An outline of the Latin American Population Documentation Service (DOCPAL); a request to the Information Science Division of the International Development Research Centre (IDRC), Ottawa, Canada

Includes bibliography

Exome analysis of HIV patients submitted to dendritic cells therapeutic vaccine reveals an association of CNOT1 gene with response to the treatment

INTRODUCTION: With the aim of searching genetic factors associated with the response to an immune treatment based on autologous monocyte-derived dendritic cells pulsed with autologous inactivated HIV, we performed exome analysis by screening more than 240,000 putative functional exonic variants in 18 HIV-positive Brazilian patients that underwent the immune treatment. METHODS: Exome analysis has been performed using the ILLUMINA Infinium HumanExome BeadChip. zCall algorithm allowed us to recall rare variants. Quality control and SNP-centred analysis were done with GenABEL R package. An in-house implementation of the Wang method permitted gene-centred analysis. RESULTS: CCR4-NOT transcription complex, subunit 1 (CNOT1) gene (16q21), showed the strongest association with the modification of the response to the therapeutic vaccine (p=0.00075). CNOT1 SNP rs7188697 A/G was significantly associated with DC treatment response. The presence of a G allele indicated poor response to the therapeutic vaccine (p=0.0031; OR=33.00; CI=1.74-624.66), and the SNP behaved in a dominant model (A/A vs. A/G+G/G p=0.0009; OR=107.66; 95% CI=3.85-3013.31), being the A/G genotype present only in weak/transient responders, conferring susceptibility to poor response to the immune treatment. DISCUSSION: CNOT1 is known to be involved in the control of mRNA deadenylation and mRNA decay. Moreover, CNOT1 has been recently described as being involved in the regulation of inflammatory processes mediated by tristetraprolin (TTP). The TTP-CCR4-NOT complex (CNOT1 in the CCR4-NOT complex is the binding site for TTP) has been reported as interfering with HIV replication, through post-transcriptional control. Therefore, we can hypothesize that genetic variation occurring in the CNOT1 gene could impair the TTP-CCR4-NOT complex, thus interfering with HIV replication and/or host immune response. CONCLUSIONS: Being aware that our findings are exclusive to the 18 patients studied with a need for replication, and that the genetic variant of CNOT1 gene, localized at intron 3, has no known functional effect, we propose a novel potential candidate locus for the modulation of the response to the immune treatment, and open a discussion on the necessity to consider the host genome as another potential variant to be evaluated when designing an immune therapy study

Icatibant , the bradykinin B2 receptor antagonist with target to the interconnected kinin systems

INTRODUCTION: HOE-140/ Icatibant is a selective, competitive antagonist to bradykinin (BK) against its binding to the kinin B2 receptor. Substitution of five non-proteogeneic amino acid analogues makes icatibant resistant to degradation by metalloproteases of kinin catabolism. Icatibant has clinical applications in inflammatory and vascular leakage conditions caused by an acute (non-controlled) production of kinins and their accumulation at the endothelium B2 receptor. The clinical manifestation of vascular leakage, called angioedema (AE), is characterized by edematous attacks of subcutaneous and submucosal tissues, which can cause painful intestinal consequences, and life-threatening complications if affecting the larynx. Icatibant is registered for the treatment of acute attacks of the hereditary BK-mediated AE, i.e., AE due to C1 inhibitor deficiency. AREAS COVERED: This review discusses emerging knowledge on the kinin system: kinin pharmacological properties, biochemical characteristics of the contact phase and kinin catabolism proteases. It underlines the responsibility of the kinins in AE initiation and the potency of icatibant to inhibit AE formation by kinin-receptor interactions. EXPERT OPINION: Icatibant antagonist properties protect BK-mediated AE patients against severe attacks, and could be developed for use in inflammatory conditions. More studies are required to confirm whether or not prolonged and frequent applications of icatibant could result in the impairment of the cardioprotective effect of BK.

A BAYESIAN SHRINKAGE MODEL FOR INCOMPLETE LONGITUDINAL BINARY DATA WITH APPLICATION TO THE BREAST CANCER PREVENTION TRIAL

We consider inference in randomized studies, in which repeatedly measured outcomes may be informatively missing due to drop out. In this setting, it is well known that full data estimands are not identified unless unverified assumptions are imposed. We assume a non-future dependence model for the drop-out mechanism and posit an exponential tilt model that links non-identifiable and identifiable distributions. This model is indexed by non-identified parameters, which are assumed to have an informative prior distribution, elicited from subject-matter experts. Under this model, full data estimands are shown to be expressed as functionals of the distribution of the observed data. To avoid the curse of dimensionality, we model the distribution of the observed data using a Bayesian shrinkage model. In a simulation study, we compare our approach to a fully parametric and a fully saturated model for the distribution of the observed data. Our methodology is motivated and applied to data from the Breast Cancer Prevention Trial.

Fast parallel kriging-based stepwise uncertainty reduction with application to the identification of an excursion set

Stepwise uncertainty reduction (SUR) strategies aim at constructing a sequence of points for evaluating a function  f in such a way that the residual uncertainty about a quantity of interest progressively decreases to zero. Using such strategies in the framework of Gaussian process modeling has been shown to be efficient for estimating the volume of excursion of f above a fixed threshold. However, SUR strategies remain cumbersome to use in practice because of their high computational complexity, and the fact that they deliver a single point at each iteration. In this article we introduce several multipoint sampling criteria, allowing the selection of batches of points at which f can be evaluated in parallel. Such criteria are of particular interest when f is costly to evaluate and several CPUs are simultaneously available. We also manage to drastically reduce the computational cost of these strategies through the use of closed form formulas. We illustrate their performances in various numerical experiments, including a nuclear safety test case. Basic notions about kriging, auxiliary problems, complexity calculations, R code, and data are available online as supplementary materials.

Redox front geochemistry and weathering: theory with application to the Osamu Utsumi uranium mine, Poços de Caldas, Brazil

Numerical calculations describing weathering of the Poços de Caldas alkaline complex (Minas Gerais, Brazil) by infiltrating groundwater are carried out for time spans up to two million years in the absence of pyrite, and up to 500,000 years with pyrite present. Deposition of uranium resulting from infiltration of oxygenated, uranium bearing groundwater through the hydrothermally altered phonolitic host rock at the Osamu Utsumi uranium mine is also included in the latter calculation. The calculations are based on the quasi-stationary state approximation to mass conservation equations for pure advective transport. This approximation enables the prediction of solute concentrations, mineral abundances and porosity as functions of time and distance over geologic time spans. Mineral reactions are described by kinetic rate laws for both precipitation and dissolution. Homogeneous equilibrium is assumed to be maintained within the aqueous phase. No other constraints are imposed on the calculations other than the initial composition of the unaltered host rock and the composition of the inlet fluid, taken as rainwater modified by percolation through a soil zone. The results are in qualitative agreement with field observations at the Osamu Utsumi uranium mine. They predict a lateritic cover followed by a highly porous saprolitic zone, a zone of oxidized rock with pyrite replaced by iron-hydroxide, a sharp redox front at which uranium is deposited, and the reduced unweathered host rock. Uranium is deposited in a narrow zone located on the reduced side of the redox front in association with pyrite, in agreement with field observations. The calculations predict the formation of a broad dissolution front of primary kaolinite that penetrates deep into the host rock accompanied by the precipitation of secondary illite. Secondary kaolinite occurs in a saprolitic zone near the surface and in the vicinity of the redox front. Gibbsite forms a bi-modal distribution consisting of a maximum near the surface followed by a thin tongue extending downward into the weathered profile in agreement with field observations. The results are found to be insensitive to the kinetic rate constants used to describe mineral reactions.

MLN64 contains a domain with homology to the steroidogenic acute regulatory protein (StAR) that stimulates steroidogenesis

MLN64 is a protein that is highly expressed in certain breast carcinomas. The C terminus of MLN64 shares significant homology with the steroidogenic acute regulatory protein (StAR), which plays a key role in steroid hormone biosynthesis by enhancing the intramitochondrial translocation of cholesterol to the cholesterol side-chain cleavage enzyme. We tested the ability of MLN64 to stimulate steroidogenesis by using COS-1 cells cotransfected with plasmids expressing the human cholesterol side-chain cleavage enzyme system and wild-type and mutant MLN64 proteins. Wild-type MLN64 increased pregnenolone secretion in this system 2-fold. The steroidogenic activity of MLN64 was found to reside in the C terminus of the protein, because constructs from which the C-terminal StAR homology domain was deleted had no steroidogenic activity. In contrast, removal of N-terminal sequences increased MLN64’s steroidogenesis-enhancing activity. MLN64 mRNA was found in many human tissues, including the placenta and brain, which synthesize steroid hormones but do not express StAR. Western blot analysis revealed the presence of lower molecular weight immunoreactive MLN64 species that contain the C-terminal sequences in human tissues. Homologs of both MLN64 and StAR were identified in Caenorhabditis elegans, indicating that the two proteins are ancient. Mutations that inactivate StAR were correlated with amino acid residues that are identical or similar among StAR and MLN64, indicating that conserved motifs are important for steroidogenic activity. We conclude that MLN64 stimulates steroidogenesis by virtue of its homology to StAR.

A meanfield approach to the thermodynamics of a protein-solvent system with application to the oligomerization of the tumor suppressor p53

The thermodynamic stability and oligomerization status of the tumor suppressor p53 tetramerization domain have been studied experimentally and theoretically. A series of hydrophilic mutations at Met-340 and Leu-344 of human p53 were designed to disrupt the hydrophobic dimer–dimer interface of the tetrameric oligomerization domain of p53 (residues 325–355). Meanfield calculations of the free energy of the solvated mutants as a function of interdimer distance were compared with experimental data on the thermal stability and oligomeric state (tetramer, dimer, or equilibrium mixture of both) of each mutant. The calculations predicted a decreasing stability and oligomeric state for the following amino acids at residue 340: Met (tetramer) > Ser Asp, His, Gln, > Glu, Lys (dimer), whereas the experimental results showed the following order: Met (tetramer) > Ser > Gln > His, Lys > Asp, Glu (dimers). For residue 344, the calculated trend was Leu (tetramer) > Ala > Arg, Gln, Lys (dimer), and the experimental trend was Leu (tetramer) > Ala, Arg, Gln, Lys (dimer). The discrepancy for the lysine side chain at residue 340 is attributed to the dual nature of lysine, both hydrophobic and charged. The incorrect prediction of stability of the mutant with Asp at residue 340 is attributed to the fact that within the meanfield approach, we use the wild-type backbone configuration for all mutants, but low melting temperatures suggest a softening of the α-helices at the dimer–dimer interface. Overall, this initial application of meanfield theory toward a protein-solvent system is encouraging for the application of the theoretical model to more complex systems.

HLH106, a Drosophila transcription factor with similarity to the vertebrate sterol responsive element binding protein.

We cloned a Drosophila homolog to the sterol responsive element binding proteins (SREBPs). In vertebrates, the SREBPs are regulated by a mechanism that involves cleavage of the protein that normally residues in the cellular membranes and translocation of the released transcription factor into the nucleus. Regulation of the Drosophila factor HLH106 apparently follows the same mechanism, and we find the full-length gene product in the membrane fraction and a shorter cross-reacting form in the nuclear fraction. This nuclear form, which may correspond to proteolytically activated HLH106, is abundant in the blood cell line mbn-2. The general domain structure of HLH106 is very similar to that in SREBP. HLH106 is expressed throughout development, and it is present at high levels in Drosophila cell lines. In contrast to the rat homolog, HLH106 transcripts are not more abundant in adipose tissue than in other tissues.