Top PDF Global analysis of small molecule binding to related protein targets.

Global analysis of small molecule binding to related protein targets.

Global analysis of small molecule binding to related protein targets.

by a mutation in or near the binding site, as molecules of greater size rely on a larger number of interactions with the target protein [42]. Following this hypothesis, we examined differences in ligand binding between paralogs in terms of molecular size (approximat- ed here by molecular weight) of the ligand and divided all compounds in our analysis into molecular weight bins. Adaptive binning was used to obtain five groups containing equal numbers of compounds. An analysis of variance (Anova) F test (F = 15.0, p,2.8e-12) suggests that there are significant differences between the groups and multiple testing was carried out to examine the differences between individual groups (see Figure 4). Analogous to the above, the data for human to rat orthologs was binned by molecular weight of the ligand and an Anova F test (F = 5.6, p,1.6e-4) suggest that there is a significant difference between groups but sample sizes are smaller and multiple testing is less conclusive (see Figure S9). The differences observed when grouping ligands by molecular weight are in support of our magic residue hypothesis according to which larger molecules would be more likely to interact with residues in or near the binding site and thus would sample otherwise neutral mutations. In this context, it is difficult to distinguish between physiologically neutral substitu- tions in orthologs and non-homologous changes in paralogs, because a number of paralogs bind, like orthologs, their endogenous ligand with equal affinity (eg. muscarinic acetylcholine receptors, where different receptor subtypes exist) and thus behave like pseudo-orthologs. Our findings also implies that increasing the molecular size of a ligand can promote selectivity against targets within the same family if substitutions are present near the binding site. The correlation observed between the absolute difference in binding affinity and molecular weight is small (Spearman’s Rho of only 0.062) but highly significant, suggesting
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Deep sequencing analysis of small noncoding RNA and mRNA targets of the global post-transcriptional regulator, Hfq.

Deep sequencing analysis of small noncoding RNA and mRNA targets of the global post-transcriptional regulator, Hfq.

Recent advances in high-throughput pyrosequencing (HTPS) technology now allow a thorough analysis of RNA bound to cellular proteins, and, therefore, of post-transcriptional regulons. We used HTPS to discover the Salmonella RNAs that are targeted by the common bacterial Sm-like protein, Hfq. Initial transcriptomic analysis revealed that Hfq controls the expression of almost a fifth of all Salmonella genes, including several horizontally acquired pathogenicity islands (SPI-1, -2, - 4, -5), two sigma factor regulons, and the flagellar gene cascade. Subsequent HTPS analysis of 350,000 cDNAs, derived from RNA co-immunoprecipitation (coIP) with epitope-tagged Hfq or control coIP, identified 727 mRNAs that are Hfq-bound in vivo. The cDNA analysis discovered new, small noncoding RNAs (sRNAs) and more than doubled the number of sRNAs known to be expressed in Salmonella to 64; about half of these are associated with Hfq. Our analysis explained aspects of the pleiotropic effects of Hfq loss-of-function. Specifically, we found that the mRNAs of hilD (master regulator of the SPI-1 invasion genes) and flhDC (flagellar master regulator) were bound by Hfq. We predicted that defective SPI-1 secretion and flagellar phenotypes of the hfq mutant would be rescued by overexpression of HilD and FlhDC, and we proved this to be correct. The combination of epitope-tagging and HTPS of immunoprecipitated RNA detected the expression of many intergenic chromosomal regions of Salmonella. Our approach overcomes the limited availability of high-density microarrays that have impeded expression-based sRNA discovery in microorganisms. We present a generic strategy that is ideal for the systems-level analysis of the post-transcriptional regulons of RNA-binding proteins and for sRNA discovery in a wide range of bacteria.
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An in silico analysis of the binding modes and binding affinities of small molecule modulators of PDZ-peptide interactions.

An in silico analysis of the binding modes and binding affinities of small molecule modulators of PDZ-peptide interactions.

Before carrying out docking studies for identifying the preferred binding sites of these 38 known inhibitors on second and third PDZ domains of PSD95, we analyzed crystal structures of PDZ domains in complex with the inhibitors to check whether these small molecule inhibitors occupy the same binding pocket as the native peptide substrates. Figure S3 shows the superposition of the crystal structures of PDZ domain of Shank protein in complex with the peptide (PDB ID: 1Q3P) and also the crystal structure of the same PDZ domain in complex with the inhibitor tetrahy- droquinoline carboxylate (PDB ID: 3O5N). As is evident, the small molecule and peptide occupy the same binding pocket. The molecule is mostly interacting with the hydrophobic pocket formed by the GLGF loop and the helix. In the native peptide complex the C-terminal hydrophobic residue of the substrate peptide occupies this hydrophobic pocket. In order to understand the structural basis of differential selectivity of PDZ2 and PDZ3 domains of PSD-95 for the same inhibitors, the sequence and structural differences between these two PDZ domains were also compared. Figure 3A shows the BLAST alignment between the sequences of 2 nd (PDB ID: 1QLC) and 3 rd (PDB ID: 1BE9) PDZ domain of PSD-95 protein, while Figure 3B shows the corresponding structures in the cartoon representation. As can be seen, the local alignment of the sequences of these two PDZ domains cover 77 residues which encompass the core of the PDZ domains, while they do not show sequence similarity in their N- and C-terminal stretches. In fact N- and C-terminal regions of the PDZ3 that do not align with the corresponding regions of PDZ2 are longer in size and PDZ3 contains the extra domain helix in the C-terminal stretch. Apart from these differences in the N- and C- terminal sequence stretches, the core region of these two domains show an identity of 40% and similarity of 56% over 77 residues. In fact the binding pocket residues are almost identical
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Antiviral activity of a small molecule deubiquitinase inhibitor occurs via induction of the unfolded protein response.

Antiviral activity of a small molecule deubiquitinase inhibitor occurs via induction of the unfolded protein response.

Ubiquitin (Ub) is a vital regulatory component in various cellular processes, including cellular responses to viral infection. As obligate intracellular pathogens, viruses have the capacity to manipulate the ubiquitin (Ub) cycle to their advantage by encoding Ub-modifying proteins including deubiquitinases (DUBs). However, how cellular DUBs modulate specific viral infections, such as norovirus, is poorly understood. To examine the role of DUBs during norovirus infection, we used WP1130, a small molecule inhibitor of a subset of cellular DUBs. Replication of murine norovirus in murine macrophages and the human norovirus Norwalk virus in a replicon system were significantly inhibited by WP1130. Chemical proteomics identified the cellular DUB USP14 as a target of WP1130 in murine macrophages, and pharmacologic inhibition or siRNA- mediated knockdown of USP14 inhibited murine norovirus infection. USP14 is a proteasome-associated DUB that also binds to inositol-requiring enzyme 1 (IRE1), a critical mediator of the unfolded protein response (UPR). WP1130 treatment of murine macrophages did not alter proteasome activity but activated the X-box binding protein-1 (XBP-1) through an IRE1- dependent mechanism. In addition, WP1130 treatment or induction of the UPR also reduced infection of other RNA viruses including encephalomyocarditis virus, Sindbis virus, and La Crosse virus but not vesicular stomatitis virus. Pharmacologic inhibition of the IRE1 endonuclease activity partially rescued the antiviral effect of WP1130. Taken together, our studies support a model whereby induction of the UPR through cellular DUB inhibition blocks specific viral infections, and suggest that cellular DUBs and the UPR represent novel targets for future development of broad spectrum antiviral therapies.
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Automatic filtering and substantiation of drug safety signals.

Automatic filtering and substantiation of drug safety signals.

Recent studies highlight the use of disparate data sets in the study of ADRs, enabled by bioinformatics methodologies. Combining the study of protein–drug interactions on a structural proteome-wide scale with protein functional site similarity search, small molecule screening, and protein–ligand binding affinity profile analysis, Xie and colleagues [35] have elucidated a possible molecular mechanism for the previously observed, but molecularly uncharacterized, side effect of selective estrogen receptor modulators (SERMs). In another study, the side effect information from prescription drug labels was exploited to identify novel molecular activities of existing drugs [25]. The Unified Medical Language System (UMLS) Metathesaurus H [36] was used as a vocabulary for the side effects, and a weighting scheme to account for the rareness and interdependence of side effects was developed. Since similarity in side effects correlated with shared targets between drugs, side effect similarity was used to predict novel targets between any two ‘‘unexpected’’ drug pair [25]. In another study, Berger and colleagues used a computa- tional systems biology approach to analyze drug-induced long both levels (tissue and cell type) are used to query Reactome database, and pathways that contain at least one protein from the Drug-Target-Profile and one protein from the Event-Protein Profile are retrieved. Then, these pathways are explored to determine if they support the causal inference of the signal.
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Predicting protein ligand binding sites by combining evolutionary sequence conservation and 3D structure.

Predicting protein ligand binding sites by combining evolutionary sequence conservation and 3D structure.

Identifying a protein’s functional sites is an important step towards characterizing its molecular function. Numerous structure- and sequence-based methods have been developed for this problem. Here we introduce ConCavity, a small molecule binding site prediction algorithm that integrates evolutionary sequence conservation estimates with structure- based methods for identifying protein surface cavities. In large-scale testing on a diverse set of single- and multi-chain protein structures, we show that ConCavity substantially outperforms existing methods for identifying both 3D ligand binding pockets and individual ligand binding residues. As part of our testing, we perform one of the first direct comparisons of conservation-based and structure-based methods. We find that the two approaches provide largely complementary information, which can be combined to improve upon either approach alone. We also demonstrate that ConCavity has state-of-the-art performance in predicting catalytic sites and drug binding pockets. Overall, the algorithms and analysis presented here significantly improve our ability to identify ligand binding sites and further advance our understanding of the relationship between evolutionary sequence conservation and structural and functional attributes of proteins. Data, source code, and prediction visualizations are available on the ConCavity web site (http://compbio.cs. princeton.edu/concavity/).
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Structure-based druggability assessment of the mammalian structural proteome with inclusion of light protein flexibility.

Structure-based druggability assessment of the mammalian structural proteome with inclusion of light protein flexibility.

Table S1 Protein-protein interaction targets from 2P2I that have less well-defined druggability as determined by conclusive results from multiple research groups, or where known drugs are metal chelators (HIV Integrase). These targets have protein-protein co-crystal structures shown in the top half of the table, and corresponding protein-ligand co-crystal structures shown in the bottom half. Score is Dscore+, ‘cmpd’ indicates a small molecule compound, and volumes are in units of A ˚ 3 . ‘‘*’’ indicates ‘not applicable’ because the site’s initial Dscore+ values did not meet the cut-off for flexibility modeling. 1 Menin- MLL inhibitors has been reported in academic discovery efforts, but there does not appear to be enough evidence yet to definitively assign druggability. One group reports nM inhibitors with small molecule compounds (see Murai et al., J. Biol Chem. 2011 286: 31742–8), while another group reports nM inhibitors with large macrocyclic peptidomimetics that do not fall into drug-like property ranges (see Zhou et al., J. Med Chem. 2013 56: 1113–23). Several of the Menin-MLL inhibitor co-crystal structures contained several extra dummy atoms in the inhibitor binding site, and we removed them for the purposes of running our analysis. 2 HIV Integrase complex involves a DNA-protein interaction, and thus inhibitors are not protein-protein inhibitors. In addition, the approved drugs, raltegravir and elvitegravir, bind to two Mg2+ ions bound to HIV integrase, and thus are metal chelators (see Hare et al., Nature. 2010 464: 232–6). Metal chelators are not captured by structure-based druggability approaches, as discussed in the Introduction, although allosteric LEDGF/p75-Integrase inhibitors are showing promise. (DOCX)
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Conformational Sampling and Binding Site Assessment of Suppression of Tumorigenicity 2 Ectodomain.

Conformational Sampling and Binding Site Assessment of Suppression of Tumorigenicity 2 Ectodomain.

We used Sitemap program[47] to perform small molecule binding site analysis on the protein conformations. The Sitemap program developed by Halgren[47] is an in silico method that detects the cavities in proteins and calculates their sizes, physicochemical properties (hydro- phobic surface, hydrogen bond acceptors, donors) probed by chemical atoms, solvent exposure that are important to analyze protein-ligand interaction. These properties were weighted to derive scoring functions (including Dscore) for evaluating the binding sites by training and testing to a dataset with known protein-ligand crystal structures and associated binding affini- ties. The correlation between the calculated Dscore values and the experimental binding affini- ties of known ligands to their target proteins gives a measure to predict the likelihood of novel protein binding sites to bind with potent small molecules and the druggability of proteins.
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In silico mechanistic profiling to probe small molecule binding to sulfotransferases.

In silico mechanistic profiling to probe small molecule binding to sulfotransferases.

Notably, experimental and computational approaches have been proposed to predict Absorption, Distribution, Metabolism, Excretion and Toxicity (ADME-Tox) properties of drugs or the response to environmental toxins [1,20–22]. ADME-Tox predictions [12,22–26] are challenging but extremely important in prioritizing appropriate small molecules not only during the selection of potent candidates in drug discovery projects but also, to some extent, for chemical biology studies. Classical in silico ADME-Tox predictions are mostly based on statistical approaches using annotated databases, like Quantitative Structure-Activity Relationships and Quantitative Structure- Property Relationships (QSAR/QSPR) [26–28]. However, the complexity of ADME-Tox molecular mechanisms, for instance specific interactions with DMEs or with other ADME-Tox- related proteins, requires a deep mechanistic understanding [10–12,29] of the ligand-protein interactions at atomic level. Such knowledge should become more accessible for basically all proteins within the next 15 years as structural genomics projects gain full speed [30]. Indeed, in recent years in silico approaches exploiting the 3D structure of ADME-Tox related proteins, like docking/scoring or pharmacophore approaches, were successfully developed to complement QSAR models [10–12,29,31–34].
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LETTERS TO THE EDITOR

LETTERS TO THE EDITOR

glycine cross-peaks were positive (red contours in box 2). This result indicates that most glycine residues are in disordered regions of the molecule while only three glycines are located in relatively ordered regions. The sequence of ∆60HDAg is especially rich in glycine residues in segments outside the RNA binding domain (RBD, residues 97-146, Figure 1 bottom). The RBD comprises two potential RNA binding motifs, residues 97-107 (KERQDHRRRKA) and 136-146 (EDERRERRIAg). Only 3 out of approximately 53 residues in the RBD are glycines. When Agadir (http://agadir.crg.es/agadir. jsp), an empirical algorithm based on the helix-forming tendencies of peptides, was applied to ∆60HDAg it provided a helix content of 62.2% at pH 7.0 and 5 ℃ for the sequence containing residues 94-146. The predicted helix content was highly temperature dependent, dropping to 44.7% at 26 ℃. After removing the first three residues from the N-terminus, so that the sequence only contained the two RNA binding motifs and the linker (97-146), the estimated helix content dropped to 48.84% at pH 7.0 and 5 ℃, and to 34.19% at 25 ℃, indicating that the first three residues, FTD, are important for stabilizing the helical conformation.
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Expanding the substantial interactome of NEMO using protein microarrays.

Expanding the substantial interactome of NEMO using protein microarrays.

Signal transduction by the NF-kappaB pathway is a key regulator of a host of cellular responses to extracellular and intracellular messages. The NEMO adaptor protein lies at the top of this pathway and serves as a molecular conduit, connecting signals transmitted from upstream sensors to the downstream NF-kappaB transcription factor and subsequent gene activation. The position of NEMO within this pathway makes it an attractive target from which to search for new proteins that link NF-kappaB signaling to additional pathways and upstream effectors. In this work, we have used protein microarrays to identify novel NEMO interactors. A total of 112 protein interactors were identified, with the most statistically significant hit being the canonical NEMO interactor IKKbeta, with IKKalpha also being identified. Of the novel interactors, more than 30% were kinases, while at least 25% were involved in signal transduction. Binding of NEMO to several interactors, including CALB1, CDK2, SAG, SENP2 and SYT1, was confirmed using GST pulldown assays and coimmunoprecipitation, validating the initial screening approach. Overexpression of CALB1, CDK2 and SAG was found to stimulate transcriptional activation by NF-kappaB, while SYT1 overexpression repressed TNFalpha-dependent NF-kappaB transcriptional activation in human embryonic kidney cells. Corresponding with this finding, RNA silencing of CDK2, SAG and SENP2 reduced NF-kappaB transcriptional activation, supporting a positive role for these proteins in the NF-kappaB pathway. The identification of a host of new NEMO interactors opens up new research opportunities to improve understanding of this essential cell signaling pathway.
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Decipher the mechanisms of protein conformational changes induced by nucleotide binding through free-energy landscape analysis: ATP binding to Hsp70.

Decipher the mechanisms of protein conformational changes induced by nucleotide binding through free-energy landscape analysis: ATP binding to Hsp70.

performed. We observed the docking of the SBD of DnaK onto the lobe I of its NBD upon ATP-binding: the structure found is an intermediate plausible ATP-bound state, named ATP*, which is compared to several experimental data. A strategy was presented in which the FEL computed from unbiased MD simulations is represented by FEPs of CGDAs of the main chain along the amino-acid sequence of the protein. The FEPs can be quantita- tively compared in different nucleotide-binding states by using a similarity index. The analysis of the FEPs allowed us to identify a small network of 27 CGDAs c. The coupling between these 27 CGDAs was deciphered by using dihedral principal component analysis. The conformational change induced by ATP binding was represented by a pathway of minimum energy on the FES built from the two lowest dihedral principal components of the ATP- bound DnaK trajectories. The 27 coordinates correspond to 91 residues which are involved in the interdomain communication upon nucleotide binding to DnaK. Most of these 91 residues revealed by MD were shown experimentally to be relevant for the communication between the NBD and the SBD in the Hsp70 chaperone cycle. The present work also suggests 26 new key residues that could be tested experimentally. For example, the residues A503 to G506, defining c 504 , belonging to the kink
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LETTERS TO THE EDITOR

LETTERS TO THE EDITOR

To get a deeper insight into the non-specific nucleic acid binding ability of the protein, structural information is also required. We used CD and NMR to characterize measurable structural features in ∆60HDAg. Disordered protein regions with a measured propensity for helical secondary structure have been found to act as pre- formed molecular recognition elements. Although ∆ 60HDAg is predicted to be extensively disordered, the relative large chemical shift dispersion in both proton and nitrogen in NMR HSQC spectrum indicates that this is not the case. Moreover, the CD spectrum further showed that ∆60HDAg has a measurable helical content. In conjunction with the sequence analysis, the heteronuclear NOE NMR experiment showed that the RBD domain contained a dynamic helical conformation, which is consistent with secondary structure prediction of a helix-turn-helix RNA binding motif. In addition, our study shows that qualitative NMR analysis such as
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Cloning of the quail PIWI gene and characterization of PIWI binding to small RNAs.

Cloning of the quail PIWI gene and characterization of PIWI binding to small RNAs.

In mammals, the PIWI protein and piRNAs are RISC components that regulate spermatogenesis. To determine the mechanism of PIWI-mediated piRNA pathway in quail, we obtained the PIWIL1-RNA complex from testicular extract of adult quail and purified the associated RNAs. The length distribution of PIWIL1 binding to small RNAs showed a predominant peak at 24–25 nt, which was similar to the length distribution of rasiRNAs in Drosophila [6] and shorter than that of piRNAs in mice [13]. To identify the genetic characteristics of the small RNAs bound by PIWIL1, we mapped our sequences (23– 32 nt) to known non-coding RNAs databases and the Gallus gallus genome. Given the unique peak at 24–27 nt in the testicular RNA library, very few unique reads were annotated, suggesting that the remaining reads likely belonged to a novel class of small RNAs. However, a less extreme 59 uracil bias had been noted in unknown unique reads, which differed from the extreme 5 9 uracil bias for piRNAs [13]. In mammals, piRNAs were mainly distributed in the intergenic sequences and had only one hit in the genome, while our unknown unique reads mapped to the Gallus gallus genome more than once. The unique reads were mainly concentrated in chromosome W followed by chromosome Z from the testis and ovary, which was consistent with the distribution of repeat sequences. It appeared that the unknown unique reads may be involved in the transcription or translation of repeat sequences in the germline. Given the nucleotide length, testicular specificity, PIWI protein interaction and genomic origin, we hypothesized that the unknown unique sequences were quail rasiRNAs. However, many of the unknown unique sequences from the testis mapped to chromosome W in our study. At present, we are unable to explain this phenomenon. Whether there is a relationship between PIWIL1 binding to small RNAs and the sex determina- tion mechanism requires more experimental evidence.
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Quantitative predictions of peptide binding to any HLA-DR molecule of known sequence: NetMHCIIpan.

Quantitative predictions of peptide binding to any HLA-DR molecule of known sequence: NetMHCIIpan.

CD4 positive T helper cells control many aspects of specific immunity. These cells are specific for peptides derived from protein antigens and presented by molecules of the extremely polymorphic major histocompatibility complex (MHC) class II system. The identification of peptides that bind to MHC class II molecules is therefore of pivotal importance for rational discovery of immune epitopes. HLA-DR is a prominent example of a human MHC class II. Here, we present a method, NetMHCIIpan, that allows for pan-specific predictions of peptide binding to any HLA-DR molecule of known sequence. The method is derived from a large compilation of quantitative HLA-DR binding events covering 14 of the more than 500 known HLA-DR alleles. Taking both peptide and HLA sequence information into account, the method can generalize and predict peptide binding also for HLA-DR molecules where experimental data is absent. Validation of the method includes identification of endogenously derived HLA class II ligands, cross-validation, leave-one-molecule-out, and binding motif identification for hitherto uncharacterized HLA-DR molecules. The validation shows that the method can successfully predict binding for HLA-DR molecules—even in the absence of specific data for the particular molecule in question. Moreover, when compared to TEPITOPE, currently the only other publicly available prediction method aiming at providing broad HLA- DR allelic coverage, NetMHCIIpan performs equivalently for alleles included in the training of TEPITOPE while outperforming TEPITOPE on novel alleles. We propose that the method can be used to identify those hitherto uncharacterized alleles, which should be addressed experimentally in future updates of the method to cover the polymorphism of HLA-DR most efficiently. We thus conclude that the presented method meets the challenge of keeping up with the MHC polymorphism discovery rate and that it can be used to sample the MHC ‘‘space,’’ enabling a highly efficient iterative process for improving MHC class II binding predictions.
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An Analysis Of The Difference In Gender Level Of Cassava Production And Access To Land In Abia State Nigeria

An Analysis Of The Difference In Gender Level Of Cassava Production And Access To Land In Abia State Nigeria

Women also provide most of the labour for harvesting and post-harvest activities (FAO, 1996). Cassava is important, not only as a food crop but even more as a major source of income for rural households (Davies et al., 2008). As a cash crop, cassava generates cash income for the largest number of households in comparison with other staples. However the sustainability of this staple crop depends on the enormous availability of land for its cultivation. Land is the foundation of all human, social and economic activities that lie at the heart of social, political, or economic life of most nations especially African nations. Land is recognized as a primary source of wealth, social status and power, the basis for shelter, food, and economic activities and significantly provides employment opportunities in the rural areas. Land is fundamental to agriculture, yet the different challenges women face in accessing them are rarely fully addressed. For women, it is often particularly difficult to access, own or control land due to legal or cultural restrictions ( Emeasoba, 2012). This problem is widespread; women hold title to approximately two percent of land globally and are frequently denied the right to inherit property (World Bank, 2005). The wealth obtainable from cassava production, processing and marketing as a result of gender inequality remains under serious threat if nothing is done to improve the operating environmental and socio- economic conditions of the farmers in terms of asset holding, welfare and credit availability. The broad objective of the study is to analyze male and female access to land for cassava production in Abia state and specifically to describe the socio-economic characteristics of the respondents and the difference in quantity of cassava produced by both male and female respondents.
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IDENTIFICATION OF EXPLORATION GOLD TARGETS IN THE ALTA FLORESTA GOLD PROVINCE, MATO GROSSO STATE, BRAZIL, BASED ON AN INTEGRATED INTERPRETATION OF MAGNETIC AND GEOELECTRICAL DATA

IDENTIFICATION OF EXPLORATION GOLD TARGETS IN THE ALTA FLORESTA GOLD PROVINCE, MATO GROSSO STATE, BRAZIL, BASED ON AN INTEGRATED INTERPRETATION OF MAGNETIC AND GEOELECTRICAL DATA

ABSTRACT. The significant amount of filonean bodies in the gold mining area of Flor da Serra, east portion of the Alta Floresta Gold Province, located in the state of Mato Grosso, Brazil, and the production history of the area indicates high potential for gold exploration. Our work aimed to identify new gold exploration targets in this area through the analysis and interpretation of geoelectric and magnetic data, constrained by descriptions of drill core samples and prospecting pits. The geophysical survey consisted of the acquisition of geoelectrical (induced polarization/resistivity) and magnetic data at deposit scale. Anomalous values of chargeability and resistivity defined zones of intense silicification and quartz-sericite-pyrite alteration closely related to a disseminated ore type, extending far below the saprolite-bedrock interface. The amplitude of the analytic signal of the magnetic anomalous field allowed the identification of granitic intrusive stock within heterogeneous basement. Magnetic structures were extracted from magnetic anomalies reduced to the equator over which directional features were highlighted after application of a directional cosine filter and upward continuation. The structural pattern is associated with different crustal levels, controls the main filonean bodies of the region and is attached to quartz- sericite-pyrite alteration. The integrated interpretation of main structural lineaments; zones of high chargeability/resistivity; detailed mapping of deactivated mining pits; and boundaries of the intrusion zone led to the definition of some prospective gold targets.
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Design and synthesis of small molecule modulators of p53

Design and synthesis of small molecule modulators of p53

Among the tumor suppressor genes, p53 is one of the most studied. It is widely regarded as the “guardian of the genome”, playing a pivotal part in the preservation of genomic integrity by regulating cell cycle, apoptosis, DNA repair, senescence and angiogenesis, and consequently has a major role in carcinogenesis. The function played by p53 in tumor suppression is further highlighted by the fact that direct inactivation of this gene occurs in more than 50% of malignancies. In addition, in tumors that retain wild type p53 status, its function is usually inactivated by overexpression of negative regulators, primarily murine double minute-2 (MDM2), mainly through MDM2 gene amplification or by activity loss of MDM2 inhibitor ARF. Hence, restoring p53 function in cancer cells represents a valuable anticancer approach. Several strategies are being developed, and in particular targeting p53-MDM2 interaction has emerged as a promising viable approach when dealing with cancers that retain wild type p53 function. These two proteins regulate each other through an autoregulatory feedback loop: activation of p53 stimulates the transcription of MDM2, which in turn binds to the N- terminal transactivation domain of p53, disabling its transcriptional function. p53- MDM2 interaction inhibitors share common structural features: a rigid heterocyclic scaffold with three lipophilic groups that mimic the three pivotal p53 Phe19, Trp23 and Leu26 that interact with MDM2. Seven compounds have already entered clinical trials.
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Computational predictions of volatile anesthetic interactions with the microtubule cytoskeleton: implications for side effects of general anesthesia

Computational predictions of volatile anesthetic interactions with the microtubule cytoskeleton: implications for side effects of general anesthesia

Tubulin, a peanut-shaped heterodimer with a and b monomers, has been identified as a direct binding target for halothane [22]. Additionally, experiment shows volatile anesthetics, particularly halothane, alter the tubulin self-assembly rates into MTs in a number of systems, both in vivo [41–46] and in vitro [47], albeit at extremely high concentrations. When polymerized into MT form, each tubulin subunit interacts with surrounding dimers, forming longitudinal contacts between dimers along the protofilament length, and lateral contacts between protofilaments (see Figure 1). There also exists an intradimer interaction between the a- and b- monomers of a single tubulin dimer. In the more prevalent B- lattice MT formation the lateral contacts are formed between like subunits (i.e. a-monomer to a-monomer, and b-monomer to b- monomer on adjacent protofilaments). In the less common A- lattice, lateral interactions are between a and b monomers. Volatile anesthetics may inhibit MT assembly dynamics by a direct molecular interaction between the anesthetic molecule and the tubulin dimer hindering dimer-dimer, or intradimer interactions. It is also feasible that volatile anesthetics exert their action on MT dynamics through an alteration of the local environment affecting the highly flexible C-terminal tail regions of tubulin. Clearly, the site and mechanism of anesthetic action on MT assembly and stability remain to be determined.
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Global transcriptome profile of Cryptococcus neoformans during exposure to hydrogen peroxide induced oxidative stress.

Global transcriptome profile of Cryptococcus neoformans during exposure to hydrogen peroxide induced oxidative stress.

transcriptional response at 30 min after treatment, compared to those grown in YNB. This observed influence of growth conditions on the sensitivity of yeast cells to peroxide stress may be of special importance in C. neoformans pathogenesis since various species of Cryptococcus has been discovered to be associated with diverse ecological niches such as avian guano, vegetables, wood, dairy products, and soil [68,69]. The composition of these environmen- tal conditions may therefore determine the level of yeast cells’ constitutive redox potential. The ability to cause infection in a mammalian host will depend on their capacity to resist initial oxidative burst inside the macrophages. Therefore, increased resistance to oxidative stress as a result of environmental factors may play a role in enhanced virulence during infection.
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