The linear dichroism spectra of free base and manganese(III) porphyrins

Linear dichroism of tetraphenylporphyrin and mesoporphyrin IX dimethyl ester are reported together with their manganese (III) derivatives, using both stretched polythene films and liquid crystals as the orienting solvents. All observed electronic transitions in the range 350–900 nm are found to be polarised in the plane of the porphyrin ring.     

Hexameric MnII Dendrimer as MRI Contrast Agent

A Mn^II chelating dendrimer was prepared as a contrast agent for MRI applications. The dendrimer comprises six tyrosine‐derived [Mn(EDTA)(H₂O)]^2? moieties coupled to a cyclotriphosphazene core. Variable temperature ¹⁷O NMR spectroscopy revealed a single water co‐ligand per Mn^II that undergoes fast water exchange (k_ex=(3.0±0.1)×10⁸ s^?1 at 37 °C). The 37 °C per Mn^II relaxivity ranged from 8.2 to 3.8 mM ^?1 s^?1 from 0.47 to 11.7 T, and is sixfold higher on a per molecule basis. From this field dependence a rotational correlation time was estimated as 0.45(±0.02) ns. The imaging and pharmacokinetic properties of the dendrimer were compared to clinically used [Gd(DTPA)(H₂O)]^2? in mice at 4.7 T. On first pass, the higher per ion relaxivity of the dendrimer resulted in twofold greater blood signal than for [Gd(DTPA)(H₂O)]^2?. Blood clearance was fast and elimination occurred through both the renal and hepatobiliary routes. This Mn^II containing dendrimer represents a potential alternative to Gd‐based contrast agents, especially in patients with chronic kidney disease where the use of current Gd‐based agents may be contraindicated.     

Generation of intense highly coherent femtosecond pulses in the mid infrared

Highly coherent mid-infrared femtosecond pulses, tunable between 2.5 and 4.4 mum, and with an average energy and duration between 2.6 and 3.6 microm of 11 microJ and 200fs, respectively, have been produced by an optical parametric amplifier setup driven at 1kHz by a 400- microJ , 800-nm pulse from a Ti:sapphire amplifier. In this system, first tunable moderate-energy femtosecond pulses in the near infrared are produced by continuum amplification in beta -barium borate, and subsequently the near-infrared pulses are amplified and frequency mixed with 800-nm radiation in potassium titanyl phosphate to produce intense tunable mid-infrared pulses. The time-bandwidth product of the mid-infrared pulses is 0.28+/-0.02 over the whole high-energy tuning range. Experimental results are compared with numerical simulations and a simple model.     

Implantation of undifferentiated and pre-differentiated human neural stem cells in the R6/2 transgenic mouse model of Huntington’s disease

Background

The expression pattern and function of miRNAs in the rat model of temporal lobe epilepsy have not been well defined. Profiling miRNA expression in the rat model of temporal lobe epilepsy and investigating the function of specific miRNAs in epilepsy offers the prospect of a deeper understanding of the mechanisms of epilepsy.

Methods

The lithium-pilocarpine-induced status epilepticus model and the temporal lobe epilepsy model were established in Sprague?CDawley rats. Samples were analysed to detect deregulated miRNAs in the hippocampal temporal lobe, and several of these deregulated miRNAs were confirmed by qPCR. The expression of the pro-apoptotic miR-34a was detected at 1?day, 7?days and 2?weeks post-status epilepticus and at 2?months after temporal lobe epilepsy. The antagomir of miR-34a was then utilised. The expression of miR-34a after targeting and the expression change of activated caspase-3 protein were examined. The effects of altering the expression of miR-34a and activated caspase-3 protein on neuronal survival and neuronal death or apoptosis post-status epilepticus were assessed.

Results

The miRNA microarray detected 9 up-regulated miRNAs (miR-146a, -211, -203, -210, -152, -31, -23a, -34a, -27a) and 15 down-regulated miRNAs (miR-138*, -301a, -136, -153, -19a, -135b, -325-5p, -380, -190, -542-3p, -33, -144, -542-5p, -543, -296*). Some of the deregulated miRNAs (miR-146a, miR-210, miR-27a, miR-135b and miR-33) were confirmed using qPCR. Furthermore, an increase in expression of the pro-apoptotic miR-34a was demonstrated in the post-status epilepticus rat hippocampus. miR-34a was significantly up-regulated at 1?day, 7?days and 2?weeks post-status epilepticus and at 2?months after temporal lobe epilepsy. Experiments with the miR-34a antagomir revealed that targeting miR-34a led to an inhibition of activated caspase-3 protein expression, which may contribute to increased neuronal survival and reduced neuronal death or apoptosis.

Conclusions

Our study showed the expression profile of miRNAs in the hippocampus in a rat model of temporal lobe epilepsy and an increase in the expression of the pro-apoptotic miR-34a in post-status epilepticus rats. The results show that miR-34a is up-regulated during seizure-induced neuronal death or apoptosis, and targeting miR-34a is neuroprotective and is associated with an inhibition of an increase in activated caspase-3 protein.     

A configurational and conformational study of aframodial and its diasteriomers via experimental and theoretical VA and VCD spectroscopies

In this work we present the experimental and theoretical vibrational absorption (VA) and the theoretical vibrational circular dichroism (VCD) spectra for aframodial. In addition, we present the theoretical VA and VCD spectra for the diasteriomers of aframodial. Aframodial has four chiral centers and hence has 2⁴ = 16 diasteriomers, which occur in eight pairs of enantiomers. In addition to the four chiral centers, there is an additional chirality due to the helicity of the entire molecule, which we show by presenting 12 configurations of the 5S,8S,9R,10S enantiomer of aframodial. The VCD spectra for the diasteriomers and the 12 configurations of one enantiomer are shown to be very sensitive not only to the local stereochemistry at each chiral center, but in addition, to the helicity of the entire molecule. Here one must be careful in analyzing the signs of the VCD bands due to the ‘non-chiral’ chromophores in the molecule, since one has two contributions; one due to the inherent chirality at the four chiral centers, and one due to the chirality of the side chain groups in specific conformers, that is, its helicity. Theoretical simulations for various levels of theory are compared to the experimental VA recorded to date. The VCD spectra simulations are presented, but no experimental VCD and Raman spectra have been reported to date, though some preliminary VCD measurements have been made in Stephens’ lab in Los Angeles. The flexible side chain is proposed to be responsible for the small size of the VCD spectra of this molecule, even though the chiral part of the molecule is very rigid and has four chiral centers. In addition to VCD and Raman measurements, Raman optical activity (ROA) measurements would be very enlightening, as in many cases bands which are weak in both the VA and VCD, may be large in the Raman and/or ROA spectra. The feasibility of using vibrational spectroscopy to monitor biological structure, function and activity is a worthy goal, but this work shows that a careful theoretical analysis is also required, if one is to fully utilize and understand the experimental results. The reliability, reproduceability and uniqueness of the vibrational spectroscopic experiments and the information which can be gained from them is discussed, as well as the details of the computation of VA, VCD and Raman (and ROA) spectroscopy for molecules of the complexity of aframodial, which have multiple chiral centers and flexible side chains. Festschrift in Honor of Philip J. Stephens’ 65th Birthday.     

Oligoether-strapped calix[4]pyrrole: an ion-pair receptor displaying cation-dependent chloride anion transport

A ditopic ion-pair receptor (1), which has tunable cation- and anion-binding sites, has been synthesized and characterized. Spectroscopic analyses provide support for the conclusion that receptor 1 binds fluoride and chloride anions strongly and forms stable 1:1 complexes ([1·F](-) and [1·Cl](-)) with appropriately chosen salts of these anions in acetonitrile. When the anion complexes of 1 were treated with alkali metal ions (Li(+), Na(+), K(+), Cs(+), as their perchlorate salts), ion-dependent interactions were observed that were found to depend on both the choice of added cation and the initially complexed anion. In the case of [1·F](-), no appreciable interaction with the K(+) ion was seen. On the other hand, when this complex was treated with Li(+) or Na(+) ions, decomplexation of the bound fluoride anion was observed. In contrast to what was seen with Li(+), Na(+), K(+), treating [1·F](-) with Cs(+) ions gave rise to a stable, host-separated ion-pair complex, [F·1·Cs], which contains the Cs(+) ion bound in the cup-like portion of the calix[4]pyrrole. Different complexation behavior was seen in the case of the chloride complex, [1·Cl](-). Here, no appreciable interaction was observed with Na(+) or K(+). In contrast, treating with Li(+) produces a tight ion-pair complex, [1·Li·Cl], in which the cation is bound to the crown moiety. In analogy to what was seen for [1·F](-), treatment of [1·Cl](-) with Cs(+) ions gives rise to a host-separated ion-pair complex, [Cl·1·Cs], in which the cation is bound to the cup of the calix[4]pyrrole. As inferred from liposomal model membrane transport studies, system 1 can act as an effective carrier for several chloride anion salts of Group 1 cations, operating through both symport (chloride+cation co-transport) and antiport (nitrate-for-chloride exchange) mechanisms. This transport behavior stands in contrast to what is seen for simple octamethylcalix[4]pyrrole, which acts as an effective carrier for cesium chloride but does not operates through a nitrate-for-chloride anion exchange mechanism.     

An approach to developing a force field for molecular simulation of martensitic phase transitions between phases with subtle differences in energy and structure

d,l-Norleucine is one of only a few molecules whose crystals exhibit a martensitic or displacive-type phase transformation where the emerging phase shows a topotaxial relationship with the parent phase. The molecular mechanism for such phase transformations, particularly in molecular crystals, is not well understood. Crystalline phases that exhibit displacive phase transitions tend to be very similar in structure and energy. Consequently, the development of a force field for such phases is challenging as the phase behavior is determined by subtle differences in their lattice energies and entropies. We report an approach for developing a force field for such phases with an application to d,l-norleucine. The proposed procedure includes calculation of the phase diagram of the crystalline phases as a function of temperature to identify the best force field. d,l-Norleucine also presents an additional problem since in the solid state it exists as a zwitterion that is unstable in vacuo and therefore cannot be characterized using high-level ab initio calculations in the gas phase. However, a stable zwitterion could be obtained using Onsager's reaction-field continuum model for a solvent (SCRF) using both Hartree-Fock and density functional theory. A number of force fields and the various sets of partial charges obtained from the SCRF calculations were screened for their ability to reproduce the crystal structures of the two known phases, alpha and beta, of d,l-norleucine. Selected parameter sets were then employed in free energy minimizations to identify the best set on the basis of a correct prediction of the alpha-beta phase transition. The Williams' nonbonded parameters combined with partial charges from SCRF-Polarized Continuum Model calculation were found to reproduce the structures of the phases accurately and also maintained their stability in extended molecular dynamics simulations in the Parrinello-Rahman constant stress ensemble. Moreover, we were also able to successfully simulate the phase transformation of the beta- to the alpha-phase. The identified force field should enable detailed studies of the phase transformations exhibited by crystals of d,l-norleucine and hence enhance our understanding of martensitic-type transformations in molecular crystals.     

A theoretical study of solvation energies of FCH2COO−, FCH2COOH,and F2CHCOO−

A continuum and a discrete-continuum models are used to determine the solvation energies of FCH₂COO^?, FCH₂COOH, and F₂CHCOO^?. For the anions, the continuum model provides results closer to the experiment, while for the acid, the addition of one water molecule improves the continuum-only energy.     

Influence of Cyclodextrins on the Kinetics of Oxidation of Amino Acids and BSA by Hydrazyl Radicals

The kinetics of oxidation of amino acids (Arg, His, Lys, Phe, Thr and Tyr), a dipeptide (Gly-His), and BSA (bovine serum albumin) by two persistent water soluble free radicals of the hydrazyl type has been studied.The rate decreases in the order Arg>Lys>Tyr>Thr>HisBSAPheGly-His with bothfree radicals. Addition to the reaction mixture of - and -cyclodextrin decreases the oxidation rate, probably due to amino acidencapsulation in the cyclodextrin cavity. -Cyclodextrin protects more efficiently against oxidation than -cyclodextrin.