Combinatorial library screening offers a rapid process for identifying potential therapies to toxins. Hinge peptide libraries,
which rely on conformational diversity rather than traditional molecular diversity, reduce the need for huge numbers of syntheses
and screening steps and greatly expedite the discovery process of active molecules. Hinge peptide libraries having the structures:
Acetyl-X1–X2–hinge–X3–X4–NH2 (capped) and X1–hinge–X2–X3 (uncapped), where X1 through X4 are near-equimolar mixtures of twelve L-amino acids and hinge = 4-aminobutyric acid, were screened for inhibitory activity in bioassays for botulinum neurotoxins
A and B (BoNT/A, BoNT/B) and saxitoxin. The zinc protease activity of the reduced light chains of BoNT/A and /B was assayed
by measuring the cleavage of synthetic substrates. Saxitoxin activity was measured by the restoration of the viability of
neuroblastoma cells treated with ouabain and veratridine. Deconvolution of libraries was accomplished by fixing one position
at a time beginning with the C-terminus. Primary library subsets in which position 4 was fixed showed moderate levels of inhibition
for BoNT/A. Secondary library subsets showed stronger inhibition in the bioassays. In each of the bioassays, inhibitory potency
was stronger when the second position to be fixed was on the opposite side of the hinge, rather than on the same side with
respect to the C-terminus, suggesting that the hinge facilitates the interaction of side chains. Inhibitors for all three
of the toxins studied were discovered within library subsets, although not necessarily in primary subsets. These studies demonstrate
that (1) the best strategy for deconvoluting hinge peptide libraries is by fixing residues alternately on each side of the
hinge moiety, and (2) it is essential to investigate secondary subsets even when primary subsets are inactive. The present
findings support the concept that the increased flexibility imposed by the inclusion of a central hinge residue in small peptides
increases the opportunity for side chain interactions, providing a distinct advantage for hinge peptide libraries over conventional
peptide libraries. Hinge peptide libraries are a rich source of novel ligands for modulation of biomechanisms. The library
subsets uncovered in this study may possess peptides that will lead to effective therapies to neurotoxin poisoning. 相似文献
The emission of ions from laser-produced carbon plasmas is investigated by a deconvolution of ion collector signals. The deconvolution is based on the use of Kelly and Dreyfus function expressing the time-resolved ion current to recover hidden peaks in an ion collector signal. The parameters of recovered Cq+ (1?≤?q?≤?6) currents make possible the quantification of properties of laser-produced plasmas. The drift and peak velocities of Cq+ ions, the abundance of ions and the plasma temperature are presented in the dependence on focused laser beam energy. The carbon plasma was generated employing either single 9-ns pulses of second harmonics (532 nm) of Nd:YAG laser or pulses repeated at a stable repetition rate of 30 Hz. 相似文献
The blind source separation problem is discussed in this article. Focusing on the assumption of independency of the sources in the time-frequency domain, we present a mathematical formulation for the estimation problem of the number of sources. The proposed method uses the quotient of complex valued time-frequency information of only two observed signals to detect the number of sources. No fewer number of observed signals than the detected number of sources is needed to separate sources. The assumption on sources is quite general independence in the time-frequency plane, which is different from that of independent component analysis. We propose algorithms with feedback and give numerical simulations to show the method works well even for noisy case. 相似文献
Thermoluminescence (TL) glow curves of LiF:Mg,Cu,Si were deconvoluted with the introduction of enhanced physical model which envisages that both electrons and holes, produced by ionization radiation and trapped at the respective traps, can be thermally released into the conduction and the valence band, respectively and the holes may also radiatively recombine with electrons at the electron recombination centers. The model is more generalized than the ordinary trap interaction model which only permits the traffic of electrons through the conduction band. An effective numerical analysis method was developed to calculate the glow curve to be compatible with the measured curves. The validity of the numerical method was verified through artificially generated TL glow curves for a wide range of trap parameters. In order to identify TL kinetics of LiF:Mg,Cu,Si with higher accuracy, its glow curves were deconvoluted for two more generalized models, namely, the Schön–Klasens model and the Chen–Pagonis–Lawless model as well as the ordinary trap interactive model. The parameters in the more generalized multi-trap multi-recombination center (MTMR) model were found to be consistent with the quasi-static approximation(QSA) method. 相似文献
In this article, a new framework to design high-order approximations in the context of node-centered finite volumes on simplicial meshes is proposed. The major novelty of this method is that it relies on very simple and compact differential operators, which is a critical point to achieve good performances in the High-performance computing context. This method is based on deconvolution between nodal and volume-average values, which can be conducted to any order. The interest of the new method is illustrated through three different applications: mesh-to-mesh interpolation, levelset curvature computation, and numerical scheme for convection. Higher order can also be achieved within the present framework by introducing high-rank tensors. Although these tensors feature much symmetries, their manipulation can quickly become an overwhelming task. For this reason and without loss of generality, the present articles are limited to third-order expansion. This method, although tightly connected to the k-exact schemes theory, does not rely on successive corrections: the high-order property is obtained in a single operation, which makes them more attractive in terms of performances. 相似文献
Isotope pattern deconvolution is a mathematical technique for isolating distinct isotope signatures from mixtures of natural
abundance and enriched tracers. In iron metabolism studies measurement of all four isotopes of the element by high-resolution
multicollector or collision cell ICP–MS allows the determination of the tracer/tracee ratio with simultaneous internal mass
bias correction and lower uncertainties. This technique was applied here for the first time to study iron uptake by cucumber
plants using 57Fe-enriched iron chelates of the o,o and o,p isomers of ethylenediaminedi(o-hydroxyphenylacetic) acid (EDDHA) and ethylenediamine tetraacetic acid (EDTA). Samples of root, stem, leaves, and xylem sap,
after exposure of the cucumber plants to the mentioned 57Fe chelates, were collected, dried, and digested using nitric acid. The isotopic composition of iron in the samples was measured
by ICP–MS using a high-resolution multicollector instrument. Mass bias correction was computed using both a natural abundance
iron standard and by internal correction using isotope pattern deconvolution. It was observed that, for plants with low 57Fe enrichment, isotope pattern deconvolution provided lower tracer/tracee ratio uncertainties than the traditional method
applying external mass bias correction. The total amount of the element in the plants was determined by isotope dilution analysis,
using a collision cell quadrupole ICP–MS instrument, after addition of 57Fe or natural abundance Fe in a known amount which depended on the isotopic composition of the sample. 相似文献
Direct speciation of soil phosphorus (P) by linear combination fitting (LCF) of P K‐edge XANES spectra requires a standard set of spectra representing all major P species supposed to be present in the investigated soil. Here, available spectra of free‐ and cation‐bound inositol hexakisphosphate (IHP), representing organic P, and of Fe, Al and Ca phosphate minerals are supplemented with spectra of adsorbed P binding forms. First, various soil constituents assumed to be potentially relevant for P sorption were compared with respect to their retention efficiency for orthophosphate and IHP at P levels typical for soils. Then, P K‐edge XANES spectra for orthophosphate and IHP retained by the most relevant constituents were acquired. The spectra were compared with each other as well as with spectra of Ca, Al or Fe orthophosphate and IHP precipitates. Orthophosphate and IHP were retained particularly efficiently by ferrihydrite, boehmite, Al‐saturated montmorillonite and Al‐saturated soil organic matter (SOM), but far less efficiently by hematite, Ca‐saturated montmorillonite and Ca‐saturated SOM. P retention by dolomite was negligible. Calcite retained a large portion of the applied IHP, but no orthophosphate. The respective P K‐edge XANES spectra of orthophosphate and IHP adsorbed to ferrihydrite, boehmite, Al‐saturated montmorillonite and Al‐saturated SOM differ from each other. They also are different from the spectra of amorphous FePO4, amorphous or crystalline AlPO4, Ca phosphates and free IHP. Inclusion of reference spectra of orthophosphate as well as IHP adsorbed to P‐retaining soil minerals in addition to spectra of free or cation‐bound IHP, AlPO4, FePO4 and Ca phosphate minerals in linear combination fitting exercises results in improved fit quality and a more realistic soil P speciation. A standard set of P K‐edge XANES spectra of the most relevant adsorbed P binding forms in soils is presented. 相似文献
In this article a systematic method is proposed to deconvolute the time‐dependent molecular weight distributions (MWD) and average comonomer fraction profiles of ethylene/1‐olefin copolymers made with heterogeneous Ziegler–Natta catalysts. These distributions with a high‐temperature gel permeation chromatography equipped with an infrared detector at four different polymerization times have been measured and used this information to infer how the fractions of polymer made on each site type varied with polymerization time. The model estimates here the minimum number of active site types needed to describe these copolymers, the MWD of polymer populations made on each site type, and their average comonomer fractions. This method is useful to quantify the microstructure of olefin copolymers made with multiple site type catalysts using the least number of adjustable parameters.