Transient spike adding in the presence of equilibria

Many models of neuronal activity exhibit complex oscillations in response to an input from other neurons in a network or to an input from a stimulus. We consider the effect of a single short stimulus on a simple model designed to mimic some features of neuronal dynamics. We focus on the transient response induced by the stimulus, particularly on the spike-adding behaviour of the response. Our main goal is to explain how the transient response is affected by the presence of unstable equilibria. We also investigate the dependence of the number of spikes on the amplitude and duration of the stimulus. In our analysis, we use numerical continuation methods and exploit the presence of different time scales in the model.     

Neutral Hexacoordinate Phosphorus(V) Compounds Containing Tridentate Dianionic Ligands Obtained from Salicylideneamines, 2,2′-Azodiphenol and a Thio(Diphenol)

Abstract

Neutral hexacoordinate phosphorus(V) compounds of a number of univalent bidentate ligands are known.^l,2 The silylated forms of tridentate, dianionic Schiff base ligands: N-(2-hydroxyphenyl)salicylideneamine H₂L^I, N-(4-tert-butyl-2-hydroxyphenyl)-salicylideneamine H₂L^II, N-(2-hydroxy-4-nitrophenyl)salicylidene-amine H₂L^III, and 2,2′-azodiphenol H₂L^IV gave, with halogeno- and (trifluoromethyl)halogenophosphoranes, neutral hexa-coordinate derivatives with bis-chelate structures. The ligands form bicyclic five- and six-membered chelate rings in a meridional conformation, with two P-O bonds and one N→P donor bond. Hexacoordinate structures were evidenced by high-field ³¹P NMR chemical shifts (-136 to -148 ppm), characteristic J _PF coupling patterns and was further substantiated by crystal structures of Cl₃L^II (A) and F₃PL^II (B).     

Performance monitoring of a mammalian cell based bioprocess using Raman spectroscopy

Being able to predict the final product yield at all stages in long-running, industrial, mammalian cell culture processes is vital for both operational efficiency, process consistency, and the implementation of quality by design (QbD) practices. Here we used Raman spectroscopy to monitor (in terms of glycoprotein yield prediction) a fed-batch fermentation from start to finish. Raman data were collected from 12 different time points in a Chinese hamster ovary (CHO) based manufacturing process and across 37 separate production runs. The samples comprised of clarified bioprocess broths extracted from the CHO cell based process with varying amounts of fresh and spent cell culture media. Competitive adaptive reweighted sampling (CoAdReS) and ant colony optimization (ACO) variable selection methods were used to enhance the predictive ability of the chemometric models by removing unnecessary spectral information. Using CoAdReS accurate prediction models (relative error of predictions between 2.1% and 3.3%) were built for the final glycoprotein yield at every stage of the bioprocess from small scale up to the final 5000 L bioreactor. This result reinforces our previous studies which indicate that media quality is one of the most significant factors determining the efficiency of industrial CHO-cell processes. This Raman based approach could thus be used to manage production in terms of selecting which small scale batches are progressed to large-scale manufacture, thus improving process efficiency significantly.     

An Investigation of 1:1 Adducts of Gallium Trihalides with Triarylphosphines by Solid‐State 69/71Ga and 31P NMR Spectroscopy

Several 1:1 adducts of gallium trihalides with triarylphosphines, X₃Ga(PR₃) (X=Cl, Br, and I; PR₃=triarylphosphine ligand), were investigated by using solid‐state ^69/71Ga and ³¹P NMR spectroscopy at different magnetic‐field strengths. The ^69/71Ga nuclear quadrupolar coupling parameters, as well as the gallium and phosphorus magnetic shielding tensors, were determined. The magnitude of the ⁷¹Ga quadrupolar coupling constants (C_Q(⁷¹Ga)) range from approximately 0.9 to 11.0 MHz . The spans of the gallium magnetic shielding tensors for these complexes, δ₁₁?δ₃₃, range from approximately 30 to 380 ppm; those determined for phosphorus range from 10 to 40 ppm. For any given phosphine ligand, the gallium nuclei are most shielded for X=I and least shielded for X=Cl, a trend previously observed for In^III–phosphine complexes. This experimental trend, attributed to spin‐orbit effects of the halogen ligands, is reproduced by DFT calculations. The signs of C_Q(^69/71Ga) for some of the adducts were determined from the analysis of the ³¹P NMR spectra acquired with magic angle spinning (MAS). The ¹J(^69/71Ga,³¹P) and ΔJ(^69/71Ga, ³¹P) values, as well as their signs, were also determined; values of ¹J(⁷¹Ga,³¹P) range from approximately 380 to 1590 Hz. Values of ¹J(^69/71Ga,³¹P) and ΔJ(^69/71Ga,³¹P) calculated by using DFT have comparable magnitudes and generally reproduce experimental trends. Both the Fermi‐contact and spin‐dipolar Fermi‐contact mechanisms make important contributions to the ¹J(^69/71Ga,³¹P) tensors. The ³¹P NMR spectra of several adducts in solution, obtained as a function of temperature, are contrasted with those obtained in the solid state. Finally, to complement the analysis of NMR spectra for these adducts, single‐crystal X‐ray diffraction data for Br₃Ga[P(p‐Anis)₃] and I₃Ga[P(p‐Anis)₃] were obtained.     

A Dilute and Shoot Strategy for Determining Alternaria Toxins in Tomato-Based Samples and in Different Flours Using LC-IDMS Separation

Alternaria toxins are emerging mycotoxins whose regulation and standardization are in progress by the European Commission and the European Committee for Standardization. This paper describes a dilute and shoot approach to determine five Alternaria toxins in selected food samples using liquid chromatography–tandem mass spectrometry (LC-MS/MS). The strategy involves sample extraction with acidified aqueous methanol, followed by a solvent change accomplished via sample evaporation and reconstitution. The quantification is based on isotope dilution, applying all corresponding isotopically labeled internal standards to compensate possible matrix effects of the analysis. The main advantages of the present method over other existing methods includes simple and effective sample preparation, as well as detection with high sensitivity. The five-fold sample dilution can decrease matrix effects, which were evaluated with both external and internal standard methods. The results demonstrated a limit of quantification lower than 1.0 µg/kg for all five analytes for the first time. The newly presented method showed acceptable accuracy (52.7–111%) when analyzing naturally contaminated and spiked standard samples at the described levels. The method was validated for tomato-based and flour samples (wheat, rye, and maize). The absolute recovery ranged from 66.7% to 91.6% (RSD < 10%). The developed method could be an alternative approach for those laboratories that exclude sample cleanup and pre-concentration of state-of-the-art instruments with enhanced sensitivity.     

Copper‐Catalyzed α‐Amination of Phosphonates and Phosphine Oxides: A Direct Approach to α‐Amino Phosphonic Acids and Derivatives

A direct approach to important α‐amino phosphonic acids and its derivatives has been developed by using copper‐catalyzed electrophilic amination of α‐phosphonate zincates with O‐acyl hydroxylamines. This amination provides the first example of C? N bond formation which directly introduces acyclic and cyclic amines to the α‐position of phosphonates in one step. The reaction is readily promoted at room temperature with as little as 0.5 mol % of catalyst, and demonstrates high efficiency on a broad substrate scope.     

Nucleophilic Reactivity of a Copper(II)–Superoxide Complex

Metal‐bound superoxide intermediates are often implicated as electrophilic oxidants in dioxygen‐activating metalloenzymes. In the nonheme iron α‐ketoglutarate dependent oxygenases and pterin‐dependent hydroxylases, however, Fe^III–superoxide intermediates are postulated to react by nucleophilic attack on electrophilic carbon atoms. By reacting a Cu^II–superoxide complex ( 1 ) with acyl chloride substrates, we have found that a metal–superoxide complex can be a very reactive nucleophile. Furthermore, 1 was found to be an efficient nucleophilic deformylating reagent, capable of Baeyer–Villiger oxidation of a number of aldehyde substrates. The observed nucleophilic chemistry represents a new domain for metal–superoxide reactivity. Our observations provide support for the postulated role of metal–superoxide intermediates in nonheme iron α‐ketoglutarate dependent and pterin‐dependent enzymes.     

Copper‐Catalyzed Electrophilic Amination of Heteroarenes and Arenes by CH Zincation

Direct amination of heteroarenes and arenes has been achieved in a one‐pot C? H zincation/copper‐catalyzed electrophilic amination procedure. This amination method provides an efficient and rapid approach to access a diverse range of heteroaromatic and aromatic amines including those previously inaccessible using C? H amination methods. The mild reaction conditions and good functional‐group compatibility demonstrate its great potential for the synthesis of important and complex amines.     

Molecularly Precise Dendrimer–Drug Conjugates with Tunable Drug Release for Cancer Therapy

The structural preciseness of dendrimers makes them perfect drug delivery carriers, particularly in the form of dendrimer–drug conjugates. Current dendrimer–drug conjugates are synthesized by anchoring drug and functional moieties onto the dendrimer peripheral surface. However, functional groups exhibiting the same reactivity make it impossible to precisely control the number and the position of the functional groups and drug molecules anchored to the dendrimer surface. This structural heterogeneity causes variable pharmacokinetics, preventing such conjugates to be translational. Furthermore, the highly hydrophobic drug molecules anchored on the dendrimer periphery can interact with blood components and alter the pharmacokinetic behavior. To address these problems, we herein report molecularly precise dendrimer–drug conjugates with drug moieties buried inside the dendrimers. Surprisingly, the drug release rates of these conjugates were tailorable by the dendrimer generation, surface chemistry, and acidity.