Caractérisation du rôle de l’amyline (IAPP) dans le diabète de type 2 : études de dérivés peptidiques et de composés inhibiteurs de la formation d’amyloïde

L’amyloïdose, une maladie progressive et incurable, implique une vaste panoplie de pathologies et de pathogénèses, qui est expliquée par la grande variabilité biologique et structurale des protéines responsables de la formation des dépôts d’amyloïde. L’amyline (polypeptide amyloïde des îlots pancréatiques, IAPP) est une protéine très susceptible de subir des changements de conformation impliquant les feuillets bêta et conférant aussi des propriétés physicochimiques distinctes. Cette protéine prend alors une forme fibrillaire et se dépose dans les îlots de Langerhans chez les humains atteints de diabète de type 2 ou d’insulinome. Ces dépôts d’amyloïde pancréatique (AIAPP) ont été décrits chez certaines espèces animales telles que les félins domestiques, les grands félins, le raton laveur et les primates non humains. La formation de dépôts d’amyloïde contribue à la pathogénèse du diabète de type 2, mais les mécanismes qui induisent la conversion de l’amyline (IAPP) en amyloïde (AIAPP) ne sont pas complètement compris. Les hypothèses du projet sont que certaines variations présentes dans les séquences peptidiques de l’IAPP provenant de différentes espèces animales jouent un rôle critique pour la formation de fibrilles et que plusieurs composés chimiques aromatiques/phénoliques sont capables d’abroger la formation de dépôts d’amyloïde. Le projet de recherche consiste donc à caractériser la propension des différentes isoformes animales d’IAPP à former de l’amyloïde in vitro afin d’identifier les acides aminés jouant un rôle clé dans cette transformation structurale et ultimement d’inhiber la formation d’amyloïde pancréatique. Le projet se divise en deux volets principaux. Le premier consiste à identifier les différentes séquences peptidiques de l’IAPP retrouvées chez les espèces animales. L’objectif est d’identifier les acides aminés jouant un rôle clé dans la formation d’amyloïde. Le gène de l’IAPP a été séquencé chez plus d’une quarantaine d’espèces. Le potentiel d’agrégation des séquences obtenues a été simulé à l’aide d’outils bioinformatique. Une librairie de 23 peptides a été commandée afin de procéder à des analyses physicochimiques in vitro permettant d’évaluer le potentiel amyloïdogénique (test fluorimétrique à la thioflavine T, essai de liaison au rouge Congo, dichroïsme circulaire, microscopie électronique à transmission) et cytotoxique (sur une lignée cellulaire provenant d’insulinome : INS-1). Les analyses effectuées à partir de la librairie constituée de 23 peptides ont permis d’identifier trois séquences ne formant pas d’amyloïde et qui proviennent des espèces animales suivantes : le tamarin lion doré (Leontopithecus rosalia), le grand dauphin (Tursiops truncatus) et l’alpaga (Vicugna pacos). Un site potentiellement critique est le segment 8-20 présentant le motif NFLVH qui ne forme plus d’amyloïde lorsqu’il est remplacé par le motif DFLGR ou KFLIR. Les acides aminés 29P, 14K et 18R sont également impliqués dans l’inhibition de la transformation structurale en fibrille. La dernière partie du projet consiste à inhiber la formation de l’amyloïde en utilisant des composés chimiques commercialisés (hypoglycémiants, anti-inflammatoires non stéroïdiens) ou nouvellement synthétisés dans notre laboratoire (les aryles éthyles urées). Un criblage d’une soixantaine de composés chimiques a été conduit dans cette étude. Leur efficacité a été testée sur l’IAPP humaine, qui possède un fort potentiel amyloïdogénique. Les techniques utilisées sont les mêmes que celles exploitées précédemment. L’essai de liaison croisée photo-induite ("photo-induced cross-linking of unmodified proteins", PICUP) a été réalisé afin d’étudier les formes intermédiaires (monomères, oligomères). Un total de 11 composés chimiques a démontré un potentiel à inhiber l’agrégation des fibrilles. Pour la classe des hypoglycémiants, le glyburide, le répaglinide et la troglitazone ont montré l’activité thérapeutique la plus élevée pour retarder et réduire la formation de fibrilles. Les anti-inflammatoires antiamyloïdogènes actifs incluaient le diclofenac, le méloxicam, le phénylbutazone, le sulindac et le ténoxicam. Les aryles étyles urées les plus intéressantes étaient la EU-362 et la EU-418. Tous ces composés ont conféré une protection cellulaire contre l’activité cytotoxique des fibrilles. Les molécules actives possèdent des éléments structuraux communs tels des substituants donneurs d’électrons (alcool, amine, halogène) sur un noyau benzène. En conclusion, ce projet de recherche a permis de caractériser l’IAPP chez diverses espèces animales, dont plusieurs chez lesquelles elle n’avait pas encore été décrite, de déterminer les sites jouant un rôle clé dans sa transformation en amyloïde et, ultimement, de tester le potentiel thérapeutique de nouveaux agents antiamyloïdogènes dans le diabète de type 2. Nous espérons que ce projet ouvrira ainsi la porte à de nouvelles stratégies de traitement.

Impacts de l'urbanisation sur la diversité spécifique et fonctionnelle dans les forêts riveraines

L'urbanisation représente une menace majeure pour la biodiversité. Ce mémoire de maîtrise vise à comprendre ses effets sur la composition fonctionnelle et l'homogénéisation biotique dans les forêts riveraines. Des inventaires floristiques ont été réalisés dans 57 forêts riveraines de la région de Montréal. Afin d'étudier la variation de la composition fonctionnelle avec l'urbanisation, des moyennes pondérées de traits par communauté ont été calculées pour les arbres, arbustes et herbacées. Chaque forêt a été caractérisée par des variables relatives au paysage urbain environnant, aux conditions locales des forêts et aux processus spatiaux. Les conditions locales, notamment les inondations, exerçaient une pression de sélection dominante sur les traits. L'effet du paysage était indirect, agissant via l'altération des régimes hydrologiques. La dispersion le long des rivières était aussi un processus important dans la structuration des forêts riveraines. Les changements dans la diversité β taxonomique et fonctionnelle des herbacées ont été étudiés entre trois niveaux d'urbanisation et d'inondation. Alors que l'urbanisation a favorisé une différenciation taxonomique, les inondations ont favorisé une homogénéisation taxonomique, sans influencer la diversité β fonctionnelle. L'urbanisation était l'élément déclencheur des changements de la diversité β, directement, en causant un gain en espèces exotiques et une diminution de la richesse totale dans les forêts très urbanisées, et, indirectement, en entraînant un important turnover d'espèces par l'altération des régimes hydrologiques. Globalement, ces résultats suggèrent que la modification des processus naturels par les activités anthropiques est le principal moteur de changements dans les communautés riveraines urbaines.

Rôle des cellules endothéliales dans l’immunité innée précoce induite lors d’infections par des coronavirus murins

Les cellules endothéliales (EC) constituent une première barrière physique à la dissémination de virus pléiotropiques circulant par voie hématogène mais leur contribution à la défense innée anti-virale est peu connue. Des dysfonctions des EC de la barrière hémato-encéphalique (BMEC) et des sinusoïdes hépatiques (LSEC) ont été rapportées dans des neuropathologies et des hépatites aiguës ou chroniques d’origine virale, suggérant que des atteintes à leur intégrité contribuent à la pathogenèse. Les sérotypes de coronavirus de l’hépatite murine (MHV), se différenciant par leur capacité à induire des hépatites et des maladies neurologiques de sévérité variable et/ou leur tropisme pour les EC, représentent des modèles viraux privilégiés pour déterminer les conséquences de l’infection des EC sur la pathogenèse virale. Lors d’infection par voie hématogène, le sérotype MHV3, le plus virulent des MHV, induit une hépatite fulminante, caractérisée par une réponse inflammatoire sévère, et des lésions neurologiques secondaires alors que le sérotype moins virulent, MHV-A59, induit une hépatite modérée sans atteintes secondaires du système nerveux central (SNC). Par ailleurs, le sérotype MHV3, à la différence du MHV-A59, démontre une capacité à stimuler la production de cytokines par la voie TLR2. Les variants atténués du MHV3, les virus 51.6-MHV3 et YAC-MHV3, sont caractérisés par un faible tropisme pour les LSEC et induisent respectivement une hépatite modérée et subclinique. Compte tenu de l’importance des LSEC dans le maintien de la tolérance hépatique et de l’élimination des pathogènes circulants, il a été postulé que la sévérité de l’hépatite et de la réponse inflammatoire lors d’infections par les MHV est associée à la réplication virale et à l’altération des propriétés tolérogéniques et vasculaires des LSEC. Les désordres inflammatoires hépatiques pourraient résulter d’une activation différentielle du TLR2, plutôt que des autres TLR et des hélicases, selon les sérotypes. D’autre part, compte tenu du rôle des BMEC dans la prévention des infections du SNC, il a été postulé que l’invasion cérébrale secondaire par les coronavirus est reliée à l’infection des BMEC et le bris subséquent de la barrière hémato-encéphalique (BHE). À l’aide d’infections in vivo et in vitro par les différents sérotypes MHV, chez des souris ou des cultures de BMEC et de LSEC, nous avons démontré, d’une part, que l’infection in vitro des LSEC par le sétotype MHV3, à la différence des variants 51.6- et YAC-MHV3, altérait la production du facteur vasodilatant NO et renversait leur phénotype tolérogénique en favorisant la production de cytokines et de chimiokines inflammatoires. Ces dysfonctions se traduisaient in vivo par une réponse inflammatoire incontrôlée et une dérégulation du recrutement intrahépatique de leucocytes, favorisant la réplication virale et les dommages hépatiques. Nous avons aussi démontré, à l’aide de souris TLR2 KO et de LSEC dont l’expression du TLR2 a été abrogée par des siRNA, que la sévérité de l’hépatite et de la réponse inflammatoire induite par le sérotype MHV3, dépendait en partie de l’induction et de l’activation préférentielle du TLR2 par le virus dans le foie. D’autre part, la sévérité de la réplication virale au foie et des désordres dans le recrutement leucocytaire intrahépatique induits par le MHV3, et non par le MHV-A59 et le 51.6-MHV3, corrélaient avec une invasion virale subséquente du SNC, au niveau de la BHE. Nous avons démontré que l’invasion cérébrale du MHV3 était associée à une infection productive des BMEC et l’altération subséquente des protéines de jonctions serrées occludine, VE-cadhérine et ZO-1 se traduisant par une augmentation de la perméabilité de la BHE et l’entrée consécutive du virus dans le cerveau. Dans l’ensemble, les résultats de cette étude mettent en lumière l’importance du maintien de l’intégrité structurale et fonctionnelle des LSEC et des BMEC lors d’infections virales aigües par des MHV afin de limiter les dommages hépatiques associés à l’induction d’une réponse inflammatoire exagérée et de prévenir le passage des virus au cerveau suite à une dissémination par voie hématogène. Ils révèlent en outre un nouveau rôle aggravant pour le TLR2 dans l’évolution de l’hépatite virale aigüe ouvrant la voie à de nouvelles avenues thérapeutiques visant à moduler l’activité inflammatoire du TLR2.

Brain Glutamate Dehydrogenase Changes In Streptozotocin Diabetic Rats As A Function Of Age

Kinetic parameters of brain glutamate dehydrogenase (GDH) were compared in the brain stem, cerebellum and cerebral cortex of three weeks and one year old streptozotocin (STZ) induced four day diabetic rats with respective controls. A single intrafemoral dose of STZ (60mg/Kg body weight) was administered to induce diabetes in both age groups. After four days the blood glucose levels showed a significant increase in the diabetic animals of both age groups compared with the respective controls. The increase in blood glucose was significant in one year old compared to the three weeks old diabetic rats. The Vmm of the enzyme was decreased in all the brain regions studied, of the three weeks old diabetic rats without any significant change in the Km. In the adult the Vmax of GDH was increased in cerebellum and brain stem but was unchanged in the cerebral cortex. The K. was unchanged in cerebellum and cerebral cortex but was increased in the brain stem. These results suggest there may be an important regulatory role of the glutamate pathway in brain neural network disturbances and neuronal degeneration in diabetes as a function of age.

Hydrogeochemical evaluation of inorganics and bioorganics in selected aquatic environments

The present study is an investigation to address relevant chemical aspects of the three varied aquatic environments, such as mangroves, river and the estuary. The sampling locations include a thick mangrove forest with high tidal activity, a mangrove nursery with minimal disturbances and low tidal inundation, a highly polluted riverine system and an estuarine site, as reference. Nutrients and bioorganic compounds in the water column and surface sediment were estimated in an attempt to understand the regeneration properties of these different aquatic systems.Assessment of the trace metal pollution was also carried out.

Regulation of GABA(A) and glutamate receptor expression, synaptic facilitation and long-term potentiation in the hippocampus of prion mutant mice

Background: Prionopathies are characterized by spongiform brain degeneration, myoclonia, dementia, and periodic electroencephalographic (EEG) disturbances. The hallmark of prioniopathies is the presence of an abnormal conformational isoform (PrP(sc)) of the natural cellular prion protein (PrP(c)) encoded by the Prnp gene. Although several roles have been attributed to PrP(c), its putative functions in neuronal excitability are unknown. Although early studies of the behavior of Prnp knockout mice described minor changes, later studies report altered behavior. To date, most functional PrP(c) studies on synaptic plasticity have been performed in vitro. To our knowledge, only one electrophysiological study has been performed in vivo in anesthetized mice, by Curtis and coworkers. They reported no significant differences in paired-pulse facilitation or LTP in the CA1 region after Schaffer collateral/commissural pathway stimulation. Principal Findings: Here we explore the role of PrP(c) expression in neurotransmission and neural excitability using wild-type, Prnp -/- and PrP(c)-overexpressing mice (Tg20 strain). By correlating histopathology with electrophysiology in living behaving mice, we demonstrate that both Prnp -/- mice but, more relevantly Tg20 mice show increased susceptibility to KA, leading to significant cell death in the hippocampus. This finding correlates with enhanced synaptic facilitation in paired-pulse experiments and hippocampal LTP in living behaving mutant mice. Gene expression profiling using Illumina microarrays and Ingenuity pathways analysis showed that 129 genes involved in canonical pathways such as Ubiquitination or Neurotransmission were co-regulated in Prnp -/- and Tg20 mice. Lastly, RT-qPCR of neurotransmission-related genes indicated that subunits of GABA(A) and AMPA-kainate receptors are co-regulated in both Prnp -/- and Tg20 mice. Conclusions/Significance: Present results demonstrate that PrP(c) is necessary for the proper homeostatic functioning of hippocampal circuits, because of its relationships with GABA(A) and AMPA-Kainate neurotransmission. New PrP(c) functions have recently been described, which point to PrP(c) as a target for putative therapies in Alzheimer's disease. However, our results indicate that a "gain of function" strategy in Alzheimer's disease, or a "loss of function" in prionopathies, may impair PrP(c) function, with devastating effects. In conclusion, we believe that present data should be taken into account in the development of future therapies.

Studies on the Effects of Bottom Trawling on the Benthic Fauna off Veraval Coast, Gujarat

Bottom trawling is one among the most destructive human induced physical disturbances inflicted to seabed and its living communities. The bottom trawls are designed to tow along the sea floor, which on its operation indiscriminately smashes everything on their way crushing, killing, burying and exposing to predators the benthic fauna. Bottom trawling causes physical and biological damages that are irreversible, extensive and long lasting. The commercial trawling fleet of India consists of 29,241 small and medium-fishing boats. The northwest coast of India has the largest fishing fleet consisting of 23,618 mechanized vessels, especially the bottom trawlers. However, attempts were not made to study the impact of bottom trawling along Northwest coast of India. The estimated optimum fleet size of Gujarat is 1,473 mechanised trawlers while 7402 commercial trawlers are operated from the coast of Gujarat. Veraval port was designed initially for 1,200 fishing trawlers but 2793 trawlers are being operated from this port making it the largest trawler port of Gujarat. The aim of this study was to investigate the effects of bottom trawling on the substratum and the associated benthic communities of commercial trawling grounds of Veraval coast. The study compared the differences between the samples collected before and after experimental trawling to detect the impacts of bottom trawling. Attempts were made to assess the possible impact of bottom trawling on:(i) the sediment characteristics (ii)the sediment heavy metals (iii) epifauna (iv) macrobenthos and (v) meiobenthos. This study is expected to generate information on trawling impacts of the studied area that will help in better management of the biological diversity and integrity of the benthic fauna off Veraval coast. An exhaustive review on the studies conducted around the world and in India on impact of bottom trawling on the benthic fauna is also detailed.In the present study, the bottom trawling induced variations on sediment organic matter, epifauna, macrobenthos and meiobenthos were evident. It was also observed that the seasonal/ natural variations were more prominent masking the trawling effect on sediment texture and heavy metals. Enforcement of control of excess bottom trawlers and popularization of semi pelagic trawls designed to operate a little distance above the sea bottom for off bottom resources will minimize disturbance on the sea bottom. Training and creating awareness in responsible fishing should be made mandatory requirements, to the coastal communities. They should be made wardens to protect the valuable resources for the benefit of sustainability. To protect the biodiversity and ecosystem health, the imminent need is to survey and make catalogue, identification of sensitive areas or hot spots and to adopt management strategies for the conservation and biodiversity protection of benthic fauna. The present study is a pioneering work carried out along Veraval coast. This thesis will provide a major fillip to the studies on impact of bottom trawling on the benthic fauna along the coast of India.

Biochemical Studies on the Protective Effect of Taurine on Experimentally Induced Fulminat Hepatic Failure in Rats

Fulminant hepatic failure (FHF) is a dramatic and challenging syndrome in clinical medicine. Although an uncommon disorder, it is usually fatal and occurs in previously healthy person. While the causes of FHF remain unclear, viral hepatitis and drug-induced liver injury account for the majority of cases. Hepatitis E causes large-scale epidemics of hepatitis in the Indian subcontinent, involving hundreds of thousands of cases with high mortality. FHF is associated with several clinical features like jaundice, shrunken liver, easy bruising, low levels of serum proteins, fatigue, multi-organ failure etc and metabolic derangements like hypoglycemia, hyperlipidemia, hyponatremia, defective protein synthesis, reduced energy production, decreased rate of urea production etc. These disturbances are predominantly attributed to oxidative stress, membrane destabilization and osmolytic imbalances. The options available for these patients are quite minimal with liver transplantation being one of them. But the procedure is ridden with issues causing it to find less favor among the patients and the caregivers. Use of hepatoprotective and cytoprotective drugs, is being considered to be a more acceptable alternative as a strategy to enhance liver regeneration. In this regard use of taurine a naturally occurring amino acid that plays a crucial role in many physiological processes would prove to be effective. In the present study, hepatoprotective effect of taurine on a rat model of induced FHF was studied. Taurine supplementation has effectively counteracted the metabolic and structural aberrations in the liver caused by D-galactosamine intoxication.

Survey of coral lagoons of Laksbadweep Atolls using line intercept transect (LIT) technique

The present study aims at surveying the coral lagoons of four islands viz. Kavarathi, Kalpeni, Kadmat and Agathi, which include quantitative survey of the major benthic forms using Line Intercept Transect (LIT) technique and hydrographical study of these lagoon waters The distribution of PHC in the lagoons has also been followed to understand, the effects of introduction of flat bottomed ferry boats to the islands.From a biological monitoring stand point for the assessment of manmade disturbance of the coral reefs, it IS highly essential to identify faunal assemblages which will contain 'flag-stones' specIes as indicators of such disturbances. Among the known faunal assemblages In coral reefs the most diverse groups of sensitive species belongs to bryozoan assemblage. Therefore, the most common species of bryozoans distributed along the atolls and reef flats were collected and described in this work Along with this, bryozoans associated with coral from other parts of Indian ocean have also been added so as to provide a comprehensive picture of the distribution of bryozoans in the coral reefs.

Numerical Simulation of Two-Part Underwater Towing System

The motion instability is an important issue that occurs during the operation of towed underwater vehicles (TUV), which considerably affects the accuracy of high precision acoustic instrumentations housed inside the same. Out of the various parameters responsible for this, the disturbances from the tow-ship are the most significant one. The present study focus on the motion dynamics of an underwater towing system with ship induced disturbances as the input. The study focus on an innovative system called two-part towing. The methodology involves numerical modeling of the tow system, which consists of modeling of the tow-cables and vehicles formulation. Previous study in this direction used a segmental approach for the modeling of the cable. Even though, the model was successful in predicting the heave response of the tow-body, instabilities were observed in the numerical solution. The present study devises a simple approach called lumped mass spring model (LMSM) for the cable formulation. In this work, the traditional LMSM has been modified in two ways. First, by implementing advanced time integration procedures and secondly, use of a modified beam model which uses only translational degrees of freedoms for solving beam equation. A number of time integration procedures, such as Euler, Houbolt, Newmark and HHT-α were implemented in the traditional LMSM and the strength and weakness of each scheme were numerically estimated. In most of the previous studies, hydrodynamic forces acting on the tow-system such as drag and lift etc. are approximated as analytical expression of velocities. This approach restricts these models to use simple cylindrical shaped towed bodies and may not be applicable modern tow systems which are diversed in shape and complexity. Hence, this particular study, hydrodynamic parameters such as drag and lift of the tow-system are estimated using CFD techniques. To achieve this, a RANS based CFD code has been developed. Further, a new convection interpolation scheme for CFD simulation, called BNCUS, which is blend of cell based and node based formulation, was proposed in the study and numerically tested. To account for the fact that simulation takes considerable time in solving fluid dynamic equations, a dedicated parallel computing setup has been developed. Two types of computational parallelisms are explored in the current study, viz; the model for shared memory processors and distributed memory processors. In the present study, shared memory model was used for structural dynamic analysis of towing system, distributed memory one was devised in solving fluid dynamic equations.

Investigation on key molecular targets responsible for antidiabetic properties of Symplocos cochinchinensis (Lour.) S. Moore

Diabetes mellitus is a heterogeneous metabolic disorder characterized by hyperglycemia with disturbances in carbohydrate, protein and lipid metabolism resulting from defects in insulin secretion, insulin action or both. Currently there are 387 million people with diabetes worldwide and is expected to affect 592 million people by 2035. Insulin resistance in peripheral tissues and pancreatic beta cell dysfunction are the major challenges in the pathophysiology of diabetes. Diabetic secondary complications (like liver cirrhosis, retinopathy, microvascular and macrovascular complications) arise from persistent hyperglycemia and dyslipidemia can be disabling or even life threatening. Current medications are effective for control and management of hyperglycemia but undesirable effects, inefficiency against secondary complications and high cost are still serious issues in the present prognosis of this disorder. Hence the search for more effective and safer therapeutic agents of natural origin has been found to be highly demanding and attract attention in the present drug discovery research. The data available from Ayurveda on various medicinal plants for treatment of diabetes can efficiently yield potential new lead as antidiabetic agents. For wider acceptability and popularity of herbal remedies available in Ayurveda scientific validation by the elucidation of mechanism of action is very much essential. Modern biological techniques are available now to elucidate the biochemical basis of the effectiveness of these medicinal plants. Keeping this idea the research programme under this thesis has been planned to evaluate the molecular mechanism responsible for the antidiabetic property of Symplocos cochinchinensis, the main ingredient of Nishakathakadi Kashayam, a wellknown Ayurvedic antidiabetic preparation. A general introduction of diabetes, its pathophysiology, secondary complications and current treatment options, innovative solutions based on phytomedicine etc has been described in Chapter 1. The effect of Symplocos cochinchinensis (SC), on various in vitro biochemical targets relevant to diabetes is depicted in Chapter 2 including the preparation of plant extract. Since diabetes is a multifactorial disease, ethanolic extract of the bark of SC (SCE) and its fractions (hexane, dichloromethane, ethyl acetate and 90 % ethanol) were evaluated by in vitro methods against multiple targets such as control of postprandial hyperglycemia, insulin resistance, oxidative stress, pancreatic beta cell proliferation, inhibition of protein glycation, protein tyrosine phosphatase-1B (PTP-1B) and dipeptidyl peptidase-IV (DPPxxi IV). Among the extracts, SCE exhibited comparatively better activity like alpha glucosidase inhibition, insulin dependent glucose uptake (3 fold increase) in L6 myotubes, pancreatic beta cell regeneration in RIN-m5F and reduced triglyceride accumulation in 3T3-L1 cells, protection from hyperglycemia induced generation of reactive oxygen species in HepG2 cells with moderate antiglycation and PTP-1B inhibition. Chemical characterization by HPLC revealed the superiority of SCE over other extracts due to presence of bioactives (beta-sitosterol, phloretin 2’glucoside, oleanolic acid) in addition to minerals like magnesium, calcium, potassium, sodium, zinc and manganese. So SCE has been subjected to oral sucrose tolerance test (OGTT) to evaluate its antihyperglycemic property in mild diabetic and diabetic animal models. SCE showed significant antihyperglycemic activity in in vivo diabetic models. Chapter 3 highlights the beneficial effects of hydroethanol extract of Symplocos cochinchinensis (SCE) against hyperglycemia associated secondary complications in streptozotocin (60 mg/kg body weight) induced diabetic rat model. Proper sanction had been obtained for all the animal experiments from CSIR-CDRI institutional animal ethics committee. The experimental groups consist of normal control (NC), N + SCE 500 mg/kg bwd, diabetic control (DC), D + metformin 100 mg/kg bwd, D + SCE 250 and D + SCE 500. SCEs and metformin were administered daily for 21 days and sacrificed on day 22. Oral glucose tolerance test, plasma insulin, % HbA1c, urea, creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, total protein etc. were analysed. Aldose reductase (AR) activity in the eye lens was also checked. On day 21, DC rats showed significantly abnormal glucose response, HOMA-IR, % HbA1c, decreased activity of antioxidant enzymes and GSH, elevated AR activity, hepatic and renal oxidative stress markers compared to NC. DC rats also exhibited increased level of plasma urea and creatinine. Treatment with SCE protected from the deleterious alterations of biochemical parameters in a dose dependent manner including histopathological alterations in pancreas. SCE 500 exhibited significant glucose lowering effect and decreased HOMA-IR, % HbA1c, lens AR activity, and hepatic, renal oxidative stress and function markers compared to DC group. Considerable amount of liver and muscle glycogen was replenished by SCE treatment in diabetic animals. Although metformin showed better effect, the activity of SCE was very much comparable with this drug. xxii The possible molecular mechanism behind the protective property of S. cochinchinensis against the insulin resistance in peripheral tissue as well as dyslipidemia in in vivo high fructose saturated fat diet model is described in Chapter 4. Initially animal were fed a high fructose saturated fat (HFS) diet for a period of 8 weeks to develop insulin resistance and dyslipidemia. The normal diet control (ND), ND + SCE 500 mg/kg bwd, high fructose saturated fat diet control (HFS), HFS + metformin 100 mg/kg bwd, HFS + SCE 250 and HFS + SCE 500 were the experimental groups. SCEs and metformin were administered daily for the next 3 weeks and sacrificed at the end of 11th week. At the end of week 11, HFS rats showed significantly abnormal glucose and insulin tolerance, HOMA-IR, % HbA1c, adiponectin, lipid profile, liver glycolytic and gluconeogenic enzyme activities, liver and muscle triglyceride accumulation compared to ND. HFS rats also exhibited increased level of plasma inflammatory cytokines, upregulated mRNA level of gluconeogenic and lipogenic genes in liver. HFS exhibited the increased expression of GLUT-2 in liver and decreased expression of GLUT-4 in muscle and adipose. SCE treatment also preserved the architecture of pancreas, liver, and kidney tissues. Treatment with SCE reversed the alterations of biochemical parameters, improved insulin sensitivity by modifying gene expression in liver, muscle and adipose tissues. Overall results suggest that SC mediates the antidiabetic activity mainly via alpha glucosidase inhibition, improved insulin sensitivity, with antiglycation and antioxidant activities.

Subpixel-Filterung für eine autostereoskopische Multiperspektiven-3-D-Darstellung hoher Qualität

Die stereoskopische 3-D-Darstellung beruht auf der naturgetreuen Präsentation verschiedener Perspektiven für das rechte und linke Auge. Sie erlangt in der Medizin, der Architektur, im Design sowie bei Computerspielen und im Kino, zukünftig möglicherweise auch im Fernsehen, eine immer größere Bedeutung. 3-D-Displays dienen der zusätzlichen Wiedergabe der räumlichen Tiefe und lassen sich grob in die vier Gruppen Stereoskope und Head-mounted-Displays, Brillensysteme, autostereoskopische Displays sowie echte 3-D-Displays einteilen. Darunter besitzt der autostereoskopische Ansatz ohne Brillen, bei dem N≥2 Perspektiven genutzt werden, ein hohes Potenzial. Die beste Qualität in dieser Gruppe kann mit der Methode der Integral Photography, die sowohl horizontale als auch vertikale Parallaxe kodiert, erreicht werden. Allerdings ist das Verfahren sehr aufwendig und wird deshalb wenig genutzt. Den besten Kompromiss zwischen Leistung und Preis bieten präzise gefertigte Linsenrasterscheiben (LRS), die hinsichtlich Lichtausbeute und optischen Eigenschaften den bereits früher bekannten Barrieremasken überlegen sind. Insbesondere für die ergonomisch günstige Multiperspektiven-3-D-Darstellung wird eine hohe physikalische Monitorauflösung benötigt. Diese ist bei modernen TFT-Displays schon recht hoch. Eine weitere Verbesserung mit dem theoretischen Faktor drei erreicht man durch gezielte Ansteuerung der einzelnen, nebeneinander angeordneten Subpixel in den Farben Rot, Grün und Blau. Ermöglicht wird dies durch die um etwa eine Größenordnung geringere Farbauflösung des menschlichen visuellen Systems im Vergleich zur Helligkeitsauflösung. Somit gelingt die Implementierung einer Subpixel-Filterung, welche entsprechend den physiologischen Gegebenheiten mit dem in Luminanz und Chrominanz trennenden YUV-Farbmodell arbeitet. Weiterhin erweist sich eine Schrägstellung der Linsen im Verhältnis von 1:6 als günstig. Farbstörungen werden minimiert, und die Schärfe der Bilder wird durch eine weniger systematische Vergrößerung der technologisch unvermeidbaren Trennelemente zwischen den Subpixeln erhöht. Der Grad der Schrägstellung ist frei wählbar. In diesem Sinne ist die Filterung als adaptiv an den Neigungswinkel zu verstehen, obwohl dieser Wert für einen konkreten 3-D-Monitor eine Invariante darstellt. Die zu maximierende Zielgröße ist der Parameter Perspektiven-Pixel als Produkt aus Anzahl der Perspektiven N und der effektiven Auflösung pro Perspektive. Der Idealfall einer Verdreifachung wird praktisch nicht erreicht. Messungen mit Hilfe von Testbildern sowie Schrifterkennungstests lieferten einen Wert von knapp über 2. Dies ist trotzdem als eine signifikante Verbesserung der Qualität der 3-D-Darstellung anzusehen. In der Zukunft sind weitere Verbesserungen hinsichtlich der Zielgröße durch Nutzung neuer, feiner als TFT auflösender Technologien wie LCoS oder OLED zu erwarten. Eine Kombination mit der vorgeschlagenen Filtermethode wird natürlich weiterhin möglich und ggf. auch sinnvoll sein.

"Schwarzer Untertan versus schwarzer Bruder". Bernhard Dernburgs Reformen in den Kolonien Deutsch-Ostafrika, Deutsch-Südwestafrika, Togo und Kamerun

Nachdem sich in der Kolonialkrise von 1906 das Scheitern der ersten Periode deutscher Kolonialherrschaft (1885-1906) offenbarte, wurde Bernhard Dernburg die grundlegende Reorganisation der Kolonialpolitik anvertraut. Als Mann aus der Welt der Banken und Finanzen sollte er die stagnierende Entwicklung der Kolonien mit Hilfe von administrativen und wirtschaftlichen Reformmaßnahmen vorantreiben und gleichzeitig der indigenen Bevölkerung eine humane Behandlung zu garantieren. Um diese Ziele zu erreichen, verabschiedete er Reformen, die eine Rationalisierung und Humanisierung der Arbeiterpolitik vorsahen. Sowohl in der zeitgenössischen Literatur als auch in der aktuellen wissenschaftlichen Forschung wird der Amtsantritt Bernhard Dernburgs zum Leiter der Kolonialabteilung im Jahre 1906 als der „Beginn einer neuen humanen Ära“ deutscher Kolonialpolitik oder als „Wandel zum Besseren“ bezeichnet. Die Dissertation „Schwarzer Untertan versus Schwarzer Bruder. Bernhard Dernburgs Reformen in den Kolonien Deutsch-Ostafrika, Deutsch-Südwestafrika, Togo und Kamerun“ untersucht die Intention, Akzeptanz, Umsetzung und Auswirkung der reformatorischen Eingeborenenpolitik und klärt, ob die Beurteilung der Ära Dernburg (1906-1910) in der zeitgenössischen und aktuellen Forschung eine Berechtigung hat. Obwohl zumindest in der Theorie sein Konzept einer rationalen und humanen Kolonialpolitik sicherlich eine Abkehr von der bisher betriebenen Kolonialpolitik bedeutete, zeigt sich jedoch bei der Umsetzung der Reformen eine deutliche Diskrepanz zwischen Intention und Realität. Auch wenn zumindest die Bestrebung Dernburgs zur Verrechtlichung der indigenen Arbeitsverhältnisse gewürdigt werden sollte, so muss doch konstatiert werden, dass es in der „Ära Dernburg“ definitiv nicht zu einer grundlegenden Verbesserung der indigenen Lebenssituation in den deutschen Kolonien kam. Im Gegenteil, die Dernburgsche Reformpolitik beschleunigte vielmehr den Verelendungsprozess der indigenen Bevölkerung. In allen afrikanischen Kolonien verschlechterten sich mit der Intensivierung der Verwaltung die sozialen und menschlichen Beziehungen zwischen Afrikanern und Europäern. Vieles von dem, was Dernburg in seinem Programm propagierte, konnte nicht erreicht werden. Zwar führte Dernburg in Deutsch-Ostafrika, Deutsch-Südwestafrika und in Kamerun eine rechtlich bindende Arbeiterverordnung ein, jedoch unterschieden sich die Bestimmungen zum Teil erheblich voneinander, so dass von einer einheitlichen Modernisierung des kolonialen Arbeitsrechts nicht die Rede sein kann. Viele arbeitsrechtliche Bereiche, wie z.B. die Arbeiteranwerbung, Lohnzahlung, Minderjährigenschutz, Vertragsdauer, Arbeitszeit, Verpflegung und Unterkunft wurden nur unzureichend geregelt. Ähnlich negativ muss auch die Reformierung der Strafrechtspflege bewertet werden. Die Kodifizierung eines Eingeborenenstrafrechts scheiterte sowohl am Widerstand der lokalen Verwaltung als auch am Grundkonsens der Rechtmäßigkeit einer Rassenjustiz. Kolonialpolitik war auch in der „Ära Dernburg“ nichts anderes als „rohe Ausbeutungspolitik“, die zur Lösung der Arbeiterfrage beitragen sollte. Aber gerade hier, bei der Mobilisierung von afrikanischen Lohnarbeitern, war der Kolonialstaatssekretär nicht etwa mit einer „Arbeiterfürsorgepolitik“, sondern mit der Fortführung der Enteignungs- und Zwangsmaßnahmen erfolgreich gewesen. Insgesamt ist ein deutlicher Anstieg an afrikanischen Arbeitern in europäischen Unternehmen zu verzeichnen, was darauf schließen lässt, dass Dernburgs Verordnungen einen günstigen Einfluss auf die Arbeiterfrage ausgeübt haben. Obwohl nicht von einem grundlegenden Neuanfang der Kolonialpolitik gesprochen werden kann, sollte ebenso wenig bezweifelt werden, dass sich die deutsche Kolonialpolitik nicht unter Dernburg veränderte. Größere indigene Aufstände und Unruhen blieben aus, so dass während seiner Amtszeit eine systematische wirtschaftliche Erschließung der Kolonien beginnen konnte.

Exploratory and dust-bathing behaviour in laying hens kept in commercial aviaries and furnished cages

The aim of the present thesis was to identify management factors that affect the extent of exploratory behaviour (ground pecking, scratching) as well as quantitative and qualitative as-pects of dust-bathing behaviour in laying hens kept in commercial furnished cages (‘small group housing’) and aviaries. Based on the results, it should be considered which management measures can be recommended for farmers to enhance hen welfare. The feasibility of direct observations of dust-bathing behaviour as well as video observations of exploratory and dust-bathing behaviour was tested in two aviaries. The direct observations were judged to be unfeasible under the conditions encountered. For the analysis of the video recordings, different sampling intervals for instantaneous scan sampling, different extents of observation time, and intra- and inter-observer reliabilities were compared and the most ap-propriate observation scheme selected. Applying the selected scheme (observing the first 16 minutes of every hour distributed over two consecutive light days with a sample interval of two minutes), within the range of environmental conditions found in 22 aviaries, pecking, scratching and dust-bathing behaviour was performed on average 25, 2 and 7 % of the obser-vation time. Hen numbers in the litter were positively associated with stocking density and group size. More scratching was performed with increasing litter height as well as in humid litter. If no litter had been provided, thus substrate consisted of dust and faeces, a reduced proportion of dust-bathing was found. The same method was then used in 16 furnished cage systems. On average 12 % of the total hen number were found on the scratching mats. The hens spent 8 % of the observed time pecking at the mat, 4 % dust-bathing and 0.4 % scratch-ing. Higher proportions were found on the mats and more dust-bathing behaviour occurred, if substrate was provided. Also with increasing light intensity and stocking density more hens were observed on the mats. More pecking and scratching occurred in conditions of higher stocking density, probably due to social facilitation, and of increased mat area per hen. With increasing mat numbers per cage less pecking was observed. Wider mats led to increased dust-bathing behaviour. Finally, 129 dust-baths recorded in 17 aviaries were analysed in detail. On average they lasted 17 minutes, with the tossing phase taking 69 % of this time, including on average 2 vertical wing shakes and 3 scratches with one leg per minute tossing phase. Dust-bath duration de-creased with increasing litter height. Litter type influenced all recorded parameters: dust-bath duration was highest on straw and lowest on fine material and fine material mixed with straw, where on both also the proportion of the tossing phase was lowest. The number of vertical wing shakes during the dust-bath was highest on straw and lowest on fine material mixed with straw as against the frequency of vertical wing shaking that was lowest on straw and highest on fine material. If dust-bathing hens were disturbed twice or more, dust-bathing duration decreased. With increasing light intensity a decreased proportion of the tossing phase as well as a reduced number of vertical wing shakes were recorded. Possibly the light stimulated the hens to dust-bath more often with less tossing behaviour per performance. The observed variation of the dust-bathing parameters could reflect successful adaptation or frustration of the hens. The litter and light conditions on the investigated farms were predominantly restrictive in terms of stimulation of exploration and dust-bathing behaviour. Thus, it was only possible to analyse possible associations between these factors and exploration and dust-bathing behav-iour within the range found. Based on the results the following management recommendations can be given: To allow hens in furnished cages more normal activity, substrate availability should be improved and mat space and light intensity increased. With regard to aviaries as well litter availability should be improved. Litter height should not be too low. Disturbances during dust-bathing should be prevented, but no influencing factors could be identified.

Metabolic disorders in the transition period indicate that the dairy cows' ability to adapt is overstressed

Metabolic disorders are a key problem in the transition period of dairy cows and often appear before the onset of further health problems. They mainly derive from difficulties the animals have in adapting to changes and disturbances occurring both outside and inside the organisms and due to varying gaps between nutrient supply and demand. Adaptation is a functional and target-oriented process involving the whole organism and thus cannot be narrowed down to single factors. Most problems which challenge the organisms can be solved in a number of different ways. To understand the mechanisms of adaptation, the interconnectedness of variables and the nutrient flow within a metabolic network need to be considered. Metabolic disorders indicate an overstressed ability to balance input, partitioning and output variables. Dairy cows will more easily succeed in adapting and in avoiding dysfunctional processes in the transition period when the gap between nutrient and energy demands and their supply is restricted. Dairy farms vary widely in relation to the living conditions of the animals. The complexity of nutritional and metabolic processes Animals 2015, 5 979 and their large variations on various scales contradict any attempts to predict the outcome of animals’ adaptation in a farm specific situation. Any attempts to reduce the prevalence of metabolic disorders and associated production diseases should rely on continuous and comprehensive monitoring with appropriate indicators on the farm level. Furthermore, low levels of disorders and diseases should be seen as a further significant goal which carries weight in addition to productivity goals. In the long run, low disease levels can only be expected when farmers realize that they can gain a competitive advantage over competitors with higher levels of disease.