Complete absence of linear immunodominant epitope regions recognized by IgG after flavivirus infection and vaccination in whole proteome analyses

The flavivirus genera comprises more than 70 viruses and has an important impact on public health in their endemic and epidemic regions all over the world. Serodiagnosis of specific flavivirus infections is difficult or even impossible, due to the high degree of antibody cross-reactivity. It is however conceivable that serodiagnosis based on one or more individual flavivirus species derived peptides allows to differentiate with high specificity between different viral infections. The primary objective of my doctoral thesis therefore was to map specific immunoglobulin G (IgG) antibody responses after natural flavivirus infections and yellow fever vaccination to identify type-specific signatures of different flaviviruses as well as to study dynamics of cross-reactivity and crossrecognition between them. Therefore, a panel of sera from flavivirus-infected study subjects as well as sera before (D0) and 28 days after (D28) YFV vaccination were tested with the RepliTope™pan-Flavivirus peptide array by the company JPT Peptide Technologies displaying 6253 peptides of various flaviviruses. In general, peptide array technique allows high-resolution, high-throughput, ultra-high-density mapping of linear antibody epitopes. Serum samples prior yellow fever vaccination (timepoint D0) served as negative controls. Data analyses were performed using R-script as well as GraphPad Prism software to further dissect the IgG immune response and to identify potential serodiagnostic peptides. The analysis was focused on detection of potential targets of IgG immune responses located in prM, E, NS1 and NS5 proteins. To summarize the data obtained by heat maps and graphs, our data has shown a high level of individual variation in antibody specificities as well as no flavivirus type-specific IgG peptide recognition signature between different flaviviruses across flavivirus-infected and YFV vaccinated study subjects. This study points out the difficulties of detecting a flavivirusspecific immune response but gives further insight into a more detailed epitope mapping and understanding of antibody responses in flavivirus infections.Die Gattung der Flaviviren umfasst über 70 Viren und hat einen wichtigen Einfluss auf das öffentliche Gesundheitswesen in endemischen sowie epidemischen Regionen weltweit. Die Serodiagnostik von speziellen Flavivirus Infektionen stellt sich aufgrund eines hohen Grades an Kreuzreaktivität der Antikörper als schwierig dar. Es ist jedoch vorstellbar, dass Serodiagnostik basierend auf einem oder mehreren individuellen Flavivirus-Peptiden die Differenzierung zwischen verschiedenen Flavivirus Infektionen mit hoher Spezifität möglich macht. Das vorrangige Ziel dieser Doktorarbeit ist die Kartierung spezifischer Immunglobulin G (IgG) Reaktionen nach natürlichen Flavivirus- Infektionen und nach Gelbfieberimpfung, um spezifische Signaturen verschiedener Flaviviren zu identifizieren sowie die Dynamik der Kreuzreaktivität und Kreuzerkennung zwischen diesen zu untersuchen. Daher wurde eine Auswahl an Seren von Flavivirus-infizierten Studienteilnehmer*innen sowie Seren von gesunden Proband*innen vor (Zeitpunkt D0) und 28 Tage nach Gelbfieber Impfung (Zeitpunkt D28) mit dem RepliTope™pan-Flavivirus Peptidarray der Firma JPT Peptide Technologies getestet, welches 6253 Peptide verschiedener Flaviviren abbildet. Im Allgemeinen ermöglicht die Peptid-Array-Technik eine hochauflösende Abbildung von linearen Antikörper-Epitopen. Serumproben vor der Gelbfieberimpfung (Zeitpunkt D0) dienten als Negativkontrollen. Die Analyse der mit den Peptidarrays gewonnenen Daten umfasste Auswertungs-methoden unter Verwendung von R-Skripten sowie der GraphPad-Prism-Software zur weiteren Aufschlüsselung der IgG-Immunantwort und zur Identifizierung serodiagnostischer Peptide. Die Analyse konzentrierte sich auf den Nachweis potenzieller, spezifischer Erkennungsstrukturen der IgG-Immunantwort, die in prM-, E, NS1- und NS5-Proteinen lokalisiert sind. Unsere Daten zeigten ein hohes Maß an individueller Variation der Antikörperspezifitäten sowie eine fehlende Flavivirus typ-spezifische IgG-Peptid-Signatur bei Flavivirus infizierten und Gelbfieber geimpften Studienteilnehmer*innen bzw. Proband*innen. Diese Studie weist auf die Schwierigkeiten des Nachweises einer Flavivirus-spezifischen Immunantwort hin, gibt jedoch Einblicke in eine detailliertere Epitop Kartierung und ein besseres Verständnis der Antikörper-Antworten bei Flavivirus-Infektionen

On the Convergence of Learning Algorithms in Bayesian Auction Games

Equilibrium problems in Bayesian auction games can be described as systems of differential equations. Depending on the model assumptions, these equations might be such that we do not have a rigorous mathematical solution theory. The lack of analytical or numerical techniques with guaranteed convergence for the equilibrium problem has plagued the field and limited equilibrium analysis to rather simple auction models such as single-object auctions. Recent advances in equilibrium learning led to algorithms that find equilibrium under a wide variety of model assumptions. We analyze first- and second-price auctions where simple learning algorithms converge to an equilibrium. The equilibrium problem in auctions is equivalent to solving an infinite-dimensional variational inequality (VI). Monotonicity and the Minty condition are the central sufficient conditions for learning algorithms to converge to an equilibrium in such VIs. We show that neither monotonicity nor pseudo- or quasi-monotonicity holds for the respective VIs. The second-price auction's equilibrium is a Minty-type solution, but the first-price auction is not. However, the Bayes--Nash equilibrium is the unique solution to the VI within the class of uniformly increasing bid functions, which ensures that gradient-based algorithms attain the {equilibrium} in case of convergence, as also observed in numerical experiments

Your Failure is My Opportunity - Eff ects of Elimination in Contests

In this paper, we consider a sequence of multi-prize all-pay auctions, where the contestants who exert the lowest e fforts in a round are eliminated. We analyze if and how the behavior of contestants is influenced by the possibility that strong rivals are eliminated along the way. The conditions under which behavior is not influenced are rather restrictive. For cases where these conditions are not met, we derive equilibria in a two-period model. We compare our equilibrium predictions to those of a static model and a two-stage contest where the sequential structure is not announced in the first round

ピエロト社の経営パートナーシャフト

Ⅰ．序論　Ⅱ．ピエロト社の生成と発展　１．17世紀から第２次大戦終了までの歩み　２．第２次大戦後から1980年代までの展開　３．1980年代以降の発展　Ⅲ．“ピエロト・モデル”の展開　１．従業員参加の基礎　２．パートナーシャフト委員会　３．経営成果への参加　３－１．参加資格　３－２．成果参加総額の算出　３－３．経営成果の個別分配　３－４．貸付参加　３－５．資本参加　４．パートナーシャフト契約の解消および定款の変更　４－１．パートナーシャフト契約の解消　４－２．定款の変更　Ⅳ．“ピエロト・モデル”と経営パートナーシャフト思想　１．“ピエロト・モデル”と財産形成思??　２．“ピエロト・モデル”と労資共同体思??　Ⅴ．“ピエロト・モデル”の実践　Ⅵ．結

Orbital Apex Syndrome in a Patient with Sphenoid Fungal Balls

Orbital apex syndrome (OAS) is a rare disease that presents with a complex of symptoms, including ophthalmoplegia, ptosis and visual loss. Due to the poor prognosis, making a prompt diagnosis and administering the appropriate treatment must be initiated without delay if OAS is suspected. We report here on a case of a patient with sphenoid fungal balls, and he presented with acute visual loss and ophthalmoplegia

Retinal nerve fibre layer thickness profile in normal eyes using third-generation optical coherence tomography

Aims To establish four normal retinal nerve fibre layer (RNFL) thickness radial profiles based on third-generation optical coherence tomography (OCT) and to compare them with previously reported histologic measurements.Methods A total of 20 normal eyes were studied. A circular scan was adjusted to the size of the optic disc and three scans were performed with this radius and every 200 mu m thereafter, up to a distance of 1400 mu m. Four different radial sections (superotemporal, superonasal, inferonasal, and inferotemporal) were studied to establish RNFL thickness OCT profiles. Additionally, two radial scans orientated at 45 and 1351 crossing the optic disc centre were performed in six of 20 eyes, and RNFL thickness was measured at disc margin.Results Quadrant location and distance from disc margin interaction in RNFL thickness was statistically significant (P < 0.001). the RNFL thickness decreased (P < 0.001) as the distance from the disc margin increased for all sections. the measurements automatically generated by the OCT built-in software were thinner (P < 0.001) than histologic ones close to the disc margin.Conclusions Four normal OCT RNFL profiles were established and compared with histological data obtained from the same area. RNFL measurements assessed by OCT 3 were significantly thinner close to the optic disc margin.Hosp Olhos Araraquara, Glaucoma Sect, BR-14802530 Araraquara, SP, BrazilHosp Olhos Araraquara, Retina Diagnost & Treatment Div, BR-14802530 Araraquara, SP, BrazilUniversidade Federal de São Paulo, São Paulo, BrazilUSP, Inst Fis Sao Carlos, Sao Carlos, SP, BrazilUniv So Calif, Doheny Eye Inst, Dept Ophthalmol, Los Angeles, CA USAUniversidade Federal de São Paulo, São Paulo, BrazilWeb of Scienc

Cerebellar Nocardiosis and Myopathy from Long-Term Corticosteroids for Idiopathic Thrombocytopenia

Infection of the central nervous system with Nocardia sp. usually manifests as supratentorial abscesses. Supratentorial and cerebellar abscesses from infection with Nocardia sp. following immunosuppression with long-term corticosteroids for idiopathic thrombocytopenia (ITP) have not been reported. An 83 years-old, human immunodeficiency virus (HIV)-negative, polymorbid male with ITP for which he required corticosteroids since age 53 years developed tiredness, dyspnoea, hemoptysis, abdominal pain, and progressive gait disturbance. Imaging studies of the lung revealed an enhancing tumour in the right upper lobe with central and peripheral necrosis, multiple irregularly contoured hyperdensities over both lungs, and right-sided pleural effusions. Sputum culture grew Nocardia sp. Neurological diagnostic work-up revealed dysarthria, dysphagia, ptosis, hypoacusis, tremor, dysdiadochokinesia, proximal weakness of the lower limbs, diffuse wasting, and stocking-type sensory disturbances. The neurological deficits were attributed to an abscess in the upper cerebellar vermis, myopathy from corticosteroids, and polyneuropathy. Meropenem for 37 days and trimethoprime-sulfamethoxazole for 3 months resulted in a reduction of the pulmonary, but not the cerebral lesions. Therefore, sultamicillin was begun, but without success. Long-term therapy with corticosteroids for ITP may induce not only steroid myopathy but also immune-incompetence with the development of pulmonary and cerebral nocardiosis. Cerebral nocardiosis may not sufficiently respond to long-term antibiotic therapy why switching to alternative antibiotics or surgery may be necessary