The document discusses obtaining estimations of cell metabolic activities from gene expression data using summarized metabolic pathway models. It describes normalizing gene expression data and using an algorithm to estimate metabolic module activities for two conditions, identifying differentially active modules using statistical tests. Metabolic module activities are correlated with protein activation status and metabolite abundance changes, associated with cancer types and treatment responses, and predictive of cell survival. A web server called Metabolizer is introduced that performs various metabolic pathway analyses on gene expression data.
Glycan Structural Analysis Throughout Biotherapeutic Development SGS
Glycosylation is a key structural and functional element found on a wide variety of biotherapeutics. As such, alterations in glycan profile can significantly affect the efficacy of a drug through, for example, half life in the bloodstream or biological activity as well as being a potential source of immunogenicity. The glycan profile can be selected and controlled through the choice of cell line as well as control of bioreactor conditions. The use of analytical techniques that provide structural data on this type of post translational modification are vital in the development and characterisation of biologics. Techniques in glycan structural characterisation are discussed in this presentation.
The IOSR Journal of Pharmacy (IOSRPHR) is an open access online & offline peer reviewed international journal, which publishes innovative research papers, reviews, mini-reviews, short communications and notes dealing with Pharmaceutical Sciences( Pharmaceutical Technology, Pharmaceutics, Biopharmaceutics, Pharmacokinetics, Pharmaceutical/Medicinal Chemistry, Computational Chemistry and Molecular Drug Design, Pharmacognosy & Phytochemistry, Pharmacology, Pharmaceutical Analysis, Pharmacy Practice, Clinical and Hospital Pharmacy, Cell Biology, Genomics and Proteomics, Pharmacogenomics, Bioinformatics and Biotechnology of Pharmaceutical Interest........more details on Aim & Scope).
Analytical Development of Biosimilar Mabs: From Vision to Reality SGS
The approval of the first biosimilar mAbs in Europe last June (Celltrion’s Remsima™ and Hospira’s Inflectra™ versions of infliximab) paves the way for the advent of more widespread access to biological treatments in indications such as rheumatology and oncology. One year on, lessons learned from these approvals will guide the global regulatory framework for such complex biomolecules. Indeed, several more biosimilar mAbs are currently in late-stage clinical trials and can be expected to be submitted to Regulatory Authorities shortly. Read more or listen to live streaming http://bit.ly/SGSBiosimilarWebinar
Glycan Structural Analysis Throughout Biotherapeutic Development SGS
Glycosylation is a key structural and functional element found on a wide variety of biotherapeutics. As such, alterations in glycan profile can significantly affect the efficacy of a drug through, for example, half life in the bloodstream or biological activity as well as being a potential source of immunogenicity. The glycan profile can be selected and controlled through the choice of cell line as well as control of bioreactor conditions. The use of analytical techniques that provide structural data on this type of post translational modification are vital in the development and characterisation of biologics. Techniques in glycan structural characterisation are discussed in this presentation.
The IOSR Journal of Pharmacy (IOSRPHR) is an open access online & offline peer reviewed international journal, which publishes innovative research papers, reviews, mini-reviews, short communications and notes dealing with Pharmaceutical Sciences( Pharmaceutical Technology, Pharmaceutics, Biopharmaceutics, Pharmacokinetics, Pharmaceutical/Medicinal Chemistry, Computational Chemistry and Molecular Drug Design, Pharmacognosy & Phytochemistry, Pharmacology, Pharmaceutical Analysis, Pharmacy Practice, Clinical and Hospital Pharmacy, Cell Biology, Genomics and Proteomics, Pharmacogenomics, Bioinformatics and Biotechnology of Pharmaceutical Interest........more details on Aim & Scope).
Analytical Development of Biosimilar Mabs: From Vision to Reality SGS
The approval of the first biosimilar mAbs in Europe last June (Celltrion’s Remsima™ and Hospira’s Inflectra™ versions of infliximab) paves the way for the advent of more widespread access to biological treatments in indications such as rheumatology and oncology. One year on, lessons learned from these approvals will guide the global regulatory framework for such complex biomolecules. Indeed, several more biosimilar mAbs are currently in late-stage clinical trials and can be expected to be submitted to Regulatory Authorities shortly. Read more or listen to live streaming http://bit.ly/SGSBiosimilarWebinar
The IOSR Journal of Pharmacy (IOSRPHR) is an open access online & offline peer reviewed international journal, which publishes innovative research papers, reviews, mini-reviews, short communications and notes dealing with Pharmaceutical Sciences( Pharmaceutical Technology, Pharmaceutics, Biopharmaceutics, Pharmacokinetics, Pharmaceutical/Medicinal Chemistry, Computational Chemistry and Molecular Drug Design, Pharmacognosy & Phytochemistry, Pharmacology, Pharmaceutical Analysis, Pharmacy Practice, Clinical and Hospital Pharmacy, Cell Biology, Genomics and Proteomics, Pharmacogenomics, Bioinformatics and Biotechnology of Pharmaceutical Interest........more details on Aim & Scope).
All manuscripts are subject to rapid peer review. Those of high quality (not previously published and not under consideration for publication in another journal) will be published without delay.
Proteomics of small proteins from plant tissuesExpedeon
Small genes and the proteins that they encode can play important biological roles including signaling, development, and mediation of plant-microbe interactions in organisms ranging from bacteria to plants to mammals (Frith et al.; Basrai et al.; Galindo et al.; Hemm et al. 2008, 2010; Kastenmeyer et al.). However, genes that encode proteins containing <100 residues are difficult to identify reliably solely by DNA sequence analysis (Dinger et al.)
ABSTRACT- Aberrant glycosylation has been recognized as hallmark of cancer. Exploiting differences in glycosylation between malignant and healthy tissues offers excellent opportunities to identify sensitive and specific cancer biomarkers. Plant lectins have demonstrated the ability to specifically agglutinate malignant transformed cells. Lectins are sugar binding proteins or glycoprotein of non-immune origin which agglutinate cells or precipitate glycol-conjugates. Some lectins shown to the anti- proliferative effect on cancer cells. A wide scope of this application of lectins is that it can be used for diagnosis as well as therapeutics of cancer. The objective of the present study was to purify a lectin from tubers of Arisaema intermedium and evaluate in vitro anti-proliferative potential towards HCT-15, a human colon cancer cell line. The present study was conceived as an offshoot to the ongoing work on lectins in our laboratory. The already reported Arisaema intermedium (AIL) lectin was purified on asialofetuin linked amino-activated silica bead matrix. The purity of the affinity purified lectin was ascertained by SDS-PAGE, pH-8.3. The lectin activity was assessed by hemagglutination and protein concentration was determined by Lowry’s method. The cytotoxicity of AIL towards HCT-15 was evaluated by MTT assay. The mechanism of anti-proliferative effect was assessed by evaluation of cell morphology, trypan blue exclusion assay, DNA fragmentation and nucleic acid content determination.
Key-words- Araceae, Arisaema, Asialofetuin, Antiproliferative effect, Apoptosis, Cytotoxicity Lectins, Mechanistic
Myself Omkar Tipugade , M- Pharm ,Sem - II, Department of pharmaceutics , from Shree Santkrupa College Of Pharmacy , ghogaon . Today I upload presentation on Active Transport like P-gp , BCPR, Nucleoside transporters etc .
The IOSR Journal of Pharmacy (IOSRPHR) is an open access online & offline peer reviewed international journal, which publishes innovative research papers, reviews, mini-reviews, short communications and notes dealing with Pharmaceutical Sciences( Pharmaceutical Technology, Pharmaceutics, Biopharmaceutics, Pharmacokinetics, Pharmaceutical/Medicinal Chemistry, Computational Chemistry and Molecular Drug Design, Pharmacognosy & Phytochemistry, Pharmacology, Pharmaceutical Analysis, Pharmacy Practice, Clinical and Hospital Pharmacy, Cell Biology, Genomics and Proteomics, Pharmacogenomics, Bioinformatics and Biotechnology of Pharmaceutical Interest........more details on Aim & Scope).
All manuscripts are subject to rapid peer review. Those of high quality (not previously published and not under consideration for publication in another journal) will be published without delay.
Proteomics of small proteins from plant tissuesExpedeon
Small genes and the proteins that they encode can play important biological roles including signaling, development, and mediation of plant-microbe interactions in organisms ranging from bacteria to plants to mammals (Frith et al.; Basrai et al.; Galindo et al.; Hemm et al. 2008, 2010; Kastenmeyer et al.). However, genes that encode proteins containing <100 residues are difficult to identify reliably solely by DNA sequence analysis (Dinger et al.)
ABSTRACT- Aberrant glycosylation has been recognized as hallmark of cancer. Exploiting differences in glycosylation between malignant and healthy tissues offers excellent opportunities to identify sensitive and specific cancer biomarkers. Plant lectins have demonstrated the ability to specifically agglutinate malignant transformed cells. Lectins are sugar binding proteins or glycoprotein of non-immune origin which agglutinate cells or precipitate glycol-conjugates. Some lectins shown to the anti- proliferative effect on cancer cells. A wide scope of this application of lectins is that it can be used for diagnosis as well as therapeutics of cancer. The objective of the present study was to purify a lectin from tubers of Arisaema intermedium and evaluate in vitro anti-proliferative potential towards HCT-15, a human colon cancer cell line. The present study was conceived as an offshoot to the ongoing work on lectins in our laboratory. The already reported Arisaema intermedium (AIL) lectin was purified on asialofetuin linked amino-activated silica bead matrix. The purity of the affinity purified lectin was ascertained by SDS-PAGE, pH-8.3. The lectin activity was assessed by hemagglutination and protein concentration was determined by Lowry’s method. The cytotoxicity of AIL towards HCT-15 was evaluated by MTT assay. The mechanism of anti-proliferative effect was assessed by evaluation of cell morphology, trypan blue exclusion assay, DNA fragmentation and nucleic acid content determination.
Key-words- Araceae, Arisaema, Asialofetuin, Antiproliferative effect, Apoptosis, Cytotoxicity Lectins, Mechanistic
Myself Omkar Tipugade , M- Pharm ,Sem - II, Department of pharmaceutics , from Shree Santkrupa College Of Pharmacy , ghogaon . Today I upload presentation on Active Transport like P-gp , BCPR, Nucleoside transporters etc .
System response of metabolic networks in Chlamydomonas reinhardtii during Nit...Nishikant Wase
Nitrogen starvation induces a global stress response in microalga that results in the accumulation of triglycerides in lipid bodies. To identify components and mechanisms leading to lipid accumulation during nitrogen stress, we used GC-MS based metabolite profiling and iTRAQ based quantitative proteomics to examine Chlamydomonas reinhardtii cultured up to 144 hours without nitrogen. When nitrogen is limiting, starch and lipid accumulated rapidly, with lipid becoming the major storage compound by 144 hours. Our FAMEs data showed that the percentage of highly unsaturated fatty acids was reduced and the percentage of saturated and monounsaturated fatty acids were increased. Using information from the GC-MS based metabolite profiling; a Partial Least Squares Discriminant Analysis model was created to evaluate the role of different intracellular metabolites during lipid accumulation. We observed decreased abundance of key amino acids whereas some important metabolites including citric acid, trehalose, triethanolamine, nicotinamine, methnionine, citramalic acid and sorbitol were increased in abundance. Addition of citric acid (from 4 mM to 6 mM) to the growth media significantly improves the lipid yield in Chlamydomonas reinhardtii while growing in TAP media containing nitrogen. Examination of differentially expressed proteins revealed that 100 of 793 identified proteins were induced after 144 hours, while 77 proteins were reduced in abundance. Proteins involved in nitrogen assimilation, oxidative phosphorylation, the glycolytic pathway, TCA cycle, starch, and lipid metabolism were found to be higher in abundance than in non-stressed cultures. Another effect of nitrogen starvation was reduction of proteins of the photosynthetic apparatus (including PS-I and PS-II) and light harvesting complex proteins. We conclude that during nitrogen starvation, carbon availability is the most important factor controlling oil biosynthesis and that there is carbon partitioning between starch and oil synthesis.
Deploying Automated Workstreams and Computational Approaches for Generation of Toxicity Data Used for Hazard Identification, by Robert T. Dunn, II, Ph.D., DABT
BioNetVisA 2018 ECCB workshop
From biological network reconstruction to data visualization and analysis in molecular biology and medicine.
http://eccb18.org/workshop-2/
https://bionetvisa.github.io/
Oncodesign aacr 2018 development of a high throughput in vitro screening pl...Florence Fombertasse
Immunological cell death (ICD) is a form of cancer cell death induced by radiotherapy, photodynamic therapy and a few chemotherapeutic agents such as Doxorubicin, Mitoxantrone, and Oxaliplatin. Unlike apoptosis or necrosis, ICD can induce an effective immune response directed against the tumor whereby both dendritic cells and T lymphocytes are mediators of this response. Dying cancer cells recruit and activate immune cells by releasing damage-associated molecular patterns (DAMPS) that help and promote the immune response to antigenic tumor neo-epitopes. Three key DAMPS are associated with the ICD process: calreticulin exposition on the cell surface, ATP secretion and high-mobility group box 1 (HMGB1) release. In order to identify new therapeutic agents that promote ICD in malignant cells, we developed a screening strategy facilitated by an automated in vitro platform with four assays on three different tumor cell lines (human osteosarcoma U-2 OS, human breast MDA-MB-231 and murine liver Hepa 1-6). ICD inducers Doxorubicin and Mitoxantrone used as positive controls increased ATP secretion by 2 to 10-fold at a non-cytotoxic dose after 72 hours incubation on the three cell lines. Both compounds also increased calreticulin exposition by 2 to 4-fold (determined by immunofluorescence using the Operetta High-Content Imaging System) and HMGB1 release by two-fold on the three cell lines. Here we will present recent data from the screening of Oncodesign’s Nanocyclix® library using this platform to identify novel ICD inducers.
Quantitative Analysis of Transporter Protein using TripleTOF® 6600 SystemSCIEX
Transport plays an important role in the absorption, distribution, and elimination of a variety of drugs.
In recent years, a large number of transporters, both efflux (ATP-binding cassette (ABC) family) and influx (solute carrier (SLC) family members) have been identified and well characterized in vitro.
However, the abundance of these transporters in the hepatocyte and cell lines as well as in the tissues such as intestine, liver, and kidney has not been accurately quantitated due to technical challenges.
This work aims to build a robust liquid chromatography-mass spectrometry (LC-MS) workflow on the SCIEX TripleTOF® 6600 platform to enable the quantitation of a variety of SLC and ABC drug transporters expressed in the hepatocyte and cell line plasma membranes.
Bioinformática y supercomputación. Razones para hacerse bioinformático en la UMAM. Gonzalo Claros
¿En qué consiste la bioinformática? ¿Cómo puedo especializarme? ¿Dónde? Capacidad de supercomputación en la UMA. Recientes logros bioinformáticos relacionados con la medicina y con la ciencia en general, muchos de ellos realizados por equipos de la UMA.
Accelerating the benefits of genomics worldwideJoaquin Dopazo
Grand Challenges in Genomics
A Joint NHGRI and Wellcome Trust Strategic Meeting
25 and 26 February 2019
https://www.wellcomeevents.org/WELLCOME/media/uploaded/EVWELLCOME/event_661/Draft_agenda_for_WT_December_2018.pdf
Join lecture: Nicky Mulder, Han Brunner and Joaquin Dopazo
Big data genómico
Presente y futuro en el manejo de datos genómicos en la práctica clínica
XXIII Jornadas Nacionales de Informática Sanitaria,
Málaga, 16 junio, 2016
http://www.seis.es/JornadasAndalucia16/
The server of the Spanish Population VariabilityJoaquin Dopazo
DNA Day
Hospital Universitario La Paz, Madrid, Spain April 28th, 2014
The first server of the Spanish Population Variability.
Freely available: http://ciberer.es/bier/exome-server/
See alse related tools:
BiERapp: http://bierapp.babelomics.org (to help in the prioritization of disease genes)
TEAM: http://team.babelomics.org (to manage panels of genes for targeter resequencing based diagnostic)
How to transform genomic big data into valuable clinical informationJoaquin Dopazo
How to transform genomic big data into valuable clinical information
The impact of genomics in translational medicine: present view
13th October 2014, Vall d’Hebron Institute of Research (VHIR), Barcelona, Spain
Forum on Personalized Medicine: Challenges for the next decadeJoaquin Dopazo
Bioinformatics and Big Data in the era of Personalized Medicine
10th Anniversary Instituto Roche Forum on Personalized Medicine: Challenges for the next decade.
Santiago de Compostela (Spain), September 25th 2014
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.
Earliest Galaxies in the JADES Origins Field: Luminosity Function and Cosmic ...Sérgio Sacani
We characterize the earliest galaxy population in the JADES Origins Field (JOF), the deepest
imaging field observed with JWST. We make use of the ancillary Hubble optical images (5 filters
spanning 0.4−0.9µm) and novel JWST images with 14 filters spanning 0.8−5µm, including 7 mediumband filters, and reaching total exposure times of up to 46 hours per filter. We combine all our data
at > 2.3µm to construct an ultradeep image, reaching as deep as ≈ 31.4 AB mag in the stack and
30.3-31.0 AB mag (5σ, r = 0.1” circular aperture) in individual filters. We measure photometric
redshifts and use robust selection criteria to identify a sample of eight galaxy candidates at redshifts
z = 11.5 − 15. These objects show compact half-light radii of R1/2 ∼ 50 − 200pc, stellar masses of
M⋆ ∼ 107−108M⊙, and star-formation rates of SFR ∼ 0.1−1 M⊙ yr−1
. Our search finds no candidates
at 15 < z < 20, placing upper limits at these redshifts. We develop a forward modeling approach to
infer the properties of the evolving luminosity function without binning in redshift or luminosity that
marginalizes over the photometric redshift uncertainty of our candidate galaxies and incorporates the
impact of non-detections. We find a z = 12 luminosity function in good agreement with prior results,
and that the luminosity function normalization and UV luminosity density decline by a factor of ∼ 2.5
from z = 12 to z = 14. We discuss the possible implications of our results in the context of theoretical
models for evolution of the dark matter halo mass function.
Introduction:
RNA interference (RNAi) or Post-Transcriptional Gene Silencing (PTGS) is an important biological process for modulating eukaryotic gene expression.
It is highly conserved process of posttranscriptional gene silencing by which double stranded RNA (dsRNA) causes sequence-specific degradation of mRNA sequences.
dsRNA-induced gene silencing (RNAi) is reported in a wide range of eukaryotes ranging from worms, insects, mammals and plants.
This process mediates resistance to both endogenous parasitic and exogenous pathogenic nucleic acids, and regulates the expression of protein-coding genes.
What are small ncRNAs?
micro RNA (miRNA)
short interfering RNA (siRNA)
Properties of small non-coding RNA:
Involved in silencing mRNA transcripts.
Called “small” because they are usually only about 21-24 nucleotides long.
Synthesized by first cutting up longer precursor sequences (like the 61nt one that Lee discovered).
Silence an mRNA by base pairing with some sequence on the mRNA.
Discovery of siRNA?
The first small RNA:
In 1993 Rosalind Lee (Victor Ambros lab) was studying a non- coding gene in C. elegans, lin-4, that was involved in silencing of another gene, lin-14, at the appropriate time in the
development of the worm C. elegans.
Two small transcripts of lin-4 (22nt and 61nt) were found to be complementary to a sequence in the 3' UTR of lin-14.
Because lin-4 encoded no protein, she deduced that it must be these transcripts that are causing the silencing by RNA-RNA interactions.
Types of RNAi ( non coding RNA)
MiRNA
Length (23-25 nt)
Trans acting
Binds with target MRNA in mismatch
Translation inhibition
Si RNA
Length 21 nt.
Cis acting
Bind with target Mrna in perfect complementary sequence
Piwi-RNA
Length ; 25 to 36 nt.
Expressed in Germ Cells
Regulates trnasposomes activity
MECHANISM OF RNAI:
First the double-stranded RNA teams up with a protein complex named Dicer, which cuts the long RNA into short pieces.
Then another protein complex called RISC (RNA-induced silencing complex) discards one of the two RNA strands.
The RISC-docked, single-stranded RNA then pairs with the homologous mRNA and destroys it.
THE RISC COMPLEX:
RISC is large(>500kD) RNA multi- protein Binding complex which triggers MRNA degradation in response to MRNA
Unwinding of double stranded Si RNA by ATP independent Helicase
Active component of RISC is Ago proteins( ENDONUCLEASE) which cleave target MRNA.
DICER: endonuclease (RNase Family III)
Argonaute: Central Component of the RNA-Induced Silencing Complex (RISC)
One strand of the dsRNA produced by Dicer is retained in the RISC complex in association with Argonaute
ARGONAUTE PROTEIN :
1.PAZ(PIWI/Argonaute/ Zwille)- Recognition of target MRNA
2.PIWI (p-element induced wimpy Testis)- breaks Phosphodiester bond of mRNA.)RNAse H activity.
MiRNA:
The Double-stranded RNAs are naturally produced in eukaryotic cells during development, and they have a key role in regulating gene expression .
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.
Professional air quality monitoring systems provide immediate, on-site data for analysis, compliance, and decision-making.
Monitor common gases, weather parameters, particulates.
(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.
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.
Deep Behavioral Phenotyping in Systems Neuroscience for Functional Atlasing a...Ana Luísa Pinho
Functional Magnetic Resonance Imaging (fMRI) provides means to characterize brain activations in response to behavior. However, cognitive neuroscience has been limited to group-level effects referring to the performance of specific tasks. To obtain the functional profile of elementary cognitive mechanisms, the combination of brain responses to many tasks is required. Yet, to date, both structural atlases and parcellation-based activations do not fully account for cognitive function and still present several limitations. Further, they do not adapt overall to individual characteristics. In this talk, I will give an account of deep-behavioral phenotyping strategies, namely data-driven methods in large task-fMRI datasets, to optimize functional brain-data collection and improve inference of effects-of-interest related to mental processes. Key to this approach is the employment of fast multi-functional paradigms rich on features that can be well parametrized and, consequently, facilitate the creation of psycho-physiological constructs to be modelled with imaging data. Particular emphasis will be given to music stimuli when studying high-order cognitive mechanisms, due to their ecological nature and quality to enable complex behavior compounded by discrete entities. I will also discuss how deep-behavioral phenotyping and individualized models applied to neuroimaging data can better account for the subject-specific organization of domain-general cognitive systems in the human brain. Finally, the accumulation of functional brain signatures brings the possibility to clarify relationships among tasks and create a univocal link between brain systems and mental functions through: (1) the development of ontologies proposing an organization of cognitive processes; and (2) brain-network taxonomies describing functional specialization. To this end, tools to improve commensurability in cognitive science are necessary, such as public repositories, ontology-based platforms and automated meta-analysis tools. I will thus discuss some brain-atlasing resources currently under development, and their applicability in cognitive as well as clinical neuroscience.
Differential metabolic activity and discovery of therapeutic targets using summarized metabolic pathway models
1. Joaquín Dopazo
Clinical Bioinformatics Area,
Fundación Progreso y Salud,
Functional Genomics Node, (INB-ELIXIR-es),
Bioinformatics in Rare Diseases (BiER-CIBERER),
Sevilla, Spain.
Differential metabolic activity and
discovery of therapeutic targets using
summarized metabolic pathway models
http://www.clinbioinfosspa.es
http://www. babelomics.org
@xdopazo, @ClinicalBioinfo
3rd Disease Maps Community Meeting.
Paris, 21-22 June 2018
2. Our aim: obtaining estimations on cell
metabolic activities from affordable gene
expression data
Cases / controls
Normalizedgenes
Ps1 344 344 4556 667 88
Ps2 543 67 88 90 12 36
Ps3 36 833 78 38 99 00
Ps4 59 73 336 677 00 31
Ps1 344 344 4556 667 88
Ps2 543 67 88 90 12 36
Ps3 36 833 78 38 99 00
Ps4 59 73 336 677 00 31
…….
…….
…….
Cases / controls
Activity
Ps1 344 344 4556 667 88
Ps2 543 67 88 90 12 36
Ps3 36 833 78 38 99 00
Ps4 59 73 336 677 00 31
Ps1 344 344 4556 667 88
Ps2 543 67 88 90 12 36
…….
…….
…….
We seek for a simple transformation of raw data (normalization) and an
algorithm that result in accurate estimations of metabolic module
activities.
It should be possible to include mutational profiles in the algorithm (either
by integrating them with transcriptomic data or assuming gene
expression taken from databases)
Metabolic
modulesCases / controls
Rawdata
Ps1 344 344 4556 667 88
Ps2 543 67 88 90 12 36
Ps3 36 833 78 38 99 00
Ps4 59 73 336 677 00 31
Ps1 344 344 4556 667 88
Ps2 543 67 88 90 12 36
Ps3 36 833 78 38 99 00
Ps4 59 73 336 677 00 31
…….
…….
…….
3. On maps and and navigation
A map
describes
connections
between
elements
An influence map
describes origin and
destinations that define
processes
4. KEGG Metabolic modules summarize
the human metabolism
A total of 95 modules that represent
building blocks of metabolic pathways
were used, that comprise a total of
446 reactions and 553 genes. The
pathway modules were downloaded
form the KEGG MODULE web page
(http://www.genome.jp/kegg/module.html)
5. Modeling metabolic modules
Where ni is the activity of the current node n, A is the total
number of edges arriving to the node that account for the flux
of metabolites produced in other nodes with activity values na.
Differential metabolic activity: two
conditions are compared by means of a
Wilcoxon test (FDR adjusted across
modules)
Parts of the map
are collapsed in
the influence
map because
transcriptomic
profiles are
uninformative
for using them
6. Protein activation status is
correlated with module activity
Cancer types
Metabolic module Description End molecule Protein BLCA BRCA COAD GBM HNSC KIRC LGG LUSC PRAD READ STAD THCA UCEC
M00082_1 Fatty acid biosynthesis, initiation
C05744:
Acetoacetyl-[acp] ACACA 0,46 0,45 0,28 0,44 0,51 0,2 0,48 0,43 0,51 0,41 0,35 0,11 0,23
M00082_2 Fatty acid biosynthesis, initiation
C05744:
Acetoacetyl-[acp] ACACA 0,43 0,42 0,23 0,36 0,47 0,16 0,49 0,34 0,41 0,33 0,22 0,08 0,22
M00004
Pentose phosphate pathway
(Pentose phosphate cycle)
Cycle: Pentose
phosphate
pathway G6PD 0,27 NA NA NA NA NA 0,15 NA NS NA 0,26 0,24 NA
M00006
Pentose phosphate pathway,
oxidative phase, glucose 6P =>
ribulose 5P
C00199: D-
Ribulose 5-
phosphate G6PD 0,33 NA NA NA NA NA NS NA NS NA 0,26 NS NA
M00001
Glycolysis (Embden-Meyerhof
pathway), glucose => pyruvate C00022: Pyruvate GAPDH 0,37 NA NA NA NA NA 0,21 NA 0,17 NA 0,31 0,18 NA
M00002
Glycolysis, core module involving
three-carbon compounds C00022: Pyruvate GAPDH 0,37 NA NA NA NA NA 0,2 NA 0,26 NA 0,3 0,16 NA
M00003
Gluconeogenesis, oxaloacetate
=> fructose-6P
C05345: beta-D-
Fructose 6-
phosphate GAPDH NS NA NA NA NA NA 0,16 NA 0,16 NA 0,14 NS NA
M00009
Citrate cycle (TCA cycle, Krebs
cycle)
Cycle: Citrate
cycle (TCA cycle,
Krebs cycle) IDH3A NS NA NA NA NA NA NA NA NA NA NA NA NA
M00010
Citrate cycle, first carbon
oxidation, oxaloacetate => 2-
oxoglutarate
C00026: 2-
Oxoglutarate IDH3A NS NA NA NA NA NA NA NA NA NA NA NA NA
M00131
Inositol phosphate metabolism,
Ins(1,3,4,5)P4 => Ins(1,3,4)P3 =>
myo-inositol
C00137: myo-
Inositol INPP4B 0,44 0,25 0,13 0,39 0,39 NS 0,53 NS NS 0,39 0,24 0,16 0,34
*Numbers are Spearman's rank correlation coefficients; NS, not significant (p > 0.05); NA, not available
Correlations between RPPA values and module activity predictions
7. Correspondence between
module activity and change in
metabolite abundance
Module Cancer type First metabolite
Intermediate
metabolite
End
metabolite
Prediction
M00035_1
C00073
C00019 /
C00021 /
C00155
C02291
BRCA 1,9 NA / 2.7 / NA 7,8 Up Correct
KIRC 0,5 0.9 / 1.7 / 0.6 NA Down NA
M00100
C00319 C06124 C00346
BRCA 11,1 NA 17,3 Up Correct
KIRC 2,2 NA 0,8 Down Correct
M00135
C00134
C02714 /
C05936 /
C02946
C00334
BRCA 12,9 NA / NA / NA 1,2 Down Correct
KIRC 3,6 NA / NA / NA 0,3 Down Correct
8. In a large meta-analysis of 9424 samples of
14 cancer types, metabolic modules capture
differential metabolic activity
10. Metabolic modules also capture cell
functionality associated to cancer prognostic
High activity of Guanine ribonucleotide biosynthesis and Pyrimidine
ribonucleotide biosynthesis modules is associated to low survival.
These modules are target of Mercaptopurine and Gemcitabine.
The mechanism of action of these drugs involves inhibition of DNA synthesis
and that leads to cell death
11. Model validation (I)
The activity of some modules is correlated with cell survival
Increasedsurvival
Increased module activity
Survival data from Achilles cell line KOs (Broad Institute) can be
compared to the change in module activities predicted by the model
Essential modules: once found, other ways of deactivating these modules
can be find, opening the door to knowledge-based target discovery
Onco-module Tumor suppressor module
12. Model validation (2)
Deactivation of tumor
suppressor modules
Deactivation in onco-modules
Prostate cell line Skin cell line
1) Prediction of other gene targets, whose inhibition (modeled KO) deactivate
tumor suppressor or onco-modules
2) Validation of the real KO effects with Achilles II (Tsherniak A, et al. 2017, Cell
170: 564-576): 48 of the 77 predictions (62% validation rate), covering 24 of
the 28 modules predicted to affect cell viability
13. The metabolizer web server
http://metabolizer.babelomics.org/
Input: gene expression matrix
Analyses:
• Differential metabolic activity
• Case control
• Correlation
• KnockOut.
• Tests the effect of a KO
in the metabolic profile
• Auto KO: in a
case/control search for
the KO that makes
cases’ the metabolic
activity profile as close
as possible to controls
(phenotype reversion)
• Prediction: Builds a class
predictor (RF or SVM) based
on metabolic profiles
14. An example of KO prediction
Pyrimidine degradation pathway was predicted to be an onco-module in gastric
cancer cell lines. Predicted genes that switch the pathway off are DPYD, DPYS
(confirmed in Achilles) and UPB1 (not present in Achilles)
15. Confirmation of gene essentiality from
predicted metabolic pathway essentiality
UPB1 encodes an enzyme (β-ureidopropionase) that catalyzes the last step in the
pyrimidine degradation pathway, required for epithelial-mesenchymal transition
Pyrimidine degradation pathway was predicted to be an onco-module in gastric
cancer cell lines. Predicted genes that switch the pathway off are DPYD, DPYS
(confirmed in Achilles) and UPB1
16. Clinical Bioinformatics Area
Fundación Progreso y Salud, Sevilla, Spain, and…
...the INB-ELIXIR-ES, National Institute of Bioinformatics
and the BiER (CIBERER Network of Centers for Research in Rare Diseases)
@xdopazo
@ClinicalBioinfo
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