Pathos: a web facility that uses metabolic maps to display experimental changes in metabolites identified by mass spectrometry

This work describes a freely available web-based facility which can be used to analyse raw or processed mass spectrometric data from metabolomics experiments and display the metabolites identified – and changes in their experimental abundance – in the context of the metabolic pathways in which they occur. The facility, Pathos (http://motif.gla.ac.uk/Pathos/), employs Java servlets and is underpinned by a relational database populated from the Kyoto Encyclopaedia of Genes and Genomes (KEGG). Input files can contain either raw m/z values from experiments conducted in different modes, or KEGG or MetaCyc IDs assigned by the user on the basis of the m/z values and other criteria. The textual output lists the KEGG pathways on an XHTML page according to the number of metabolites or potential metabolites that they contain. Filtering by organism is also available. For metabolic pathways of interest, the user is able to retrieve a pathway map with identified metabolites highlighted. A particular feature of Pathos is its ability to process relative quantification data for metabolites identified under different experimental conditions, and to present this in an easily comprehensible manner. Results are colour-coded according to the degree of experimental change, and bar charts of the results can be generated interactively from either the text listings or the pathway maps. The visual presentation of the output from Pathos is designed to allow the rapid identification of metabolic areas of potential interest, after which particular results may be examined in detail

Kant and Tetens on Transcendental Philosophy

This dissertation examines the significance of Johann Nikolas Tetens, a German empiricist philosopher working in the 1770\u27s, to the theoretical philosophy of Immanuel Kant. I begin by examining Tetens\u27 discussion of philosophical methodology in his 1775 essay \textit{Über die allgemeine speculativische Philosophie}. I make the case that Tetens\u27 criticism of the methodology of the Scottish common sense philosophers and his subsequent attempt to incorporate what he takes to be their valuable insights into the approach of the broadly Wolffian philosophical tradition provides important context for interpreting Kant\u27s methodology in the \textit{Critique of Pure Reason}. I then examine two different cases of Tetens\u27 applying this methodology in his 1777 text \textit{Philosophische Versuche über die menschliche Natur und ihre Entwickelung}. I argue that Tetens\u27 discussion and critique of Humean causation in the fourth essay of the \textit{Philosophische Versuche} heavily influenced Kant\u27s understanding of ``Hume\u27s Problem\u27\u27 and that many of the more obscure issues about the Kant-Hume relationship can be greatly clarified by giving sufficient attention to Tetens. I then examine Tetens\u27 engagement with Thomas Reid\u27s account of perception. I argue that Tetens\u27 attempt to develop a representationalist account of perception which withstands Reid\u27s objections leads him toward the view that representation requires object concepts and the problem of accounting for the origin of these concepts pushes Tetens to articulate an account of synthesis. In the final chapter, I examine Kant\u27s proof that the real of appearances has intensive magnitude in the Anticipations of Perception. I raise several difficulties for the interpretation of the proof and then argue that Tetens\u27 discussion of perception can provide us with the context for such a proof and the nature of the ``correspondence\u27\u27 between sensation and objects

Influence of a Brane Tension on Phantom and Massive Scalar Field Emission

We elaborate the signature of the extra dimensions and brane tension in the process of phantom and massive scalar emission in the spacetime of (4+n)-dimensional tense brane black hole. Absorption cross section, luminosity of Hawking radiation and cross section in the low-energy approximation were found. We envisage that parameter connected with the existence of a brane imprints its role in the Hawking radiation of the considered fields.Comment: 7 pages, * figures, RevTex, to be published in General Relativity and Gravitatio

Black hole solutions in the warped DGP braneworld

We study the static, analytical solution of black holes in the warped DGP braneworld scenario. We show that the linearized field equations and matching conditions lead to solutions that are not compatible with Schwarzschild-(A)dS$_{(4)}$ solutions on the brane. This incompatibility is similar to vDVZ discontinuity in massive gravity theory. Following the standard procedure to remove this discontinuity, which firstly was proposed by Vainshtein, we keep some appropriate nonlinear terms in the field equations. This strategy has its origin in the fact that the spatial extrinsic curvature of the brane plays a crucial role in the nonlinear nature of the solutions and also in recovering the well-measured predictions of General Relativity (GR) at small scales. Using this feature, we obtained an interesting black string solution in the bulk when it is compatible with 4D GR solutions on the brane.Comment: 15 pages, no figure

BCKDH: the missing link in apicomplexan mitochondrial metabolism is required for full virulence of Toxoplasma gondii and Plasmodium berghei

While the apicomplexan parasites Plasmodium falciparum and Toxoplasma gondii are thought to primarily depend on glycolysis for ATP synthesis, recent studies have shown that they can fully catabolize glucose in a canonical TCA cycle. However, these parasites lack a mitochondrial isoform of pyruvate dehydrogenase and the identity of the enzyme that catalyses the conversion of pyruvate to acetyl-CoA remains enigmatic. Here we demonstrate that the mitochondrial branched chain ketoacid dehydrogenase (BCKDH) complex is the missing link, functionally replacing mitochondrial PDH in both T. gondii and P. berghei. Deletion of the E1a subunit of T. gondii and P. berghei BCKDH significantly impacted on intracellular growth and virulence of both parasites. Interestingly, disruption of the P. berghei E1a restricted parasite development to reticulocytes only and completely prevented maturation of oocysts during mosquito transmission. Overall this study highlights the importance of the molecular adaptation of BCKDH in this important class of pathogens

Emergent Universe in Brane World Scenario with Schwarzschild-de Sitter Bulk

A model of an emergent universe is obtained in brane world. Here the bulk energy is in the form of cosmological constant, while the brane consists of a fluid satisfying an equation of state of the form $p_{b}={1/3} \rho_{b}$, which is effectively a radiation equation of state at high energies. It is shown that with the positive bulk cosmological constant, one of our models represents an emergent universe.Comment: 4 pages, no figure, accepted for publication in Gen.Relt.Gra

Benznidazole biotransformation and multiple targets in <i>Trypanosoma</i> cruzi revealed by metabolomics

&lt;b&gt;Background&lt;/b&gt;&lt;p&gt;&lt;/p&gt; The first line treatment for Chagas disease, a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi, involves administration of benznidazole (Bzn). Bzn is a 2-nitroimidazole pro-drug which requires nitroreduction to become active, although its mode of action is not fully understood. In the present work we used a non-targeted MS-based metabolomics approach to study the metabolic response of T. cruzi to Bzn.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Methodology/Principal findings&lt;/b&gt;&lt;p&gt;&lt;/p&gt; Parasites treated with Bzn were minimally altered compared to untreated trypanosomes, although the redox active thiols trypanothione, homotrypanothione and cysteine were significantly diminished in abundance post-treatment. In addition, multiple Bzn-derived metabolites were detected after treatment. These metabolites included reduction products, fragments and covalent adducts of reduced Bzn linked to each of the major low molecular weight thiols: trypanothione, glutathione, γ-glutamylcysteine, glutathionylspermidine, cysteine and ovothiol A. Bzn products known to be generated in vitro by the unusual trypanosomal nitroreductase, TcNTRI, were found within the parasites, but low molecular weight adducts of glyoxal, a proposed toxic end-product of NTRI Bzn metabolism, were not detected.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Conclusions/significance&lt;/b&gt;&lt;p&gt;&lt;/p&gt; Our data is indicative of a major role of the thiol binding capacity of Bzn reduction products in the mechanism of Bzn toxicity against T. cruzi

Scaling-up co-trimoxazole prophylaxis in HIV-exposed and HIV-infected children in high HIV-prevalence countries.

Co-trimoxazole (trimethoprim-sulfamethoxazole) is a widely available antibiotic that substantially reduces HIV-related morbidity and mortality in both adults and children. Prophylaxis with co-trimoxazole is a recommended intervention of proven benefit that could serve not only as an initial step towards improving paediatric care in young children with limited access to antiretroviral treatment, but also as an important complement to antiretroviral therapy in resource-limited settings. Despite co-trimoxazole's known clinical benefits, the potential operational benefits, and favourable recommendations by WHO, UNAIDS, and UNICEF, its routine use in developing countries--particularly sub-Saharan Africa--has remained limited. Out of an estimated 4 million children in need of co-trimoxazole prophylaxis (HIV-exposed and HIV-infected), only 4% are currently receiving this intervention. We discuss some of the major barriers preventing the scale-up of co-trimoxazole prophylaxis for children in countries with a high prevalence of HIV and propose specific actions required to tackle these challenges

Hawking emission from quantum gravity black holes

We address the issue of modelling quantum gravity effects in the evaporation of higher dimensional black holes in order to go beyond the usual semi-classical approximation. After reviewing the existing six families of quantum gravity corrected black hole geometries, we focus our work on non-commutative geometry inspired black holes, which encode model independent characteristics, are unaffected by the quantum back reaction and have an analytical form compact enough for numerical simulations. We consider the higher dimensional, spherically symmetric case and we proceed with a complete analysis of the brane/bulk emission for scalar fields. The key feature which makes the evaporation of non-commutative black holes so peculiar is the possibility of having a maximum temperature. Contrary to what happens with classical Schwarzschild black holes, the emission is dominated by low frequency field modes on the brane. This is a distinctive and potentially testable signature which might disclose further features about the nature of quantum gravity.Comment: 36 pages, 18 figures, v2: updated reference list, minor corrections, version matching that published on JHE

Time-symmetric initial data of large brane-localized black hole in RS-II model

In the aim of shedding a new light on the classical black hole evaporation conjecture stating that a static brane-localized black hole (BH) larger than the bulk curvature scale does not exist in Randall-Sundrum II (RS-II) model, we investigate time-symmetric initial data with a brane-localized apparent horizon (AH) and analyzed its properties. We find that a three-parameter family of such initial data can be constructed by simply placing a brane on a constant time surface of Schwarzschild anti-de Sitter space. By this method, we unambiguously confirm that initial data with an arbitrarily large AH area do exist. We compare the ADM mass and the horizon area of our initial data with that of the black string (BS) solution, and find that any initial data constructed by this method do not have a smaller mass than the BS solution when the horizon area is larger than the size determined by the bulk curvature scale. We further investigate what kind of configuration realizes the minimum mass for the same AH area. The configuration that realizes the smallest mass turns out to be the one close to the BS truncated by a cap. We also demonstrate that the same method applies to construct initial data in (3+1)-dimensional RS-II brane world. In this case an exact solution of a brane-localized BH exists but BS solution does not. Nevertheless, the behavior of the initial data is quite similar in both cases. We find that the known exact solution always has a smaller mass than our initial data with the same horizon area. This result enforces the standard belief that the exact BH solution is the most stable black object in the four-dimensional RS-II model. These results are all consistent with the classical BH evaporation conjecture, but unfortunately it turns out that they do not provide a strong support of it.Comment: 14 pages, 9 figures. Typo correcte