Chimpanzees use observed temporal directionality to learn novel causal relations

We investigated whether chimpanzees use the temporal sequence of external events to determine causation. Seventeen chimpanzees (Pan troglodytes) witnessed a human experimenter press a button in two different conditions. When she pressed the “causal button” the delivery of juice and a sound immediately followed (cause-then-effect). In contrast, she pressed the “non-causal button” only after the delivery of juice and sound (effect-then-cause). When given the opportunity to produce the desired juice delivery themselves, the chimpanzees preferentially pressed the causal button, i.e., the one that preceded the effect. Importantly, they did so in their first test trial and even though both buttons were equally associated with juice delivery. This outcome suggests that chimpanzees, like human children, do not rely solely on their own actions to make use of novel causal relations, but they can learn causal sequences based on observation alone. We discuss these findings in relation to the literature on causal inferences as well as associative learning.Publisher PDFPeer reviewe

The migration potential of human rheumatoid synovial fibroblasts in the SCID-mouse-model

Im Rahmen der SCID-Maus-Experimente zum Migrationspotential von synovialen Fibroblasten von Patienten mit rheumatoider Arthritis (Synovial fibroblasts spread rheumatoid arthritis to unaffected joints, Lefèvre et al, Nature Medicine 15, 1414 – 1420 (2009)), wurden neben dem implantierten humanen Knorpel auch verschiedene Organe sowie Blut der Versuchstiere entnommen. Die Auswertung dieser Proben war Gegenstand der vorliegenden Arbeit. Ziel der Arbeit war, den Weg der Migration von RASF durch den murinen Organismus zu analysieren. Insgesamt wurden mit Hilfe des SCID-Maus-Modells folgende Fragestellungen bearbeitet bzw. lassen sich folgende Aussagen treffen: 1. Die Ergebnisse der mittels Immunhistochemie untersuchten Organe und Blutproben unterstützen die Hypothese einer gezielten Migration der humanen RASF über das Blutgefäßsystem. Hinweise für eine ungezielte Migration und generalisierte Verteilung der RASF nach der Applikation konnten nicht gefunden. 2. Insbesondere die Detektion von RASF in immunzytochemisch gefärbten Blutproben von Versuchstieren, denen die RASF mittels unterschiedlicher (intravenös, subkutan, intraperitoneal) Applikationswege zugeführt worden waren, weisen auf eine Fibroblastenmigration über den Blutkreislauf hin. Diesen Funden muss eine Migration der RASF vom Ort der Applikation mit Übertritt in das Kreislaufsystem des Versuchstieres zugrunde liegen. 3. Der Nachweis humaner RASF in murinem Gewebe des Ohrknorpels legt die Vermutung einer Kreuzreaktion der humanen Zellen mit dem Knorpelgewebe des Versuchstieres, also Adhäsion an speziesfremdes Gewebe, nahe. 4. Die Ergebnisse weisen darauf hin, dass intakte Gelenke durch die räumliche Trennung vor der Invasion durch RASF geschützt werden, da in nur einem Tier humane Zellen im murinen, intakten Gelenk nachgewiesen wurden. Mikroläsionen oder die Migration durch die verschiedenen natürlichen Barrieren des Gelenkes verlangsamen die Invasion von RASF in das intakte Gelenk, was möglicherweise in den wenigen Funden von RASF 60 Tage nach Applikation resultierte. Die Ergebnisse stehen im Einklang mit der Beobachtung der Progression der RA, die sich über Jahre hinziehen kann. Die Ergebnisse konnten die Fragestellung zur Aufklärung des Migrationsweges von humanen RASF über das Blutgefäßsystem beantworten. In künftigen Experimenten gilt es, die in dieser Arbeit beschriebenen Migrationswege bezüglich der Faktoren zu untersuchen, welche für die Migration, Adhäsion und Invasion der RASF an humanem Knorpel verantwortlich sind. Nach der Feststellung des Migrationsweges sind vor allem die Ursachen von Interesse, die migrierende RASF an bestimmte Gewebe und Matrixstrukturen adhärieren und invadieren lassen und andere nicht. Ein weiterer interessanter Aspekt der Wanderung der RASF ist die bisher unbekannte Transmigration der RASF in das und aus dem Blutgefäßsystem heraus, die im SCID-Maus-Modell erstmals für RASF beschrieben wird. Ein besseres Verständnis der Interaktion von RASF mit den verschiedenen Geweben des menschlichen Körpers würde neue Perspektiven einer gezielteren therapeutischen Beeinflussung der Ausbreitung der RA beim Menschen eröffnen. Damit wäre ein weiterer wichtiger Schritt auf dem Wege der Verbesserung der Situation an RA leidender Patienten getan.In the context of the SCID-Mouse-Experiments investigating the migratory potential of rheumatoid synovial fibroblasts (RASF) of patients with Rheumatoid Arthritis (RA) (Synovial fibroblasts spread rheumatoid arthritis to unaffected joints, Lefèvre et al, Nature Medicine 15, 1414 – 1420 (2009)), implanted human cartilage as well as several organs and blood samples from the laboratory animals were collected. Subject of this study was the analysis of these samples. The aim was to further examine the way of transmigration of the RASF through the laboratory animals. Altogether, by means of the SCID-Mouse-Model, the following conclusions can be drawn: 1. The results, gained from the immunohistochemical examination of organs and blood-samples support the hypothesis of a directed migration of activated RASF via the vasculature. Evidence for unsighted or unspecific spread could not be found. 2. In particular, the detection of RASF in immunocytologically stained bloodsamples taken from the SCID-Mice suggests a migration of the RASF through the vascular system. This migration seems to be independent from the way of application (intravenously, subcutaneously, intraperitoneal). These detections can only be explained by a transmigration of the RASF from the site of application to the circulatory system of the laboratory animal. 3. The detection of human RASF in murine ear cartilage leads to the assumption of a cross reaction between the human cells and the murine cartilage, implying species cross-adhesion to mouse tissue. 4. Furthermore, regarding the fact that only in one animal human cells could be found in an intact murine joint, the results indicate a protection of unspoiled joints from RASF invasion by physical separation. Microlesions or the migration through the different natural barriers of the joint could slow down the invasion of RASF into the intact joint, possibly leading to the few detections of RASF 60 days after application. These findings coincide with the idea of RA as an over years progressing disease. The results corroborated the hypothesis of a migration of human RASF via the vascular system. In future experiments it will be necessary to further investigate the ways of migration, examining the factors responsible for migration, adhesion and invasion of RASF into the human cartilage. After the identification of the migration-pathway it will be of primary interest to identify the causes leading to the adhesion to and invasion into specific tissues and matrix structures, while disregarding others. Another interesting aspect of the spreading of RASF is the up to now unknown transmigration in and out of the circulatory system, described for RASF in the SCID-Mouse-Model for the first time. A better understanding of the interactions between human RASF and the different tissues of the human body could open up new perspectives on a more selective therapeutic intervention inhibiting the spreading of RA in human joints. This would be an important step towards improving the situation of patients suffering from RA

Chimpanzees use observed temporal directionality to learn novel causal relations

We investigated whether chimpanzees use the temporal sequence of external events to determine causation. Seventeen chimpanzees (Pan troglodytes) witnessed a human experimenter press a button in two different conditions. When she pressed the “causal button” the delivery of juice and a sound immediately followed (cause-then-effect). In contrast, she pressed the “non-causal button” only after the delivery of juice and sound (effect-then-cause). When given the opportunity to produce the desired juice delivery themselves, the chimpanzees preferentially pressed the causal button, i.e., the one that preceded the effect. Importantly, they did so in their first test trial and even though both buttons were equally associated with juice delivery. This outcome suggests that chimpanzees, like human children, do not rely solely on their own actions to make use of novel causal relations, but they can learn causal sequences based on observation alone. We discuss these findings in relation to the literature on causal inferences as well as associative learning

Synovial fibroblasts spread rheumatoid arthritis to unaffected joints

Active rheumatoid arthritis originates from few joints but subsequently affects the majority of joints. Thus far, the pathways of the progression of the disease are largely unknown. As rheumatoid arthritis synovial fibroblasts (RASFs) which can be found in RA synovium are key players in joint destruction and are able to migrate in vitro, we evaluated the potential of RASFs to spread the disease in vivo. To simulate the primary joint of origin, we implanted healthy human cartilage together with RASFs subcutaneously into severe combined immunodeficient (SCID) mice. At the contralateral flank, we implanted healthy cartilage without cells. RASFs showed an active movement to the naive cartilage via the vasculature independent of the site of application of RASFs into the SCID mouse, leading to a marked destruction of the target cartilage. These findings support the hypothesis that the characteristic clinical phenomenon of destructive arthritis spreading between joints is mediated, at least in part, by the transmigration of activated RASFs