Differential regulation of PGC-1α expression in rat liver and skeletal muscle in response to voluntary running

Abstract Background The beneficial actions of exercise training on lipid, glucose and energy metabolism and insulin sensitivity appear to be in part mediated by PGC-1α. Previous studies have shown that spontaneously exercised rats show at rest enhanced responsiveness to exogenous insulin, lower plasma insulin levels and increased skeletal muscle insulin sensitivity. This study was initiated to examine the functional interaction between exercise-induced modulation of skeletal muscle and liver PGC-1α protein expression, whole body insulin sensitivity, and circulating FFA levels as a measure of whole body fatty acid (lipid) metabolism. Methods Two groups of male Wistar rats (2 Mo of age, 188.82 ± 2.77 g BW) were used in this study. One group consisted of control rats placed in standard laboratory cages. Exercising rats were housed individually in cages equipped with running wheels and allowed to run at their own pace for 5 weeks. At the end of exercise training, insulin sensitivity was evaluated by comparing steady-state plasma glucose (SSPG) concentrations at constant plasma insulin levels attained during the continuous infusion of glucose and insulin to each experimental group. Subsequently, soleus and plantaris muscle and liver samples were collected and quantified for PGC-1α protein expression by Western blotting. Collected blood samples were analyzed for glucose, insulin and FFA concentrations. Results Rats housed in the exercise wheel cages demonstrated almost linear increases in running activity with advancing time reaching to maximum value around 4 weeks. On an average, the rats ran a mean (Mean ± SE) of 4.102 ± 0.747 km/day and consumed significantly more food as compared to sedentary controls (P < 0.001) in order to meet their increased caloric requirement. Mean plasma insulin (P < 0.001) and FFA (P < 0.006) concentrations were lower in the exercise-trained rats as compared to sedentary controls. Mean steady state plasma insulin (SSPI) and glucose (SSPG) concentrations were not significantly different in sedentary control rats as compared to exercise-trained animals. Plantaris PGC-1α protein expression increased significantly from a 1.11 ± 0.12 in the sedentary rats to 1.74 ± 0.09 in exercising rats (P < 0.001). However, exercise had no effect on PGC-1α protein content in either soleus muscle or liver tissue. These results indicate that exercise training selectively up regulates the PGC-1α protein expression in high-oxidative fast skeletal muscle type such as plantaris muscle. Conclusion These data suggest that PGC-1α most likely plays a restricted role in exercise-mediated improvements in insulin resistance (sensitivity) and lowering of circulating FFA levels.

Libro, diaspora e ri-costruzioni identitarie. Per una storia della tipografia sefardita portoghese nell'Italia del Cinquecento

Il lavoro ripercorre le tracce che gli ebrei portoghesi, esuli dopo il biennio 1496-97, lasciarono nel loro cammino attraverso l'Europa. In particolare, l'interesse si concentra sulla breve parentesi italiana, che grazie all'apertura e alla disponibilità  di alcuni Signori, come i Gonzaga di Mantova, i Medici, i Dogi della Serenissima e gli Este, risulta ricchissima di avvenimenti e personaggi, decisivi anche per la storia culturale del Portogallo. L'analisi parte evidenziando l'importanza che ebbe la tipografia ebraica in Portogallo all'epoca della sua introduzione nel Paese; in secondo luogo ripercorre la strada che, dal biennio del primo decreto di espulsione e del conseguente battesimo di massa, porta alla nascita dell'€™Inquisizione in Portogallo. Il secondo capitolo tenta di fare una ricostruzione, il più possibile completa e coerente, dei movimenti degli esuli, bollati come marrani e legati alle due maggiori famiglie, i Mendes e i Bemveniste, delineando poi il primo nucleo di quella che diventerà  nel Seicento la comunità  sefardita portoghese di Amsterdam, dove nasceranno le personalità  dissidenti di Uriel da Costa e del suo allievo Spinoza. Il terzo capitolo introduce il tema delle opere letterarie, effettuando una rassegna dei maggiori volumi editi dalle officine tipografiche ebraiche stanziatesi in Italia fra il 1551 e il 1558, in modo particolare concentrando l'attenzione sull'€™attività  della tipografia Usque, da cui usciranno numerosi testi di precettistica in lingua ebraica, ma soprattutto opere cruciali come la famosa «Bibbia Ferrarese» in castigliano, la «Consolação às Tribulações de Israel», di Samuel Usque e la raccolta composta dal romanzo cavalleresco «Menina e Moça» di Bernardim Ribeiro e dall'ecloga «Crisfal», di un autore ancora non accertato. L'ultimo capitolo, infine, si propone di operare una disamina di queste ultime tre opere, ritenute fondamentali per ricostruire il contesto letterario e culturale in cui la comunità  giudaica in esilio agiva e proiettava le proprie speranze di futuro. Per quanto le opere appartengano a generi diversi e mostrino diverso carattere, l'€™ipotesi è che siano parte di un unicum filosofico e spirituale, che intendeva sostanzialmente indicare ai confratelli sparsi per l'Europa la direzione da prendere, fornendo un sostegno teoretico, psicologico ed emotivo nelle difficili condizioni di sopravvivenza, soprattutto dell'integrità religiosa, di ciascun membro della comunità.

Effetto della temperatura di conservazione del latte, dalla raccolta all'affioramento, sulla microflora del latte, del sieroinnesto e del formaggio Trentingrana

This PhD research is part of a project addressed to improve the quality of Grana Trentino production. The objectives were to evaluated if milk storage and collection procedures may affect cheese-making technology and quality. Actually the milk is collected and delivered to the cheese factory just after milking in 50 L cans without refrigeration or in tanks cooled at 18 °C. This procedure is expensive (two deliveries each day) and the milk quality is difficult to preserve as temperatures are not controlled. The milk refrigeration at the farm could allow a single delivery to the dairy. Therefore it could be a good strategy to preserve raw milk quality and reduce cheese spoilage. This operation may, however, have the drawbacks of favouring the growth of psychrotrophic bacteria and changing the aptitude of milk to coagulation. With the aim of studying the effect on milk and cheese of traditional and new refrigerated technologies of milk storage, two different collection and creaming technologies were compared. The trials were replicated in three cheese factories manufacturing Grana Trentino. Every cheese-making day, about 1000 milk liters were collected from always the same two farms in the different collection procedures (single or double). Milk was processed to produce 2 wheels of Grana trentino every day. During the refrigerated trials, milk was collected and stored at the farm in a mixed tank at 12 or 8 °C and then was carried to the dairy in truck once a day. 112 cheese making day were followed: 56 for traditional technology and 56 for the refrigerated one. Each one of these two thechnologies lead to different ways of creaming: long time in the traditional one and shorter in the new one. For every cheese making day we recorded time, temperatures and pH during the milk processing to cheese. Whole milk before ceraming, cream and skim milk after creaming, vat milk and whey were sampled during every cheese-making day for analysis. After 18 months ripening we opened 46 cheese wheels for further chemical and microbiological analyses. The trials were performed with the aim of: 1 estimate the effect of storage temperatures on microbial communities, physico-chemical or/and rheological differences of milk and skim milk after creaming. 2 detect by culture dependent (plate counts) and indipendent (DGGE) methodolgies the microbial species present in whole, skimmed milk, cream and cheese sampled under the rind and in the core; 3 estimate the physico-chemical characteristics, the proteolytic activity, the content of free aminoacids and volatile compounds in 18 months ripened Grana Trentino cheeses from different storing and creaming of milk technologies. The results presented are remarkable since this is the first in-deep study presenting microbiological and chemical analysis of Grana Trentino that even if belonging to Grana Padano Consortium, it is clearly different in the milk and in the manufacturing technology.

Synthetic strategies of new molecular paramagnetic mechanically-interlocked complexes

Supramolecular chemistry is a multidisciplinary field which impinges on other disciplines, focusing on the systems made up of a discrete number of assembled molecular subunits. The forces responsible for the spatial organization are intermolecular reversible interactions. The supramolecular architectures I was interested in are Rotaxanes, mechanically-interlocked architectures consisting of a "dumbbell shaped molecule", threaded through a "macrocycle" where the stoppers at the end of the dumbbell prevent disassociation of components and catenanes, two or more interlocked macrocycles which cannot be separated without breaking the covalent bonds. The aim is to introduce one or more paramagnetic units to use the ESR spectroscopy to investigate complexation properties of these systems cause this technique works in the same time scale of supramolecular assemblies. Chapter 1 underlines the main concepts upon which supramolecular chemistry is based, clarifying the nature of supramolecular interactions and the principles of host-guest chemistry. In chapter 2 it is pointed out the use of ESR spectroscopy to investigate the properties of organic non-covalent assemblies in liquid solution by spin labels and spin probes. The chapter 3 deals with the synthesis of a new class of p-electron-deficient tetracationic cyclophane ring, carrying one or two paramagnetic side-arms based on 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) moiety. In the chapter 4, the Huisgen 1,3-dipolar cycloaddition is exploited to synthesize rotaxanes having paramagnetic cyclodextrins as wheels. In the chapter 5, the catalysis of Huisgen’s cycloaddition by CB[6] is exploited to synthesize paramagnetic CB[6]-based [3]-rotaxanes. In the chapter 6 I reported the first preliminary studies of Actinoid series as a new class of templates in catenanes’ synthesis. Being f-block elements, so having the property of expanding the valence state, they constitute promising candidates as chemical templates offering the possibility to create a complex with coordination number beyond 6.

Moschee a Milano: La costruzione geografica del diritto alla città

La tesi descrive e analizza la geografia delle moschee in Italia, un tema di grande attualità, in particolare per quanto riguardo il quadro degli studi geografici. La tesi ripercorre quello che è stato il processo di insediamento delle moschee in Italia, attraverso lo studio di casi esemplari, e analizza l’impatto che tale presenza ha esercitato sul territorio italiano, ed in particolare nel contesto urbano di Milano. Questo lavoro, infatti, permette di osservare il “processo di visibilizzazione” che una religione, assente fino a pochi decenni fa dal paesaggio italiano, imprime sul territorio, attraverso i luoghi di culto, le moschee. Il cuore di questo lavoro riflette sulla dimensione della “costruzione dello spazio” evidenziata dalla realizzazione di moschee. Infatti, i frequenti conflitti che accompagnano la proposta o la realizzazione di moschee dimostrano che non tutti hanno ugualmente “diritto alla città”, a un “posto” nello spazio. Le moschee non rappresentano solamente il simbolo della presenza di musulmani nello spazio europeo. Attraverso di esse è possibile leggere la posizione dei musulmani nella società italiana. Le sale di preghiera sorte inizialmente nelle città italiane, e in questo caso a Milano, in luoghi residuali e precari (cantine, garage, etc.) rappresentano una prima fase dell’insediamento dei musulmani nello spazio urbano. Un insediamento poco visibile e poco organizzato visto dalle istituzioni e dalla società senza grandi reazioni negative. I conflitti si innescano invece nel passaggio al tempo del riconoscimento, dell’istituzionalizzazione, in cui una presenza che si pensava temporanea o accidentale si fa stabile, organizzata, visibile e centrale. La realizzazione di moschee rappresenterebbe il passaggio da un’epoca di insediamento spontaneo di una minoranza religiosa arrivata recentemente al momento dell’istituzionalizzazione, dell’attribuzione di un “posto” riconosciuto e legittimo. Dunque, il passaggio dal tempo dell’ospitalità al “tempo del diritto alla città” e del riconoscimento.

Evaluation of energy level to be absorbed by tractor ROPS: Actual Tests, Simulation and Computation

A highly dangerous situations for tractor driver is the lateral rollover in operating conditions. Several accidents, involving tractor rollover, have indeed been encountered, requiring the design of a robust Roll-Over Protective Structure (ROPS). The aim of the thesis was to evaluate tractor behaviour in the rollover phase so as to calculate the energy absorbed by the ROPS to ensure driver safety. A Mathematical Model representing the behaviour of a generic tractor during a lateral rollover, with the possibility of modifying the geometry, the inertia of the tractor and the environmental boundary conditions, is proposed. The purpose is to define a method allowing the prediction of the elasto-plastic behaviour of the subsequent impacts occurring in the rollover phase. A tyre impact model capable of analysing the influence of the wheels on the energy to be absorbed by the ROPS has been also developed. Different tractor design parameters affecting the rollover behaviour, such as mass and dimensions, have been considered. This permitted the evaluation of their influence on the amount of energy to be absorbed by the ROPS. The mathematical model was designed and calibrated with respect to the results of actual lateral upset tests carried out on a narrow-track tractor. The dynamic behaviour of the tractor and the energy absorbed by the ROPS, obtained from the actual tests, showed to match the results of the model developed. The proposed approach represents a valuable tool in understanding the dynamics (kinetic energy) and kinematics (position, velocity, angular velocity, etc.) of the tractor in the phases of lateral rollover and the factors mainly affecting the event. The prediction of the amount of energy to be absorbed in some cases of accident is possible with good accuracy. It can then help in designing protective structures or active security devices.

Simulazione dinamica di un veicolo dotato di powertrain ibrido endotermico-elettrico

Nel panorama motoristico ed automobilistico moderno lo sviluppo di motori a combustione interna e veicoli è fortemente influenzato da diverse esigenze che spesso sono in contrasto le une con le altre. Infatti gli obiettivi di economicità e riduzione dei costi riguardanti la produzione e la commercializzazione dei prodotti sono in contrasto con gli sforzi che devono essere operati dalle case produttrici per soddisfare le sempre più stringenti normative riguardanti le emissioni inquinanti ed i consumi di carburante dei veicoli. Fra le numerose soluzioni presenti i veicoli ibridi rappresentano una alternativa che allo stato attuale è già presente sul mercato in varie forme, a seconda della tipologie di energie accoppiate. In letteratura è possibile trovare numerosi studi che trattano l’ottimizzazione dei componenti o delle strategie di controllo di queste tipologie di veicoli: in moltissimi casi l’obiettivo è quello di minimizzare consumi ed emissioni inquinanti. Normalmente non viene posta particolare attenzione agli effetti che l’aggiunta delle macchine elettriche e dei componenti necessari per il funzionamento delle stesse hanno sulla dinamica del veicolo. Il presente lavoro di tesi è incentrato su questi aspetti: si è considerata la tipologia di veicoli ibridi termici-elettrici di tipo parallelo andando ad analizzare come cambiasse il comportamento dinamico del veicolo in funzione del tipo di installazione considerato per la parte elettrica del powertrain. In primo luogo è stato quindi necessario costruire ed implementare un modello dinamico di veicolo che permettesse di applicare coppie alle quattro ruote in maniera indipendente per considerare diverse tipologie di powertrain. In seguito si sono analizzate le differenze di comportamento dinamico fra il veicolo considerato e l’equivalente versione ibrida e i possibili utilizzi delle macchine elettriche per correggere eventuali deterioramenti o cambiamenti indesiderati nelle prestazioni del veicolo.

Fault detection, diagnosis and active fault tolerant control for a satellite attitude control system

Modern control systems are becoming more and more complex and control algorithms more and more sophisticated. Consequently, Fault Detection and Diagnosis (FDD) and Fault Tolerant Control (FTC) have gained central importance over the past decades, due to the increasing requirements of availability, cost efficiency, reliability and operating safety. This thesis deals with the FDD and FTC problems in a spacecraft Attitude Determination and Control System (ADCS). Firstly, the detailed nonlinear models of the spacecraft attitude dynamics and kinematics are described, along with the dynamic models of the actuators and main external disturbance sources. The considered ADCS is composed of an array of four redundant reaction wheels. A set of sensors provides satellite angular velocity, attitude and flywheel spin rate information. Then, general overviews of the Fault Detection and Isolation (FDI), Fault Estimation (FE) and Fault Tolerant Control (FTC) problems are presented, and the design and implementation of a novel diagnosis system is described. The system consists of a FDI module composed of properly organized model-based residual filters, exploiting the available input and output information for the detection and localization of an occurred fault. A proper fault mapping procedure and the nonlinear geometric approach are exploited to design residual filters explicitly decoupled from the external aerodynamic disturbance and sensitive to specific sets of faults. The subsequent use of suitable adaptive FE algorithms, based on the exploitation of radial basis function neural networks, allows to obtain accurate fault estimations. Finally, this estimation is actively exploited in a FTC scheme to achieve a suitable fault accommodation and guarantee the desired control performances. A standard sliding mode controller is implemented for attitude stabilization and control. Several simulation results are given to highlight the performances of the overall designed system in case of different types of faults affecting the ADCS actuators and sensors.

Realizzazione di una piattaforma di test per ruota di momento su architettura NI cRIO

L'elaborato descrive la realizzazione di una piattaforma e software relativo, per testare i componenti di una ruota di momento.

Differentiation in Male and Female Speech Styles

From the moment of their birth, a person's life is determined by their sex. Ms. Goroshko wants to know why this difference is so striking, why society is so concerned to sustain it, and how it is able to persist even when certain national or behavioural stereotypes are erased between people. She is convinced of the existence of not only social, but biological differences between men and women, and set herself the task, in a manuscript totalling 126 pages, written in Ukrainian and including extensive illustrations, of analysing these distinctions as they are manifested in language. She points out that, even before 1900, certain stylistic differences between the ways that men and women speak had been noted. Since then it has become possible, for instance in the case of Japanese, to point to examples of male and female sub-languages. In general, one can single out the following characteristics. Males tend to write with less fluency, to refer to events in a verb-phrase, to be time-oriented, to involve themselves more in their references to events, to locate events in their personal sphere of activity, and to refer less to others. Therefore, concludes Ms Goroshko, the male is shown to be more active, more ego-involved in what he does, and less concerned about others. Women, in contrast, were more fluent, referred to events in a noun-phrase, were less time-oriented, tended to be less involved in their event-references, locate events within their interactive community and refer more to others. They spent much more time discussing personal and domestic subjects, relationship problems, family, health and reproductive matters, weight, food and clothing, men, and other women. As regards discourse strategies, Ms Goroshko notes the following. Men more often begin a conversation, they make more utterances, these utterances are longer, they make more assertions, speak less carefully, generally determine the topic of conversation, speak more impersonally, use more vulgar expressions, and use fewer diminutives and more imperatives. Women's speech strategies, apart from being the opposite of those enumerated above, also contain more euphemisms, polite forms, apologies, laughter and crying. All of the above leads Ms. Goroshko to conclude that the differences between male and female speech forms are more striking than the similarities. Furthermore she is convinced that the biological divergence between the sexes is what generates the verbal divergence, and that social factors can only intensify or diminish the differentiation in verbal behaviour established by the sex of a person. Bearing all this in mind, Ms Goroshko set out to construct a grammar of male and female styles of speaking within Russian. One of her most important research tools was a certain type of free association test. She took a list comprising twelve stimuli (to love, to have, to speak, to fuck, a man, a woman, a child, the sky, a prayer, green, beautiful) and gave it to a group of participants specially selected, according to a preliminary psychological testing, for the high levels of masculinity or femininity they displayed. Preliminary responses revealed that the female reactions were more diverse than the male ones, there were more sentences and word combinations in the female reactions, men gave more negative responses to the stimulus and sometimes didn't want to react at all, women reacted more to adjectives and men to nouns, and that, surprisingly, women coloured more negatively their reactions to the words man, to love and a child (Ms. Goroshko is inclined to attribute this to the present economic situation in Russia). Another test performed by Ms. Goroshko was the so-called "defective text" developed by A.A. Brudny. All participants were distributed with packets of complete sentences, which had been taken from a text and then mixed at random. The task was to reconstruct the original text. There were three types of test, the first descriptive, the second narrative, and the third logical. Ms. Goroshko created computer programmes to analyse the results. She found that none of the reconstructed texts was coincident with the original, differing both from the original text and amongst themselves and that there were many more disparities in the male than the female texts. In the descriptive and logical texts the differences manifested themselves more clearly in the male texts, and in the narrative texts in the female texts. The widest dispersal of values was observed at the outset, while the female text ending was practically coincident with the original (in contrast to the male ending). The greatest differences in text reconstruction for both males and females were registered in the middle of the texts. Women, Ms. Goroshko claims, were more sensitive to the semantic structure of the texts, since they assembled the narrative text much more accurately than the other two, while the men assembled more accurately the logical text. Texts written by women were assembled more accurately by women and texts by men by men. On the basis of computer analysis, Ms. Goroshko found that female speech was substantially more emotional. It was expressed by various means, hyperbole, metaphor, comparisons, epithets, ways of enumeration, and with the aid of interjections, rhetorical questions, exclamations. The level of literacy was higher for female speech, and there were fewer mistakes in grammar and spelling in female texts. The last stage of Ms Goroshko's research concerned the social stereotypes of beliefs about men and women in Russian society today. A large number of respondents were asked questions such as "What merits must a woman possess?", "What are male vices and virtues?", etc. After statistical manipulation, an image of modern man and woman, as it exists in the minds of modern Russian men and women, emerged. Ms. Goroshko believes that her findings are significant not only within the field of linguistics. She has already successfully worked on anonymous texts and been able to decide on the sex of the author and consequently believes that in the future her research may even be of benefit to forensic science.

Predictive control of hybrid vehicle powertrain for intelligent energy management

This thesis studies the minimization of the fuel consumption for a Hybrid Electric Vehicle (HEV) using Model Predictive Control (MPC). The presented MPC – based controller calculates an optimal sequence of control inputs to a hybrid vehicle using the measured plant outputs, the current dynamic states, a system model, system constraints, and an optimization cost function. The MPC controller is developed using Matlab MPC control toolbox. To evaluate the performance of the presented controller, a power-split hybrid vehicle, 2004 Toyota Prius, is selected. The vehicle uses a planetary gear set to combine three power components, an engine, a motor, and a generator, and transfer energy from these components to the vehicle wheels. The planetary gear model is developed based on the Willis’s formula. The dynamic models of the engine, the motor, and the generator, are derived based on their dynamics at the planetary gear. The MPC controller for HEV energy management is validated in the MATLAB/Simulink environment. Both the step response performance (a 0 – 60 mph step input) and the driving cycle tracking performance are evaluated. Two standard driving cycles, Urban Dynamometer Driving Schedule (UDDS) and Highway Fuel Economy Driving Schedule (HWFET), are used in the evaluation tests. For the UDDS and HWFET driving cycles, the simulation results, the fuel consumption and the battery state of charge, using the MPC controller are compared with the simulation results using the original vehicle model in Autonomie. The MPC approach shows the feasibility to improve vehicle performance and minimize fuel consumption.

Schmiede ─ Heiligtum ─ Wassermühle. Cham-Hagendorn (Kanton Zug) in römischer Zeit. Ausgrabungen 1944/45 und 2003/04

1944/1945 wurde in Cham-Hagendorn eine Wassermühle ausgegraben, die dank ihrer aussergewöhnlich guten Holzerhaltung seit langem einen prominenten Platz in der Forschung einnimmt. 2003 und 2004 konnte die Kantonsarchäologie Zug den Platz erneut archäologisch untersuchen. Dabei wurden nicht nur weitere Reste der Wassermühle, sondern auch Spuren älterer und jüngerer Anlagen geborgen: eine ältere und eine jüngere Schmiedewerkstatt (Horizont 1a/Horizont 3) sowie ein zweiphasiges Heiligtum (Horizonte 1a/1b). All diese Anlagen lassen sich nun in das in den neuen Grabungen erkannte stratigraphische Gerüst einhängen (s. Beil. 2). Dank der Holzerhaltung können die meisten Phasen dendrochronologisch datiert werden (s. Abb. 4.1/1a): Horizont 1a mit Schlagdaten zwischen 162(?)/173 und 200 n. Chr., Horizont 1b um 215/218 n. Chr. und Horizont 2 um 231 n. Chr. Ferner konnten in den neuen Grabungen Proben für mikromorphologische und archäobotanische Untersuchungen entnommen werden (Kap. 2.2; 3.11). In der vorliegenden Publikation werden der Befund und die Baustrukturen vorgelegt, (Kap. 2), desgleichen sämtliche stratifizierten Funde und eine umfassende Auswahl der 1944/1945 geborgenen Funde (Kap. 3). Dank anpassender Fragmente, sog. Passscherben, lassen sich diese zum Teil nachträglich in die Schichtenabfolge einbinden. Die mikromorphologischen und die archäobotanischen Untersuchungen (Kap. 2.2; 3.11) zeigen, dass der Fundplatz in römischer Zeit inmitten einer stark vom Wald und dem Fluss Lorze geprägten Landschaft lag. In unmittelbarer Nähe können weder eine Siedlung noch einzelne Wohnbauten gelegen haben. Die demnach nur gewerblich und sakral genutzten Anlagen standen an einem Bach, der vermutlich mit jenem Bach identisch ist, der noch heute das Groppenmoos entwässert und bei Cham-Hagendorn in die Lorze mündet (s. Abb. 2.4/1). Der antike Bach führte wiederholt Hochwasser ─ insgesamt sind fünf grössere Überschwemmungsphasen auszumachen (Kap. 2.2; 2.4). Wohl anlässlich eines Seehochstandes durch ein Überschwappen der Lorze in den Bach ausgelöst, müssen diese Überschwemmungen eine enorme Gewalt entwickelt haben, der die einzelnen Anlagen zum Opfer fielen. Wie die Untersuchung der Siedlungslandschaft römischer Zeit rund um den Zugersee wahrscheinlich macht (Kap. 6 mit Abb. 6.2/2), dürften die Anlagen von Cham-Hagendorn zu einer in Cham-Heiligkreuz vermuteten Villa gehören, einem von fünf grösseren Landgütern in diesem Gebiet. Hinweise auf Vorgängeranlagen fehlen, mit denen die vereinzelten Funde des 1. Jh. n. Chr. (Kap. 4.5) in Verbindung gebracht werden könnten. Diese dürften eher von einer der Überschwemmungen bachaufwärts weggerissen und nach Cham-Hagendorn eingeschwemmt worden sein. Die Nutzung des Fundplatzes (Horizont 1a; s. Beil. 6) setzte um 170 n. Chr. mit einer Schmiedewerkstatt ein (Kap. 2.5.1). Der Fundanfall, insbesondere die Schmiedeschlacken (Kap. 3.9) belegen, dass hier nur hin und wieder Geräte hergestellt und repariert wurden (Kap. 5.2). Diese Werkstatt war vermutlich schon aufgelassen und dem Verfall preisgegeben, als man 200 n. Chr. (Kap. 4.2.4) auf einer Insel zwischen dem Bach und einem Lorzearm ein Heiligtum errichtete (Kap. 5.3). Beleg für den sakralen Status dieser Insel ist in erster Linie mindestens ein eigens gepflanzter Pfirsichbaum, nachgewiesen mit Pollen, einem Holz und über 400 Pfirsichsteinen (Kap. 3.11). Die im Bach verlaufende Grenze zwischen dem sakralen Platz und der profanen Umgebung markierte man zusätzlich mit einer Pfahlreihe (Kap. 2.5.3). In diese war ein schmaler Langbau integriert (Kap. 2.5.2), der an die oft an Temenosmauern antiker Heiligtümer angebauten Portiken erinnert und wohl auch die gleiche Funktion wie diese gehabt hatte, nämlich das Aufbewahren von Weihegaben und Kultgerät (Kap. 5.3). Das reiche Fundmaterial, das sich in den Schichten der ersten Überschwemmung fand (s. Abb. 5./5), die um 205/210 n. Chr. dieses Heiligtum zerstört hatte, insbesondere die zahlreiche Keramik (Kap. 3.2.4), und die zum Teil auffallend wertvollen Kleinfunde (Kap. 3.3.3), dürften zum grössten Teil einst in diesem Langbau untergebracht gewesen sein. Ein als Glockenklöppel interpretiertes, stratifiziertes Objekt spricht dafür, dass die fünf grossen, 1944/1945 als Stapel aufgefundenen Eisenglocken vielleicht auch dem Heiligtum zuzuweisen sind (Kap. 3.4). In diesen Kontext passen zudem die überdurchschnittlich häufig kalzinierten Tierknochen (Kap. 3.10). Nach der Überschwemmung befestigte man für 215 n. Chr. (Kap. 4.2.4) das unterspülte Bachufer mit einer Uferverbauung (Kap. 2.6.1). Mit dem Bau eines weiteren, im Bach stehenden Langbaus (Kap. 2.6.2) stellte man 218 n. Chr. das Heiligtum auf der Insel in ähnlicher Form wieder her (Horizont 1b; s. Beil. 7). Von der Pfahlreihe, die wiederum die sakrale Insel von der profanen Umgebung abgrenzte, blieben indes nur wenige Pfähle erhalten. Dennoch ist der sakrale Charakter der Anlage gesichert. Ausser dem immer noch blühenden Pfirsichbaum ist es ein vor dem Langbau aufgestelltes Ensemble von mindestens 23 Terrakottafigurinen (s. Abb. 3.6/1), elf Veneres, zehn Matres, einem Jugendlichen in Kapuzenmantel und einem kindlichen Risus (Kap. 3.6; s. auch Kap. 2.6.3). In den Sedimenten der zweiten Überschwemmung, der diese Anlage um 225/230 n. Chr. zum Opfer gefallen war, fanden sich wiederum zahlreiche Keramikgefässe (Kap. 3.2.4) und zum Teil wertvolle Kleinfunde wie eine Glasperle mit Goldfolie (Kap. 3.8.2) und eine Fibel aus Silber (Kap. 3.3.3), die wohl ursprünglich im Langbau untergebracht waren (Kap. 5.3.2 mit Abb. 5/7). Weitere Funde mit sicherem oder möglichem sakralem Charakter finden sich unter den 1944/1945 geborgenen Funden (s. Abb. 5/8), etwa ein silberner Fingerring mit Merkurinschrift, ein silberner Lunula-Anhänger, eine silberne Kasserolle (Kap. 3.3.3), eine Glasflasche mit Schlangenfadenauflage (Kap. 3.8.2) und einige Bergkristalle (Kap. 3.8.4). Im Bereich der Terrakotten kamen ferner mehrere Münzen (Kap. 3.7) zum Vorschein, die vielleicht dort niedergelegt worden waren. Nach der zweiten Überschwemmung errichtete man um 231 n. Chr. am Bach eine Wassermühle (Horizont 2; Kap. 2.7; Beil. 8; Abb. 2.7/49). Ob das Heiligtum auf der Insel wieder aufgebaut oder aufgelassen wurde, muss mangels Hinweisen offen bleiben. Für den abgehobenen Zuflusskanal der Wassermühle verwendete man mehrere stehen gebliebene Pfähle der vorangegangenen Anlagen der Horizonte 1a und 1b. Obwohl die Wassermühle den 28 jährlichen Überschwemmungshorizonten (Kap. 2.2) und den Funden (Kap. 4.3.2; 4.4.4; 45) zufolge nur bis um 260 n. Chr., während gut einer Generation, bestand, musste sie mindestens zweimal erneuert werden – nachgewiesen sind drei Wasserräder, drei Mühlsteinpaare und vermutlich drei Podeste, auf denen jeweils das Mahlwerk ruhte. Grund für diese Umbauten war wohl der weiche, instabile Untergrund, der zu Verschiebungen geführt hatte, so dass das Zusammenspiel von Wellbaum bzw. Sternnabe und Übersetzungsrad nicht mehr funktionierte und das ganze System zerbrach. Die Analyse von Pollen aus dem Gehhorizont hat als Mahlgut Getreide vom Weizentyp nachgewiesen (Kap. 3.11.4). Das Abzeichen eines Benefiziariers (Kap. 3.3.2 mit Abb. 3.3/23,B71) könnte dafür sprechen, dass das verarbeitete Getreide zumindest zum Teil für das römische Militär bestimmt war (s. auch Kap. 6.2.3). Ein im Horizont 2 gefundener Schreibgriffel und weitere stili sowie eine Waage für das Wägen bis zu 35-40 kg schweren Waren aus dem Fundbestand von 1944/1945 könnten davon zeugen, dass das Getreide zu wägen und zu registrieren war (Kap. 3.4.2). Kurz nach 260 n. Chr. fiel die Wassermühle einem weiteren Hochwasser zum Opfer. Für den folgenden Horizont 3 (Beil. 9) brachte man einen Kiesboden ein und errichtete ein kleines Gebäude (Kap. 2.8). Hier war wohl wiederum eine Schmiede untergebracht, wie die zahlreichen Kalottenschlacken belegen (Kap. 3.9), die im Umfeld der kleinen Baus zum Vorschein kamen. Aufgrund der Funde (Kap. 4.4.4; 4.5) kann diese Werkstatt nur kurze Zeit bestanden haben, höchstens bis um 270 n. Chr., bevor sie einem weiteren Hochwasser zum Opfer fiel. Von der jüngsten Anlage, die wohl noch in römische Zeit datiert (Horizont 4; Beil. 10), war lediglich eine Konstruktion aus grossen Steinplatten zu fassen (Kap. 2.9.1). Wozu sie diente, muss offen bleiben. Auch der geringe Fundanfall spricht dafür, dass die Nutzung des Platzes, zumindest für die römische Zeit, allmählich ein Ende fand (Kap. 4.5). Zu den jüngsten Strukturen gehören mehrere Gruben (Kap. 2.9.2), die vielleicht der Lehmentnahme dienten. Mangels Funden bleibt ihre Datierung indes ungewiss. Insbesondere wissen wir nicht, ob sie noch in römische Zeit datieren oder jünger sind. Spätestens mit der fünften Überschwemmung, die zur endgültigen Verlandung führte und wohl schon in die frühe Neuzeit zu setzen ist, wurde der Platz aufgelassen und erst mit dem Bau der bestehenden Fensterfabrik Baumgartner wieder besetzt.

Metabolomics and its potential in drug development

Metabolomics is the global and unbiased survey of the complement of small molecules (say, <1 kDa) in a biofluid, tissue, organ or organism and measures the end-products of the cellular metabolism of both endogenous and exogenous substrates. Many drug candidates fail during Phase II and III clinical trials at an enormous cost to the pharmaceutical industry in terms of both time lost and of financial resources. The constantly evolving model of drug development now dictates that biomarkers should be employed in preclinical development for the early detection of likely-to-fail candidates. Biomarkers may also be useful in the preselection of patients and through the subclassification of diseases in clinical drug development. Here we show with examples how metabolomics can assist in the preclinical development phases of discovery, pharmacology, toxicology, and ADME. Although not yet established as a clinical trial patient prescreening procedure, metabolomics shows considerable promise in this regard. We can be certain that metabolomics will join genomics and transcriptomics in lubricating the wheels of clinical drug development in the near future.

Second annual examination of the Sunday School for Religious Instruction of Israelites in Philadelphia : held at the synagoge Mikveh Israel ... 29th of March, 1840

together wirth a prayer by Isaac Leeser and an adress by Moses N. Nathan