Asymptotic behaviour of the density in a parabolic SPDE

Consider the density of the solution $X(t,x)$ of a stochastic heat equation with small noise at a fixed $t\in [0,T]$, $x \in [0,1]$.In the paper we study the asymptotics of this density as the noise is vanishing. A kind of Taylor expansion in powers of the noiseparameter is obtained. The coefficients and the residue of the expansion are explicitly calculated.In order to obtain this result some type of exponential estimates of tail probabilities of the difference between the approximatingprocess and the limit one is proved. Also a suitable local integration by parts formula is developped.

Computational toolbox towards evolutionary domain mapping of membrane proteins

Membrane proteins account for about 20% to 30% of all proteins encoded in a typical genome. They play central roles in multiple cellular processes mediating the interaction of the cell with its surrounding. Over 60% of all drug targets contain a membrane domain. The experimental difficulties of obtaining a crystal structural severely limits our ability or understanding of membrane protein function. Computational evolutionary studies of proteins are crucial for the prediction of 3D structures. In this project, we construct a tool able to quantify the evolutionary positive selective pressure on each residue of membrane proteins through maximum likelihood phylogeny reconstruction. The conservation plot combined with a structural homology model is also a potent tool to predict those residues that have essentials roles in the structure and function of a membrane protein and can be very useful in the design of validation experiments.

Brideshead Revisited (1945) by Evelyn Waugh (1903-1966): the benefit of an Arcadian experience in confronting the human tragedy

As the frontispiece of Book One of Evelyn Waugh’s Brideshead Revisited, the phrase ‘Et in Arcadia ego’ announces the author’s intention of making the classical Arcadian theme a key reference in a text that speaks of nostalgia for a joyful past in times marked by sadness and pain. However, an interpretation may be approached from several directions even within the classical tradition. Thus, without ignoring philological or artistic aspects of the topic, this article focuses on a close study of the author’s most original message: the notion that a youthful Arcadian experience confers on young men and women a ‘residue of happiness’ able to sustain their future development and assist them in dealing with the challenges of personal tragedy.

Estudi de la relació estructura-funció de les proteïnes CPT1

En aquest treball s’ha analitzat la relació estructura-funció dels enzims CPT1, o Carnitina palmitoïltransferasa 1, que catalitza la reacció de transesterificació dels àcids grassos de cadena llarga a acil-carnitines, per tal que puguin accedir a la matriu mitocondrial i ser oxidats. Aquest enzim es troba estrictament regulat per malonil-CoA, primer intermediari de la síntesi d’àcids grassos, establint-se així una regulació coordinada entre la formació i la degradació de grasses. S’han estudiat els tres isotips de CPT1 descrits fins al moment: CPT1A, CPT1B i CPT1C. Mitjançant l’expressió heteròloga de mutants de CPT1A de rata i CPT1B de porc en el llevat P. pastoris, s’ha estudiat l’efecte sobre la inhibició per malonil-CoA de petits canvis en la seva estructura, per tal de trobar una relació entre la seva funció enzimàtica i la disposició conformacional de la proteïna. Segons els resultats obtinguts, el residu Glu590 de CPT1A de rata estaria impedint la unió de l’inhibidor, mentre que el residu Met593 estaria afavorint aquesta unió. Els estudis amb l’enzim CPT1B de porc demostraren l’existència d’un determinant positiu per la sensibilitat al malonil-CoA en els primers 18 residus de la proteïna, i definiren la posició Glu17 com la responsable de l’alta afinitat a la carnitina i la baixa sensibilitat a la inhibició per malonil-CoA (8). Es clonà i caracteritzà la regió promotora del gen de CPT1C humana, amb la intenció d’analitzar la funcionalitat de putatius elements de resposta identificats in silico. Cap dels elements estudiats resultà ser funcional in vivo. A més, es demostrà que la manca d’activitat catalítica de la proteïna no és deguda a l’extensió C-terminal que presenta respecte els isotips A i B, tot i presentar un alt percentatge d’identitat de seqüència. S’ha amplificat una isoforma humana de CPT1C (Pubmed Acc. Num. AK299866), corresponent a la regió carboxiterminal de la proteïna, que es pretén utilitzar per obtenir el primer cristall de la part soluble d’una proteïna CPT1.     

Comparative study of the LC-MS/MS and UPLC-MS/MS for the multi-residue analysis of quinolones, penicillins and cephalosporins in cow milk, and validation according to the regulation 2002/657/EC

The aim of this study was to develop and validate an analytical method to simultaneously determine European Union-regulated beta-lactams (penicillins and cephalosporins) and quinolones in cow milk. The procedure involves a new solid phase extraction (SPE) to clean-up and pre-concentrate the three series of antibiotics before analysis by liquid chromatography¿tandem mass spectrometry (LC-MS/MS) and ultra-high-performance liquid chromatography¿tandem mass spectrometry (UPLC-MS/MS). LC-MS/MS and UPLC-MS/MS techniques were also compared. The method was validated according to the Directive 2002/657/EC and subsequently applied to 56 samples of raw cow milk supplied by the Laboratori Interprofessional Lleter de Catalunya (ALLIC) (Laboratori Interprofessional Lleter de Catalunya, Control Laboratory Interprofessional of Milk of Catalunya).

Comparative analysis of cancer genes in the human and chimpanzee genomes

Background: Cancer is a major medical problem in modern societies. However, the incidence of this disease in non-human primates is very low. To study whether genetic differences between human and chimpanzee could contribute to their distinct cancer susceptibility, we have examined in the chimpanzee genome the orthologous genes of a set of 333 human cancer genes. Results: This analysis has revealed that all examined human cancer genes are present in chimpanzee, contain intact open reading frames and show a high degree of conservation between both species. However, detailed analysis of this set of genes has shown some differences in genes of special relevance for human cancer. Thus, the chimpanzee gene encoding p53 contains a Pro residue at codon 72, while this codon is polymorphic in humans and can code for Arg or Pro, generating isoforms with different ability to induce apoptosis or interact with p73. Moreover, sequencing of the BRCA1 gene has shown an 8 Kb deletion in the chimpanzee sequence that prematurely truncates the co-regulated NBR2 gene. Conclusion: These data suggest that small differences in cancer genes, as those found in tumor suppressor genes, might influence the differences in cancer susceptibility between human and chimpanzee. Nevertheless, further analysis will be required to determine the exact contribution of the genetic changes identified in this study to the different cancer incidence in non-human primates.

Fluid dynamical prediction of changed v1 flow at energies available at the CERN Large Hadron Collider

Substantial collective flow is observed in collisions between lead nuclei at Large Hadron Collider (LHC) as evidenced by the azimuthal correlations in the transverse momentum distributions of the produced particles. Our calculations indicate that the global v1-flow, which at RHIC peaked at negative rapidities (named third flow component or antiflow), now at LHC is going to turn toward forward rapidities (to the same side and direction as the projectile residue). Potentially this can provide a sensitive barometer to estimate the pressure and transport properties of the quark-gluon plasma. Our calculations also take into account the initial state center-of-mass rapidity fluctuations, and demonstrate that these are crucial for v1 simulations. In order to better study the transverse momentum flow dependence we suggest a new "symmetrized" v1S(pt) function, and we also propose a new method to disentangle global v1 flow from the contribution generated by the random fluctuations in the initial state. This will enhance the possibilities of studying the collective Global v1 flow both at the STAR Beam Energy Scan program and at LHC.

Whole-rat protein content estimation: applicability of the Nx6.25 factor

The amino acid composition of the protein from three strains of rat (Wistar, Zucker lean and Zucker obese), subjected to reference and high-fat diets has been used to determine the mean empirical formula, molecular weight and N content of whole-rat protein. The combined whole protein of the rat was uniform for the six experimental groups, containing an estimate of 17.3% N and a mean aminoacyl residue molecular weight of 103.7. This suggests that the appropriate protein factor for the calculation of rat protein from its N content should be 5.77 instead of the classical 6.25. In addition, an estimate of the size of the non-protein N mass in the whole rat gave a figure in the range of 5.5 % of all N. The combination of the two calculations gives a protein factor of 5.5 for the conversion of total N into rat protein.

Essential residues in the H-NS binding site of Hha, a co-regulator of horizontally acquired genes in Enterobacteria

Proteins of the Hha/YmoA family co-regulate with H-NS the expression of horizontally acquired genes in Enterobacteria. Systematic mutations of conserved acidic residues in Hha have allowed the identification of D48 as an essential residue for H-NS binding and the involvement of E25. Mutations of these residues resulted in deregulation of sensitive genes in vivo. D48 is only partially solvent accessible, yet it defines the functional binding interface between Hha and H-NS confirming that Hha has to undergo a conformational change to bind H-NS. Exposed acidic residues, such as E25, may electrostatically facilitate and direct the approach of Hha to the positively charged region of H-NS enabling the formation of the final complex when D48 becomes accessible by a conformational change of Hha.

Deposition and residues of azoxystrobin and imidacloprid on greenhouse lettuce with implications for human consumption

Lettuce greenhouse experiments were carried out from March to June 2011 in order to analyze how pesticides behave from the time of application until their intake via human consumption taking into account the primary distribution of pesticides, field dissipation, and post-harvest processing. In addition, experimental conditions were used to evaluate a new dynamic plant uptake model comparing its results with the experimentally derived residues. One application of imidacloprid and two of azoxystrobin were conducted. For evaluating primary pesticide distribution, two approaches based on leaf area index and vegetation cover were used and results were compared with those obtained from a tracer test. High influence of lettuce density, growth stage and type of sprayer was observed in primary distribution showing that low densities or early growth stages implied high losses of pesticides on soil. Washed and unwashed samples of lettuce were taken and analyzed from application to harvest to evaluate removal of pesticides by food processing. Results show that residues found on the Spanish preharvest interval days were in all cases below officially set maximum residue limits, although it was observed that time between application and harvest is as important for residues as application amounts. An overall reduction of 40–60% of pesticides residues was obtained from washing lettuce. Experimentally derived residues were compared with modeled residues and deviate from 1.2 to 1.4 for imidacloprid and azoxystrobin, respectively, presenting good model predictions. Resulting human intake fractions range from... for imidacloprid to ... for azoxystrobin.

The role of Cysteine 6.47 in class A GPCRs

Abstract Background: The CWxP motif of transmembrane helix 6 (x: any residue) is highly conserved in class A GPCRs. Within this motif, W6.48 is a big star in the theory of the global “toggle switch” because of its key role in the activation mechanism of GPCRs upon ligand binding. With all footlights focused on W6.48, the reason why the preceding residue, C6.47, is largely conserved is still unknown. The present study is aimed to fill up this lack of knowledge by characterizing the role of C6.47 of the CWxP motif. Results: A complete analysis of available crystal structures has been made alongside with molecular dynamics simulations of model peptides to explore a possible structural role for C6.47. Conclusions: We conclude that C6.47 does not modulate the conformation of the TM6 proline kink and propose that C6.47 participates in the rearrangement of the TM6 and TM7 interface accompanying activation.

Fluid dynamical prediction of changed v1-flow at energies available at the CERN Large Hadron Collider

Substantial collective flow is observed in collisions between lead nuclei at Large Hadron Collider (LHC) as evidenced by the azimuthal correlations in the transverse momentum distributions of the produced particles. Our calculations indicate that the global v1-flow, which at RHIC peaked at negative rapidities (named third flow component or antiflow), now at LHC is going to turn toward forward rapidities (to the same side and direction as the projectile residue). Potentially this can provide a sensitive barometer to estimate the pressure and transport properties of the quark-gluon plasma. Our calculations also take into account the initial state center-of-mass rapidity fluctuations, and demonstrate that these are crucial for v1 simulations. In order to better study the transverse momentum flow dependence we suggest a new"symmetrized" vS1(pt) function, and we also propose a new method to disentangle global v1 flow from the contribution generated by the random fluctuations in the initial state. This will enhance the possibilities of studying the collective Global v1 flow both at the STAR Beam Energy Scan program and at LHC.

Structural Insight into the Mode of Action of a Direct Inhibitor of Coregulator Binding to the Thyroid Hormone Receptor.

The development of nuclear hormone receptor antagonists that directly inhibit the association of the receptor with its essential coactivators would allow useful manipulation of nuclear hormone receptor signaling. We previously identified 3-(dibutylamino)-1-(4-hexylphenyl)-propan-1-one (DHPPA), an aromatic β-amino ketone that inhibits coactivator recruitment to thyroid hormone receptor β (TRβ), in a high-throughput screen. Initial evidence suggested that the aromatic β-enone 1-(4-hexylphenyl)-prop-2-en-1-one (HPPE), which alkylates a specific cysteine residue on the TRβ surface, is liberated from DHPPA. Nevertheless, aspects of the mechanism and specificity of action of DHPPA remained unclear. Here, we report an x-ray structure of TRβ with the inhibitor HPPE at 2.3-Å resolution. Unreacted HPPE is located at the interface that normally mediates binding between TRβ and its coactivator. Several lines of evidence, including experiments with TRβ mutants and mass spectroscopic analysis, showed that HPPE specifically alkylates cysteine residue 298 of TRβ, which is located near the activation function-2 pocket. We propose that this covalent adduct formation proceeds through a two-step mechanism: 1) β-elimination to form HPPE; and 2) a covalent bond slowly forms between HPPE and TRβ. DHPPA represents a novel class of potent TRβ antagonist, and its crystal structure suggests new ways to design antagonists that target the assembly of nuclear hormone receptor gene-regulatory complexes and block transcription.

A peroxisomal glutathione transferase of Saccharomyces cerevisiae is functionally related to sulfur amino acid metabolism

Saccharomyces cerevisiae cells contain three omega-class glutathione transferases with glutaredoxin activity (Gto1, Gto2, and Gto3), in addition to two glutathione transferases (Gtt1 and Gtt2) not classifiable into standard classes. Gto1 is located at the peroxisomes, where it is targeted through a PTS1-type sequence, whereas Gto2 and Gto3 are in the cytosol. Among the GTO genes, GTO2 shows the strongest induction of expression by agents such as diamide, 1-chloro-2,4-dinitrobenzene, tert-butyl hydroperoxide or cadmium, in a manner that is dependent on transcriptional factors Yap1 and/or Msn2/4. Diamide and 1-chloro-2,4-dinitrobenzene (causing depletion of reduced glutathione) also induce expression of GTO1 over basal levels. Phenotypic analyses with single and multiple mutants in the S. cerevisiae glutathione transferase genes show that, in the absence of Gto1 and the two Gtt proteins, cells display increased sensitivity to cadmium. A gto1-null mutant also shows growth defects on oleic acid-based medium, which is indicative of abnormal peroxisomal functions, and altered expression of genes related to sulfur amino acid metabolism. As a consequence, growth of the gto1 mutant is delayed in growth medium without lysine, serine, or threonine, and the mutant cells have low levels of reduced glutathione. The role of Gto1 at the S. cerevisiae peroxisomes could be related to the redox regulation of the Str3 cystathionine -lyase protein. This protein is also located at the peroxisomes in S. cerevisiae, where it is involved in transulfuration of cysteine into homocysteine, and requires a conserved cysteine residue for its biological activity.

Structural Insight into the Mode of Action of a Direct Inhibitor of Coregulator Binding to the Thyroid Hormone Receptor.

The development of nuclear hormone receptor antagonists that directly inhibit the association of the receptor with its essential coactivators would allow useful manipulation of nuclear hormone receptor signaling. We previously identified 3-(dibutylamino)-1-(4-hexylphenyl)-propan-1-one (DHPPA), an aromatic β-amino ketone that inhibits coactivator recruitment to thyroid hormone receptor β (TRβ), in a high-throughput screen. Initial evidence suggested that the aromatic β-enone 1-(4-hexylphenyl)-prop-2-en-1-one (HPPE), which alkylates a specific cysteine residue on the TRβ surface, is liberated from DHPPA. Nevertheless, aspects of the mechanism and specificity of action of DHPPA remained unclear. Here, we report an x-ray structure of TRβ with the inhibitor HPPE at 2.3-Å resolution. Unreacted HPPE is located at the interface that normally mediates binding between TRβ and its coactivator. Several lines of evidence, including experiments with TRβ mutants and mass spectroscopic analysis, showed that HPPE specifically alkylates cysteine residue 298 of TRβ, which is located near the activation function-2 pocket. We propose that this covalent adduct formation proceeds through a two-step mechanism: 1) β-elimination to form HPPE; and 2) a covalent bond slowly forms between HPPE and TRβ. DHPPA represents a novel class of potent TRβ antagonist, and its crystal structure suggests new ways to design antagonists that target the assembly of nuclear hormone receptor gene-regulatory complexes and block transcription.