The photochemical reaction cycle of retinal reconstituted bacteriorhodopsin

The function of three types of bacteriorhodopsins was compared: the wild-type, the bleached and retinal reconstituted and retinal deficient bacteriorhodopsin after retinal addition. The apparent pK(a) of the proton acceptor group for the bleached BR and retinal deficient BR shifted toward higher pH values compared to the wild-type BR. Fitting the photocycle model to the absorption kinetic signals for all three proteins showed the existence of the same intermediates, but the time-dependent concentration of the intermediates was different. Although measurements were made at pH 7, the absorption kinetics and photoelectric signals in both retinal reconstituted samples acted as wild-type bacteriorhodopsin at significantly higher pH. Below pH 3 the retinal deficient and reconstituted sample bleached. These results suggested that the added retinal was not able to rebind in the same position in the protein as in native bacteriorhodopsin. This points out that care should be taken, when bleached bacteriorhodopsin is reconstituted with different retinal analogs.     

Identification and structural elucidation of two process impurities and stress degradants in darifenacin hydrobromide active pharmaceutical ingredient by LC-ESI/MS(n)

The present study describes the identification and characterization of two process impurities and major stress degradants in darifenacin hydrobromide using high performance liquid chromatography (HPLC) analysis. Forced degradation studies confirmed that the drug substance was stable under acidic, alkaline, aqueous hydrolysis, thermal and photolytic conditions and susceptible only to oxidative degradation. Impurities were identified using liquid chromatography coupled with ion trap mass spectrometry (LC-MS/MS(n)). Proposed structures were unambiguously confirmed by synthesis followed by characterization using nuclear magnetic resonance spectroscopy (NMR), infrared spectroscopy (IR) and elemental analysis (EA). Based on the spectroscopic, spectrometric and elemental analysis data, the unknown impurities were characterized as 2-{1-[2-(2,3-dihydrobenzofuran-5-yl)-2-oxo-ethyl]-pyrrolidin-3-yl}-2,2-diphenylacetamide (Imp-A), 2-[1-(2-benzofuran-5-yl-ethyl)-pyrrolidin-3-yl]-2,2-diphenylacetamide (Imp-B), 2-{1-[2-(2,3-dihydrobenzofuran-5-yl)-ethyl]-1-oxy-pyrrolidin-3-yl}-2,2-diphenylacetamide (Imp-C) and 2-{1-[2-(7-bromo-2,3-dihydrobenzofuran-5-yl)-ethyl]-pyrrolidin-3-yl}-2,2-diphenylacetamide (Imp-D). Plausible mechanisms for the formation and control of these impurities have also been proposed. The method was validated as per regulatory guidelines to demonstrate specificity, sensitivity, linearity, precision, accuracy and the stability-indicating nature. Regression analysis showed a correlation coefficient value greater than 0.99 for darifenacin hydrobromide and its impurities. The accuracy of the method was established based on the recovery obtained between 86.6 and 106.7% for all impurities.     

Diffusive limits for “true” (or myopic) self-avoiding random walks and self-repellent Brownian polymers in d?≥?3

The problems considered in the present paper have their roots in two different cultures. The `true’ (or myopic) self-avoiding walk model (TSAW) was introduced in the physics literature by Amit et?al. (Phys Rev B 27:1635–1645, 1983). This is a nearest neighbor non-Markovian random walk in ${{\mathbb Z}^d}$ which prefers to jump to those neighbors which were less visited in the past. The self-repelling Brownian polymer model (SRBP), initiated in the probabilistic literature by Durrett and Rogers (Probab Theory Relat Fields 92:337–349, 1992) (independently of the physics community), is the continuous space–time counterpart: a diffusion in ${{\mathbb R}^d}$ pushed by the negative gradient of the (mollified) occupation time measure of the process. In both cases, similar long memory effects are caused by a path-wise self-repellency of the trajectories due to a push by the negative gradient of (softened) local time. We investigate the asymptotic behaviour of TSAW and SRBP in the non-recurrent dimensions. First, we identify a natural stationary (in time) and ergodic distribution of the environment (the local time profile) as seen from the moving particle. The main results are diffusive limits. In the case of TSAW, for a wide class of self-interaction functions, we establish diffusive lower and upper bounds for the displacement and for a particular, more restricted class of interactions, we prove full CLT for the finite dimensional distributions of the displacement. In the case of SRBP, we prove full CLT without restrictions on the interaction functions. These results settle part of the conjectures, based on non-rigorous renormalization group arguments (equally ‘valid’ for the TSAW and SRBP cases), in Amit et?al. (1983). The proof of the CLT follows the non-reversible version of Kipnis–Varadhan theory. On the way to the proof, we slightly weaken the so-called graded sector condition.     

Effect of hydrophilic polymer on complexing efficiency of cyclodextrins towards efavirenz-characterization and thermodynamic parameters

The present work describes the effect of PVP on the complexation efficiency of cyclodextrins towards efavirenz, a poorly soluble antiretroviral agent imparting irritating sensation to buccal cavity. The phase solubility study indicates 1:1 stoichiometry for binary and ternary systems. DSC and XRPD revealed complete inclusion only in the lyophilized systems. The ternary systems were autoclaved before being lyophilized for the best results. Proton NMR suggests that the chlorobenzene part of benzoxazinone ring of the drug is involved in inclusion and was confirmed by 2D-COESY. The thermodynamic parameters, indicative of complexation efficiency were calculated calorimetrically by determining the interaction enthalpy of efavirenz with cyclodextrins in the presence and absence of PVP. The value of stability constants increased in the order β-CD?<?HP-β-CD?<?M-β-CD and is still higher in the presence of PVP illustrating the facilitation of the inclusion. Molar enthalpy of interaction of autoclaved solid formulation determined calorimetrically indicated stronger interaction for efavirenz:M-βCD-PVP system (?12.20?kJ/mol) which showed highest solubility and dissolution rate. The in vitro measurement of permeability showed a ten fold increase in the flux for the autoclaved formulation containing efavirenz-M-β-CD-PVP. In conclusion, encapsulation by cyclodextrins increases the solubility and suppresses the oral irritation of efavirenz. PVP further increases the complexation efficiency and decreases the bulk of cyclodextrins.     

Stability and Convergence of Product Formulas for Operator Matrices

We present easy to verify conditions implying stability estimates for operator matrix splittings which ensure convergence of the associated Trotter, Strang and weighted product formulas. The results are applied to inhomogeneous abstract Cauchy problems and to boundary feedback systems.     

The Scaling Limit of the Critical One-Dimensional Random Schrödinger Operator

We consider two models of one-dimensional discrete random Schrödinger operators

$(H_n\psi)_\ell =\psi_{\ell -1}+\psi_{\ell +1}+v_\ell \psi_\ell$

, \({\psi_0=\psi_{n+1}=0}\) in the cases \({ v_k=\sigma \omega_k/\sqrt{n}}\) and \({ v_k=\sigma \omega_k/ \sqrt{k}}\) . Here ω _k are independent random variables with mean 0 and variance 1.

We show that the eigenvectors are delocalized and the transfer matrix evolution has a scaling limit given by a stochastic differential equation. In both cases, eigenvalues near a fixed bulk energy E have a point process limit. We give bounds on the eigenvalue repulsion, large gap probability, identify the limiting intensity and provide a central limit theorem.In the second model, the limiting processes are the same as the point processes obtained as the bulk scaling limits of the β-ensembles of random matrix theory. In the first model, the eigenvalue repulsion is much stronger.     

A procedure for determining reaction paths and saddle points

To determine reaction paths, a method that does not require the previous location of extrema is presented and illustrated by an example. The procedure is based on a local symmetry property of the potential surface.     

Failure of saturated ferromagnetism for the Hubbard model with two holes

We consider the Hubbard model on a finite set of sites with nonpositive hopping matrix elements and infinitely strong on-site repulsion. Nagaoka's theorem states that in this model the relative ground state in the sector with one unoccupied site is maximally ferromagnetic. We show that this phenomenon is a consequence of a combinatorial coincidence valid in the one-hole regime only. In the case of more than one hole there is no reason to expect maximally ferromagnetic ground states. We prove this claim for the case of two holes for models defined on a class of graphs which contains all tori that are not too small.     

Asymmetric hydroformylation with Pt-phosphine-SnCl2 and Pt-bisphosphine-CuCl2 (or CuCl) catalytic systems

A study has been made of asymmetric hydroformylation of styrene with PtCl₂(PPh₃)₂ + bisphosphine + SnCl₂ (bisphosphine: BDPP = (−)-(2S,4S)-2,4-bis(diphenylphosphino)pentane or DIOP = (−)-(4R,5R)-2,2-dimethyl-4,5-bis(diphenylphosphinomethyl)-1,3-dioxolane) and PtCl₂(bisphosphine) + PPh₃ + SnCl₂ catalysts prepared “in situ”. The presence of an excess of the phosphine ligand slightly lowered the reaction rate, but the enantioselectivity of these systems is significantly higher than those involving PtCl(SnCl₃)(bisphosphine) catalysts. Under mild reaction conditions 88.8% enantiomeric excess was achieved. Replacing SnCl₂ in these catalysts by CuCl₂ or CuCl gave a new homogeneous catalytic system which is active at higher reaction temperature (> 100°C), but has a rather moderate enantioselectivity.