Light energy management in peach: utilization, photoprotection , photodamage and recovery. Maximizing light absorption in orchard is not always the best solution

The relation between the intercepted light and orchard productivity was considered linear, although this dependence seems to be more subordinate to planting system rather than light intensity. At whole plant level not always the increase of irradiance determines productivity improvement. One of the reasons can be the plant intrinsic un-efficiency in using energy. Generally in full light only the 5 – 10% of the total incoming energy is allocated to net photosynthesis. Therefore preserving or improving this efficiency becomes pivotal for scientist and fruit growers. Even tough a conspicuous energy amount is reflected or transmitted, plants can not avoid to absorb photons in excess. The chlorophyll over-excitation promotes the reactive species production increasing the photoinhibition risks. The dangerous consequences of photoinhibition forced plants to evolve a complex and multilevel machine able to dissipate the energy excess quenching heat (Non Photochemical Quenching), moving electrons (water-water cycle , cyclic transport around PSI, glutathione-ascorbate cycle and photorespiration) and scavenging the generated reactive species. The price plants must pay for this equipment is the use of CO2 and reducing power with a consequent decrease of the photosynthetic efficiency, both because some photons are not used for carboxylation and an effective CO2 and reducing power loss occurs. Net photosynthesis increases with light until the saturation point, additional PPFD doesn’t improve carboxylation but it rises the efficiency of the alternative pathways in energy dissipation but also ROS production and photoinhibition risks. The wide photo-protective apparatus, although is not able to cope with the excessive incoming energy, therefore photodamage occurs. Each event increasing the photon pressure and/or decreasing the efficiency of the described photo-protective mechanisms (i.e. thermal stress, water and nutritional deficiency) can emphasize the photoinhibition. Likely in nature a small amount of not damaged photosystems is found because of the effective, efficient and energy consuming recovery system. Since the damaged PSII is quickly repaired with energy expense, it would be interesting to investigate how much PSII recovery costs to plant productivity. This PhD. dissertation purposes to improve the knowledge about the several strategies accomplished for managing the incoming energy and the light excess implication on photo-damage in peach. The thesis is organized in three scientific units. In the first section a new rapid, non-intrusive, whole tissue and universal technique for functional PSII determination was implemented and validated on different kinds of plants as C3 and C4 species, woody and herbaceous plants, wild type and Chlorophyll b-less mutant and monocot and dicot plants. In the second unit, using a “singular” experimental orchard named “Asymmetric orchard”, the relation between light environment and photosynthetic performance, water use and photoinhibition was investigated in peach at whole plant level, furthermore the effect of photon pressure variation on energy management was considered on single leaf. In the third section the quenching analysis method suggested by Kornyeyev and Hendrickson (2007) was validate on peach. Afterwards it was applied in the field where the influence of moderate light and water reduction on peach photosynthetic performances, water requirements, energy management and photoinhibition was studied. Using solar energy as fuel for life plant is intrinsically suicidal since the high constant photodamage risk. This dissertation would try to highlight the complex relation existing between plant, in particular peach, and light analysing the principal strategies plants developed to manage the incoming light for deriving the maximal benefits as possible minimizing the risks. In the first instance the new method proposed for functional PSII determination based on P700 redox kinetics seems to be a valid, non intrusive, universal and field-applicable technique, even because it is able to measure in deep the whole leaf tissue rather than the first leaf layers as fluorescence. Fluorescence Fv/Fm parameter gives a good estimate of functional PSII but only when data obtained by ad-axial and ab-axial leaf surface are averaged. In addition to this method the energy quenching analysis proposed by Kornyeyev and Hendrickson (2007), combined with the photosynthesis model proposed by von Caemmerer (2000) is a forceful tool to analyse and study, even in the field, the relation between plant and environmental factors such as water, temperature but first of all light. “Asymmetric” training system is a good way to study light energy, photosynthetic performance and water use relations in the field. At whole plant level net carboxylation increases with PPFD reaching a saturating point. Light excess rather than improve photosynthesis may emphasize water and thermal stress leading to stomatal limitation. Furthermore too much light does not promote net carboxylation improvement but PSII damage, in fact in the most light exposed plants about 50-60% of the total PSII is inactivated. At single leaf level, net carboxylation increases till saturation point (1000 – 1200 μmolm-2s-1) and light excess is dissipated by non photochemical quenching and non net carboxylative transports. The latter follows a quite similar pattern of Pn/PPFD curve reaching the saturation point at almost the same photon flux density. At middle-low irradiance NPQ seems to be lumen pH limited because the incoming photon pressure is not enough to generate the optimum lumen pH for violaxanthin de-epoxidase (VDE) full activation. Peach leaves try to cope with the light excess increasing the non net carboxylative transports. While PPFD rises the xanthophyll cycle is more and more activated and the rate of non net carboxylative transports is reduced. Some of these alternative transports, such as the water-water cycle, the cyclic transport around the PSI and the glutathione-ascorbate cycle are able to generate additional H+ in lumen in order to support the VDE activation when light can be limiting. Moreover the alternative transports seems to be involved as an important dissipative way when high temperature and sub-optimal conductance emphasize the photoinhibition risks. In peach, a moderate water and light reduction does not determine net carboxylation decrease but, diminishing the incoming light and the environmental evapo-transpiration request, stomatal conductance decreases, improving water use efficiency. Therefore lowering light intensity till not limiting levels, water could be saved not compromising net photosynthesis. The quenching analysis is able to partition absorbed energy in the several utilization, photoprotection and photo-oxidation pathways. When recovery is permitted only few PSII remained un-repaired, although more net PSII damage is recorded in plants placed in full light. Even in this experiment, in over saturating light the main dissipation pathway is the non photochemical quenching; at middle-low irradiance it seems to be pH limited and other transports, such as photorespiration and alternative transports, are used to support photoprotection and to contribute for creating the optimal trans-thylakoidal ΔpH for violaxanthin de-epoxidase. These alternative pathways become the main quenching mechanisms at very low light environment. Another aspect pointed out by this study is the role of NPQ as dissipative pathway when conductance becomes severely limiting. The evidence that in nature a small amount of damaged PSII is seen indicates the presence of an effective and efficient recovery mechanism that masks the real photodamage occurring during the day. At single leaf level, when repair is not allowed leaves in full light are two fold more photoinhibited than the shaded ones. Therefore light in excess of the photosynthetic optima does not promote net carboxylation but increases water loss and PSII damage. The more is photoinhibition the more must be the photosystems to be repaired and consequently the energy and dry matter to allocate in this essential activity. Since above the saturation point net photosynthesis is constant while photoinhibition increases it would be interesting to investigate how photodamage costs in terms of tree productivity. An other aspect of pivotal importance to be further widened is the combined influence of light and other environmental parameters, like water status, temperature and nutrition on peach light, water and phtosyntate management.

A single chain antibody against a viral RNA polymerase (TBSV-BS3-Statice)

Expression of antibodies in plant against essential viral proteins could provide an alternative approach to engineered viral resistance. Engineered single chain Fv antibodies scFV are particularly suitable for expression in plant because of their small size and the lack of assembly requirements. RNA-dependent RNA polymerases (RdRps) function as the catalytic subunit of viral replicases required for the replication of all positive strand RNA viruses. By using Phage technology we selected scFvs from a phage library using purified E.coli expressed TBSV(Tomato bushy stunt virus) replicase as antigen. The scFvs mediated-inhibition of RdRp activity was studied in vitro and in planta. In vitro experiments showed the inhibition of CNV(Cucumber necrosis virus) and TCV(Turnip crinkle virus) RdRp. Transient in planta assays based on agroinfiltration and an infectious clone of TBSV demonstrated the inhibition of the replication of TBSV(Tomato bushy stunt virus). Epitope mapping showed that the selected scFvs target the motif E of RdRp which is involved in template binding.Moreover T1 plants of transgenic lines of N. benthamiana expressing different scFvs either in the cytoplasm or the ER (endoplasmic reticulum) showed a high level of resistance against infection with TBSV and RCNMV(Red clover necrotic mosaic virus) upon inoculation with virus particles. This is the first report that scFvs against a RdRp of a plant viruses can inhibit viral replication in vivo. The resistance is even efficient against viruses belonging to different virus families.

Characterization of geothermal reservoirs’ parameters by inverse problem resolution and geostatistical simulations

BTES (borehole thermal energy storage)systems exchange thermal energy by conduction with the surrounding ground through borehole materials. The spatial variability of the geological properties and the space-time variability of hydrogeological conditions affect the real power rate of heat exchangers and, consequently, the amount of energy extracted from / injected into the ground. For this reason, it is not an easy task to identify the underground thermal properties to use when designing. At the current state of technology, Thermal Response Test (TRT) is the in situ test for the characterization of ground thermal properties with the higher degree of accuracy, but it doesn’t fully solve the problem of characterizing the thermal properties of a shallow geothermal reservoir, simply because it characterizes only the neighborhood of the heat exchanger at hand and only for the test duration. Different analytical and numerical models exist for the characterization of shallow geothermal reservoir, but they are still inadequate and not exhaustive: more sophisticated models must be taken into account and a geostatistical approach is needed to tackle natural variability and estimates uncertainty. The approach adopted for reservoir characterization is the “inverse problem”, typical of oil&gas field analysis. Similarly, we create different realizations of thermal properties by direct sequential simulation and we find the best one fitting real production data (fluid temperature along time). The software used to develop heat production simulation is FEFLOW 5.4 (Finite Element subsurface FLOW system). A geostatistical reservoir model has been set up based on literature thermal properties data and spatial variability hypotheses, and a real TRT has been tested. Then we analyzed and used as well two other codes (SA-Geotherm and FV-Geotherm) which are two implementation of the same numerical model of FEFLOW (Al-Khoury model).

The role of dendritic cells (DC) in Friend retrovirus-induced immunosuppression and immunotherapeutic applications of functionalized nanoparticles

Friend murine leukemia Virus (FV) infection of immunocompetent mice is a well- established model to acquire further knowledge about viral immune suppression mechanisms, with the aim to develop therapeutics against retrovirus-induced diseases. Interestingly, BALB/c mice are infected by low doses of FV and die from FV-induced erythroleukemia, while C57/BL6 mice are infected by FV only at high viral dose, and remain persistently infected for their whole life. Due to the central role of dendritic cells (DC) in the induction of anti-viral responses, we asked for their functional role in the genotype-dependent sensitivity towards FV infection. In my PhD study I showed that bone marrow (BM)-derived DC differentiated from FV-infected BM cells obtained from FV-inoculated BALB/c (FV susceptible) and C57BL/6 (FV resistant) mice showed an increased endocytotic activity and lowered expression of MHCII and of costimulatory receptors as compared with non-infected control BMDC. FV-infected BMDC from either mouse strain were partially resistant towards stimulation-induced upregulation of MHCII and costimulators, and accordingly were poor T cell stimulators in vitro and in vivo. In addition, FV-infected BMDC displayed an altered expression profile of proinflammator cytokines and favoured Th2 polarization. Ongoing work is focussed on elucidating the functional role of proteins identified as differentially expressed in FV-infected DC in a genotype-dependent manner, which therefore may contribute to the differential course of FV infection in vivo in BALB/c versus C57BL/6 mice. So far, more than 300 proteins have been identified which are differently regulated in FV-infected vs. uninfected DC from both mouse strains. One of these proteins, S100A9, was strongly upregulated specifically in BMDC derived from FV-infected C57BL/6 BM cells. S100A9-/- mice were more sensitive towards inoculation with FV than corresponding wild type (WT) mice (both C57BL/6 background), which suggests a decisive role of this factor for anti-viral defense. In addition, FV-infected S100A9-/- BMDC showed lower motility than WT DC. The future work is aimed to further elucidate the functional importance of S100A9 for DC functions. To exploit the potential of DC for immunotherapeutic applications, in another project of this PhD study the usability of different types of functionalized nanoparticles

Studio di celle fotovoltaiche di terza generazione: celle tandem

Il fotovoltaico (FV) costituisce il modo più diretto di conversione dell’energia solare in energia elettrica e si basa sull’effetto osservato da Becquerel nel 1839. Si può affermare che tale effetto è rimasto una curiosità di laboratorio dalla metà del XIX secolo fino al 1954, quando la prima cella solare in silicio con un’efficienza di conversione del 6% fu costruita ai Laboratori Bell. Da allora la ricerca in questo settore ha sperimentato una crescita costante ed oggi si può contare su tecnologie mature, in grado di sviluppare alte prestazioni in via di ulteriore miglioramento. Le celle tandem costituiscono ora il migliore esempio di dispositivi fotovoltaici in grado di convertire buona parte della potenza irraggiata dal sole. Aumentare l’efficienza con le celle tandem significa sfruttare le differenti lunghezze d’onda dello spettro solare. Questi dispositivi sono infatti costruiti impilando semiconduttori, disponendoli dal basso in modo crescente secondo i loro valori di energia di gap. A partire dall’analisi delle caratteristiche principali della radiazione solare e del principio di funzionamento delle celle fotovoltaiche, questo lavoro si propone di mettere in evidenza le potenzialità della tecnologia a multigiunzione, che ha già dimostrato rilevanti capacità di ottimizzazione delle prestazioni delle celle solari, facendo ben sperare per il futuro.

Active regulation of cerebral venous tone: simultaneous arterial and venous transcranial Doppler sonography during a Valsalva manoeuvre

The aim of this study was to analyse the cerebral venous outflow in relation to the arterial inflow during a Valsalva manoeuvre (VM). In 19 healthy volunteers (mean age 24.1 +/- 2.6 years), the middle cerebral artery (MCA) and the straight sinus (SRS) were insonated by transcranial Doppler sonography. Simultaneously the arterial blood pressure was recorded using a photoplethysmographic method. Two VM of 10 s length were performed per participant. Tracings of the variables were then transformed to equidistantly re-sampled data. Phases of the VM were analysed regarding the increase of the flow velocities and the latency to the peak. The typical four phases of the VM were also found in the SRS signal. The relative flow velocity (FV) increase was significantly higher in the SRS than in the MCA for all phases, particularly that of phase IV (p < 0.01). Comparison of the time latency of the VM phases of the MCA and SRS only showed a significant difference for phase I (p < 0.01). In particular, there was no significant difference for phase IV (15.8 +/- 0.29 vs. 16.0 +/- 0.28 s). Alterations in venous outflow in phase I are best explained by a cross-sectional change of the lumen of the SRS, while phases II and III are compatible with a Starling resistor. However, the significantly lager venous than the arterial overshoot in phase IV may be explained by the active regulation of the venous tone.

Chemosensitization of carcinoma cells using epithelial cell adhesion molecule-targeted liposomal antisense against bcl-2/bcl-xL

Nanoscale drug delivery systems, such as sterically stabilized immunoliposomes binding to internalizing tumor-associated antigens, can increase therapeutic efficacy and reduce toxicity to normal tissues compared with nontargeted liposomes. The epithelial cell adhesion molecule (EpCAM) is of interest as a ligand for targeted drug delivery because it is abundantly expressed in solid tumors but shows limited distribution in normal tissues. To generate EpCAM-specific immunoliposomes for targeted cancer therapy, the humanized single-chain Fv antibody fragment 4D5MOCB was covalently linked to the exterior of coated cationic liposomes. As anticancer agent, we encapsulated the previously described antisense oligonucleotide 4625 specific for both bcl-2 and bcl-xL. The EpCAM-targeted immunoliposomes (SIL25) showed specific binding to EpCAM-overexpressing tumor cells, with a 10- to 20-fold increase in binding compared with nontargeted control liposomes. No enhanced binding was observed on EpCAM-negative control cells. On cell binding, SIL25 was efficiently internalized by receptor-mediated endocytosis, ultimately leading to down-regulation of both bcl-2 and bcl-xL expression on both the mRNA and protein level, which resulted in enhanced tumor cell apoptosis. In combination experiments, the use of SIL25 led to a 2- to 5-fold sensitization of EpCAM-positive tumor cells of diverse origin to death induction by doxorubicin. Our data show the promise of EpCAM-specific drug delivery systems, such as antisense-loaded immunoliposomes, for targeted cancer therapy.

Multiple B-cell clones producing antibodies directed to the spacer and disintegrin/thrombospondin type-1 repeat 1 (TSP1) of ADAMTS13 in a patient with acquired thrombotic thrombocytopenic purpura

BACKGROUND: The cysteine-rich/spacer domains of ADAMTS13 contain a major binding site for antibodies in patients with acquired thrombotic thrombocytopenic purpura (TTP). OBJECTIVE: To study the heterogeneity of the antibody response towards these domains an immunoglobulin V-gene phage-display library was constructed to isolate monoclonal anti-ADAMTS13 antibodies from the immunoglobulin repertoire of a patient with acquired TTP. METHODS: Combined variable heavy chain (VH) and variable light chain (VL) segments, expressed as single-chain Fv fragments (scFv), were selected for binding to an ADAMTS13 fragment consisting of the disintegrin/thrombospondin type-1 repeat 1 (TSP1)/cysteine-rich/spacer domains. RESULTS: Seven different scFv antibody clones were identified that were assigned to four groups based on their homology to VH germline gene segments. Epitope-mapping revealed that scFv I-9 (VH1-69), I-26 (VH1-02), and I-41 (VH3-09) bind to an overlapping binding site in the ADAMTS13 spacer domain, whereas scFv I-16 (VH3-07) binds to the disintegrin/TSP1 domains. The affinity of scFv for the disintegrin/TSP1/cysteine-rich/spacer domain was determined by surface plasmon resonance analysis and the dissociation constants ranged from 3 to 254 nM. The scFv partially inhibited ADAMTS13 activity. However, full-length IgG prepared from the variable domains of scFv I-9 inhibited ADAMTS13 activity more profoundly. Plasma of six patients with acquired TTP competed for binding of scFv I-9 to ADAMTS13. CONCLUSION: Our data indicate that multiple B-cell clones producing antibodies directed against the spacer domain are present in the patient analyzed in this study. Our findings also suggest that antibodies with a similar epitope specificity as scFv I-9 are present in plasma of other patients with acquired TTP.

Surface expression and functional characterization of alpha-granule factor V in human platelets: effects of ionophore A23187, thrombin, collagen, and convulxin

Factor V (FV) present in platelet alpha-granules has a significant but incompletely understood role in hemostasis. This report demonstrates that a fraction of platelets express very high levels of surface-bound, alpha-granule FV on simultaneous activation with 2 agonists, thrombin and convulxin, an activator of the collagen receptor glycoprotein VI. This subpopulation of activated platelets represents 30.7% +/- 4.7% of the total population and is referred to as convulxin and thrombin-induced-FV (COAT-FV) platelets. COAT-FV platelets are also observed on activation with thrombin plus collagen types I, V, or VI, but not with type III. No single agonist examined was able to produce COAT-FV platelets, although ionophore A23187 in conjunction with either thrombin or convulxin did generate this population. COAT-FV platelets bound annexin-V, indicating exposure of aminophospholipids and were enriched in young platelets as identified by the binding of thiazole orange. The functional significance of COAT-FV platelets was investigated by demonstrating that factor Xa preferentially bound to COAT-FV platelets, that COAT-FV platelets had more FV activity than either thrombin or A23187-activated platelets, and that COAT-FV platelets were capable of generating more prothrombinase activity than any other physiologic agonist examined. Microparticle production by dual stimulation with thrombin and convulxin was less than that observed with A23187, indicating that microparticles were not responsible for all the activities observed. These data demonstrate a new procoagulant component produced from dual stimulation of platelets with thrombin and collagen. COAT-FV platelets may explain the unique role of alpha-granule FV and the hemostatic effectiveness of young platelets. (Blood. 2000;95:1694-1702)

Antitumor activity of an epithelial cell adhesion molecule targeted nanovesicular drug delivery system

Site-specific delivery of anticancer agents to tumors represents a promising therapeutic strategy because it increases efficacy and reduces toxicity to normal tissues compared with untargeted drugs. Sterically stabilized immunoliposomes (SIL), guided by antibodies that specifically bind to well internalizing antigens on the tumor cell surface, are effective nanoscale delivery systems capable of accumulating large quantities of anticancer agents at the tumor site. The epithelial cell adhesion molecule (EpCAM) holds major promise as a target for antibody-based cancer therapy due to its abundant expression in many solid tumors and its limited distribution in normal tissues. We generated EpCAM-directed immunoliposomes by covalently coupling the humanized single-chain Fv antibody fragment 4D5MOCB to the surface of sterically stabilized liposomes loaded with the anticancer agent doxorubicin. In vitro, the doxorubicin-loaded immunoliposomes (SIL-Dox) showed efficient cell binding and internalization and were significantly more cytotoxic against EpCAM-positive tumor cells than nontargeted liposomes (SL-Dox). In athymic mice bearing established human tumor xenografts, pharmacokinetic and biodistribution analysis of SIL-Dox revealed long circulation times in the blood with a half-life of 11 h and effective time-dependent tumor localization, resulting in up to 15% injected dose per gram tissue. These favorable pharmacokinetic properties translated into potent antitumor activity, which resulted in significant growth inhibition (compared with control mice), and was more pronounced than that of doxorubicin alone and nontargeted SL-Dox at low, nontoxic doses. Our data show the promise of EpCAM-directed nanovesicular drug delivery for targeted therapy of solid tumors.

Stability of coagulation assays performed in plasma from citrated whole blood transported at ambient temperature

Many preanalytical variables affect the results of coagulation assays. A possible way to control some of them would be to accept blood specimens shipped in the original collection tube. The aim of our study was to investigate the stability of coagulation assays in citrated whole blood transported at ambient temperature for up to two days after specimen collection. Blood samples from 59 patients who attended our haematology outpatient ward for thrombophilia screening were transported at ambient temperature (outdoor during the day, indoor overnight) for following periods of time: <1 hour, 4-6, 8-12, 24-28 and 48-52 hours prior to centrifugation and plasma-freezing. The following coagulation tests were performed: PT, aPTT, fibrinogen, FII:C, FV:C, FVII:C, FVIII:C, FIX:C, FX:C, FXI:C, VWF:RCo, VWF:Ag, AT, PC activity, total and free PS antigen, modified APC-sensitivity-ratio, thrombin-antithrombin-complex and D-dimer. Clinically significant changes, defined as a percentage change of more than 10% from the initial value, were observed for FV:C, FVIII:C and total PS antigen starting at 24-28 hours, and for PT, aPTT and FVII:C at 48-52 hours. No statistically significant differences were seen for fibrinogen, antithrombin, or thrombin-antithrombin complexes (Friedman repeated measures analysis of variance). The present data suggest that the use of whole blood samples transported at ambient temperature may be an acceptable means of delivering specimens for coagulation analysis. With the exception of factor V and VIII coagulant activity, and total PS antigen all investigated parameters can be measured 24-28 hours after specimen collection without observing clinically relevant changes.

Effect of constant and variable domain glycosylation on pharmacokinetics of therapeutic antibodies in mice

Previous studies on the effect of glycosylation on the elimination rate of antibodies have produced conflicting results. Here, we performed pharmacokinetic studies in mice with two preparations of a monoclonal IgG1 antibody enriched for complex type or high mannose type oligosaccharides at the Fc glycosylation site. No significant difference in the serum half-life was found between the two antibody glycoforms, nor was any difference observed in the serum half-lives of different complex type glycoforms. To evaluate the influence of glycosylation within the variable domain, a second monoclonal antibody, glycosylated in both the Fc and Fv domains, was separated into fractions containing different amounts of Fv-associated sialic acid and administered to mice. Again, no significant difference was found in the clearance rates of variants carrying different amounts of Fv-associated sialic acid or lacking Fv-glycosylation. These results suggest that glycosylation has little or no impact on the pharmacokinetic behavior of these two monoclonal antibodies in mice.

Hospital use of young children in Switzerland: a nation-wide study based on a complete survey over 4 years

Background Young children are known to be the most frequent hospital users compared to older children and young adults. Therefore, they are an important population from economic and policy perspectives of health care delivery. In Switzerland complete hospitalization discharge records for children [<5 years] of four consecutive years [2002–2005] were evaluated in order to analyze variation in patterns of hospital use. Methods Stationary and outpatient hospitalization rates on aggregated ZIP code level were calculated based on census data provided by the Swiss federal statistical office (BfS). Thirty-seven hospital service areas for children [HSAP] were created with the method of "small area analysis", reflecting user-based health markets. Descriptive statistics and general linear models were applied to analyze the data. Results The mean stationary hospitalization rate over four years was 66.1 discharges per 1000 children. Hospitalizations for respiratory problem are most dominant in young children (25.9%) and highest hospitalization rates are associated with geographical factors of urban areas and specific language regions. Statistical models yielded significant effect estimates for these factors and a significant association between ambulatory/outpatient and stationary hospitalization rates. Conclusion The utilization-based approach, using HSAP as spatial representation of user-based health markets, is a valid instrument and allows assessing the supply and demand of children's health care services. The study provides for the first time estimates for several factors associated with the large variation in the utilization and provision of paediatric health care resources in Switzerland.

Maximum principle preserving high order schemes for convection-dominated diffusion equations

The maximum principle is an important property of solutions to PDE. Correspondingly, it's of great interest for people to design a high order numerical scheme solving PDE with this property maintained. In this thesis, our particular interest is solving convection-dominated diffusion equation. We first review a nonconventional maximum principle preserving(MPP) high order finite volume(FV) WENO scheme, and then propose a new parametrized MPP high order finite difference(FD) WENO framework, which is generalized from the one solving hyperbolic conservation laws. A formal analysis is presented to show that a third order finite difference scheme with this parametrized MPP flux limiters maintains the third order accuracy without extra CFL constraint when the low order monotone flux is chosen appropriately. Numerical tests in both one and two dimensional cases are performed on the simulation of the incompressible Navier-Stokes equations in vorticity stream-function formulation and several other problems to show the effectiveness of the proposed method.

Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6)

BACKGROUND: Unlike most antihyperglycaemic drugs, glucagon-like peptide-1 (GLP-1) receptor agonists have a glucose-dependent action and promote weight loss. We compared the efficacy and safety of liraglutide, a human GLP-1 analogue, with exenatide, an exendin-based GLP-1 receptor agonist. METHODS: Adults with inadequately controlled type 2 diabetes on maximally tolerated doses of metformin, sulphonylurea, or both, were stratified by previous oral antidiabetic therapy and randomly assigned to receive additional liraglutide 1.8 mg once a day (n=233) or exenatide 10 microg twice a day (n=231) in a 26-week open-label, parallel-group, multinational (15 countries) study. The primary outcome was change in glycosylated haemoglobin (HbA(1c)). Efficacy analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00518882. FINDINGS: Mean baseline HbA(1c) for the study population was 8.2%. Liraglutide reduced mean HbA(1c) significantly more than did exenatide (-1.12% [SE 0.08] vs -0.79% [0.08]; estimated treatment difference -0.33; 95% CI -0.47 to -0.18; p<0.0001) and more patients achieved a HbA(1c) value of less than 7% (54%vs 43%, respectively; odds ratio 2.02; 95% CI 1.31 to 3.11; p=0.0015). Liraglutide reduced mean fasting plasma glucose more than did exenatide (-1.61 mmol/L [SE 0.20] vs -0.60 mmol/L [0.20]; estimated treatment difference -1.01 mmol/L; 95% CI -1.37 to -0.65; p<0.0001) but postprandial glucose control was less effective after breakfast and dinner. Both drugs promoted similar weight losses (liraglutide -3.24 kg vs exenatide -2.87 kg). Both drugs were well tolerated, but nausea was less persistent (estimated treatment rate ratio 0.448, p<0.0001) and minor hypoglycaemia less frequent with liraglutide than with exenatide (1.93 vs 2.60 events per patient per year; rate ratio 0.55; 95% CI 0.34 to 0.88; p=0.0131; 25.5%vs 33.6% had minor hypoglycaemia). Two patients taking both exenatide and a sulphonylurea had a major hypoglycaemic episode. INTERPRETATION: Liraglutide once a day provided significantly greater improvements in glycaemic control than did exenatide twice a day, and was generally better tolerated. The results suggest that liraglutide might be a treatment option for type 2 diabetes, especially when weight loss and risk of hypoglycaemia are major considerations.