Gravity Amplitudes from a Gaussian Matrix Model

We reformulate MHV scattering amplitudes in 4D gauge theory and supergravity as correlation functions of bilinear operators in a supersymmetric gaussian matrix model. The model retains the symmetries of an S(4) of radius L and the matrix variables are represented as linear operators acting on a finite-dimensional Hilbert space. Bilinear fields of the model generate a current algebra. In the large N double scaling limit where l_pl ~ L / sqrt(N) is held fixed, there is an emergent flat 4D space-time with a built in short distance cutoff.Comment: v3: 55 pages, 4 figures, clarifications adde

Field template-based design and biological evaluation of new sphingosine kinase 1 inhibitors

Purpose: Sphingosine kinase 1 (SK1) is a protooncogenic enzyme expressed in many human tumours and is associated with chemoresistance and poor prognosis. It is a potent therapy target and its inhibition chemosensitises solid tumours. Despite recent advances in SK1 inhibitors synthesis and validation, their clinical safety and chemosensitising options are not well described. In this study, we have designed, synthesised and tested a new specific SK1 inhibitor with a low toxicity profile. Methods: Field template molecular modelling was used for compound design. Lead compounds were tested in cell and mouse cancer models. Results: Field template analysis of three known SK1 inhibitors, SKI-178, 12aa and SK1-I, was performed and compound screening identified six potential new SK1 inhibitors. SK1 activity assays in both cell-free and in vitro settings showed that two compounds were effective SK1 inhibitors. Compound SK-F has potently decreased cancer cell viability in vitro and sensitised mouse breast tumours to docetaxel (DTX) in vivo, without significant whole-body toxicity. Conclusion: Through field template screening, we have identified a new SK1 inhibitor, SK-F, which demonstrated antitumour activity in vitro and in vivo without overt toxicity when combined with DTX

The influence of alkalosis on repeated high-intensity exercise performance and acid–base balance recovery in acute moderate hypoxic conditions

Purpose Exacerbated hydrogen cation (H⁺) production is suggested to be a key determinant of fatigue in acute hypoxic conditions. This study, therefore, investigated the effects of NaHCO3 ingestion on repeated 4 km TT cycling performance and post-exercise acid–base balance recovery in acute moderate hypoxic conditions. Methods Ten male trained cyclists completed four repeats of 2 × 4 km cycling time trials (TT1 and TT2) with 40 min passive recovery, each on different days. Each TT series was preceded by supplementation of one of the 0.2 g kg⁻¹ BM NaHCO3 (SBC2), 0.3 g kg⁻¹ BM NaHCO3 (SBC3), or a taste-matched placebo (0.07 g kg⁻¹ BM sodium chloride; PLA), administered in a randomized order. Supplements were administered at a pre-determined individual time to peak capillary blood bicarbonate concentration ([HCO3⁻]). Each TT series was also completed in a normobaric hypoxic chamber set at 14.5% FiO2 (~ 3000 m). Results Performance was improved following SBC3 in both TT1 (400.2 ± 24.1 vs. 405.9 ± 26.0 s; p = 0.03) and TT2 (407.2 ± 29.2 vs. 413.2 ± 30.8 s; p = 0.01) compared to PLA, displaying a very likely benefit in each bout. Compared to SBC2, a likely and possible benefit was also observed following SBC3 in TT1 (402.3 ± 26.5 s; p = 0.15) and TT2 (410.3 ± 30.8 s; p = 0.44), respectively. One participant displayed an ergolytic effect following SBC3, likely because of severe gastrointestinal discomfort, as SBC2 still provided ergogenic effects. Conclusion NaHCO3 ingestion improves repeated exercise performance in acute hypoxic conditions, although the optimal dose is likely to be 0.3 g kg⁻¹ BM

Direct observations of the effect of fine sediment deposition on the vertical movement of Gammarus pulex (Amphipoda: Gammaridae) during substratum drying

Benthic macroinvertebrates inhabit the streambed sediments of temporary streams during drying events. Fine sediment (< 2 mm in diameter) deposition and clogging of interstitial pathways reduces the connectivity between benthic and subsurface habitats, potentially inhibiting macroinvertebrate vertical movements. Direct observations within subsurface sediments are, however, inherently difficult. As a result, confirmation of macroinvertebrate vertical movement, and the effect of fine sediment, is limited. We used laboratory mesocosms containing transparent gravel sized particles (10–15 mm) to facilitate the direct observation and tracking of vertical movements by Gammarus pulex in response to water level reduction and sedimentation. Seven sediment treatments comprised two fine sediment fractions (small: 0.125–0.5 mm, coarse sand: 0.5–1 mm) deposited onto the surface of the substrate, and a control treatment where no fine sediment was applied. We found that G. pulex moved into the subsurface gravel sediments in response to drying, but their ability to remain submerged during water level reduction was impeded by fine sediment deposition. In particular deposition of the coarser sand fraction clogged the sediment surface, limiting vertical movements. Our results highlight the potential effect of sedimentation on G. pulex resistance to drying events in streams

Genetic Evidence for Involvement of Neuronally Expressed S1P1 Receptor in Nociceptor Sensitization and Inflammatory Pain

Sphingosine-1-phosphate (S1P) is a key regulator of immune response. Immune cells, epithelia and blood cells generate high levels of S1P in inflamed tissue. However, it is not known if S1P acts on the endings of nociceptive neurons, thereby contributing to the generation of inflammatory pain. We found that the S1P1 receptor for S1P is expressed in subpopulations of sensory neurons including nociceptors. Both S1P and agonists at the S1P1 receptor induced hypersensitivity to noxious thermal stimulation in vitro and in vivo. S1P-induced hypersensitivity was strongly attenuated in mice lacking TRPV1 channels. S1P and inflammation-induced hypersensitivity was significantly reduced in mice with a conditional nociceptor-specific deletion of the S1P1 receptor. Our data show that neuronally expressed S1P1 receptors play a significant role in regulating nociceptor function and that S1P/S1P1 signaling may be a key player in the onset of thermal hypersensitivity and hyperalgesia associated with inflammation

Genome Wide Analysis of Acute Myeloid Leukemia Reveal Leukemia Specific Methylome and Subtype Specific Hypomethylation of Repeats

Methylated DNA immunoprecipitation followed by high-throughput sequencing (MeDIP-seq) has the potential to identify changes in DNA methylation important in cancer development. In order to understand the role of epigenetic modulation in the development of acute myeloid leukemia (AML) we have applied MeDIP-seq to the DNA of 12 AML patients and 4 normal bone marrows. This analysis revealed leukemia-associated differentially methylated regions that included gene promoters, gene bodies, CpG islands and CpG island shores. Two genes (SPHKAP and DPP6) with significantly methylated promoters were of interest and further analysis of their expression showed them to be repressed in AML. We also demonstrated considerable cytogenetic subtype specificity in the methylomes affecting different genomic features. Significantly distinct patterns of hypomethylation of certain interspersed repeat elements were associated with cytogenetic subtypes. The methylation patterns of members of the SINE family tightly clustered all leukemic patients with an enrichment of Alu repeats with a high CpG density (P<0.0001). We were able to demonstrate significant inverse correlation between intragenic interspersed repeat sequence methylation and gene expression with SINEs showing the strongest inverse correlation (R2 = 0.7). We conclude that the alterations in DNA methylation that accompany the development of AML affect not only the promoters, but also the non-promoter genomic features, with significant demethylation of certain interspersed repeat DNA elements being associated with AML cytogenetic subtypes. MeDIP-seq data were validated using bisulfite pyrosequencing and the Infinium array

Disruption of Higher Order DNA Structures in Friedreich's Ataxia (GAA)n Repeats by PNA or LNA Targeting

Expansion of (GAA)n repeats in the first intron of the Frataxin gene is associated with reduced mRNA and protein levels and the development of Friedreich’s ataxia. (GAA)n expansions form non-canonical structures, including intramolecular triplex (H-DNA), and R-loops and are associated with epigenetic modifications. With the aim of interfering with higher order H-DNA (like) DNA structures within pathological (GAA)n expansions, we examined sequence-specific interaction of peptide nucleic acid (PNA) with (GAA)n repeats of different lengths (short: n=9, medium: n=75 or long: n=115) by chemical probing of triple helical and single stranded regions. We found that a triplex structure (H-DNA) forms at GAA repeats of different lengths; however, single stranded regions were not detected within the medium size pathological repeat, suggesting the presence of a more complex structure. Furthermore, (GAA)4-PNA binding of the repeat abolished all detectable triplex DNA structures, whereas (CTT)5-PNA did not. We present evidence that (GAA)4-PNA can invade the DNA at the repeat region by binding the DNA CTT strand, thereby preventing non-canonical-DNA formation, and that triplex invasion complexes by (CTT)5-PNA form at the GAA repeats. Locked nucleic acid (LNA) oligonucleotides also inhibited triplex formation at GAA repeat expansions, and atomic force microscopy analysis showed significant relaxation of plasmid morphology in the presence of GAA-LNA. Thus, by inhibiting disease related higher order DNA structures in the Frataxin gene, such PNA and LNA oligomers may have potential for discovery of drugs aiming at recovering Frataxin expression

Aberrant expression of the S1P regulating enzymes, SPHK1 and SGPL1, contributes to a migratory phenotype in OSCC mediated through S1PR2.

Oral squamous cell carcinoma (OSCC) is a lethal disease with a 5-year mortality rate of around 50%. Molecular targeted therapies are not in routine use and novel therapeutic targets are required. Our previous microarray data indicated sphingosine 1-phosphate (S1P) metabolism and signalling was deregulated in OSCC. In this study, we have investigated the contribution of S1P signalling to the pathogenesis of OSCC. We show that the expression of the two major enzymes that regulate S1P levels were altered in OSCC: SPHK1 was significantly upregulated in OSCC tissues compared to normal oral mucosa and low levels of SGPL1 mRNA correlated with a worse overall survival. In in vitro studies, S1P enhanced the migration/invasion of OSCC cells and attenuated cisplatin-induced death. We also demonstrate that S1P receptor expression is deregulated in primary OSCCs and that S1PR2 is over-expressed in a subset of tumours, which in part mediates S1P-induced migration of OSCC cells. Lastly, we demonstrate that FTY720 induced significantly more apoptosis in OSCC cells compared to non-malignant cells and that FTY720 acted synergistically with cisplatin to induce cell death. Taken together, our data show that S1P signalling promotes tumour aggressiveness in OSCC and identify S1P signalling as a potential therapeutic target.This article is freely available via Open Access. Click on the 'Additional Link' above to access the full-text via the publisher's site.Published (Open Access