Solid-state photoreactivity of 9-substituted acridizinium bromide salts

A series of substituted acridizinium bromides was studied to determine how substituents affect the regioselectivity of the solid-state [4 + 4] photodimerisation.This is the final version. It was first published by RSC at http://pubs.rsc.org/en/Content/ArticleLanding/2014/CE/C4CE01622J#!divAbstrac

Mechanochemical reactivity inhibited, prohibited and reversed by liquid additives: examples from crystal-form screens

We demonstrate that liquid additives can exert inhibitive or prohibitive effects on the mechanochemical formation of multi-component molecular crystals, and report that certain additives unexpectedly prompt the dismantling of such solids into physical mixtures of their constituents. Computational methods were employed in an attempt to identify possible reasons for these previously unrecognised effects of liquid additives on mechanochemical transformations

On the predictability of supramolecular interactions in molecular cocrystals-the view from the bench

A series of cocrystals involving theophylline and fluorobenzoic acids highlights the difficulty of predicting supramolecular interactions in molecular crystals.MKC and DKB gratefully acknowledge financial support from the UCL Faculty of Mathematical and Physical Sciences. DKB and WJ thank the Royal Society for a Newton International Fellowship and the Isaac Newton Trust (Trinity College, University of Cambridge) for funding. MA thanks the EPSRC for a studentship, while SAS acknowledges funding through the EPSRC CASE scheme with Pfizer. We are grateful for computational support from the UK national high performance computing service, ARCHER, for which access was obtained via the UKCP consortium and funded by EPSRC grant (EP/K013564/1).This is the final version of the article. It first appeared from the Royal Society of Chemistry via https://doi.org//10.1039/C6CE00293

c-Fos Expression in the Nucleus of the Solitary Tract in Response to Salt Stimulation in Rats

Salt signals in tongue are relayed to the nucleus of the solitary tract (NST). This signaling is very important to determine whether to swallow salt-related nutrition or not and suggests some implications in discrimination of salt concentration. Salt concentration-dependent electrical responses in the chorda tympani and the NST were well reported. But salt concentration-dependency and spatial distribution of c-Fos in the NST were not well established. In the present study, NaCl signaling in the NST was studied in urethane-anesthetized rats. The c-Fos immunoreactivity in the six different NST areas along the rostral-caudal axis and six subregions in each of bilateral NST were compared between applications of distilled water and different concentrations of NaCl to the tongue of experimental animals. From this study, salt stimulation with high concentration (1.0 M NaCl) induced significantly higher c-Fos expression in intermediate NST and dorsal-medial and dorsal-middle subregions of the NST compared to distilled water stimulation. The result represents the specific spatial distribution of salt taste perception in the NST

Aptamer-based multiplexed proteomic technology for biomarker discovery

Interrogation of the human proteome in a highly multiplexed and efficient manner remains a coveted and challenging goal in biology. We present a new aptamer-based proteomic technology for biomarker discovery capable of simultaneously measuring thousands of proteins from small sample volumes (15 [mu]L of serum or plasma). Our current assay allows us to measure ~800 proteins with very low limits of detection (1 pM average), 7 logs of overall dynamic range, and 5% average coefficient of variation. This technology is enabled by a new generation of aptamers that contain chemically modified nucleotides, which greatly expand the physicochemical diversity of the large randomized nucleic acid libraries from which the aptamers are selected. Proteins in complex matrices such as plasma are measured with a process that transforms a signature of protein concentrations into a corresponding DNA aptamer concentration signature, which is then quantified with a DNA microarray. In essence, our assay takes advantage of the dual nature of aptamers as both folded binding entities with defined shapes and unique sequences recognizable by specific hybridization probes. To demonstrate the utility of our proteomics biomarker discovery technology, we applied it to a clinical study of chronic kidney disease (CKD). We identified two well known CKD biomarkers as well as an additional 58 potential CKD biomarkers. These results demonstrate the potential utility of our technology to discover unique protein signatures characteristic of various disease states. More generally, we describe a versatile and powerful tool that allows large-scale comparison of proteome profiles among discrete populations. This unbiased and highly multiplexed search engine will enable the discovery of novel biomarkers in a manner that is unencumbered by our incomplete knowledge of biology, thereby helping to advance the next generation of evidence-based medicine

Physical Links: Defining and detecting inter-chain entanglement

Fluctuating filaments, from densely-packed biopolymers to defect lines in structured fluids, are prone to become interlaced and form intricate architectures. Understanding the ensuing mechanical and relaxation properties depends critically on being able to capture such entanglement in quantitative terms. So far, this has been an elusive challenge. Here we introduce the first general characterization of non-ephemeral forms of entanglement in linear curves by introducing novel descriptors that extend topological measures of linking from close to open curves. We thus establish the concept of physical links. This general method is applied to diverse contexts: equilibrated ring polymers, mechanically-stretched links and concentrated solutions of linear chains. The abundance, complexity and space distribution of their physical links gives access to a whole new layer of understanding of such systems and open new perspectives for others, such as reconnection events and topological simplification in dissipative fields and defect lines

Does reductive metabolism predict response to tirapazamine (SR 4233) in human non-small-cell lung cancer cell lines?

The bioreductive drug tirapazamine (TPZ, SR 4233, WIN 59075) is a lead compound in a series of potent cytotoxins that selectively kill hypoxic rodent and human solid tumour cells in vitro and in vivo. Phases II and III trials have demonstrated its efficacy in combination with both fractionated radiotherapy and some chemotherapy. We have evaluated the generality of an enzyme-directed approach to TPZ toxicity by examining the importance of the one-electron reducing enzyme NADPH:cytochrome P450 reductase (P450R) in the metabolism and toxicity of this lead prodrug in a panel of seven human non-small-cell lung cancer cell lines. We relate our findings on TPZ sensitivity in these lung lines with our previously published results on TPZ sensitivity in six human breast cancer cell lines (Patterson et al (1995) Br J Cancer 72: 1144–1150) and with the sensitivity of all these cell types to eight unrelated cancer chemotherapeutic agents with diverse modes of action. Our results demonstrate that P450R plays a significant role in the activation of TPZ in this panel of lung lines, which is consistent with previous observations in a panel of breast cancer cell lines (Patterson et al (1995) Br J Cancer 72: 1144–1150; Patterson et al (1997) Br J Cancer 76: 1338–1347). However, in the lung lines it is likely that it is the inherent ability of these cells to respond to multiple forms of DNA damage, including that arising from P450R-dependent TPZ metabolism, that underlies the ultimate expression of toxicity. © 1999 Cancer Research Campaig

Efficacy of movement control exercises versus general exercises on recurrent sub-acute nonspecific low back pain in a sub-group of patients with movement control dysfunction. protocol of a randomized controlled trial

Background: Practice guidelines recommend various types of exercise for chronic back pain but there have been few head-to-head comparisons of these interventions. General exercise seems to be an effective option for management of chronic low back pain (LBP) but very little is known about the management of a sub-acute LBP within sub-groups. Recent research has developed clinical tests to identify a subgroup of patients with chronic non-specific LBP who have movement control dysfunction (MD). Method/Design: We are conducting a randomized controlled trial (RCT) to compare the effects of general exercise and specific movement control exercise (SMCE) on disability and function in patients with MD within recurrent sub-acute LBP. The main outcome measure is the Roland Morris Disability Questionnaire. Discussion: European clinical guideline for management of chronic LBP recommends that more research is required to develop tools to improve the classification and identification of specific clinical sub-groups of chronic LBP patients. Good quality RCTs are then needed to determine the effectiveness of specific interventions aimed at these specific target groups. This RCT aims to test the hypothesis whether patients within a sub-group of MD benefit more through a specific individually tailored movement control exercise program than through general exercises

Molecular Composition of Staufen2-Containing Ribonucleoproteins in Embryonic Rat Brain

Messenger ribonucleoprotein particles (mRNPs) are used to transport mRNAs along neuronal dendrites to their site of translation. Numerous mRNA-binding and regulatory proteins within mRNPs finely regulate the fate of bound-mRNAs. Their specific combination defines different types of mRNPs that in turn are related to specific synaptic functions. One of these mRNA-binding proteins, Staufen2 (Stau2), was shown to transport dendritic mRNAs along microtubules. Its knockdown expression in neurons was shown to change spine morphology and synaptic functions. To further understand the molecular mechanisms by which Stau2 modulates synaptic function in neurons, it is important to identify and characterize protein co-factors that regulate the fate of Stau2-containing mRNPs. To this end, a proteomic approach was used to identify co-immunoprecipitated proteins in Staufen2-containing mRNPs isolated from embryonic rat brains. The proteomic approach identified mRNA-binding proteins (PABPC1, hnRNP H1, YB1 and hsc70), proteins of the cytoskeleton (α- and β-tubulin) and RUFY3 a poorly characterized protein. While PABPC1 and YB1 associate with Stau2-containing mRNPs through RNAs, hsc70 is directly bound to Stau2 and this interaction is regulated by ATP. PABPC1 and YB1 proteins formed puncta in dendrites of embryonic rat hippocampal neurons. However, they poorly co-localized with Stau2 in the large dendritic complexes suggesting that they are rather components of Stau2-containing mRNA particles. All together, these results represent a further step in the characterization of Stau2-containing mRNPs in neurons and provide new tools to study and understand how Stau2-containing mRNPs are transported, translationally silenced during transport and/or locally expressed according to cell needs