Computational Prediction of Broadly Neutralizing HIV-1 Antibody Epitopes from Neutralization Activity Data

Broadly neutralizing monoclonal antibodies effective against the majority of circulating isolates of HIV-1 have been isolated from a small number of infected individuals. Definition of the conformational epitopes on the HIV spike to which these antibodies bind is of great value in defining targets for vaccine and drug design. Drawing on techniques from compressed sensing and information theory, we developed a computational methodology to predict key residues constituting the conformational epitopes on the viral spike from cross-clade neutralization activity data. Our approach does not require the availability of structural information for either the antibody or antigen. Predictions of the conformational epitopes of ten broadly neutralizing HIV-1 antibodies are shown to be in good agreement with new and existing experimental data. Our findings suggest that our approach offers a means to accelerate epitope identification for diverse pathogenic antigens

The rights and freedoms guaranteed in the First Amendment to the Constitution of the United States

The work concerns the First Amendment to the Constitution of the United States. Is discussed religious freedom, speech, press, assembly and the right to petition the authorities to redress grievances. Religious freedom has been characterized by analyzing separately the clause of freedom of religious practice and the establishment clause. Freedom of expression is defined by the specification of particular types of expression and the degree of constitutional protection, ie, provocative statements, statements against the ruling authorities, obscene and defamatory statements. Based on the Supreme Court case law has also been shown the level of protection symbolic speech and advertising, which was not uniform throughout the history of the United States. Freedom of assembly was analyzed in the context of freedom of expression, by discussing the regulation of restrictions based on the time, place and manner of expression. Describing the freedom of the press focused primarily on the prohibition of control of published content by the governing authority and responsibility for the content defamatory. Also highlighted the important issue of freedom of expression on the Internet, by reference to the widely held blogs. Discusses the dangerous of stalking and cyberstalking, which may take place in the virtual and real world. We analyzed the essence of freedoms guaranteed in the First Amendment to the Constitution on the basis of artistic creation, through the characterization of satirical works and publications referring to the authentic history of offenses. It also discusses the impact of violence presented in the media on crime rates in society. Also mentioned about the immense role that fulfilled the right to petition government for redress grievances in the shaping of American civil society.Praca dotyczy I poprawki do Konstytucji Stanów Zjednoczonych. Omówiona została wolność religijna, słowa, prasy, zgromadzeń i prawo wnoszenia petycji do władz o zadośćuczynienie skargom. Wolność religijna scharakteryzowana została poprzez przeanalizowanie osobno klauzuli swobody praktyk religijnych i klauzuli ustanowienia. Wolność wyrażania swoich poglądów zdefiniowano przez wyszczególnienie poszczególnych rodzajów wypowiedzi i stopnia ich konstytucyjnej ochrony, tzn. wypowiedzi prowokujących, wypowiedzi skierowanych przeciwko władzom rządzącym, wypowiedzi obscenicznych i znieważających. Na podstawie orzecznictwa Sądu Najwyższego przedstawiona została również ochrona wypowiedzi symbolicznych i reklamowych, która nie była jednolita na przestrzeni historii Stanów Zjednoczonych. Wolność zgromadzeń przeanalizowano w kontekście wolności ekspresji, poprzez omówienie regulacji dotyczących ograniczeń ze względu na czas, miejsce i sposób wypowiedzi. Opisując wolność prasy skupiono się przede wszystkim na zakazie kontroli publikowanych treści przez władze rządzące oraz odpowiedzialności za treści zniesławiające. Zwrócono również uwagę na ważną kwestię wolności wyrażania swoich poglądów w Internecie, poprzez odniesienie się do powszechnie prowadzonych blogów internetowych. Omówiono groźne zjawisko nękania wywołującego poczucie zagrożenia, które może mieć miejsce w świecie wirtualnym i rzeczywistym. Przeanalizowano istotę wolności gwarantowanych w I poprawce do Konstytucji na gruncie twórczości artystycznej, poprzez charakterystykę dzieł satyrycznych i publikacji nawiązujących do autentycznych historii kryminalnych. Omówiono również wpływ przemocy prezentowanej w mediach na wskaźnik przestępczości w społeczeństwie. Wspomniano również o ogromnej roli jaką spełniło prawo wnoszenia petycji do władz o zadośćuczynienie skargom w kształtowaniu amerykańskiego społeczeństwa obywatelskiego

Monistic and dualistic model of managerial bodies in a joint stock company

Niniejsza praca przedstawia ewolucję, problemy i perspektywy rozwoju systemu organizacyjnego spółek akcyjnych, poprzez analizę modelu dualistycznego i monistycznego organów menedżerskich spółki akcyjnej. Model dualistyczny został omówiony w oparciu o podstawowe założenia systemu polskiego i niemieckiego, natomiast model monistyczny na przykładzie systemu amerykańskiego, angielskiego i francuskiego. Zarówno model monistyczny, jak i dualistyczny organów menedżerskich jest nieco odmiennie uregulowany w każdym z porządków prawnych, natomiast w pracy przedstawione zostały przede wszystkim elementy wspólne obu modeli, umożliwiające ich analizę porównawczą.This work presents the evolution, problems and perspectives of organizational development in joint stock companies, by analyzing the dualistic and monistic model of managerial bodies in a joint stock company. Discussion about the dualistic model is based on the Polish and German system, while the one-tier model on the example of American, English and French system. Both the monistic and dualistic managerial bodies are regulated differently in each of the legal systems, while in the work are presented all the elements common to both models, allowing their comparative analysis

Hepatitis C Virus Envelope Glycoprotein E2 Glycans Modulate Entry, CD81 Binding, and Neutralization▿

Hepatitis C virus (HCV) is a major human pathogen that causes serious liver disease, including cirrhosis and hepatocellular carcinoma. The primary target cells of HCV are hepatocytes, and entry is restricted by interactions of the envelope glycoproteins, E1 and E2, with cellular receptors. E1 and E2 form noncovalently linked heterodimers and are heavily glycosylated. Glycans contribute to protein folding and transport as well as protein function. In addition, glycans associated with viral envelopes mask important functional domains from the immune system and attenuate viral immunogenicity. Here, we explored the role of N- and O-linked glycans on E2, which is the receptor binding subunit of the HCV envelope. We identified a number of glycans that are critical for viral entry. Importantly, we showed that the removal of several glycans significantly increased the inhibition of entry by sera from HCV-positive individuals. Only some of the glycans that affected entry and neutralization were also important for CD81 binding. Our results show that HCV envelope-associated glycans play a crucial role in masking functionally important regions of E2 and suggest a new strategy for eliciting highly neutralizing antibodies against this virus

Lead (Pb) Exposure Enhances Expression of Factors Associated with Inflammation

The human immune system is constantly exposed to xenobiotics and pathogens from the environment. Although the mechanisms underlying their influence have already been at least partially recognized, the effects of some factors, such as lead (Pb), still need to be clarified. The results of many studies indicate that Pb has a negative effect on the immune system, and in our review, we summarize the most recent evidence that Pb can promote inflammatory response. We also discuss possible molecular and biochemical mechanisms of its proinflammatory action, including the influence of Pb on cytokine metabolism (interleukins IL-2, IL-4, IL-8, IL-1b, IL-6), interferon gamma (IFNγ), and tumor necrosis factor alpha (TNF-α); the activity and expression of enzymes involved in the inflammatory process (cyclooxygenases); and the effect on selected acute phase proteins: C-reactive protein (CRP), haptoglobin, and ceruloplasmin. We also discuss the influence of Pb on the immune system cells (T and B lymphocytes, macrophages, Langerhans cells) and the secretion of IgA, IgE, IgG, histamine, and endothelin

Compressed sensing (CS), mutual information (MI), and ensemble classifier predictions of HIV-1 Env positions constituting bnMAb epitopes for PGT 135, 143, and 145.

<p>The experimentally identified positions are defined as those at which alanine point mutations were observed to increase the measured IC₅₀ of the mutant by more than 30-fold relative to that of the wild type JR-CSF. Alanine scans were performed as part of the present work for PGT 143 and 145; data for PGT 121–135 were taken from Ref. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0080562#pone.0080562-Walker2" target="_blank">[51]</a>.</p><p><i>Footnote</i>: See footnote to <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0080562#pone-0080562-t001" target="_blank">Table 1</a>.</p

Compressed sensing (CS), mutual information (MI), and ensemble classifier predictions of HIV-1 Env positions constituting bnMAb epitopes for PGT 123, 123, 125, and 126.

<p>The experimentally identified positions are defined as those at which alanine point mutations were observed to increase the measured IC₅₀ of the mutant by more than 30-fold relative to that of the wild type JR-CSF. Alanine scans were performed as part of the present work for PGT 143 and 145; data for PGT 121–135 were taken from Ref. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0080562#pone.0080562-Walker2" target="_blank">[51]</a>.</p><p><i>Footnote</i>: For each of the ten HIV-1 broadly neutralizing monoclonal antibodies (bnMAb) considered in this study, we report the residues identified by the compressed sensing (CS) classifier, positions identified by the mutual information (MI) classifier, and positions identified by the ensemble classifier (formed by combining the CS and MI predictions) predicted to lie within the bnMAb epitope. The number of residues identified by the CS classifier, <i>n_CS</i>, number of positions identified by the MI classifier, <i>n_MI</i>, number of positions predicted by the ensemble classifier, <i>n_ENS</i>, and number of positions identified by alanine scans, <i>n_EXPT</i>, may differ between bnMAbs.</p