Genomische Analyse von natürlichen Killerzell-Rezeptorgenen in nicht-humanen Primaten

Natürliche Killerzell-Rezeptoren, die MHC-Klasse-I-Moleküle binden, sind im Leukozyten Rezeptor Komplex (LRC) und im Natürlichen Killer Komplex (NKC) kodiert. Die Bindung klassischer MHC-Klasse-I-Moleküle erfolgt im Menschen durch die im LRC kodierten polymorphen Killerzell-Immunglobulin-ähnlichen Rezeptoren (KIR) und in Nagetieren durch die im NKC kodierten polymorphen C-Typ Lektin-ähnlichen Ly49-Rezeptoren. Die ebenfalls im NKC kodierten C-Typ Lektin-ähnlichen CD94/NKG2-Rezeptoren sowie der NKG2D-Rezeptor sind sowohl im Menschen als auch in Nagetieren konserviert und wenig polymorph. Im Rahmen dieser Arbeit wurde das CD94-Ly49L-Intervall der NKC-Region in einem Neuweltaffen, dem Weißbüschelaffen (Callithrix jacchus), sowie einem Feuchtnasenaffen, dem Grauen Mausmaki (Microcebus murinus), über Screening von BAC-Banken und Sequenzanalyse von BAC-Contigs untersucht. Das CD94-Ly49L-Intervall im Weißbüschelaffen hat eine Länge von 171 kb und weist orthologe Gene zu den humanen NKC-Genen auf. Eine Ausnahme bildet das Gen NKG2CE, welches äquidistant zu den humanen Genen NKG2C und NKG2E ist. NKG2F und Ly49L sind Pseudogene. Expressionsanalysen der NKC-Gene in neun Weißbüschelaffen-Individuen lieferten einen mäßigen Grad an allelischen Polymorphismen. Alternative Spleißprodukte wurden für CD94, NKG2D und NKG2A identifiziert. Für NKG2A wurden verschiedene Transkripte mit potentiell unterschiedlichen Translationsstartpunkten gefunden. Im Grauen Mausmaki beträgt die Länge des CD94-Ly49L-Intervalls 489 kb. CD94 und die NKG2-Gene sind vervielfacht und wesentlich polymorpher als im Menschen und im Weißbüschelaffen. Expressionsanalysen der NKC-Gene wurden im Grauen Mausmaki und einem weiteren madagassischen Lemuren, dem Schwarzweißen Vari (Varecia variegata), durchgeführt und zeigten, dass CD94 und die NKG2-Gene im Vari ebenfalls vervielfacht sind. Die NKG2-Moleküle der Lemuren weisen unterschiedliche Kombinationen an aktivierenden und inhibierenden Signalmotiven auf und üben somit möglicherweise diverse Funktionen aus. Ly49L stellt in den Lemuren einen potentiell funktionellen inhibierenden Rezeptor dar und NKG2D besitzt im Vergleich zum humanen NKG2D-Protein eine verkürzte Zytoplasmaregion. Alternative Spleißprodukte der NKC-Gene existieren auch in den Lemuren. Darüber hinaus wurden mehrere CD94-Gene in einem weiteren Feuchtnasenaffen, dem Potto (Perodicticus potto) und einem Trockennasenaffen, dem Philippinen-Koboldmaki (Tarsius syrichta), nachgewiesen. Ein Alu-Element, welches ausschließlich in Intron 4 der CD94-Sequenzen des Philippinen-Koboldmakis auftritt, deutet darauf hin, dass sich CD94 in der Linie der Koboldmakis und in der Linie der Feuchtnasenaffen unabhängig voneinander vervielfacht hat. Die vervielfachten, polymorphen CD94/NKG2-Rezeptoren der niederen Primaten stellen möglicherweise das funktionelle Äquivalent zu den polymorphen KIR der höheren Primaten und den polymorphen Ly49-Rezeptoren der Nagetiere dar.

Vergleichende computergestützte funktionsmorphologische Analyse an Molaren cercopithecoider Primaten

Die Analyse funktioneller Zusammenhänge zwischen Ernährung und Zahnmorphologie ist ein wichtiger Aspekt primatologischer und paläontologischer Forschung. Als überdauernder Teil des Verdauungssystems geben Zähne die bestmöglichen Hinweise auf die Ernährungsstrategien (ausgestorbener) Arten und eine Fülle weiterer Informationen. Aufgrund dessen ist es für die wissenschaftliche Arbeit von größter Bedeutung, die Zähne so detailliert und exakt wie möglich in ihrer gesamten Struktur zu erfassen. Bisher wurden zumeist zweidimensionale Parameter verwendet, um die komplexe Kronenmorphologie von Primatenmolaren vergleichend zu untersuchen. Die vorliegende Arbeit hatte das Ziel, Zähne verschiedener Arten von Altweltaffen mittels computerbasierter Methoden dreidimensional zu erfassen und neue Parameter zu definieren, mit denen die Form dieser Zähne objektiv erfasst und funktionell interpretiert werden kann. Mit einem Oberflächen-Scanner wurden die Gebisse einer Stichprobe von insgesamt 48 Primaten von fünf verschiedenen Arten eingescannt und mit Bildverarbeitungsmethoden so bearbeitet, dass dreidimensionale digitale Modelle einzelner Backenzähne zur Analyse vorlagen. Es wurden dabei sowohl Arten ausgewählt, die eine für ihre Gattung typische Ernährungsweise besitzen - also Frugivorie bei den Cercopithecinen und Folivorie bei den Colobinen - als auch solche, die eine davon abweichende Alimentation bevorzugen. Alle Altweltaffen haben sehr ähnliche Molaren. Colobinen haben jedoch höhere und spitzere Zahnhöcker, dünneren Zahnschmelz und scheinen ihre Zähne weniger stark abzukauen als die Meerkatzen. Diese Beobachtungen konnten mit Hilfe der neuen Parameter quantifiziert werden. Aus der 3D-Oberfläche und der Grundfläche der Zähne wurde ein Index gebildet, der die Stärke des Oberflächenreliefs angibt. Dieser Index hat bei Colobinen deutlich höhere Werte als bei Cercopithecinen, auch bei Zähnen, die schon stark abgekaut sind. Die Steilheit der Höcker und ihre Ausrichtung wurden außerdem gemessen. Auch diese Winkelmessungen bestätigten das Bild. Je höher der Blätteranteil an der Ernährung ist, desto höher sind die Indexwerte und umso steiler sind die Höcker. Besonders wichtig war es, dies auch für abgekaute Zähne zu bestätigen, die bisher nicht in funktionelle Analysen miteinbezogen wurden. Die Ausrichtung der Höckerseiten gibt Hinweise auf die Kaubewegung, die zum effizienten Zerkleinern der Nahrung notwendig ist. Die Ausrichtung der Höcker der Colobinen deutet darauf hin, dass diese Primaten flache, gleitende Kaubewegungen machen, bei denen die hohen Höcker aneinander vorbei scheren. Dies ist sinnvoll zum Zerschneiden von faserreicher Nahrung wie Blättern. Cercopithecinen scheinen ihre Backenzähne eher wie Mörser und Stößel zu verwenden, um Früchte und Samen zu zerquetschen und zu zermahlen. Je nachdem, was neben der hauptsächlichen Nahrung noch gekaut wird, unterscheiden sich die Arten graduell. Anders als bisher vermutet wurde, konnte gezeigt werden, dass Colobinen trotz des dünnen Zahnschmelzes ihre Zähne weniger stark abkauen und weniger Dentin freigelegt wird. Dies gibt eindeutige Hinweise auf die Unterschiede in der mechanischen Belastung, die während des Kauvorgangs auf die Zähne wirkt, und lässt sich gut mit der Ernährung der Arten in Zusammenhang bringen. Anhand dieser modellhaften Beobachtungen können in Zukunft ausgestorbene Arten hinsichtlich ihrer Ernährungsweise mit 3D-Techniken untersucht werden.

Comparative genomics and phylogenetics of the vertebrate CYP3 family

CYP3A verstoffwechselt mehr als 50% aller gegenwärtig in der Therapie eingesetzten Wirkstoffe, die häufig an klinisch relevanten Arzneimitttel-Wechselwirkungen beteiligt sind. Das Verständnis über die Bedeutung und die Regulation von einzelnen CYP3A Genen in der Pharmakologie und Physiologie ist unvollständig. Wir untersuchten die Evolution des CYP3 Genlokus über einen Zeitraum von 450 Millionen Jahre mittels genomischer Sequenzen von 16 Tierarten. Neue CYP3 Unterfamilien (CYP3B, C und D) entstanden über eine beschleunigte Evolution aus CYP3A Vorstufen von Clupeocephala Spezies. Ausgeprägte funktionelle Unterschiede traten zwischen CYP3A in Säugern und Clupeocephala CYP3 auf. Alle amnioten CYP3A Gene entwickelten sich aus zwei CYP3A Urgenen. Aufgrund der Entstehung von Säugern mit Plazenta ging eines von ihnen verloren während das andere eine neue genomische Umgebung infolge einer Translokation erlangte. In Primaten unterzog sich CYP3A mit mehreren Genduplikationen, Deletionen, Pseudogenisierung und Genkonversionen einer raschen evolutionären Veränderung. Die Entwicklung von CYP3A in Schmalnasenaffen (Alte Welt Affen, große Menschenaffen und Menschen) unterschieden sich wesentlich von Neue Welt Primaten (z.B. gewöhnlichen Krallenaffen) und Feuchtnasenaffen (z.B. Galago). Stellvertretend für die CYP3A Protein-codierende Sequenz entdeckten wir zwei frühe Episoden von besonders starker positiver Selektion: (1) auf CYP3A7 in der frühen hominoiden Evolution, welche im fetalen Zeitraum von einer Einschränkung der hepatischen Expression begleitet war, und (2) auf humanes CYP3A4 im Anschluss an die Teilung der Abstammungslinie in Schimpansen und Mensch. In Übereinstimmung mit diesen Befunden beeinflussen drei von vier positiv ausgewählten Aminosäuren, die in früheren biochemischen CYP3A Studien untersucht wurden, die Aktivität und Regioselektivität. Es ist somit naheliegend, dass CYP3A7 und CYP3A4 katalytische Funktionen erworben haben können, die besonders wichtig waren für die Evolution von Hominoiden und Menschen. Die Charakterisierung von CYP3A Promotoren in Primaten zeigte eine Anreicherung von ER6 Elementen in CYP3A Promotoren von Primaten und einen Trend in Richtung Erhöhung der ER6 Enstehung entlang den Abstammungslinien, die zu humanen und Schimpansen CYP3A4 führten. Die steigende Anzahl an ER6 Elementen kann durch die ausgeprägte CYP3A4 Induzierbarkeit und Expressionsvariabilität im Menschen verursacht sein.

On the development of novel cocaine-analogues for in vivo imaging of the dopamine transporter status

The present thesis is concerned with the development of novel cocaine-derived dopamine transporter ligands for the non-invasive exploration of the striatal and extra-striatal dopamine transporter (DAT) in living systems. The presynaptic dopamine transporter acquires an important function within the mediation of dopaminergic signal transduction. Its availability can serve as a measure for the overall integrity of the dopaminergic system. The DAT is upregulated in early Parkinson’s disease (PD), resulting in an increased availability of DAT-binding sites in the striatal DAT domains. Thereby, DAT imaging has become an important routine diagnostic tool for the early diagnosis of PD in patients, as well as for the differentiation of PD from symptomatically similar medical conditions. Furthermore, the dopaminergic system is involved in a variety of psychiatric diseases. In this regard, DAT-selective imaging agents may provide detailed insights into the scientific understanding of the biochemical background of both, the progress as well as the origins of the symptoms. DAT-imaging may also contribute to the determination of the dopaminergic therapeutic response for a given medication and thereby contribute to more convenient conditions for the patient. From an imaging point of view, the former demands a high availability of the radioactive probe to facilitate broad application of the modality, whereas the latter profits from short-lived probes, suitable for multi-injection studies. Therefore, labelling with longer-lived 18F-fluoride and in particular the generator nuclide 68Ga is worthwhile for clinical routine imaging. In contrast, the introduction of a 11C-label is a prerequisite for detailed scientific studies of neuronal interactions. The development of suitable DAT-ligands for medical imaging has often been complicated by the mixed binding profile of many compounds that that interact with the DAT. Other drawbacks have included high non-specific binding, extensive metabolism and slow accumulation in the DAT-rich brain areas. However, some recent examples have partially overcome the mentioned complications. Based on the structural speciality of these leads, novel ligand structures were designed and successfully synthesised in the present work. A structure activity relationship (SAR) study was conducted wherein the new structural modifications were examined for their influence on DAT-affinity and selectivity. Two of the compounds showed improvements in in vitro affinity for the DAT as well as selectivity versus the serotonin transporter (SERT) and norepinephrine transporter (NET). The main effort was focussed on the high-affinity candidate PR04.MZ, which was subsequently labelled with 18F and 11C in high yield. An initial pharmacological characterisation of PR04.MZ in rodents revealed highly specific binding to the target brain structures. As a result of low non-specific binding, the DAT-rich striatal area was clearly visualised by autoradiography and µPET. Furthermore, the radioactivity uptake into the DAT-rich brain regions was rapid and indicated fast binding equilibrium. No radioactive metabolite was found in the rat brain. [18F]PR04.MZ and [11C]PR04.MZ were compared in the primate brain and the plasma metabolism was studied. It was found that the ligands specifically visualise the DAT in high and low density in the primate brain. The activity uptake was rapid and quantitative evaluation by Logan graphical analysis and simplified reference tissue model was possible after a scanning time of 30 min. These results further reflect the good characteristics of PR04.MZ as a selective ligand of the neuronal DAT. To pursue 68Ga-labelling of the DAT, initial synthetic studies were performed as part of the present thesis. Thereby, a concept for the convenient preparation of novel bifunctional chelators (BFCs) was developed. Furthermore, the suitability of novel 1,4,7-triazacyclononane based N3S3-type BFCs for biomolecule-chelator conjugates of sufficient lipophilicity for the penetration of the blood-brain-barrier was elucidated.

When the Practice of Theorizing Meets the Theorizing of Practice. Social Knowledge Making in Organization Science Academia and Managerial Communities

The aim of the present work is to contribute to a better understanding of the relation between organization theory and management practice. It is organized as a collection of two papers, a theoretical and conceptual contribution and an ethnographic study. The first paper is concerned with systematizing different literatures inside and outside the field of organization studies that deal with the theory-practice relation. After identifying a series of positions to the theory-practice debate and unfolding some of their implicit assumptions and limitations, a new position called entwinement is developed in order to overcome status quo through reconciliation and integration. Accordingly, the paper proposes to reconceptualize theory and practice as a circular iterative process of action and cognition, science and common-sense enacted in the real world both by organization scholars and practitioners according to purposes at hand. The second paper is the ethnographic study of an encounter between two groups of expert academics and practitioners occasioned by a one-year executive business master in an international business school. The research articulates a process view of the knowledge exchange between management academics and practitioners in particular and between individuals belonging to different communities of practice, in general, and emphasizes its dynamic, relational and transformative mechanisms. Findings show that when they are given the chance to interact, academics and practitioners set up local provisional relations that enable them to act as change intermediaries vis-a-vis each other’s worlds, without tying themselves irremediably to each other and to the scenarios they conjointly projected during the master’s experience. Finally, the study shows that provisional relations were accompanied by a recursive shift in knowledge modes. While interacting, academics passed from theory to practical theorizing, practitioners passed from an involved practical mode to a reflexive and quasi-theoretical one, and then, as exchanges proceeded, the other way around.

Die praktische Komponente deutscher Verständigungspolitik: Leopold von Hoesch in Paris

Diese Arbeit versucht, die Bedingungen und Umstände des deutsch-französischen Verständigungsprozesses zwischen Ruhrbesetzung und Locarno-Vertrag zu erklären, und geht dabei besonders auf den deutschen Gesandten in Paris, Leopold von Hoesch, und seinen Einfluss ein.

Reti transeuropee e servizi nei settori dell'energia, delle telecomunicazioni e dei trasporti

Le reti transeuropee sono uno dei vettori della competitività, dell’integrazione e dello sviluppo sostenibile dell’Unione. La tesi mette in luce la progressiva affermazione di una coerente politica infrastrutturale europea a carattere strumentale, esaminando tale evoluzione sotto tre profili: normativo, istituzionale e finanziario. In primo luogo, sotto il profilo normativo, la tesi evidenzia, da un lato, la progressiva emancipazione delle istituzioni dell’Unione dall’influenza degli Stati membri nell’esercizio delle proprie competenze in materia di reti transeuropee e, dall’altro, lo sviluppo di relazioni di complementarietà e specialità tra la politica di reti e altre politiche dell’Unione. L’elaborato sottolinea, in secondo luogo, sotto il profilo istituzionale, il ruolo del processo di «integrazione organica» dei regolatori nazionali e del processo di «agenzificazione» nel perseguimento degli obiettivi di interconnessione e accesso alle reti nazionali. La tesi osserva, infine, sotto il profilo finanziario, l’accresciuta importanza del sostegno finanziario dell’UE alla costituzione delle reti, che si è accompagnata al parziale superamento dei limiti derivanti dal diritto dell’UE alla politiche di spesa pubblica infrastrutturale degli Stati membri. Da un lato rispetto al diritto della concorrenza e, in particolare, al divieto di aiuti di stato, grazie al rapporto funzionale tra reti e prestazione di servizi di interesse economico generale, e dall’altro lato riguardo ai vincoli di bilancio, attraverso un’interpretazione evolutiva della cd. investment clause del Patto di stabilità e crescita. La tesi, in conclusione, rileva gli sviluppi decisivi della politica di reti europea, ma sottolinea il ruolo che gli Stati membri sono destinati a continuare ad esercitare nel suo sviluppo. Da questi ultimi, infatti, dipende la concreta attuazione di tale politica, ma anche il definitivo superamento, in occasione di una prossima revisione dei Trattati, dei retaggi intergovernativi che continuano a caratterizzare il diritto primario in materia.

Rapid assessment of internodal myelin integrity in central nervous system tissue

Monitoring pathology/regeneration in experimental models of de-/remyelination requires an accurate measure not only of functional changes but also of the amount of myelin. We tested whether X-ray diffraction (XRD), which measures periodicity in unfixed myelin, can assess the structural integrity of myelin in fixed tissue. From laboratories involved in spinal cord injury research and in studying the aging primate brain, we solicited "blind" samples and used an electronic detector to record rapidly the diffraction patterns (30 min each pattern) from them. We assessed myelin integrity by measuring its periodicity and relative amount. Fixation of tissue itself introduced +/-10% variation in periodicity and +/-40% variation in relative amount of myelin. For samples having the most native-like periods, the relative amounts of myelin detected allowed distinctions to be made between normal and demyelinating segments, between motor and sensory tracts within the spinal cord, and between aged and young primate CNS. Different periodicities also allowed distinctions to be made between samples from spinal cord and nerve roots and between well-fixed and poorly fixed samples. Our findings suggest that, in addition to evaluating the effectiveness of different fixatives, XRD could also be used as a robust and rapid technique for quantitating the relative amount of myelin among spinal cords and other CNS tissue samples from experimental models of de- and remyelination.

The interface between morphology and action planning: a comparison of two species of New World monkeys

Recent research with several species of nonhuman primates suggests sophisticated motor-planning abilities observed in human adults may be ubiquitous among primates. However, there is considerable variability in the extent to which these abilities are expressed across primate species. In the present experiment, we explore whether the variability in the expression of anticipatory motor-planning abilities may be attributed to cognitive differences (such as tool use abilities) or whether they may be due to the consequences of morphological differences (such as being able to deploy a precision grasp). We compared two species of New World monkeys that differ in their tool use abilities and manual dexterity: squirrel monkeys, Saimiri sciureus (less dexterous with little evidence for tool use) and tufted capuchins, Sapajus apella (more dexterous and known tool users). The monkeys were presented with baited cups in an untrained food extraction task. Consistent with the morphological constraint hypothesis, squirrel monkeys frequently showed second-order motor planning by inverting their grasp when picking up an inverted cup, while capuchins frequently deployed canonical upright grasping postures. Findings suggest that the lack of ability for precision grasping may elicit more consistent second-order motor planning, as the squirrel monkeys (and other species that have shown a high rate of second-order planning) have fewer means of compensating for inefficient initial postures. Thus, the interface between morphology and motor planning likely represents an important factor for understanding both the ontogenetic and phylogenetic origins of sophisticated motor-planning abilities.

The Interface Between Morphology and Action Planning: a Comparison of Two Species of New World Monkeys

Recent research with several species of nonhuman primates suggests sophisticated motor-planning abilities observed in human adults may be ubiquitous among primates. However, there is considerable variability in the extent to which these abilities are expressed across primate species. In the present experiment, we explore whether the variability in the expression of anticipatory motor-planning abilities may be attributed to cognitive differences (such as tool use abilities) or whether they may be due to the consequences of morphological differences (such as being able to deploy a precision grasp). We compared two species of New World monkeys that differ in their tool use abilities and manual dexterity: squirrel monkeys, Saimiri sciureus (less dexterous with little evidence for tool use) and tufted capuchins, Sapajus apella (more dexterous and known tool users). The monkeys were presented with baited cups in an untrained food extraction task. Consistent with the morphological constraint hypothesis, squirrel monkeys frequently showed second-order motor planning by inverting their grasp when picking up an inverted cup, while capuchins frequently deployed canonical upright grasping postures. Findings suggest that the lack of ability for precision grasping may elicit more consistent second-order motor planning, as the squirrel monkeys (and other species that have shown a high rate of second-order planning) have fewer means of compensating for inefficient initial postures. Thus, the interface between morphology and motor planning likely represents an important factor for understanding both the ontogenetic and phylogenetic origins of sophisticated motor-planning abilities. (C) 2013 The Association for the Study of Animal Behaviour. Published by Elsevier Ltd. All rights reserved.

Life stage differences in mammary gland gene expression profile in non-human primates

Breast cancer (BC) is the most common malignancy of women in the developed world. To better understand its pathogenesis, knowledge of normal breast development is crucial, as BC is the result of disregulation of physiologic processes. The aim of this study was to investigate the impact of reproductive life stages on the transcriptional profile of the mammary gland in a primate model. Comparative transcriptomic analyses were carried out using breast tissues from 28 female cynomolgus macaques (Macaca fascicularis) at the following life stages: prepubertal (n = 5), adolescent (n = 4), adult luteal (n = 5), pregnant (n = 6), lactating (n = 3), and postmenopausal (n = 5). Mammary gland RNA was hybridized to Affymetrix GeneChip(®) Rhesus Macaque Genome Arrays. Differential gene expression was analyzed using ANOVA and cluster analysis. Hierarchical cluster analysis revealed distinct separation of life stage groups. More than 2,225 differentially expressed mRNAs were identified. Gene families or pathways that changed across life stages included those related to estrogen and androgen (ESR1, PGR, TFF1, GREB1, AR, 17HSDB2, 17HSDB7, STS, HSD11B1, AKR1C4), prolactin (PRLR, ELF5, STAT5, CSN1S1), insulin-like growth factor signaling (IGF1, IGFBP1, IGFBP5), extracellular matrix (POSTN, TGFB1, COL5A2, COL12A1, FOXC1, LAMC1, PDGFRA, TGFB2), and differentiation (CD24, CD29, CD44, CD61, ALDH1, BRCA1, FOXA1, POSTN, DICER1, LIG4, KLF4, NOTCH2, RIF1, BMPR1A, TGFB2). Pregnancy and lactation displayed distinct patterns of gene expression. ESR1 and IGF1 were significantly higher in the adolescent compared to the adult animals, whereas differentiation pathways were overrepresented in adult animals and pregnancy-associated life stages. Few individual genes were distinctly different in postmenopausal animals. Our data demonstrate characteristic patterns of gene expression during breast development. Several of the pathways activated during pubertal development have been implicated in cancer development and metastasis, supporting the idea that other developmental markers may have application as biomarkers for BC.

Investigating human audio-visual object perception with a combination of hypothesis-generating and hypothesis-testing fMRI analysis tools

Primate multisensory object perception involves distributed brain regions. To investigate the network character of these regions of the human brain, we applied data-driven group spatial independent component analysis (ICA) to a functional magnetic resonance imaging (fMRI) data set acquired during a passive audio-visual (AV) experiment with common object stimuli. We labeled three group-level independent component (IC) maps as auditory (A), visual (V), and AV, based on their spatial layouts and activation time courses. The overlap between these IC maps served as definition of a distributed network of multisensory candidate regions including superior temporal, ventral occipito-temporal, posterior parietal and prefrontal regions. During an independent second fMRI experiment, we explicitly tested their involvement in AV integration. Activations in nine out of these twelve regions met the max-criterion (A < AV > V) for multisensory integration. Comparison of this approach with a general linear model-based region-of-interest definition revealed its complementary value for multisensory neuroimaging. In conclusion, we estimated functional networks of uni- and multisensory functional connectivity from one dataset and validated their functional roles in an independent dataset. These findings demonstrate the particular value of ICA for multisensory neuroimaging research and using independent datasets to test hypotheses generated from a data-driven analysis.

Radiation metabolomics. 5. Identification of urinary biomarkers of ionizing radiation exposure in nonhuman primates by mass spectrometry-based metabolomics

Mass spectrometry-based metabolomics has previously demonstrated utility for identifying biomarkers of ionizing radiation exposure in cellular, mouse and rat in vivo radiation models. To provide a valuable link from small laboratory rodents to humans, γ-radiation-induced urinary biomarkers were investigated using a nonhuman primate total-body-irradiation model. Mass spectrometry-based metabolomics approaches were applied to determine whether biomarkers could be identified, as well as the previously discovered rodent biomarkers of γ radiation. Ultra-performance liquid chromatography-electrospray ionization quadrupole time-of-flight mass spectrometry analysis was carried out on a time course of clean-catch urine samples collected from nonhuman primates (n = 6 per cohort) exposed to sham, 1.0, 3.5, 6.5 or 8.5 Gy doses of (60)Co γ ray (∼0.55 Gy/min) ionizing radiation. By multivariate data analysis, 13 biomarkers of radiation were discovered: N-acetyltaurine, isethionic acid, taurine, xanthine, hypoxanthine, uric acid, creatine, creatinine, tyrosol sulfate, 3-hydroxytyrosol sulfate, tyramine sulfate, N-acetylserotonin sulfate, and adipic acid. N-Acetyltaurine, isethionic acid, and taurine had previously been identified in rats, and taurine and xanthine in mice after ionizing radiation exposure. Mass spectrometry-based metabolomics has thus successfully revealed and verified urinary biomarkers of ionizing radiation exposure in the nonhuman primate for the first time, which indicates possible mechanisms for ionizing radiation injury.

A Test of Absolute Numerousness Judgments in Lion-Tailed Macaques (Macaca Silenus)

Numerous studies have shown that animals have a sense of quantity and can distinguish between relative amounts. The concepts of relative numerousness, estimation, and subitizing are well established in species as diverse as chimpanzees and salamanders. Mobile animals have practical use for an understanding of number in common situations such as predation, mating, and competition. However, the ability to identify discrete quantities has only been firmly established in humans. The purpose of this study was to test for such “absolute numerousness” judgments in three lion-tailed macaques (Macaca silenus), a non-human primate. The three macaques tested had previously been trained on a computerized matchto- sample (MTS) task using geometric shapes. In this study, they were introduced to a MTS task containing a numerical cue, which required the monkeys to match stimuli containing either one or two items for rewards. If monkeys were successful at the initial matching task, they were tested with stimuli in which the position of the items and then the surface area of the items was controlled. If the monkeys could match successfully without using these non-numerical cues, they would demonstrate the capability to make absolute numerousness judgments. None of the monkeys matched successfully using the numerical cue, so no evidence of absolute numerosity was found. Each macaque progressed through the experiment in an individualized manner, attempting a variety of strategies to obtain rewards. These included side preferences and an alternating-side strategy that were unrelated to the numerical cues in the stimuli. When it became clear that the monkeys were not matching based on a stimulus-based cue, they were tested again on matching geometric shapes. All three macaques stopped using their alternate strategies and were able to match shapes successfully, demonstrating that they were still capable of completing the matching task. The data suggest that the monkeys could not transfer this ability to the numerical stimuli. This indicates that the macaques lack a sense of exact quantity, or that they could not recognize the numerical cues in the stimuli as being relevant to the task.