3,457 research outputs found
Quantitative imaging of the 3-D distribution of cation adsorption sites in undisturbed soil
Several studies have shown that the distribution of cation
adsorption sites (CASs) is patchy at a millimetre to centimetre scale. Often,
larger concentrations of CASs in biopores or aggregate coatings have been
reported in the literature. This heterogeneity has implications on the
accessibility of CASs and may influence the performance of soil system models
that assume a spatially homogeneous distribution of CASs. In this study, we
present a new method to quantify the abundance and 3-D distribution of CASs in
undisturbed soil that allows for investigating CAS densities with distance to
the soil macropores. We used X-ray imaging with Ba<sup>2+</sup> as a contrast
agent. Ba<sup>2+</sup> has a high adsorption affinity to CASs and is widely used as
an index cation to measure the cation exchange capacity (CEC). Eight soil
cores (approx. 10 cm<sup>3</sup>) were sampled from three locations with
contrasting texture and organic matter contents. The CASs of our samples were
saturated with Ba<sup>2+</sup> in the laboratory using BaCl<sub>2</sub> (0.3 mol L<sup>−1</sup>). Afterwards, KCl (0.1 mol L<sup>−1</sup>) was used to rinse out Ba<sup>2+</sup>
ions that were not bound to CASs. Before and after this process the samples
were scanned using an industrial X-ray scanner. Ba<sup>2+</sup> bound to CASs was
then visualized in 3-D by the difference image technique. The resulting
difference images were interpreted as depicting the Ba<sup>2+</sup> bound to CASs
only. The X-ray image-derived CEC correlated significantly with results of
the commonly used ammonium acetate method to determine CEC in well-mixed
samples. The CEC of organic-matter-rich samples seemed to be systematically
overestimated and in the case of the clay-rich samples with less organic
matter the CEC seemed to be systematically underestimated. The results showed
that the distribution of the CASs varied spatially within most of our samples
down to a millimetre scale. There was no systematic relation between the
location of CASs and the soil macropore structure. We are convinced that the approach proposed here will strongly aid the development of more realistic
soil system models
Mutations in hepatitis C virus E2 located outside the CD81 binding sites lead to escape from broadly neutralizing antibodies but compromise virus infectivity.
Broadly neutralizing antibodies are commonly present in the sera of patients with chronic hepatitis C virus (HCV) infection. To elucidate possible mechanisms of virus escape from these antibodies, retrovirus particles pseudotyped with HCV glycoproteins (HCVpp) isolated from sequential samples collected over a 26-year period from a chronically infected patient, H, were used to characterize the neutralization potential and binding affinity of a panel of anti-HCV E2 human monoclonal antibodies (HMAbs). Moreover, AP33, a neutralizing murine monoclonal antibody (MAb) to a linear epitope in E2, was also tested against selected variants. The HMAbs used were previously shown to broadly neutralize HCV and to recognize a cluster of highly immunogenic overlapping epitopes, designated domain B, containing residues that are also critical for binding of viral E2 glycoprotein to CD81, a receptor essential for virus entry. Escape variants were observed at different time points with some of the HMAbs. Other HMAbs neutralized all variants except for the isolate 02.E10, obtained in 2002, which was also resistant to MAb AP33. The 02.E10 HCVpp that have reduced binding affinities for all antibodies and for CD81 also showed reduced infectivity. Comparison of the 02.E10 nucleotide sequence with that of the strain H-derived consensus variant, H77c, revealed the former to have two mutations in E2, S501N and V506A, located outside the known CD81 binding sites. Substitution A506V in 02.E10 HCVpp restored binding to CD81, but its antibody neutralization sensitivity was only partially restored. Double substitutions comprising N501S and A506V synergistically restored 02.E10 HCVpp infectivity. Other mutations that are not part of the antibody binding epitope in the context of N501S and A506V were able to completely restore neutralization sensitivity. These findings showed that some nonlinear overlapping epitopes are more essential than others for viral fitness and consequently are more invariant during earlier years of chronic infection. Further, the ability of the 02.E10 consensus variant to escape neutralization by the tested antibodies could be a new mechanism of virus escape from immune containment. Mutations that are outside receptor binding sites resulted in structural changes leading to complete escape from domain B neutralizing antibodies, while simultaneously compromising viral fitness by reducing binding to CD81
State of the art of nanocrystals – special features, production, nanotoxicology aspects and intracellular delivery
Drug nanocrystals are the latest, broadly introduced nanoparticulate carrier to the pharmaceutical market from the year 2000 onwards. The special features of nanocrystals for the delivery of poorly soluble drugs are briefly reviewed (saturation solubility, dissolution velocity, adhesiveness). The industrially relevant bottom up (precipitation) and top down production technologies (pearl milling, high pressure homogenization, combination technologies) are presented. As nanotoxicological aspects, the effect of size, degradability versus biopersistency and intracellular uptake are discussed, classifying the nanocrystals in the low/non-risk group. Intracellular uptake plays a minor or no role for dermal and oral nanocrystals, but it plays a key role for intravenously injected nanocrystals (e.g. nevirapine, paclitaxel, itraconazole). Uptake by the macrophages of the mononuclear phagocytic system (MPS, liver spleen) can modify/optimize blood profiles via prolonged release from the MPS (itraconazole), but also target toxicity by too high organ concentrations and thus cause nanotoxicity. The balance in the competitive intracellular uptake by MPS and the target cells (e.g. blood–brain barrier) decides about therapeutic efficiency. The concept of “differential protein adsorption” to modulate this balance is shown for its applicability to nanocrystals for intracellular delivery to the cells of the blood–brain barrier (atovaquone)
On a Generalization of the Frobenius Number
We consider a generalization of the Frobenius Problem where the object of
interest is the greatest integer which has exactly representations by a
collection of positive relatively prime integers. We prove an analogue of a
theorem of Brauer and Shockley and show how it can be used for computation.Comment: 5 page
Neutralizing Antibody Response to Hepatitis C Virus
A critical first step in a “rational vaccine design” approach for hepatitis C virus (HCV) is to identify the most relevant mechanisms of immune protection. Emerging evidence provides support for a protective role of virus neutralizing antibodies, and the ability of the B cell response to modify the course of acute HCV infection. This has been made possible by the development of in vitro cell culture models, based on HCV retroviral pseudotype particles expressing E1E2 and infectious cell culture-derived HCV virions, and small animal models that are robust tools in studies of antibody-mediated virus neutralization. This review is focused on the immunogenic determinants on the E2 glycoprotein mediating virus neutralization and the pathways in which the virus is able to escape from immune containment. Encouraging findings from recent studies provide support for the existence of broadly neutralization antibodies that are not associated with virus escape. The identification of conserved epitopes mediating virus neutralization that are not associated with virus escape will facilitate the design of a vaccine immunogen capable of eliciting broadly neutralizing antibodies against this highly diverse virus
Action-derived molecular dynamics in the study of rare events
We present a practical method to generate classical trajectories with fixed
initial and final boundary conditions. Our method is based on the minimization
of a suitably defined discretized action. The method finds its most natural
application in the study of rare events. Its capabilities are illustrated by
non-trivial examples. The algorithm lends itself to straightforward
parallelization, and when combined with molecular dynamics (MD) it promises to
offer a powerful tool for the study of chemical reactions.Comment: 7 Pages, 4 Figures (3 in color), submitted to Phys. Rev. Let
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