Actionable Metabolic Pathways in Heart Failure and Cancer-Lessons From Cancer Cell Metabolism.

Front Cardiovasc Med. 2018;5:71

Authors: Karlstaedt A, Schiffer W, Taegtmeyer H

Abstract
Recent advances in cancer cell metabolism provide unprecedented opportunities for a new understanding of heart metabolism and may offer new approaches for the treatment of heart failure. Key questions driving the cancer field to understand how tumor cells reprogram metabolism and to benefit tumorigenesis are also applicable to the heart. Recent experimental and conceptual advances in cancer cell metabolism provide the cardiovascular field with the unique opportunity to target metabolism. This review compares cancer cell metabolism and cardiac metabolism with an emphasis on strategies of cellular adaptation, and how to exploit metabolic changes for therapeutic benefit.

PMID: 29971237 [PubMed]

Integrated Multi-Omic Analysis of Mycobacterium tuberculosis H37Ra Redefines Virulence Attributes.

Front Microbiol. 2018;9:1314

Authors: Pinto SM, Verma R, Advani J, Chatterjee O, Patil AH, Kapoor S, Subbannayya Y, Raja R, Gandotra S, Prasad TSK

Abstract
H37Ra is a virulence attenuated strain of Mycobacterium tuberculosis widely employed as a model to investigate virulence mechanisms. Comparative high-throughput studies have earlier correlated its avirulence to the presence of specific mutations or absence of certain proteins. However, a recent sequencing study of H37Ra, has disproved several genomic differences earlier reported to be associated with virulence. This warrants further investigations on the H37Ra proteome as well. In this study, we carried out an integrated analysis of the genome, transcriptome, and proteome of H37Ra. In addition to confirming single nucleotide variations (SNVs) and insertion-deletions that were reported earlier, our study provides novel insights into the mutation spectrum in the promoter regions of 7 genes. We also provide transcriptional and proteomic evidence for 3,900 genes representing ~80% of the total predicted gene count including 408 proteins that have not been identified previously. We identified 9 genes whose coding potential was hitherto reported to be absent in H37Ra. These include 2 putative virulence factors belonging to ESAT-6 like family of proteins. Furthermore, proteogenomic analysis enabled us to identify 63 novel proteins coding genes and correct 25 existing gene models in H37Ra genome. A majority of these were found to be conserved in the virulent strain H37Rv as well as in other mycobacterial species suggesting that the differences in the virulent and avirulent strains of M. tuberculosis are not entirely dependent on the expression of certain proteins or their absence but may possibly be ascertained to functional changes.

PMID: 29971057 [PubMed]

The CoLoMoTo Interactive Notebook: Accessible and Reproducible Computational Analyses for Qualitative Biological Networks.

Front Physiol. 2018;9:680

Authors: Naldi A, Hernandez C, Levy N, Stoll G, Monteiro PT, Chaouiya C, Helikar T, Zinovyev A, Calzone L, Cohen-Boulakia S, Thieffry D, Paulevé L

Abstract
Analysing models of biological networks typically relies on workflows in which different software tools with sensitive parameters are chained together, many times with additional manual steps. The accessibility and reproducibility of such workflows is challenging, as publications often overlook analysis details, and because some of these tools may be difficult to install, and/or have a steep learning curve. The CoLoMoTo Interactive Notebook provides a unified environment to edit, execute, share, and reproduce analyses of qualitative models of biological networks. This framework combines the power of different technologies to ensure repeatability and to reduce users' learning curve of these technologies. The framework is distributed as a Docker image with the tools ready to be run without any installation step besides Docker, and is available on Linux, macOS, and Microsoft Windows. The embedded computational workflows are edited with a Jupyter web interface, enabling the inclusion of textual annotations, along with the explicit code to execute, as well as the visualization of the results. The resulting notebook files can then be shared and re-executed in the same environment. To date, the CoLoMoTo Interactive Notebook provides access to the software tools GINsim, BioLQM, Pint, MaBoSS, and Cell Collective, for the modeling and analysis of Boolean and multi-valued networks. More tools will be included in the future. We developed a Python interface for each of these tools to offer a seamless integration in the Jupyter web interface and ease the chaining of complementary analyses.

PMID: 29971009 [PubMed]

Logical Modeling and Analysis of Cellular Regulatory Networks With GINsim 3.0.

Front Physiol. 2018;9:646

Authors: Naldi A, Hernandez C, Abou-Jaoudé W, Monteiro PT, Chaouiya C, Thieffry D

Abstract
The logical formalism is well adapted to model large cellular networks, in particular when detailed kinetic data are scarce. This tutorial focuses on this well-established qualitative framework. Relying on GINsim (release 3.0), a software implementing this formalism, we guide the reader step by step toward the definition, the analysis and the simulation of a four-node model of the mammalian p53-Mdm2 network.

PMID: 29971008 [PubMed]

A system-wide approach to monitor responses to synergistic BRAF and EGFR inhibition in colorectal cancer cells.

Mol Cell Proteomics. 2018 Jul 03;:

Authors: Ressa A, Bosdriesz E, de Ligt J, Mainardi S, Maddalo G, Prahallad A, Jager M, de la Fonteijne L, Fitzpatrick M, Groten S, Altelaar AFM, Bernards R, Cuppen E, Wessels L, Heck AJR

Abstract
Intrinsic and/or acquired resistance represents one of the great challenges in targeted cancer therapy. A deeper understanding of the molecular biology of cancer has resulted in more efficient strategies, where one or multiple drugs are adopted in novel therapies to tackle resistance. This beneficial effect of using combination treatments has also been observed in colorectal cancer patients harboring the BRAF(V600E) mutation, whereby dual inhibition of BRAF(V600E) and EGFR increases antitumor activity. Notwithstanding this success, it is not clear whether this combination treatment is the only or most effective treatment to block intrinsic resistance to BRAF inhibitors. Here, we investigate molecular responses upon single and multi-target treatments, over time, using BRAF(V600E) mutant colorectal cancer cells as a model system. Through integration of transcriptomic, proteomic and phosphoproteomics data we obtain a comprehensive overview, revealing both known and novel responses. We primarily observe widespread upregulation of receptor tyrosine kinases and metabolic pathways upon BRAF inhibition. These findings point to mechanisms by which the drug-treated cells switch energy sources and enter a quiescent-like state as a defensive response, while additionally compensating for the MAPK pathway inhibition.

PMID: 29970458 [PubMed - as supplied by publisher]

Short linear motifs in intrinsically disordered regions modulate HOG signaling capacity.

BMC Syst Biol. 2018 Jul 03;12(1):75

Authors: Strome B, Hsu IS, Li Cheong Man M, Zarin T, Nguyen Ba A, Moses AM

Abstract
BACKGROUND: The effort to characterize intrinsically disordered regions of signaling proteins is rapidly expanding. An important class of disordered interaction modules are ubiquitous and functionally diverse elements known as short linear motifs (SLiMs).
RESULTS: To further examine the role of SLiMs in signal transduction, we used a previously devised bioinformatics method to predict evolutionarily conserved SLiMs within a well-characterized pathway in S. cerevisiae. Using a single cell, reporter-based flow cytometry assay in conjunction with a fluorescent reporter driven by a pathway-specific promoter, we quantitatively assessed pathway output via systematic deletions of individual motifs. We found that, when deleted, 34% (10/29) of predicted SLiMs displayed a significant decrease in pathway output, providing evidence that these motifs play a role in signal transduction. Assuming that mutations in SLiMs have quantitative effects on mechanisms of signaling, we show that perturbations of parameters in a previously published stochastic model of HOG signaling could reproduce the quantitative effects of 4 out of 7 mutations in previously unknown SLiMs.
CONCLUSIONS: Our study suggests that, even in well-characterized pathways, large numbers of functional elements remain undiscovered, and that challenges remain for application of systems biology models to interpret the effects of mutations in signaling pathways.

PMID: 29970070 [PubMed - in process]

Specific autophagy and ESCRT components participate in the unconventional secretion of CFTR.

Autophagy. 2018 Jul 04;:

Authors: Noh SH, Gee HY, Kim Y, Piao H, Kim J, Kang CM, Lee G, Mook-Jung I, Lee Y, Cho JW, Lee MG

Abstract
The most common mutation in cystic fibrosis patients is a phenylalanine deletion at position 508 (ΔF508) in the CFTR (cystic fibrosis transmembrane conductance regulator) gene. This mutation impairs cell-surface trafficking of CFTR. During cellular stress, core-glycosylated CFTRΔF508 is transported to the cell surface from the endoplasmic reticulum (ER) via an unconventional route that bypasses the Golgi. However, the mechanisms for this unconventional secretory pathway of CFTR are not well delineated. Here, we report that components of the macroautophagy/autophagy and ESCRT (endosomal sorting complex required for transport) pathways are involved in unconventional secretion of CFTR. In mammalian cells, we found that autophagic pathways were modulated by conditions that also stimulate unconventional secretion, namely ER stress and an ER-to-Golgi transport blockade. Additionally, we found that knockdown of early autophagy components, ATG5 and ATG7, and treatment with pharmacological autophagy inhibitors, wortmannin and 3-methyladenine, abolished the unconventional secretion of CFTR that had been stimulated by ER stress and an ER-to-Golgi blockade. Interestingly, immunoelectron microscopy revealed that GORASP2/GRASP55, which mediates unconventional CFTR trafficking, is present in multivesicular bodies (MVB) and autophagosomal structures under ER stress conditions. A custom small-interfering RNA screen of mammalian ESCRT proteins that mediate MVB biogenesis showed that silencing of some ESCRTs, including MVB12B, inhibited unconventional CFTRΔF508 secretion. Furthermore, MVB12B overexpression partially rescued cell-surface expression and Cl- channel function of CFTRΔF508. Taken together, these results suggest that components involved in early autophagosome formation and the ESCRT/MVB pathway play a key role in the stress-induced unconventional secretion of CFTR.

PMID: 29969945 [PubMed - as supplied by publisher]

PTENα Regulates Mitophagy and Maintains Mitochondrial Quality Control.

Autophagy. 2018 Jul 04;:

Authors: Yin Y, Li G, Yang J, Yang C, Zhu M, Jin Y, McNutt MA

Abstract
PTEN plays an important role in tumor suppression, and PTEN family members are involved in multiple biological processes in various subcellular locations. Here we report that PTENαααthe first identified PTEN isoform, αregulates mitophagy through promotion of PARK2 recruitment to damaged mitochondria. We show that PTENα-deficient mice exhibit accumulation of cardiac mitochondria with structural and functional abnormalities, and PTENα-deficient mouse hearts are more susceptible to injury induced by isoprenaline and ischemia-reperfusion. Mitochondrial clearance by mitophagy is also impaired in PTENα-deficient cardiomyocytes. In addition, we found PTENα physically interacts with the E3 ubiquitin ligase PRKN, which is an important mediator of mitophagy. PTENααbinds PRKN through the membrane binding helix in its N terminus, and promotes PRKN mitochondrial translocation through enhancing PRKN self-association in a phosphatase-independent manner. Loss of PTENααcompromises mitochondrial translocation of PRKN and resultant mitophagy following mitochondrial depolarization. We propose that PTENααfunctions as a mitochondrial quality controller that maintains mitochondrial function and cardiac homeostasis.

PMID: 29969932 [PubMed - as supplied by publisher]

Comparative genomic analysis of two emergent human adenovirus type 14 respiratory pathogen isolates in China reveals similar yet divergent genomes.

Emerg Microbes Infect. 2017 Nov 01;6(11):e92

Authors: Zhang Q, Jing S, Cheng Z, Yu Z, Dehghan S, Shamsaddini A, Yan Y, Li M, Seto D

Abstract
Human adenovirus type 14 (HAdV-B14p) was originally identified as an acute respiratory disease (ARD) pathogen in The Netherlands in 1955. For approximately fifty years, few sporadic infections were observed. In 2005, HAdV-B14p1, a genomic variant, re-emerged and was associated with several large ARD outbreaks across the U.S. and, subsequently, in Canada, the U.K., Ireland, and China. This strain was associated with an unusually higher fatality rate than previously reported for both this prototype and other HAdV types in general. In China, HAdV-B14 was first observed in 2010, when two unrelated HAdV-B14-associated ARD cases were reported in Southern China (GZ01) and Northern China (BJ430), followed by three subsequent outbreaks. While comparative genomic analysis, including indel analysis, shows that the three China isolates, with whole genome data available, are similar to the de Wit prototype, all are divergent from the U.S. strain (303600; 2007). Although the genomes of strains GZ01 and BJ430 are nearly identical, as per their genome type characterization and percent identities, they are subtly divergent in their genome mutation patterns. These genomes indicate possibly two lineages of HAdV-B14 and independent introductions into China from abroad, or subsequent divergence from one; CHN2012 likely represents a separate sub-lineage. Observations of these simultaneously reported emergent strains in China add to the understanding of the circulation, epidemiology, and evolution of these HAdV pathogens, as well as provide a foundation for developing effective vaccines and public health strategies, including nationwide surveillance in anticipation of larger outbreaks with potentially higher fatality rates associated with HAdV-B14p1.

PMID: 29089589 [PubMed - indexed for MEDLINE]

29 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

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IKZF1 Enhances Immune Infiltrate Recruitment in Solid Tumors and Susceptibility to Immunotherapy.

Cell Syst. 2018 Jun 25;:

Authors: Chen JC, Perez-Lorenzo R, Saenger YM, Drake CG, Christiano AM

Abstract
Immunotherapies are some of the most promising emergent treatments for several cancers, yet there remains a majority of patients who do not benefit from them due to immune-resistant tumors. One avenue for enhancing treatment for these patients is by converting these tumors to an immunoreactive state, thereby restoring treatment efficacy. By leveraging regulatory networks we previously characterized in autoimmunity, here we show that overexpression of the master regulator IKZF1 leads to enhanced immune infiltrate recruitment and tumor sensitivity to PD1 and CTLA4 inhibitors in several tumors that normally lack IKZF1 expression. This work provides proof of concept that tumors can be rendered susceptible by hijacking immune cell recruitment signals through molecular master regulators. On a broader scale, this work also demonstrates the feasibility of using computational approaches to drive the discovery of novel molecular mechanisms toward treatment.

PMID: 29960886 [PubMed - as supplied by publisher]

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"systems biology"

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"systems biology"

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"systems biology"

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"systems biology"

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"systems biology"

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"systems biology"

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