Different Epidermal Growth Factor Receptor (EGFR) Agonists Produce Unique Signatures for the Recruitment of Downstream Signaling Proteins.

J Biol Chem. 2016 Mar 11;291(11):5528-40

Authors: Ronan T, Macdonald-Obermann JL, Huelsmann L, Bessman NJ, Naegle KM, Pike LJ

Abstract
The EGF receptor can bind seven different agonist ligands. Although each agonist appears to stimulate the same suite of downstream signaling proteins, different agonists are capable of inducing distinct responses in the same cell. To determine the basis for these differences, we used luciferase fragment complementation imaging to monitor the recruitment of Cbl, CrkL, Gab1, Grb2, PI3K, p52 Shc, p66 Shc, and Shp2 to the EGF receptor when stimulated by the seven EGF receptor ligands. Recruitment of all eight proteins was rapid, dose-dependent, and inhibited by erlotinib and lapatinib, although to differing extents. Comparison of the time course of recruitment of the eight proteins in response to a fixed concentration of each growth factor revealed differences among the growth factors that could contribute to their differing biological effects. Principal component analysis of the resulting data set confirmed that the recruitment of these proteins differed between agonists and also between different doses of the same agonist. Ensemble clustering of the overall response to the different growth factors suggests that these EGF receptor ligands fall into two major groups as follows: (i) EGF, amphiregulin, and EPR; and (ii) betacellulin, TGFα, and epigen. Heparin-binding EGF is distantly related to both clusters. Our data identify differences in network utilization by different EGF receptor agonists and highlight the need to characterize network interactions under conditions other than high dose EGF.

PMID: 26786109 [PubMed - indexed for MEDLINE]

Systems Pharmacology Dissection of the Protective Effect of Myricetin Against Acute Ischemia/Reperfusion-Induced Myocardial Injury in Isolated Rat Heart.

Cardiovasc Toxicol. 2016 Aug 2;

Authors: Qiu Y, Cong N, Liang M, Wang Y, Wang J

Abstract
In this paper, we investigated the multi-target effect of myricetin as a therapeutic for cardiovascular disease, using an acute ischemia/reperfusion-induced myocardial injury model to gain insight into its mechanism of action. The compound-target interaction profiles of myricetin were determined using a combination of text mining, chemometric and chemogenomic methods. The effect of myricetin on cardiac function was investigated by carrying out experiments in rats subjected to ischemia/reperfusion (I/R) using Langendorff retrograde perfusion technology. Compared to the I/R group, pretreatment with 5 μM myricetin was observed to improve the maximum up/down rate of left ventricular pressure (dp/dt max) and coronary flow, raise left ventricular developed pressure, and decrease creatine kinase and lactate dehydrogenase levels in coronary flow. In addition, myricetin treatment was shown to have beneficial effects through its ability to reduce both infarct size and levels of cardiomyocyte apoptosis. Myricetin was also observed to have antioxidant properties, as evidenced by its ability to reduce MDA levels, while increasing both SOD levels and the GSH/GSSG ratio. Finally, an upregulation of 6-phosphogluconate dehydrogenase and fatty acid synthase expression and a downregulation of cyclooxygenase-2, cytochrome P450 and p38 mitogen-activated protein kinase expression suggest that myricetin acts through mechanisms which alter relevant signaling pathways. In summary, our results demonstrate that myricetin has protective cardiovascular effects against I/R-induced myocardial injury.

PMID: 27484498 [PubMed - as supplied by publisher]

iLIR database: a web resource for LIR motif-containing proteins in eukaryotes.

Autophagy. 2016 Aug 2;:0

Authors: Jacomin AC, Samavedam S, Promponas V, Nezis IP

Abstract
Atg8-family proteins are the best-studied proteins of the core autophagic machinery. They are essential for the elongation and closure of the phagophore into a proper autophagosome. Moreover, Atg8-family proteins are associated with the phagophore from the initiation of the autophagic process to, or just prior to, the fusion between autophagosomes with lysosomes. In addition to their implication in autophagosome biogenesis, they are crucial for selective autophagy through their ability to interact with selective autophagy receptor proteins necessary for the specific targeting of substrates for autophagic degradation. In the last few years it has been revealed that Atg8-interacting proteins include not only receptors but also components of the core autophagic machinery, proteins associated with vesicles and their transport, and specific proteins that are selectively degraded by autophagy. Atg8-interacting proteins contain a short linear LC3-interacting region/LC3 recognition sequence/Atg8-interacting motif (LIR/LRS/AIM) motif which is responsible for their interaction with Atg8-family proteins. These proteins are referred as LIR-containing proteins (LIRCPs). So far, many experimental efforts have been carried out to identify new LIRCPs, leading to the characterization of some of them in the past 10 years. Given the need for the identification of LIRCPs in various organisms, we developed the iLIR database ( https://ilir.warwick.ac.uk ) as a freely available web resource, listing all the putative canonical LIRCPs identified in silico in the proteomes of 8 model organisms using the iLIR server, combined with a Gene Ontology (GO) term analysis. Additionally, a curated text-mining analysis of the literature permitted us to identify novel putative LICRPs in mammals that have not previously been associated with autophagy.

PMID: 27484196 [PubMed - as supplied by publisher]

METSP: a maximum-entropy classifier based text mining tool for transporter-substrate identification with semistructured text.

Biomed Res Int. 2015;2015:254838

Authors: Zhao M, Chen Y, Qu D, Qu H

Abstract
The substrates of a transporter are not only useful for inferring function of the transporter, but also important to discover compound-compound interaction and to reconstruct metabolic pathway. Though plenty of data has been accumulated with the developing of new technologies such as in vitro transporter assays, the search for substrates of transporters is far from complete. In this article, we introduce METSP, a maximum-entropy classifier devoted to retrieve transporter-substrate pairs (TSPs) from semistructured text. Based on the high quality annotation from UniProt, METSP achieves high precision and recall in cross-validation experiments. When METSP is applied to 182,829 human transporter annotation sentences in UniProt, it identifies 3942 sentences with transporter and compound information. Finally, 1547 confidential human TSPs are identified for further manual curation, among which 58.37% pairs with novel substrates not annotated in public transporter databases. METSP is the first efficient tool to extract TSPs from semistructured annotation text in UniProt. This tool can help to determine the precise substrates and drugs of transporters, thus facilitating drug-target prediction, metabolic network reconstruction, and literature classification.

PMID: 26495291 [PubMed - indexed for MEDLINE]

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Neuropathy: A name for their pain.

Nature. 2016 Jul 14;535(7611):S10-1

Authors: Eisenstein M

PMID: 27410524 [PubMed - indexed for MEDLINE]

Screening of the Open Source Malaria Box Reveals an Early Lead Compound for the Treatment of Alveolar Echinococcosis.

PLoS Negl Trop Dis. 2016 Mar;10(3):e0004535

Authors: Stadelmann B, Rufener R, Aeschbacher D, Spiliotis M, Gottstein B, Hemphill A

Abstract
The metacestode (larval) stage of the tapeworm Echinococcus multilocularis causes alveolar echinococcosis (AE), a very severe and in many cases incurable disease. To date, benzimidazoles such as albendazole and mebendazole are the only approved chemotherapeutical treatment options. Benzimidazoles inhibit metacestode proliferation, but do not act parasiticidal. Thus, benzimidazoles have to be taken a lifelong, can cause adverse side effects such as hepatotoxicity, and are ineffective in some patients. We here describe a newly developed screening cascade for the evaluation of the in vitro efficacy of new compounds that includes assessment of parasiticidal activity. The Malaria Box from Medicines for Malaria Venture (MMV), comprised of 400 commercially available chemicals that show in vitro activity against Plasmodium falciparum, was repurposed. Primary screening was carried out at 10 μM by employing the previously described PGI assay, and resulted in the identification of 24 compounds that caused physical damage in metacestodes. Seven out of these 24 drugs were also active at 1 μM. Dose-response assays revealed that only 2 compounds, namely MMV665807 and MMV665794, exhibited an EC50 value below 5 μM. Assessments using human foreskin fibroblasts and Reuber rat hepatoma cells showed that the salicylanilide MMV665807 was less toxic for these two mammalian cell lines than for metacestodes. The parasiticidal activity of MMV665807 was then confirmed using isolated germinal layer cell cultures as well as metacestode vesicles by employing viability assays, and its effect on metacestodes was morphologically evaluated by electron microscopy. However, both oral and intraperitoneal application of MMV665807 to mice experimentally infected with E. multilocularis metacestodes did not result in any reduction of the parasite load.

PMID: 26967740 [PubMed - indexed for MEDLINE]

Structural analysis of dihydrofolate reductases enables rationalization of antifolate binding affinities and suggests repurposing possibilities.

FEBS J. 2016 Mar;283(6):1139-67

Authors: Bhosle A, Chandra N

Abstract
Antifolates are competitive inhibitors of dihydrofolate reductase (DHFR), a conserved enzyme that is central to metabolism and widely targeted in pathogenic diseases, cancer and autoimmune disorders. Although most clinically used antifolates are known to be target specific, some display a fair degree of cross-reactivity with DHFRs from other species. A method that enables identification of determinants of affinity and specificity in target DHFRs from different species and provides guidelines for the design of antifolates is currently lacking. To address this, we first captured the potential druggable space of a DHFR in a substructure called the 'supersite' and classified supersites of DHFRs from 56 species into 16 'site-types' based on pairwise structural similarity. Analysis of supersites across these site-types revealed that DHFRs exhibit varying extents of dissimilarity at structurally equivalent positions in and around the binding site. We were able to explain the pattern of affinities towards chemically diverse antifolates exhibited by DHFRs of different site-types based on these structural differences. We then generated an antifolate-DHFR network by mapping known high-affinity antifolates to their respective supersites and used this to identify antifolates that can be repurposed based on similarity between supersites or antifolates. Thus, we identified 177 human-specific and 458 pathogen-specific antifolates, a large number of which are supported by available experimental data. Thus, in the light of the clinical importance of DHFR, we present a novel approach to identifying differences in the druggable space of DHFRs that can be utilized for rational design of antifolates.

PMID: 26797763 [PubMed - indexed for MEDLINE]

Network analysis of immunotherapy-induced regressing tumours identifies novel synergistic drug combinations.

Sci Rep. 2015;5:12298

Authors: Lesterhuis WJ, Rinaldi C, Jones A, Rozali EN, Dick IM, Khong A, Boon L, Robinson BW, Nowak AK, Bosco A, Lake RA

Abstract
Cancer immunotherapy has shown impressive results, but most patients do not respond. We hypothesized that the effector response in the tumour could be visualized as a complex network of interacting gene products and that by mapping this network we could predict effective pharmacological interventions. Here, we provide proof of concept for the validity of this approach in a murine mesothelioma model, which displays a dichotomous response to anti-CTLA4 immune checkpoint blockade. Network analysis of gene expression profiling data from responding versus non-responding tumours was employed to identify modules associated with response. Targeting the modules via selective modulation of hub genes or alternatively by using repurposed pharmaceuticals selected on the basis of their expression perturbation signatures dramatically enhanced the efficacy of CTLA4 blockade in this model. Our approach provides a powerful platform to repurpose drugs, and define contextually relevant novel therapeutic targets.

PMID: 26193793 [PubMed - indexed for MEDLINE]

Semantic-Web Architecture for Electronic Discharge Summary Based on OWL 2.0 Standard.

Acta Inform Med. 2016 Jun;24(3):182-5

Authors: Tahmasebian S, Langarizadeh M, Ghazisaeidi M, Safdari R

Abstract
INTRODUCTION: Patients' electronic medical record contains all information related to treatment processes during hospitalization. One of the most important documents in this record is the record summary. In this document, summary of the whole treatment process is presented which is used for subsequent treatments and other issues pertaining to the treatment. Using suitable architecture for this document, apart from the aforementioned points we can use it in other fields such as data mining or decision making based on the cases.
MATERIAL AND METHODS: In this study, at first, a model for patient's medical record summary has been suggested using semantic web-based architecture. Then, based on service-oriented architecture and using Java programming language, a software solution was designed and run in a way to generate medical record summary with this structure and at the end, new uses of this structure was explained.
RESULTS: in this study a structure for medical record summaries along with corrective points within semantic web has been offered and a software running within Java along with special ontologies are provided.
DISCUSSION AND CONCLUSION: After discussing the project with the experts of medical/health data management and medical informatics as well as clinical experts, it became clear that suggested design for medical record summary apart from covering many issues currently faced in the medical records has also many advantages including its uses in research projects, decision making based on the cases etc.

PMID: 27482132 [PubMed]

Implementation and Quality Control of Lung Cancer EGFR Genetic Testing by MALDI-TOF Mass Spectrometry in Taiwan Clinical Practice.

Sci Rep. 2016;6:30944

Authors: Su KY, Kao JT, Ho BC, Chen HY, Chang GC, Ho CC, Yu SL

Abstract
Molecular diagnostics in cancer pharmacogenomics is indispensable for making targeted therapy decisions especially in lung cancer. For routine clinical practice, the flexible testing platform and implemented quality system are important for failure rate and turnaround time (TAT) reduction. We established and validated the multiplex EGFR testing by MALDI-TOF MS according to ISO15189 regulation and CLIA recommendation in Taiwan. Totally 8,147 cases from Aug-2011 to Jul-2015 were assayed and statistical characteristics were reported. The intra-run precision of EGFR mutation frequency was CV 2.15% (L858R) and 2.77% (T790M); the inter-run precision was CV 3.50% (L858R) and 2.84% (T790M). Accuracy tests by consensus reference biomaterials showed 100% consistence with datasheet (public database). Both analytical sensitivity and specificity were 100% while taking Sanger sequencing as the gold-standard method for comparison. EGFR mutation frequency of peripheral blood mononuclear cell for reference range determination was 0.002 ± 0.016% (95% CI: 0.000-0.036) (L858R) and 0.292 ± 0.289% (95% CI: 0.000-0.871) (T790M). The average TAT was 4.5 working days and the failure rate was less than 0.1%. In conclusion, this study provides a comprehensive report of lung cancer EGFR mutation detection from platform establishment, method validation to clinical routine practice. It may be a reference model for molecular diagnostics in cancer pharmacogenomics.

PMID: 27480787 [PubMed - in process]

(Per)chlorate in Biology on Earth and Beyond.

Annu Rev Microbiol. 2016 Jul 25;

Authors: Youngblut MD, Wang O, Barnum TP, Coates JD

Abstract
Respiration of perchlorate and chlorate [collectively, (per)chlorate] was only recognized in the last 20 years, yet substantial advances have been made in our understanding of the underlying metabolisms. Although it was once considered solely anthropogenic, pervasive natural sources, both terrestrial and extraterrestrial, indicate an ancient (per)chlorate presence across our solar system. These discoveries stimulated interest in (per)chlorate microbiology and the application of advanced approaches highlight exciting new facets. Forward and reverse genetics revealed new information regarding underlying molecular biology and associated regulatory mechanisms. Structural and functional analysis characterized core enzymes and identified novel reaction sequences. Comparative genomics elucidated evolutionary aspects, and stress analysis identified novel response mechanisms to reactive chlorine species. Finally, systems biology identified unique metabolic versatility and novel mechanisms of (per)chlorate respiration, including symbiosis and a hybrid enzymatic-abiotic metabolism. While many published studies focus on (per)chlorate and their basic metabolism, this review highlights seminal advances made over the last decade and identifies new directions and potential novel applications. Expected final online publication date for the Annual Review of Microbiology Volume 70 is September 08, 2016. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.

PMID: 27482739 [PubMed - as supplied by publisher]

SYSTEMS BIOLOGY. Protein isoforms: more than meets the eye.

Nat Methods. 2016 Apr;13(4):291

Authors: Larochelle S

PMID: 27482571 [PubMed - in process]

Lineage tracing of human B cells reveals the in vivo landscape of human antibody class switching.

Elife. 2016;5

Authors: Horns F, Vollmers C, Croote D, Mackey SF, Swan GE, Dekker CL, Davis MM, Quake SR

Abstract
Antibody class switching is a feature of the adaptive immune system which enables diversification of the effector properties of antibodies. Even though class switching is essential for mounting a protective response to pathogens, the in vivo patterns and lineage characteristics of antibody class switching have remained uncharacterized in living humans. Here we comprehensively measured the landscape of antibody class switching in human adult twins using antibody repertoire sequencing. The map identifies how antibodies of every class are created and delineates a two-tiered hierarchy of class switch pathways. Using somatic hypermutations as a molecular clock, we discovered that closely related B cells often switch to the same class, but lose coherence as somatic mutations accumulate. Such correlations between closely related cells exist when purified B cells class switch in vitro, suggesting that class switch recombination is directed toward specific isotypes by a cell-autonomous imprinted state.

PMID: 27481325 [PubMed - in process]

Place recognition using batlike sonar.

Elife. 2016;5

Authors: Vanderelst D, Steckel J, Boen A, Peremans H, Holderied MW

Abstract
Echolocating bats have excellent spatial memory and are able to navigate to salient locations using bio-sonar. Navigating and route-following require animals to recognize places. Currently, it is mostly unknown how bats recognize places using echolocation. In this paper, we propose template based place recognition might underlie sonar-based navigation in bats. Under this hypothesis, bats recognize places by remembering their echo signature - rather than their 3D layout. Using a large body of ensonification data collected in three different habitats, we test the viability of this hypothesis assessing two critical properties of the proposed echo signatures: (1) they can be uniquely classified and (2) they vary continuously across space. Based on the results presented, we conclude that the proposed echo signatures satisfy both criteria. We discuss how these two properties of the echo signatures can support navigation and building a cognitive map.

PMID: 27481189 [PubMed - in process]

Reconstructing Causal Biological Networks through Active Learning.

PLoS One. 2016;11(3):e0150611

Authors: Cho H, Berger B, Peng J

Abstract
Reverse-engineering of biological networks is a central problem in systems biology. The use of intervention data, such as gene knockouts or knockdowns, is typically used for teasing apart causal relationships among genes. Under time or resource constraints, one needs to carefully choose which intervention experiments to carry out. Previous approaches for selecting most informative interventions have largely been focused on discrete Bayesian networks. However, continuous Bayesian networks are of great practical interest, especially in the study of complex biological systems and their quantitative properties. In this work, we present an efficient, information-theoretic active learning algorithm for Gaussian Bayesian networks (GBNs), which serve as important models for gene regulatory networks. In addition to providing linear-algebraic insights unique to GBNs, leading to significant runtime improvements, we demonstrate the effectiveness of our method on data simulated with GBNs and the DREAM4 network inference challenge data sets. Our method generally leads to faster recovery of underlying network structure and faster convergence to final distribution of confidence scores over candidate graph structures using the full data, in comparison to random selection of intervention experiments.

PMID: 26930205 [PubMed - indexed for MEDLINE]

An Analysis of the Truncated Bid- and ROS-dependent Spatial Propagation of Mitochondrial Permeabilization Waves during Apoptosis.

J Biol Chem. 2016 Feb 26;291(9):4603-13

Authors: Jacob SF, Würstle ML, Delgado ME, Rehm M

Abstract
Apoptosis is a form of programmed cell death that is essential for the efficient elimination of surplus, damaged, and transformed cells during metazoan embryonic development and adult tissue homeostasis. Situated at the interface of apoptosis initiation and execution, mitochondrial outer membrane permeabilization (MOMP) represents one of the most fundamental processes during apoptosis signal transduction. It was shown that MOMP can spatiotemporally propagate through cells, in particular in response to extrinsic apoptosis induction. Based on apparently contradictory experimental evidence, two distinct molecular mechanisms have been proposed to underlie the propagation of MOMP signals, namely a reaction-diffusion mechanism governed by anisotropies in the production of the MOMP-inducer truncated Bid (tBid), or a process that drives the spatial propagation of MOMP by sequential bursts of reactive oxygen species. We therefore generated mathematical models for both scenarios and performed in silico simulations of spatiotemporal MOMP signaling to identify which one of the two mechanisms is capable of qualitatively and quantitatively reproducing the existing data. We found that the explanatory power of each model was limited in that only a subset of experimental findings could be replicated. However, the integration of both models into a combined mathematical description of spatiotemporal tBid and reactive oxygen species signaling accurately reproduced all available experimental data and furthermore, provided robustness to spatial MOMP propagation when mitochondria are spatially separated. Our study therefore provides a theoretical framework that is sufficient to describe and mechanistically explain the spatiotemporal propagation of one of the most fundamental processes during apoptotic cell death.

PMID: 26699404 [PubMed - indexed for MEDLINE]

Mechanotransduction in primary human osteoarthritic chondrocytes is mediated by metabolism of energy, lipids, and amino acids.

J Biomech. 2015 Dec 16;48(16):4253-61

Authors: Zignego DL, Hilmer JK, June RK

Abstract
Chondrocytes are the sole cell type found in articular cartilage and are repeatedly subjected to mechanical loading in vivo. We hypothesized that physiological dynamic compression results in changes in energy metabolism to produce proteins for maintenance of the pericellular and extracellular matrices. The objective of this study was to develop an in-depth understanding for the short term (<30min) chondrocyte response to sub-injurious, physiological compression by analyzing metabolomic profiles for human chondrocytes harvested from femoral heads of osteoarthritic donors. Cell-seeded agarose constructs were randomly assigned to experimental groups, and dynamic compression was applied for 0, 15, or 30min. Following dynamic compression, metabolites were extracted and detected by HPLC-MS. Untargeted analyzes examined changes in global metabolomics profiles and targeted analysis examined the expression of specific metabolites related to central energy metabolism. We identified hundreds of metabolites that were regulated by applied compression, and we report the detection of 16 molecules not found in existing metabolite databases. We observed patient-specific mechanotransduction with aging dependence. Targeted studies found a transient increase in the ratio of NADP+ to NADPH and an initial decrease in the ratio of GDP to GTP, suggesting a flux of energy into the TCA cycle. By characterizing metabolomics profiles of primary chondrocytes in response to applied dynamic compression, this study provides insight into how OA chondrocytes respond to mechanical load. These results are consistent with increases in glycolytic energy utilization by mechanically induced signaling, and add substantial new data to a complex picture of how chondrocytes transduce mechanical loads.

PMID: 26573901 [PubMed - indexed for MEDLINE]

Altered cytoskeletal organization characterized lethal but not surviving Brtl+/- mice: insight on phenotypic variability in osteogenesis imperfecta.

Hum Mol Genet. 2015 Nov 1;24(21):6118-33

Authors: Bianchi L, Gagliardi A, Maruelli S, Besio R, Landi C, Gioia R, Kozloff KM, Khoury BM, Coucke PJ, Symoens S, Marini JC, Rossi A, Bini L, Forlino A

Abstract
Osteogenesis imperfecta (OI) is a heritable bone disease with dominant and recessive transmission. It is characterized by a wide spectrum of clinical outcomes ranging from very mild to lethal in the perinatal period. The intra- and inter-familiar OI phenotypic variability in the presence of an identical molecular defect is still puzzling to the research field. We used the OI murine model Brtl(+/-) to investigate the molecular basis of OI phenotypic variability. Brtl(+/-) resembles classical dominant OI and shows either a moderately severe or a lethal outcome associated with the same Gly349Cys substitution in the α1 chain of type I collagen. A systems biology approach was used. We took advantage of proteomic pathway analysis to functionally link proteins differentially expressed in bone and skin of Brtl(+/-) mice with different outcomes to define possible phenotype modulators. The skin/bone and bone/skin hybrid networks highlighted three focal proteins: vimentin, stathmin and cofilin-1, belonging to or involved in cytoskeletal organization. Abnormal cytoskeleton was indeed demonstrated by immunohistochemistry to occur only in tissues from Brtl(+/-) lethal mice. The aberrant cytoskeleton affected osteoblast proliferation, collagen deposition, integrin and TGF-β signaling with impairment of bone structural properties. Finally, aberrant cytoskeletal assembly was detected in fibroblasts obtained from lethal, but not from non-lethal, OI patients carrying an identical glycine substitution. Our data demonstrated that compromised cytoskeletal assembly impaired both cell signaling and cellular trafficking in mutant lethal mice, altering bone properties. These results point to the cytoskeleton as a phenotypic modulator and potential novel target for OI treatment.

PMID: 26264579 [PubMed - indexed for MEDLINE]