Antibody-mediated and cellular immune responses induced in naive volunteers by vaccination with long synthetic peptides derived from the Plasmodium vivax circumsporozoite protein.

Plasmodium vivax circumsporozoite (CS) protein is a leading malaria vaccine candidate. We describe the characterization of specific immune responses induced in 21 malaria-naive volunteers vaccinated with long synthetic peptides derived from the CS protein formulated in Montanide ISA 720. Both antibody- and cell-mediated immune responses were analyzed. Antibodies were predominantly of IgG1 and IgG3 isotypes, recognized parasite proteins on the immunofluorescent antibody test, and partially blocked sporozoite invasion of hepatoma cell lines in vitro. Peripheral blood mononuclear cells from most volunteers (94%) showed IFN-γ production in vitro upon stimulation with both long signal peptide and short peptides containing CD8+ T-cell epitopes. The relatively limited sample size did not allow conclusions about HLA associations with the immune responses observed. In summary, the inherent safety and tolerability together with strong antibody responses, invasion blocking activity, and the IFN-γ production induced by these vaccine candidates warrants further testing in a phase II clinical trial.

Zonation for 3D aquifer characterization based on joint inversions of multimethod crosshole geophysical data

Predictive groundwater modeling requires accurate information about aquifer characteristics. Geophysical imaging is a powerful tool for delineating aquifer properties at an appropriate scale and resolution, but it suffers from problems of ambiguity. One way to overcome such limitations is to adopt a simultaneous multitechnique inversion strategy. We have developed a methodology for aquifer characterization based on structural joint inversion of multiple geophysical data sets followed by clustering to form zones and subsequent inversion for zonal parameters. Joint inversions based on cross-gradient structural constraints require less restrictive assumptions than, say, applying predefined petro-physical relationships and generally yield superior results. This approach has, for the first time, been applied to three geophysical data types in three dimensions. A classification scheme using maximum likelihood estimation is used to determine the parameters of a Gaussian mixture model that defines zonal geometries from joint-inversion tomograms. The resulting zones are used to estimate representative geophysical parameters of each zone, which are then used for field-scale petrophysical analysis. A synthetic study demonstrated how joint inversion of seismic and radar traveltimes and electrical resistance tomography (ERT) data greatly reduces misclassification of zones (down from 21.3% to 3.7%) and improves the accuracy of retrieved zonal parameters (from 1.8% to 0.3%) compared to individual inversions. We applied our scheme to a data set collected in northeastern Switzerland to delineate lithologic subunits within a gravel aquifer. The inversion models resolve three principal subhorizontal units along with some important 3D heterogeneity. Petro-physical analysis of the zonal parameters indicated approximately 30% variation in porosity within the gravel aquifer and an increasing fraction of finer sediments with depth.

Advances in Near-surface Seismology and Ground-penetrating Radar

Advances in Near-surface Seismology and Ground-penetrating Radar (SEG Geophysical Developments Series No. 15) is a collection of original papers by renowned and respected authors from around the world. Technologies used in the application of near-surface seismology and ground-penetrating radar have seen significant advances in the last several years. Both methods have benefited from new processing tools, increased computer speeds, and an expanded variety of applications. This book, divided into four sections ? ?Reviews,? ?Methodology,? ?Integrative Approaches,? and ?Case Studies? ? captures the most significant cutting-edge issues in active areas of research, unveiling truly pertinent studies that address fundamental applied problems. This collection of manuscripts grew from a core group of papers presented at a postconvention workshop, ?Advances in Near-surface Seismology and Ground-penetrating Radar,? held during the 2009 SEG Annual Meeting in Houston, Texas. This is the first cooperative publication effort between the near-surface communities of SEG, AGU, and EEGS. It will appeal to a large and diverse audience that includes researchers and practitioners inside and outside the near-surface geophysics community.

Source-wavelet estimation during full-waveform inversion of ground-penetrating radar data

A major issue in the application of waveform inversion methods to crosshole ground-penetrating radar (GPR) data is the accurate estimation of the source wavelet. Here, we explore the viability and robustness of incorporating this step into a recently published time-domain inversion procedure through an iterative deconvolution approach. Our results indicate that, at least in non-dispersive electrical environments, such an approach provides remarkably accurate and robust estimates of the source wavelet even in the presence of strong heterogeneity of both the dielectric permittivity and electrical conductivity. Our results also indicate that the proposed source wavelet estimation approach is relatively insensitive to ambient noise and to the phase characteristics of the starting wavelet. Finally, there appears to be little to no trade-off between the wavelet estimation and the tomographic imaging procedures.

Elicitation of specific cytotoxic T cells by immunization with malaria soluble synthetic polypeptides.

We have studied the immunogenicity of Plasmodium falciparum circumsporozoite (CS) protein-derived synthetic polypeptides in mice. These synthetic peptides correspond to the N- and the C-terminal domains 22-125 and 289-390, respectively of the P. falciparum 7G8 isolate CS protein expressed on the sporozoite surface. They comprise what is believed to be the mature protein, except for the central repetitive B cell domain. BALB/c (H-2d) mice were immunized s.c. with 50 micrograms soluble CS polypeptides emulsified in IFA. After a single immunization, CS-specific helper and cytotoxic T lymphocytes (CTLs) could be obtained. The resultant CTLs obtained by in vitro restimulation of primed lymph node (LN) cells recognized H-2Kd target cells in the presence of short synthetic peptides defined in the present study. These epitopes are contained within the N- and C-terminal regions of the CS protein, and correspond to sequences 39-47 and 333-342. In addition, these CTLs can specifically lyse H-2d target cells transfected with the CS gene. These results suggest that, by immunization of mice with large soluble CS synthetic polypeptides in IFA, it is possible to obtain MHC class I-restricted T cell responses specific for the CS protein. This approach might be advantageous in the formulation of efficient malaria subunit vaccines.

Serum antimüllerian hormone levels remain stable through the menstrual cycle and after oral or vaginal administration of synthetic sex steroids

Rapport de synthèse : Objectif de l'étude : étudier si l'administration orale ou vaginale d'hormones contraceptives influence les concentrations sériques d'hormone antimüllérienne (AMH). Design : essai prospectif chez des femmes recrutées par annonce. Les femmes désireuses d'avoir une contraception ont été randomisées entre une contraception orale et une contraception vaginale. Celles qui ne souhaitaient pas de contraception ont été incluses dans le groupe témoin. Cadre de l'étude : unité de médecine de la reproduction d'un hôpital universitaire. Patientes : vingt-quatre jeunes femmes en bonne santé avec des cycles menstruels réguliers qui n'avaient pas utilisé de contraception hormonale pendant les trois mois précédant l'étude. Intervention : contraception orale ou vaginale du 5ème au 25ème jour du cycle menstruel dans les groupes contraception versus pas de contraception dans le groupe témoin. Mesure d'issue : variations inter et intra-cycle des concentrations sériques d'AMH dans les trois groupes: groupe témoin en cycle spontané et groupes sous contraception oestroprogestative orale ou vaginale. Résultats : les fluctuations d'AMH observées pendant le cycle menstruel (variations intra-cycle) restent dans les valeurs des variations entre deux cycles (variations inter-cycles) tant chez les femmes en cycle spontané que chez les femmes sous contraception orale ou vaginale. Conclusions : nos résultats confirment que les concentrations sériques d'AMH restent stables pendant le cycle menstruel et indiquent qu'elles ne sont pas influencées par l'administration exogène de stéroïdes sexuels contraceptifs, que ce soit par voie orale ou vaginale.

Full-waveform inversion of cross-hole ground-penetrating radar data to characterize a gravel aquifer close to the Thur River, Switzerland

Cross-hole radar tomography is a useful tool for mapping shallow subsurface electrical properties viz. dielectric permittivity and electrical conductivity. Common practice is to invert cross-hole radar data with ray-based tomographic algorithms using first arrival traveltimes and first cycle amplitudes. However, the resolution of conventional standard ray-based inversion schemes for cross-hole ground-penetrating radar (GPR) is limited because only a fraction of the information contained in the radar data is used. The resolution can be improved significantly by using a full-waveform inversion that considers the entire waveform, or significant parts thereof. A recently developed 2D time-domain vectorial full-waveform crosshole radar inversion code has been modified in the present study by allowing optimized acquisition setups that reduce the acquisition time and computational costs significantly. This is achieved by minimizing the number of transmitter points and maximizing the number of receiver positions. The improved algorithm was employed to invert cross-hole GPR data acquired within a gravel aquifer (4-10 m depth) in the Thur valley, Switzerland. The simulated traces of the final model obtained by the full-waveform inversion fit the observed traces very well in the lower part of the section and reasonably well in the upper part of the section. Compared to the ray-based inversion, the results from the full-waveform inversion show significantly higher resolution images. At either side, 2.5 m distance away from the cross-hole plane, borehole logs were acquired. There is a good correspondence between the conductivity tomograms and the natural gamma logs at the boundary of the gravel layer and the underlying lacustrine clay deposits. Using existing petrophysical models, the inversion results and neutron-neutron logs are converted to porosity. Without any additional calibration, the values obtained for the converted neutron-neutron logs and permittivity results are very close and similar vertical variations can be observed. The full-waveform inversion provides in both cases additional information about the subsurface. Due to the presence of the water table and associated refracted/reflected waves, the upper traces are not well fitted and the upper 2 m in the permittivity and conductivity tomograms are not reliably reconstructed because the unsaturated zone is not incorporated into the inversion domain.

Evaluation of "FIBERMESH" Synthetic Fibers in P.C. Concrete Bridge Barrier Rail, MLR-88-17, 1988

Ten bridges were chosen to have their concrete barrier rails constructed with one rail having "Fibermesh" synthetic fibers added and the other rail without the fibers. The rails were constructed in 1985, 1986, or 1987. All the bridges were inspected in 1988 and no consistent reduction in cracking was achieved using Fibermesh fibers in the p.c. concrete bridge barrier rails.

Membrane interaction of polymyxin B and synthetic analogues studied in biomimetic systems: implications for antibacterial action

Membrane-active antimicrobial peptides, such as polymyxin B (PxB), are currently in the spotlight as potential candidates toovercome bacterial resistance. We have designed synthetic analogs ofPxB in order to determine the structural requirements for membraneaction. Since the mechanism of action of PxB involves interaction withboth the outer membrane and the cytoplasmic membrane of Gramnegative bacteria, we have used an approach based on mimicking theouter layers of these membranes using monolayers, Langmuir-Blodgettfilms and unilamelar vesicles, and applying a battery of biophysicalmethods in order to dissect the different events of membraneinteraction. Collectively, results indicate that the PxB analogues act inthe bacterial membrane by the same mechanism than PxB, and that cationic amphipathicity determines peptide activity.

Effects of anomalous propagation conditions on weather radar observations

In this chapter our objective is to provide an overview of the effects of anomalous propagation conditions on weather radar observations, based mostly on studies performed by the authors during the last decade, summarizing results from recent publications, presentations, or unpublished material. We believe this chapter may be useful as an introductory text for graduate students, or researchers and practitioners dealing with this topic. Throughout the text a spherical symmetric atmosphere is assumed and the focus is on the occurrence of ground and sea clutter and subsequent problems for weather radar applications. Other related topics such as long-path, over-the-horizon propagation and detection of radar targets (either clutter or weather systems) at long ranges is not considered here; however readers should be aware of the potential problems these phenomena may have as range aliasing may cause these echoes appear nearer than they are ¿ for more details see the discussion about second trip echoes by Zrnic, this volume.

Effects of intranasal administration of synthetic (4-28)human atrial natriuretic peptide to normal volunteers.

The effects of intranasal administration of increasing doses of synthetic human natriuretic peptide (4-28 hANP) were studied in six healthy volunteers. The peptide was administered as a nasal spray at doses of 50, 100, 200, and 500 micrograms in ascending order at 48-h intervals. Vehicle was administered by the same route randomly between any two of the doses. Intranasal hANP administration had no effect on either blood pressure, heart rate (HR), or hematocrit. Diuresis did not change consistently, whereas natriuresis tended to rise with vehicle as well as with hANP administration. This was attributed to the infusion of isotonic saline during the experiment. There was no significant increase in plasma ANP levels after intranasal administration of any of the different doses. Thus, no evidence that the atrial natriuretic peptide tested (4-28 hANP) can cross the nasal mucosal barrier was found.

Membrane interaction of polymyxin B and synthetic analogues studied in biomimetic systems: implications for antibacterial action

Membrane-active antimicrobial peptides, such as polymyxin B (PxB), are currently in the spotlight as potential candidates toovercome bacterial resistance. We have designed synthetic analogs ofPxB in order to determine the structural requirements for membraneaction. Since the mechanism of action of PxB involves interaction withboth the outer membrane and the cytoplasmic membrane of Gramnegative bacteria, we have used an approach based on mimicking theouter layers of these membranes using monolayers, Langmuir-Blodgettfilms and unilamelar vesicles, and applying a battery of biophysicalmethods in order to dissect the different events of membraneinteraction. Collectively, results indicate that the PxB analogues act inthe bacterial membrane by the same mechanism than PxB, and that cationic amphipathicity determines peptide activity.

Protection against Plasmodium falciparum challenge induced in Aotus monkeys by liver-stage antigen-3-derived long synthetic peptides.

The vaccine potential of Plasmodium falciparum liver stage antigen-3 (LSA3) was investigated in Aotus monkeys using two long synthetic peptides corresponding respectively to an N-terminal non-repeat peptide (NRP) and repeat 2 (R2) region of the LSA3, adjuvanted by ASO2. Both 100-222 (NRP) and 501-596 repeat peptides induced effector B- and T-cell responses in terms of antigen-driven antibodies and/or specific IFN-gamma secretion. Animals challenged with P. falciparum sporozoites were protected following immunization with either the NRP region alone or the NRP combined with the R2 repeat region, as compared with controls receiving the adjuvant alone. These results indicate that the NRP may be sufficient to induce full, sterile protection and confirm the vaccine potential of LSA3 previously demonstrated in chimpanzees and in Aotus.

Medicinal application of long synthetic peptide technology.

This review covers the latest developments of long synthetic peptide technology for the rapid identification and development of malaria vaccine candidates and immunological modulators. A brief description of the two most common solid-phase synthetic procedures, together with the latest advances in optimisation of peptide chain assembly and analytical instrumentation, is given, with special attention to non-specialists. Several examples of vaccine candidates developed in the authors' or their collaborators' laboratories are also provided.

Long synthetic peptides for the production of vaccines and drugs: a technological platform coming of age.

Long synthetic peptides (LSPs) have a variety of important clinical uses as synthetic vaccines and drugs. Techniques for peptide synthesis were revolutionized in the 1960s and 1980s, after which efficient techniques for purification and characterization of the product were developed. These improved techniques allowed the stepwise synthesis of increasingly longer products at a faster rate, greater purity, and lower cost for clinical use. A synthetic peptide approach, coupled with bioinformatics analysis of genomes, can tremendously expand the search for clinically relevant products. In this Review, we discuss efforts to develop a malaria vaccine from LSPs, among other clinically directed work.