Slides from my talk describing CE-Symm and my research on internal symmetry. It was given for jLBR, the weekly seminar series for our department at PSI.
3DSIG 2014 Presentation: Systematic detection of internal symmetry in proteinsSpencer Bliven
These slides are from 3DSIG 2014, presented on July 11.
I describe our investigation of internal symmetry in protein structures. This is quite common (24% of domains), and has many implications for function, folding, and evolution.
I introduce the CE-Symm method, described in
Myers-Turnbull, D., Bliven, S. E., Rose, P. W., Aziz, Z. K., Youkharibache, P., Bourne, P. E., & Prlić, A. (2014). Systematic Detection of Internal Symmetry in Proteins Using CE-Symm. Journal of Molecular Biology, 426(11), 2255–2268. doi:10.1016/j.jmb.2014.03.010
I discuss the results from running CE-Symm across the PDB, as well as some particularly compelling examples.
See also my poster by the same title for more details.
1) The study analyzed insertions of accessory domains in the haloalkanoic dehalogenase superfamily (HADSF) to understand the effects on the core Rossmann fold structure.
2) Structural similarity networks revealed that sequences with the same inserted domain type shared greater core structure similarity compared to different domain types.
3) Variation in the core structure occurred in alpha helices flanking the central beta sheet, rather than at the core-domain interface, suggesting independent divergence of core and inserted domains during evolution.
This document describes a study that investigated the interaction between nick-directed DNA loop repair and mismatch repair in human cells. The study constructed DNA substrates containing combinations of mismatches and loops. It was demonstrated that a nick 3' to a large loop can direct loop repair in human cell extracts in a bidirectional manner. However, when a mismatch was near a loop, the efficiency of nick-directed mismatch repair was reduced. This suggests interference between loop repair and mismatch repair when sites are adjacent to avoid double-stranded DNA breaks.
Systematic detection of internal symmetry in proteins - Rheinknie Regiomeetin...Spencer Bliven
This document summarizes a presentation on protein symmetry given by Spencer Bliven on September 24-26, 2014 at the 28th Rhine-Knee Regional Meeting on Biocrystallography. The summary includes that 24% of protein domains in the SCOP database exhibit internal symmetry or large structural repeats, and that the CE-Symm algorithm can accurately detect internal symmetry in proteins. Protein symmetry is deeply tied to function and provides clues about duplication events in protein evolution.
NSA Feb 2010: DNA Methylation Patterns & Epigenetic Regulation in the Pacific...mgavery
This document summarizes research characterizing DNA methylation patterns in the Pacific oyster. The researchers found evidence that DNA methylation plays a regulatory role in oysters, particularly for stress response and immune genes. Understanding these epigenetic influences could help improve selective breeding programs by increasing predictability of traits. Future work involves further evaluating DNA methylation using new techniques like whole genome bisulfite sequencing to better understand environmental impacts and the role of epigenetics in hybrid vigor in oysters.
This document discusses the state of characterization of the eukaryotic proteome. It notes that as of 2019, around 20% of proteins in fission yeast and humans are still classified as having unknown biological processes. While the number of known or inferred protein roles has increased since 1992, progress in characterizing unknowns has been slow. Many recently characterized proteins in fission yeast are involved in non-core functions like environmental response, aging, and damage accumulation. The document calls for more research on these unknown and less studied proteins that are "hidden in plain sight" within the eukaryotic proteome.
The document discusses mechanisms that promote mono-orientation of sister kinetochores during meiosis I. It reports that Zip1, a protein involved in synaptonemal complex formation, interacts with components of the Ndc80 kinetochore complex and its deletion reduces mono-orientation. Experiments show that Zip1 expression in mitosis delays bi-orientation of sisters and influences kinetochore orientation in meiosis I mutants. The results suggest Zip1 may prevent bi-orientation of functional sister kinetochores during meiosis I.
The Impact of Lysogenic and Tail Assembly Chaperone Proteins on the Life Cycl...Wyatt Nelson
This document summarizes research characterizing a novel mycobacteriophage named Emma. Key findings include:
- Emma has a siphoviridae morphology and forms clear and bullseye plaques.
- Genome annotation revealed genes for lysogeny and a programmed +1 frameshift mutation in tail assembly genes.
- Analysis suggests this frameshift mutation conserves production of two tail assembly proteins important for phage viability.
3DSIG 2014 Presentation: Systematic detection of internal symmetry in proteinsSpencer Bliven
These slides are from 3DSIG 2014, presented on July 11.
I describe our investigation of internal symmetry in protein structures. This is quite common (24% of domains), and has many implications for function, folding, and evolution.
I introduce the CE-Symm method, described in
Myers-Turnbull, D., Bliven, S. E., Rose, P. W., Aziz, Z. K., Youkharibache, P., Bourne, P. E., & Prlić, A. (2014). Systematic Detection of Internal Symmetry in Proteins Using CE-Symm. Journal of Molecular Biology, 426(11), 2255–2268. doi:10.1016/j.jmb.2014.03.010
I discuss the results from running CE-Symm across the PDB, as well as some particularly compelling examples.
See also my poster by the same title for more details.
1) The study analyzed insertions of accessory domains in the haloalkanoic dehalogenase superfamily (HADSF) to understand the effects on the core Rossmann fold structure.
2) Structural similarity networks revealed that sequences with the same inserted domain type shared greater core structure similarity compared to different domain types.
3) Variation in the core structure occurred in alpha helices flanking the central beta sheet, rather than at the core-domain interface, suggesting independent divergence of core and inserted domains during evolution.
This document describes a study that investigated the interaction between nick-directed DNA loop repair and mismatch repair in human cells. The study constructed DNA substrates containing combinations of mismatches and loops. It was demonstrated that a nick 3' to a large loop can direct loop repair in human cell extracts in a bidirectional manner. However, when a mismatch was near a loop, the efficiency of nick-directed mismatch repair was reduced. This suggests interference between loop repair and mismatch repair when sites are adjacent to avoid double-stranded DNA breaks.
Systematic detection of internal symmetry in proteins - Rheinknie Regiomeetin...Spencer Bliven
This document summarizes a presentation on protein symmetry given by Spencer Bliven on September 24-26, 2014 at the 28th Rhine-Knee Regional Meeting on Biocrystallography. The summary includes that 24% of protein domains in the SCOP database exhibit internal symmetry or large structural repeats, and that the CE-Symm algorithm can accurately detect internal symmetry in proteins. Protein symmetry is deeply tied to function and provides clues about duplication events in protein evolution.
NSA Feb 2010: DNA Methylation Patterns & Epigenetic Regulation in the Pacific...mgavery
This document summarizes research characterizing DNA methylation patterns in the Pacific oyster. The researchers found evidence that DNA methylation plays a regulatory role in oysters, particularly for stress response and immune genes. Understanding these epigenetic influences could help improve selective breeding programs by increasing predictability of traits. Future work involves further evaluating DNA methylation using new techniques like whole genome bisulfite sequencing to better understand environmental impacts and the role of epigenetics in hybrid vigor in oysters.
This document discusses the state of characterization of the eukaryotic proteome. It notes that as of 2019, around 20% of proteins in fission yeast and humans are still classified as having unknown biological processes. While the number of known or inferred protein roles has increased since 1992, progress in characterizing unknowns has been slow. Many recently characterized proteins in fission yeast are involved in non-core functions like environmental response, aging, and damage accumulation. The document calls for more research on these unknown and less studied proteins that are "hidden in plain sight" within the eukaryotic proteome.
The document discusses mechanisms that promote mono-orientation of sister kinetochores during meiosis I. It reports that Zip1, a protein involved in synaptonemal complex formation, interacts with components of the Ndc80 kinetochore complex and its deletion reduces mono-orientation. Experiments show that Zip1 expression in mitosis delays bi-orientation of sisters and influences kinetochore orientation in meiosis I mutants. The results suggest Zip1 may prevent bi-orientation of functional sister kinetochores during meiosis I.
The Impact of Lysogenic and Tail Assembly Chaperone Proteins on the Life Cycl...Wyatt Nelson
This document summarizes research characterizing a novel mycobacteriophage named Emma. Key findings include:
- Emma has a siphoviridae morphology and forms clear and bullseye plaques.
- Genome annotation revealed genes for lysogeny and a programmed +1 frameshift mutation in tail assembly genes.
- Analysis suggests this frameshift mutation conserves production of two tail assembly proteins important for phage viability.
The document discusses mutations and their role in evolution. It begins with defining mutations as sudden changes in hereditary materials like DNA and chromosomes. Mutations can occur due to errors in DNA replication or repair and some are caused by mutagens like chemicals and UV radiation. The document then covers different types of mutations like point mutations, insertions, deletions, and chromosomal mutations. It also discusses how mutations contribute to genetic variation and evolution by providing raw materials for natural selection to act upon. The role of mutations in development of antibiotic resistance in pathogens is also mentioned.
Mutagenesis is the process by which the genetic information of an organism is changed, resulting in a mutation. Mutations are caused by mutagens, which are physical or chemical agents that alter DNA. There are several types of mutations, including missense mutations, nonsense mutations, insertion mutations, deletion mutations, repeat expansion mutations, and frame shift mutations. Genetic toxicology assesses the effects of chemicals and physical agents on DNA and genetic processes. Genotoxicants can alter DNA sequences, cause chromosomal damage, affect chromosome number, and influence gene expression. Genetic toxicology tests are used to predict mutagenic and carcinogenic potential for regulatory purposes.
Sperm DNA fragmentation can negatively impact fertility and pregnancy outcomes. DNA becomes vulnerable during spermatogenesis when protamine replaces histones in chromatin compaction. Tests can evaluate sperm DNA fragmentation levels, which are correlated with lower fertilization and implantation rates. Factors like oxidative stress, temperature, and infections can intrinsically or extrinsically damage sperm DNA. Repair mechanisms attempt to resolve DNA double-strand breaks, but extensive unrepaired damage may be incompatible with embryo development. Treatments aim to address underlying causes of DNA fragmentation or use testicular sperm or ICSI to bypass ejaculated sperm issues.
The document summarizes a study on DNA methylation variation in clonal seagrass shoots. The researchers found strong epigenetic differences between genetically identical clones in a Baltic Sea seagrass meadow, with DNA methylation patterns not explained by spatial proximity of shoots. They also found that experimental heat stress led to permanent methylation changes and an epigenetic stress memory correlated with photosynthetic performance. The study suggests DNA methylation variation plays a functional role in seagrass response to environmental stress independently of genetic variation, and has implications for seagrass conservation.
This document summarizes the process of gene expression from transcription of DNA to RNA through translation of RNA to protein. It discusses how DNA is transcribed into messenger RNA by RNA polymerase. It describes mRNA processing through capping, polyadenylation, and splicing before the mRNA is translated into protein by ribosomes. The translation process of initiating protein synthesis, elongating the polypeptide chain, and terminating translation is also summarized along with posttranslational modification of proteins.
This document summarizes research on gene duplications in Drosophila flies and humans. It finds that tandem gene duplications are more common around centromeres in Drosophila yakuba flies. In D. simulans flies, there is an excess of high-frequency duplications on the X chromosome compared to autosomes, suggesting widespread selection for duplications on the D. simulans X chromosome. The document also reviews cases of partial gene duplications associated with human diseases, finding they can result in novel gene structures and expression patterns with implications for disease.
Spontaneous mutations in microorganismsprasanna1017
Griffith's experiment in 1928 showed that bacteria can undergo transformation through uptake of DNA. He found that non-lethal heat-killed bacteria, when mixed with live harmless bacteria, could make the mixture lethal. Later it was found the "transforming principle" was DNA, which could be taken up by other bacteria and confer new traits like capsule formation and virulence. This provided early evidence that DNA carries genetic information that can be transferred between bacteria.
Trade-Offs and Kinetic Control for Kinetic Proofreading Networks in Biologica...JoelMallory2
This document summarizes research on kinetic proofreading networks in biological systems. It finds that while properties like error rate, speed, and energy dissipation cannot all be optimized at once due to trade-offs, enzymes prioritize speed followed by dissipation and error rate. Additionally, it shows that ratios of stationary fluxes and dependent properties like error rate are invariant to energy perturbations of individual states and only affected by transition state barriers, demonstrating kinetic rather than thermodynamic control. Genetic mutations must therefore change transition state barriers to impact enzyme accuracy and dissipation.
Oncology: Spatial Localization of Ras proteinsNachiket Vartak
This is a presentation of work done at the MPI Dortmund from 2008-2013 on the mechanism through with localization of the Ras protein in generated in cells. It presents the inhibiton Palmostatin-B, which inhibits this mechanism, leading to reveral of oncogenic signaling and cancerous phenotypes.
The role of DNA methylation in complex diseasesJordana Bell
A 1-hour lecture to 4th-year undergraduate and/or MSc students in human genetics, focusing on exploring the role of DNA methylation in human complex disease.
1. The document describes a method for using coiled-coil peptide probes inserted into proteins to study the mechanical unfolding pathways of large proteins through single-molecule force spectroscopy.
2. During experiments, the forced unfolding of the coiled-coil probes captures the progress of the unfolding front through the host protein, allowing its unfolding pathway to be directly identified.
3. As a demonstration, the unfolding pathway of an NI10C protein was probed using coiled-coil peptides and shown to follow a sequential, vectorial unfolding process from the C to N terminus.
A suppressor mutation counters the effects of an original mutation by restoring the wild-type phenotype. There are two main types of suppressor mutations: intragenic mutations occur within the same gene and restore function through alternate amino acid substitutions, while intergenic mutations occur elsewhere in the genome and restore function through interacting gene products. Suppressor mutations are useful for studying protein-protein interactions and dissecting biological pathways.
Presentation made by Jernej Ule on the 20th of April, 2017, at the live webinar hosted by Alzforum: http://www.alzforum.org/webinars/webinar-cortex-aging-too-fast-blame-tmem106b-and-progranulin
Speriolin is a testis-specific centrosomal protein that is transferred from sperm to fertilized oocyte. It binds to and transports cdc20 protein to kinetochores during meiosis, and localizes to spindle centrioles during anaphase. In fertilized eggs, speriolin drives anaphase by transporting cdc20 to activate the APC ligase, leading to securin degradation and sister chromatid segregation. As a centrosomal protein inherited from sperm, speriolin may regulate early cell division and plays a role in male reproductive responsibilities like maintaining epigenetic integrity and transferring centrioles to progeny.
The document discusses a study investigating SVP, a gene involved in floral transition timing, in the Arabidopsis thaliana accession Dja-1. SVP is hypermethylated in Dja-1, which flowers early, whereas it is not methylated in other accessions. The study aimed to determine if DNA methylation of SVP (SVPepi) in Dja-1 causes its early flowering phenotype. Results showed SVPepi has the lowest expression in Dja-1. Treatment with demethylating agents reduced genomic methylation but did not significantly alter SVP expression or flowering time. However, the presence of a transposable element in SVPepi's promoter region suggests it may not be a
Kenyatta university. hmb201 dna repairdocxLando Elvis
Gene mutations can be hereditary or acquired. DNA has multiple repair mechanisms to correct damage from environmental factors and replication errors. These include mismatch repair, nucleotide excision repair, photoreactivation repair, base excision repair, and double-strand break repair through nonhomologous end joining or homologous recombination. Errors in DNA repair can lead to mutations and genetic disorders if damage is not corrected. The cell cycle is also regulated to check for DNA damage and delay progression until repairs are complete.
The document summarizes experiments studying the movement and directionality of the FtsK translocase protein on DNA molecules. Key findings include:
1) FtsK moves rapidly at 5 kilobases per second and can work against forces up to 60 piconewtons.
2) FtsK forms loops of DNA as it translocates and can reverse direction without dissociating from DNA.
3) When bound to lambda DNA, FtsK consistently moved in the same direction, toward the terminus region as predicted, even when the DNA was inverted.
The document discusses epigenetics and DNA methylation in oncology. It provides an introduction to epigenetics and how epigenetic modifications can regulate gene expression without changing DNA sequence. It then discusses using DNA methylation as an epigenetic biomarker for cancer, including prostate and bladder cancers. Specific methylated genes are highlighted as biomarkers for bladder cancer detection in urine samples from patients with hematuria. Validation study results show the biomarkers can accurately detect bladder cancer with high sensitivity and negative predictive value, reducing unnecessary cystoscopies.
Understanding the role and evolution of internal symmetry in protein structure is a fundamental question in structural biology. We present here CE-Symm 2.0, a key tool to address that question, which is able to detect all types of protein internal symmetry and provides a robust and intuitive sequence-to-structure analysis of all repeats. Notable features compared to the previous version include an optimized multiple alignment between repeats, determination of the full point group, and identification of multiple symmetry axes. We expect CE-Symm to find ample use in evolutionary studies, functional annotation, and structural classification of proteins.
This work was presented at the 3DSIG 2016 conference in Orlando, FL, on July 8, 2016.
See also the poster form: http://www.slideshare.net/sbliven/3dsig-2016-poster-exploring-internal-symmetry-and-structural-repeats-with-cesymm
The document discusses classifying biological information from DNA sequences and summarizes some of the challenges involved. It notes that classifying organisms based on their genomes involves determining which genes are responsible for unique properties and can identify organisms. Machine learning techniques like association rule mining are used to discover relationships between genes and phenotypes. However, classifying organisms is challenging due to interactions between genes and effects of taxonomy. Metagenomics, which involves classifying short DNA sequences from environmental samples, poses additional challenges due to analyzing mixtures of many microbial species simultaneously.
The document discusses mutations and their role in evolution. It begins with defining mutations as sudden changes in hereditary materials like DNA and chromosomes. Mutations can occur due to errors in DNA replication or repair and some are caused by mutagens like chemicals and UV radiation. The document then covers different types of mutations like point mutations, insertions, deletions, and chromosomal mutations. It also discusses how mutations contribute to genetic variation and evolution by providing raw materials for natural selection to act upon. The role of mutations in development of antibiotic resistance in pathogens is also mentioned.
Mutagenesis is the process by which the genetic information of an organism is changed, resulting in a mutation. Mutations are caused by mutagens, which are physical or chemical agents that alter DNA. There are several types of mutations, including missense mutations, nonsense mutations, insertion mutations, deletion mutations, repeat expansion mutations, and frame shift mutations. Genetic toxicology assesses the effects of chemicals and physical agents on DNA and genetic processes. Genotoxicants can alter DNA sequences, cause chromosomal damage, affect chromosome number, and influence gene expression. Genetic toxicology tests are used to predict mutagenic and carcinogenic potential for regulatory purposes.
Sperm DNA fragmentation can negatively impact fertility and pregnancy outcomes. DNA becomes vulnerable during spermatogenesis when protamine replaces histones in chromatin compaction. Tests can evaluate sperm DNA fragmentation levels, which are correlated with lower fertilization and implantation rates. Factors like oxidative stress, temperature, and infections can intrinsically or extrinsically damage sperm DNA. Repair mechanisms attempt to resolve DNA double-strand breaks, but extensive unrepaired damage may be incompatible with embryo development. Treatments aim to address underlying causes of DNA fragmentation or use testicular sperm or ICSI to bypass ejaculated sperm issues.
The document summarizes a study on DNA methylation variation in clonal seagrass shoots. The researchers found strong epigenetic differences between genetically identical clones in a Baltic Sea seagrass meadow, with DNA methylation patterns not explained by spatial proximity of shoots. They also found that experimental heat stress led to permanent methylation changes and an epigenetic stress memory correlated with photosynthetic performance. The study suggests DNA methylation variation plays a functional role in seagrass response to environmental stress independently of genetic variation, and has implications for seagrass conservation.
This document summarizes the process of gene expression from transcription of DNA to RNA through translation of RNA to protein. It discusses how DNA is transcribed into messenger RNA by RNA polymerase. It describes mRNA processing through capping, polyadenylation, and splicing before the mRNA is translated into protein by ribosomes. The translation process of initiating protein synthesis, elongating the polypeptide chain, and terminating translation is also summarized along with posttranslational modification of proteins.
This document summarizes research on gene duplications in Drosophila flies and humans. It finds that tandem gene duplications are more common around centromeres in Drosophila yakuba flies. In D. simulans flies, there is an excess of high-frequency duplications on the X chromosome compared to autosomes, suggesting widespread selection for duplications on the D. simulans X chromosome. The document also reviews cases of partial gene duplications associated with human diseases, finding they can result in novel gene structures and expression patterns with implications for disease.
Spontaneous mutations in microorganismsprasanna1017
Griffith's experiment in 1928 showed that bacteria can undergo transformation through uptake of DNA. He found that non-lethal heat-killed bacteria, when mixed with live harmless bacteria, could make the mixture lethal. Later it was found the "transforming principle" was DNA, which could be taken up by other bacteria and confer new traits like capsule formation and virulence. This provided early evidence that DNA carries genetic information that can be transferred between bacteria.
Trade-Offs and Kinetic Control for Kinetic Proofreading Networks in Biologica...JoelMallory2
This document summarizes research on kinetic proofreading networks in biological systems. It finds that while properties like error rate, speed, and energy dissipation cannot all be optimized at once due to trade-offs, enzymes prioritize speed followed by dissipation and error rate. Additionally, it shows that ratios of stationary fluxes and dependent properties like error rate are invariant to energy perturbations of individual states and only affected by transition state barriers, demonstrating kinetic rather than thermodynamic control. Genetic mutations must therefore change transition state barriers to impact enzyme accuracy and dissipation.
Oncology: Spatial Localization of Ras proteinsNachiket Vartak
This is a presentation of work done at the MPI Dortmund from 2008-2013 on the mechanism through with localization of the Ras protein in generated in cells. It presents the inhibiton Palmostatin-B, which inhibits this mechanism, leading to reveral of oncogenic signaling and cancerous phenotypes.
The role of DNA methylation in complex diseasesJordana Bell
A 1-hour lecture to 4th-year undergraduate and/or MSc students in human genetics, focusing on exploring the role of DNA methylation in human complex disease.
1. The document describes a method for using coiled-coil peptide probes inserted into proteins to study the mechanical unfolding pathways of large proteins through single-molecule force spectroscopy.
2. During experiments, the forced unfolding of the coiled-coil probes captures the progress of the unfolding front through the host protein, allowing its unfolding pathway to be directly identified.
3. As a demonstration, the unfolding pathway of an NI10C protein was probed using coiled-coil peptides and shown to follow a sequential, vectorial unfolding process from the C to N terminus.
A suppressor mutation counters the effects of an original mutation by restoring the wild-type phenotype. There are two main types of suppressor mutations: intragenic mutations occur within the same gene and restore function through alternate amino acid substitutions, while intergenic mutations occur elsewhere in the genome and restore function through interacting gene products. Suppressor mutations are useful for studying protein-protein interactions and dissecting biological pathways.
Presentation made by Jernej Ule on the 20th of April, 2017, at the live webinar hosted by Alzforum: http://www.alzforum.org/webinars/webinar-cortex-aging-too-fast-blame-tmem106b-and-progranulin
Speriolin is a testis-specific centrosomal protein that is transferred from sperm to fertilized oocyte. It binds to and transports cdc20 protein to kinetochores during meiosis, and localizes to spindle centrioles during anaphase. In fertilized eggs, speriolin drives anaphase by transporting cdc20 to activate the APC ligase, leading to securin degradation and sister chromatid segregation. As a centrosomal protein inherited from sperm, speriolin may regulate early cell division and plays a role in male reproductive responsibilities like maintaining epigenetic integrity and transferring centrioles to progeny.
The document discusses a study investigating SVP, a gene involved in floral transition timing, in the Arabidopsis thaliana accession Dja-1. SVP is hypermethylated in Dja-1, which flowers early, whereas it is not methylated in other accessions. The study aimed to determine if DNA methylation of SVP (SVPepi) in Dja-1 causes its early flowering phenotype. Results showed SVPepi has the lowest expression in Dja-1. Treatment with demethylating agents reduced genomic methylation but did not significantly alter SVP expression or flowering time. However, the presence of a transposable element in SVPepi's promoter region suggests it may not be a
Kenyatta university. hmb201 dna repairdocxLando Elvis
Gene mutations can be hereditary or acquired. DNA has multiple repair mechanisms to correct damage from environmental factors and replication errors. These include mismatch repair, nucleotide excision repair, photoreactivation repair, base excision repair, and double-strand break repair through nonhomologous end joining or homologous recombination. Errors in DNA repair can lead to mutations and genetic disorders if damage is not corrected. The cell cycle is also regulated to check for DNA damage and delay progression until repairs are complete.
The document summarizes experiments studying the movement and directionality of the FtsK translocase protein on DNA molecules. Key findings include:
1) FtsK moves rapidly at 5 kilobases per second and can work against forces up to 60 piconewtons.
2) FtsK forms loops of DNA as it translocates and can reverse direction without dissociating from DNA.
3) When bound to lambda DNA, FtsK consistently moved in the same direction, toward the terminus region as predicted, even when the DNA was inverted.
The document discusses epigenetics and DNA methylation in oncology. It provides an introduction to epigenetics and how epigenetic modifications can regulate gene expression without changing DNA sequence. It then discusses using DNA methylation as an epigenetic biomarker for cancer, including prostate and bladder cancers. Specific methylated genes are highlighted as biomarkers for bladder cancer detection in urine samples from patients with hematuria. Validation study results show the biomarkers can accurately detect bladder cancer with high sensitivity and negative predictive value, reducing unnecessary cystoscopies.
Understanding the role and evolution of internal symmetry in protein structure is a fundamental question in structural biology. We present here CE-Symm 2.0, a key tool to address that question, which is able to detect all types of protein internal symmetry and provides a robust and intuitive sequence-to-structure analysis of all repeats. Notable features compared to the previous version include an optimized multiple alignment between repeats, determination of the full point group, and identification of multiple symmetry axes. We expect CE-Symm to find ample use in evolutionary studies, functional annotation, and structural classification of proteins.
This work was presented at the 3DSIG 2016 conference in Orlando, FL, on July 8, 2016.
See also the poster form: http://www.slideshare.net/sbliven/3dsig-2016-poster-exploring-internal-symmetry-and-structural-repeats-with-cesymm
The document discusses classifying biological information from DNA sequences and summarizes some of the challenges involved. It notes that classifying organisms based on their genomes involves determining which genes are responsible for unique properties and can identify organisms. Machine learning techniques like association rule mining are used to discover relationships between genes and phenotypes. However, classifying organisms is challenging due to interactions between genes and effects of taxonomy. Metagenomics, which involves classifying short DNA sequences from environmental samples, poses additional challenges due to analyzing mixtures of many microbial species simultaneously.
Genome editing methods such as ZFNs, TALENs, and CRISPR/Cas9 use engineered nucleases to create targeted double-stranded breaks in DNA which are then repaired through endogenous cellular processes. These nucleases can be used to modify genomes through techniques like gene knockout, targeted mutation insertion/deletion/correction, and studying gene function. CRISPR/Cas9 uses a guide RNA and Cas9 nuclease to target specific DNA sequences for editing. The four main steps for CRISPR are: 1) selecting target sequences near a PAM site, 2) designing and cloning gRNA, 3) delivering Cas9 and gRNA into cells, and 4) DNA repair after cleavage results in gene modification
20140613 Analysis of High Throughput DNA Methylation ProfilingYi-Feng Chang
This document provides an overview of analysis of high-throughput DNA methylation profiling using bisulfite sequencing (BS-Seq) technology. It discusses DNA methylation and the bisulfite conversion process. It also reviews current BS-Seq resources, information that can be presented in BS-Seq studies, and published tools for analyzing BS-Seq data, including alignment, calling methylation status, and identifying differential methylation regions. The document concludes by introducing MethPipe, a comprehensive tool for BS-Seq data analysis.
This document discusses protein-ligand docking and its applications in drug discovery. It notes that drug discovery is a lengthy and costly process with high attrition rates. Protein-ligand docking can be used to aid rational drug design by predicting how drug molecules may interact with protein targets. The document outlines different types of docking problems in biology and summarizes concepts and challenges in protein-ligand docking, including accounting for flexibility. It provides examples of how docking has been used to design new protease inhibitors and for virtual screening in drug development pipelines.
Following the Evolution of New Protein Folds via ProtodomainsSpencer Bliven
Protein evolution proceeds through genetic mechanisms, but selection acts on biological assemblies. I define a protodomain as a minimal independently evolving unit with conserved structure. Protodomain rearrangements have minimal impact on biological assemblies, so they represent a valid evolutionary path through fold space.
These slides are from my Candidacy Exam on Jan 28, 2013 at University of California, San Diego. It discusses my current research in Philip Bourne's lab, as well as proposes research for my thesis over the next two years. An audio version is available at http://www.scivee.tv/node/57082
Research report (alternative splicing, protein structure; retinitis pigmentosa)avalgar
This presentation explains the two major scientific projects I have been involved in.
It extends way further than a CV, but shorter than an actual scientific paper.
The document discusses using computational methods to help eradicate disease. It outlines the typical long timelines and high costs involved in drug discovery. It then describes using the ChemGenome software to analyze genome sequences and identify potential drug targets, generate lead molecules that bind to targets, and identify 24 hit molecules that could be tested for treating hepatitis B virus. The overall process takes genome sequences as input and outputs potential drug candidates to help streamline the drug discovery process in silico.
A novel phylum-level archaea characterized by combining single-cell and metag...Guillaume Reboul
This document summarizes the characterization of a novel archaeal phylum through a combined approach of single-cell genomics and metagenomics. The archaeon, referred to as N21, was found in a hot spring environmental sample through single-cell sorting and amplification. Its genome was then partially assembled from single-cell data. Metagenomic sequencing of the same sample provided additional genomic data, which was binned using the single-cell data, allowing reconstruction of a 1.55 Mbp high-quality draft genome. Phylogenetic analysis showed N21 represents a novel phylum-level lineage within the Euryarchaeota.
This document summarizes a thesis that developed a database comparing gene expression data from axolotl and zebrafish limb regeneration studies. The thesis used a "Rosetta stone" approach to identify 78 axolotl genes that matched human genes and had homologous zebrafish genes. These genes were organized based on gene ontologies, functions during regeneration, and expression changes with TCDD exposure. Key findings included roles for ribosomal proteins, mitochondria, neurite regeneration, extracellular matrix proteins, and genes related to cell differentiation, apoptosis and maintenance.
This study performed a comparative metagenomic analysis of fecal samples from 13 healthy individuals of various ages to identify genomic features common and variable among human gut microbiomes. It found that gut microbiomes from unweaned infants were simple and highly variable, while adults and weaned children were more complex but functionally uniform. 237 gene families were commonly enriched in adult microbiomes and 136 in infant microbiomes, with a small overlap. 647 new gene families were exclusively present in human intestinal microbiomes.
This document discusses high-resolution views of the cancer genome using various technologies including DNA microarrays, comparative genomic hybridization, tiling arrays, next-generation sequencing, and DNAse-Seq. It describes how these technologies can be used to analyze gene expression, copy number variation, chromatin structure, and more to better understand cancer at the genomic level. Integrating data from all these sources presents challenges but may help improve individual health outcomes.
This document summarizes research on developing a human cancer coessentiality network using data from pooled shRNA screens across 107 cancer cell lines. Key points:
- A network of 866 genes and 1877 edges was constructed based on correlations in essentiality profiles across cell lines.
- Network clustering identified groups of genes essential for similar cell line subtypes (e.g. breast, ovarian, pancreatic cancers).
- One cluster involved in oxidative phosphorylation was particularly essential for luminal/HER2 breast cancers.
- The network provides a functional genomics resource, though opportunities exist to improve coverage and accuracy.
The document summarizes research characterizing newly isolated bacteriophages (viruses that infect bacteria) that prey on Mycobacterium smegmatis bacteria. Twelve bacteriophages were found and nine were analyzed by electron microscopy, showing a tailed "siphoviridae" structure. The genome of one phage, Bipolar, was fully sequenced and found to be similar to the F1 subcluster. The document then analyzes whether two genes, Tape Measure Protein (TMP) and Lysin A, can accurately predict phage cluster relationships on their own. Results showed that TMP was highly accurate, while Lysin A was less so, supporting the hypothesis that Lysin A is more diverse
This document discusses optimal tiling algorithms for selecting genomic DNA fragments for applications such as microarray design and homology searching. It defines several tiling problems involving finding the maximum weighted set of tiles (sequence fragments) within certain size bounds from a given genomic sequence. Typical parameter values are provided for applications involving sequencing lengths up to 3.4GB, tile sizes from 200bp to 1.5kb, and allowing overlaps of up to 100bp for homology searching. Efficient algorithms are sought with linear or near-linear runtimes to solve these tiling problems.
This document provides an overview of CRISPR/Cas9 genome editing. It begins with definitions of key genetic concepts like genomes, genes, and chromosomes. It then discusses the history and timeline of discoveries around CRISPR dating back to 1987, including its identification in bacteria and role in adaptive immunity. The document explains the basic principles and mechanism of CRISPR/Cas9, how it was harnessed for genome editing in 2012-2013, and current and potential applications in research and medicine. It concludes by noting some ethical concerns around genome editing technologies.
The document describes a microarray study to analyze gene expression in atherosclerotic plaques and correlate it with factors related to plaque vulnerability. Specimens will be obtained from human carotid/coronary arteries and atherosclerotic plaques in mouse models. Gene expression will be profiled using microarrays and correlated with histopathology, pH, temperature, spectroscopy and other variables. The goal is to identify genes associated with vulnerable plaques and rupture. Plaques from influenza-infected and drug-treated mice will also be analyzed to study effects on gene expression and plaque structure.
132 gene expression in atherosclerotic plaquesSHAPE Society
This document discusses microarray studies to analyze gene expression in atherosclerotic plaques and correlate it with factors related to plaque vulnerability. It begins with background on the history and applications of DNA microarrays. Key steps discussed include probe design, sample preparation including tissue collection, labeling RNA samples, hybridizing samples to a microarray chip, scanning and analyzing image data. The document outlines creating a custom microarray based on selected genes and correlating gene expression with temperature, pH, spectroscopy and histopathology of plaques. It will also analyze gene expression in influenza-infected mice and mice where plaques are induced to rupture with drugs. Human carotid artery specimens from surgery will be analyzed from symptomatic and asymptomatic patients.
The document describes a microarray study to analyze gene expression in atherosclerotic plaques and correlate it with factors related to plaque vulnerability. Specimens will be obtained from human carotid/coronary arteries and atherosclerotic plaques in mouse models. Gene expression will be profiled using microarrays and correlated with histopathology, pH, temperature, spectroscopy and other variables. Plaques from influenza-infected and drug-treated mice will also be analyzed to identify genes associated with plaque rupture. The goal is to better understand plaque vulnerability and identify potential drug targets.
This document summarizes the activities of BIOCLUES, a bioinformatics club focused on mentoring and collaborations. Some key points:
1. BIOCLUES was launched in 2005 and has grown to over 4000 members, with 2000 receiving virtual mentoring. It facilitates mentor-mentee relationships and collaborations between researchers.
2. The document describes three research stories involving identifying long non-coding RNAs from exome data and their role in conditions like SARS-CoV-2 infection.
3. BIOCLUES aims to make the research community more open and inclusive through diverse collaborations, addressing issues like predatory publishing and lack of STEM education. It works to build capacity in
The cost of acquiring information by natural selectionCarl Bergstrom
This is a short talk that I gave at the Banff International Research Station workshop on Modeling and Theory in Population Biology. The idea is to try to understand how the burden of natural selection relates to the amount of information that selection puts into the genome.
It's based on the first part of this research paper:
The cost of information acquisition by natural selection
Ryan Seamus McGee, Olivia Kosterlitz, Artem Kaznatcheev, Benjamin Kerr, Carl T. Bergstrom
bioRxiv 2022.07.02.498577; doi: https://doi.org/10.1101/2022.07.02.498577
Authoring a personal GPT for your research and practice: How we created the Q...Leonel Morgado
Thematic analysis in qualitative research is a time-consuming and systematic task, typically done using teams. Team members must ground their activities on common understandings of the major concepts underlying the thematic analysis, and define criteria for its development. However, conceptual misunderstandings, equivocations, and lack of adherence to criteria are challenges to the quality and speed of this process. Given the distributed and uncertain nature of this process, we wondered if the tasks in thematic analysis could be supported by readily available artificial intelligence chatbots. Our early efforts point to potential benefits: not just saving time in the coding process but better adherence to criteria and grounding, by increasing triangulation between humans and artificial intelligence. This tutorial will provide a description and demonstration of the process we followed, as two academic researchers, to develop a custom ChatGPT to assist with qualitative coding in the thematic data analysis process of immersive learning accounts in a survey of the academic literature: QUAL-E Immersive Learning Thematic Analysis Helper. In the hands-on time, participants will try out QUAL-E and develop their ideas for their own qualitative coding ChatGPT. Participants that have the paid ChatGPT Plus subscription can create a draft of their assistants. The organizers will provide course materials and slide deck that participants will be able to utilize to continue development of their custom GPT. The paid subscription to ChatGPT Plus is not required to participate in this workshop, just for trying out personal GPTs during it.
Sexuality - Issues, Attitude and Behaviour - Applied Social Psychology - Psyc...PsychoTech Services
A proprietary approach developed by bringing together the best of learning theories from Psychology, design principles from the world of visualization, and pedagogical methods from over a decade of training experience, that enables you to: Learn better, faster!
ESA/ACT Science Coffee: Diego Blas - Gravitational wave detection with orbita...Advanced-Concepts-Team
Presentation in the Science Coffee of the Advanced Concepts Team of the European Space Agency on the 07.06.2024.
Speaker: Diego Blas (IFAE/ICREA)
Title: Gravitational wave detection with orbital motion of Moon and artificial
Abstract:
In this talk I will describe some recent ideas to find gravitational waves from supermassive black holes or of primordial origin by studying their secular effect on the orbital motion of the Moon or satellites that are laser ranged.
Current Ms word generated power point presentation covers major details about the micronuclei test. It's significance and assays to conduct it. It is used to detect the micronuclei formation inside the cells of nearly every multicellular organism. It's formation takes place during chromosomal sepration at metaphase.
EWOCS-I: The catalog of X-ray sources in Westerlund 1 from the Extended Weste...Sérgio Sacani
Context. With a mass exceeding several 104 M⊙ and a rich and dense population of massive stars, supermassive young star clusters
represent the most massive star-forming environment that is dominated by the feedback from massive stars and gravitational interactions
among stars.
Aims. In this paper we present the Extended Westerlund 1 and 2 Open Clusters Survey (EWOCS) project, which aims to investigate
the influence of the starburst environment on the formation of stars and planets, and on the evolution of both low and high mass stars.
The primary targets of this project are Westerlund 1 and 2, the closest supermassive star clusters to the Sun.
Methods. The project is based primarily on recent observations conducted with the Chandra and JWST observatories. Specifically,
the Chandra survey of Westerlund 1 consists of 36 new ACIS-I observations, nearly co-pointed, for a total exposure time of 1 Msec.
Additionally, we included 8 archival Chandra/ACIS-S observations. This paper presents the resulting catalog of X-ray sources within
and around Westerlund 1. Sources were detected by combining various existing methods, and photon extraction and source validation
were carried out using the ACIS-Extract software.
Results. The EWOCS X-ray catalog comprises 5963 validated sources out of the 9420 initially provided to ACIS-Extract, reaching a
photon flux threshold of approximately 2 × 10−8 photons cm−2
s
−1
. The X-ray sources exhibit a highly concentrated spatial distribution,
with 1075 sources located within the central 1 arcmin. We have successfully detected X-ray emissions from 126 out of the 166 known
massive stars of the cluster, and we have collected over 71 000 photons from the magnetar CXO J164710.20-455217.
The binding of cosmological structures by massless topological defectsSérgio Sacani
Assuming spherical symmetry and weak field, it is shown that if one solves the Poisson equation or the Einstein field
equations sourced by a topological defect, i.e. a singularity of a very specific form, the result is a localized gravitational
field capable of driving flat rotation (i.e. Keplerian circular orbits at a constant speed for all radii) of test masses on a thin
spherical shell without any underlying mass. Moreover, a large-scale structure which exploits this solution by assembling
concentrically a number of such topological defects can establish a flat stellar or galactic rotation curve, and can also deflect
light in the same manner as an equipotential (isothermal) sphere. Thus, the need for dark matter or modified gravity theory is
mitigated, at least in part.
Travis Hills of MN is Making Clean Water Accessible to All Through High Flux ...Travis Hills MN
By harnessing the power of High Flux Vacuum Membrane Distillation, Travis Hills from MN envisions a future where clean and safe drinking water is accessible to all, regardless of geographical location or economic status.
2. 1
From Google Earth. Data SIO, NOAA, U.S. Navy, NGA,
GEBCO, Image Landsat, Image IBCAO
3. d2hmva1
2
PDP:PDP:d2r4qa1
PDP:3A1DAa
d1djla_
PDP:2VOYIa
d1shux_
d1d4oa_
! What’s the nature of protein fold space?
! How do new folds evolve?
d1nrjb_
! How do gene rearrangements relate to protein
structure?
! What can internal symmetry tell us about protein
function and evolution?
! What algorithms are best for detecting remote
homology?
PDP:2IYEAa
PDP:3QJGAa
PDP:2FN9Aa
d1wa5a_
PDP:3QELBa
PDP:3RBZAb
d1id1a_
PDP:2WI8Aa
PDP:3IPCAa
d1ls1a2
SCOP:d1su3a2 d1pt2a_ d1c5ka1 d1k3ia3 d1h9ya2
8. ! Evolution
! Identify duplications & fusions
! Many examples of homologous quaternary symmetric/
internally symmetric proteins
! Tradeoff between monomer & oligomer
Lee and Blaber. PNAS (2011) vol. 108 (1) pp. 126-30
7
3OL0 3O49
9. E. Coli DNA polymerase III beta
subunit
! 2 chains (C2 crystal axis)
Human proliferating cell nuclear
antigen
! 3 chains (C3 crystal axis)
1MMI
1VYM
8
10. E. Coli DNA polymerase III beta
subunit
! 2 chains
! 6 domains (pseudo C6)
Human proliferating cell nuclear
antigen
! 3 chains
! 6 domains (pseudo C6)
1MMI
1VYM
9
11. ! 2-3 chains
! 6 domains
! 12 structural repeats (pseudo D6)
Ancient 12-mer?
Ancient 6-mer
Eukaryotic/Archaeal/ Bacterial Dimer
Viral Trimer
Kelman, Z., & O'Donnell, M. (1995). Nucleic Acids Research, 23(18), 3613–3620.
Neuwald, A. F., & Poleksic, A. (2000). Nucleic Acids Research, 28(18), 3570–3580.
10
12. Glyoxalase I from
Clostridium
acetobutylicum [3HDP]
(Nickel; Dimer)
Glyoxalase I from E.
coli [1F9Z]
(Nickel; Dimer)
1,2-dihydroxy-naphthalene
dioxygenase from
Pseudomonas sp. strain
C18 [2EHZ]
(Iron; Octamer)
11
13. 12
Glyoxalase I from
Clostridium
acetobutylicum [3HDP]
(Nickel; Dimer)
Glyoxalase I from E.
coli [1F9Z]
(Nickel; Dimer)
1,2-dihydroxy-naphthalene
dioxygenase from
Pseudomonas sp. strain
C18 [2EHZ]
(Iron; Octamer)
14. ! Extends Combinatorial
Extension (CE) algorithm for
structural alignment
! Web server: source.rcsb.org/
jfatcatserver/symmetry.jsp
! Download & Source code:
github.com/rcsb/symmetry
(LGPL)
! Myers-Turnbull, D., Bliven, S. E.,
Rose, P. W., Aziz, Z. K.,
Youkharibache, P., Bourne, P. E., &
Prlić, A. (2014). Systematic Detection
of Internal Symmetry in Proteins Using
CE-Symm. Journal of Molecular
Biology, 426(11), 2255–2268.
13
20. 19
BtuF
BtuC
BtuD
Vitamin B12 transporter BtuCD–F from E. coli [4FI3]
21. 20
BtuF [1N4A]
BtuF
BtuC
BtuD
Vitamin B12 transporter BtuCD–F from E. coli [4FI3]
22. ! PTS sorbitol transporter subunit IIA
! Novel fold
! Solved by the Protein Structure Initiative
! Structural alignment reveals a conserved sequence
motif between halves
2F9H
21
23. 22
! Systematically compare
symmetry units across
the PDB
! CE-Symm
improvements
! Improve order detection
(C8, not C4 or C2)
! Visualization & usability
! Find mixed quaternary &
internal symmetry
24. ! Paul Scherrer Institute
! Guido Capitani
! Kumaran Baskaran
! Jose Duarte
! Joseph Somody
! LBR members
! UC San Diego/RCSB
! Douglas Myers-Turnbull
! Andreas Prlić
! Peter Rose
! Zaid Aziz
! RCSB & Bourne Lab members
! NIH
! Philip Bourne
! Philippe Youkharibache
! David Landsman
Resources:
! source.rcsb.org/jfatcatserver/
symmetry.jsp
! github.com/rcsb/symmetry
! www.slideshare.net/sbliven
Funding: NSF, NIH, DOE, Open
Science Grid
23
28. 120° 120°
Fibroblast Growth
Factor [3JUT]
Myers-Turnbull, D., Bliven, S. E., Rose, P. W., Aziz, Z. K., Youkharibache, P., Bourne, P.
E., & Prlić, A. (2014). Journal of Molecular Biology, 426(11), 2255–2268.
27
29. 120° 120°
Fibroblast Growth
Factor [3JUT]
Myers-Turnbull, D., Bliven, S. E., Rose, P. W., Aziz, Z. K., Youkharibache, P., Bourne, P.
E., & Prlić, A. (2014). Journal of Molecular Biology, 426(11), 2255–2268.
28
30. This work is licensed under a
Creative Commons Attribution-ShareAlike 3.0 Unported License.
29