The analysis of modular gene co-expression networks is a well-established method commonly used for discovering the systems-level functionality of genes. In addition, these studies provide a basis for ...the discovery of clinically relevant molecular pathways underlying different diseases and conditions.
In this paper, we present a fast and easy-to-use Bioconductor package named CEMiTool that unifies the discovery and the analysis of co-expression modules. Using the same real datasets, we demonstrate that CEMiTool outperforms existing tools, and provides unique results in a user-friendly html report with high quality graphs. Among its features, our tool evaluates whether modules contain genes that are over-represented by specific pathways or that are altered in a specific sample group, as well as it integrates transcriptomic data with interactome information, identifying the potential hubs on each network. We successfully applied CEMiTool to over 1000 transcriptome datasets, and to a new RNA-seq dataset of patients infected with Leishmania, revealing novel insights of the disease's physiopathology.
The CEMiTool R package provides users with an easy-to-use method to automatically implement gene co-expression network analyses, obtain key information about the discovered gene modules using additional downstream analyses and retrieve publication-ready results via a high-quality interactive report.
Temporal (or time-evolving) networks are commonly used to model complex systems and the evolution of their components throughout time. Although these networks can be analyzed by different means, ...visual analytics stands out as an effective way for a pre-analysis before doing quantitative/statistical analyses to identify patterns, anomalies, and other behaviors in the data, thus leading to new insights and better decision-making. However, the large number of nodes, edges, and/or timestamps in many real-world networks may lead to polluted layouts that make the analysis inefficient or even infeasible. In this paper, we propose LargeNetVis, a web-based visual analytics system designed to assist in analyzing small and large temporal networks. It successfully achieves this goal by leveraging three taxonomies focused on network communities to guide the visual exploration process. The system is composed of four interactive visual components: the first (Taxonomy Matrix) presents a summary of the network characteristics, the second (Global View) gives an overview of the network evolution, the third (a node-link diagram) enables community- and node-level structural analysis, and the fourth (a Temporal Activity Map - TAM) shows the community- and node-level activity under a temporal perspective. We demonstrate the usefulness and effectiveness of LargeNetVis through two usage scenarios and a user study with 14 participants.
IQG-607 is a metal complex previously reported as a promising anti-tuberculosis (TB) drug against isoniazid (INH)-resistant strains of
Unexpectedly, we found that INH-resistant clinical isolates were ...resistant to IQG-607. Spontaneous mutants resistant to IQG-607 were subjected to whole-genome sequencing, and all sequenced colonies carried alterations in the
gene. The
(S315T) mutation was sufficient to confer resistance to IQG-607 in both MIC assays and inside macrophages. Moreover, overexpression of the InhA(S94A) protein caused IQG-607's resistance.
IQG-607 is an analog of isoniazid with anti-tuberculosis activity. This work describes the development and validation of an HPLC method to quantify pentacyano(isoniazid)ferrate(II) compound (IQG-607) ...and the pharmacokinetic studies of this compound in mice. The method showed linearity in the 0.5–50μg/mL concentration range (r=0.9992). Intra- and inter-day precision was <5%, and the recovery ranged from 92.07 to 107.68%. IQG-607 was stable in plasma for at least 30days at −80°C and, after plasma processing, for 4h in the auto-sampler maintained on ice (recovery >85%). The applicability of the method for pharmacokinetic studies was determined after intravenous (i.v.) and oral (fasted and fed conditions) administration to mice. IQG-607 levels in plasma were quantified at time points for up to 2.5h. A short half-life (t1/2) (1.14h), a high clearance (CL) (3.89L/h/kg), a moderate volume of distribution at steady state (Vdss) of 1.22L/kg, were observed after i.v. (50mg/kg) administration. Similar results were obtained for oral administration (250mg/kg) under fasted and fed conditions. The oral bioavailability (F), approximately 4%, was not altered by feeding. Plasma protein binding was 88.87±0.9%. The results described here provide novel insights into a pivotal criterion to warrant further efforts to be pursued towards attempts to translate this chemical compound into a chemotherapeutic agent to treat TB.
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β-ketoacyl-acyl carrier protein (ACP) reductase from Mycobacterium tuberculosis (MabA) is responsible for the second step of the type-II fatty acid elongation system of bacteria, plants, and ...apicomplexan organisms, catalyzing the NADPH-dependent reduction of β-ketoacyl-ACP to generate β-hydroxyacyl-ACP and NADP+. In the present work, the mabA-encoded MabA has been cloned, expressed, and purified to homogeneity. Initial velocity studies, product inhibition, and primary deuterium kinetic isotope effects suggested a steady-state random bi-bi kinetic mechanism for the MabA-catalyzed reaction. The magnitudes of the primary deuterium kinetic isotope effect indicated that the C4-proS hydrogen is transferred from the pyridine nucleotide and that this transfer contributes modestly to the rate-limiting step of the reaction. The pH-rate profiles demonstrated groups with pK values of 6.9 and 8.0, important for binding of NADPH, and with pK values of 8.8 and 9.6, important for binding of AcAcCoA and for catalysis, respectively. Temperature studies were employed to determine the activation energy of the reaction. Solvent kinetic isotope effects and proton inventory analysis established that a single proton is transferred in a partially rate-limiting step and that the mechanism of carbonyl reduction is probably concerted. The observation of an inverse D 2 O V/K and an increase in D 2 O V when 4S-2HNADPH was the varied substrate obscured the distinction between stepwise and concerted mechanisms; however, the latter was further supported by the pH dependence of the primary deuterium kinetic isotope effect. Kinetic and chemical mechanisms for the MabA-catalyzed reaction are proposed on the basis of the experimental data.
Purine nucleoside phosphorylase (PNP) catalyzes the phosphorolysis of the
N-ribosidic bonds of purine nucleosides and deoxynucleosides. A genetic deficiency due to mutations in the gene encoding for ...human PNP causes T-cell deficiency as the major physiological defect. Inappropriate activation of T-cells has been implicated in several clinically relevant human conditions such as transplant tissue rejection, psoriasis, rheumatoid arthritis, lupus, and T-cell lymphomas. Human PNP is therefore a target for inhibitor development aiming at T-cell immune response modulation. In addition, bacterial PNP has been used as reactant in a fast and sensitive spectrophotometric method that allows both quantitation of inorganic phosphate (P
i) and continuous assay of reactions that generate P
i such as those catalyzed by ATPases and GTPases. Human PNP may therefore be an important biotechnological tool for P
i detection. However, low expression of human PNP in bacterial hosts, protein purification protocols involving many steps, and low protein yields represent technical obstacles to be overcome if human PNP is to be used in either high-throughput drug screening or as a reagent in an affordable P
i detection method. Here, we describe PCR amplification of human PNP from a liver cDNA library, cloning, expression in
Escherichia coli host, purification, and activity measurement of homogeneous enzyme. Human PNP represented approximately 42% of total soluble cell proteins with no induction being necessary to express the target protein. Enzyme activity measurements demonstrated a 707-fold increase in specific activity of cloned human PNP as compared to control. Purification of cloned human PNP was achieved by a two-step purification protocol, yielding 48
mg homogeneous enzyme from 1
L cell culture, with a specific activity value of 80
U
mg
−1.
Temporal (or time-evolving) networks are commonly used to model complex systems and the evolution of their components throughout time. Although these networks can be analyzed by different means, ...visual analytics stands out as an effective way for a pre-analysis before doing quantitative/statistical analyses to identify patterns, anomalies, and other behaviors in the data, thus leading to new insights and better decision-making. However, the large number of nodes, edges, and/or timestamps in many real-world networks may lead to polluted layouts that make the analysis inefficient or even infeasible. In this paper, we propose LargeNetVis, a web-based visual analytics system designed to assist in analyzing small and large temporal networks. It successfully achieves this goal by leveraging three taxonomies focused on network communities to guide the visual exploration process. The system is composed of four interactive visual components: the first (Taxonomy Matrix) presents a summary of the network characteristics, the second (Global View) gives an overview of the network evolution, the third (a node-link diagram) enables community- and node-level structural analysis, and the fourth (a Temporal Activity Map -- TAM) shows the community- and node-level activity under a temporal perspective.
O Código Florestal Brasileiro de 1965 conceitua e regulamenta as Áreas de Preservação Permanente (APP) e Reserva Legal (RL). Para regulamentar a adequação das propriedades agrícolas ao código ...florestal, o estado do Paraná instituiu o SISLEG - Sistema de Manutenção, Recuperação e Proteção da Reserva Legal e Áreas de Preservação Permanente. Neste estudo foram quantificadas, com auxílio do sistema de posicionamento global (GPS) e programas de Sistemas de Informações Geográficas (SIG), as APPs e RLs de 147 propriedades em oito municípios das regiões centro-oriental e sudeste do Paraná, visando analisá-las frente ao Código Florestal vigente. Observou-se expressiva cobertura florestal formada por fragmentos de Floresta Ombrófila Mista; as superfícies disponíveis para definição de RL apresentam valores superiores àqueles requeridos pela legislação. Há necessidade de recomposição das APPs em 67% das propriedades; 26% das propriedades estão de acordo com as exigências do Código Florestal. A quantificação da cobertura florestal necessária e remanescente, tal como a pequena demanda de área para readequação de APP (5% da área total) permitem inferir que esses quesitos não são entraves para a regularização ambiental da agricultura familiar, nas propriedades analisadas.
The Brazilian Forest Code of 1965 has defined and regulated the concepts of Permanent Preservation Areas (APP) and the Legal Reserve (RL). To regulate rural properties' compliance to the forest code, the State of Paraná introduced the SISLEG- Maintenance, Rehabilitation and Protection of Legal Reserve and Permanent Preservation Areas System. This study quantified, with the help of global positioning system (GPS) and Geographic Information Systems (GIS), the APPs and RLs of 147 properties in eight cities in East-central and Southeastern Paraná, aiming to analyze the environmental compliance of family-based rural properties to the Forest Code. A significant amount of forest cover was mapped, mainly as fragments of Araucaria Forest. The amount of forest cover is higher than the minimum required by law. Concerning the APPs about 67% of farms required some restoration while 26% of them are in accordance with the Code. The quantification of existing forest cover and that required by law, as well as the relatively small area necessary for the adjustment of the APPs (5% of total area) allows inferring that these questions are not barriers for the environmental regulation of the family-based surveyed farms.
O Código Florestal Brasileiro de 1965 conceitua e regulamenta as Áreas de Preservação Permanente (APP) e Reserva Legal (RL). Para regulamentar a adequação das propriedades agrícolas ao código ...florestal, o estado do Paraná instituiu o SISLEG - Sistema de Manutenção, Recuperação e Proteção da Reserva Legal e Áreas de Preservação Permanente. Neste estudo foram quantificadas, com auxílio do sistema de posicionamento global (GPS) e programas de Sistemas de Informações Geográficas (SIG), as APPs e RLs de 147 propriedades em oito municípios das regiões centro-oriental e sudeste do Paraná, visando analisá-las frente ao Código Florestal vigente. Observou-se expressiva cobertura florestal formada por fragmentos de Floresta Ombrófila Mista; as superfícies disponíveis para definição de RL apresentam valores superiores àqueles requeridos pela legislação. Há necessidade de recomposição das APPs em 67% das propriedades; 26% das propriedades estão de acordo com as exigências do Código Florestal. A quantificação da cobertura florestal necessária e remanescente, tal como a pequena demanda de área para readequação de APP (5% da área total) permitem inferir que esses quesitos não são entraves para a regularização ambiental da agricultura familiar, nas propriedades analisadas.
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