The metabolomics window into diabetic complications.

J Diabetes Investig. 2017 Aug 05;:

Authors: Wu T, Qiao S, Shi C, Wang S, Ji G

Abstract
Diabetes has become a major global health problem. The elucidation of characteristic metabolic alterations during the diabetic progression is critical for better understanding its pathogenesis and identifying potential biomarkers and drug targets. Metabolomics is a promising tool to reveal the metabolic changes and the underlying mechanism involved in the pathogenesis of diabetic complications. The present review provides an update on the application of metabolomics in diabetic complications, including diabetic coronary artery disease, diabetic nephropathy, diabetic retinopathy, and diabetic neuropathy, and this review provides notes on the prevention and prediction of diabetic complications. This article is protected by copyright. All rights reserved.

PMID: 28779528 [PubMed - as supplied by publisher]

Cellular redox dysfunction in the development of cardiovascular diseases.

Biochim Biophys Acta. 2017 Aug 01;:

Authors: Kanaan GN, Harper ME

Abstract
To meet its exceptionally high energy demands, the heart relies largely on fatty acid oxidation, which then drives the oxidative phosphorylation system in mitochondria. Each day, this system produces about 6kg of ATP to sustain heart function. Fatty acid oxidation is sometimes associated with high rates of mitochondrial reactive oxygen species (ROS) production. By definition, ROS are singlet electron intermediates formed during the partial reduction of oxygen to water and they include radical and non-radical intermediates like superoxide, hydrogen peroxide and hydroxyl radical. Superoxide can also interact with nitric oxide to produce peroxynitrite that in turn can give rise to other radical or non-radical reactive nitrogen species (RNS) like nitrogen dioxide, dinitrogen trioxide and others. While mitochondrial and cellular functions can be impaired by ROS if they accumulate, under normal physiological conditions ROS are important signaling molecules in the cardiovascular system. A fine balance between ROS production and antioxidant systems, including glutathione redox, is essential in the heart; otherwise the ensuing damage can contribute to pathogenic processes, which can culminate in endothelial dysfunction, atherosclerosis, hypertension, cardiac hypertrophy, arrhythmias, myocardial ischemia/reperfusion damage, and heart failure. Here we provide a succinct review of recent findings.

PMID: 28778485 [PubMed - as supplied by publisher]

The first succinylome profile of Trichophyton rubrum reveals lysine succinylation on proteins involved in various key cellular processes.

BMC Genomics. 2017 Aug 04;18(1):577

Authors: Xu X, Liu T, Yang J, Chen L, Liu B, Wei C, Wang L, Jin Q

Abstract
BACKGROUND: Dermatophytes, the most common cause of fungal infections, affect millions of individuals worldwide. They pose a major threat to public health because of the severity and longevity of infections caused by dermatophytes and their refractivity to therapy. Trichophyton rubrum (T. rubrum), the most common dermatophyte species, is a promising model organism for dermatophyte research. Post-translational modifications (PTMs) have been shown to be essential for many biological processes, particularly in the regulation of key cellular processes that contribute to pathogenicity. Although PTMs have important roles, little is known about their roles in T. rubrum and other dermatophytes. Succinylation is a new PTM that has recently been identified. In this study, we assessed the proteome-wide succinylation profile of T. rubrum. This study sought to systematically identify the succinylated sites and proteins in T. rubrum and to reveal the roles of succinylated proteins in various cellular processes as well as the differences in the succinylation profiles in different growth stages of the T. rubrum life cycle.
RESULTS: A total of 569 succinylated lysine sites were identified in 284 proteins. These succinylated proteins are involved in various cellular processes, such as metabolism, translation and epigenetic regulation. Additionally, 24 proteins related to pathogenicity were found to be succinylated. Comparison of the succinylome at the conidia and mycelia stages revealed that most of the succinylated proteins and sites were growth-stage specific. In addition, the succinylation modifications on histone and ribosomal proteins were significantly different between these two growth stages. Moreover, the sequence features surrounding the succinylated sites were different in the two stages, thus indicating the specific recognition of succinyltransferases in each growth phase.
CONCLUSIONS: In this study, we explored the first T. rubrum succinylome, which is also the first PTM analysis of dermatophytes reported to date. These results revealed the major roles of the succinylated proteins involved in T. rubrum and the differences in the succinylomes between the two major growth stages. These findings should improve understanding of the physiological and pathogenic properties of dermatophytes and facilitate future development of novel drugs and therapeutics for treating superficial fungal infections.

PMID: 28778155 [PubMed - in process]

A computational study of VEGF production by patterned retinal epithelial cell colonies as a model for neovascular macular degeneration.

J Biol Eng. 2017;11:26

Authors: Baker QB, Podgorski GJ, Vargis E, Flann NS

Abstract
BACKGROUND: The configuration of necrotic areas within the retinal pigmented epithelium is an important element in the progression of age-related macular degeneration (AMD). In the exudative (wet) and non-exudative (dry) forms of the disease, retinal pigment epithelial (RPE) cells respond to adjacent atrophied regions by secreting vascular endothelial growth factor (VEGF) that in turn recruits new blood vessels which lead to a further reduction in retinal function and vision. In vitro models exist for studying VEGF expression in wet AMD (Vargis et al., Biomaterials 35(13):3999-4004, 2014), but are limited in the patterns of necrotic and intact RPE epithelium they can produce and in their ability to finely resolve VEGF expression dynamics.
RESULTS: In this work, an in silico hybrid agent-based model was developed and validated using the results of this cell culture model of VEGF expression in AMD. The computational model was used to extend the cell culture investigation to explore the dynamics of VEGF expression in different sized patches of RPE cells and the role of negative feedback in VEGF expression. Results of the simulation and the cell culture studies were in excellent qualitative agreement, and close quantitative agreement.
CONCLUSIONS: The model indicated that the configuration of necrotic and RPE cell-containing regions have a major impact on VEGF expression dynamics and made precise predictions of VEGF expression dynamics by groups of RPE cells of various sizes and configurations. Coupled with biological studies, this model may give insights into key molecular mechanisms of AMD progression and open routes to more effective treatments.

PMID: 28775765 [PubMed]

Complete genome sequence of the sand-sediment actinobacterium Nocardioides dokdonensis FR1436(T).

Stand Genomic Sci. 2017;12:44

Authors: Kwak MJ, Kwon SK, Kim JF

Abstract
Nocardioides dokdonensis, belonging to the class Actinobacteria, was first isolated from sand sediment of a beach in Dokdo, Korea, in 2005. In this study, we determined the genome sequence of FR1436, the type strain of N. dokdonensis, and analyzed its gene contents. The genome sequence is the second complete one in the genus Nocardioides after that of Nocardioides sp. JS614. It is composed of a 4,376,707-bp chromosome with a G + C content of 72.26%. From the genome sequence, 4,104 CDSs, three rRNA operons, 51 tRNAs, and one tmRNA were predicted, and 71.38% of the genes were assigned putative functions. Through the sequence analysis, dozens of genes involved in steroid metabolism, especially its degradation, were detected. Most of the identified genes were located in large gene clusters, which showed high similarities with the gene clusters in Pimelobacter simplex VKM Ac-2033D. Genomic features of N. dokdonensis associated with steroid catabolism indicate that it could be used for research and application of steroids in science and industry.

PMID: 28770029 [PubMed]

A Proteomic View on the Role of Legume Symbiotic Interactions.

Front Plant Sci. 2017;8:1267

Authors: Larrainzar E, Wienkoop S

Abstract
Legume plants are key elements in sustainable agriculture and represent a significant source of plant-based protein for humans and animal feed worldwide. One specific feature of the family is the ability to establish nitrogen-fixing symbiosis with Rhizobium bacteria. Additionally, like most vascular flowering plants, legumes are able to form a mutualistic endosymbiosis with arbuscular mycorrhizal (AM) fungi. These beneficial associations can enhance the plant resistance to biotic and abiotic stresses. Understanding how symbiotic interactions influence and increase plant stress tolerance are relevant questions toward maintaining crop yield and food safety in the scope of climate change. Proteomics offers numerous tools for the identification of proteins involved in such responses, allowing the study of sub-cellular localization and turnover regulation, as well as the discovery of post-translational modifications (PTMs). The current work reviews the progress made during the last decades in the field of proteomics applied to the study of the legume-Rhizobium and -AM symbioses, and highlights their influence on the plant responses to pathogens and abiotic stresses. We further discuss future perspectives and new experimental approaches that are likely to have a significant impact on the field including peptidomics, mass spectrometric imaging, and quantitative proteomics.

PMID: 28769967 [PubMed]

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"systems biology"

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Towards an evidence based approach for the development of adjuvanted vaccines.

Curr Opin Immunol. 2017 Jul 26;47:93-102

Authors: O'Hagan DT, Friedland LR, Hanon E, Didierlaurent AM

Abstract
In the last two decades, several vaccines formulated with a new generation of adjuvants have been licensed or approved to target diseases such as influenza, hepatitis B, cervical cancer, and malaria. These new generation adjuvants appear to work by delivering a localized activation signal to the innate immune system, which in turn promotes antigen-specific adaptive immunity. Advances in understanding of the innate immune system together with high-throughput discovery of synthetic immune potentiators are now expanding the portfolio of new generation adjuvants available for evaluation. Meanwhile, omics and systems biology are providing molecular benchmarks or signatures to assess vaccine safety and effectiveness. This accumulating knowledge and experience raises the prospect that the future selection of the right antigen/adjuvant combination can be more evidence based and can speed up the clinical development program for new adjuvanted vaccines.

PMID: 28755542 [PubMed - as supplied by publisher]

Date Fruit Proteomics During Development and Ripening Stages.

Methods Mol Biol. 2017;1638:381-398

Authors: Marondedze C

Abstract
Gel-based comparative proteomics approach is a valuable technique for studying the changes in abundance of proteins in any given system. The combination of this technique with mass spectrometry has provided immense insight into protein dynamics during fruit development and ripening. This chapter describes, informatively, the procedures for carrying out comparative proteomics analysis of date palm (Phoenix dactylifera L.) fruits at different developmental stages using a combination of two-dimensional gel electrophoresis (2-DE) and mass spectrometry. A comparative proteomics approach provides an overview of protein abundances during fruit maturation and insights into proteins that play key roles during fruit maturation. Moreover, 2-DE technique enables the visualization of total protein distribution and abundance in addition to providing a comparative platform following separation of complex proteins based on their molecular weight and isoelectric point. Overall, this chapter describes methodologies for extraction of proteins from a high carbohydrate-containing fruit, protein quality assessment using one-dimensional gel electrophoresis (1-DE), separation using 2-DE, comparative analysis using Delta2D v4.6, processing of spots of interest, and protein identification using mass spectrometry. This protocol is important for studies aiming at comparative proteomics to gain insights into changes of protein abundances in tissues and organs in general and date palm fruits, in particular.

PMID: 28755236 [PubMed - in process]

A comparative study on the WCRF International/University of Bristol methodology for systematic reviews of mechanisms underpinning exposure-cancer associations.

Cancer Epidemiol Biomarkers Prev. 2017 Jul 28;:

Authors: Ertaylan G, Le Cornet C, van Roekel EH, Jung AY, Bours MJL, Damms-Machado A, van den Brandt PA, Schock H, de Kok TM, Theys J, Arts ICW, Kaaks R, Weijenberg MP, Fortner RT

Abstract
The World Cancer Research Fund International and the University of Bristol have developed a novel framework for providing an overview of mechanistic pathways and conducting a systematic literature review of the biologically plausible mechanisms underlying exposure-cancer associations. Two teams independently applied the two-stage framework on mechanisms underpinning the association between body fatness and breast cancer to test the framework feasibility and reproducibility as part of a WCRF-Commissioned validation study. In Stage 1, a "hypothesis-free" approach was used to provide an overview of potential intermediate mechanisms between body fatness and breast cancer. Dissimilar rankings of potential mechanisms were observed between the two teams due to different applications of the framework. In Stage 2, a systematic review was conducted on the insulin-like growth factor 1 receptor chosen as intermediate mechanism. Although the studies included differed, both teams found inconclusive evidence for the body fatness-IGF1R association and modest evidence linking IGF1R to breast cancer, therefore concluded that there is currently weak evidence for IGF1R as mechanism linking body fatness to breast cancer. The framework is a good starting point for conducting systematic review by integrating evidence from mechanistic studies on exposure-cancer associations. Based on our experience, we provide recommendations for future users.

PMID: 28754794 [PubMed - as supplied by publisher]

NRF1 coordinates with DNA methylation to regulate spermatogenesis.

FASEB J. 2017 Jul 28;:

Authors: Wang J, Tang C, Wang Q, Su J, Ni T, Yang W, Wang Y, Chen W, Liu X, Wang S, Zhang J, Song H, Zhu J, Wang Y

Abstract
Spermatogenesis is a highly coordinated process that requires tightly regulated gene expression programmed by transcription factors and epigenetic modifiers. In this study, we found that nuclear respiratory factor (NRF)-1, a key transcription factor for mitochondrial biogenesis, cooperated with DNA methylation to directly regulate the expression of multiple germ cell-specific genes including Asz1 In addition, conditional ablation of NRF1 in gonocytes dramatically down-regulated these germline genes, blocked germ cell proliferation, and subsequently led to male infertility in mice. Our data highlight a precise crosstalk between transcriptional regulation by NRF1 and epigenetic modulation during germ cell development and unequivocally demonstrate a novel role of NRF1 in spermatogenesis.-Wang, J., Tang, C., Wang, Q., Su, J., Ni, T., Yang, W., Wang, Yo., Chen, W., Liu, X., Wang, S., Zhang, J., Song, H., Zhu, J., Wang, Yu. NRF1 coordinates with DNA methylation to regulate spermatogenesis.

PMID: 28754714 [PubMed - as supplied by publisher]

Direct interaction of ezrin and AQP2 and its role in AQP2 trafficking.

J Cell Sci. 2017 Jul 28;:

Authors: Li W, Jin WW, Tsuji K, Chen Y, Nomura N, Su L, Yui N, Arthur J, Cotecchia S, Păunescu TG, Brown D, Lu HAJ

Abstract
The water channel aquaporin-2 (AQP2) is a major regulator of water homeostasis in response to vasopressin (VP). Dynamic trafficking of AQP2 relies on its close interaction with trafficking machinery proteins and the actin cytoskeleton. Here, we report the identification of ezrin, an actin binding protein from the ezrin/radixin/moesin (ERM) family as an AQP2 interacting protein. Ezrin was first detected in a co-immunoprecipitation (co-IP) complex using an anti-AQP2 antibody by proteomic analysis. Immunofluorescence staining revealed the co-expression of ezrin and AQP2 in collecting duct principal cells, and VP treatment caused redistribution of both proteins to the apical membrane. The ezrin-AQP2 interaction was confirmed by co-IP experiments using an anti-ezrin antibody, and by pull-down assays using purified full-length and FERM (four-point one/ezrin/radixin/moesin) domain-containing recombinant ezrin. Using purified recombinant proteins, we showed that ezrin directly interacts with AQP2 C-terminus through its N-terminal FERM domain. Knocking down ezrin expression with shRNA resulted in increased membrane accumulation of AQP2 and reduced AQP2 endocytosis. Therefore, through direct interaction with AQP2, ezrin facilitates AQP2 endocytosis, thus linking the dynamic actin cytoskeleton network with AQP2 trafficking.

PMID: 28754689 [PubMed - as supplied by publisher]

Deciphering the regulation of metabolism with dynamic optimization: an overview of recent advances.

Biochem Soc Trans. 2017 Jul 28;:

Authors: Ewald J, Bartl M, Kaleta C

Abstract
Understanding optimality principles shaping the evolution of regulatory networks controlling metabolism is crucial for deriving a holistic picture of how metabolism is integrated into key cellular processes such as growth, adaptation and pathogenicity. While in the past the focus of research in pathway regulation was mainly based on stationary states, more recently dynamic optimization has proved to be an ideal tool to decipher regulatory strategies for metabolic pathways in response to environmental cues. In this short review, we summarize recent advances in the elucidation of optimal regulatory strategies and identification of optimal control points in metabolic pathways. We discuss biological implications of the discovered optimality principles on genome organization and provide examples how the derived knowledge can be used to identify new treatment strategies against pathogens. Furthermore, we briefly discuss the variety of approaches for solving dynamic optimization problems and emphasize whole-cell resource allocation models as an important emerging area of research that will allow us to study the regulation of metabolism on the whole-cell level.

PMID: 28754658 [PubMed - as supplied by publisher]

Magnetic resonance T2 mapping and diffusion-weighted imaging for early detection of cystogenesis and response to therapy in a mouse model of polycystic kidney disease.

Kidney Int. 2017 Jul 26;:

Authors: Franke M, Baeßler B, Vechtel J, Dafinger C, Höhne M, Borgal L, Göbel H, Koerber F, Maintz D, Benzing T, Schermer B, Persigehl T

Abstract
Polycystic kidney disease (PKD) is among the leading causes of end-stage renal disease. Increasing evidence exists that molecular therapeutic strategies targeted to cyst formation and growth might be more efficacious in early disease stages, highlighting the growing need for sensitive biomarkers. Here we apply quantitative magnetic resonance imaging techniques of T2 mapping and diffusion-weighted imaging in the jck mouse model for PKD using a clinical 3.0 T scanner. We tested whether kidney T2 values and the apparent diffusion coefficient (ADC) are superior to anatomical imaging parameters in the detection of early cystogenesis, as shown on macro- and histopathology. We also tested whether kidney T2 values and ADC have the potential to monitor early treatment effects of therapy with the V2 receptor antagonist Mozavaptane. Kidney T2 values and to a lesser degree ADC were found to be highly sensitive markers of early cystogenesis and superior to anatomical-based imaging parameters. Furthermore, kidney T2 values exhibited a nearly perfect correlation to the histological cystic index, allowing a clear separation of the two mouse genotypes. Additionally, kidney T2 values and ADC were able to monitor early treatment effects in the jck mouse model in a proof-of-principle experiment. Thus, given the superiority of kidney T2 values and ADC over anatomical-based imaging in mice, further studies are needed to evaluate the translational impact of these techniques in patients with PKD.

PMID: 28754558 [PubMed - as supplied by publisher]

Manatee invariants reveal functional pathways in signaling networks.

BMC Syst Biol. 2017 Jul 28;11(1):72

Authors: Amstein L, Ackermann J, Scheidel J, Fulda S, Dikic I, Koch I

Abstract
BACKGROUND: Signal transduction pathways are important cellular processes to maintain the cell's integrity. Their imbalance can cause severe pathologies. As signal transduction pathways feature complex regulations, they form intertwined networks. Mathematical models aim to capture their regulatory logic and allow an unbiased analysis of robustness and vulnerability of the signaling network. Pathway detection is yet a challenge for the analysis of signaling networks in the field of systems biology. A rigorous mathematical formalism is lacking to identify all possible signal flows in a network model.
RESULTS: In this paper, we introduce the concept of Manatee invariants for the analysis of signal transduction networks. We present an algorithm for the characterization of the combinatorial diversity of signal flows, e.g., from signal reception to cellular response. We demonstrate the concept for a small model of the TNFR1-mediated NF- κB signaling pathway. Manatee invariants reveal all possible signal flows in the network. Further, we show the application of Manatee invariants for in silico knockout experiments. Here, we illustrate the biological relevance of the concept.
CONCLUSIONS: The proposed mathematical framework reveals the entire variety of signal flows in models of signaling systems, including cyclic regulations. Thereby, Manatee invariants allow for the analysis of robustness and vulnerability of signaling networks. The application to further analyses such as for in silico knockout was shown. The new framework of Manatee invariants contributes to an advanced examination of signaling systems.

PMID: 28754124 [PubMed - in process]

Captivity Shapes the Gut Microbiota of Andean Bears: Insights into Health Surveillance.

Front Microbiol. 2017;8:1316

Authors: Borbón-García A, Reyes A, Vives-Flórez M, Caballero S

Abstract
The Andean bear is an endemic species of the tropical Andes who has an almost exclusively plant-based diet. Since herbivorous mammals do not carry enzymes for fiber degradation, the establishment of symbiosis with cellulolytic microorganisms in their gastrointestinal (GI) tract is necessary to help them fulfill their nutritional needs. Furthermore, as described for other mammals, a stable, diverse, and balanced gut microbial composition is an indicator of a healthy status of the host; under disturbances this balance can be lost, leading to potential diseases of the host. The goal of this study was to describe the gut microbiota of wild and captive Andean bears and determine how habitat status influences the composition and diversity of the gut symbiotic community. Fecal samples from wild (n = 28) and captive (n = 8) Andean bears were collected in "Reserva Pantano de Martos" and "Fundación Bioandina", Colombia. Composition and diversity analyses were performed using amplicons from the V4 region of the 16S rDNA gene sequenced using the Ion PGM platform. PICRUSt algorithm was applied to predict the gene content of the gut microbiome of wild and captive Andean bears. A total of 5,411 and 838 OTUs were identified for wild and captive bears, respectively. Captive bears contained a lower number of bacterial phyla (n = 7) compared to wild individuals (n = 9). Proteobacteria (59.03%) and Firmicutes (14.03%) were the phyla that contributed the most to differences between wild and captive bears (overall dissimilarity = 87.72%). At family level, Enterobacteriaceae drove the main differences between the two groups (13.7%). PICRUSt metagenomics predictions suggested a similar pattern of relative abundance of gene families associated with the metabolism of carbohydrates across samples in wild individuals, despite the taxonomic differences of their gut microbiota. Captivity alters the availability and diversity of food resources, which likely reduces microbiota richness and diversity compared to wild individuals. Further considerations should be taken into account for nutritional schemes improving ex-situ conservation and its potential as a surveillance tool of endangered populations of wild Andean bears.

PMID: 28751883 [PubMed]