Transcriptomic Insights into Genetic Diversity of Protein-Coding Genes in X. laevis.

Dev Biol. 2017 Mar 07;:

Authors: Savova V, Pearl EJ, Boke E, Nag A, Adzhubei I, Horb ME, Peshkin L

Abstract
We characterize the genetic diversity of Xenopus laevis strains using RNA-seq data and allele-specific analysis. This data provides a catalogue of coding variation, which can be used for improving the genomic sequence, as well as for better sequence alignment, probe design, and proteomic analysis. In addition, we paint a broad picture of the genetic landscape of the species by functionally annotating different classes of mutations with a well-established prediction tool (PolyPhen-2). Further, we specifically compare the variation in the progeny of four crosses: inbred genomic (J)-strain, outbred albino (B)-strain, and two hybrid crosses of J and B strains. We identify a subset of mutations specific to the B strain, which allows us to investigate the selection pressures affecting duplicated genes in this allotetraploid. From these crosses we find the ratio of non-synonymous to synonymous mutations is lower in duplicated genes, which suggests that they are under greater purifying selection. Surprisingly, we also find that function-altering ("damaging") mutations constitute a greater fraction of the non-synonymous variants in this group, which suggests a role for subfunctionalization in coding variation affecting duplicated genes.

PMID: 28283406 [PubMed - as supplied by publisher]

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Dynamic metabolic responses of brown planthoppers towards susceptible and resistant rice plants.

Plant Biotechnol J. 2017 Mar 09;:

Authors: Liu C, Du B, Hao F, Lei H, Wan Q, He G, Wang Y, Tang H

Abstract
Brown planthopper (Nilaparvata lugens Stål, BPH) causes huge economic losses in rice-growing regions and new strategies for combating BPH are required. To understand how BPHs respond towards BPH-resistant plants, we systematically analyzed the metabolic differences between BPHs feeding on the resistant and susceptible plants using NMR and GC-FID/MS. We also measured the expression of some related genes involving glycolysis and biosyntheses of trehalose, amino acids, chitin and fatty acids using real-time PCR. BPH metabonome was dominated by more than 60 metabolites including fatty acids, amino acids, carbohydrates, nucleosides/nucleotides and TCA cycle intermediates. After initial 12 h, BPHs feeding on the resistant plants had lower levels of amino acids, glucose, fatty acids and TCA cycle intermediates than on the susceptible ones. The levels of these metabolites recovered after 24 h feeding. This accompanied with level rises for trehalose, choline metabolites and nucleosides/nucleotides compared with BPH feeding on the susceptible plants. Decreased levels of BPH metabolites at the early feeding probably resulted from less BPH uptakes of sap from resistant plants and recovery of BPH metabolites at the later stage probably resulted from their adaptation to the adverse environment with their increased hopping frequency to ingest more sap together with contributions from yeast-like symbionts in BPHs. Throughout 96 h, BPH feeding on the resistant plants showed significant up-regulation of chitin synthase catalyzing biosynthesis of chitin for insect exoskeleton, peritrophic membrane lining gut and tracheae. These findings provided useful metabolic information for understanding the BPH-rice interactions and perhaps for developing new BPH-combating strategies. This article is protected by copyright. All rights reserved.

PMID: 28278368 [PubMed - as supplied by publisher]

Evolutionary and biogeographical implications of degraded LAGLIDADG endonuclease functionality and group I intron occurrence in stony corals (Scleractinia) and mushroom corals (Corallimorpharia).

PLoS One. 2017;12(3):e0173734

Authors: Celis JS, Edgell DR, Stelbrink B, Wibberg D, Hauffe T, Blom J, Kalinowski J, Wilke T

Abstract
Group I introns and homing endonuclease genes (HEGs) are mobile genetic elements, capable of invading target sequences in intron-less genomes. LAGLIDADG HEGs are the largest family of endonucleases, playing a key role in the mobility of group I introns in a process known as 'homing'. Group I introns and HEGs are rare in metazoans, and can be mainly found inserted in the COXI gene of some sponges and cnidarians, including stony corals (Scleractinia) and mushroom corals (Corallimorpharia). Vertical and horizontal intron transfer mechanisms have been proposed as explanations for intron occurrence in cnidarians. However, the central role of LAGLIDADG motifs in intron mobility mechanisms remains poorly understood. To resolve questions regarding the evolutionary origin and distribution of group I introns and HEGs in Scleractinia and Corallimorpharia, we examined intron/HEGs sequences within a comprehensive phylogenetic framework. Analyses of LAGLIDADG motif conservation showed a high degree of degradation in complex Scleractinia and Corallimorpharia. Moreover, the two motifs lack the respective acidic residues necessary for metal-ion binding and catalysis, potentially impairing horizontal intron mobility. In contrast, both motifs are highly conserved within robust Scleractinia, indicating a fully functional endonuclease capable of promoting horizontal intron transference. A higher rate of non-synonymous substitutions (Ka) detected in the HEGs of complex Scleractinia and Corallimorpharia suggests degradation of the HEG, whereas lower Ka rates in robust Scleractinia are consistent with a scenario of purifying selection. Molecular-clock analyses and ancestral inference of intron type indicated an earlier intron insertion in complex Scleractinia and Corallimorpharia in comparison to robust Scleractinia. These findings suggest that the lack of horizontal intron transfers in the former two groups is related to an age-dependent degradation of the endonuclease activity. Moreover, they also explain the peculiar geographical patterns of introns in stony and mushroom corals.

PMID: 28278261 [PubMed - in process]

High-efficient production and biophysical characterisation of nicastrin and its interaction with APPC100.

Sci Rep. 2017 Mar 09;7:44297

Authors: Yu K, Yang G, Labahn J

Abstract
Nicastrin, the largest member among the four components of the γ-secretase complex, has been identified to be the substrate recognizer for the proteolytic activity of the complex. Here we report that full-length human nicastrin (hNCT) can be obtained by heterologous expression in E. coli. Milligram quantities of the target protein are purified in a two-step purification protocol using affinity chromatography followed by SEC. The FOS-choline 14 purified tetrameric hNCT exhibits a proper folding with 31% α-helix and 23% β-sheet content. Thermal stability studies reveal stable secondary and tertiary structure of the detergent purified hNCT. A physical interaction between nicastrin and the γ-secretase substrate APPC100 confirmed the functionality of hNCT as a substrate recognizer.

PMID: 28276527 [PubMed - in process]

Extracellular proteasome-osteopontin circuit regulates cell migration with implications in multiple sclerosis.

Sci Rep. 2017 Mar 09;7:43718

Authors: Dianzani C, Bellavista E, Liepe J, Verderio C, Martucci M, Santoro A, Chiocchetti A, Luca Gigliotti C, Boggio E, Ferrara B, Riganti L, Keller C, Janek K, Niewienda A, Fenoglio C, Sorosina M, Cantello R, Kloetzel PM, Stumpf MP, Paul F, Ruprecht K, Galimberti D, Martinelli Boneschi F, Comi C, Dianzani U, Mishto M

Abstract
Osteopontin is a pleiotropic cytokine that is involved in several diseases including multiple sclerosis. Secreted osteopontin is cleaved by few known proteases, modulating its pro-inflammatory activities. Here we show by in vitro experiments that secreted osteopontin can be processed by extracellular proteasomes, thereby producing fragments with novel chemotactic activity. Furthermore, osteopontin reduces the release of proteasomes in the extracellular space. The latter phenomenon seems to occur in vivo in multiple sclerosis, where it reflects the remission/relapse alternation. The extracellular proteasome-mediated inflammatory pathway may represent a general mechanism to control inflammation in inflammatory diseases.

PMID: 28276434 [PubMed - in process]

From ions to insulin.

Elife. 2017 Mar 09;6:

Authors: Kanelis V

Abstract
Electron cryo-microscopy has revealed the three-dimensional structure of a potassium channel that has a central role in regulating the release of insulin from the pancreas.

PMID: 28276322 [PubMed - in process]

Caudal Nucleus Accumbens Core Is Critical in the Regulation of Cue-Elicited Approach-Avoidance Decisions.

eNeuro. 2017 Jan-Feb;4(1):

Authors: Hamel L, Thangarasa T, Samadi O, Ito R

Abstract
The nucleus accumbens (NAc) is thought to be a site of integration of positively and negatively valenced information and action selection. Functional differentiation in valence processing has previously been found along the rostrocaudal axis of the shell region of the NAc in assessments of unconditioned motivation. Given that the core region of the NAc has been implicated in the elicitation of motivated behavior in response to conditioned cues, we sought to assess the role of caudal, intermediate, and rostral sites within this subregion in cue-elicited approach-avoidance decisions. Rats were trained to associate visuo-tactile cues with appetitive, aversive, and neutral outcomes. Following the successful acquisition of the cue-outcome associations, rats received microinfusions of GABAA and GABAB receptor agonists (muscimol/baclofen) or saline into the caudal, intermediate, or rostral NAc core and were then exposed to a superimposition of appetitively and aversively valenced cues versus neutral cues in a "conflict test," as well as to the appetitive versus neutral cues, and aversive cues versus neutral cues, in separate conditioned preference/avoidance tests. Disruption of activity in the intermediate to caudal parts of the NAc core resulted in a robust avoidance bias in response to motivationally conflicting cues, as well as a potentiated avoidance of aversive cues as compared with control animals, coupled with an attenuated conditioned preference for the appetitive cue. These results suggest that the caudal NAc core may have the capacity to exert bidirectional control over appetitively and aversively motivated responses to valence signals.

PMID: 28275709 [PubMed - in process]

Metabolic profiling of body fluids and multivariate data analysis.

MethodsX. 2017;4:95-103

Authors: Trezzi JP, Jäger C, Galozzi S, Barkovits K, Marcus K, Mollenhauer B, Hiller K

Abstract
Metabolome analyses of body fluids are challenging due pre-analytical variations, such as pre-processing delay and temperature, and constant dynamical changes of biochemical processes within the samples. Therefore, proper sample handling starting from the time of collection up to the analysis is crucial to obtain high quality samples and reproducible results. A metabolomics analysis is divided into 4 main steps: 1) Sample collection, 2) Metabolite extraction, 3) Data acquisition and 4) Data analysis. Here, we describe a protocol for gas chromatography coupled to mass spectrometry (GC-MS) based metabolic analysis for biological matrices, especially body fluids. This protocol can be applied on blood serum/plasma, saliva and cerebrospinal fluid (CSF) samples of humans and other vertebrates. It covers sample collection, sample pre-processing, metabolite extraction, GC-MS measurement and guidelines for the subsequent data analysis. Advantages of this protocol include: •Robust and reproducible metabolomics results, taking into account pre-analytical variations that may occur during the sampling process•Small sample volume required•Rapid and cost-effective processing of biological samples•Logistic regression based determination of biomarker signatures for in-depth data analysis.

PMID: 28275554 [PubMed - in process]

Intrinsic Dynamics Analysis of a DNA Octahedron by Elastic Network Model.

Molecules. 2017 Jan 16;22(1):

Authors: Hu G, He L, Iacovelli F, Falconi M

Abstract
DNA is a fundamental component of living systems where it plays a crucial role at both functional and structural level. The programmable properties of DNA make it an interesting building block for the construction of nanostructures. However, molecular mechanisms for the arrangement of these well-defined DNA assemblies are not fully understood. In this paper, the intrinsic dynamics of a DNA octahedron has been investigated by using two types of Elastic Network Models (ENMs). The application of ENMs to DNA nanocages include the analysis of the intrinsic flexibilities of DNA double-helices and hinge sites through the calculation of the square fluctuations, as well as the intrinsic collective dynamics in terms of cross-collective map calculation coupled with global motions analysis. The dynamics profiles derived from ENMs have then been evaluated and compared with previous classical molecular dynamics simulation trajectories. The results presented here revealed that ENMs can provide useful insights into the intrinsic dynamics of large DNA nanocages and represent a useful tool in the field of structural DNA nanotechnology.

PMID: 28275219 [PubMed - in process]

Plant Chemical Genetics: From Phenotype-based Screens to Synthetic Biology.

Plant Physiol. 2017 Mar 08;:

Authors: Dejonghe W, Russinova E

PMID: 28275150 [PubMed - as supplied by publisher]

Epiregulin-blocking antibody inhibits epiregulin-dependent EGFR signaling.

Biochem Biophys Res Commun. 2017 Mar 05;:

Authors: Iijima M, Anai M, Kodama T, Shibasaki Y

Abstract
The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase involved in many cellular functions including cell growth and migration. EGFR may be activated by EGF family ligands such as EGF and epiregulin (EREG). EREG is overexpressed in human colon and breast cancers, implying that EREG plays roles in tumorigenesis. Although EGF family members share a receptor, it is not well known whether their signaling pathways differ. In order to investigate EREG signaling, we established the anti-EREG antibody that inhibits EGFR downstream signaling stimulated by EREG but not by EGF. While the anti-EREG antibody has little effect on cell growth, it inhibits cell adhesion of EREG-expressing autocrine cancer cell lines. Our results suggest that anti-EREG antibodies represent valuable tools for elucidating EREG-specific signaling pathways, and may serve as therapeutic candidates for the treatment of cancers.

PMID: 28274874 [PubMed - as supplied by publisher]

Systemic QSAR and phenotypic virtual screening: chasing butterflies in drug discovery.

Drug Discov Today. 2017 Mar 05;:

Authors: Cruz-Monteagudo M, Schürer S, Tejera E, Pérez-Castillo Y, Medina-Franco JL, Sánchez-Rodríguez A, Borges F

Abstract
Current advances in systems biology suggest a new change of paradigm reinforcing the holistic nature of the drug discovery process. According to the principles of systems biology, a simple drug perturbing a network of targets can trigger complex reactions. Therefore, it is possible to connect initial events with final outcomes and consequently prioritize those events, leading to a desired effect. Here, we introduce a new concept, 'Systemic Chemogenomics/Quantitative Structure-Activity Relationship (QSAR)'. To elaborate on the concept, relevant information surrounding it is addressed. The concept is challenged by implementing a systemic QSAR approach for phenotypic virtual screening (VS) of candidate ligands acting as neuroprotective agents in Parkinson's disease (PD). The results support the suitability of the approach for the phenotypic prioritization of drug candidates.

PMID: 28274840 [PubMed - as supplied by publisher]

Systems Biology of Metabolism: A Driver for Developing Personalized and Precision Medicine.

Cell Metab. 2017 Mar 07;25(3):572-579

Authors: Nielsen J

Abstract
Systems biology uses mathematical models to analyze large datasets and simulate system behavior. It enables integrative analysis of different types of data and can thereby provide new insight into complex biological systems. Here will be discussed the challenges of using systems medicine for advancing the development of personalized and precision medicine to treat metabolic diseases like insulin resistance, obesity, NAFLD, NASH, and cancer. It will be illustrated how the concept of genome-scale metabolic models can be used for integrative analysis of big data with the objective of identifying novel biomarkers that are foundational for personalized and precision medicine.

PMID: 28273479 [PubMed - in process]

Emerging avian influenza infections: Current understanding of innate immune response and molecular pathogenesis.

Int Rev Immunol. 2017 Mar 08;:1-19

Authors: Mishra A, Vijayakumar P, Raut AA

Abstract
The highly pathogenic avian influenza viruses (HPAIVs) cause severe disease in gallinaceous poultry species, domestic ducks, various aquatic and terrestrial wild bird species as well as humans. The outcome of the disease is determined by complex interactions of multiple components of the host, the virus, and the environment. While the host-innate immune response plays an important role for clearance of infection, excessive inflammatory immune response (cytokine storm) may contribute to morbidity and mortality of the host. Therefore, innate immunity response in avian influenza infection has two distinct roles. However, the viral pathogenic mechanism varies widely in different avian species, which are not completely understood. In this review, we summarized the current understanding and gaps in host-pathogen interaction of avian influenza infection in birds. In first part of this article, we summarized influenza viral pathogenesis of gallinaceous and non-gallinaceous avian species. Then we discussed innate immune response against influenza infection, cytokine storm, differential host immune responses against different pathotypes, and response in different avian species. Finally, we reviewed the systems biology approach to study host-pathogen interaction in avian species for better characterization of molecular pathogenesis of the disease. Wild aquatic birds act as natural reservoir of AIVs. Better understanding of host-pathogen interaction in natural reservoir is fundamental to understand the properties of AIV infection and development of improved vaccine and therapeutic strategies against influenza.

PMID: 28272907 [PubMed - as supplied by publisher]

Identifying disease network perturbations through regression on gene expression and pathway topology analysis.

Conf Proc IEEE Eng Med Biol Soc. 2016 Aug;2016:5969-5972

Authors: Dimitrakopoulos GN, Balomenos P, Vrahatis AG, Sgarbas K, Bezerianos A

Abstract
In Systems Biology, network-based approaches have been extensively used to effectively study complex diseases. An important challenge is the detection of network perturbations which disrupt regular biological functions as a result of a disease. In this regard, we introduce a network based pathway analysis method which isolates casual interactions with significant regulatory roles within diseased-perturbed pathways. Specifically, we use gene expression data with Random Forest regression models to assess the interactivity strengths of genes within disease-perturbed networks, using KEGG pathway maps as a source of prior-knowledge pertaining to pathway topology. We deliver as output a network with imprinted perturbations corresponding to the biological phenomena arising in a disease-oriented experiment. The efficacy of our approach is demonstrated on a serous papillary ovarian cancer experiment and results highlight the functional roles of high impact interactions and key gene regulators which cause strong perturbations on pathway networks, in accordance with experimentally validated knowledge from recent literature.

PMID: 28269612 [PubMed - in process]

An in silico model of the effects of vitamin D3 on mycobacterium infected macrophage.

Conf Proc IEEE Eng Med Biol Soc. 2016 Aug;2016:1443-1446

Authors: Gough M, May E

Abstract
Mycobacterium tuberculosis is a global health concern, causing over one million deaths a year. Alveolar macrophages, as the primary host cell of this intracellular bacterium, play an important role in the course of disease. Vitamin D3 is known to have a potent effect on macrophage behavior during infection, modulating the production of pro- and anti-inflammatory cytokines and immune effector molecules. In a vitamin D3 deficient host, the immune systems response to infection is greatly impaired. We used a quantitative systems biology approach to model the intracellular effects of vitamin D3 and compared our simulation output to our in vitro model of mycobacterium infection of macrophages in the presence and absence of Vitamin D3. Our in silico model results agreed with the in vitro assay results of interleukin-10, an anti-inflammatory protein whose production is known to be influenced by vitamin D3. This model will provide a platform for further investigation of the effects of vitamin D3 deficiency on host immune response to infection.

PMID: 28268597 [PubMed - in process]

Mapping the function of neuronal ion channels in model and experiment.

Elife. 2017 Mar 06;6:

Authors: Podlaski WF, Seeholzer A, Groschner LN, Miesenböck G, Ranjan R, Vogels TP

Abstract
Ion channel models are the building blocks of computational neuron models. Their biological fidelity is therefore crucial for the interpretation of simulations. However, the number of published models, and the lack of standardization, make the comparison of ion channel models with one another and with experimental data difficult. Here, we present a framework for the automated large-scale classification of ion channel models. Using annotated metadata and responses to a set of voltage-clamp protocols, we assigned 2378 models of voltage- and calcium-gated ion channels coded in NEURON to 211 clusters. The IonChannelGenealogy (ICGenealogy) web interface provides an interactive resource for the categorization of new and existing models and experimental recordings. It enables quantitative comparisons of simulated and/or measured ion channel kinetics, and facilitates field-wide standardization of experimentally-constrained modeling.

PMID: 28267430 [PubMed - in process]

A Systems Biology Methodology Combining Transcriptome and Interactome Datasets to Assess the Implications of Cytokinin Signaling for Plant Immune Networks.

Methods Mol Biol. 2017;1569:165-173

Authors: Kunz M, Dandekar T, Naseem M

Abstract
Cytokinins (CKs) play an important role in plant growth and development. Also, several studies highlight the modulatory implications of CKs for plant-pathogen interaction. However, the underlying mechanisms of CK mediating immune networks in plants are still not fully understood. A detailed analysis of high-throughput transcriptome (RNA-Seq and microarrays) datasets under modulated conditions of plant CKs and its mergence with cellular interactome (large-scale protein-protein interaction data) has the potential to unlock the contribution of CKs to plant defense. Here, we specifically describe a detailed systems biology methodology pertinent to the acquisition and analysis of various omics datasets that delineate the role of plant CKs in impacting immune pathways in Arabidopsis.

PMID: 28265997 [PubMed - in process]

Precision medicine driven by cancer systems biology.

Cancer Metastasis Rev. 2017 Mar 07;:

Authors: Filipp FV

Abstract
Molecular insights from genome and systems biology are influencing how cancer is diagnosed and treated. We critically evaluate big data challenges in precision medicine. The melanoma research community has identified distinct subtypes involving chronic sun-induced damage and the mitogen-activated protein kinase driver pathway. In addition, despite low mutation burden, non-genomic mitogen-activated protein kinase melanoma drivers are found in membrane receptors, metabolism, or epigenetic signaling with the ability to bypass central mitogen-activated protein kinase molecules and activating a similar program of mitogenic effectors. Mutation hotspots, structural modeling, UV signature, and genomic as well as non-genomic mechanisms of disease initiation and progression are taken into consideration to identify resistance mutations and novel drug targets. A comprehensive precision medicine profile of a malignant melanoma patient illustrates future rational drug targeting strategies. Network analysis emphasizes an important role of epigenetic and metabolic master regulators in oncogenesis. Co-occurrence of driver mutations in signaling, metabolic, and epigenetic factors highlights how cumulative alterations of our genomes and epigenomes progressively lead to uncontrolled cell proliferation. Precision insights have the ability to identify independent molecular pathways suitable for drug targeting. Synergistic treatment combinations of orthogonal modalities including immunotherapy, mitogen-activated protein kinase inhibitors, epigenetic inhibitors, and metabolic inhibitors have the potential to overcome immune evasion, side effects, and drug resistance.

PMID: 28265786 [PubMed - as supplied by publisher]