Isolation and characterization of the full-length cDNA encoding a member of a novel cytochrome p450 family (CYP320A1) from the tropical freshwater snail, Biomphalaria glabrata, intermediate host for Schistosoma mansoni

Cytochrome p450s (cyp450s) are a family of structurally related proteins, with diverse functions, including steroid synthesis and breakdown of toxins. This paper reports the full-length sequence of a novel cyp450 gene, the first to be isolated from the tropical freshwater snail Biomphalaria glabrata, an important intermediate host of Schistosoma mansoni. The nucleotide sequence is 2291 bp with a predicted amino acid sequence of 584aa. The sequence demonstrates conserved cyp450 structural motifs, but is sufficiently different from previously reported cyp450 sequences to be given a new classification, CYP320A1. Initially identified as down-regulated in partially resistant snails in response to S. mansoni infection, amplification of this gene using RT-PCR in both totally resistant or susceptible snail lines when exposed to infection, and all tissues examined, suggests ubiquitous expression. Characterization of the first cyp450 from B. glabrata is significant in understanding the evolution of these metabolically important proteins

Reading in two writing systems: Accommodation and assimilation of the brain's reading network

Bilingual reading can require more than knowing two languages. Learners must acquire also the writing conventions of their second language, which can differ in its deep mapping principles (writing system) and its visual configurations (script). We review ERP (event-related potential) and fMRI studies of both Chinese-English bilingualism and Chinese second language learning that bear on the system accommodation hypothesis: the neural networks acquired for one system must be modified to accommodate the demands of a new system. ERP bilingual studies demonstrate temporal indicators of the brain's experience with L1 and L2 and with the frequency of encounters of words in L2. ERP learning studies show that early visual processing differences between L1 and L2 diminish during a second term of study. fMRI studies of learning converge in finding that learners recruit bilateral occipital-temporal and also middle frontal areas when reading Chinese, similar to the pattern of native speakers and different from alphabetic reading. The evidence suggests an asymmetry: alphabetic readers have a neural network that accommodates the demands of Chinese by recruiting neural structures less needed for alphabetic reading. Chinese readers have a neural network that partly assimilates English into the Chinese system, especially in the visual stages of word identification. © Cambridge University Press 2007.published_or_final_versio

Noncommutative geometry and stochastic processes

The recent analysis on noncommutative geometry, showing quantization of the volume for the Riemannian manifold entering the geometry, can support a view of quantum mechanics as arising by a stochastic process on it. A class of stochastic processes can be devised, arising as fractional powers of an ordinary Wiener process, that reproduce in a proper way a stochastic process on a noncommutative geometry. These processes are characterized by producing complex values and so, the corresponding Fokker-Planck equation resembles the Schroedinger equation. Indeed, by a direct numerical check, one can recover the kernel of the Schroedinger equation starting by an ordinary Brownian motion. This class of stochastic processes needs a Clifford algebra to exist. In four dimensions, the full set of Dirac matrices is needed and the corresponding stochastic process in a noncommutative geometry is easily recovered as is the Dirac equation in the Klein-Gordon form being it the Fokker--Planck equation of the process.Comment: 16 pages, 2 figures. Updated a reference. A version of this paper will appear in the proceedings of GSI2017, Geometric Science of Information, November 7th to 9th, Paris (France

Copper signaling axis as a target for prostate cancer therapeutics.

Previously published reports indicate that serum copper levels are elevated in patients with prostate cancer and that increased copper uptake can be used as a means to image prostate tumors. It is unclear, however, to what extent copper is required for prostate cancer cell function as we observed only modest effects of chelation strategies on the growth of these cells in vitro. With the goal of exploiting prostate cancer cell proclivity for copper uptake, we developed a "conditional lethal" screen to identify compounds whose cytotoxic actions were manifested in a copper-dependent manner. Emerging from this screen was a series of dithiocarbamates, which, when complexed with copper, induced reactive oxygen species-dependent apoptosis of malignant, but not normal, prostate cells. One of the dithiocarbamates identified, disulfiram (DSF), is an FDA-approved drug that has previously yielded disappointing results in clinical trials in patients with recurrent prostate cancer. Similarly, in our studies, DSF alone had a minimal effect on the growth of prostate cancer tumors when propagated as xenografts. However, when DSF was coadministered with copper, a very dramatic inhibition of tumor growth in models of hormone-sensitive and of castrate-resistant disease was observed. Furthermore, we determined that prostate cancer cells express high levels of CTR1, the primary copper transporter, and additional chaperones that are required to maintain intracellular copper homeostasis. The expression levels of most of these proteins are increased further upon treatment of androgen receptor (AR)-positive prostate cancer cell lines with androgens. Not surprisingly, robust CTR1-dependent uptake of copper into prostate cancer cells was observed, an activity that was accentuated by activation of AR. Given these data linking AR to intracellular copper uptake, we believe that dithiocarbamate/copper complexes are likely to be effective for the treatment of patients with prostate cancer whose disease is resistant to classical androgen ablation therapies

Development of an invasively monitored porcine model of acetaminophen-induced acute liver failure

Background: The development of effective therapies for acute liver failure (ALF) is limited by our knowledge of the pathophysiology of this condition, and the lack of suitable large animal models of acetaminophen toxicity. Our aim was to develop a reproducible invasively-monitored porcine model of acetaminophen-induced ALF. Method: 35kg pigs were maintained under general anaesthesia and invasively monitored. Control pigs received a saline infusion, whereas ALF pigs received acetaminophen intravenously for 12 hours to maintain blood concentrations between 200-300 mg/l. Animals surviving 28 hours were euthanased. Results: Cytochrome p450 levels in phenobarbital pre-treated animals were significantly higher than non pre-treated animals (300 vs 100 pmol/mg protein). Control pigs (n=4) survived 28-hour anaesthesia without incident. Of nine pigs that received acetaminophen, four survived 20 hours and two survived 28 hours. Injured animals developed hypotension (mean arterial pressure; 40.8+/-5.9 vs 59+/-2.0 mmHg), increased cardiac output (7.26+/-1.86 vs 3.30+/-0.40 l/min) and decreased systemic vascular resistance (8.48+/-2.75 vs 16.2+/-1.76 mPa/s/m3). Dyspnoea developed as liver injury progressed and the increased pulmonary vascular resistance (636+/-95 vs 301+/-26.9 mPa/s/m3) observed may reflect the development of respiratory distress syndrome. Liver damage was confirmed by deterioration in pH (7.23+/-0.05 vs 7.45+/-0.02) and prothrombin time (36+/-2 vs 8.9+/-0.3 seconds) compared with controls. Factor V and VII levels were reduced to 9.3 and 15.5% of starting values in injured animals. A marked increase in serum AST (471.5+/-210 vs 42+/-8.14) coincided with a marked reduction in serum albumin (11.5+/-1.71 vs 25+/-1 g/dL) in injured animals. Animals displayed evidence of renal impairment; mean creatinine levels 280.2+/-36.5 vs 131.6+/-9.33 mumol/l. Liver histology revealed evidence of severe centrilobular necrosis with coagulative necrosis. Marked renal tubular necrosis was also seen. Methaemoglobin levels did not rise >5%. Intracranial hypertension was not seen (ICP monitoring), but there was biochemical evidence of encephalopathy by the reduction of Fischer's ratio from 5.6 +/- 1.1 to 0.45 +/- 0.06. Conclusion: We have developed a reproducible large animal model of acetaminophen-induced liver failure, which allows in-depth investigation of the pathophysiological basis of this condition. Furthermore, this represents an important large animal model for testing artificial liver support systems

Gut microbiota of Type 1 diabetes patients with good glycaemic control and high physical fitness is similar to people without diabetes: an observational study

Type 1 diabetes is the product of a complex interplay between genetic susceptibility and exposure to environmental factors. Existing bacterial profiling studies focus on people who are most at risk at the time of diagnosis; there are limited data on the gut microbiota of people with long-standing Type 1 diabetes. This study compared the gut microbiota of patients with Type 1 diabetes and good glycaemic control and high levels of physical-fitness with that of matched controls without diabetes.Ten males with Type 1 diabetes and ten matched controls without diabetes were recruited; groups were matched for gender, age, BMI, peak oxygen uptake (VO2max ), and exercise habits. Stool samples were analysed using next-generation sequencing of the 16S rRNA gene to obtain bacterial profiles from each individual. Phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt) was implemented to predict the functional content of the bacterial operational taxonomic units.Faecalibacterium sp., Roseburia sp. and Bacteroides sp. were typically the most abundant members of the community in both patients with Type 1 diabetes and controls, and were present in every sample in the cohort. Each bacterial profile was relatively individual and no significant difference was reported between the bacterial profiles or the Shannon diversity indices of Type 1 diabetes compared with controls. The functional profiles were more conserved and the Type 1 diabetes group were comparable with the control group.We show that both gut microbiota and resulting functional bacterial profiles from patients with long-standing Type 1 diabetes in good glycaemic control and high physical fitness levels are comparable with those of matched people without diabetes. This article is protected by copyright. All rights reserved

Rectified voltage induced by a microwave field in a confined two-dimensional electron gas with a mesoscopic static vortex

We investigate the effect of a microwave field on a confined two dimensional electron gas which contains an insulating region comparable to the Fermi wavelength. The insulating region causes the electron wave function to vanish in that region. We describe the insulating region as a static vortex. The vortex carries a flux which is determined by vanishing of the charge density of the electronic fluid due to the insulating region. The sign of the vorticity for a hole is opposite to the vorticity for adding additional electrons. The vorticity gives rise to non-commuting kinetic momenta. The two dimensional electron gas is described as fluid with a density which obeys the Fermi-Dirac statistics. The presence of the confinement potential gives rise to vanishing kinetic momenta in the vicinity of the classical turning points. As a result, the Cartesian coordinate do not commute and gives rise to a Hall current which in the presence of a modified Fermi-Surface caused by the microwave field results in a rectified voltage. Using a Bosonized formulation of the two dimensional gas in the presence of insulating regions allows us to compute the rectified current. The proposed theory may explain the experimental results recently reported by J. Zhang et al.Comment: 14 pages, 2 figure

Stellar Property Statistics of Massive Halos from Cosmological Hydrodynamics Simulations: Common Kernel Shapes

We study stellar property statistics, including satellite galaxy occupation, of massive halo populations realized by three cosmological hydrodynamics simulations: BAHAMAS + MACSIS, TNG300 of the IllustrisTNG suite, and Magneticum Pathfinder. The simulations incorporate independent sub-grid methods for astrophysical processes with spatial resolutions ranging from $1.5$ to $6$ kpc, and each generates samples of $1000$ or more halos with $M_{\rm halo}> 10^{13.5} M_{\odot}$ at redshift $z=0$. Applying localized, linear regression (LLR), we extract halo mass-conditioned statistics (normalizations, slopes, and intrinsic covariance) for a three-element stellar property vector consisting of: i) $N_{sat}$, the number of satellite galaxies with stellar mass, $M_{\star, \rm sat} > 10^{10} M_{\odot}$ within radius $R_{200c}$ of the halo; ii) $M_{\star,\rm tot}$, the total stellar mass within that radius, and; iii) $M_{\star,\rm BCG}$, the gravitationally-bound stellar mass of the central galaxy within a $100 \, \rm kpc$ radius. Scaling parameters for the three properties with halo mass show mild differences among the simulations, in part due to numerical resolution, but there is qualitative agreement on property correlations, with halos having smaller than average central galaxies tending to also have smaller total stellar mass and a larger number of satellite galaxies. Marginalizing over total halo mass, we find the satellite galaxy kernel, $p(\ln N_{sat}\,|\,M_{\rm halo},z)$ to be consistently skewed left, with skewness parameter $\gamma = -0.91 \pm 0.02$, while that of $\ln M_{\star,\rm tot}$ is closer to log-normal, in all three simulations. The highest resolution simulations find $\gamma \simeq -0.8$ for the $z=0$ shape of $p(\ln M_{\star,\rm BCG}\,|\,M_{\rm halo},z)$ and also that the fractional scatter in total stellar mass is below $10\%$ in halos more massive than $10^{14.3} M_{\odot}$

Evaluating the performance of tools used to call minority variants from whole genome short-read data.

Background: High-throughput whole genome sequencing facilitates investigation of minority virus sub-populations from virus positive samples. Minority variants are useful in understanding within and between host diversity, population dynamics and can potentially assist in elucidating person-person transmission pathways. Several minority variant callers have been developed to describe low frequency sub-populations from whole genome sequence data. These callers differ based on bioinformatics and statistical methods used to discriminate sequencing errors from low-frequency variants. Methods: We evaluated the diagnostic performance and concordance between published minority variant callers used in identifying minority variants from whole-genome sequence data from virus samples. We used the ART-Illumina read simulation tool to generate three artificial short-read datasets of varying coverage and error profiles from an RSV reference genome. The datasets were spiked with nucleotide variants at predetermined positions and frequencies. Variants were called using FreeBayes, LoFreq, Vardict, and VarScan2. The variant callers' agreement in identifying known variants was quantified using two measures; concordance accuracy and the inter-caller concordance. Results: The variant callers reported differences in identifying minority variants from the datasets. Concordance accuracy and inter-caller concordance were positively correlated with sample coverage. FreeBayes identified the majority of variants although it was characterised by variable sensitivity and precision in addition to a high false positive rate relative to the other minority variant callers and which varied with sample coverage. LoFreq was the most conservative caller. Conclusions: We conducted a performance and concordance evaluation of four minority variant calling tools used to identify and quantify low frequency variants. Inconsistency in the quality of sequenced samples impacts on sensitivity and accuracy of minority variant callers. Our study suggests that combining at least three tools when identifying minority variants is useful in filtering errors when calling low frequency variants