Heterologous prime-boost regimen adenovector 35-circumsporozoite protein vaccine/recombinant Bacillus Calmette-Guérin expressing the Plasmodium falciparum circumsporozoite induces enhanced long-term memory immunity in BALB/c mice.

BACKGROUND: Sustained antibody levels are a hallmark of immunity against many pathogens, and induction of long-term durable antibody titers is an essential feature of effective vaccines. Heterologous prime-boost approaches with vectors are optimal strategies to improve a broad and prolonged immunogenicity of malaria vaccines. RESULTS: In this study, we demonstrate that the heterologous prime-boost regimen Ad35-CS/BCG-CS induces stronger immune responses by enhancing type 1 cellular producing-cells with high levels of CSp-specific IFN-γ and cytophilic IgG2a antibodies as compared to a homologous BCG-CS and a heterologous BCG-CS/CSp prime-boost regimen. Moreover, the heterologous prime-boost regimen elicits the highest level of LLPC-mediated immune responses. CONCLUSION: The increased IFN-γ-producing cell responses induced by the combination of Ad35-CS/BCG-CS and sustained type 1 antibody profile together with high levels of LLPCs may be essential for the development of long-term protective immunity against liver-stage parasites.

HDR brachytherapy boost and external radiotherapy for unfavorable prostate cancer patients

Purpose/Objective: To evaluate the outcome of prostate cancer patients treated with a combination of HDR Brachytherapy boost (HDR-BT) and 3D conformal external pelvic radiotherapy (EBRT) in a dose escalation study. Materials and Methods: 162 patients were followed between November 2004 and December 2010 . Two different dose escalation groups were done: group 1 (n= 92), 1 fraction HDR boost (9-10 Gy ) followed by EBRT (60 Gy in 6 weeks) - BED: 203-216 Gy and group 2 (n=70): 2 fraction HDR boost (18-19 Gy), 6 hours interval between fractions, followed by EBRT (46 Gy in 4.5 weeks) - BED: 233.3 -247 Gy; 116 pts (71.6%) received concomitant androgen deprivation. Patients were classified according to the MSKCC criteria into high (N=137) and intermediate (N=25) risk. Phoenix biochemical failure definition was used. Toxicity was scored by Radiation Morbidity Scoring Criteria (RTOG) Results: The mean follow-up was 41 (range 7-84) months. The 7- years cancer-specific and overall survival was 100% an 92%, respectively. The 7 years actuarial biochemical control rate was 89% and 100% for group 1 and 2, respectively. One patient from group 1 and two patients from group 2 never reached a low nadir. Two patients developed distant metastases 12 and 16 months after the treatment. In a multivariate Cox-regression analysis neither treatment nor risk group (intermediate vs. high risk) were associated with increased risk for biochemical failure. The RTOG grade 3 genitourinary early toxicity was 1.0% and 8.5% while gastrointestinal/genitourinary late toxicity was 7.6% and 1.4% for group 1 and 2, respectively Conclusions: HDR BT boost followed by EBRT appears to be a safe, feasible and effective treatment for patients with unfavorable localized prostate cancer. This study shows a beneficial effect on biochemical control in group 2 pts, however without statistical significance. Higher radiation doses (BED 233.3-247 Gy) do not seem to carry extra toxicity.

Feasibility and efficacy of accelerated weekly concomitant boost postoperative radiation therapy combined with concomitant chemotherapy in patients with locally advanced head and neck cancer.

BACKGROUND: The aim of this study was to assess feasibility and efficacy of weekly concomitant boost accelerated postoperative radiation therapy (PORT) with concomitant chemotherapy (CT) in patients with locally advanced head and neck cancer (LAHNC). METHODS AND MATERIALS: Conformal or intensity-modulated 66-Gy RT was performed in 5.5 weeks in 40 patients. Cisplatin was given at days 1, 22, and 43. Median follow-up was 36 months. RESULTS AND DISCUSSION: Grade 3 mucositis, dysphagia, and erythema was observed in ten (25%), nine (23%), and six (13%) patients, respectively. Grade 3 or more anemia was observed in two (6%) patients, and leukopenia in five (13%) patients. No grade 3 or 4 thrombocytopenia was observed. Grade 3 nephrotoxicity was observed in one patient (3%). No treatment-related mortality was observed. Grade 2 or more xerostomia and edema were observed in ten (25%) and one (3%) patient, respectively. Locoregional relapse occurred in eight patients, and seven patients developed distant metastases. Median time to locoregional relapse was 6 months. Three-year overall, disease-free survival, and locoregional control rates were 63%, 62%, and 81%, respectively. Multivariate analysis revealed that the only prognostic factor was nodal status. CONCLUSION: Reducing overall treatment time using accelerated PORT/CT by weekly concomitant boost (six fractions per week) combined with concomitant cisplatin CT is easily feasible with acceptable morbidity.

Robust vaccine-elicited cellular immune responses in breast milk following systemic Simian Immunodeficiency Virus DNA prime and live virus vector boost vaccination of lactating rhesus monkeys.

Breast milk transmission of HIV remains an important mode of infant HIV acquisition. Enhancement of mucosal HIV-specific immune responses in milk of HIV-infected mothers through vaccination may reduce milk virus load or protect against virus transmission in the infant gastrointestinal tract. However, the ability of HIV/SIV strategies to induce virus-specific immune responses in milk has not been studied. In this study, five uninfected, hormone-induced lactating, Mamu A*01(+) female rhesus monkey were systemically primed and boosted with rDNA and the attenuated poxvirus vector, NYVAC, containing the SIVmac239 gag-pol and envelope genes. The monkeys were boosted a second time with a recombinant Adenovirus serotype 5 vector containing matching immunogens. The vaccine-elicited immunodominant epitope-specific CD8(+) T lymphocyte response in milk was of similar or greater magnitude than that in blood and the vaginal tract but higher than that in the colon. Furthermore, the vaccine-elicited SIV Gag-specific CD4(+) and CD8(+) T lymphocyte polyfunctional cytokine responses were more robust in milk than in blood after each virus vector boost. Finally, SIV envelope-specific IgG responses were detected in milk of all monkeys after vaccination, whereas an SIV envelope-specific IgA response was only detected in one vaccinated monkey. Importantly, only limited and transient increases in the proportion of activated or CCR5-expressing CD4(+) T lymphocytes in milk occurred after vaccination. Therefore, systemic DNA prime and virus vector boost of lactating rhesus monkeys elicits potent virus-specific cellular and humoral immune responses in milk and may warrant further investigation as a strategy to impede breast milk transmission of HIV.

Permanent magnet synchronous motor for industrial inverter applications - analysis and design

During the latest few years the need for new motor types has grown, since both high efficiency and an accurate dynamic performance are demanded in industrial applications. For this reason, new effective control systems such as direct torque control (DTC) have been developed. Permanent magnet synchronous motors (PMSM) are well suitable for new adjustable speed AC inverter drives, because their efficiency and power factor are not depending on the pole pair number and speed to the same extent as it is the case in induction motors. Therefore, an induction motor (IM) with a mechanical gearbox can often be replaced with a direct PM motor drive. Space as well as costs will be saved, because the efficiency increases and the cost of maintenance decreases as well. This thesis deals with design criterion, analytical calculation and analysis of the permanent magnet synchronous motor for both sinusoidal air-gap flux density and rectangular air-gapflux density. It is examined how the air-gap flux, flux densities, inductances and torque can be estimated analytically for salient pole and non-salient pole motors. It has been sought by means of analytical calculations for the ultimate construction for machines rotating at relative low 300 rpm to 600 rpm speeds, which are suitable speeds e.g. in Pulp&Paper industry. The calculations are verified by using Finite Element calculations and by measuring of prototype motor. The prototype motor is a 45 kW, 600 rpm PMSM with buried V-magnets, which is a very appropriate construction for high torque motors with a high performance. With the purposebuilt prototype machine it is possible not only to verify the analytical calculations but also to show whether the 600 rpm PMSM can replace the 1500 rpm IM with a gear. It can also be tested if the outer dimensions of the PMSM may be the same as for the IM and if the PMSM in this case can produce a 2.5 fold torque, in consequence of which it may be possible to achieve the same power. The thesis also considers the question how to design a permanent magnet synchronous motor for relatively low speed applications that require a high motor torqueand efficiency as well as bearable costs of permanent magnet materials. It is shown how a selection of different parameters affects the motor properties. Key words: Permanent magnet synchronous motor, PMSM, surface magnets, buried magnets

Analysis of the voltage source inverter with small DC-link capacitor

IIn electric drives, frequency converters are used to generatefor the electric motor the AC voltage with variable frequency and amplitude. When considering the annual sale of drives in values of money and units sold, the use of low-performance drives appears to be in predominant. These drives have tobe very cost effective to manufacture and use, while they are also expected to fulfill the harmonic distortion standards. One of the objectives has also been to extend the lifetime of the frequency converter. In a traditional frequency converter, a relatively large electrolytic DC-link capacitor is used. Electrolytic capacitors are large, heavy and rather expensive components. In many cases, the lifetime of the electrolytic capacitor is the main factor limiting the lifetime of the frequency converter. To overcome the problem, the electrolytic capacitor is replaced with a metallized polypropylene film capacitor (MPPF). The MPPF has improved properties when compared to the electrolytic capacitor. By replacing the electrolytic capacitor with a film capacitor the energy storage of the DC-linkwill be decreased. Thus, the instantaneous power supplied to the motor correlates with the instantaneous power taken from the network. This yields a continuousDC-link current fed by the diode rectifier bridge. As a consequence, the line current harmonics clearly decrease. Because of the decreased energy storage, the DC-link voltage fluctuates. This sets additional conditions to the controllers of the frequency converter to compensate the fluctuation from the supplied motor phase voltages. In this work three-phase and single-phase frequency converters with small DC-link capacitor are analyzed. The evaluation is obtained with simulations and laboratory measurements.

Comparison of Immunogenicity in Rhesus Macaques of Transmitted-Founder, HIV-1 Group M Consensus, and Trivalent Mosaic Envelope Vaccines Formulated as a DNA Prime, NYVAC, and Envelope Protein Boost.

An effective human immunodeficiency virus type 1 (HIV-1) vaccine must induce protective antibody responses, as well as CD4(+) and CD8(+) T cell responses, that can be effective despite extraordinary diversity of HIV-1. The consensus and mosaic immunogens are complete but artificial proteins, computationally designed to elicit immune responses with improved cross-reactive breadth, to attempt to overcome the challenge of global HIV diversity. In this study, we have compared the immunogenicity of a transmitted-founder (T/F) B clade Env (B.1059), a global group M consensus Env (Con-S), and a global trivalent mosaic Env protein in rhesus macaques. These antigens were delivered using a DNA prime-recombinant NYVAC (rNYVAC) vector and Env protein boost vaccination strategy. While Con-S Env was a single sequence, mosaic immunogens were a set of three Envs optimized to include the most common forms of potential T cell epitopes. Both Con-S and mosaic sequences retained common amino acids encompassed by both antibody and T cell epitopes and were central to globally circulating strains. Mosaics and Con-S Envs expressed as full-length proteins bound well to a number of neutralizing antibodies with discontinuous epitopes. Also, both consensus and mosaic immunogens induced significantly higher gamma interferon (IFN-γ) enzyme-linked immunosorbent spot assay (ELISpot) responses than B.1059 immunogen. Immunization with these proteins, particularly Con-S, also induced significantly higher neutralizing antibodies to viruses than B.1059 Env, primarily to tier 1 viruses. Both Con-S and mosaics stimulated more potent CD8-T cell responses against heterologous Envs than did B.1059. Both antibody and cellular data from this study strengthen the concept of using in silico-designed centralized immunogens for global HIV-1 vaccine development strategies. IMPORTANCE: There is an increasing appreciation for the importance of vaccine-induced anti-Env antibody responses for preventing HIV-1 acquisition. This nonhuman primate study demonstrates that in silico-designed global HIV-1 immunogens, designed for a human clinical trial, are capable of eliciting not only T lymphocyte responses but also potent anti-Env antibody responses.

Biotic interactions boost spatial models of species richness

Biotic interactions are known to affect the composition of species assemblages via several mechanisms, such as competition and facilitation. However, most spatial models of species richness do not explicitly consider inter-specific interactions. Here, we test whether incorporating biotic interactions into high-resolution models alters predictions of species richness as hypothesised. We included key biotic variables (cover of three dominant arctic-alpine plant species) into two methodologically divergent species richness modelling frameworks - stacked species distribution models (SSDM) and macroecological models (MEM) - for three ecologically and evolutionary distinct taxonomic groups (vascular plants, bryophytes and lichens). Predictions from models including biotic interactions were compared to the predictions of models based on climatic and abiotic data only. Including plant-plant interactions consistently and significantly lowered bias in species richness predictions and increased predictive power for independent evaluation data when compared to the conventional climatic and abiotic data based models. Improvements in predictions were constant irrespective of the modelling framework or taxonomic group used. The global biodiversity crisis necessitates accurate predictions of how changes in biotic and abiotic conditions will potentially affect species richness patterns. Here, we demonstrate that models of the spatial distribution of species richness can be improved by incorporating biotic interactions, and thus that these key predictor factors must be accounted for in biodiversity forecasts

Head-to-Head Comparison of Poxvirus NYVAC and ALVAC Vectors Expressing Identical HIV-1 Clade C Immunogens in Prime-Boost Combination with Env Protein in Nonhuman Primates.

UNLABELLED: We compared the HIV-1-specific cellular and humoral immune responses elicited in rhesus macaques immunized with two poxvirus vectors (NYVAC and ALVAC) expressing the same HIV-1 antigens from clade C, Env gp140 as a trimeric cell-released protein and a Gag-Pol-Nef polyprotein as Gag-induced virus-like particles (VLPs) (referred to as NYVAC-C and ALVAC-C). The immunization protocol consisted of two doses of the corresponding poxvirus vector plus two doses of a combination of the poxvirus vector and a purified HIV-1 gp120 protein from clade C. This immunogenicity profile was also compared to that elicited by vaccine regimens consisting of two doses of the ALVAC vector expressing HIV-1 antigens from clades B/E (ALVAC-vCP1521) plus two doses of a combination of ALVAC-vCP1521 and HIV-1 gp120 protein from clades B/E (similar to the RV144 trial regimen) or clade C. The results showed that immunization of macaques with NYVAC-C stimulated at different times more potent HIV-1-specific CD4(+) T-cell responses and induced a trend toward higher-magnitude HIV-1-specific CD8(+) T-cell immune responses than did ALVAC-C. Furthermore, NYVAC-C induced a trend toward higher levels of binding IgG antibodies against clade C HIV-1 gp140, gp120, or murine leukemia virus (MuLV) gp70-scaffolded V1/V2 and toward best cross-clade-binding IgG responses against HIV-1 gp140 from clades A, B, and group M consensus, than did ALVAC-C. Of the linear binding IgG responses, most were directed against the V3 loop in all immunization groups. Additionally, NYVAC-C and ALVAC-C also induced similar levels of HIV-1-neutralizing antibodies and antibody-dependent cellular cytotoxicity (ADCC) responses. Interestingly, binding IgA antibody levels against HIV-1 gp120 or MuLV gp70-scaffolded V1/V2 were absent or very low in all immunization groups. Overall, these results provide a comprehensive survey of the immunogenicity of NYVAC versus ALVAC expressing HIV-1 antigens in nonhuman primates and indicate that NYVAC may represent an alternative candidate to ALVAC in the development of a future HIV-1 vaccine. IMPORTANCE: The finding of a safe and effective HIV/AIDS vaccine immunogen is one of the main research priorities. Here, we generated two poxvirus-based HIV vaccine candidates (NYVAC and ALVAC vectors) expressing the same clade C HIV-1 antigens in separate vectors, and we analyzed in nonhuman primates their immunogenicity profiles. The results showed that immunization with NYVAC-C induced a trend toward higher HIV-1-specific cellular and humoral immune responses than did ALVAC-C, indicating that this new NYVAC vector could be a novel optimized HIV/AIDS vaccine candidate for human clinical trials.

Applying Active Front End To Multilevel Inverter

The aim of this work was to make an active front end from IGBTs for a multilevel inverter. The work was done for Mosart II, a long term still ongoing Vacon Oyj project. The purpose of the AFE is to balance the DC-voltage and to put the returning power back to the grid instead of the breaking chopper and the capacitor. With a diode rectifier the bridge only allows power to pass in one direction and the switching times are not controllable. That means the rectifier always takes the highest phase and the phases are always conducting the same 120◦. With an AFE it is possible to actively change the rectifiers switching pattern. A diode bridge also generates much greater losses than an IGBT bridge. With these arguments it is rational to start researching the possibility of an AFE in a multilevel inverter.

Thermal modelling of semiconductor switches in three-level Neutral Point Clamped Medium Voltage DTC-inverter

The aim of this thesis is to investigate the thermal loading of medium voltage three-level NPC inverter’s semiconductor IGCT switches in different operation points. The objective is to reach both a fairly accurate off-line simulation program and also so simple a simulation model that its implementation into an embedded system could be reasonable in practice and a real time use should become feasible. Active loading limitation of the inverter can be realized with a thermal model which is practical in a real time use. Determining of the component heating has been divided into two parts; defining of component losses and establishing the structure of a thermal network. Basics of both parts are clarified. The simulation environment is Matlab-Simulink. Two different models are constructed – a more accurate one and a simplified one. Potential simplifications are clarified with the help of the first one. Simplifications are included in the latter model and the functionalities of both models are compared. When increasing the calculation time step a decreased number of considered components and time constants of the thermal network can be used in the simplified model. Heating of a switching component is dependent on its topological position and inverter’s operation point. The output frequency of the converter defines mainly which one of the switching components is – because of its losses and heating – the performance limiting component of the converter. Comparison of results given by different thermal models demonstrates that with larger time steps, describing of fast occurring switching losses becomes difficult. Generally articles and papers dealing with this subject are written for two-level inverters. Also inverters which apply direct torque control (DTC) are investigated rarely from the heating point of view. Hence, this thesis completes the former material.

Active inverter output filtering methods

Frequency converters are widely used in the industry to enable better controllability and efficiency of variable speed AC motor drives. Despite these advantages, certain challenges concerning the inverter and motor interfacing have been present for decades. As insulated gate bipolar transistors entered the market, the inverter output voltage transition rate significantly increased compared with their predecessors. Inverters operate based on pulse width modulation of the output voltage, and the steep voltage edge fed by the inverter produces a motor terminal overvoltage. The overvoltage causes extra stress to the motor insulation, which may lead to a prematuremotor failure. The overvoltage is not generated by the inverter alone, but also by the sum effect of the motor cable length and the impedance mismatch between the cable and the motor. Many solutions have been shown to limit the overvoltage, and the mainstream products focus on passive filters. This doctoral thesis studies an alternative methodology for motor overvoltage reduction. The focus is on minimization of the passive filter dimensions, physical and electrical, or better yet, on operation without any filter. This is achieved by additional inverter control and modulation. The studied methods are implemented on different inverter topologies, varying in nominal voltage and current.For two-level inverters, the studied method is termed active du/dt. It consists of a small output LC filter, which is controlled by an independent modulator. The overvoltage is limited by a reduced voltage transition rate. For multilevel inverters, an overvoltage mitigation method operating without a passive filter, called edge modulation, is implemented. The method uses the capability of the inverter to produce two switching operations in the same direction to cancel the oscillating voltages of opposite phases. For parallel inverters, two methods are studied. They are both intended for two-level inverters, but the first uses individual motor cables from each inverter while the other topology applies output inductors. The overvoltage is reduced by interleaving the switching operations to produce a similar oscillation accumulation as with the edge modulation. The implementation of these methods is discussed in detail, and the necessary modifications to the control system of the inverter are presented. Each method is experimentally verified by operating industrial frequency converters with the modified control. All the methods are found feasible, and they provide sufficient overvoltage protection. The limitations and challenges brought about by the methods are discussed.

Optimal inverter design for an induction machine using resonant frequency matching

The frequency responses of two 50 Hz and one 400 Hz induction machines have been measured experimentally over a frequency range of 1 kHz to 400 kHz. This study has shown that the stator impedances of the machines behave in a similar manner to a parallel resonant circuit, and hence have a resonant point at which the Input impedance of the machine is at a maximum. This maximum impedance point was found experimentally to be as low as 33 kHz, which is well within the switching frequency ranges of modern inverter drives. This paper investigates the possibility of exploiting the maximum impedance point of the machine, by taking it into consideration when designing an inverter, in order to minimize ripple currents due to the switching frequency. Minimization of the ripple currents would reduce torque pulsation and losses, increasing overall performance. A modified machine model was developed to take into account the resonant point, and this model was then simulated with an inverter to demonstrate the possible advantages of matching the inverter switching frequency to the resonant point. Finally, in order to experimentally verify the simulated results, a real inverter with a variable switching frequency was used to drive an induction machine. Experimental results are presented.

An improved reliability Cuk based solar inverter with sliding mode control

Many photovoltaic inverter designs make use of a buck based switched mode power supply (SMPS) to produce a rectified sinusoidal waveform. This waveform is then unfolded by a low frequency switching structure to produce a fully sinusoidal waveform. The Cuk SMPS could offer advantages over the buck in such applications. Unfortunately the Cuk converter is considered to be difficult to control using classical methods. Correct closed loop design is essential for stable operation of Cuk converters. Due to these stability issues, Cuk converter based designs often require stiff low bandwidth control loops. In order to achieve this stable closed loop performance, traditional designs invariably need large, unreliable electrolytic capacitors. In this paper, an inverter with a sliding mode control approach is presented which enables the designer to make use of the Cuk converters advantages, while ameliorating control difficulties. This control method allows the selection of passive components based predominantly on ripple and reliability specifications while requiring only one state reference signal. This allows much smaller, more reliable non-electrolytic capacitors to be used. A prototype inverter has been constructed and results obtained which demonstrate the design flexibility of the Cuk topology when coupled with sliding mode control.