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systems biology phenotypes

Yixin Zhao, Xu Shen, Tian Tang, Chung-I Wu
Why do microRNAs (miRNAs) weakly repress so many targets such that most targets do not have phenotypic effects? An increasingly accepted view posits that weak targeting has no biological function and each miRNA effectively has only a few functional targets. Here, we review the evolutionary arguments for this postulate and find these arguments seriously flawed. In contrast, from the systems perspective, the power of broad and weak targeting may reside in the cumulative effects of all expressions, which collectively stabilize gene regulatory networks...
September 28, 2017: Molecular Biology and Evolution
Daan R van der Veen, Sjaak J Riede, Paul D Heideman, Michaela Hau, Vincent van der Vinne, Roelof A Hut
Under natural conditions, many aspects of the abiotic and biotic environment vary with time of day, season or even era, while these conditions are typically kept constant in laboratory settings. The timing information contained within the environment serves as critical timing cues for the internal biological timing system, but how this system drives daily rhythms in behaviour and physiology may also depend on the internal state of the animal. The disparity between timing of these cues in natural and laboratory conditions can result in substantial differences in the scheduling of behaviour and physiology under these conditions...
November 19, 2017: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
Brent M Kuenzi, Lily L Remsing Rix, Paul A Stewart, Bin Fang, Fumi Kinose, Annamarie T Bryant, Theresa A Boyle, John M Koomen, Eric B Haura, Uwe Rix
Targeted drugs are effective when they directly inhibit strong disease drivers, but only a small fraction of diseases feature defined actionable drivers. Alternatively, network-based approaches can uncover new therapeutic opportunities. Applying an integrated phenotypic screening, chemical and phosphoproteomics strategy, here we describe the anaplastic lymphoma kinase (ALK) inhibitor ceritinib as having activity across several ALK-negative lung cancer cell lines and identify new targets and network-wide signaling effects...
October 9, 2017: Nature Chemical Biology
A Sequeida, K Maisey, M Imarai
In superior vertebrates, Interleukin 4 (IL-4) and Interleukin 13 (IL-13) play key and diverse roles to support immune responses acting on cell surface receptors. When stimulated, receptors activate intracellular signalling cascades switching cell phenotypes according to stimuli. In teleost fish, Interleukin 4/13 (IL-4/13) is the ancestral family cytokine related to both IL-4 and IL-13. Every private and common receptor subunit for IL-4/13 have in fish at least two paralogues and, as in mammals, soluble forms are also part of the receptor system...
September 28, 2017: Cytokine & Growth Factor Reviews
Mirko Pesce, Raffaella Tatangelo, Irene La Fratta, Alessia Rizzuto, Giovanna Campagna, Cinzia Turli, Alessio Ferrone, Sara Franceschelli, Lorenza Speranza, Antonia Patruno, Patrizia Ballerini, Maria Anna De Lutiis, Mario Felaco, Alfredo Grilli
The cognitive impairment characterizing the phenotype of older adults has been related to the efficiency of the antioxidant system. This study aimed at investigating the effect of memory training (MT) on memory, global cognitive functioning, and the oxidant and antioxidant capacity of plasma. We recruited 52 healthy subjects aged over 60. Twenty-nine subjects were submitted to 6-months of MT (Experimental Group, EG), and 23 were used as a Control Group (CG). Global cognitive functioning was assessed by the Mini-Mental State Examination (MMSE) and Short- and Long-Term Memory (STM and LTM, respectively) by the Rey Auditory Verbal Learning Test (RAVLT) at baseline (T0) and after 6-months (T1)...
October 5, 2017: Neuroscience
Sergio E Baranzini, Jorge R Oksenberg
Multiple sclerosis (MS) is a common autoimmune disease that targets myelin in the central nervous system (CNS). Multiple genome-wide association studies (GWAS) over the past 10 years have uncovered more than 200 loci that independently contribute to disease pathogenesis. As with many other complex diseases, risk of developing MS is driven by multiple common variants whose biological effects are not immediately clear. Here, we present a historical perspective on the progress made in MS genetics and discuss current work geared towards creating a more complete model that accurately represents the genetic landscape of MS susceptibility...
October 5, 2017: Trends in Genetics: TIG
Maryam Zarkesh, Azita Zadeh-Vakili, Fereidoun Azizi, Forough Foroughi, Maziar Mohammad Akhavan, Mehdi Hedayati
Thyroid carcinoma (TC) is the most frequent malignant neoplasm of the endocrine system. Molecular methods for diagnosis of invasive thyroid disease can be effectively adopted. Epigenetic factors play an important role in the diversity patterns of gene expression and the phenotypic and biological characteristics of TC subtypes. We aimed to review epigenetic changes in the main subtypes of TC, along with a presentation of the methods that have examined these changes, and active clinical trials for the treatment of advanced TCs targeting epigenetic changes...
October 6, 2017: Molecular Diagnosis & Therapy
Réjean M Guerriero, Archana A Patel, Brian Walsh, Fiona M Baumer, Ankoor S Shah, Jurriaan M Peters, Lance H Rodan, Pankaj B Agrawal, Phillip L Pearl, Masanori Takeoka
OBJECTIVE: Pyridoxine is converted to its biologically active form pyridoxal-5-phosphate (P5P) by the enzyme pyridox(am)ine 5'-phosphate oxidase and serves as a cofactor in nearly 200 reactions in the central nervous system. Pyridox(am)ine 5'-phosphate oxidase deficiency leads to P5P dependent epilepsy, typically a neonatal- or infantile-onset epileptic encephalopathy treatable with P5P or in some cases, pyridoxine. Following identification of retinopathy in a patient with pyridox(am)ine 5'-phosphate oxidase deficiency that was reversible with P5P therapy, we describe the systemic manifestations of pyridox(am)ine 5'-phosphate oxidase deficiency...
June 3, 2017: Pediatric Neurology
Jonathan D Young, Chunhui Cai, Xinghua Lu
BACKGROUND: One approach to improving the personalized treatment of cancer is to understand the cellular signaling transduction pathways that cause cancer at the level of the individual patient. In this study, we used unsupervised deep learning to learn the hierarchical structure within cancer gene expression data. Deep learning is a group of machine learning algorithms that use multiple layers of hidden units to capture hierarchically related, alternative representations of the input data...
October 3, 2017: BMC Bioinformatics
Hasan Hashem, Susan J Kelly, Nancy J Ganson, Michael S Hershfield
PURPOSE OF REVIEW: A new autoinflammatory disease, deficiency of adenosine deaminase 2 (DADA2), caused by mutations in the CECR1 gene, was first reported in 2014. This review aims to update progress in defining, treating, and understanding this multi-faceted disorder. RECENT FINDINGS: DADA2 was first described in patients with systemic inflammation, mild immune deficiency, and vasculopathy manifested as recurrent stroke or polyarteritis nodosa (PAN). More than 125 patients have now been reported, and the phenotype has expanded to include children and adults presenting primarily with pure red cell aplasia (PRCA), or with antibody deficiency...
October 5, 2017: Current Rheumatology Reports
Cynthia L Fisher, Hendrik Marks, Lily Ting-Yin Cho, Robert Andrews, Sam Wormald, Thomas Carroll, Vivek Iyer, Peri Tate, Barry Rosen, Hendrik G Stunnenberg, Amanda G Fisher, William C Skarnes
Mouse embryonic stem (ES) cells are a popular model system to study biological processes, though uncovering recessive phenotypes requires inactivating both alleles. Building upon resources from the International Knockout Mouse Consortium (IKMC), we developed a targeting vector for second allele inactivation in conditional-ready IKMC 'knockout-first' ES cell lines. We applied our technology to several epigenetic regulators, recovering bi-allelic targeted clones with a high efficiency of 60% and used Flp recombinase to restore expression in two null cell lines to demonstrate how our system confirms causality through mutant phenotype reversion...
September 13, 2017: Nucleic Acids Research
Francesca Managò, Francesco Papaleo
Human studies of schizophrenia are now reporting a previously unidentified genetic convergence on postsynaptic signaling complexes such as the activity-regulated cytoskeletal-associated (Arc) gene. However, because this evidence is still very recent, the neurobiological implication of Arc in schizophrenia is still scattered and unrecognized. Here, we first review current and developing findings connecting Arc in schizophrenia. We then highlight recent and previous findings from preclinical mouse models that elucidate how Arc genetic modifications might recapitulate schizophrenia-relevant behavioral phenotypes following the novel Research Domain Criteria (RDoC) framework...
2017: Frontiers in Behavioral Neuroscience
Azza Mohamed Akasha, J Julie Kim
Breast cancer research has historically relied on two model systems: two-dimensional cell culture systems and mouse models. These models, although very convenient, lack the functional phenotypic architecture of human tissue. Extrapolation of hormonal responses from models to human relevance also requires further investigation due to the anatomical, physiological, and biological differences. Three-dimensional spheroids provide alternative models as they better represent the architecture and maintain the histomorphological, functional, and micro-environmental features of the in vivo human tumor tissue...
October 4, 2017: Molecular Reproduction and Development
Stanley M Kanai, Alethia J Edwards, Joel G Rurik, Patrick Osei-Owusu, Kendall J Blumer
Regulator of G protein signaling 2 (RGS2) controls signaling by receptors coupled to the Gq/11 class heterotrimeric G proteins. RGS2 deficiency causes several phenotypes in mice and occurs in several diseases, including hypertension where a proteolytically unstable RGS2 mutant has been reported. However, the mechanisms and functions of RGS2 proteolysis remain poorly understood. Here we addressed these questions by identifying degradation signals in RGS2, and studying dynamic regulation of Gq/11-evoked Ca2+ signaling and vascular contraction...
October 3, 2017: Journal of Biological Chemistry
Nassim E Ajami, Shakti Gupta, Mano R Maurya, Phu Nguyen, Julie Yi-Shuan Li, John Y-J Shyy, Zhen Chen, Shu Chien, Shankar Subramaniam
Blood flow and vascular shear stress patterns play a significant role in inducing and modulating physiological responses of endothelial cells (ECs). Pulsatile shear (PS) is associated with an atheroprotective endothelial phenotype, while oscillatory shear (OS) is associated with an atheroprone endothelial phenotype. Although mechanisms of endothelial shear response have been extensively studied, most studies focus on characterization of single molecular pathways, mainly at fixed time points after stress application...
September 26, 2017: Proceedings of the National Academy of Sciences of the United States of America
Paola Caruso, Benjamin J Dunmore, Kenny Schlosser, Sandra Schoors, Claudia C Dos Santos, Carol Perez-Iratxeta, Jessie R Lavoie, Hui Zhang, Lu Long, Amanda R Flockton, Maria G Frid, Paul D Upton, Angelo D'Alessandro, Charaka Hadinnapola, Fedir N Kiskin, Mohamad Taha, Liam A Hurst, Mark L Ormiston, Akiko Hata, Kurt R Stenmark, Peter Carmeliet, Duncan J Stewart, Nicholas W Morrell
Background -Pulmonary arterial hypertension (PAH) is characterized by abnormal growth and enhanced glycolysis of pulmonary artery endothelial cells (PAECs). However, the mechanisms underlying alterations in energy production have not been identified. Methods -Here, we examined the miRNA and proteomic profiles of blood outgrowth endothelial cells (BOECs) from patients with heritable PAH (HPAH) due to mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene and patients with idiopathic PAH (IPAH) to determine mechanisms underlying abnormal endothelial glycolysis...
September 26, 2017: Circulation
Antigoni Avramouli, Panayiotis M Vlamos
Scientific advances in biomedical disciplines have allowed us to identify the underlying causes of many diseases with increased comprehension-leading the way towards precision medicine. In this context, unique disease and medical traits pave the way for the development of adapted disease management, drugs and therapies tailored to each patient. Bearing in mind that reductionism, an approach that has dominated biomedical research for many years and has resulted in the identification of definite cellular phenotypes and human diseases which are linked with specific integral molecules, we strongly believe that Alzheimer's Disease, one of the most common neurodegenerative diseases, could not be applied to the model of one disease-one assay-one drug...
2017: Advances in Experimental Medicine and Biology
D L Bailey, B J Pichler, B Gückel, G Antoch, H Barthel, Z M Bhujwalla, S Biskup, S Biswal, M Bitzer, R Boellaard, R F Braren, C Brendle, K Brindle, A Chiti, C la Fougère, R Gillies, V Goh, M Goyen, M Hacker, L Heukamp, G M Knudsen, A M Krackhardt, I Law, J C Morris, K Nikolaou, J Nuyts, A A Ordonez, K Pantel, H H Quick, K Riklund, O Sabri, B Sattler, E G C Troost, M Zaiss, L Zender, Thomas Beyer
The 6th annual meeting to address key issues in positron emission tomography (PET)/magnetic resonance imaging (MRI) was held again in Tübingen, Germany, from March 27 to 29, 2017. Over three days of invited plenary lectures, round table discussions and dialogue board deliberations, participants critically assessed the current state of PET/MRI, both clinically and as a research tool, and attempted to chart future directions. The meeting addressed the use of PET/MRI and workflows in oncology, neurosciences, infection, inflammation and chronic pain syndromes, as well as deeper discussions about how best to characterise the tumour microenvironment, optimise the complementary information available from PET and MRI, and how advanced data mining and bioinformatics, as well as information from liquid biomarkers (circulating tumour cells and nucleic acids) and pathology, can be integrated to give a more complete characterisation of disease phenotype...
October 2, 2017: Molecular Imaging and Biology: MIB: the Official Publication of the Academy of Molecular Imaging
Brian J Mendoza, Cong T Trinh
Motivation: Genetic diversity of non-model organisms offers a repertoire of unique phenotypic features for exploration and cultivation for synthetic biology and metabolic engineering applications. To realize this enormous potential, it is critical to have an efficient genome editing tool for rapid strain engineering of these organisms to perform novel programmed functions. Results: To accommodate the use of CRISPR/Cas systems for genome editing across organisms, we have developed a novel method, named CASPER (CRISPR Associated Software for Pathway Engineering and Research), for identifying on- and off-targets with enhanced predictability coupled with an analysis of non-unique (repeated) targets to assist in editing any organism with various endonucleases...
September 8, 2017: Bioinformatics
Tim A M Bouwens van der Vlis, Ann Hoeben, Jan C Beckervordersandforth, Linda Ackermans, Daniëlle B P Eekers, Rianne M J Wennekes, Olaf E M G Schijns
BACKGROUND: In the 2016 update of the World Health Organization Classification of Tumors of the central nervous system, phenotypic and genotypic parameters are integrated in diffuse low-grade glioma (LGG) tumor classification. Implementation of this combined phenotypic-genotypic characterization identifies prognostic relevant subgroups. CASE DESCRIPTION: We report a case of a 67-year-old patient with an LGG that showed molecular characteristics similar to glioblastoma multiforme (GBM)...
2017: Surgical Neurology International
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