This document summarizes various constraint-based modeling methods for metabolic networks. It describes flux balance analysis and its extensions, which optimize an objective function like biomass production while incorporating additional constraints. Methods are presented that integrate gene expression data, thermodynamic constraints, and regulatory information to construct condition-specific metabolic models. Applications to cancer metabolism are discussed, such as identifying synthetic lethal drug targets. Community modeling examples are also provided that simulate microbial community dynamics and host-pathogen interactions.
It encloses a brief description of flux balance analysis tools, flux measuring software, methods, advantages and comparable applications to the other software's and analysis techniques and discussion so on steady - constraint based analysis modelling, reconstruction of metabolic pathways and different constraints. etc.
It encloses a brief description of flux balance analysis tools, flux measuring software, methods, advantages and comparable applications to the other software's and analysis techniques and discussion so on steady - constraint based analysis modelling, reconstruction of metabolic pathways and different constraints. etc.
Validation of Clomipramine interactions identified by BioBind against experim...Marie-Julie Denelle
Based on the now accepted principle that
similar receptors bind similars ligands, we have developed BioBind, a patented comparison algorithm
dedicated to the retrieval and assessment of local surface similarities. Clomipramine appears to be a
good “real life” candidate to challenge BioBind. In a couple of hours, BioBind was able to retrieve all
known targets having structural data described in the literature and to provide a valuable list of unknown
yet sensible putative targets currently being experimentally validated. This analysis hence demonstrates the
robustness and relevance of BioBind.
Validation of Clomipramine interactions identified by BioBind against experim...Marie-Julie Denelle
Based on the now accepted principle that
similar receptors bind similars ligands, we have developed BioBind, a patented comparison algorithm
dedicated to the retrieval and assessment of local surface similarities. Clomipramine appears to be a
good “real life” candidate to challenge BioBind. In a couple of hours, BioBind was able to retrieve all
known targets having structural data described in the literature and to provide a valuable list of unknown
yet sensible putative targets currently being experimentally validated. This analysis hence demonstrates the
robustness and relevance of BioBind.
Project report: Investigating the effect of cellular objectives on genome-sca...Jarle Pahr
Report from a half-semester master-level project carried out at the department of biotechnology, Norwegian University of Science and Technology. Describes a MATLAB-based framework for comparing experimental metabolic flux data with model predictions and evaluating objective functions.
Richard's entangled aventures in wonderlandRichard Gill
Since the loophole-free Bell experiments of 2020 and the Nobel prizes in physics of 2022, critics of Bell's work have retreated to the fortress of super-determinism. Now, super-determinism is a derogatory word - it just means "determinism". Palmer, Hance and Hossenfelder argue that quantum mechanics and determinism are not incompatible, using a sophisticated mathematical construction based on a subtle thinning of allowed states and measurements in quantum mechanics, such that what is left appears to make Bell's argument fail, without altering the empirical predictions of quantum mechanics. I think however that it is a smoke screen, and the slogan "lost in math" comes to my mind. I will discuss some other recent disproofs of Bell's theorem using the language of causality based on causal graphs. Causal thinking is also central to law and justice. I will mention surprising connections to my work on serial killer nurse cases, in particular the Dutch case of Lucia de Berk and the current UK case of Lucy Letby.
Multi-source connectivity as the driver of solar wind variability in the heli...Sérgio Sacani
The ambient solar wind that flls the heliosphere originates from multiple
sources in the solar corona and is highly structured. It is often described
as high-speed, relatively homogeneous, plasma streams from coronal
holes and slow-speed, highly variable, streams whose source regions are
under debate. A key goal of ESA/NASA’s Solar Orbiter mission is to identify
solar wind sources and understand what drives the complexity seen in the
heliosphere. By combining magnetic feld modelling and spectroscopic
techniques with high-resolution observations and measurements, we show
that the solar wind variability detected in situ by Solar Orbiter in March
2022 is driven by spatio-temporal changes in the magnetic connectivity to
multiple sources in the solar atmosphere. The magnetic feld footpoints
connected to the spacecraft moved from the boundaries of a coronal hole
to one active region (12961) and then across to another region (12957). This
is refected in the in situ measurements, which show the transition from fast
to highly Alfvénic then to slow solar wind that is disrupted by the arrival of
a coronal mass ejection. Our results describe solar wind variability at 0.5 au
but are applicable to near-Earth observatories.
Nutraceutical market, scope and growth: Herbal drug technologyLokesh Patil
As consumer awareness of health and wellness rises, the nutraceutical market—which includes goods like functional meals, drinks, and dietary supplements that provide health advantages beyond basic nutrition—is growing significantly. As healthcare expenses rise, the population ages, and people want natural and preventative health solutions more and more, this industry is increasing quickly. Further driving market expansion are product formulation innovations and the use of cutting-edge technology for customized nutrition. With its worldwide reach, the nutraceutical industry is expected to keep growing and provide significant chances for research and investment in a number of categories, including vitamins, minerals, probiotics, and herbal supplements.
Observation of Io’s Resurfacing via Plume Deposition Using Ground-based Adapt...Sérgio Sacani
Since volcanic activity was first discovered on Io from Voyager images in 1979, changes
on Io’s surface have been monitored from both spacecraft and ground-based telescopes.
Here, we present the highest spatial resolution images of Io ever obtained from a groundbased telescope. These images, acquired by the SHARK-VIS instrument on the Large
Binocular Telescope, show evidence of a major resurfacing event on Io’s trailing hemisphere. When compared to the most recent spacecraft images, the SHARK-VIS images
show that a plume deposit from a powerful eruption at Pillan Patera has covered part
of the long-lived Pele plume deposit. Although this type of resurfacing event may be common on Io, few have been detected due to the rarity of spacecraft visits and the previously low spatial resolution available from Earth-based telescopes. The SHARK-VIS instrument ushers in a new era of high resolution imaging of Io’s surface using adaptive
optics at visible wavelengths.
Professional air quality monitoring systems provide immediate, on-site data for analysis, compliance, and decision-making.
Monitor common gases, weather parameters, particulates.
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/
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.
5. Flux balance analysis and the
addition of constraints
Optimization of a “biological
objective”
Many solutions
Geometric FBA
Lewis, et al. Nat Rev
Microb, 2012
8. Exploring a variety of solutions
and coupled reactions
Flux variability analysis
Bayesian FBA
Flux coupling finder
Lewis, et al. Nat Rev
Microb, 2012
11. Considerations in strain design
Coupling production to a cell objective or selective
marker (growth? Enzymes?)
Is the perturbation realistic?
Lewis, et al. Nat Rev
Microb, 2012
12. Adding reactions for strain
design
OptStrain
– Test to see if a product can be made
using a universal reaction database
and host reactions
– Minimize the number of reactions
you must add from a universal
reaction database
– Growth couple the product by
reaction removal, if possible
14. Thermodynamic constraints
Based on metabolite
http://www.ncbi.nlm.nih.gov/pubmed/21281568
Based on network topology
http://en.wikipedia.org/wiki/Group_contribution_method
17. Expression data as a constraint: Constraining flux
E-flux
Colijin, et al. Plos Comp Bio, 2009
+ Uses continuous
values for
expression levels
- Requires arbitrary
function mapping
expression to
upper bound of
reaction flux
18. Expression data as a constraint: Constraining flux
E-flux
Colijin, et al. Plos Comp Bio, 2009
19. Expression data as a constraint:
Context-specific model construction
Objectives:
* Flux objective function
(e.g. biomass)
– GIMME
– GIM3E
Add reactions with an
expression-based
penalty
* Minimize addition of low
expression reactions
– iMAT
* Maximize model
consistency with data
– MBA
– mCADRE
* Pathway addition from
differential expression
– MADE
24. iMAT
MILP framework generates a context-
specific model
No biomass objective function needed
Maximizes the number of highly
expressed reactions that are active
and the number of lowly expressed
reactions that are inactive
Shlomi, et al., Nat Biotech, 2009
25. Metabolic Adjustment by
Differential Expression (MADE)
Adds/removes pathways based
on differential expression
Gives a view on how
metabolism changes
between states
Jensen and Papin, Bioinformatics, 2011
27. Model construction methods
Identify high
expression/confidence “core”
reactions
Ensure that all “core” reactions
are active
Eliminate as many others as
possible
http://journal.frontiersin.org/article/10.3389/fpls.2014.00491/full
31. Deregulated growth in cancer results from a
myriad of molecular changes
SNPs, indels, translocations, chromosomal aberrations
Aberrant post-translational modifications
Changes in DNA and histone modification
Altered xenobiotic metabolism
Variations in glycans
Metabolic rewiring
Oncometabolites
32. Contributions of
metabolism to cancer
Kroemer and Pouyssegur, Cancer Cell, 2008
Many mutations and changes are
connected to metabolism
Metabolic alterations are associated
with the hallmarks of cancer
Lewis and Abdel-Haleem. Front. Phys., 2013
33.
34. Needless to say, it is not always clear how variations
in genomic sequence result in different phenotypes
What causes cancer?
36. ZnPP is an inhibitor of Hmox1
Zn2+
Frezza, et al. Nature, 2012
37. HMOX and FH are synthetically lethal
Only killed cells missing FH
(i.e., the cancer cells)
38. Omic analysis: improved resolution of your data
Essential knowledge understand causation in biology
– Physical laws (mass balance and thermodynamics)
– Interactions (genome-scale metabolic pathways)
– Components (-omes)
39. COBRA in Community Metabolism
Dynamics of
competition and
community
composition
modeled between
Geobacter
sulfurreducens and
Rhodoferax
ferrireducens.
Under low acetate
flux, Rhodoferax
dominates when
sufficient ammonia
is available.
Synthetic mutualism modeled with auxotrophic E. coli mutants.
The benefit of symbiosis is contrasted with the cost of sharing.
Evolution in
community modeled
by simulating genome
reduction from E. coli
to Buchnera aphidicola
in its aphid host.
Minimal gene set was
enriched in genome,
and simulated gene
loss order correlated
with phylogenically
reconstructed gene
loss order
Host-pathogen interaction modeled with M. tuberculosis.
Internalized Mtb biomass inferred by transcriptomic data and simulation.
Simulations showed a decreased glycolytic flux and increase glyoxylate shunt.
Lewis, et al. Nat Rev
Microb, 2012
40. Shameless plug for my website
There are ~200 COBRA methods out there now…
http://cobramethods.wikidot.com/