Bidimensional lamellar assembly by coordination of peptidic homopolymers to platinum nanoparticles

A key challenge for designing hybrid materials is the development of chemical tools to control the organization of inorganic nanoobjects at low scales, from mesoscopic (~µm) to nanometric (~nm). So far, the most efficient strategy to align assemblies of nanoparticles consists in a bottom-up approach by decorating block copolymer lamellae with nanoobjects. This well accomplished procedure is nonetheless limited by the thermodynamic constraints that govern copolymer assembly, the entropy of mixing as described by the Flory–Huggins solution theory supplemented by the critical influence of the volume fraction of the block components. Here we show that a completely different approach can lead to tunable 2D lamellar organization of nanoparticles with homopolymers only, on condition that few elementary rules are respected: 1) the polymer spontaneously allows a structural preorganization, 2) the polymer owns functional groups that interact with the nanoparticle surface, 3) the nanoparticles show a surface accessible for coordination

Characterization of a Human Antibody Fragment Fab and Its Calcium Phosphate Nanoparticles that Inhibit Rabies Virus Infection with Vaccine

Recombinant antibody phage display technology has been used to mimic many aspects of the processes that govern the generation and selection of high-affinity natural human antibodies in the human immune system, especially for infectious disease prophylaxis. An anti-rabies virus immunized phage-display Fab library was constructed from peripheral blood lymphocytes from vaccinated volunteers. The immunized antibody library, with a diversity of 6.7×108, was used to select and produce antibodies that bound to rabies virus glycoprotein. After five rounds of immobilized fixed rabies virion panning, four unique DNA sequences were found in the higher binding clones, and only one, Fab094, showed neutralization activity. Fab094 components were analyzed by ELISA, immunoprecipitation and immunofluorescent staining. ELISA and immunofluorescence showed that Fab094 bound specifically to rabies virions. Immunoprecipitation and mass spectrometry showed that Fab094 reacted with rabies virus glycoprotein. To improve the penetration power of Fab094 antibodies, we developed Fab094 calcium phosphate nanoparticles (Fab094-CPNPs) and tested their efficacy. The rapid fluorescent focus inhibition test indicated that the neutralizing antibody titers of Fab094 and Fab094-CPNPs were reached at 200.17 IU/Kg and 246.12 IU/Kg, respectively. These findings were confirmed in vivo in a Kunming mouse challenge model. Our results demonstrate that human Fab094 and Fab094-CPNPs are efficacious candidate drugs to replace rabies immunoglobulin in post-exposure prophylaxis (PEP)

Monoclonal antibodies for prophylactic and therapeutic use against viral infections

Neutralizing antibodies play an essential part in antiviral immunity and are instrumental in preventing or modulating viral diseases. Polyclonal antibody preparations are increasingly being replaced by highly potent monoclonal antibodies (mAbs). Cocktails of mAbs and bispecific constructs can be used to simultaneously target multiple viral epitopes and to overcome issues of neutralization escape. Advances in antibody engineering have led to a large array of novel mAb formats, while deeper insight into the biology of several viruses and increasing knowledge of their neutralizing epitopes has extended the list of potential targets. In addition, progress in developing inexpensive production platforms will make antiviral mAbs more widely available and affordable

Single domain antibody multimers confer protection against rabies infection

Post-exposure prophylactic (PEP) neutralizing antibodies against Rabies are the most effective way to prevent infection-related fatality. The outer envelope glycoprotein of the Rabies virus (RABV) is the most significant surface antigen for generating virus-neutralizing antibodies. The small size and uncompromised functional specificity of single domain antibodies (sdAbs) can be exploited in the fields of experimental therapeutic applications for infectious diseases through formatting flexibilities to increase their avidity towards target antigens. In this study, we used phage display technique to select and identify sdAbs that were specific for the RABV glycoprotein from a naïve llama-derived antibody library. To increase their neutralizing potencies, the sdAbs were fused with a coiled-coil peptide derived from the human cartilage oligomeric matrix protein (COMP48) to form homogenous pentavalent multimers, known as combodies. Compared to monovalent sdAbs, the combodies, namely 26424 and 26434, exhibited high avidity and were able to neutralize 85-fold higher input of RABV (CVS-11 strain) pseudotypes in vitro, as a result of multimerization, while retaining their specificities for target antigen. 26424 and 26434 were capable of neutralizing CVS-11 pseudotypes in vitro by 90–95% as compared to human rabies immunoglobulin (HRIG), currently used for PEP in Rabies. The multimeric sdAbs were also demonstrated to be partially protective for mice that were infected with lethal doses of rabies virus in vivo. The results demonstrate that the combodies could be valuable tools in understanding viral mechanisms, diagnosis and possible anti-viral candidate for RABV infection

DNA Display Selection of Peptide Ligands for a Full-Length Human G Protein-Coupled Receptor on CHO-K1 Cells

The G protein-coupled receptors (GPCRs), which form the largest group of transmembrane proteins involved in signal transduction, are major targets of currently available drugs. Thus, the search for cognate and surrogate peptide ligands for GPCRs is of both basic and therapeutic interest. Here we describe the application of an in vitro DNA display technology to screening libraries of peptide ligands for full-length GPCRs expressed on whole cells. We used human angiotensin II (Ang II) type-1 receptor (hAT1R) as a model GPCR. Under improved selection conditions using hAT1R-expressing Chinese hamster ovary (CHO)-K1 cells as bait, we confirmed that Ang II gene could be enriched more than 10,000-fold after four rounds of selection. Further, we successfully selected diverse Ang II-like peptides from randomized peptide libraries. The results provide more precise information on the sequence-function relationships of hAT1R ligands than can be obtained by conventional alanine-scanning mutagenesis. Completely in vitro DNA display can overcome the limitations of current display technologies and is expected to prove widely useful for screening diverse libraries of mutant peptide and protein ligands for receptors that can be expressed functionally on the surface of CHO-K1 cells

Information certifiable : révélation et persuasion

In many situations, decision makers do not observe all relevant information which undermines their ability to choose the best action or policy. Moreover, it can be difficult or costly to directly acquire the missing information. In such cases, the decision maker may acquire information from privately informed parties with potentially different objectives. The issue is that they may try to influence the outcome in their favor either by withholding or selectively reporting information. For instance, employers rely on information presented by job applicants, financial authorities use firms' reports to evaluate them and elected representatives seek expert advice before selecting policies. In these examples, at least some information is certifiable or verifiable. In other words, the informed party can prove certain statements by presenting hard evidence or the decision maker can verify the accuracy of received claims and documents. Since verification can be costly or time consuming, the decision maker might be able to only partially check the claim. These constraints determine the amount of information that can be verified before the decision is made. The first two chapters focus on models that best describe settings where the decision maker has to evaluate a claim or respond to a request made by an individual or institution. In the third chapter, I consider a slightly different framework where the decision maker seeks advice by consulting informed agents.In the first chapter, I study the basic framework where the informed agent's preferences over the decision maker's actions are independent of the state. In unilateral communication, only the agent sends a message to the decision maker. In bilateral communication, both exchange messages sequentially. I study and compare these two types of mechanisms under the constraint that the agent can present the same amount of certifiable information in both cases. In the canonical bilateral communication mechanism, after receiving a claim from the agent, the decision maker asks him to certify a certain event and bases her decision on his ability to do so. The main result of this chapter essentially states that if information certification is limited and the limitation prevents the decision maker from achieving her first-best in unilateral communication then she strictly benefits from bilateral communication.In the second chapter, which results from a joint work with Frédéric Koessler (CNRS, Paris School of Economics), we study implementation in the presence of ambiguity aversion. We show that if an allocation rule can be implemented with unlimited information certification, then it can also be implemented with limited information certification if the designer can use ambiguous communication mechanisms, and if agents are averse to ambiguity in the sense of maxmin expected utility. The reverse implication is true if there is a single agent and a worst outcome.In the third chapter, I study a setting with two types of informed agents. One type prefers higher actions while the other prefers lower actions. The decision maker ignores the informed agent's preferences. In this case, it might not be sufficient to consult one agent. I study sequential consultation of more than one informed agent and examine its impact on information revelation. It is shown that in equilibrium the decision maker may consult more than one agent and that she continues to seek advice as long as her uncertainty is high enough. Learning on the equilibrium path happens through both revelation and withholding of information. It is possible for agents of the minority - in terms of preferences - to influence the decision maker by withholding information so that she chooses their favorite outcome when she should not. Moreover, sequential consultation can be used as a threat to extract more precise information while consulting only one agent.Dans de nombreuses situations, les décideurs sont amenés à choisir une action ou une politique sans être parfaitement informés. De plus, il est parfois difficile ou coûteux d'acquérir directement les informations manquantes. Dans ce cas, ils peuvent solliciter l'aide des institutions ou individus informés. Ces derniers peuvent essayer d'influencer la décision en leur faveur en cachant ou en ne présentant qu'une partie de l'information. Par exemple, les employeurs s'appuient sur l'information présentée par les demandeurs d'emploi, les autorités financières utilisent les rapports des entreprises pour les évaluer et les élus consultent les experts avant de proposer une loi. Dans ces exemples, au moins certaines informations sont certifiables ou vérifiables. En d'autres termes, la partie informée peut prouver certaines déclarations en présentant des preuves ou le décideur peut vérifier l'exactitude de ces déclarations. Puisque la vérification peut être coûteuse ou prenante, le décideur ne peut souvent vérifier qu'une partie de l'information reçue. Ces contraintes déterminent la quantité d'information qui peut être vérifiée avant la prise de décision. Les deux premiers chapitres portent sur des modèles adaptés aux situations où le décideur doit évaluer une déclaration ou répondre à une demande faite par une personne ou une institution. Dans le troisième chapitre, je considère un cadre légèrement différent où le décideur consulte des agents informés avant de choisir une action.Dans le premier chapitre, j'étudie un modèle où les préférences de l'agent informé sont indépendantes de l'état. En communication unilatérale, seul l'agent envoie un message au décideur. En communication bilatérale, les deux échangent des messages. Je compare ces deux mécanismes en supposant que la même quantité de preuves peut être présentée dans les deux cas. Dans le mécanisme canonique de communication bilatérale, après avoir reçu une déclaration de la part de l'agent, le décideur lui demande de présenter une preuve en particulier. La décision dépend seulement de sa capacité à présenter la preuve demandée. Le résultat principal de ce chapitre stipule que la communication bilatérale améliore le résultat si la certification de l'information est limitée de manière à empêcher le décideur d'atteindre son optimum en communication unilatérale.Le deuxième chapitre, qui résulte d'un travail joint avec Frédéric Koessler (CNRS, École d’Économie de Paris), étudie l'implémentation en présence d'agents averses à l'ambiguïté. Nous montrons que si une règle d'allocation peut être implémentée avec une certification illimitée, elle peut également être implémentée avec une certification limitée d'information si le décideur peut utiliser des mécanismes de communication ambigus et si les agents sont averses à l'ambiguïté au sens du maxmin. L'implication inverse est vraie s'il ya un seul agent et une action de punition.Dans le troisième chapitre, j'étudie un modèle avec deux types d'agents informés. Un type veut maximiser l'action du décideur tandis que l'autre veut la minimiser. Dans ce cas, il peut y avoir besoin de consulter plus d'un agent. J'étudie la consultation séquentielle et j'examine son impact sur la révélation d'information. À l'équilibre, le décideur continue de consulter des agents informés tant que son incertitude est suffisamment élevée. Les agents minoritaires - en termes de préférences - peuvent influencer le décideur en cachant l'information lorsqu'elle est défavorable car il anticipe, à juste titre, que la majorité est davantage susceptible de le faire. En outre, la menace de consultation séquentielle peut être utilisée afin d'extraire des informations plus précises tout en consultant un seul agent