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Lung cancer is the most lethal malignant neoplasm worldwide, with an annual estimated rate of 1.8 million deaths. Computed tomography has been widely used to diagnose and detect lung cancer, but its diagnosis remains an intricate and challenging work, even for experienced radiologists. Computer-aided diagnosis tools and radiomics tools have provided support to the radiologist's decision, acting as a second opinion. The main focus of these tools has been to analyze the intranodular zone; nevertheless, recent works indicate that the interaction between the nodule and its surroundings (perinodular zone) could be relevant to the diagnosis process. However, only a few works have investigated the importance of specific attributes of the perinodular zone and have shown how important they are in the classification of lung nodules. In this context, the purpose of this work is to evaluate the impact of using the perinodular zone on the characterization of lung lesions. Motivated by reproducible research, we used a large public dataset of solid lung nodule images and extracted fine-tuned radiomic attributes from the perinodular and intranodular zones. Our best-evaluated model obtained an average AUC of 0.916, an accuracy of 84.26%, a sensitivity of 84.45%, and specificity of 83.84%. The combination of attributes from the perinodular and intranodular zones in the image characterization resulted in an improvement in all the metrics analyzed when compared to intranodular-only characterization. Therefore, our results highlighted the importance of using the perinodular zone in the solid pulmonary nodules classification process., (© 2021. Society for Imaging Informatics in Medicine.)

The discipline of radiology and diagnostic imaging has evolved greatly in recent years. We have observed an exponential increase in the number of exams performed, subspecialization of medical fields, and increases in accuracy of the various imaging methods, making it a challenge for the radiologist to "know everything about all exams and regions". In addition, imaging exams are no longer only qualitative and diagnostic, providing now quantitative information on disease severity, as well as identifying biomarkers of prognosis and treatment response. In view of this, computer-aided diagnosis systems have been developed with the objective of complementing diagnostic imaging and helping the therapeutic decision-making process. With the advent of artificial intelligence, "big data", and machine learning, we are moving toward the rapid expansion of the use of these tools in daily life of physicians, making each patient unique, as well as leading radiology toward the concept of multidisciplinary approach and precision medicine. In this article, we will present the main aspects of the computational tools currently available for analysis of images and the principles of such analysis, together with the main terms and concepts involved, as well as examining the impact that the development of artificial intelligence has had on radiology and diagnostic imaging.

Recently, a large body of evidences indicates the existence in the mitochondrial matrix of foci that contain different proteins involved in mitochondrial RNA metabolism. Some of these proteins have a pentatricopeptide repeat motif that constitutes their RNA-binding structures. Here we report that MSC6, a mitochondrial pentatricopeptide protein of unknown function, is a multi copy suppressor of mutations in QRS1/HER2 a component of the trimeric complex that catalyzes the transamidation of glutamyl-tRNAQ to glutaminyl-tRNAQ. This is an essential step in mitochondrial translation because of the lack of a specific mitochondrial aminoacyl glutaminyl-tRNA synthetase. MSC6 over-expression did not abolish translation of an aberrant variant form of Cox2p detected in QRS1/HER2 mutants, arguing against a suppression mechanism that bypasses Qrs1p function. A slight decrement of the mitochondrial translation capacity as well as diminished growth on respiratory carbon sources media for respiratory activity was observed in the msc6 null mutant. Additionally, the msc6 null mutant did not display any impairment in RNA transcription, processing or turnover. We concluded that Msc6p is a mitochondrial matrix protein and further studies are required to indicate the specific function of Msc6p in mitochondrial translation.

Coenzyme Q (Q) is an isoprenylated benzoquinone electron carrier required for electronic transport in the mitochondrial respiratory chain, shuttling electrons from complexes I and II to complex III. Q synthesis requires proteins termed Coq (Coq1-Coq11). Coq7p is part of the multimeric complex involved in Q synthesis catalyzing the hydroxylation of demethoxy-Q6 (DMQ6), the last monooxygenase step in Q synthesis with a catalytic center containing a carboxylate-bridged di-iron at the active site of the enzyme. Here we indicate a group of Coq7p residues that modulate protein activity: D53, R57, V111 and S114. R57, V111 and S114 are very conserved residues; V111 and S114 are present in separated communities of amino acid correlation analysis. The coq7 double mutant V111G/S114A and S114E show respiratory deficiency at non permissive temperature, DMQ6 accumulation and lower content of Q6. Therefore we conclude that phosphomimetic S114E inhibit Coq7p activity, and propose that S114 phosphorylation is required to move a non-structured loop of 25 amino acids between helix 2 and 3, and that affects the di-iron coordination in Coq7p catalytic center., (Copyright © 2015 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

Mitochondrial retrograde signaling is a communication pathway between the mitochondrion and the nucleus that regulates the expression of a subset of nuclear genes that codify mitochondrial proteins, mediating cell response to mitochondrial dysfunction. In Saccharomyces cerevisiae, the pathway depends on Rtg1p and Rtg3p, which together form the transcription factor that regulates gene expression, and Rtg2p, an activator of the pathway. Here, we provide novel studies aimed at assessing the functional impact of the lack of RTG-dependent signaling on mitochondrial activity. We show that mutants defective in RTG-dependent retrograde signaling present higher oxygen consumption and reduced hydrogen peroxide release in the stationary phase compared to wild-type cells. Interestingly, RTG mutants are less able to decompose hydrogen peroxide or maintain viability when challenged with hydrogen peroxide. Overall, our results indicate that RTG signaling is involved in the hormetic induction of antioxidant defenses and stress resistance., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Bacterial GatCAB amidotransferases are responsible for the transamidation of mischarged glutamyl-tRNA(Gln) into glutaminyl-tRNA(Gln). Mitochondria matrix also has a multienzymatic complex necessary for the transamidation of glutamyl-tRNA(Gln). Gtf1p, Her2p and Pet112p are the constituents of mitochondrial GatFAB amidotransferase complex. Her2p is subunit A of GatFAB complex, while Gtf1p is subunit F, a connector protein between Pet112p (subunit B) and Her2p. Here we evaluate through molecular modeling and amino acid correlation analysis the HER2 protein family. Localization studies indicated that Her2p is predominantly localized in the mitochondrial outer membrane, but it is also located in the mitochondrial matrix where together with Pet112p and Gtf1p constitutes the GatFAB complex. Finally, HER2 random mutagenesis unveiled important residues that provide thermo stability for the complex and are differently suppressed by overexpression of GTF1 or PET112. For instance, her2/ts11 mutant showed its fermentative growth impaired, and poorly rescued by GTF1 indicating that Her2p unknown function in the mitochondria outer membrane affects cell viability., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Superoxide dismutases (SODs; EC 1.15.1.1) are part of the antioxidant system of aerobic organisms and are used as a defense against oxidative injury caused by reactive oxygen species (ROS). The cloning and sequencing of the 788-bp genomic DNA from Trichoderma reesei strain QM9414 (anamorph of Hypocrea jecorina) revealed an open reading frame encoding a protein of 212 amino acid residues, with 65-90% similarity to manganese superoxide dismutase from other filamentous fungi. The TrMnSOD was purified and shown to be stable from 20 to 90°C for 1h at pH from 8 to 11.5, while maintaining its biological activity., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The IL-10 family of cytokines is comprised of IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, and IFN-lambdas (IL-28A, IL-28B, and IL-29). The IL-10 family members bind to shared class II cytokine receptor chains that associate in various combinations in heterodimeric complexes. Upon interleukin/receptor complex formation, these proteins switch on the Jak/STAT pathway and elicit pleiotropic biological responses whose variety sharply contrasts with their structural similarities. IL-10 family members are involved in several human diseases and health conditions and hence their structural analyses may provide valuable information to design specific therapeutic strategies. In this review, we describe the human interleukin-10 family of cytokines, focusing on their structures and functions, with particular attention given to IL-22 and IL-10. We report on the recently published structures of IL-10 cytokine family members and their complexes with cognate transmembrane and soluble receptors as well as on interleukin physiology and physiopathology.

Coq10p is a protein required for coenzyme Q function, but its specific role is still unknown. It is a member of the START domain superfamily that contains a hydrophobic tunnel implicated in the binding of lipophilic molecules. We used site-directed mutagenesis, statistical coupling analysis and molecular modeling to probe structural determinants in the Coq10p putative tunnel. Four point mutations were generated (coq10-K50E, coq10-L96S, coq10-E105K and coq10-K162D) and their biochemical properties analysed, as well as structural consequences. Our results show that all mutations impaired Coq10p function and together with molecular modeling indicate an important role for the Coq10p putative tunnel., (Copyright 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)

Genes for the enzymes that metabolize galactose in Saccharomyces cerevisiae are strongly induced by galactose and tightly repressed by glucose. Because glucose also represses mitochondrial activity, we examined if derepression of the GAL1 galactokinase gene requires physiologically active mitochondria. The effect of mitochondria on the expression of GAL1 was analyzed by a novel approach in which the activity of the organelles was altered by functional expression of URF13, a mitochondrial protein unique to the Texas-type cytoplasmic male sterility phenotype in maize. Mitochondrial targeting and functional expression of the URF13 protein in yeast result in a decrease of the mitochondrial membrane potential similar to those observed in cells treated with mitochondrial inhibitors such as antimycin A or sodium azide. Activation of URF13 in galactose-induced cells results in the inhibition of GAL1 expression in the absence of repressing concentrations of glucose. Our data reveal the existence of a regulatory pathway that connects the derepression of the GAL1 gene with mitochondrial activity.

Interleukin-22 (IL-22) is a cytokine that regulates the production of acute phase proteins of the immunological response. On binding to its cognate receptor (IL-22R1), which is associated to the interleukin-10 receptor 2 (IL-10R2), IL-22 promotes activation of signal transducer and activator of transcription (STAT) pathway and several other cellular responses. A soluble receptor termed interleukin-22 binding protein (IL-22BP) is also able to bind to IL-22 as a natural protein antagonist, and probably provides systemic regulation of IL-22 activity. This inflammatory response system is analyzed here in terms of its molecular physiology and structural assembly. Three-dimensional (3D) model of IL-22 and structural basis of its interactions with the cognate receptors are discussed.

Retrograde signaling mediates nuclear gene expression in response to changes in the functional state of mitochondria. In budding yeast, retrograde signaling, also termed the RTG pathway, relies on the heterodimeric, basic helix-loop-helix zipper transcription factors, Rtg1p and Rtg3p, for the activation of target gene expression. Activation of the RTG pathway leads to partial dephosphorylation of Rtg3p and its translocation, together with Rtg1p, from the cytoplasm to the nucleus. These processes depend on a positive regulatory factor, Rtg2p, a novel protein with a ATP binding domain similar to that of the Hsp70/actin/sugar kinase superfamily. Four negative regulatory factors, Lst8p, Mks1p, and two redundant 14-3-3 proteins, Bmh1/2p, function between Rtg2p and Rtg1/3p. Alternative interaction between Mks1p and Rtg2p or Bmh1/2p provides a means for regulation of the RTG pathway. When the RTG pathway is on, Mks1p is inactivated by its association with Rtg2p; and when the RTG pathway is off, Mks1p dissociates from Rtg2p and forms a complex with Bmh1/2p, which is the negative regulatory form of Mks1p. Here we show that Rtg2p and Mks1p can interact in the absence of other factors, and is thereby the minimal binary switch for regulation of the RTG pathway. Gel filtration experiments indicate that both Rtg2p and Mks1p exist in high molecular weight complexes. In response to changes in the activity of the RTG pathway, both Rtg2p and Mks1p shift to different sized high molecular weight complexes. Together, our data suggest that dynamic association between Mks1p and Rtg2p in high molecular weight complexes provides a means to regulate the RTG pathway.

Despite the intense interest in the metabolic regulation and evolution of the ATP-producing pathways, the long standing question of why most multicellular microorganisms metabolize glucose by respiration rather than fermentation remains unanswered. One such microorganism is the cellulolytic fungus Trichoderma reesei (Hypocrea jecorina). Using EST analysis and cDNA microarrays, we find that in T. reesei expression of the genes encoding the enzymes of the tricarboxylic acid cycle and the proteins of the electron transport chain is programmed in a way that favors the oxidation of pyruvate via the tricarboxylic acid cycle rather than its reduction to ethanol by fermentation. Moreover, the results indicate that acetaldehyde may be channeled into acetate rather than ethanol, thus preventing the regeneration of NAD(+), a pivotal product required for anaerobic metabolism. The studies also point out that the regulatory machinery controlled by glucose was most probably the target of evolutionary pressure that directed the flow of metabolites into respiratory metabolism rather than fermentation. This finding has significant implications for the development of metabolically engineered cellulolytic microorganisms for fuel production from cellulose biomass.

The upstream activating region that controls cellulose-induced expression of the glucose-repressible cellobiohydrolase I gene (UARcb1) of the filamentous fungus Trichoderma reesei is shown to mediate transcription and glucose repression of a reporter gene in Saccharomyces cerevisiae, a unicellular microorganism that lacks the genes required for the utilization of cellulose. Glucose-controlled transcription mediated by UARcb1 requires the products of the genes SNF1 and SSN6, a protein kinase and a repressor, respectively, that regulate glucose-repressible yeast genes. Previously, it has been shown that mitochondrial function is implicated in cellobiohydrolase I gene expression in T. reesei and this sensitivity to the metabolic state of the mitochondria was shown to be transcriptionally controlled by the 5'-flanking sequence of the cbh1 gene [Abrahão-Neto et al. (1995) Biochemistry 34, 10456-10462]. Remarkably, transcription of the reporter gene controlled by UARcb1 in S. cerevisiae also showed a requirement for active mitochondria, suggesting that a common mechanism involving mitochondrial activity controls glucose-repressible genes in both microorganisms., (Copyright 1998 Academic Press.)