further, mass spectrometric analysis revealed novel association partners of TECPR2: SEC24D, HOPS and BLOC-1, all of those participating in different endomembrane trafficking pathways. Interaction and colocalization of TECPR2 with these components was validated with several immunoprecipitation experiments and the N-terminal part of the protein comprising the WD40-domain could be defined as the binding site for all three of the association partners. In further approaches, the requirement of the LIR-motif and the necessity of the availability of LC3 protein for the particular interactions were determined. Interestingly, in the absence of LC3C the binding of TECPR2 to SEC24D was completely disrupted whereas a loss of LC3B only resulted in a decreased association. Notably, the binding proteins were not subjected to autophagosomal degradation, indicating that TECPR2 may operate as a multifunctional scaffold protein. While depletion of TECPR2 destabilized HOPS and BLOC-1, the autophagy defect observed in TECRP2-deficient cells could not be attributed to functional impairment of these two complexes.
Moreover, loss of TECPR2 led to a decline in protein levels of SEC24D and of its heterodimer partner SEC23A. Thus, TECPR2 is required to regulate the protein levels of SEC23A and SEC24D and subsequently the formation of the heterodimers. Together, SEC24D and SEC23A form the inner coat of COPII vesicles. These vesicles are responsible for the anterograde transport of cargo from the ER toward the Golgi compartment. COPII-coated vesicles are secreted form ER at distinct sites, termed ER exit sites (ERES). The small GTPase SAR1A maintains the vesicle budding, coating and secretion at the ERES. Together with SEC13, SEC31 forms the outer coat of the COPII vesicles and therefore serves as a general ERES marker.
Consistent with a defect in COPII coat assembly, the number of ERES diminished in the absence of TECPR2. These phenotypes could be rescued by the wildtype TECPR2 protein but not by the LIR-mutant. Intriguingly, these results were mimicked by depletion of LC3C, which localized to ERES. By monitoring the release of various cargos from ER in dependency of TECPR2 or LC3C, a role of both proteins in ER export was determined. These facts indicated that TECPR2 cooperates with LC3C to facilitate COPII assembly, ERES maintenance and ER export. Notably, fibroblast derived from a HSP patient carrying mutated TECPR2 showed diminished SEC24D protein levels and delayed ER export.
Concurrent with emerging evidence for a role of ERES in autophagosome formation, depletion of TECPR2 or LC3C or overexpression of a constitutive inactive SAR1 mutant reduced puncta formation of the early autophagosomal protein WIPI2.
In summary, this study uncovered a role for TECPR2 in ER export at ERES through interaction and stabilization of SEC24D, a COPII coat protein. This process also depended on ATG8-family protein LC3C, which is localized at ERES. Both proteins are required for correct COPII-mediated secretion. Moreover, the presence of TECPR2 and LC3C on ER allows development of omegasomes, membranous structures budding ER to form autophagosomes, by stabilization of WIPI2 and therefore contribute to autophagosome formation.
This report was written by the organizers of the workshop "Accounting for Combat-Related Killings," which took place at the Goethe University Frankfurt in July 2014. Scholars from Israel, the United Kingdom, the United States,, Canada, and Germany came together to present and discuss case studies on the discourse practices involved in accounting for combat-related killings in different national and transnational contexts. Intending to reflect on the methodological skills needed to analyze newly available process data, the workshop brought together scholars using different methodological approaches (here mainly ethnomethodology and critical discourse analysis). In regard to the global trend towards increasing numbers of so called permanent, asymmetric, small, and permanent wars, the report turns to concepts, methods, and empirical findings that foster understandings of the difficulties war generates at social, cultural and political levels as well as the manner in which these predicaments are negotiated, denied, or deflected. The report summarizes the workshop by presenting the papers in a specific order, beginning with accounting in combat, followed by tribunals of accounting, and finally the sedimentation of accounting in cultural representations.
Hygroscopicity of nanoparticles produced from homogeneous nucleation in the CLOUD experiments
(2015)
Sulfuric acid, amines and oxidized organics have been found to be important compounds in the nucleation and initial growth of atmospheric particles. Because of the challenges involved in determining the chemical composition of objects with very small mass, however, the properties of the freshly nucleated particles and the detailed pathways of their formation processes are still not clear. In this study, we focus on a challenging size range, i.e. particles that have grown to diameters of 10 and 15nm following nucleation, and measure their water uptake. Water uptake constrains their chemical composition. We use a nanometer-hygroscopicity tandem differential mobility analyzer (nano-HTDMA) at subsaturated conditions (ca. 90% relative humidity at 293 K) to measure the hygroscopicity of particles during the seventh Cosmics Leaving OUtdoor Droplets (CLOUD7) experiments performed at CERN in 2012. In CLOUD7, the hygroscopicity of nucleated nanoparticles was measured in the presence of sulfuric acid, sulfuric acid-dimethylamine, and sulfuric acid-organics derived from α-pinene oxidation. The hygroscopicity parameter Κ decreased with increasing particle size indicating decreasing acidity of particles. No clear effect of the sulfuric acid monomer concentrations on the hygroscopicities of 10nm particles produced from sulfuric acid and dimethylamine was observed, whereas the hygroscopicity of 15nm particles sharply decreased with decreasing sulfuric acid monomer concentrations. In 20 particular, when the concentrations of sulfuric acid was 5.1 x 106 molecules cm exp -3 in the gas phase, and the dimethylamine mixing ratio was 11.8 ppt, the measured Κ of 15nm particles was 0.3 ± 0.01 close to the value reported for dimethylamine sulfate (DMAS) (Κ DMAS ~ 0.28). Furthermore, the difference in Κ between sulfuric acid and sulfuric acid-dimethylamine experiments increased with increasing particle size. The Κ values of particles in the presence of sulfuric acid and organics were much smaller than those of particles in the presence of sulfuric acid and dimethylamine. This suggests that the organics produced from α-pinene ozonolysis play a significant role in particle growth already at 10nm sizes.
Background Reaching the therapeutic target of remission or low-disease activity has improved outcomes in patients with rheumatoid arthritis (RA) significantly. The treat-to-target recommendations, formulated in 2010, have provided a basis for implementation of a strategic approach towards this therapeutic goal in routine clinical practice, but these recommendations need to be re-evaluated for appropriateness and practicability in the light of new insights.
Objective To update the 2010 treat-to-target recommendations based on systematic literature reviews (SLR) and expert opinion.
Methods A task force of rheumatologists, patients and a nurse specialist assessed the SLR results and evaluated the individual items of the 2010 recommendations accordingly, reformulating many of the items. These were subsequently discussed, amended and voted upon by >40 experts, including 5 patients, from various regions of the world. Levels of evidence, strengths of recommendations and levels of agreement were derived.
Results The update resulted in 4 overarching principles and 10 recommendations. The previous recommendations were partly adapted and their order changed as deemed appropriate in terms of importance in the view of the experts. The SLR had now provided also data for the effectiveness of targeting low-disease activity or remission in established rather than only early disease. The role of comorbidities, including their potential to preclude treatment intensification, was highlighted more strongly than before. The treatment aim was again defined as remission with low-disease activity being an alternative goal especially in patients with long-standing disease. Regular follow-up (every 1–3 months during active disease) with according therapeutic adaptations to reach the desired state was recommended. Follow-up examinations ought to employ composite measures of disease activity that include joint counts. Additional items provide further details for particular aspects of the disease, especially comorbidity and shared decision-making with the patient. Levels of evidence had increased for many items compared with the 2010 recommendations, and levels of agreement were very high for most of the individual recommendations (≥9/10).
Conclusions The 4 overarching principles and 10 recommendations are based on stronger evidence than before and are supposed to inform patients, rheumatologists and other stakeholders about strategies to reach optimal outcomes of RA.
We provide elementary algorithms for two preservation theorems for first-order sentences (FO) on the class ℭd of all finite structures of degree at most d: For each FO-sentence that is preserved under extensions (homomorphisms) on ℭd, a ℭd-equivalent existential (existential-positive) FO-sentence can be constructed in 5-fold (4-fold) exponential time. This is complemented by lower bounds showing that a 3-fold exponential blow-up of the computed existential (existential-positive) sentence is unavoidable. Both algorithms can be extended (while maintaining the upper and lower bounds on their time complexity) to input first-order sentences with modulo m counting quantifiers (FO+MODm). Furthermore, we show that for an input FO-formula, a ℭd-equivalent Feferman-Vaught decomposition can be computed in 3-fold exponential time. We also provide a matching lower bound
This paper shows equivalence of several versions of applicative similarity and contextual approximation, and hence also of applicative bisimilarity and contextual equivalence, in LR, the deterministic call-by-need lambda calculus with letrec extended by data constructors, case-expressions and Haskell's seq-operator. LR models an untyped version of the core language of Haskell. The use of bisimilarities simplifies equivalence proofs in calculi and opens a way for more convenient correctness proofs for program transformations. The proof is by a fully abstract and surjective transfer into a call-by-name calculus, which is an extension of Abramsky's lazy lambda calculus. In the latter calculus equivalence of our similarities and contextual approximation can be shown by Howe's method. Similarity is transferred back to LR on the basis of an inductively defined similarity. The translation from the call-by-need letrec calculus into the extended call-by-name lambda calculus is the composition of two translations. The first translation replaces the call-by-need strategy by a call-by-name strategy and its correctness is shown by exploiting infinite trees which emerge by unfolding the letrec expressions. The second translation encodes letrec-expressions by using multi-fixpoint combinators and its correctness is shown syntactically by comparing reductions of both calculi. A further result of this paper is an isomorphism between the mentioned calculi, which is also an identity on letrec-free expressions.
The stable isotope geochemistry of pedogenic and lacustrine carbonate and fossil herbivore tooth enamel is a powerful tool to study the evolution of terrestrial paleoenvironments. This thesis aims to reconstruct Neogene ecosystems in the Karonga Basin in the southern part the East African Rift (EAR) and the Central Anatolian Plateau (CAP).
Karonga Basin: Understanding the development of East African savanna biomes is crucial for reconstructing the evolution, migration and dietary behaviors of early hominins. These rift ecosystems range from closed woodland to open grassland savanna and vary widely in fraction of woody cover. Here I present Plio-Pleistocene carbon (δ13C) and oxygen (δ18O) records from pedogenic carbonate and fossil herbivore tooth enamel collected from the Malawi Rift. This is the first southern hemisphere long-term record in the East African Rift.
The studied ca. 4.3 Ma to 0.6 Ma deposits of the Chiwondo Beds (Karonga Basin) are home to two hominin fossil finds, a maxillary fragment of Paranthropus boisei and a mandible of Homo rudolfensis, both dated to ca. 2.4 Ma. The study site is situated between the well-known hominin-bearing localities of eastern and southern Africa and hence fills an important geographical gap for early hominin research.
The δ13C values of pedogenic carbonate (n = 321) and of enamel from 14 different large-bodied herbivorous mammal taxa (suid, equid, bovid, elephant an hippopotamus; n = 122) permit assessment of the evolutionary history of C3 and C4 biomass, which is closely linked to climate patterns. The reconstruction of C4-grassland development offers insights into the retreat of tree cover and the distribution and seasonality of precipitation. δ18O values reflect hydrological patterns, and we supplement the data of fossil proxy material with analyses of modern meteoric water to evaluate influences of seasonality and evaporation.
Consistent δ13C values around -9‰ and δ18O values of ca. 24‰ of the pedogenic carbonate from 14 sections spanning the last 4.3 Ma indicate a relatively mesic and persistent climate with C3-dominated woodland savannas in the Karonga Basin. The data from tooth enamel of suid, elephant, and hippo taxa complement these findings with constantly low δ13C and δ18O values, demonstrating intake of mainly C3 biomass and water from sources which are only very limited affected by evaporation.
In contrast, Karonga Basin equid and bovid taxa reflect much more complex dietary patterns, ranging from mixed C3/C4-feeders to strongly C4-influenced diets. Intra-tooth δ18O values also show large variations, indicating water intake from resources that differ in their isotopic composition and therefore experienced different hydrological settings.
Overall, the stable isotope data reflect a mostly C3-dominated mesic paleoecosystem, which comprises patches of more open C4-grasslands within the range of migrating mammals. Supplementary analyses of δ18O values of modern meteoric water (precipitation, lake, river and groundwater; n = 111) show a similar magnitude to the fossil herbivore oxygen isotopic values. Expected 18O values of the drinking water calculated from herbivore enamel of animals with a mixed- or C3-diet indicate water intake from barely evaporated sources. Specialized feeders with a high C4-consumtion, however, reflect s|||||||||||||||||||||values of 16O-depleted reservoirs, similar in δ18O |||||||||||| to modern evaporated lakes.
The absence of long-term trends towards more positive δ13C and δ18O values in the Karonga Basin contrasts the increasing role of C4-grasslands since ca. 2.5 Ma in the Eastern Rift. Our data hence point to regional differences in climate and vegetation dynamics during the Plio-Pleistocene. Therefore, regions that are home to early hominins such as H. rudolfensis and P. boisei may have had a different environmental history when compared to the Eastern Rift. This suggests that hominin adaptation is not necessarily directly linked to the emergence of open landscapes.
Central Anatolian Plateau: The development of relief and climate patterns in the Central Anatolian Plateau is long-standing debate in modern paleoecological studies. This thesis presents long-term δ13C and δ18O records on five lacustrine successions, which are widely distributed across the CAP. Also, new 40Ar/39Ar geochronological data from volcanic ashes are established in addition to existing biostratigraphic and paleomagnetic data.
Field relationships combined with stable isotope data of 230 lacustrine carbonates indicate a Late Oligocene environment that was characterized by large, temporally open freshwater lakes in a relatively humid subtropic climate. In the middle Aquitanian, an increase in lake δ18O values reflects more arid settings and an overall increasing dominance of closed saline lakes. This time was probably characterized by frequent climatic fluctuations, recording the influence of seasonality, topography and the waxing and waning of aridity.
Diese Dissertation befasst sich mit den Auswirkungen von nicht letalen Dosen von Neonikotinoiden auf Bienen. Neonikotinoide stellen eine Klasse von Insektiziden dar, die auf den nikotinischen Acetylcholin Rezeptor wirken. In dieser Dissertation wurden die Neonikotinoide Imidacloprid, Clothianidin und Thiacloprid benutzt. Die beiden erst genannten unterliegen zum Zeitpunkt des Verfassens dieser Arbeit einem temporären Verkaufs- und Ausbringungs-Stopp. Damit sind die Ergebnisse dieser Arbeit wichtig für die Bewertung der Gefahren von Neonikotinoiden. Neonikotinoide werden im großen Maße in der Landwirtschaft als Spritzmittel und Saatgutbeize eingesetzt. Dabei können sie in Rückständen von Bienen beim Sammeln von Nektar und Pollen aufgenommen und zum Stock gebracht werden. Um einen weiten Blick auf die Auswirkungen der Stoffe zu werfen wurden deshalb Experimente an einzelnen Sammlerinnen durchgeführt, ebenso wie an Bienenvölkern, bei denen die Substanzen verfüttert wurden. Als neuronal aktive Substanzen können sie die normale Funktion des Nervensystems von Bienen beeinflussen, was Veränderungen im Verhalten hervorrufen kann. Dies zeigt sich in Veränderungen in der Bewegung, Orientierung oder auch Interaktion mit anderen Bienen. Die Wirkung am Rezeptor variiert, trotz gleichen molekularen Ziels, stark zwischen den verwendeten Neonikotinoiden. Clothianidin wurde als Agonist beschrieben, der sogar stärkere Ströme als Acetylcholin bei gleicher Konzentration hervorrufen kann. Imidacloprid dagegen wurde bereits als partieller Agonist beschrieben, der geringere Ströme über den Rezeptor auslöst. In dieser Arbeit wurde ein erster Versuch durchgeführt um Thiacloprid ebenfalls als Agonist am nikotinischen Acetylcholin Rezeptor der Biene zu beschreiben. Hierbei wurde an einer Zelle in Kultur ein geringerer Strom ausgelöst.
Bienenvölker wurden unter kontrollierten Bedingungen gehalten, bei denen je eins der Neonikotinoide Clothianidin, Imidacloprid oder Thiacloprid in das Futter gemischt wurden. Hierfür wurden Dosen gewählt, bei denen davon ausgegangen werden konnte, dass keine akute Beeinflussung der Sammlerinnen bestand. Es konnte festgestellt werden, dass chronisches Füttern mit einer Zuckerlösung mit 8,876 mg/kg Thiacloprid zu einer verringerten Sammelleistung führte. Ebenso wurde die Entwicklung der Eier stark eingeschränkt, wobei die Königin weiterhin Eier legte. Es konnten nur vereinzelte verdeckelte Brutzellen, die ein spätes Entwicklungsstadium der Bienen darstellen, gefunden werden. Damit konnte gezeigt werden, dass geringe Dosen die Larval-Entwicklung von Bienen beeinflussen, eventuell durch Einflüsse auf die Kommunikation zwischen Ammenbienen und der Brut.
Um Auswirkungen auf einzelne Tiere zu zeigen, wurden unterschiedliche Parameter im Heimflug von Bienen nach Fütterung mit je einem der Neonikotinoide analysiert. Bienen mussten sich nach der Fütterung orientieren und von einer neuen Position den Heimweg zum Stock finden. Der Heimflug wurde per Radar verfolgt und so ein Flugprofil erstellt, das aus zwei Flugphasen bestand. Diese wurden durch die Navigation nach Vektorintegration und durch Landmarken unterteilt. Aus dem Flugprofil konnte abgelesen werden, wie lange die Bienen für die Phasen des Flugs benötigten, in welchem Hauptflugwinkel sie die erste Flugphase absolvierten, in welche Richtung sie am Ende der ersten Flugphase flogen und wie gerichtet der Flug war. Auch wurde erfasst, ob die Bienen überhaupt in der Lage waren zum Stock zurückzukehren. Hier zeigte sich, dass die Fütterung mit Zuckerwasser mit 0,6 µM und 0,9 µM Imidacloprid, ebenso wie mit 0,1 mM Thiacloprid zu einer verringerten Heimkehrwahrscheinlichkeit führte. In der ersten Flugphase konnte auch gezeigt werden, dass 0,2 µM Clothianidin im Zuckerwasser zu einem schnelleren Flug führte und dass der Flugwinkel im Vergleich zur Kontrolle in Richtung der wahren Position des Stocks verschoben war. Beide Imidacloprid-Gruppen zeigten eine ähnliche, signifikante Verschiebung des Flugwinkels, ebenso konnte im Flug selbst eine häufige Änderung der Richtung festgestellt werden. In der zweiten Flugphase zeigte sich, dass Bienen, welche mit Thiacloprid behandelt wurden häufiger eine inkorrekte Heimflugrichtung wählten, was in längeren Heimflügen resultierte. Die mit Clothianidin behandelten Bienen legten eine längere Flugstrecke zurück. Bienen, welche Imidacloprid beider Konzentrationen konsumierten, zeigten einen häufigen Wechsel ihrer Flugrichtung. Damit konnten bei allen drei gewählten Neonikotinoiden Einflüsse auf spezifische Komponenten der Navigation von Bienen gefunden und Einschränkungen im Heimkehr- und Orientierungsverhalten einzelner Sammlerinnen gezeigt werden. Somit konnten die eingehenden Fragen zumindest teilweise beantwortet werden und die Datenlage zur Frage der Schädlichkeit der, auch politisch umstrittenen, Substanzen erweitert werden.
Spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS) are neurodegenerative disorders, caused or modified by an unstable CAG-repeat expansion in the SCA2 gene, which encodes a polyglutamine (polyQ) domain expansion in ataxin-2 (ATXN2). ATXN2 is an RNA-binding protein and interacts with the poly(A)-binding protein PABPC1, localizing to ribosomes at the rough endoplasmic reticulum. Under cell stress, ATXN2, PABPC1 and small ribosomal subunits are relocated to stress granules, where mRNAs are protected from translation and from degradation. It is unknown whether ATXN2 associates preferentially with specific mRNAs or how it modulates RNA processing. Here, we investigated the RNA profile of the liver and cerebellum from Atxn2 knockout (Atxn2−/−) mice at two adult ages, employing oligonucleotide microarrays. Prominent increases were observed for Lsm12/Paip1 (>2-fold), translation modulators known as protein interactor/competitor of ATXN2 and for Plin3/Mttp (>1.3-fold), known as apolipoprotein modulators in agreement with the hepatosteatosis phenotype of the Atxn2−/− mice. Consistent modest upregulations were also observed for many factors in the ribosome and the translation/secretion apparatus. Quantitative reverse transcriptase PCR in liver tissue validated >1.2-fold upregulations for the ribosomal biogenesis modulator Nop10, the ribosomal components Rps10, Rps18, Rpl14, Rpl18, Gnb2l1, the translation initiation factors Eif2s2, Eif3s6, Eif4b, Pabpc1 and the rER translocase factors Srp14, Ssr1, Sec61b. Quantitative immunoblots substantiated the increased abundance of NOP10, RPS3, RPS6, RPS10, RPS18, GNB2L1 in SDS protein fractions, and of PABPC1. In mouse embryonal fibroblasts, ATXN2 absence also enhanced phosphorylation of the ribosomal protein S6 during growth stimulation, while impairing the rate of overall protein synthesis rates, suggesting a block between the enhanced translation drive and the impaired execution. Thus, the physiological role of ATXN2 subtly modifies the abundance of cellular translation factors as well as global translation.
Mesenchymal stem/stromal cells (MSCs) feature promising potential for cellular therapies, yet significant progress in development of MSC therapeutics and assays is hampered because of remarkable MSC heterogeneity in vivo and in vitro. This heterogeneity poses challenges for standardization of MSC characterization and potency assays as well as for MSC study comparability and manufacturing. This review discusses promising marker combinations for prospective MSC subpopulation enrichment and expansion, and reflects MSC phenotype changes due to environment and age. In order to address animal modelling in MSC biology, comparison of mouse and human MSC markers highlights current common ground of MSCs between species.
Flow hemodynamics regulates endothelial cell (EC) responses and laminar shear stress induces an atheroprotective and quiescent phenotype. The flow-responsive transcription factor KLF2 is a pivotal mediator of endothelial quiescence, but the precise mechanism is unclear. In this doctoral study, we assessed the hypothesis that laminar shear stress and KLF2 regulate endothelial quiescence by controlling endothelial metabolism.
Laminar flow exposure and KLF2 over expression in HUVECs reduced glucose uptake. Endothelial specific deletion of KLF2 (EC-KO) in mice and subsequent infusion of labeled glucose in Langendorff perfused hearts induced glucose uptake in ECs lacking KLF2. Bioenergetic measurements revealed that KLF2 reduces and glycolytic acidification in vitro.
Mechanistically, RNA sequencing analysis of shear stimulated ECs showed reduced expression of key glycolytic enzymes Hexokinase 2, PFKFB3 and PFK-1. KLF2 also reduced expression of these enzymes at protein level. KLF2 knockdown in shear stimulated ECs reversed the reduction in expression of PFKFB3 and PFK-1, indicating KLF2-dependency. Promoter analysis revealed KLF binding sites in the promoter of PFKFB3 and KLF2 over expression markedly reduced PFKFB3 promoter activity which was abolished on mutation of the KLF binding site. In addition, PFKFB3 knockdown reduced glycolysis while over expression increased glycolysis. Over expression of PFKFB3 along with KLF2 partially reversed the KLF2-mediated reduction in glycolysis. Importantly, PFKFB3 over expression reversed KLF2-mediated reduction in angiogenic sprouting and network formation in vitro. Ex-vivo aortic ring assays revealed an increase in endothelial sprouting from aortas from KLF2 EC-KO mice, which was partially reversed upon PFKFB3 inhibition by 3-PO.
In conclusion, work performed during this doctoral thesis demonstrates that laminar shear stress and KLF2 mediated repression of endothelial metabolism via regulation of PFKFB3 contributes to the anti-angiogenic and quiescent properties of the endothelium.
Ionizing radiation generates DNA double-strand breaks (DSB) which, unless faithfully repaired, can generate chromosomal rearrangements in hematopoietic stem and/or progenitor cells (HSPC), potentially priming the cells towards a leukemic phenotype. Using an enhanced green fluorescent protein (EGFP)-based reporter system, we recently identified differences in the removal of enzyme-mediated DSB in human HSPC versus mature peripheral blood lymphocytes (PBL), particularly regarding homologous DSB repair (HR). Assessment of chromosomal breaks via premature chromosome condensation or γH2AX foci indicated similar efficiency and kinetics of radiation-induced DSB formation and rejoining in PBL and HSPC. Prolonged persistence of chromosomal breaks was observed for higher LET charged particles which are known to induce more complex DNA damage compared to X-rays. Consistent with HR deficiency in HSPC observed in our previous study, we noticed here pronounced focal accumulation of 53BP1 after X-ray and carbon ion exposure (intermediate LET) in HSPC versus PBL. For higher LET, 53BP1 foci kinetics was similarly delayed in PBL and HSPC suggesting similar failure to repair complex DNA damage. Data obtained with plasmid reporter systems revealed a dose- and LET-dependent HR increase after X-ray, carbon ion and higher LET exposure, particularly in HR-proficient immortalized and primary lymphocytes, confirming preferential use of conservative HR in PBL for intermediate LET damage repair. HR measured adjacent to the leukemia-associated MLL breakpoint cluster sequence in reporter lines revealed dose dependency of potentially leukemogenic rearrangements underscoring the risk of leukemia-induction by radiation treatment.
The inhibitor of the nuclear factor-κB (IκB) kinase (IKK) complex is a key regulator of the canonical NF-κB signalling cascade and is crucial for fundamental cellular functions, including stress and immune responses. The majority of IKK complex functions are attributed to NF-κB activation; however, there is increasing evidence for NF-κB pathway-independent signalling. Here we combine quantitative mass spectrometry with random forest bioinformatics to dissect the TNF-α-IKKβ-induced phosphoproteome in MCF-7 breast cancer cells. In total, we identify over 20,000 phosphorylation sites, of which ∼1% are regulated up on TNF-α stimulation. We identify various potential novel IKKβ substrates including kinases and regulators of cellular trafficking. Moreover, we show that one of the candidates, AEG-1/MTDH/LYRIC, is directly phosphorylated by IKKβ on serine 298. We provide evidence that IKKβ-mediated AEG-1 phosphorylation is essential for IκBα degradation as well as NF-κB-dependent gene expression and cell proliferation, which correlate with cancer patient survival in vivo.
BACKGROUND: Plasminogen deficiency is a rare autosomal recessive disease, which is associated with aggressive periodontitis and gingival enlargement. Previously described treatments of plasminogen deficiency associated periodontitis have shown limited success. This is the first case report indicating a successful therapy approach consisting of a non-surgical supra- and subgingival debridement in combination with an adjunctive systemic antibiotic therapy and a strict supportive periodontal regimen over an observation period of 4 years.
CASE PRESENTATION: The intraoral examination of a 17-year-old Turkish female with severe plasminogen deficiency revealed generalized increased pocket probing depths ranging from 6 to 9 mm, bleeding on probing over 30%, generalized tooth mobility, and gingival hyperplasia. Alveolar bone loss ranged from 30% to 50%. Clinical attachment loss corresponded to pocket probing depths. Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Treponema denticola, Prevotella intermedia, Prevotella nigrescens and Eikenella corrodens have been detected by realtime polymerase chain reaction. Periodontal treatment consisted of full mouth disinfection and adjunctive systemic administration of amoxicillin (500 mg tid) and metronidazole (400 mg tid). A strict supportive periodontal therapy regimen every three month in terms of supra- and subgingival debridement was rendered. The reported therapy has significantly improved periodontal health and arrested disease progression. Intraoral examination at the end of the observation period 3.5 years after non-surgical periodontal therapy showed generalized decreased pocket probing depths ranging from 1 to 6 mm, bleeding on probing lower 30%, and tooth mobility class I and II. Furthermore, microbiological analysis shows the absence of Porphyromonas gingivalis, Prevotella intermedia and Treponema denticola after therapy.
CONCLUSION: Adjunctive antibiotic treatment may alter the oral microbiome and thus, the inflammatory response of periodontal disease associated to plasminogen deficiency and diminishes the risk of pseudomembrane formation and progressive attachment loss. This case report indicates that patients with plasminogen deficiency may benefit from non-surgical periodontal treatment in combination with an adjunctive antibiotic therapy and a strict supportive periodontal therapy regimen.
BACKGROUND: hysical activity exerts a variety of long-term health benefits in older adults. In particular, it is assumed to be a protective factor against cognitive decline and dementia.
METHODS/DESIGN: Randomised controlled assessor blinded 2-armed trial (n = 60) to explore the exercise- induced neuroprotective and metabolic effects on the brain in cognitively healthy older adults. Participants (age ≥ 65), recruited within the setting of assisted living facilities and newspaper advertisements are allocated to a 12-week individualised aerobic exercise programme intervention or a 12-week waiting control group. Total follow-up is 24 weeks. The main outcome is the change in cerebral metabolism as assessed with Magnetic Resonance Spectroscopic Imaging reflecting changes of cerebral N-acetyl-aspartate and of markers of neuronal energy reserve. Imaging also measures changes in cortical grey matter volume. Secondary outcomes include a broad range of psychometric (cognition) and movement-related parameters such as nutrition, history of physical activity, history of pain and functional diagnostics. Participants are allocated to either the intervention or control group using a computer-generated randomisation sequence. The exercise physiologist in charge of training opens sealed and opaque envelopes and informs participants about group allocation. For organisational reasons, he schedules the participants for upcoming assessments and exercise in groups of five. All assessors and study personal other than exercise physiologists are blinded.
DISCUSSION: Magnetic Resonance Spectroscopic Imaging gives a deeper insight into mechanisms of exercise-induced changes in brain metabolism. As follow-up lasts for 6 months, this study is able to explore the mid-term cerebral metabolic effects of physical activity assuming that an individually tailored aerobic ergometer training has the potential to counteract brain ageing.
NCT02343029 (clinicaltrials.gov; 12 January 2015).
The true revolution in the age of digital neuroanatomy is the ability to extensively quantify anatomical structures and thus investigate structure-function relationships in great detail. Large-scale projects were recently launched with the aim of providing infrastructure for brain simulations. These projects will increase the need for a precise understanding of brain structure, e.g., through statistical analysis and models.
From articles in this Research Topic, we identify three main themes that clearly illustrate how new quantitative approaches are helping advance our understanding of neural structure and function. First, new approaches to reconstruct neurons and circuits from empirical data are aiding neuroanatomical mapping. Second, methods are introduced to improve understanding of the underlying principles of organization. Third, by combining existing knowledge from lower levels of organization, models can be used to make testable predictions about a higher-level organization where knowledge is absent or poor. This latter approach is useful for examining statistical properties of specific network connectivity when current experimental methods have not yet been able to fully reconstruct whole circuits of more than a few hundred neurons.