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Article ; Online: Pancreatic Beta Cell G-Protein Coupled Receptors and Second Messenger Interactions: A Systems Biology Computational Analysis.

Fridlyand, Leonid E / Philipson, Louis H

PloS one

2016 Volume 11, Issue 5, Page(s) e0152869

Abstract: Insulin secretory in pancreatic beta-cells responses to nutrient stimuli and hormonal modulators include multiple messengers and signaling pathways with complex interdependencies. Here we present a computational model that incorporates recent data on ... ...

Abstract	Insulin secretory in pancreatic beta-cells responses to nutrient stimuli and hormonal modulators include multiple messengers and signaling pathways with complex interdependencies. Here we present a computational model that incorporates recent data on glucose metabolism, plasma membrane potential, G-protein-coupled-receptors (GPCR), cytoplasmic and endoplasmic reticulum calcium dynamics, cAMP and phospholipase C pathways that regulate interactions between second messengers in pancreatic beta-cells. The values of key model parameters were inferred from published experimental data. The model gives a reasonable fit to important aspects of experimentally measured metabolic and second messenger concentrations and provides a framework for analyzing the role of metabolic, hormones and neurotransmitters changes on insulin secretion. Our analysis of the dynamic data provides support for the hypothesis that activation of Ca2+-dependent adenylyl cyclases play a critical role in modulating the effects of glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and catecholamines. The regulatory properties of adenylyl cyclase isoforms determine fluctuations in cytoplasmic cAMP concentration and reveal a synergistic action of glucose, GLP-1 and GIP on insulin secretion. On the other hand, the regulatory properties of phospholipase C isoforms determine the interaction of glucose, acetylcholine and free fatty acids (FFA) (that act through the FFA receptors) on insulin secretion. We found that a combination of GPCR agonists activating different messenger pathways can stimulate insulin secretion more effectively than a combination of GPCR agonists for a single pathway. This analysis also suggests that the activators of GLP-1, GIP and FFA receptors may have a relatively low risk of hypoglycemia in fasting conditions whereas an activator of muscarinic receptors can increase this risk. This computational analysis demonstrates that study of second messenger pathway interactions will improve understanding of critical regulatory sites, how different GPCRs interact and pharmacological targets for modulating insulin secretion in type 2 diabetes.
MeSH term(s)	Cyclic AMP/metabolism ; Humans ; Islets of Langerhans/metabolism ; Phosphatidylinositols/metabolism ; Receptors, G-Protein-Coupled/metabolism ; Second Messenger Systems ; Systems Biology ; Type C Phospholipases/metabolism
Chemical Substances	Phosphatidylinositols ; Receptors, G-Protein-Coupled ; Cyclic AMP (E0399OZS9N) ; Type C Phospholipases (EC 3.1.4.-)
Language	English
Publishing date	2016
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0152869
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: A computational systems analysis of factors regulating α cell glucagon secretion.

Fridlyand, Leonid E / Philipson, Louis H

Islets

2012 Volume 4, Issue 4, Page(s) 262–283

Abstract: Glucagon, a peptide hormone secreted from the α-cells of the pancreatic islets, is critical for blood glucose homeostasis. We reviewed the literature and employed a computational systems analysis of intracellular metabolic and electrical regulation of ... ...

Abstract	Glucagon, a peptide hormone secreted from the α-cells of the pancreatic islets, is critical for blood glucose homeostasis. We reviewed the literature and employed a computational systems analysis of intracellular metabolic and electrical regulation of glucagon secretion to better understand these processes. The mathematical model of α-cell metabolic parameters is based on our previous model for pancreatic β-cells. We also formulated an ionic model for action potentials that incorporates Ca ( 2+) , K (+) , Na (+) and Cl (-) currents. Metabolic and ionic models are coupled to the equations describing Ca ( 2+) homeostasis and glucagon secretion that depends on activation of specific voltage-gated Ca ( 2+) channels. Paracrine and endocrine regulations were analyzed with an emphasis on their effects on a hyperpolarization of membrane potential. This general model simulates and gives insight into the mechanisms of regulation of glucagon secretion under a wide range of experimental conditions. We also reviewed and analyzed dysfunctional mechanisms in α-cells to determine key pharmacological targets for modulating glucagon secretion in type 1 and 2 diabetes.
MeSH term(s)	Animals ; Biological Transport ; Calcium/metabolism ; Calcium Channels/physiology ; Chloride Channels/physiology ; Computer Simulation ; Diabetes Mellitus/metabolism ; Diabetes Mellitus/physiopathology ; Electrophysiological Phenomena ; Glucagon/antagonists & inhibitors ; Glucagon/metabolism ; Glucagon-Secreting Cells/metabolism ; Glucagon-Secreting Cells/physiology ; Glucose/metabolism ; Glucose/pharmacokinetics ; Hormones/metabolism ; Humans ; Membrane Potentials ; Models, Biological ; Paracrine Communication ; Potassium Channels/physiology ; Systems Biology
Chemical Substances	Calcium Channels ; Chloride Channels ; Hormones ; Potassium Channels ; Glucagon (9007-92-5) ; Glucose (IY9XDZ35W2) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2012-07-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1938-2022
ISSN (online)	1938-2022
DOI	10.4161/isl.22193
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Article ; Online: Pancreatic Beta Cell G-Protein Coupled Receptors and Second Messenger Interactions

Leonid E Fridlyand / Louis H Philipson

PLoS ONE, Vol 11, Iss 5, p e

A Systems Biology Computational Analysis.

2016 Volume 0152869

Abstract	Insulin secretory in pancreatic beta-cells responses to nutrient stimuli and hormonal modulators include multiple messengers and signaling pathways with complex interdependencies. Here we present a computational model that incorporates recent data on glucose metabolism, plasma membrane potential, G-protein-coupled-receptors (GPCR), cytoplasmic and endoplasmic reticulum calcium dynamics, cAMP and phospholipase C pathways that regulate interactions between second messengers in pancreatic beta-cells. The values of key model parameters were inferred from published experimental data. The model gives a reasonable fit to important aspects of experimentally measured metabolic and second messenger concentrations and provides a framework for analyzing the role of metabolic, hormones and neurotransmitters changes on insulin secretion. Our analysis of the dynamic data provides support for the hypothesis that activation of Ca2+-dependent adenylyl cyclases play a critical role in modulating the effects of glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and catecholamines. The regulatory properties of adenylyl cyclase isoforms determine fluctuations in cytoplasmic cAMP concentration and reveal a synergistic action of glucose, GLP-1 and GIP on insulin secretion. On the other hand, the regulatory properties of phospholipase C isoforms determine the interaction of glucose, acetylcholine and free fatty acids (FFA) (that act through the FFA receptors) on insulin secretion. We found that a combination of GPCR agonists activating different messenger pathways can stimulate insulin secretion more effectively than a combination of GPCR agonists for a single pathway. This analysis also suggests that the activators of GLP-1, GIP and FFA receptors may have a relatively low risk of hypoglycemia in fasting conditions whereas an activator of muscarinic receptors can increase this risk. This computational analysis demonstrates that study of second messenger pathway interactions will improve understanding of ...
Keywords	Medicine ; R ; Science ; Q
Subject code	612
Language	English
Publishing date	2016-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Mechanisms of glucose sensing in the pancreatic β-cell: A computational systems-based analysis.

Fridlyand, Leonid E / Phillipson, Louis H

Islets

2011 Volume 3, Issue 5, Page(s) 224–230

Abstract: ... has implications for β-cell function and the treatment of type 2 diabetes (Fridlyand and Philipson ...

Abstract	Pancreatic β-cells respond to rising blood glucose by increasing oxidative metabolism, leading to an increased ATP/ADP ratio in the cytoplasm with a subsequent influx of calcium and the eventual secretion of insulin. The mechanisms of glucose sensing in the pancreatic β-cell involve the coupling of cytoplasmic and mitochondrial processes. Our analysis, based on mathematical models of data from multiple sources has implications for β-cell function and the treatment of type 2 diabetes (Fridlyand and Philipson, 2010). This β-cell glucose response model correctly predicts changes in the ATP/ADP ratio, cytoplasmic and mitochondrial calcium levels, and other metabolic parameters in response to alterations in substrate delivery at steady-state and during cytoplasmic calcium oscillations. Here we consider how peculiarities of β-cell pathways that result in dysfunction can be a consequence of specific mechanisms of glucose sensitivity, using our computational systems-based analysis. We found that the mitochondrial membrane potential must be relatively low in β-cells compared with other cell types to permit precise mitochondrial regulation of the cytoplasmic ATP/ADP ratio. This key difference may follow from a relative reduction in cellular respiratory activity. Our analysis additionally demonstrates how activity of lactate dehydrogenase, uncoupling proteins, and the redox shuttles all working in concert can regulate β-cell function. We further show that a decreased mitochondrial membrane potential may lead to a low rate of production of reactive oxygen species in β-cells under physiological conditions. This computational systems analysis aids in providing a more complete understanding of the complex process of β-cell glucose sensing.
MeSH term(s)	Blood Glucose/metabolism ; Calcium/metabolism ; Diabetes Mellitus, Type 2/metabolism ; Homeostasis/physiology ; Humans ; Insulin-Secreting Cells/metabolism ; Mitochondria/physiology ; Models, Biological
Chemical Substances	Blood Glucose ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2011-09-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ISSN	1938-2022
ISSN (online)	1938-2022
DOI	10.4161/isl.3.5.16409
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Article ; Online: Coupling of metabolic, second messenger pathways and insulin granule dynamics in pancreatic beta-cells: a computational analysis.

Fridlyand, Leonid E / Philipson, Louis H

Progress in biophysics and molecular biology

2011 Volume 107, Issue 2, Page(s) 293–303

Abstract: Insulin secretory responses to nutrient stimuli and hormonal modulators in pancreatic beta-cells are controlled by a variety of secondary messengers. We have analyzed numerous mechanisms responsible for regulated exocytosis in these cells and present an ... ...

Abstract	Insulin secretory responses to nutrient stimuli and hormonal modulators in pancreatic beta-cells are controlled by a variety of secondary messengers. We have analyzed numerous mechanisms responsible for regulated exocytosis in these cells and present an integrated mathematical model of cytosolic Ca²⁺, cAMP and granule dynamics. The insulin-containing granules in the beta-cell were divided into four classes: a large "reserve" granule pool, a smaller pool of the morphologically docked granules that is chemically 'primed' for release or the "readily releasable pool", and a pool of "restless newcomer granules" that undergoes preferential exocytosis. The model incorporates glucose and other aspects of metabolism, the cAMP amplifying pathway, insulin granule dynamics and the exocyst concept for granule binding. The values of most of the model parameters were inferred from available experimental data. The model can generate both the fast first phase and slow biphasic insulin secretion found experimentally in response to a step increase of membrane potential or of glucose. The numerical simulations have also reproduced a variety of experimental conditions, such as periodic stimulation by high K⁺ and the potentiation induced in islets by pre-incubation with cAMP pathway activators. The explicit incorporation of Ca²⁺ channels, Ca²⁺ and cAMP dynamics allows the model to be further connected to current models for calcium and metabolic dynamics and provides an interpretation of the roles of the triggering and amplifying pathways of glucose-stimulated insulin secretion. The model may be important in the identification of pharmacological targets for improving insulin secretion in type 2 diabetes.
MeSH term(s)	Animals ; Computer Simulation ; Glucose/metabolism ; Humans ; Insulin/metabolism ; Insulin Secretion ; Insulin-Secreting Cells/cytology ; Insulin-Secreting Cells/metabolism ; Second Messenger Systems ; Secretory Vesicles/metabolism
Chemical Substances	Insulin ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2011-09-08
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	209302-9
ISSN	1873-1732 ; 0079-6107
ISSN (online)	1873-1732
ISSN	0079-6107
DOI	10.1016/j.pbiomolbio.2011.09.001
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Article: Growth Hormone-Releasing Hormone in Diabetes.

Fridlyand, Leonid E / Tamarina, Natalia A / Schally, Andrew V / Philipson, Louis H

Frontiers in endocrinology

2016 Volume 7, Page(s) 129

Abstract: Growth hormone-releasing hormone (GHRH) is produced by the hypothalamus and stimulates growth hormone synthesis and release in the anterior pituitary gland. In addition, GHRH is an important regulator of cellular functions in many cells and organs. ... ...

Abstract	Growth hormone-releasing hormone (GHRH) is produced by the hypothalamus and stimulates growth hormone synthesis and release in the anterior pituitary gland. In addition, GHRH is an important regulator of cellular functions in many cells and organs. Expression of GHRH G-Protein Coupled Receptor (GHRHR) has been demonstrated in different peripheral tissues and cell types, including pancreatic islets. Among the peripheral activities, recent studies demonstrate a novel ability of GHRH analogs to increase and preserve insulin secretion by beta-cells in isolated pancreatic islets, which makes them potentially useful for diabetes treatment. This review considers the role of GHRHR in the beta-cell and addresses the unique engineered GHRH agonists and antagonists for treatment of type 2 diabetes mellitus. We discuss the similarity of signaling pathways activated by GHRHR in pituitary somatotrophs and in pancreatic beta-cells and possible ways as to how the GHRHR pathway can interact with glucose and other secretagogues to stimulate insulin secretion. We also consider the hypothesis that novel GHRHR agonists can improve glucose metabolism in Type 2 diabetes by preserving the function and survival of pancreatic beta-cells. Wound healing and cardioprotective action with new GHRH agonists suggest that they may prove useful in ameliorating certain diabetic complications. These findings highlight the future potential therapeutic effectiveness of modulators of GHRHR activity for the development of new therapeutic approaches in diabetes and its complications.
Language	English
Publishing date	2016
Publishing country	Switzerland
Document type	Review ; Journal Article
ZDB-ID	2592084-4
ISSN	1664-2392
ISSN	1664-2392
DOI	10.3389/fendo.2016.00129
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Article ; Online: Glucose sensing in the pancreatic beta cell: a computational systems analysis.

Fridlyand, Leonid E / Philipson, Louis H

Theoretical biology & medical modelling

2010 Volume 7, Page(s) 15

Abstract: Background: Pancreatic beta-cells respond to rising blood glucose by increasing oxidative metabolism, leading to an increased ATP/ADP ratio in the cytoplasm. This leads to a closure of KATP channels, depolarization of the plasma membrane, influx of ... ...

Abstract	Background: Pancreatic beta-cells respond to rising blood glucose by increasing oxidative metabolism, leading to an increased ATP/ADP ratio in the cytoplasm. This leads to a closure of KATP channels, depolarization of the plasma membrane, influx of calcium and the eventual secretion of insulin. Such mechanism suggests that beta-cell metabolism should have a functional regulation specific to secretion, as opposed to coupling to contraction. The goal of this work is to uncover contributions of the cytoplasmic and mitochondrial processes in this secretory coupling mechanism using mathematical modeling in a systems biology approach. Methods: We describe a mathematical model of beta-cell sensitivity to glucose. The cytoplasmic part of the model includes equations describing glucokinase, glycolysis, pyruvate reduction, NADH and ATP production and consumption. The mitochondrial part begins with production of NADH, which is regulated by pyruvate dehydrogenase. NADH is used in the electron transport chain to establish a proton motive force, driving the F1F0 ATPase. Redox shuttles and mitochondrial Ca2+ handling were also modeled. Results: The model correctly predicts changes in the ATP/ADP ratio, Ca2+ and other metabolic parameters in response to changes in substrate delivery at steady-state and during cytoplasmic Ca2+ oscillations. Our analysis of the model simulations suggests that the mitochondrial membrane potential should be relatively lower in beta cells compared with other cell types to permit precise mitochondrial regulation of the cytoplasmic ATP/ADP ratio. This key difference may follow from a relative reduction in respiratory activity. The model demonstrates how activity of lactate dehydrogenase, uncoupling proteins and the redox shuttles can regulate beta-cell function in concert; that independent oscillations of cytoplasmic Ca2+ can lead to slow coupled metabolic oscillations; and that the relatively low production rate of reactive oxygen species in beta-cells under physiological conditions is a consequence of the relatively decreased mitochondrial membrane potential. Conclusion: This comprehensive model predicts a special role for mitochondrial control mechanisms in insulin secretion and ROS generation in the beta cell. The model can be used for testing and generating control hypotheses and will help to provide a more complete understanding of beta-cell glucose-sensing central to the physiology and pathology of pancreatic beta-cells.
MeSH term(s)	Adenosine Diphosphate/metabolism ; Adenosine Triphosphate/metabolism ; Calcium/metabolism ; Glucose/metabolism ; Humans ; Islets of Langerhans/metabolism ; Membrane Potentials ; Mitochondria/metabolism ; Mitochondria/physiology ; Systems Analysis
Chemical Substances	Adenosine Diphosphate (61D2G4IYVH) ; Adenosine Triphosphate (8L70Q75FXE) ; Glucose (IY9XDZ35W2) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2010-05-24
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2156462-0
ISSN	1742-4682 ; 1742-4682
ISSN (online)	1742-4682
ISSN	1742-4682
DOI	10.1186/1742-4682-7-15
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Article ; Online: Ion channels and regulation of insulin secretion in human β-cells: a computational systems analysis.

Fridlyand, Leonid E / Jacobson, David A / Philipson, L H

Islets

2013 Volume 5, Issue 1, Page(s) 1–15

Abstract: In mammals an increase in glucose leads to block of ATP dependent potassium channels in pancreatic β cells leading to membrane depolarization. This leads to the repetitive firing of action potentials that increases calcium influx and triggers insulin ... ...

Abstract	In mammals an increase in glucose leads to block of ATP dependent potassium channels in pancreatic β cells leading to membrane depolarization. This leads to the repetitive firing of action potentials that increases calcium influx and triggers insulin granule exocytosis. Several important differences between species in this process suggest that a dedicated human-oriented approach is advantageous as extrapolating from rodent data may be misleading in several respects. We examined depolarization-induced spike activity in pancreatic human islet-attached β-cells employing whole-cell patch-clamp methods. We also reviewed the literature concerning regulation of insulin secretion by channel activity and constructed a data-based computer model of human β cell function. The model couples the Hodgkin-Huxley-type ionic equations to the equations describing intracellular Ca²⁺ homeostasis and insulin release. On the basis of this model we employed computational simulations to better understand the behavior of action potentials, calcium handling and insulin secretion in human β cells under a wide range of experimental conditions. This computational system approach provides a framework to analyze the mechanisms of human β cell insulin secretion.
MeSH term(s)	Animals ; Calcium Signaling ; Computer Simulation ; Humans ; Insulin/metabolism ; Insulin Secretion ; Insulin-Secreting Cells/metabolism ; Ion Channels/metabolism ; Models, Biological ; Secretory Pathway ; Species Specificity
Chemical Substances	Insulin ; Ion Channels
Language	English
Publishing date	2013-04-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ISSN	1938-2022
ISSN (online)	1938-2022
DOI	10.4161/isl.24166
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Article: Reactive species, cellular repair and risk factors in the onset of type 2 diabetes mellitus: review and hypothesis.

Fridlyand, Leonid E / Philipson, Louis H

Current diabetes reviews

2008 Volume 2, Issue 2, Page(s) 241–259

Abstract: Insulin resistance (IRe) and a failure of insulin secretion are the major features of the early pathophysiology of type-2 diabetes mellitus (T2D) but the etiology is still not well understood. We suggest that: 1. The cellular mechanisms that protect ... ...

Abstract	Insulin resistance (IRe) and a failure of insulin secretion are the major features of the early pathophysiology of type-2 diabetes mellitus (T2D) but the etiology is still not well understood. We suggest that: 1. The cellular mechanisms that protect against oxidative stress per se are capable of creating a reactive species-dependent IRe. 2. Reactive species-induced mitochondrial dysfunction can lead to disruption of lipid metabolism, increased intracellular lipid content, and can also contribute to lipid-dependent IRe in myocytes and adipocytes. 3. Metabolic secretagogues that stimulate insulin secretion by the activation of initial steps in the glucose-stimulated insulin secretion pathway can also lead to increased reactive species production and cellular destruction contributing to beta-cell damage and apoptosis. These events that underlie the repair mechanisms in beta-cells, muscle and adipocytes, are important factors in the early etiology of T2D, leading to both IRe and decreased insulin secretion. This hypothesis is supported by data from multiple disciplines and includes aging, obesity and genetic factors in promoting multiple failures in this system leading to the onset of T2D. On the basis of this hypothesis therapeutic strategies should be directed towards increasing insulin secretion and reducing IRe without increasing reactive species production or concentration. Pharmacological or other approaches that result in the activation of mitochondrial biogenesis could be beneficial for both IRe and T2D.
MeSH term(s)	Adipocytes/physiology ; Animals ; Diabetes Mellitus, Type 2/epidemiology ; Diabetes Mellitus, Type 2/physiopathology ; Hepatocytes/physiology ; Humans ; Insulin-Secreting Cells/physiology ; Mitochondria/pathology ; Mitochondria/physiology ; Oxidative Phosphorylation ; Reactive Oxygen Species/metabolism ; Risk Factors ; Uncoupling Agents/metabolism
Chemical Substances	Reactive Oxygen Species ; Uncoupling Agents
Language	English
Publishing date	2008-01-02
Publishing country	United Arab Emirates
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ISSN	1573-3998
ISSN	1573-3998
DOI	10.2174/157339906776818541
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Article: Coupling of metabolic, second messenger pathways and insulin granule dynamics in pancreatic beta-cells: A computational analysis

Fridlyand, Leonid E / Philipson, Louis H

Progress in biophysics and molecular biology. 2011 Nov., v. 107, no. 2

2011

Abstract	Insulin secretory responses to nutrient stimuli and hormonal modulators in pancreatic beta-cells are controlled by a variety of secondary messengers. We have analyzed numerous mechanisms responsible for regulated exocytosis in these cells and present an integrated mathematical model of cytosolic Ca2+, cAMP and granule dynamics. The insulin-containing granules in the beta-cell were divided into four classes: a large “reserve” granule pool, a smaller pool of the morphologically docked granules that is chemically ‘primed’ for release or the “readily releasable pool”, and a pool of “restless newcomer granules” that undergoes preferential exocytosis. The model incorporates glucose and other aspects of metabolism, the cAMP amplifying pathway, insulin granule dynamics and the exocyst concept for granule binding. The values of most of the model parameters were inferred from available experimental data. The model can generate both the fast first phase and slow biphasic insulin secretion found experimentally in response to a step increase of membrane potential or of glucose. The numerical simulations have also reproduced a variety of experimental conditions, such as periodic stimulation by high K+ and the potentiation induced in islets by pre-incubation with cAMP pathway activators. The explicit incorporation of Ca2+ channels, Ca2+ and cAMP dynamics allows the model to be further connected to current models for calcium and metabolic dynamics and provides an interpretation of the roles of the triggering and amplifying pathways of glucose-stimulated insulin secretion. The model may be important in the identification of pharmacological targets for improving insulin secretion in type 2 diabetes.
Keywords	calcium ; calcium channels ; exocytosis ; glucose ; granules ; insulin ; insulin secretion ; islets of Langerhans ; mathematical models ; membrane potential ; metabolism ; noninsulin-dependent diabetes mellitus ; potassium ; second messengers
Language	English
Dates of publication	2011-11
Size	p. 293-303.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	209302-9
ISSN	1873-1732 ; 0079-6107
ISSN (online)	1873-1732
ISSN	0079-6107
DOI	10.1016/j.pbiomolbio.2011.09.001
Database	NAL-Catalogue (AGRICOLA)

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