I elaborated these slides for an introductory class on Network Medicine given at UPV (Valencia) in October 2017. The fundamental principle behind Network Medicine is that disease phenotypes emerge from genotypes via the network properties of interactions between the underlying biological components. These phenotypes are best conceptualized as consequences of perturbations to disease modules of the biological networks in the cell, whether at the node level (disease genes) or the link level (disease edgotypes). With the further analysis of drug-disease association and drug-target association data, one can investigate the effects - therapeutic and undesired - of the associated medication. Understanding the molecular level networks allows to understand the connections between different diseases and the effects of drugs designed to target them, paving the way for personalized treatments based on one's own interactome.
Perturbing The Interactome: Multi-Omics And Personalized Methods For Network ...Marc Santolini
In this talk, I will describe several recently developed methods to study disease perturbations through the lens of network science. First I will present evidence that one can accurately predict perturbation patterns from the topology of biological networks, even when lacking measurements on the kinetic parameters governing the dynamics of these interactions. Using 87 biochemical networks with experimentally measured kinetic parameters, we show that a knowledge of the network topology offers 65% to 80% accuracy in predicting the impact of perturbations. In other words, we can use the increasingly accurate topological models to approximate perturbation patterns, bypassing expensive kinetic constant measurement. These results open new avenues in modeling drug action, and in identifying drug targets relying on the human interactome only.
Then, I will present a novel approach to identify the collective impact of miRNAs in disease. Instead of focusing on the magnitude of miRNA differential expression, here we address the secondary consequences for the interactome. We developed the Impact of Differential Expression Across Layers (IDEAL), a network-based algorithm to prioritize disease-relevant miRNAs based on the central role of their targets in the molecular interactome. This method was used in the context of asthmatic Th2 inflammation and identified five Th2-related miRNAs (mir27b, mir206, mir106b, mir203, and mir23b) whose antagonization led to a sharp reduction of the Th2 phenotype. This result offers novel approaches for therapeutic interventions.
Finally, I will present an investigation of the personalized gene expression responses when inducing hypertrophy and heart failure in 100+ strains of genetically distinct mice from the Hybrid Mouse Diversity Panel (HMDP). I will show that genes whose expression change significantly correlates with the severity of the disease are either up- or down-regulated across strains, and therefore missed by traditional population-wide analyses of differential gene expression. These uncovered personalised genes are enriched in human cardiac disease genes and form a dense co-regulated module strongly interacting with the cardiac hypertrophic signaling network in the human interactome, the set of molecular interactions in the cell. We validate our approach by showing that the knockdown of Hes1, predicted as a strong candidate, induces a dramatic reduction of hypertrophy by 80-90% in neonatal rat ventricular myocytes, demonstrating that individualized approaches are crucial to identify genes underlying complex diseases as well as to develop personalized therapies.
Systems biology & Approaches of genomics and proteomicssonam786
This presentation provides the basic understanding of varous genomics and proteomics techniques.Systems biology studies life as a system .It includes the study of living system using various omic technologies .
Interactomics, Integromics to Systems Biology: Next Animal Biotechnology Fron...Varij Nayan
“Organisms function in an integrated manner-our senses, our muscles, our metabolism and our minds work together seamlessly. But biologists have historically studied organisms part by part and celebrated the modern ability to study them molecule by molecule, gene by gene. Systems biology is critical science of future that seeks to understand the integration of the pieces to form biological
systems”
(David Baltimore, Nobel Laureate)
A Systems Biology Approach to Natural Products ResearchHuda Nazeer
Explains the systems biology approach (holistic approach), its advantages and tools used compared to the reductionist approach in natural products research.
Perturbing The Interactome: Multi-Omics And Personalized Methods For Network ...Marc Santolini
In this talk, I will describe several recently developed methods to study disease perturbations through the lens of network science. First I will present evidence that one can accurately predict perturbation patterns from the topology of biological networks, even when lacking measurements on the kinetic parameters governing the dynamics of these interactions. Using 87 biochemical networks with experimentally measured kinetic parameters, we show that a knowledge of the network topology offers 65% to 80% accuracy in predicting the impact of perturbations. In other words, we can use the increasingly accurate topological models to approximate perturbation patterns, bypassing expensive kinetic constant measurement. These results open new avenues in modeling drug action, and in identifying drug targets relying on the human interactome only.
Then, I will present a novel approach to identify the collective impact of miRNAs in disease. Instead of focusing on the magnitude of miRNA differential expression, here we address the secondary consequences for the interactome. We developed the Impact of Differential Expression Across Layers (IDEAL), a network-based algorithm to prioritize disease-relevant miRNAs based on the central role of their targets in the molecular interactome. This method was used in the context of asthmatic Th2 inflammation and identified five Th2-related miRNAs (mir27b, mir206, mir106b, mir203, and mir23b) whose antagonization led to a sharp reduction of the Th2 phenotype. This result offers novel approaches for therapeutic interventions.
Finally, I will present an investigation of the personalized gene expression responses when inducing hypertrophy and heart failure in 100+ strains of genetically distinct mice from the Hybrid Mouse Diversity Panel (HMDP). I will show that genes whose expression change significantly correlates with the severity of the disease are either up- or down-regulated across strains, and therefore missed by traditional population-wide analyses of differential gene expression. These uncovered personalised genes are enriched in human cardiac disease genes and form a dense co-regulated module strongly interacting with the cardiac hypertrophic signaling network in the human interactome, the set of molecular interactions in the cell. We validate our approach by showing that the knockdown of Hes1, predicted as a strong candidate, induces a dramatic reduction of hypertrophy by 80-90% in neonatal rat ventricular myocytes, demonstrating that individualized approaches are crucial to identify genes underlying complex diseases as well as to develop personalized therapies.
Systems biology & Approaches of genomics and proteomicssonam786
This presentation provides the basic understanding of varous genomics and proteomics techniques.Systems biology studies life as a system .It includes the study of living system using various omic technologies .
Interactomics, Integromics to Systems Biology: Next Animal Biotechnology Fron...Varij Nayan
“Organisms function in an integrated manner-our senses, our muscles, our metabolism and our minds work together seamlessly. But biologists have historically studied organisms part by part and celebrated the modern ability to study them molecule by molecule, gene by gene. Systems biology is critical science of future that seeks to understand the integration of the pieces to form biological
systems”
(David Baltimore, Nobel Laureate)
A Systems Biology Approach to Natural Products ResearchHuda Nazeer
Explains the systems biology approach (holistic approach), its advantages and tools used compared to the reductionist approach in natural products research.
In interactome, basically for interaction of proteins there is certain key elements requited, they are: Interactomics and Proteomics, Complementation groups, Modifier screens 1. Interactomics and Proteomics
Field of interactomics is concerned with interactions between genes or proteins. They can be genetic interactions, in which two genes are mainly involved in the same functional pathway (leading to a particular phenotype), or physical interactions, in which there is direct physical contact between two proteins (or between protein and DNA) (Janga et al.,2008). 2. Complementation groups Using forward saturation genetics, one may recover several independent mutants with the same (or similar) phenotype (Hernández et al., 2007). There are two possibilities: a) Mutations are in the same gene b) Mutations are in different genes involved in the same pathway. Scenario
(b) Can be tested genetically with a complementation test:
Cross two homozygous mutants (samples) and observe heterozygous offspring phenotypes(samples)
Mutations in the same gene will not complement
offspring have mutant phenotype
Mutations in different genes will complement
offspring have wild
Type phenotype
Do pairwise crosses for all mutants to identify complementation groups
Typically each complementation group represents a different gene
If many mutations are recovered in the same genes, this implies saturation
Introduction
Overview
Reductionist approach
Holistic approach
What is systems biology?
○ Advantages of Systems Biology
Tools of holistic approach
○ Proteomics, Transcriptomics and Metabolomics
Conclusion
References
Protein protein interaction, functional proteomicsKAUSHAL SAHU
IntroductionTypes of Protein-protein interactionsEffects of Protein-Protein InteractionsProtein-Protein Interaction Identification Methods :- Experimental (In vivo) Yeast two hybrid system- Experimental (In vitro) Co-immunoprecipitation, ChIP, Affinity Blotting, Protein Probing - Computational (In silico) Database of interacting proteins, VisANT etc.
ConclusionReferences
insilico protein structure prediction and and structure analysis and its type which are commonly used in dry lab. docking is a procedure in which two protein,or protein to ligand binding intrection analysis by software tools.
Introduction.
Types of Protein – Protein Interaction.
Methods to investigate Protein – Protein Interaction.
Protein – Protein Interaction modulated by Chemical energy.
Two Hybrid Screening.
Overview of Protein – Protein Interaction analysis.
Biological effect of Protein – Protein interaction.
Conclusion.
Reference.
A set of ideas on the use of artificial intelligence for data curation that has been presented at the Pharma-IT conference (London, 2017), in the artificial intelligence track.
It begins with some broad discussion about semantic web, knowledge representation, machine learning and artificial intelligence. It the focus on how a "data curation" problem can be framed and hints at some possible examples.
In interactome, basically for interaction of proteins there is certain key elements requited, they are: Interactomics and Proteomics, Complementation groups, Modifier screens 1. Interactomics and Proteomics
Field of interactomics is concerned with interactions between genes or proteins. They can be genetic interactions, in which two genes are mainly involved in the same functional pathway (leading to a particular phenotype), or physical interactions, in which there is direct physical contact between two proteins (or between protein and DNA) (Janga et al.,2008). 2. Complementation groups Using forward saturation genetics, one may recover several independent mutants with the same (or similar) phenotype (Hernández et al., 2007). There are two possibilities: a) Mutations are in the same gene b) Mutations are in different genes involved in the same pathway. Scenario
(b) Can be tested genetically with a complementation test:
Cross two homozygous mutants (samples) and observe heterozygous offspring phenotypes(samples)
Mutations in the same gene will not complement
offspring have mutant phenotype
Mutations in different genes will complement
offspring have wild
Type phenotype
Do pairwise crosses for all mutants to identify complementation groups
Typically each complementation group represents a different gene
If many mutations are recovered in the same genes, this implies saturation
Introduction
Overview
Reductionist approach
Holistic approach
What is systems biology?
○ Advantages of Systems Biology
Tools of holistic approach
○ Proteomics, Transcriptomics and Metabolomics
Conclusion
References
Protein protein interaction, functional proteomicsKAUSHAL SAHU
IntroductionTypes of Protein-protein interactionsEffects of Protein-Protein InteractionsProtein-Protein Interaction Identification Methods :- Experimental (In vivo) Yeast two hybrid system- Experimental (In vitro) Co-immunoprecipitation, ChIP, Affinity Blotting, Protein Probing - Computational (In silico) Database of interacting proteins, VisANT etc.
ConclusionReferences
insilico protein structure prediction and and structure analysis and its type which are commonly used in dry lab. docking is a procedure in which two protein,or protein to ligand binding intrection analysis by software tools.
Introduction.
Types of Protein – Protein Interaction.
Methods to investigate Protein – Protein Interaction.
Protein – Protein Interaction modulated by Chemical energy.
Two Hybrid Screening.
Overview of Protein – Protein Interaction analysis.
Biological effect of Protein – Protein interaction.
Conclusion.
Reference.
A set of ideas on the use of artificial intelligence for data curation that has been presented at the Pharma-IT conference (London, 2017), in the artificial intelligence track.
It begins with some broad discussion about semantic web, knowledge representation, machine learning and artificial intelligence. It the focus on how a "data curation" problem can be framed and hints at some possible examples.
A (vintage) presentation about a database system for the study of gene expression data. Including distributed metadata annotation and some interactive analytics. Some ideas are still actual today.
The Opera of Phantome - 2017 (presented at the 22nd Biennial Evergreen Phage ...Ramy K. Aziz
Tools and Methods developed under the SEED/RAST/PhAnToMe (http://www.phantome.org) project and sequels adopted in RASTtk and PATRIC. The tools and database rely on the Subsystems Technology, the SEED (http://theseed.org) environment, and RAST server (http://rast.nmpdr.org).
This is a part of the Phage Genomics Workshop at the 22nd Biennial Evergreen International Phage Meeting, Aug 6 2017.
Dr. Leroy Hood lectured to a group of Ohio State University College of Medicine students and faculty on May 13, 2010 in advance of an announcement of a partnership between the Ohio State University Medical Center and the Institute for Systems Biology. The partnership will be known as
National Resource for Networks Biology's TR&D Theme 3: Although networks have been very useful for representing molecular interactions and mechanisms, network diagrams do not visually resemble the contents of cells. Rather, the cell involves a multi-scale hierarchy of components – proteins are subunits of protein complexes which, in turn, are parts of pathways, biological processes, organelles, cells, tissues, and so on. In this technology research project, we will pursue methods that move Network Biology towards such hierarchical, multi-scale views of cell structure and function.
An information-theoretic, all-scales approach to comparing networksJim Bagrow
My presentation at NetSci 2018 on Portrait Divergence, a new approach to comparing networks that is simple, general-purpose, and easy to interpret.
The preprint: https://arxiv.org/abs/1804.03665
The code: https://github.com/bagrow/portrait-divergence
It is increasingly recognized that complex systems cannot be described in a reductionist view.
Understanding the behavior of such systems starts with understanding the topology of the corresponding network.
Topological information is fundamental in constructing realistic models for the function of the network.
A Multiset Rule Based Petri net Algorithm for the Synthesis and Secretary Pat...ijsc
Membrane computing is a branch of Natural computing aiming to abstract computing models from the structure and functioning of the living cell. A comprehensive introduction to membrane computing is meant to offer both computer scientists and non-computer scientists an up-to date overview of the field. In this paper, we consider a uniform way of treating objects and rules in P Systems with the help of Multiset rewriting rules. Here the synthesis and secretary pathway of glycoprotein in epithelial cells of small intestine is considered as an example. A natural and finite link is explored between Petri nets and membrane Computing. A Petri net (PN) algorithm combined with P Systems is implemented for the synthesis and secretary pathway of Glycoprotein. To capture the compartmentalization of P Systems, the Petri net is extended with localities and to show how to adopt the notion of a Petri net process accordingly. The algorithm uses symbolic representations of multisets of rules to efficiently generate all the regions associated with the membrane. In essence, this algorithm is built from transport route sharing a set of places modeling the availability of system resources. The algorithm when simulated shows a significant pathway of safe Petri nets.
A Multiset Rule Based Petri net Algorithm for the Synthesis and Secretary Pat...ijsc
Membrane computing is a branch of Natural computing aiming to abstract computing models from the structure and functioning of the living cell. A comprehensive introduction to membrane computing is meant to offer both computer scientists and non-computer scientists an up-to date overview of the field. In
this paper, we consider a uniform way of treating objects and rules in P Systems with the help of Multiset rewriting rules. Here the synthesis and secretary pathway of glycoprotein in epithelial cells of small intestine is considered as an example. A natural and finite link is explored between Petri nets and membrane Computing. A Petri net (PN) algorithm combined with P Systems is implemented for the synthesis and secretary pathway of Glycoprotein. To capture the compartmentalization of P Systems, the Petri net is extended with localities and to show how to adopt the notion of a Petri net process accordingly.
The algorithm uses symbolic representations of multisets of rules to efficiently generate all the regions associated with the membrane. In essence, this algorithm is built from transport route sharing a set of places modeling the availability of system resources. The algorithm when simulated shows a significant
pathway of safe Petri nets.
The Majority Rule is applied to a topology that consists of two coupled
random networks, thereby mimicking the modular structure observed in social
networks. We calculate analytically the asymptotic behaviour of the model and derive a
phase diagram that depends on the frequency of random opinion flips and on the inter-
connectivity between the two communities. It is shown that three regimes may take
place: a disordered regime, where no collective phenomena takes place; a symmetric
regime, where the nodes in both communities reach the same average opinion; an
asymmetric regime, where the nodes in each community reach an opposite average
opinion. The transition from the asymmetric regime to the symmetric regime is shown
to be discontinuous.
Large scale cell tracking using an approximated Sinkhorn algorithmParth Nandedkar
Cell tracking for a large scale (of over 1 million cells) has not yet been achievable within reasonable a time scope with current NN/RNN/Bi-RNN based methods. This individual research conducted by me at Osaka University, ISIR seeks to solve this problem using the Sinkhorn algorithm, and taking inspiration from the MPM method (Hayashida, 2020)
GRAPH ALGORITHM TO FIND CORE PERIPHERY STRUCTURES USING MUTUAL K-NEAREST NEIG...ijaia
Core periphery structures exist naturally in many complex networks in the real-world like social,
economic, biological and metabolic networks. Most of the existing research efforts focus on the
identification of a meso scale structure called community structure. Core periphery structures are another
equally important meso scale property in a graph that can help to gain deeper insights about the
relationships between different nodes. In this paper, we provide a definition of core periphery structures
suitable for weighted graphs. We further score and categorize these relationships into different types based
upon the density difference between the core and periphery nodes. Next, we propose an algorithm called
CP-MKNN (Core Periphery-Mutual K Nearest Neighbors) to extract core periphery structures from
weighted graphs using a heuristic node affinity measure called Mutual K-nearest neighbors (MKNN).
Using synthetic and real-world social and biological networks, we illustrate the effectiveness of developed
core periphery structures.
(May 29th, 2024) Advancements in Intravital Microscopy- Insights for Preclini...Scintica Instrumentation
Intravital microscopy (IVM) is a powerful tool utilized to study cellular behavior over time and space in vivo. Much of our understanding of cell biology has been accomplished using various in vitro and ex vivo methods; however, these studies do not necessarily reflect the natural dynamics of biological processes. Unlike traditional cell culture or fixed tissue imaging, IVM allows for the ultra-fast high-resolution imaging of cellular processes over time and space and were studied in its natural environment. Real-time visualization of biological processes in the context of an intact organism helps maintain physiological relevance and provide insights into the progression of disease, response to treatments or developmental processes.
In this webinar we give an overview of advanced applications of the IVM system in preclinical research. IVIM technology is a provider of all-in-one intravital microscopy systems and solutions optimized for in vivo imaging of live animal models at sub-micron resolution. The system’s unique features and user-friendly software enables researchers to probe fast dynamic biological processes such as immune cell tracking, cell-cell interaction as well as vascularization and tumor metastasis with exceptional detail. This webinar will also give an overview of IVM being utilized in drug development, offering a view into the intricate interaction between drugs/nanoparticles and tissues in vivo and allows for the evaluation of therapeutic intervention in a variety of tissues and organs. This interdisciplinary collaboration continues to drive the advancements of novel therapeutic strategies.
Slide 1: Title Slide
Extrachromosomal Inheritance
Slide 2: Introduction to Extrachromosomal Inheritance
Definition: Extrachromosomal inheritance refers to the transmission of genetic material that is not found within the nucleus.
Key Components: Involves genes located in mitochondria, chloroplasts, and plasmids.
Slide 3: Mitochondrial Inheritance
Mitochondria: Organelles responsible for energy production.
Mitochondrial DNA (mtDNA): Circular DNA molecule found in mitochondria.
Inheritance Pattern: Maternally inherited, meaning it is passed from mothers to all their offspring.
Diseases: Examples include Leber’s hereditary optic neuropathy (LHON) and mitochondrial myopathy.
Slide 4: Chloroplast Inheritance
Chloroplasts: Organelles responsible for photosynthesis in plants.
Chloroplast DNA (cpDNA): Circular DNA molecule found in chloroplasts.
Inheritance Pattern: Often maternally inherited in most plants, but can vary in some species.
Examples: Variegation in plants, where leaf color patterns are determined by chloroplast DNA.
Slide 5: Plasmid Inheritance
Plasmids: Small, circular DNA molecules found in bacteria and some eukaryotes.
Features: Can carry antibiotic resistance genes and can be transferred between cells through processes like conjugation.
Significance: Important in biotechnology for gene cloning and genetic engineering.
Slide 6: Mechanisms of Extrachromosomal Inheritance
Non-Mendelian Patterns: Do not follow Mendel’s laws of inheritance.
Cytoplasmic Segregation: During cell division, organelles like mitochondria and chloroplasts are randomly distributed to daughter cells.
Heteroplasmy: Presence of more than one type of organellar genome within a cell, leading to variation in expression.
Slide 7: Examples of Extrachromosomal Inheritance
Four O’clock Plant (Mirabilis jalapa): Shows variegated leaves due to different cpDNA in leaf cells.
Petite Mutants in Yeast: Result from mutations in mitochondrial DNA affecting respiration.
Slide 8: Importance of Extrachromosomal Inheritance
Evolution: Provides insight into the evolution of eukaryotic cells.
Medicine: Understanding mitochondrial inheritance helps in diagnosing and treating mitochondrial diseases.
Agriculture: Chloroplast inheritance can be used in plant breeding and genetic modification.
Slide 9: Recent Research and Advances
Gene Editing: Techniques like CRISPR-Cas9 are being used to edit mitochondrial and chloroplast DNA.
Therapies: Development of mitochondrial replacement therapy (MRT) for preventing mitochondrial diseases.
Slide 10: Conclusion
Summary: Extrachromosomal inheritance involves the transmission of genetic material outside the nucleus and plays a crucial role in genetics, medicine, and biotechnology.
Future Directions: Continued research and technological advancements hold promise for new treatments and applications.
Slide 11: Questions and Discussion
Invite Audience: Open the floor for any questions or further discussion on the topic.
THE IMPORTANCE OF MARTIAN ATMOSPHERE SAMPLE RETURN.Sérgio Sacani
The return of a sample of near-surface atmosphere from Mars would facilitate answers to several first-order science questions surrounding the formation and evolution of the planet. One of the important aspects of terrestrial planet formation in general is the role that primary atmospheres played in influencing the chemistry and structure of the planets and their antecedents. Studies of the martian atmosphere can be used to investigate the role of a primary atmosphere in its history. Atmosphere samples would also inform our understanding of the near-surface chemistry of the planet, and ultimately the prospects for life. High-precision isotopic analyses of constituent gases are needed to address these questions, requiring that the analyses are made on returned samples rather than in situ.
Cancer cell metabolism: special Reference to Lactate PathwayAADYARAJPANDEY1
Normal Cell Metabolism:
Cellular respiration describes the series of steps that cells use to break down sugar and other chemicals to get the energy we need to function.
Energy is stored in the bonds of glucose and when glucose is broken down, much of that energy is released.
Cell utilize energy in the form of ATP.
The first step of respiration is called glycolysis. In a series of steps, glycolysis breaks glucose into two smaller molecules - a chemical called pyruvate. A small amount of ATP is formed during this process.
Most healthy cells continue the breakdown in a second process, called the Kreb's cycle. The Kreb's cycle allows cells to “burn” the pyruvates made in glycolysis to get more ATP.
The last step in the breakdown of glucose is called oxidative phosphorylation (Ox-Phos).
It takes place in specialized cell structures called mitochondria. This process produces a large amount of ATP. Importantly, cells need oxygen to complete oxidative phosphorylation.
If a cell completes only glycolysis, only 2 molecules of ATP are made per glucose. However, if the cell completes the entire respiration process (glycolysis - Kreb's - oxidative phosphorylation), about 36 molecules of ATP are created, giving it much more energy to use.
IN CANCER CELL:
Unlike healthy cells that "burn" the entire molecule of sugar to capture a large amount of energy as ATP, cancer cells are wasteful.
Cancer cells only partially break down sugar molecules. They overuse the first step of respiration, glycolysis. They frequently do not complete the second step, oxidative phosphorylation.
This results in only 2 molecules of ATP per each glucose molecule instead of the 36 or so ATPs healthy cells gain. As a result, cancer cells need to use a lot more sugar molecules to get enough energy to survive.
Unlike healthy cells that "burn" the entire molecule of sugar to capture a large amount of energy as ATP, cancer cells are wasteful.
Cancer cells only partially break down sugar molecules. They overuse the first step of respiration, glycolysis. They frequently do not complete the second step, oxidative phosphorylation.
This results in only 2 molecules of ATP per each glucose molecule instead of the 36 or so ATPs healthy cells gain. As a result, cancer cells need to use a lot more sugar molecules to get enough energy to survive.
introduction to WARBERG PHENOMENA:
WARBURG EFFECT Usually, cancer cells are highly glycolytic (glucose addiction) and take up more glucose than do normal cells from outside.
Otto Heinrich Warburg (; 8 October 1883 – 1 August 1970) In 1931 was awarded the Nobel Prize in Physiology for his "discovery of the nature and mode of action of the respiratory enzyme.
WARNBURG EFFECT : cancer cells under aerobic (well-oxygenated) conditions to metabolize glucose to lactate (aerobic glycolysis) is known as the Warburg effect. Warburg made the observation that tumor slices consume glucose and secrete lactate at a higher rate than normal tissues.
Seminar of U.V. Spectroscopy by SAMIR PANDASAMIR PANDA
Spectroscopy is a branch of science dealing the study of interaction of electromagnetic radiation with matter.
Ultraviolet-visible spectroscopy refers to absorption spectroscopy or reflect spectroscopy in the UV-VIS spectral region.
Ultraviolet-visible spectroscopy is an analytical method that can measure the amount of light received by the analyte.
A brief information about the SCOP protein database used in bioinformatics.
The Structural Classification of Proteins (SCOP) database is a comprehensive and authoritative resource for the structural and evolutionary relationships of proteins. It provides a detailed and curated classification of protein structures, grouping them into families, superfamilies, and folds based on their structural and sequence similarities.
Comparing Evolved Extractive Text Summary Scores of Bidirectional Encoder Rep...University of Maribor
Slides from:
11th International Conference on Electrical, Electronics and Computer Engineering (IcETRAN), Niš, 3-6 June 2024
Track: Artificial Intelligence
https://www.etran.rs/2024/en/home-english/
2. Reductionism,which has dominated biological research
for over a century, has provided a wealth of knowledge
about individual cellular components and their func-
tions. Despite its enormous success, it is increasingly
clear that a discrete biological function can only rarely
be attributed to an individual molecule. Instead, most
biological characteristics arise from complex interac-
tions between the cell’s numerous constituents, such as
proteins,DNA,RNA and small molecules1–8
.Therefore,
akeychallengeforbiologyinthetwenty-firstcenturyisto
understand the structure and the dynamics of the com-
plex intercellular web of interactions that contribute to
the structure and function of a living cell.
The development of high-throughput data-collection
techniques, as epitomized by the widespread use of
microarrays,allows for the simultaneous interrogation
of the status of a cell’s components at any given time.
In turn,new technology platforms,such as PROTEIN CHIPS
or semi-automatedYEAST TWO-HYBRID SCREENS,help to deter-
mine how and when these molecules interact with each
other.Various types of interaction webs, or networks,
(including protein–protein interaction,metabolic,sig-
nalling and transcription-regulatory networks) emerge
from the sum of these interactions.None of these net-
works are independent,instead they form a‘network of
networks’ that is responsible for the behaviour of the
cell.A major challenge of contemporary biology is to
programmetomapout,understandandmodelinquan-
tifiabletermsthetopologicalanddynamicpropertiesof the
variousnetworksthatcontrolthebehaviourof thecell.
Helpalongthewayisprovidedbytherapidlydevelop-
ing theory of complex networks that, in the past few
years,has made advances towards uncovering the orga-
nizingprinciplesthatgoverntheformationandevolution
of various complex technological and social networks9–12
.
This research is already making an impact on cell biology.
It has led to the realization that the architectural features
of molecularinteractionnetworkswithinacellareshared
to a large degree by other complex systems,such as the
Internet,computer chips and society.This unexpected
universality indicates that similar laws may govern most
complex networks in nature,which allows the expertise
fromlargeandwell-mappednon-biologicalsystemstobe
usedtocharacterizetheintricateinterwovenrelationships
thatgoverncellularfunctions.
In this review,we show that the quantifiable tools of
network theory offer unforeseen possibilities to under-
stand the cell’s internal organization and evolution,
fundamentally altering our view of cell biology. The
emerging results are forcing the realization that, not-
withstanding the importance of individual molecules,
cellular function is a contextual attribute of strict
and quantifiable patterns of interactions between the
myriad of cellular constituents. Although uncovering
NETWORK BIOLOGY:
UNDERSTANDING THE CELL’S
FUNCTIONAL ORGANIZATION
Albert-László Barabási* & Zoltán N. Oltvai‡
A key aim of postgenomic biomedical research is to systematically catalogue all molecules and
their interactions within a living cell. There is a clear need to understand how these molecules and
the interactions between them determine the function of this enormously complex machinery, both
in isolation and when surrounded by other cells. Rapid advances in network biology indicate that
cellular networks are governed by universal laws and offer a new conceptual framework that could
potentially revolutionize our view of biology and disease pathologies in the twenty-first century.
oarrays,
gy
nomic set
surface
hem. The
t a high
e
inding
ysics,
Dame,
na 46556,
hology,
ersity,
611,
u;
R E V I E W S
Barabasi et al., Nat Rev Genet 2004
NATURE REVIEWS | GENETICS VOLUME 5 | FEBRUARY 2004 | 105
Ba; blue nodes). In the Barabási–Albert model of a scale-free network , at each time point a node with M links is added to the network, which
connects to an already existing node I with probability ΠI
= kI
/ΣJ
kJ
, where kI
is the degree of node I (FIG. 3) and J is the index denoting the sum over
network nodes. The network that is generated by this growth process has a power-law degree distribution that is characterized by the degree
exponent γ = 3. Such distributions are seen as a straight line on a log–log plot (see figure, part Bb). The network that is created by the
Barabási–Albert model does not have an inherent modularity, so C(k) is independent of k (see figure, part Bc). Scale-free networks with degree
exponents 2<γ<3, a range that is observed in most biological and non-biological networks, are ultra-small34,35
, with the average path length
following ഞ ~ log log N, which is significantly shorter than log N that characterizes random small-world networks.
Hierarchicalnetworks
To account for the coexistence of modularity, local clustering and scale-free topology in many real systems it has to be assumed that clusters
combine in an iterative manner, generating a hierarchical network47,53
(see figure, part C). The starting point of this construction is a small cluster
of four densely linked nodes (see the four central nodes in figure, part Ca). Next, three replicas of this module are generated and the three external
nodes of the replicated clusters
connected to the central node of
the old cluster, which produces a
large 16-node module. Three
replicas of this 16-node module
are then generated and the 16
peripheral nodes connected to
the central node of the old
module, which produces a new
module of 64 nodes. The
hierarchical network model
seamlessly integrates a scale-free
topology with an inherent
modular structure by generating
a network that has a power-law
degree distribution with degree
exponent γ = 1 + ഞn4/ഞn3 = 2.26
(see figure, part Cb) and a large,
system-size independent average
clustering coefficient <C> ~ 0.6.
The most important signature of
hierarchical modularity is the
scaling of the clustering
coefficient, which follows
C(k) ~ k –1
a straight line of slope
–1 on a log–log plot (see figure,
part Cc). A hierarchical
architecture implies that sparsely
connected nodes are part of
highly clustered areas, with
communication between the
different highly clustered
neighbourhoods being
maintained by a few hubs
(see figure, part Ca).
A Random network
Ab
Ac
Aa
Bb
Bc
Ba
Cb
Cc
Ca
B Scale-free network C Hierarchical network
1
0.1
0.01
0.001
0.0001
1 10 100 1,000
P(k)C(k)
k k
k
k k
P(k)
P(k)
100
10
10–1
10–2
10–3
10–4
10–5
10–6
10–7
10–8
100 1,000 10,000
C(k)
logC(k)
log k
SCALE-FREE NETWORKS
4. FABRICATING HUBSR E V I E W S
major engineer of the genomic landscape, it is likely to
be a key mechanism for generating the scale-free
topology.
Two further results offer direct evidence that net-
work growth is responsible for the observed topological
features. The scale-free model (BOX 2) predicts that the
nodes that appeared early in the history of the network
are the most connected ones15
.Indeed,an inspection of
the metabolic hubs indicates that the remnants of the
RNA world, such as coenzyme A, NAD and GTP, are
among the most connected substrates of the metabolic
network, as are elements of some of the most ancient
metabolic pathways, such as glycolysis and the tricar-
boxylic acid cycle17
.In the context of the protein interac-
tion networks, cross-genome comparisons have found
that, on average, the evolutionarily older proteins have
more links to other proteins than their younger coun-
terparts45,46
. This offers direct empirical evidence for
preferential attachment.
Motifs, modules and hierarchical networks
Cellular functions are likely to be carried out in a highly
modular manner1
. In general, modularity refers to a
group of physically or functionally linked molecules
(nodes) that work together to achieve a (relatively) dis-
tinct function1,6,8,47
. Modules are seen in many systems,
for example,circles of friends in social networks or web-
sites that are devoted to similar topics on the World
Wide Web. Similarly, in many complex engineered sys-
tems, from a modern aircraft to a computer chip, a
highly modular structure is a fundamental design
a
b
Proteins
1
2
Proteins
Genes
Genes
Before duplication
After duplication
Figure 3 | The origin of the scale-free topology and hubs
in biological networks. The origin of the scale-free topology
5. NETWORK MOTIFS
(2003).
16. N. Keyghobadi, M. A. Matrone, G. D. Ebel, L. D.
Kramer, D. M. Fonseca, Mol. Ecol. Notes 4, 20
(2004).
17. D. M. Fonseca, C. T. Atkinson, R. C. Fleischer, Mol.
Ecol. 7, 1617 (1998).
18. F. H. Drummond, Trans. R. Entomol. Soc. Lond. 102,
369 (1951).
19. K. Tanaka, K. Mizusawa, E. S. Saugstad, Contrib. Am.
Entomol. Inst. 16, 1 (1979).
20. J. K. Pritchard, M. Stephens, P. Donnelly, Genetics
155, 945 (2000).
21. A. R. Barr, Am. J. Trop. Med. Hyg. 6, 153 (1957).
22. A. J. Cornel et al., J. Med. Entomol. 40, 36 (2003).
23. S. Urbanelli, F. Silvestrini, W. K. Reisen, E. De Vito,
L. Bullini, J. Med. Entomol. 34, 116 (1997).
24. L. L. Cavalli-Sforza, F. Cavalli-Sforza, The Great
Human Diasporas: The History of Diversity and
Evolution (Addison-Wesley, Reading, MA, 1995).
25. J. de Zulueta, Parassitologia 36, 7 (1994).
26. S. Urbanelli et al., in Ecologia, Atti I Congr. Naz.
versity of Pennsylvania, for technical assistance;
and A. Bhandoola and four anonymous reviewers
for comments and valuable suggestions on an ear-
lier version of this manuscript. Supported by a
National Research Council Associateship through
the Walter Reed Army Institute of Research
(D.M.F.), by NIH grant nos. U50/CCU220532 and
1R01GM063258, and by NSF grant no.
DEB-0083944. This material reflects the views of
the authors and should not be construed to repre-
sent those of the Department of the Army or the
Department of Defense.
Supporting Online Material
www.sciencemag.org/cgi/content/full/303/5663/1535/
DC1
Materials and Methods
Tables S1 to S8
References and Notes
2 December 2003; accepted 16 January 2004
Superfamilies of Evolved and
Designed Networks
Ron Milo, Shalev Itzkovitz, Nadav Kashtan, Reuven Levitt,
Shai Shen-Orr, Inbal Ayzenshtat, Michal Sheffer, Uri Alon*
Complex biological, technological, and sociological networks can be of very
different sizes and connectivities, making it difficult to compare their struc-
tures. Here we present an approach to systematically study similarity in the
local structure of networks, based on the significance profile (SP) of small
subgraphs in the network compared to randomized networks. We find
several superfamilies of previously unrelated networks with very similar SPs.
One superfamily, including transcription networks of microorganisms, rep-
resents “rate-limited” information-processing networks strongly con-
strained by the response time of their components. A distinct superfamily
includes protein signaling, developmental genetic networks, and neuronal
wiring. Additional superfamilies include power grids, protein-structure net-
works and geometric networks, World Wide Web links and social networks,
and word-adjacency networks from different languages.
Many networks in nature share global prop-
erties (1, 2). Their degree sequences (the
number of edges per node) often follow a
long-tailed distribution, in which some nodes
are much more connected than the average
(3). In addition, natural networks often show
the small-world property of short paths be-
tween nodes and highly clustered connections
(1, 2, 4). Despite these global similarities,
networks from different fields can have very
different local structure (5). It was recently
found that networks display certain patterns,
termed “network motifs,” at much higher fre-
quency than expected in randomized net-
works (6, 7). In biological networks, these
motifs were suggested to be recurring circuit
elements that carry out key information-
processing tasks (6, 8–10).
Departments of Molecular Cell Biology, Physics of
Complex Systems, and Computer Science, Weizmann
Institute of Science, Rehovot 76100, Israel.
*To whom correspondence should be addressed at
Department of Molecular Cell Biology, Weizmann In-
stitute of Science, Rehovot 76100, Israel. E-mail:
urialon@weizmann.ac.il
CH 2004 VOL 303 SCIENCE www.sciencemag.org
ors that readily transmit the vi-
and between avian hosts and
ld have created the current ep-
itions.
nt study suggests that changes in
pacity and the creation of new
tors may occur with new intro-
particular, the arrival of hybrid
rms in northern Europe has the
adically change the dynamics of
rope.
s and Notes
adova, Culex pipiens pipiens Mosquitoes:
Distribution, Ecology, Physiology, Genet-
Importance, and Control (Pensoft, Mos-
n, Ann. N.Y. Acad. Sci. 951, 220 (2001).
M. L. O’Guinn, D. J. Dohm, J. W. Jones,
omol. 38, 130 (2001).
ard et al., Emerg. Infect. Dis. 7, 679
ekera et al., Emerg. Infect. Dis. 7, 722
m, M. R. Sardelis, M. J. Turell, J. Med.
9, 640 (2002).
et al., Emerg. Infect. Dis. 7, 742 (2001).
local structure of networks, based on the significance profile (SP) of small
subgraphs in the network compared to randomized networks. We find
several superfamilies of previously unrelated networks with very similar SPs.
One superfamily, including transcription networks of microorganisms, rep-
resents “rate-limited” information-processing networks strongly con-
strained by the response time of their components. A distinct superfamily
includes protein signaling, developmental genetic networks, and neuronal
wiring. Additional superfamilies include power grids, protein-structure net-
works and geometric networks, World Wide Web links and social networks,
and word-adjacency networks from different languages.
Many networks in nature share global prop-
erties (1, 2). Their degree sequences (the
number of edges per node) often follow a
long-tailed distribution, in which some nodes
are much more connected than the average
(3). In addition, natural networks often show
the small-world property of short paths be-
tween nodes and highly clustered connections
(1, 2, 4). Despite these global similarities,
networks from different fields can have very
different local structure (5). It was recently
found that networks display certain patterns,
termed “network motifs,” at much higher fre-
quency than expected in randomized net-
works (6, 7). In biological networks, these
motifs were suggested to be recurring circuit
elements that carry out key information-
processing tasks (6, 8–10).
Departments of Molecular Cell Biology, Physics of
Complex Systems, and Computer Science, Weizmann
Institute of Science, Rehovot 76100, Israel.
*To whom correspondence should be addressed at
Department of Molecular Cell Biology, Weizmann In-
stitute of Science, Rehovot 76100, Israel. E-mail:
urialon@weizmann.ac.il
5 MARCH 2004 VOL 303 SCIENCE www.sciencemag.org
To understand the design principles of com-
plex networks, it is important to compare the local
structure of networks from different fields. The
main difficulty is that these networks can be of
vastly different sizes [for example, World Wide
Web (WWW) hyperlink networks with millions
of nodes and social networks with tens of nodes]
and degree sequences. Here, we present an ap-
proach for comparing network local structure,
based on the significance profile (SP). To calcu-
late the SP of a network, the network is compared
to an ensemble of randomized networks with the
same degree sequence. The comparison to ran-
domized networks compensates for effects due to
network size and degree sequence. For each sub-
graph i, the statistical significance is described by
the Z score (11):
Zi ϭ ͑Nreali Ϫ <Nrandi>)/std(Nrandi)
where Nreali is the number of times the sub-
graph appears in the network, and ϽNrandiϾ
and std(Nrandi) are the mean and standard
deviation of its appearances in the random-
ized network ensemble. The SP is the vector
of Z scores normalized to length 1:
SPiϭZi/(⌺Zi
2
)1/2
The normalization emphasizes the relative
significance of subgraphs, rather than the ab-
solute significance. This is important for
comparison of networks of different sizes,
because motifs (subgraphs that occur much
more often than expected at random) in large
networks tend to display higher Z scores than
motifs in small networks (7).
We present in Fig. 1 the SP of the 13
possible directed connected triads (triad sig-
nificance profile, TSP) for networks from
different fields (12). The TSP of these net-
works is almost always insensitive to removal
of 30% of the edges or to addition of 50%
new edges at random, demonstrating that it is
robust to missing data or random data errors
(SOM Text). Several superfamilies of net-
works with similar TSPs emerge from this
analysis. One superfamily includes sensory
transcription networks that control gene ex-
pression in bacteria and yeast in response to
external stimuli. In these transcription net-
works, the nodes represent genes or operons
and the edges represent direct transcriptional
regulation (6, 13–15). Networks from three
microorganisms, the bacteria Escherichia
coli (6) and Bacillus subtilis (14) and the
yeast Saccharomyces cerevisiae (7, 15), were
analyzed. The networks have very similar
TSPs (correlation coefficient c Ͼ 0.99). They
show one strong motif, triad 7, termed “feed-
forward loop.” The feedforward loop has
been theoretically and experimentally shown
Fig. 1. The triad significance profile (TSP) of networks from various
disciplines. The TSP shows the normalized significance level (Z score) for
each of the 13 triads. Networks with similar characteristic profiles are
URCHIN N ϭ 45, E ϭ 83), and synaptic connections between neurons in
C. elegans (NEURONS N ϭ 280, E ϭ 2170). (iii) WWW hyperlinks
between Web pages in the www.nd.edu site (3) (WWW-1 N ϭ 325729,
8. Leading Edge
Review
Interactome Networks and Human Disease
Marc Vidal,1,2,* Michael E. Cusick,1,2 and Albert-La´ szlo´ Baraba´ si1,3,4,*
1Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
2Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
3Center for Complex Network Research (CCNR) and Departments of Physics, Biology and Computer Science, Northeastern University,
Boston, MA 02115, USA
4Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
*Correspondence: marc_vidal@dfci.harvard.edu (M.V.), alb@neu.edu (A.-L.B.)
DOI 10.1016/j.cell.2011.02.016
Complex biological systems and cellular networks may underlie most genotype to phenotype
relationships. Here, we review basic concepts in network biology, discussing different types of
interactome networks and the insights that can come from analyzing them. We elaborate on why
interactome networks are important to consider in biology, how they can be mapped and integrated
with each other, what global properties are starting to emerge from interactome network models,
and how these properties may relate to human disease.
Introduction
Since the advent of molecular biology, considerable progress
has been made in the quest to understand the mechanisms
that underlie human disease, particularly for genetically inherited
disorders. Genotype-phenotype relationships, as summarized in
the Online Mendelian Inheritance in Man (OMIM) database (Am-
berger et al., 2009), include mutations in more than 3000 human
genes known to be associated with one or more of over 2000
human disorders. This is a truly astounding number of geno-
type-phenotype relationships considering that a mere three
decades have passed since the initial description of Restriction
Fragment Length Polymorphisms (RFLPs) as molecular markers
to map genetic loci of interest (Botstein et al., 1980), only
two decades since the announcement of the first positional
cloning experiments of disease-associated genes using RFLPs
(Amberger et al., 2009), and just one decade since the release
of the first reference sequences of the human genome (Lander
et al., 2001; Venter et al., 2001). For complex traits, the informa-
tion gathered by recent genome-wide association studies
suggests high-confidence genotype-phenotype associations
between close to 1000 genomic loci and one or more of over
phenotypic associations, there would still be major problems
to fully understand and model human genetic variations and their
impact on diseases.
To understand why, consider the ‘‘one-gene/one-enzyme/
one-function’’ concept originally framed by Beadle and Tatum
(Beadle and Tatum, 1941), which holds that simple, linear
connections are expected between the genotype of an organism
and its phenotype. But the reality is that most genotype-pheno-
type relationships arise from a much higher underlying com-
plexity. Combinations of identical genotypes and nearly identical
environments do not always give rise to identical phenotypes.
The very coining of the words ‘‘genotype’’ and ‘‘phenotype’’ by
Johannsen more than a century ago derived from observations
that inbred isogenic lines of bean plants grown in well-controlled
environments give rise to pods of different size (Johannsen,
1909). Identical twins, although strikingly similar, nevertheless
often exhibit many differences (Raser and O’Shea, 2005). Like-
wise, genotypically indistinguishable bacterial or yeast cells
grown side by side can express different subsets of transcripts
and gene products at any given moment (Elowitz et al., 2002;
Blake et al., 2003; Taniguchi et al., 2010). Even straightforward
Mapping Interactome Networks
Network science deals with complexity by ‘‘simplifying’’ com-
plex systems, summarizing them merely as components (nodes)
and interactions (edges) between them. In this simplified
approach, the functional richness of each node is lost. Despite
or even perhaps because of such simplifications, useful discov-
eries can be made. As regards cellular systems, the nodes are
metabolites and macromolecules such as proteins, RNA mole-
cules and gene sequences, while the edges are physical,
biochemical and functional interactions that can be identified
with a plethora of technologies. One challenge of network
biology is to provide maps of such interactions using systematic
and standardized approaches and assays that are as unbiased
as possible. The resulting ‘‘interactome’’ networks, the networks
of interactions between cellular components, can serve as scaf-
fold information to extract global or local graph theory proper-
et al., 2010). Computational prediction maps are fast and effi-
cient to implement, and usually include satisfyingly large
numbers of nodes and edges, but are necessarily imperfect
because they use indirect information (Plewczynski and Ginalski,
2009). While high-throughput maps attempt to describe unbi-
ased, systematic, and well-controlled data, they were initially
more difficult to establish, although recent technological
advances suggest that near completion can be reached within
a few years for highly reliable, comprehensive protein-protein
were discovered in and are being applied genome-wide for these
model organisms (Mohr et al., 2010).
Metabolic Networks
Metabolic network maps attempt to comprehensively describe
all possible biochemical reactions for a particular cell or
organism (Schuster et al., 2000; Edwards et al., 2001). In many
representations of metabolic networks, nodes are biochemical
metabolites and edges are either the reactions that convert
Figure 2. Networks in Cellular Systems
To date, cellular networks are most available for the ‘‘super-model’’ organisms (Davis, 2004) yeast, worm, fly, and plant. High-throughput interactome mapping
relies upon genome-scale resources such as ORFeome resources. Several types of interactome networks discussed are depicted. In a protein interaction
network, nodes represent proteins and edges represent physical interactions. In a transcriptional regulatory network, nodes represent transcription factors
(circular nodes) or putative DNA regulatory elements (diamond nodes); and edges represent physical binding between the two. In a disease network, nodes
represent diseases, and edges represent gene mutations of which are associated with the linked diseases. In a virus-host network, nodes represent viral proteins
(square nodes) or host proteins (round nodes), and edges represent physical interactions between the two. In a metabolic network, nodes represent enzymes,
and edges represent metabolites that are products or substrates of the enzymes. The network depictions seem dense, but they represent only small portions of
available interactome network maps, which themselves constitute only a few percent of the complete interactomes within cells.
Cell 2011
DISEASES AS NETWORK
PERTURBATIONS
10. RESEARCH ARTICLE SUMMARY
◥
DISEASE NETWORKS
Uncovering disease-disease
relationships through the
incomplete interactome
Jörg Menche, Amitabh Sharma, Maksim Kitsak, Susan Dina Ghiassian, Marc Vidal,
Joseph Loscalzo, Albert-László Barabási*
INTRODUCTION: A disease is rarely a straight-
forward consequence of an abnormality in a
single gene, but rather reflects the interplay
of multiple molecular processes. The rela-
tionships among these processes are encoded
in the interactome, a network that integrates
all physical interactions within a cell, from
protein-protein to regulatory protein–DNA
and metabolic interactions. The documented
propensity of disease-associated proteins to
interact with each other suggests that they
tend to cluster in the same neighborhood of
the interactome, forming a disease module, a
connected subgraph that contains all molecu-
lar determinants of a disease. The accurate
identification of the corresponding disease
module represents the first step toward a sys-
tematic understanding of the molecular mech-
anisms underlying a complex disease. Here,
we present a network-based framework to iden-
tify the location of disease modules within the
interactome and use the overlap between the
modules to predict disease-disease relationships.
RATIONALE: Despite impressive advances
in high-throughput interactome mapping and
disease gene identification, both the interac-
tome and our knowledge of disease-associated
genes remain incomplete. This incomplete-
ness prompts us to ask to what extent the
current data are sufficient to map out the
disease modules, the first step toward an in-
tegrated approach toward human disease.
To make progress, we must formulate math-
ematically the impact of network inc
ness on the identifiability of disease
quantifying the predictive power and
itations of the current interactome.
RESULTS: Using the tools of network
we show that we can only uncover
modules for diseases whose number
ciated genes excee
ical threshold det
bythenetworkinc
ness. We find tha
proteins associa
226 diseases are
inthesame netwo
borhood, displaying a statistically sig
tendency to form identifiable disease m
The higher the degree of agglomerati
disease proteins within the interact
higher the biological and functional
ity of the corresponding genes. The
ings indicate that many local neighb
of the interactome represent the ob
part of the true, larger and denser
modules.
If two disease modules overlap, lo
turbations causing one disease can
pathways of the other disease module
resulting in shared clinical and path
ical characteristics. To test this hyp
we measure the network-based sepa
each disease pair, observing a direct
between the pathobiological simi
diseases and their relative distanc
RES
ON OUR WEB SITE
◥
Read the full article
at http://dx.doi.
org/10.1126/
science.1257601
..................................................
Menche et al., Science 2015
DISEASES AS NETWORK
NEIGHBORHOODS
21. Disease Module Detection and
Analysis
The general workflow of a detailed analysis for a disease of interest:
I Interactome construction II Disease Module
Identification
III Validation IV Biological interpretation
- Gene expression data
- Gene Ontologies
- Pathways
- Comorbidity
- OMIM, GWAS, literature
- DIAMOnD: Disease
Module Detection Algorithm
- Pathway prioritization
- Molecular mechanism
Seed gene selection
- Binary interactions, metabolic
couplings, regulatory interactions ...
25. ARTICLE
Received 7 May 2015 | Accepted 29 Nov 2015 | Published 1 Feb 2016
Network-based in silico drug efficacy screening
Emre Guney1,2, Jo¨rg Menche1,3, Marc Vidal2,4 & Albert-La´szlo´ Bara´basi1,2,3,5
The increasing cost of drug development together with a significant drop in the number of
new drug approvals raises the need for innovative approaches for target identification
and efficacy prediction. Here, we take advantage of our increasing understanding of the
network-based origins of diseases to introduce a drug-disease proximity measure that
quantifies the interplay between drugs targets and diseases. By correcting for the known
biases of the interactome, proximity helps us uncover the therapeutic effect of drugs, as well
as to distinguish palliative from effective treatments. Our analysis of 238 drugs used in 78
diseases indicates that the therapeutic effect of drugs is localized in a small network
neighborhood of the disease genes and highlights efficacy issues for drugs used in Parkinson
and several inflammatory disorders. Finally, network-based proximity allows us to predict
novel drug-disease associations that offer unprecedented opportunities for drug repurposing
and the detection of adverse effects.
DOI: 10.1038/ncomms10331 OPEN
Guney et al., Nature Comm 2015
DRUGS
26. DRUGS
ABCC8
VEGFA
RUNX1
INS
KAT6A
TOP2A
IRS1
TOP2B
CAPN10
NPM1
A
Disease gene
Drug target
Shortest path to the
closest disease gene
d
R
R
R
RR
z =s2
s3
1
t2
Random gene sets with the same degrees
...
T1
S1d1`
Tn Sndn
s1 t1
s2
s3
t2
2+3
2
d=
Drug - disease proximity
Gliclazide
Daunorubicin
Type 2 diabetes
Acute myeloid leukaemia
dc = 2.5
zc = 1.3
dc = 1.0
zc = –1.6
zc = 1.0zc = –3.3
dc = 2.0
dc = 1.0
b
c
Disease genes
Acute myeloid leukaemiaType 2 diabetes
Drug targetsDrug targets
Gliclazide Daunorubicin
Figure 1 | Network-based drug-disease proximity. (a) Illustration of the closest distance (dc) of a drug T with targets t1 and t2 to the proteins s1, s2 and s3
27. PROXIMITY TO DISEASE MODULES
a
b c
Seperation (dss)
dc dk
dcc
dss
Disease
module
Drugds
Center (dcc)Kernel (dk)Shortest (ds)Closest (dc)
AUC(%)
R2
= 0.175
th(dc)
R2
= 0.003
80
70
60
50
40
30
4
3
E COMMUNICATIONS | DOI: 10.1038/ncomms10331 A