Identification of ligands that target the HCV-E2 binding site on CD81

Hepatitis C is a global health problem. While many drug companies have active R&D efforts to develop new drugs for treating Hepatitis C virus (HCV), most target the viral enzymes. The HCV glycoprotein E2 has been shown to play an essential role in hepatocyte invasion by binding to CD81 and other cell surface receptors. This paper describes the use of AutoDock to identify ligand binding sites on the large extracellular loop of the open conformation of CD81 and to perform virtual screening runs to identify sets of small molecule ligands predicted to bind to two of these sites. The best sites selected by AutoLigand were located in regions identified by mutational studies to be the site of E2 binding. Thirty-six ligands predicted by AutoDock to bind to these sites were subsequently tested experimentally to determine if they bound to CD81-LEL. Binding assays conducted using surface Plasmon resonance revealed that 26 out of 36 (72 %) of the ligands bound in vitro to the recombinant CD81-LEL protein. Competition experiments performed using dual polarization interferometry showed that one of the ligands predicted to bind to the large cleft between the C and D helices was also effective in blocking E2 binding to CD81-LEL

Dual Polarization Interferometry for Small Molecules Drug Development

Tularemia, also known as rabbit fever, is an infectious disease caused by the gram-negative bacterium Francisella tularensis. Transmission to animals and humans occurs via several routes, including ingestion of contaminated water, or inhalation of contaminated dusts or aerosols, tick bites, and skin contact with infected animals. Because of its highly pathogenic and opportunistic nature, F. tularensis is a likely candidate for use as an airborne biological weapon. For this reason, developing a vaccine and identifying appropriate treatments are critical to effective bioterrorism preparedness and response. It may exist in nature within encysted amoeba, which may represent a similar survival strategy within human macrophages. To facilitate antimicrobial drug development, a study of the encystment process was carried out. One of the proteins discovered during this study was Rep 24, a novel Francisella cysteine protease. In this current study the interaction between Rep 24 and a possible interactive substrate, JPM-565, is observed. This interaction is detected through the optical sensing technique known as Dual Polarization Interferometry (DPI). Immobilized Rep 24 is layered on a thiol chip, followed by a wash of JPM. Changes in the refractive index of the molecules, as measured by DPI, demonstrate binding events between the two. Data from binding experiments are later used for quantitative measurements of size, density and mass. Future work includes investigation of additional Francisella tularensis proteins and screens against small molecules that may bind and abrogate function, leading to countermeasures against Francisella tularensis

Nadzieja w procesie teoretyczno-praktycznej aktualizacji objawionej prawdy według Claude’a Geffrégo

Plusieurs de théologiens modernes constatent qu’après Vatican II la réflexion théologique est passée d’une théologie de type dogmatique à une théologie de type herméneutique où la question de vérité révelée devient aussi celle de la raison historique de l’homme, ce qui la rend ouverte dans son actualisation au niveau théorique et pratique en même temps. Par conséquent le théologien devient devant Dieu le témoin des plus radicales problèmes touchants le sens de l’histoire, l’avenir (l’espérance?) de l’homme et l’éfficacité du christianisme plongée dans le risque d’ interprétation continuelle. Dominicain, professeur de l’Institut Catholique de Paris – Claude Geffré est sûrement l’un de ces principaux témoins des mutations récentes de la théologie contemporaine, étroitement liées à celles de l’herméneutique philosophique. Selon ce théologien français la dimension herméneutique de théologie permet de découvrir une permanente jeunesse de l’Évangile à l’aide de noveaux efforts de la raison humaine qui cherche la vérité révelée avec l’espérance de la compréhension totale. Autrement dit, le croyant dans le processus d’interprétation, fortifié par l’Écriture et la Tradition de la foi devient celui qui dans l’actualisation spéculative (théologie) et pragmatique (témoignage) de la Révélation participe à l’espérance de la découverte permanante de vérité. Dans ce contexte on se demande quelle place peut occuper la vérité chrétienne dans la conscience des hommes à l’âge du pluralisme et de la mondialisation? La pensée chrétienne restera-t-elle une source de l’espérance pour les hommes de XXI-ème siècle dans la recherche de verité révélée et dans son actualisation au niveau théorique-pratique

Zagadnienie ryzyka zawierzenia realizowanego w strukturze koła hermeneutycznego w teologicznej refleksji Claude’a Geffré

Przedmiotem prezentowanego opracowania jest analiza zagadnienia ryzyka zawierzenia ujętego w kołowym ruchu hermeneutycznego rozumienia, a także tych obszarów, które do tej problematyki się odnoszą, mają wpływ na jej kształt i są powiązane ze skutkami uznania w teologii hermeneutycznego paradygmatu. Przestrzeń badawczą wyznacza naukowa spuścizna Cl. Geffré, dominikanina i wieloletniego profesora Instytutu Katolickiego w Paryżu (...). Podwójne ryzyko: zawierzenia i interpretacji Bożego objawienia wyraża się w promowaniu chrześcijaństwa globalnego (nie tylko „zachodniego”), które stałoby się miejscem twórczego i wzajemnego wzrostu, będącego wypadkową zasobów chrześcijańskiej tradycji oraz duchowego bogactwa innych kultur i religijnych tradycji. Decyzja zawierzenia Bogu daje do myślenia. Osadzona w historii, zawsze pociąga za sobą ryzyko i odwagę. Tych, którzy dzięki aktowi wiary uznają i odkrywają wartość chrześcijańskiego przesłania, prowadzi najpierw do głębszego rozumienia kultury i świata. W perspektywie przyszłości zaś, rodzi nadzieję na całościowe poznanie zarówno objawionej prawdy, jak i tożsamości człowieka. Zadanie, które wyznacza Geffré, polega na rozszyfrowaniu historycznego planu Boga wobec całej ludzkości. Skierowane jest ono dla osób otwartych na przygodę teologicznej refleksji oraz zainteresowanych przyszłością Kościoła i losami Chrystusowego przesłania we współczesnym świecie

Mobile Probe for Cellular Network Coverage and Quality Measurement

This article describes a proposal of the probe application used for 2G–4G mobile network coverage and speech quality measurement. It is based on Android platform, most commonly used operation system for mobile phones. Measured results are visualized in the form of a map using GPS location. There are few tests available focusing on the applications that are most often used: test of the network coverage, speed of the websites loading, data rate test and voice quality test. The results are analyzed directly in the application and are also available over the web interface form. Individual results can be exported to standard output .csv, .json and .xml formats for further analysis

Self-assembly and anti-amyloid cytotoxicity activity of amyloid beta peptide derivatives

The self-assembly of two derivatives of KLVFF, a fragment Abeta(16-20) of the amyloid beta (Abeta) peptide, is investigated and recovery of viability of neuroblastoma cells exposed to Abeta is observed at sub-stoichiometric peptide concentrations. Fluorescence assays show that NH2-KLVFF-CONH2 undergoes hydrophobic collapse and amyloid formation at the same critical aggregation concentration (cac). In contrast, NH2-K(Boc)LVFF-CONH2 undergoes hydrophobic collapse at a low concentration, followed by amyloid formation at a higher cac. These findings are supported by the beta-sheet features observed by FTIR. Electrospray ionization mass spectrometry indicates that NH2-K(Boc)LVFF-CONH2 forms a significant population of oligomeric species above the cac. Cryo-TEM, used together with SAXS to determine fibril dimensions, shows that the length and degree of twisting of peptide fibrils seem to be influenced by the net peptide charge. Grazing incidence X-ray scattering from thin peptide films shows features of beta-sheet ordering for both peptides, along with evidence for lamellar ordering of NH2-KLVFF-CONH2. This work provides a comprehensive picture of the aggregation properties of these two KLVFF derivatives and show their utility, in unaggregated form, in restoring the viability of neuroblastoma cells against Abeta-induced toxicity

Admission Control Methods in IP Networks

Telecommunications operators and research institutions pay close attention to the issue of quality of service. The paper deals with methods of admission control in IP networks, which is only one of the subsets of quality of service. There are two large groups of AC methods: parameter-based admission control and measurement-based admission control. The core of the paper is simulation of AC methods and algorithms for topology model in MATLAB. Our simulations are mainly focused on required bandwidth and loss rates. At the end of the paper there are compared results of simulations

Study of Admission Control Methods for IPTV Services

The paper deals with admission control methods used in Internet Protocol (IP) Multimedia Subsystem. The purpose of implementing AC methods in IP Multimedia Subsystem (IMS) is to control the access of incoming connections to network resources. At the Institute of Telecommunications, we have built an experimental laboratory, which is used to test these methods. In this paper, we focus on Internet Protocol Television (IPTV) services; therefore, we have created a variable bit-rate IPTV traffic generator that is used as the input to the network, so we can test the behavior of selected AC methods. They are implemented in a simulated IPTV service provider access network, so we can examine the effects of variable bit-rate IPTV streams on the decisions made by those methods. To calculate the required bandwidth of an input stream, two simulation scenarios with different number of input packets were performed. One of these AC methods was modified where the peak input rate parameter of an IPTV stream was replaced by the average bit-rate of this stream. At the end of this paper, we discuss the achieved results

BiP and Multiple DNAJ Molecular Chaperones in the Endoplasmic Reticulum Are Required for Efficient Simian Virus 40 Infection

Simian virus 40 (SV40) is a nonenveloped DNA virus that traffics through the endoplasmic reticulum (ER) en route to the nucleus, but the mechanisms of capsid disassembly and ER exit are poorly understood. We conducted an unbiased RNA interference screen to identify cellular genes required for SV40 infection. SV40 infection was specifically inhibited by up to 50-fold by knockdown of four different DNAJ molecular cochaperones or by inhibition of BiP, the Hsp70 partner of DNAJB11. These proteins were not required for the initiation of capsid disassembly, but knockdown markedly inhibited SV40 exit from the ER. In addition, BiP formed a complex with SV40 capsids in the ER in a DNAJB11-dependent fashion. These experiments identify five new cellular proteins required for SV40 infection and suggest that the binding of BiP to the capsid is required for ER exit. Further studies of these proteins will provide insight into the molecular mechanisms of polyomavirus infection and ER function