Mutation in the loop C-terminal to the cyclophilin A binding site of HIV-1 capsid protein disrupts proper virus assembly and infectivity

We have studied the effects associated with two single amino acid substitution mutations in HIV-1 capsid (CA), the E98A and E187G. Both amino acids are well conserved among all major HIV-1 subtypes. HIV-1 infectivity is critically dependent on proper CA cone formation and mutations in CA are lethal when they inhibit CA assembly by destabilizing the intra and/or inter molecular CA contacts, which ultimately abrogate viral replication. Glu98, which is located on a surface of a flexible cyclophilin A binding loop is not involved in any intra-molecular contacts with other CA residues. In contrast, Glu187 has extensive intra-molecular contacts with eight other CA residues. Additionally, Glu187 has been shown to form a salt-bridge with Arg18 of another N-terminal CA monomer in a N-C dimer. However, despite proper virus release, glycoprotein incorporation and Gag processing, electron microscopy analysis revealed that, in contrast to the E187G mutant, only the E98A particles had aberrant core morphology that resulted in loss of infectivity

Impurity effects at finite temperature in the two-dimensional S=1/2 Heisenberg antiferromagnet

We discuss effects of various impurities on the magnetic susceptibility and the specific heat of the quantum S=1/2 Heisenberg antiferromagnet on a two-dimensional square lattice. For impurities with spin S_i > 0 (here S_i=1/2 in the case of a vacancy or an added spin, and S_i=1 for a spin coupled ferromagnetically to its neighbors), our quantum Monte Carlo simulations confirm a classical-like Curie susceptibility contribution S_i^2/4T, which originates from an alignment of the impurity spin with the local N\'eel order. In addition, we find a logarithmically divergent contribution, which we attribute to fluctuations transverse to the local N\'eel vector. We also study frustrated and nonfrustrated bond impurities with S_i=0. For a simple intuitive picture of the impurity problem, we discuss an effective few-spin model that can distinguish between the different impurities and reproduces the leading-order simulation data over a wide temperature range.Comment: 15 pages, 14 figures, submitted to PRB. v2, published version with cosmetic change

Computational Thermodynamics and Kinetics in Materials Modelling and Simulations

Over the past two decades, Computational Thermodynamics and Kinetics have been tremendously contributed to materials modeling and simulations and the demands on quantitative conceptual design and processing of various advanced materials arisen from various industries and academic institutions involved in materials manufacturing, engineering and applications are still rapidly increasing

Characterization of the invariable residue 51 mutations of human immunodeficiency virus type 1 capsid protein on in vitro CA assembly and infectivity

<p>Abstract</p> <p>Background</p> <p>The mature HIV-1 conical core formation proceeds through highly regulated protease cleavage of the Gag precursor, which ultimately leads to substantial rearrangements of the capsid (CAp24) molecule involving both inter- and intra-molecular contacts of the CAp24 molecules. In this aspect, Asp51 which is located in the N-terminal domain of HIV-1 CAp24 plays an important role by forming a salt-bridge with the free imino terminus Pro1 following proteolytic cleavage and liberation of the CAp24 protein from the Pr55Gag precursor. Thus, previous substitution mutation of Asp51 to alanine (D51A) has shown to be lethal and that this invariable residue was found essential for tube formation in vitro, virus replication and virus capsid formation.</p> <p>Results</p> <p>We extended the above investigation by introducing three different D51 substitution mutations (D51N, D51E, and D51Q) into both prokaryotic and eukaryotic expression systems and studied their effects on in vitro capsid assembly and virus infectivity. Two substitution mutations (D51E and D51N) had no substantial effect on in vitro capsid assembly, yet they impaired viral infectivity and particle production. In contrast, the D51Q mutant was defective both for in vitro capsid assembly and for virus replication in cell culture.</p> <p>Conclusion</p> <p>These results show that substitutions of D51 with glutamate, glutamine, or asparagine, three amino acid residues that are structurally related to aspartate, could partially rescue both in vitro capsid assembly and intra-cellular CAp24 production but not replication of the virus in cultured cells.</p

Forecasting linear aliphatic copolyester degradation through modular block design

AbstractThe development of efficient methods to predict the degradation of renewable polymeric materials is continuously sought in the field of polymer science. Herein, we present a modular build-up approach to create polyester-based materials with forecasted degradation rates based on the hydrolysis of the constituent polymer blocks. This involved the strategic combination of critical factors affecting polyester hydrolysis, i.e. hydrophobicity and degree of crystallinity. The starting point of this method was a toolbox of polymers with different hydrophobicities and degrees of crystallinity, as well as an understanding of their inherent differences in hydrolysis rate. Knowledge of the hydrolysis of each polymer block module enabled the prediction of the overall degradation behavior of the constructed copolymers. Taking advantage of the primary factors that affect polymer degradation, block copolymers could be independently designed to incorporate soft or rigid and faster or slower degradation properties. This approach generated a shift for how molecular design can be used to predict the degradation behavior of intended materials for different applications

Susceptibility of the 2D S=1/2 Heisenberg antiferromagnet with an impurity

We use a quantum Monte Carlo method (stochastic series expansion) to study the effects of a magnetic or nonmagnetic impurity on the magnetic susceptibility of the two-dimensional Heisenberg antiferromagnet. At low temperatures, we find a log-divergent contribution to the transverse susceptibility. We also introduce an effective few-spin model that can quantitatively capture the differences between magnetic and nonmagnetic impurities at high and intermediate temperatures.Comment: 5 pages, 4 figures, v2: Updated data in figures, minor changes in text, v3: Final version, cosmetic change

Quality assessment of atmospheric surface fields over the Baltic Sea from an ensemble of regional climate model simulations with respect to ocean dynamics

Climate model results for the Baltic Sea region from an ensemble of eight simulations using the Rossby Centre Atmosphere model version 3 (RCA3) driven with lateral boundary data from global climate models (GCMs) are compared with results from a downscaled ERA40 simulation and gridded observations from 1980-2006. The results showed that data from RCA3 scenario simulations should not be used as forcing for Baltic Sea models in climate change impact studies because biases of the control climate significantly affect the simulated changes of future projections. For instance, biases of the sea ice cover in RCA3 in the present climate affect the sensitivity of the model's response to changing climate due to the ice-albedo feedback. From the large ensemble of available RCA3 scenario simulations two GCMs with good performance in downscaling experiments during the control period 1980-2006 were selected. In this study, only the quality of atmospheric surface fields over the Baltic Sea was chosen as a selection criterion. For the greenhouse gas emission scenario A1B two transient simulations for 1961-2100 driven by these two GCMs were performed using the regional, fully coupled atmosphere-ice-ocean model RCAO. It was shown that RCAO has the potential to improve the results in downscaling experiments driven by GCMs considerably, because sea surface temperatures and sea ice concentrations are calculated more realistically with RCAO than when RCA3 has been forced with surface boundary data from GCMs. For instance, the seasonal 2 m air temperature cycle is closer to observations in RCAO than in RCA3 downscaling simulations. However, the parameterizations of air-sea fluxes in RCAO need to be improved

Uncertainties in projections of the baltic sea ecosystem driven by an ensemble of global climate models

Many coastal seas worldwide are affected by human impacts such as eutrophication causing, inter alia, oxygen depletion, and extensive areas of hypoxia. Depending on the region, global warming may reinforce these environmental changes by reducing air-sea oxygen fluxes, intensifying internal nutrient cycling, and increasing river-borne nutrient loads. The development of appropriate management plans to effectively protect the marine environment requires projections of future marine ecosystem states. However, projections with regional climate models commonly suffer from shortcomings in the driving global General Circulation Models (GCMs). The differing sensitivities of GCMs to increased greenhouse gas concentrations affect regional projections considerably. In this study, we focused on one of the most threatened coastal seas, the Baltic Sea, and estimated uncertainties in projections due to climate model deficiencies and due to unknown future greenhouse gas concentration, nutrient load and sea level rise scenarios. To address the latter, simulations of the period 1975–2098 were performed using the initial conditions from an earlier reconstruction with the same Baltic Sea model (starting in 1850). To estimate the impacts of climate model uncertainties, dynamical downscaling experiments with four driving global models were carried out for two greenhouse gas concentration scenarios and for three nutrient load scenarios, covering the plausible range between low and high loads. The results suggest that changes in nutrient supply, in particular phosphorus, control the long-term (centennial) response of eutrophication, biogeochemical fluxes and oxygen conditions in the deep water. The analysis of simulated primary production, nitrogen fixation, and hypoxic areas shows that uncertainties caused by the various nutrient load scenarios are greater than the uncertainties due to climate model uncertainties and future greenhouse gas concentrations. In all scenario simulations, a proposed nutrient load abatement strategy, i.e., the Baltic Sea Action Plan, will lead to a significant improvement in the overall environmental state. However, the projections cannot provide detailed information on the timing and the reductions of future hypoxic areas, due to uncertainties in salinity projections caused by uncertainties in projections of the regional water cycle and of the mean sea level outside the model domain.publishedVersio

Isolation and characterization of a small antiretroviral molecule affecting HIV-1 capsid morphology

Background Formation of an HIV-1 particle with a conical core structure is a prerequisite for the subsequent infectivity of the virus particle. We have previously described that glycineamide (G-NH2) when added to the culture medium of infected cells induces non-infectious HIV-1 particles with aberrant core structures. Results Here we demonstrate that it is not G-NH2 itself but a metabolite thereof that affects HIV-1 infectivity and capsid assembly. The conversion of G-NH2 to its antiviral metabolite is catalyzed by an enzyme present in bovine and porcine but surprisingly not in human serum. Structure determination by NMR suggested that the active G-NH2 metabolite was α-hydroxyglycineamide (α-HGA). Chemically synthesized α-HGA inhibited HIV-1 replication to the same degree as G-NH2, unlike a number of other synthesized analogues of G-NH2 which had no effect on HIV-1 replication. Comparisons by capillary electrophoresis and HPLC of the metabolite with the chemically synthesized α-HGA further confirmed that the antiviral GNH2-metabolite indeed was α-HGA. Conclusions α-HGA has an unusually simple structure and a novel mechanism of antiviral action. Thus, α-HGA could be a lead for new antiviral substances belonging to a new class of anti-HIV drugs, i.e. capsid assembly inhibitors

Cardiac troponin I in healthy Norwegian Forest Cat, Birman and domestic shorthair cats, and in cats with hypertrophic cardiomyopathy

Objectives The aims of this study were to assess the potential associations between the serum cardiac troponin I (cTnI) concentration in healthy cats and feline characteristics, systolic blood pressure, heart rate (HR), echocardiographic measurements and storage time; and to compare cTnI concentrations in healthy cats with concentrations in cats with hypertrophic cardiomyopathy (HCM), with or without left atrial enlargement (LAE) and in cats with HCM, to assess potential associations between cTnI concentration and echocardiographic variables. Methods Cardiac TnI was analysed using an Abbott ARCHITECT ci16200 analyser in serum from prospectively included healthy Norwegian Forest Cat (NF; n = 33), Birman (n = 33) and domestic shorthair (DSH; n = 30) cats, and from 39 cats with HCM, with or without LAE. Results In healthy cats, higher cTnI concentrations were found in Birman cats than in NF cats (P = 0.014) and in neutered male cats than in intact females (P = 0.032). Cardiac TnI was positively associated with HR (P <0.0001). In cats with HCM, cTnI concentration was positively associated with left ventricular wall thickness and with left atrial-to-aortic root ratio (all P <= 0.010). Cats with HCM had higher cTnI concentrations than healthy cats, and cTnI concentrations were higher in cats with HCM and LAE than in those with HCM without LAE (all P = 0.0003). Conclusions and relevance Breed and sex may affect serum cTnI concentrations in healthy cats. The cTnI concentration increased with increasing severity of HCM