Dynamic structure elucidation of chemical reactivity by laser pulses and X-ray probes

Visualising chemical reactions by X-ray methods is a tantalising prospect. New light sources provide the prospect for studying atomic, electronic and energy transfers accompanying chemical change by X-ray spectroscopy and inelastic scattering. Here we assess how this adventure can illuminate inorganic and catalytic chemistry. In particular X-ray inelastic scattering provides a means of exploiting X-ray free electron lasers, as a parallel to laser Raman spectroscopy

Letter. On the activation of [CrCl3{R-SN(H)S-R}] catalysts for selective trimerization of ethene: a freeze-quench Cr K-edge XAFS study

Homogeneous chromium catalysts for the selective conversion of ethene to hex-1-ene are formed from Cr(III) reagents, amino-thioether ligands of the type HN(CH2CH2SR)2, and aluminum reagents. In this study the early activation steps are investigated by EPR, UV-visible and Cr K-edge XAFS spectroscopy; rapid stopped-flow mixing and a freeze-quench allows good quality EXAFS analysis of a species formed in ~ 1 second of reaction. This is shown to involve reduction to Cr(II) and deprotonation of a NH group of the auxiliary ligand. This 4-coordinate metal-center may act as precursor for the coordination of ethene and subsequent selective oligomerization

Rapid-acting antidepressant drugs modulate affective bias in rats

How rapid-acting antidepressants (RAADs), such as ketamine, induce immediate and sustained improvements in mood in patients with major depressive disorder (MDD) is poorly understood. A core feature of MDD is the prevalence of cognitive processing biases associated with negative affective states, and the alleviation of negative affective biases may be an index of response to drug treatment. Here, we used an affective bias behavioral test in rats, based on an associative learning task, to investigate the effects of RAADs. To generate an affective bias, animals learned to associate two different digging substrates with a food reward in the presence or absence of an affective state manipulation. A choice between the two reward-associated digging substrates was used to quantify the affective bias generated. Acute treatment with the RAADs ketamine, scopolamine, or psilocybin selectively attenuated a negative affective bias in the affective bias test. Low, but not high, doses of ketamine and psilocybin reversed the valence of the negative affective bias 24 hours after RAAD treatment. Only treatment with psilocybin, but not ketamine or scopolamine, led to a positive affective bias that was dependent on new learning and memory formation. The relearning effects of ketamine were dependent on protein synthesis localized to the rat medial prefrontal cortex and could be modulated by cue reactivation, consistent with experience-dependent neural plasticity. These findings suggest a neuropsychological mechanism that may explain both the acute and sustained effects of RAADs, potentially linking their effects on neural plasticity with affective bias modulation in a rodent model

Investigating neuropsychological and reward-related deficits in a chronic corticosterone-induced model of depression

Chronic stress is a known risk factor for the development of major depression (MDD) and is commonly used to induce a depression-like phenotype in rodents. Similar phenotypic effects are also observed in rodents when treated chronically with the stress hormone corticosterone. In this study, we investigated the neuropsychological consequences of chronic corticosterone treatment in male rats using two translational rodent assays of affective bias, the judgement bias task (JBT) and affective bias test (ABT). We also used the reward learning assay (RLA) and sucrose preference test (SPT) to quantify reward-related behaviours. Negative biases in decision-making were observed in the chronic corticosterone-treated group but only when the treatment was given shortly before each behavioural session. The same dose of corticosterone, when given daily after completion of the behavioural session had no effects. Chronic corticosterone treatment did not potentiate negative affective biases in the ABT induced by either an acute pharmacological or stress manipulation but both reward learning and reward sensitivity were blunted. Analysis of the brain tissue from animals receiving chronic corticosterone found reduced hippocampal neurogenesis consistent with previous studies suggesting corticosterone-induced neurotrophic deficits. Taken together, these data suggest chronic corticosterone treatment induces neuropsychological effects related to changes in reward learning, memory and negative biases in decision making, but these decision-making biases depend on whether rewarding outcomes were experienced during the acute effects of the drug. These findings suggest an important interaction between psychological and biological factors resulting in negative biases in decision-making in this model

Activation of [CrCl3{PPh2N(iPr)PPh2}] for the selective oligomerisation of ethene: a Cr K-edge XAFS study

The activation of the ethene tetramerisation catalyst system based upon [CrCl3(THF)3] and N(iPr)(PPh2)2 has been investigated in situ via the reaction of [CrCl3{PPh2N(R)PPh2}(THF)] 1a (R=iPr) with excess AlMe3 in toluene. The Cr K-edge XAFS spectrum of the solution freeze quenched after 1 min reaction time indicated monomethylation of the metal with the resultant product being [CrClMe(ClAlCl3){PPh2N(R)PPh2}(THF)] 4a (R=iPr). After 5 minutes reaction time the XAFS spectra indicate that ~50% of 4a had been converted to a Cr(II) species, with the central core being high spin [CrCl2{PPh2N(R)PPh2}] 7a (R=iPr); a similar species, [CrClMe{PPh2N(R)PPh2}] 9a (R=iPr) was observed as its adduct with AlMe3 (10a) (R=iPr) when spectra were recorded on samples maintained a room temperature. Detailed analysis (EXAFS and XANES) indicated that 7a and 9a are stabilised by adduct formation of a Cr-Cl bond to the Lewis acids B(C6F5)3 and AlMe3, respectiveley. Modelling with DFT methods indicated that five-coordination was achieved, respectively by Cr-F (11a) and Cr-C (10a) interactions. In the presence of [Ph3C][Al{OC(tBuF)3}4], the Cr XAFS of the room temperature solution was inconsistent with the maintenance of a phosphine complex, but could be modelled with a site like [Cr2Me8]4- {Cr-Cr 2.01(2), Cr-C 2.14(4)}, thus demonstrating considerable variation in the effects of differing Lewis acids

Exogenous Ligand-Free Nickel-Catalyzed Carboxylate O-Arylation:Insight into Ni^I/Ni^III Cycles**

Nickel-catalyzed cross-coupling reactions have become a powerful methodology to construct C-heteroatom bonds. However, many protocols suffer from competitive off-cycle reaction pathways and require non-equimolar amounts of coupling partners to suppress them. Here, we report on mechanistic examination of carboxylate O-arylation under thermal conditions, in both the presence and absence of an exogeneous bipyridine-ligand. Furthermore, spectroscopic studies of the novel ligand-free carboxylate O-arylation reaction unveiled the resting state of the nickel catalyst, the crucial role of the alkylamine base and the formation of an off-cycle NiI−NiII dimer upon reduction. This study provides insights into the competition between productive catalysis and deleterious pathways (comproportionation and protodehalogenation) in the commonly proposed self-sustained NiI/NiIII catalytic cycle. Thereby we show that for productive nickel-catalyzed carboxylate O-arylation a choice must be made between either mild conditions or equimolar ratios of substrates

Cosmic microwave background anisotropy power spectrum statistics for high precision cosmology

As the era of high precision cosmology approaches, the empirically determined power spectrum of the microwave background anisotropy, $C_l$, will provide a crucial test for cosmological theories. We present a unified semi-analytic framework for the study of the statistical properties of the $C_l$ coefficients computed from the results of balloon, ground based, and satellite experiments. An illustrative application shows that commonly used approximations {\it bias} the estimation of the baryon parameter $\Omega_b$ at the 1% level even for a satellite capturing as much as $\sim 70$% of the sky.Comment: 4 pages, 3 figures. Also available at http://www.tac.dk/~wandelt/downloads.htm

Synthesis of bifunctional monomers by the palladium-catalyzed carbonylation of cardanol and its derivatives

The authors thank the Royal Society Leverhulme Africa Program for funding this project.A 1,2-bis(di-tert-butylphosphinomethyl)benzene-modified palladium catalyst has been used to synthesize bifunctional monomers of different chain lengths from cardanol. Short-chain derivatives of cardanol, such as (E)-3-(dodec-8-enyl)phenol; HOPhC12-ene, (E)-3-(undec-8-enyl)phenol; HOPhC11-ene, (E)-3-(dec-8-enyl)phenol; HOPhC10-ene, and 3-(non-8-enyl)phenol; HOPhC9-ene, were synthesized by the metathesis of cardanol with symmetrical internal alkenes. These derivatives were methoxycarbonylated to produce monomers with different chain lengths such as methyl-16-(3-hydroxyphenyl)hexadecanoate; HOPhC15COOMe, methyl-13-(3-hydroxyphenyl)tridecanoate; HOPhC12COOMe, methyl-12-(3-hydroxyphenyl)dodecanoate; HOPhC11COOMe, methyl-11-(3-hydroxyphenyl)undecanoate; HOPhC10COOMe, and methyl-10-(3-hydroxyphenyl)decanoate; HOPhC9COOMe, respectively. Polymerization of the synthesized monomers produced oligomers that consist of up to seven monomer units as confirmed by MALDI-TOF-MS. Lactone formation was also observed in some cases under polymerization conditions.PostprintPostprintPeer reviewe

Functional and structural studies of the vaccinia virus virulence factor N1 reveal a Bcl-2-like anti-apoptotic protein

Vaccinia virus (VACV) encodes many immunomodulatory proteins, including inhibitors of apoptosis and modulators of innate immune signalling. VACV protein N1 is an intracellular homodimer that contributes to virus virulence and was reported to inhibit nuclear factor (NF)-κB signalling. However, analysis of NF-κB signalling in cells infected with recombinant viruses with or without the N1L gene showed no difference in NF-κB-dependent gene expression. Given that N1 promotes virus virulence, other possible functions of N1 were investigated and this revealed that N1 is an inhibitor of apoptosis in cells transfected with the N1L gene and in the context of VACV infection. In support of this finding virally expressed N1 co-precipitated with endogenous pro-apoptotic Bcl-2 proteins Bid, Bad and Bax as well as with Bad and Bax expressed by transfection. In addition, the crystal structure of N1 was solved to 2.9 Å resolution (0.29 nm). Remarkably, although N1 shows no sequence similarity to cellular proteins, its three-dimensional structure closely resembles Bcl-xL and other members of the Bcl-2 protein family. The structure also reveals that N1 has a constitutively open surface groove similar to the grooves of other anti-apoptotic Bcl-2 proteins, which bind the BH3 motifs of pro-apoptotic Bcl-2 family members. Molecular modelling of BH3 peptides into the N1 surface groove, together with analysis of their physico-chemical properties, suggests a mechanism for the specificity of peptide recognition. This study illustrates the importance of the evolutionary conservation of structure, rather than sequence, in protein function and reveals a novel anti-apoptotic protein from orthopoxviruses