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Search Results: 1 - 10 of 1626 matches for " Martina Beltramello "
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Rational Engineering of a Human Anti-Dengue Antibody through Experimentally Validated Computational Docking
Luca Simonelli, Mattia Pedotti, Martina Beltramello, Elsa Livoti, Luigi Calzolai, Federica Sallusto, Antonio Lanzavecchia, Luca Varani
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0055561
Abstract: Antibodies play an increasing pivotal role in both basic research and the biopharmaceutical sector, therefore technology for characterizing and improving their properties through rational engineering is desirable. This is a difficult task thought to require high-resolution x-ray structures, which are not always available. We, instead, use a combination of solution NMR epitope mapping and computational docking to investigate the structure of a human antibody in complex with the four Dengue virus serotypes. Analysis of the resulting models allows us to design several antibody mutants altering its properties in a predictable manner, changing its binding selectivity and ultimately improving its ability to neutralize the virus by up to 40 fold. The successful rational design of antibody mutants is a testament to the accuracy achievable by combining experimental NMR epitope mapping with computational docking and to the possibility of applying it to study antibody/pathogen interactions.
Therapeutic Efficacy of Antibodies Lacking FcγR against Lethal Dengue Virus Infection Is Due to Neutralizing Potency and Blocking of Enhancing Antibodies
Katherine L. Williams,Soila Sukupolvi-Petty,Martina Beltramello,Syd Johnson,Federica Sallusto,Antonio Lanzavecchia,Michael S. Diamond,Eva Harris
PLOS Pathogens , 2013, DOI: 10.1371/journal.ppat.1003157
Abstract: Dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS) are life-threatening complications following infection with one of the four serotypes of dengue virus (DENV). At present, no vaccine or antiviral therapies are available against dengue. Here, we characterized a panel of eight human or mouse-human chimeric monoclonal antibodies (MAbs) and their modified variants lacking effector function and dissected the mechanism by which some protect against antibody-enhanced lethal DENV infection. We found that neutralizing modified MAbs that recognize the fusion loop or the A strand epitopes on domains II and III of the envelope protein, respectively, act therapeutically by competing with and/or displacing enhancing antibodies. By analyzing these relationships, we developed a novel in vitro suppression-of-enhancement assay that predicts the ability of modified MAbs to act therapeutically against antibody-enhanced disease in vivo. These studies provide new insight into the biology of DENV pathogenesis and the requirements for antibodies to treat lethal DENV disease.
Immunogenetic Mechanisms Driving Norovirus GII.4 Antigenic Variation
Lisa C. Lindesmith equal contributor,Martina Beltramello equal contributor,Eric F. Donaldson,Davide Corti,Jesica Swanstrom,Kari Debbink,Antonio Lanzavecchia,Ralph S. Baric
PLOS Pathogens , 2012, DOI: 10.1371/journal.ppat.1002705
Abstract: Noroviruses are the principal cause of epidemic gastroenteritis worldwide with GII.4 strains accounting for 80% of infections. The major capsid protein of GII.4 strains is evolving rapidly, resulting in new epidemic strains with altered antigenic potentials. To test if antigenic drift may contribute to GII.4 persistence, human memory B cells were immortalized and the resulting human monoclonal antibodies (mAbs) characterized for reactivity to a panel of time-ordered GII.4 virus-like particles (VLPs). Reflecting the complex exposure history of the volunteer, human anti-GII.4 mAbs grouped into three VLP reactivity patterns; ancestral (1987–1997), contemporary (2004–2009), and broad (1987–2009). NVB 114 reacted exclusively to the earliest GII.4 VLPs by EIA and blockade. NVB 97 specifically bound and blocked only contemporary GII.4 VLPs, while NBV 111 and 43.9 exclusively reacted with and blocked variants of the GII.4.2006 Minerva strain. Three mAbs had broad GII.4 reactivity. Two, NVB 37.10 and 61.3, also detected other genogroup II VLPs by EIA but did not block any VLP interactions with carbohydrate ligands. NVB 71.4 cross-neutralized the panel of time-ordered GII.4 VLPs, as measured by VLP-carbohydrate blockade assays. Using mutant VLPs designed to alter predicted antigenic epitopes, two evolving, GII.4-specific, blockade epitopes were mapped. Amino acids 294–298 and 368–372 were required for binding NVB 114, 111 and 43.9 mAbs. Amino acids 393–395 were essential for binding NVB 97, supporting earlier correlations between antibody blockade escape and carbohydrate binding variation. These data inform VLP vaccine design, provide a strategy for expanding the cross-blockade potential of chimeric VLP vaccines, and identify an antibody with broadly neutralizing therapeutic potential for the treatment of human disease. Moreover, these data support the hypothesis that GII.4 norovirus evolution is heavily influenced by antigenic variation of neutralizing epitopes and consequently, antibody-driven receptor switching; thus, protective herd immunity is a driving force in norovirus molecular evolution.
Advanced magnetic resonance imaging techniques in brain tumours surgical planning  [PDF]
Giada Zoccatelli, Franco Alessandrini, Alberto Beltramello, Andrea Talacchi
Journal of Biomedical Science and Engineering (JBiSE) , 2013, DOI: 10.4236/jbise.2013.63A051
Abstract:
Morphological assessment using Computed Tomo-graphy (CT) or Magnetic Resonance Imaging (MRI) is still the workhorse of tumor detection and diagnosis. In particular, MRI provides detailed information about cerebral tumor anatomy, cellular metabolism and hemodynamic features, making it a fundamental tool for a correct diagnosis, treatment and monitoring of the disease. Various new functional imaging modalities assessing tissue microstructure and physiology have increased the scope of neuro imaging and raised expectations among clinicians. This article provides an overview of the most advanced MR imaging techniques (functional MRI, perfusion-weighted imaging, diffusion-weighted imaging and MR spectroscopy) now available for neurosurgical planning and their role in brain tumors assessment. Their pros and cons are analyzed in order to find out which one may be chosen as best diagnostic pre-surgical protocol. At the moment none of the single techniques can be considered the golden standard; only the integration of advanced and conventional MR imaging proves to be a reliable tool in the hands of the neuro-radiologist and neurosurgeon, thus maximazing tumor resection and function preservation.
In-Depth Analysis of the Antibody Response of Individuals Exposed to Primary Dengue Virus Infection
Ruklanthi de Alwis,Martina Beltramello,William B. Messer,Soila Sukupolvi-Petty,Wahala M. P. B. Wahala,Annette Kraus,Nicholas P. Olivarez,Quang Pham,James Brian,Wen-Yang Tsai,Wei-Kung Wang,Scott Halstead,Srisakul Kliks,Michael S. Diamond,Ralph Baric,Antonio Lanzavecchia,Federica Sallusto,Aravinda M. de Silva
PLOS Neglected Tropical Diseases , 2011, DOI: 10.1371/journal.pntd.0001188
Abstract: Humans who experience a primary dengue virus (DENV) infection develop antibodies that preferentially neutralize the homologous serotype responsible for infection. Affected individuals also generate cross-reactive antibodies against heterologous DENV serotypes, which are non-neutralizing. Dengue cross-reactive, non-neutralizing antibodies can enhance infection of Fc receptor bearing cells and, potentially, exacerbate disease. The actual binding sites of human antibody on the DENV particle are not well defined. We characterized the specificity and neutralization potency of polyclonal serum antibodies and memory B-cell derived monoclonal antibodies (hMAbs) from 2 individuals exposed to primary DENV infections. Most DENV-specific hMAbs were serotype cross-reactive and weakly neutralizing. Moreover, many hMAbs bound to the viral pre-membrane protein and other sites on the virus that were not preserved when the viral envelope protein was produced as a soluble, recombinant antigen (rE protein). Nonetheless, by modifying the screening procedure to detect rare antibodies that bound to rE, we were able to isolate and map human antibodies that strongly neutralized the homologous serotype of DENV. Our MAbs results indicate that, in these two individuals exposed to primary DENV infections, a small fraction of the total antibody response was responsible for virus neutralization.
Alternative UV Sensors Based on Color-Changeable Pigments  [PDF]
Martina Vikova, Michal Vik
Advances in Chemical Engineering and Science (ACES) , 2011, DOI: 10.4236/aces.2011.14032
Abstract: Photochromism is a chemical process in which a compound undergoes a reversible change between two states having separate absorption spectra, i.e. different color [1]. In our previous work we have published some solutions of problems of measuring photochromic textile sample by standard commercial spectrophotometric systems [2]. Main problem with measurement of kinetic behavior of photochromic pigments by standard spectrophotometer is relatively long time period between individual measurements (5 s) and impossibility of measuring whole color change during exposure without interruption of illumination of sample during measurement. It means, standard commercial spectrophotometers enable off-line measurement of kinetic behavior during exposure period and quasi on-line measurement during reversion period. Based on this problem, it is only possible to obtain precise data during reversion—decay process and growth process (exposure) is affected by high variability of data. Following this knowledge, we developed original experimenttal system with short time scanning of color change of photochromic samples during growth and decay period of color change. In this study it is presented new view on the relationship between intensity of UV-A radiation and color change half-life t1/2. Via this relation, it is demonstrated the possibility of the flexible textile-based sensors construction in the area of the radiation intensity identification.
Direct Infection and Replication of Naturally Occurring Hepatitis C Virus Genotypes 1, 2, 3 and 4 in Normal Human Hepatocyte Cultures
Martina Buck
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0002660
Abstract: Background Hepatitis C virus (HCV) infection afflicts about 170 million individuals worldwide. However, the HCV life cycle is only partially understood because it has not been possible to infect normal human hepatocytes in culture. The current Huh-7 systems use cloned, synthetic HCV RNA expressed in hepatocellular carcinoma cells to produce virions, but these cells cannot be infected with naturally occurring HCV obtained from infected patients. Methodology/Principal Findings Here, we describe a human hepatocyte culture permissible to the direct infection with naturally occurring HCV genotypes 1, 2, 3 and 4 in the blood of HCV-infected patients. The culture system mimics the biology and kinetics of HCV infection in humans, and produces infectious virions that can infect na?ve human hepatocytes. Conclusions/Significance This culture system should complement the existing systems, and may facilitate the understanding of the HCV life cycle, its effects in the natural host cell, the hepatocyte, as well as the development of novel therapeutics and vaccines.
Max Planck announces cuts
Martina Habeck
Genome Biology , 2003, DOI: 10.1186/gb-spotlight-20030611-01
Abstract: The announcement vindicates concerns expressed in December 2002, when the German government decided to freeze the budgets of the public research organizations at 2002 levels. Since then, chancellor Gerhard Schr?der has promised a 3% budget increase per year beginning in 2004. But in order to fund its 80 research institutes and 12,000 employees, the MPG needs an annual budget increase of at least 4%."The freeze really hurts," Christina Beck of the MPG told The Scientist, "because it actually means less money, not least because of increased personnel costs due to tariff rises." She added that recruiting a new research director now costs roughly 1.3 times more than in the past. This means funding for only three new directors when four directors retire.The budget freeze came at a time when the MPG was already struggling financially. In the 1990s, it received extra funding to pay for its part in "Aufbau Ost," the rebuilding of eastern Germany. The MPG opened 20 new research institutes in the new L?nder; the last building works were only finished this year, and nine of 57 research director positions at the new institutes in the east still need to be filled. But the extra funding for Aufbau Ost dried up in 2000, and the MPG drew criticism from research minister Edelgard Bulmahn for having taken so much time and having wasted funds in the early 1990s."It is easy to say that we were too slow," countered Beck. "I would say we have been careful and thorough. The MPG is well advised to take its time in choosing directors carefully, if it wants to keep its international reputation for conducting excellent research."In order to continue to be able to afford the best scientists, the MPG decided to adopt a strategy of cuts that wouldn't compromise its reputation. It identified department directors due for retirement by 2007 and then assessed the potential of the research in those departments. "We wondered where we can expect scientific breakthroughs in the next few years," explaine
Swiss computing center opens
Martina Habeck
Genome Biology , 2003, DOI: 10.1186/gb-spotlight-20040428-02
Abstract: Inaugurated last Thursday (April 22), the Lausanne-based Vital-IT center is equipped with two HP clusters of 32 production and 8 development servers, based on Intel's Itanium 2 processor. These kinds of clusters allow life scientists to run complicated software 10 to 50 times faster, thereby opening new research avenues, says Christos Ouzounis at the European Bioinformatics Institute. "You can think of problems that you could not think of otherwise if you had a limited computational capacity," he told us.The impact of the new computing power may soon be felt not only by scientists directly associated with Vital-IT, but by researchers worldwide who use the services available through the Swiss Institute of Bioinformatics, such as proteomics tools on the ExPASy (Expert Protein Analysis System) servers.The Vital-IT center also employs four information technology specialists who have access to the full technological know-how of Intel and HP. According to the center's director, Victor Jongeneel, a major aim is to develop software for the life sciences that is more robust and that performs better than the current programs, which are often written by people who are not professional programmers.The new software will run on the Itanium 2 architecture, which has been on the market for 2 years. The technology is particularly suited for large-scale computational problems; however, its uptake has been slow, partly because there is not much software that runs on it."We took a chance in deciding to go for machines that have this chip," concedes Jongeneel. "But rather than going with legacy technology, even though it is very fast right now, we [have gone] with technology that is maybe a little more expensive and with a slightly lower performance right now, with the idea that 5 years from now, we will have gone beyond all the problems associated with it, while other centers will be struggling to keep up."
Compromise reached over German copyright bill
Martina Habeck
Genome Biology , 2003, DOI: 10.1186/gb-spotlight-20030411-01
Abstract: The EU directive on digital copyright should have been implemented into national law by the end of last year, but only a few of the 15 member states have done so to date. The intention is to enable scientists to share information for research and teaching purposes while at the same time protecting the interests of copyright owners.But in Germany, the digital copyright bill has angered academic publishers. They fear the new law could make the distribution of unauthorized copies easier than ever before, and may thus have "disastrous consequences" for the publishing trade. In particular, they argue that university libraries could use the new law to save money by digitizing copyrighted work and making it freely available to other libraries."This is all lies and deliberate misinformation," said Ulf Gerder, a spokesperson for the justice ministry. "Paragraph 52a [which sparked off the row] does not even mention libraries.""The right to make digital copies is a pretty harmless issue, and for libraries of no interest whatsoever," agreed Friedrich Gei?elmann, chair of the German Libraries Association. He suspects that the aim of the publishers' campaign is to strengthen their stance and attack alternative publishing models.Indeed, there is a powerful debate in Germany about how to enable scientists to make their work more widely available. The growing open-access movement involves national and international initiatives such as Hamburg University Press, Math-Net, Open Archives Initiative and the Budapest Open Access Initiative. Proponents of open-access publishing models argue that the bill blocks the way to a free information society.Following heated debates in the national press last week, the German Parliament's legal committee decided yesterday to strike a compromise between the opposing sides. The wording of the controversial paragraph 52a will not be changed, but during a transitional period that will end in 2006, its implementation will be under close scrutiny. If the
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