Origin of the thiopyrone CTP-431 “unexpectedly” isolated from the marine sponge Cacospongia mycofijiensis

An intriguing hypothesis that latrunculin A, a well-known natural product, might have undergone transformation into the unprecedented thiopyrone CTP-431 upon long-term storage in methanol is advanced. Thus opening of the hemiacetal of latrunculin A, followed by E1CB elimination, and dehydration would give a polyene that could undergo intramolecular Diels-Alder reaction, followed by methanolysis of the thiazolidinone ring and ring closure by intramolecular thiol addition to an enone. Experimental evidence that the novel thiazolidinone to thiopyrone rearrangement can occur is presented.The marine sponge Cacospongia mycofijiensis, found in the ocean surrounding Fiji, is a source of several polyketide natural products with interesting biological properties,1 including the tubulin binding macrolide fijianolide B (also known as laulimalide),2,3 the HIF1 signal inhibitor mycothiazole,4,5 and the macrolide latrunculins (Figure 1).6 The thiazolidinone-containing latruculins are of mixed polyketide synthesis (PKS) and non-ribosomal peptide synthesis (NRPS) origin, and latrunculin A 1 disrupts microfilament assembly to such an extent that it is the most widely used chemical tool to study actin binding

PI3K Enters Beta-Testing

Phosphoinositide-3-OH kinases (PI3K) are critical regulators of cell metabolism, growth, and survival. In a recent publication in Nature, Jia et al. (2008) identify specific functions of the p110β isoform of PI3K in glucose metabolism, cellular proliferation, and tumorigenesis

Galaxy redshift surveys selected by neutral hydrogen using FAST

We discuss the possibility of performing a substantial spectroscopic galaxy redshift survey selected via the 21cm emission from neutral hydrogen using the Five-hundred metre Aperture Spherical Telescope (FAST) to be built in China. We consider issues related to the estimation of the source counts and optimizations of the survey, and discuss the constraints on cosmological models that such a survey could provide. We find that a survey taking around two years could detect ~10^7 galaxies with an average redshift of ~0.15 making the survey complementary to those already carried out at optical wavelengths. These conservative estimates have used the z=0 HI mass function and have ignored the possibility of evolution. The results could be used to constrain Gamma = (Omega_m h) to 5 per cent and the spectral index, n_s, to 7 per cent independent of cosmic microwave background data. If we also use simulated power spectra from the Planck satellite, we can constrain w to be within 5 per cent of -1.Comment: 13 pages, 15 figures, Accepted by MNRAS, minor correction

Influence of dna repair on nonlinear dose-responses for mutation

Recent evidence has challenged the default assumption that all DNA-reactive alkylating agents exhibit a linear dose-response. Emerging evidence suggests that the model alkylating agents methyl- and ethylmethanesulfonate and methylnitrosourea (MNU) and ethylnitrosourea observe a nonlinear dose-response with a no observed genotoxic effect level (NOGEL). Follow-up mechanistic studies are essential to understand the mechanism of cellular tolerance and biological relevance of such NOGELs. MNU is one of the most mutagenic simple alkylators. Therefore, understanding the mechanism of mutation induction, following low-dose MNU treatment, sets precedence for weaker mutagenic alkylating agents. Here, we tested MNU at 10-fold lower concentrations than a previous study and report a NOGEL of 0.0075μg/ml (72.8nM) in human lymphoblastoid cells, quantified through the hypoxanthine (guanine) phosphoribosyltransferase assay (OECD 476). Mechanistic studies reveal that the NOGEL is dependent upon repair of O6-methylguanine (O6MeG) by the suicide enzyme O6MeG-DNA methyltransferase (MGMT). Inactivation of MGMT sensitizes cells to MNU-induced mutagenesis and shifts the NOGEL to the left on the dose axis. © The Author 2013. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved

A new fast-acting backup protection strategy for embedded MVDC links in future distribution networks

This paper presents a new fast-acting backup protection strategy for future hybrid ac-dc distribution networks. By examining the impedance measured by a distance protection relay measuring from the “ac-side” of the network, a unique characteristic is established for faults occurring on the “dc-side” of an embedded medium-voltage dc (MVDC) link, interconnecting two 33 kV distribution network sections. Based on the identified impedance characteristic, appropriate settings are developed and deployed on a verified software model of a commercially available distance protection relay. To remain stable for ac-side faults, it is found that the tripping logic of the device must be altered to provide correct time grading between standard, ac, protection zones and the fast-acting dc region, which can identify faults on the dc system within 40 ms. An additional confirmatory check is also employed to reduce the likelihood of mal-operation. Trials on a test system derived from an actual distribution network, which employs distance protection, are shown to provide stable operation for both ac-side and dc-side pole-pole and pole-pole-ground fault

Intramuscular fat in ambulant young adults with bilateral spastic cerebral palsy

BACKGROUND: It is known that individuals with bilateral spastic cerebral palsy (BSCP) have small and weak muscles. However, no studies to date have investigated intramuscular fat infiltration in this group. The objective of this study is to determine whether adults with BSCP have greater adiposity in and around their skeletal muscles than their typically developing (TD) peers as this may have significant functional and cardio-metabolic implications for this patient group. METHODS: 10 young adults with BSCP (7 male, mean age 22.5 years, Gross Motor Function Classification System (GMFCS) levels I-III), and 10 TD young adults (6 male, mean age 22.8 years) took part in this study. 11 cm sections of the left leg of all subjects were imaged using multi-echo gradient echo chemical shift imaging (mDixon). Percentage intermuscular fat (IMAT), intramuscular fat (IntraMF) and a subcutaneous fat to muscle volume ratio (SF/M) were calculated. RESULTS: IntraMF was higher with BSCP for all muscles (p = 0.001-0.013) and was significantly different between GMFCS levels (p < 0.001), with GMFCS level III having the highest IntraMF content. IMAT was also higher with BSCP p < 0.001). No significant difference was observed in SF/M between groups. CONCLUSION: Young adults with BSCP have increased intermuscular and intramuscular fat compared to their TD peers. The relationship between these findings and potential cardio-metabolic and functional sequelae are yet to be investigated

Progress in use of carbon-black-polymer composite vapor detector arrays for land mine detection

Thin films of carbon black-organic polymer composites have been deposited across two metallic leads, with swelling- induced resistance changes of the films signaling the presence of vapors. To identify and classify vapors, arrays of such vapor sensing elements have been constructed. Each element contained a different organic polymer as the insulating phase. The differing gas-solid partition coefficients for the various polymers of the detector array produced a pattern of resistance changes that was used to classify vapors and vapor mixtures. The performance of this system towards DNT, the predominant signature in the vapor phase above land miens, has been evaluated in detail, with robust detection demonstrated in the laboratory in less than 5 s in air at DNT levels in the low ppb range

Safety and physiological effects of two different doses of elosulfase alfa in patients with morquio a syndrome: A randomized, double-blind, pilot study.

The primary treatment outcomes of a phase 2, randomized, double-blind, pilot study evaluating safety, physiological, and pharmacological effects of elosulfase alfa in patients with Morquio A syndrome are herewith presented. Patients aged ≥7 years and able to walk ≥200 m in the 6-min walk test (6MWT) were randomized to elosulfase alfa 2.0 or 4.0 mg/kg/week for 27 weeks. The primary objective was to evaluate the safety of both doses. Secondary objectives were to evaluate effects on endurance (6MWT and 3-min stair climb test [3MSCT]), exercise capacity (cardio-pulmonary exercise test [CPET]), respiratory function, muscle strength, cardiac function, pain, and urine keratan sulfate (uKS) levels, and to determine pharmacokinetic parameters. Twenty-five patients were enrolled (15 randomized to 2.0 mg/kg/week and 10 to 4.0 mg/kg/week). No new or unexpected safety signals were observed. After 24 weeks, there were no improvements versus baseline in the 6MWT, yet numerical improvements were seen in the 3MSCT with 4.0 mg/kg/week. uKS and pharmacokinetic data suggested no linear relationship over the 2.0-4.0 mg/kg dose range. Overall, an abnormal exercise capacity (evaluated in 10 and 5 patients in the 2.0 and 4.0 mg/kg/week groups, respectively), impaired muscle strength, and considerable pain were observed at baseline, and there were trends towards improvements in all domains after treatment. In conclusion, preliminary data of this small study in a Morquio A population with relatively good endurance confirmed the acceptable safety profile of elosulfase alfa and showed a trend of increased exercise capacity and muscle strength and decreased pain