This document provides a scientific review of the histone demethylase enzymes; particularly the H3K4 demethlases (KDM5 family) focusing on their role in cell biology. This review was written in 2014
Characterization of mg state of mb in presence of peg 10 (z a parray) originalZahoor Parray
This document summarizes a study that characterized the intermediate state of myoglobin (Mb) in the presence of polyethylene glycol 10 (PEG 10) under physiological conditions. The researchers found that PEG 10 perturbed the tertiary structure of Mb but did not significantly change its secondary structure. PEG 10 was found to induce a molten globule state in Mb, where the intermediate state had hydrophobic patches and a larger hydrodynamic volume than the native protein. Isothermal titration calorimetry showed strong binding between Mb and PEG 10 at physiological pH. The researchers hypothesize that PEG 10 induces a molten globule conformation in Mb by interacting with its heme group. They conclude that protein-crowder interactions need careful
Histone modifications like methylation, phosphorylation, and acetylation are important epigenetic mechanisms that regulate gene expression. Histone methylation can result in activation or repression and involves histone lysine and arginine methyltransferases. Histone phosphorylation occurs on specific serine and threonine residues by histone kinases. Histone acetylation is mediated by histone acetyltransferases and deacetylases and favors transcriptional activation by reducing the interaction between histones and DNA.
Proteins fold into complex 3D structures essential for their function. There are four levels of protein structure - primary, secondary, tertiary, and quaternary. Chaperone proteins help other proteins fold correctly to prevent aggregation. Misfolded proteins can result from changes in temperature, pH, or lack of chaperones and may lead to disease if not degraded. Normally, misfolded proteins are targeted for degradation by the ubiquitin proteasome pathway, but accumulation of misfolded proteins can cause conditions like Alzheimer's disease.
Effect of DX and Phosphorylation of Gal3-Binding Partner Interactions Draft 08Matthew Rotondi
This document summarizes research examining how covalent modification and phosphorylation of galectin-3 affects its binding to various protein partners. The researchers found that modification of galectin-3 by DX-52-1, a cell-permanent inhibitor, reduced binding to some proteins but not others. Phosphorylation of galectin-3 at two sites also reduced binding to all proteins tested. DX-52-1 further decreased binding of modified galectin-3 to two proteins. The results suggest galectin-3 interacts differently with binding partners and that modification and phosphorylation impact these interactions in partner-specific ways.
Gene silencing can occur through histone modifications that create heterochromatin, making DNA inaccessible for transcription. Histone acetylation and methylation correlate with transcriptional activity. Acetylation reduces the affinity of histone tails for nucleosomes, affecting chromatin structure. Methylation recruits silencing proteins that bind methylated histones. In yeast, silencing involves deacetylation and methylation mediated by SIR proteins. DNA methylation can recruit histone deacetylases and methylases to modify nucleosomes and switch off gene expression in mammals. Epigenetic modifications are inherited as they recruit enzymes to propagate the same modifications to daughter chromosomes.
The document discusses the structure of hemoglobin and how its structure allows it to effectively transport oxygen throughout the body. It details that hemoglobin is a tetrameric protein containing heme groups that bind oxygen. The intersections of the protein's alpha helices form binding sites for oxygen molecules. There are three main types of hemoglobin that have similar structures but can be modified through bonding with other molecules or under certain conditions, altering their oxygen affinity. The structure of hemoglobin plays a crucial role in its function as an oxygen carrier in the blood.
Characterization of mg state of mb in presence of peg 10 (z a parray) originalZahoor Parray
This document summarizes a study that characterized the intermediate state of myoglobin (Mb) in the presence of polyethylene glycol 10 (PEG 10) under physiological conditions. The researchers found that PEG 10 perturbed the tertiary structure of Mb but did not significantly change its secondary structure. PEG 10 was found to induce a molten globule state in Mb, where the intermediate state had hydrophobic patches and a larger hydrodynamic volume than the native protein. Isothermal titration calorimetry showed strong binding between Mb and PEG 10 at physiological pH. The researchers hypothesize that PEG 10 induces a molten globule conformation in Mb by interacting with its heme group. They conclude that protein-crowder interactions need careful
Histone modifications like methylation, phosphorylation, and acetylation are important epigenetic mechanisms that regulate gene expression. Histone methylation can result in activation or repression and involves histone lysine and arginine methyltransferases. Histone phosphorylation occurs on specific serine and threonine residues by histone kinases. Histone acetylation is mediated by histone acetyltransferases and deacetylases and favors transcriptional activation by reducing the interaction between histones and DNA.
Proteins fold into complex 3D structures essential for their function. There are four levels of protein structure - primary, secondary, tertiary, and quaternary. Chaperone proteins help other proteins fold correctly to prevent aggregation. Misfolded proteins can result from changes in temperature, pH, or lack of chaperones and may lead to disease if not degraded. Normally, misfolded proteins are targeted for degradation by the ubiquitin proteasome pathway, but accumulation of misfolded proteins can cause conditions like Alzheimer's disease.
Effect of DX and Phosphorylation of Gal3-Binding Partner Interactions Draft 08Matthew Rotondi
This document summarizes research examining how covalent modification and phosphorylation of galectin-3 affects its binding to various protein partners. The researchers found that modification of galectin-3 by DX-52-1, a cell-permanent inhibitor, reduced binding to some proteins but not others. Phosphorylation of galectin-3 at two sites also reduced binding to all proteins tested. DX-52-1 further decreased binding of modified galectin-3 to two proteins. The results suggest galectin-3 interacts differently with binding partners and that modification and phosphorylation impact these interactions in partner-specific ways.
Gene silencing can occur through histone modifications that create heterochromatin, making DNA inaccessible for transcription. Histone acetylation and methylation correlate with transcriptional activity. Acetylation reduces the affinity of histone tails for nucleosomes, affecting chromatin structure. Methylation recruits silencing proteins that bind methylated histones. In yeast, silencing involves deacetylation and methylation mediated by SIR proteins. DNA methylation can recruit histone deacetylases and methylases to modify nucleosomes and switch off gene expression in mammals. Epigenetic modifications are inherited as they recruit enzymes to propagate the same modifications to daughter chromosomes.
The document discusses the structure of hemoglobin and how its structure allows it to effectively transport oxygen throughout the body. It details that hemoglobin is a tetrameric protein containing heme groups that bind oxygen. The intersections of the protein's alpha helices form binding sites for oxygen molecules. There are three main types of hemoglobin that have similar structures but can be modified through bonding with other molecules or under certain conditions, altering their oxygen affinity. The structure of hemoglobin plays a crucial role in its function as an oxygen carrier in the blood.
Brief introduction of post-translational modifications (PTMs)Creative Proteomics
PTMs are chemical alterations to protein structure, typically catalyzed by exceedingly substrate-specific enzymes, which themselves are under strict control by PTMs. They generate a large diversity of gene products because many types of PTMs are covalently attached to amino-acid residues in each protein. For protein post-translational modification analysis at Creative Proteomics, please visit https://www.creative-proteomics.com/services/protein-post-translational-modification-analysis.htm
This document discusses protein folding and aggregation. It describes the primary, secondary, tertiary, and quaternary structures of proteins. Protein folding is guided by amino acid sequence and cellular environment. Misfolding can occur and result in non-native protein conformations. This leads to protein aggregation and the formation of amyloid fibrils or inclusion bodies. Protein aggregation is associated with neurodegenerative diseases like Alzheimer's and Parkinson's. Factors like sequence, environment, concentration, pH, and temperature can affect protein aggregation. Understanding protein aggregation may help develop therapies for related diseases.
This document contains summaries of several scientific papers and studies related to structural determination of proteins and cellular characterization:
1) Three papers studied the 3-D structure of the 16S half proteasome from Archaeoglobus Fulgidus and conformational changes during its assembly, as well as the subunit arrangement in hexameric HRS.
2) A study characterized the role of lipids in the assembly of membrane proteins and organization of protein supercomplexes, and implications for lipid-linked disorders.
3) A paper examined the modulation of myocardial mitochondrial mechanisms during severe polymicrobial sepsis in rats.
4) The document also mentions analyzing wild type and mutant ultra-structures as well as cell characterization by scanning electron microscopy
The document discusses epigenetics, which refers to changes in gene expression that do not involve changes to DNA sequence. It describes several epigenetic mechanisms including DNA methylation and histone modifications. Epigenetic changes play a role in diseases like cancer, where aberrant patterns of DNA methylation and histone acetylation are common. Emerging therapies target epigenetic processes by inhibiting DNA methylation or histone-modifying enzymes. These therapies aim to reverse epigenetic changes and reactivate genes silenced in cancer.
The native state of α1-antitrypsin (α1AT) is considered a kinetically trapped folding intermediate. To probe the structural changes that allow α1AT to overcome this kinetic barrier and form a stable complex during protease inhibition, the authors used hydrogen-deuterium exchange coupled with mass spectrometry (H/D-EX MS) to analyze α1AT in its native, complexing, and complexed states. They found that during complex formation, substantial unfolding occurred in regions of α1AT beyond those predicted from previous studies, including the N terminus, helix A, and strands of β-sheet B. This transient unfolding may provide the energy needed to cross the transition state and allow the reactive site
1) Loss of the kinase NEK1 in mice leads to abnormal retention of the cohesin component SMC3 on chromosome arms during meiotic prophase I.
2) Mass spectrometry analysis found that WAPL, a protein involved in cohesin removal, has abnormal elevated phosphorylation at a specific residue in NEK1-deficient mice.
3) This suggests NEK1 may regulate WAPL and cohesin removal during meiosis, though not directly as its loss leads to increased rather than decreased WAPL phosphorylation. NEK1 likely acts through another protein to phosphorylate or dephosphorylate WAPL.
Tau is a microtubule-associated protein that stabilizes microtubules. In Alzheimer's disease, tau undergoes abnormal phosphorylation and forms neurofibrillary tangles in the brain. Tau has multiple isoforms and phosphorylation sites that regulate its ability to bind to microtubules. Mutations in tau can promote its dysfunction and aggregation into fibers, potentially contributing to neurodegeneration in Alzheimer's disease.
The document describes cloning, expressing, and purifying a glutathione S-transferase (GST) from Pseudomonas putida KT2440 and investigating its potential role in iron metal bioremediation. Key findings include:
- The GST gene (PP_2933) was cloned, expressed producing a 31kDa protein, and purified using ion exchange chromatography.
- The purified GST showed activity with certain substrates, including ethacrynic acid and cumene peroxide, indicating a role in oxidative stress response.
- Cells expressing the recombinant GST showed increased resistance to iron, suggesting it may bind iron complexes and aid in bioremediation of iron toxicity.
Characterising the Interactome of EZH2 in Embryonic Stem Cells (3)Daire Murphy
This study aimed to characterize the interactome of Ezh2, the core catalytic subunit of the PRC2 complex, in embryonic stem cells using mass spectrometry. Ezh2 and PRC2 are important for maintaining pluripotency and regulating stem cell differentiation through epigenetic modifications. The experimental interactome was enriched for chromatin remodeling proteins and transcriptional regulators as expected, as well as splicing factors, which prompted further analysis. Characterizing the interaction between splicing factors and PRC2 could provide insight into how stem cell differentiation is controlled while maintaining stemness, and how aberrations can cause cancer. Mass spectrometry identified potential high-confidence Ezh2 interactors and bioinformatics analysis revealed the complexity of the Ezh2 interactome
Mass spectrometry (MS) is the suitable method for the analysis of protein modifications because it can provide universal information about protein modifications without a priori knowledge and locating the sites of modification.
If you are interested in our services, please visit: https://www.creative-proteomics.com/services/protein-post-translational-modification-analysis.htm
1) The study found that CaMKIIβ, but not CaMKIIα, mediated bundling of F-actin filaments in vitro and associated with the F-actin cytoskeleton within cells.
2) The inclusion of exon v1 in CaMKIIβ was required for its association with F-actin, whereas a variant lacking exon v1 (CaMKIIβe) failed to associate.
3) CaMKIIβ targeted to F-actin was able to phosphorylate actin even without Ca2+/CaM stimulation, whereas CaMKIIα did not show this ability.
presented by HAFIZ M WASEEM
university of education LAHORE Pakistan
i am from mailsi vehari and studied in lahore
bsc in science college multan
msc from lahore
The document discusses proteins and molecular chaperones. It summarizes recent research showing that a human protein called Brichos can inhibit the aggregation of amyloid-beta peptides associated with Alzheimer's disease in mice. While promising for inhibiting the onset of Alzheimer's, Brichos would be difficult to convert into an effective drug. The document also discusses concerns about the consumption of protein powders, noting they can negatively impact kidney function if consumed in large amounts long-term. Molecular chaperones are involved in many diseases and represent potential pharmacological targets, while proteins are also useful for medical diagnosis and technological advancements like organ preservation.
A physical process by which a polypeptide chain (sequence of amino acids) folds into its characteristic & functional native structure from a random coil or a linear sequence.
post translational modifications of proteinAnandhan Ctry
Post-translational modifications (PTMs) are chemical modifications of proteins that occur after translation. PTMs play a key role in regulating protein function by modifying activity, localization, and interactions. The main types of PTMs discussed are phosphorylation, glycosylation, ubiquitination, S-nitrosylation, methylation, N-acetylation, lipidation, and proteolysis. These modifications are identified through techniques like mass spectrometry, HPLC, radioactive labeling, and gel electrophoresis. PTMs are important for processes like cell signaling, growth, and apoptosis.
This document discusses post-translational modifications and quality control mechanisms. It covers several topics: 1) Purposes of post-translational modifications like quality control, protein function, and localization. 2) Quality control mechanisms in the cytoplasm and endoplasmic reticulum, including molecular chaperones. 3) Selective post-translational proteolysis via ubiquitination and the proteasome system for degradation of misfolded proteins. The document provides details on these various post-translational modification processes.
This document summarizes Federica Campana's doctoral thesis on investigating drug-cell membrane interactions using molecular dynamics simulations. The thesis examines how membrane composition influences the effects of membrane fluidizers and heat shock protein co-inducers. It also analyzes the binding of anti-inflammatory molecules like hydroxyarachidonic acid to cyclooxygenase enzymes. The overall goal is to better understand how drug molecules interact with and modulate lipid bilayer properties at a molecular level.
Direct Involvement of Retinoblastoma Family Proteins in DNA Repair by Non-hom...Maciej Luczynski
This document reports that the retinoblastoma tumor suppressor protein (RB1) directly supports DNA double-strand break repair via non-homologous end-joining (NHEJ). The study finds that RB1 associates with Ku70 and Ku80, which are core components of the NHEJ repair machinery. Loss of RB family proteins reduces NHEJ activity and increases chromosomal abnormalities. Support of NHEJ involves RB1's amino-terminal domain and does not require its cell cycle regulatory function. Cancer-associated RB1 variants that cannot interact with Ku70/Ku80 are unable to support NHEJ. The findings identify RB1 loss as a potential driver of genomic instability in cancer.
1) Hemoglobin research has been foundational to the development of molecular medicine over the last century. Studies of hemoglobin structure and function have contributed greatly to understanding human physiology and disease at the molecular level.
2) Hemoglobin transports oxygen through reversible binding to iron atoms in its heme groups. Recent research has also explored its interactions with other gases like nitric oxide (NO) that play important biological roles.
3) Continued study of hemoglobin seeks to further elucidate its molecular functions and implications for understanding related diseases, with the goal of developing new clinical applications and treatments. Research on hemoglobin has implications for molecular medicine broadly.
Karya tulis ilmiah ini membahas asuhan keperawatan yang diberikan kepada pasien bernama TN. S yang dirawat di ruang perawatan penyakit dalam rumah sakit TK. II Dustira Cimahi dari tanggal 10-14 Juli 2014 akibat gangguan sistem pencernaan dari hepatitis A. Tulisan ini disusun oleh Faizal Dwi Wibowo untuk memenuhi salah satu syarat program Diploma III Keperawatan di Akademi Keperawatan Rumah Sakit Dustira C
Brief introduction of post-translational modifications (PTMs)Creative Proteomics
PTMs are chemical alterations to protein structure, typically catalyzed by exceedingly substrate-specific enzymes, which themselves are under strict control by PTMs. They generate a large diversity of gene products because many types of PTMs are covalently attached to amino-acid residues in each protein. For protein post-translational modification analysis at Creative Proteomics, please visit https://www.creative-proteomics.com/services/protein-post-translational-modification-analysis.htm
This document discusses protein folding and aggregation. It describes the primary, secondary, tertiary, and quaternary structures of proteins. Protein folding is guided by amino acid sequence and cellular environment. Misfolding can occur and result in non-native protein conformations. This leads to protein aggregation and the formation of amyloid fibrils or inclusion bodies. Protein aggregation is associated with neurodegenerative diseases like Alzheimer's and Parkinson's. Factors like sequence, environment, concentration, pH, and temperature can affect protein aggregation. Understanding protein aggregation may help develop therapies for related diseases.
This document contains summaries of several scientific papers and studies related to structural determination of proteins and cellular characterization:
1) Three papers studied the 3-D structure of the 16S half proteasome from Archaeoglobus Fulgidus and conformational changes during its assembly, as well as the subunit arrangement in hexameric HRS.
2) A study characterized the role of lipids in the assembly of membrane proteins and organization of protein supercomplexes, and implications for lipid-linked disorders.
3) A paper examined the modulation of myocardial mitochondrial mechanisms during severe polymicrobial sepsis in rats.
4) The document also mentions analyzing wild type and mutant ultra-structures as well as cell characterization by scanning electron microscopy
The document discusses epigenetics, which refers to changes in gene expression that do not involve changes to DNA sequence. It describes several epigenetic mechanisms including DNA methylation and histone modifications. Epigenetic changes play a role in diseases like cancer, where aberrant patterns of DNA methylation and histone acetylation are common. Emerging therapies target epigenetic processes by inhibiting DNA methylation or histone-modifying enzymes. These therapies aim to reverse epigenetic changes and reactivate genes silenced in cancer.
The native state of α1-antitrypsin (α1AT) is considered a kinetically trapped folding intermediate. To probe the structural changes that allow α1AT to overcome this kinetic barrier and form a stable complex during protease inhibition, the authors used hydrogen-deuterium exchange coupled with mass spectrometry (H/D-EX MS) to analyze α1AT in its native, complexing, and complexed states. They found that during complex formation, substantial unfolding occurred in regions of α1AT beyond those predicted from previous studies, including the N terminus, helix A, and strands of β-sheet B. This transient unfolding may provide the energy needed to cross the transition state and allow the reactive site
1) Loss of the kinase NEK1 in mice leads to abnormal retention of the cohesin component SMC3 on chromosome arms during meiotic prophase I.
2) Mass spectrometry analysis found that WAPL, a protein involved in cohesin removal, has abnormal elevated phosphorylation at a specific residue in NEK1-deficient mice.
3) This suggests NEK1 may regulate WAPL and cohesin removal during meiosis, though not directly as its loss leads to increased rather than decreased WAPL phosphorylation. NEK1 likely acts through another protein to phosphorylate or dephosphorylate WAPL.
Tau is a microtubule-associated protein that stabilizes microtubules. In Alzheimer's disease, tau undergoes abnormal phosphorylation and forms neurofibrillary tangles in the brain. Tau has multiple isoforms and phosphorylation sites that regulate its ability to bind to microtubules. Mutations in tau can promote its dysfunction and aggregation into fibers, potentially contributing to neurodegeneration in Alzheimer's disease.
The document describes cloning, expressing, and purifying a glutathione S-transferase (GST) from Pseudomonas putida KT2440 and investigating its potential role in iron metal bioremediation. Key findings include:
- The GST gene (PP_2933) was cloned, expressed producing a 31kDa protein, and purified using ion exchange chromatography.
- The purified GST showed activity with certain substrates, including ethacrynic acid and cumene peroxide, indicating a role in oxidative stress response.
- Cells expressing the recombinant GST showed increased resistance to iron, suggesting it may bind iron complexes and aid in bioremediation of iron toxicity.
Characterising the Interactome of EZH2 in Embryonic Stem Cells (3)Daire Murphy
This study aimed to characterize the interactome of Ezh2, the core catalytic subunit of the PRC2 complex, in embryonic stem cells using mass spectrometry. Ezh2 and PRC2 are important for maintaining pluripotency and regulating stem cell differentiation through epigenetic modifications. The experimental interactome was enriched for chromatin remodeling proteins and transcriptional regulators as expected, as well as splicing factors, which prompted further analysis. Characterizing the interaction between splicing factors and PRC2 could provide insight into how stem cell differentiation is controlled while maintaining stemness, and how aberrations can cause cancer. Mass spectrometry identified potential high-confidence Ezh2 interactors and bioinformatics analysis revealed the complexity of the Ezh2 interactome
Mass spectrometry (MS) is the suitable method for the analysis of protein modifications because it can provide universal information about protein modifications without a priori knowledge and locating the sites of modification.
If you are interested in our services, please visit: https://www.creative-proteomics.com/services/protein-post-translational-modification-analysis.htm
1) The study found that CaMKIIβ, but not CaMKIIα, mediated bundling of F-actin filaments in vitro and associated with the F-actin cytoskeleton within cells.
2) The inclusion of exon v1 in CaMKIIβ was required for its association with F-actin, whereas a variant lacking exon v1 (CaMKIIβe) failed to associate.
3) CaMKIIβ targeted to F-actin was able to phosphorylate actin even without Ca2+/CaM stimulation, whereas CaMKIIα did not show this ability.
presented by HAFIZ M WASEEM
university of education LAHORE Pakistan
i am from mailsi vehari and studied in lahore
bsc in science college multan
msc from lahore
The document discusses proteins and molecular chaperones. It summarizes recent research showing that a human protein called Brichos can inhibit the aggregation of amyloid-beta peptides associated with Alzheimer's disease in mice. While promising for inhibiting the onset of Alzheimer's, Brichos would be difficult to convert into an effective drug. The document also discusses concerns about the consumption of protein powders, noting they can negatively impact kidney function if consumed in large amounts long-term. Molecular chaperones are involved in many diseases and represent potential pharmacological targets, while proteins are also useful for medical diagnosis and technological advancements like organ preservation.
A physical process by which a polypeptide chain (sequence of amino acids) folds into its characteristic & functional native structure from a random coil or a linear sequence.
post translational modifications of proteinAnandhan Ctry
Post-translational modifications (PTMs) are chemical modifications of proteins that occur after translation. PTMs play a key role in regulating protein function by modifying activity, localization, and interactions. The main types of PTMs discussed are phosphorylation, glycosylation, ubiquitination, S-nitrosylation, methylation, N-acetylation, lipidation, and proteolysis. These modifications are identified through techniques like mass spectrometry, HPLC, radioactive labeling, and gel electrophoresis. PTMs are important for processes like cell signaling, growth, and apoptosis.
This document discusses post-translational modifications and quality control mechanisms. It covers several topics: 1) Purposes of post-translational modifications like quality control, protein function, and localization. 2) Quality control mechanisms in the cytoplasm and endoplasmic reticulum, including molecular chaperones. 3) Selective post-translational proteolysis via ubiquitination and the proteasome system for degradation of misfolded proteins. The document provides details on these various post-translational modification processes.
This document summarizes Federica Campana's doctoral thesis on investigating drug-cell membrane interactions using molecular dynamics simulations. The thesis examines how membrane composition influences the effects of membrane fluidizers and heat shock protein co-inducers. It also analyzes the binding of anti-inflammatory molecules like hydroxyarachidonic acid to cyclooxygenase enzymes. The overall goal is to better understand how drug molecules interact with and modulate lipid bilayer properties at a molecular level.
Direct Involvement of Retinoblastoma Family Proteins in DNA Repair by Non-hom...Maciej Luczynski
This document reports that the retinoblastoma tumor suppressor protein (RB1) directly supports DNA double-strand break repair via non-homologous end-joining (NHEJ). The study finds that RB1 associates with Ku70 and Ku80, which are core components of the NHEJ repair machinery. Loss of RB family proteins reduces NHEJ activity and increases chromosomal abnormalities. Support of NHEJ involves RB1's amino-terminal domain and does not require its cell cycle regulatory function. Cancer-associated RB1 variants that cannot interact with Ku70/Ku80 are unable to support NHEJ. The findings identify RB1 loss as a potential driver of genomic instability in cancer.
1) Hemoglobin research has been foundational to the development of molecular medicine over the last century. Studies of hemoglobin structure and function have contributed greatly to understanding human physiology and disease at the molecular level.
2) Hemoglobin transports oxygen through reversible binding to iron atoms in its heme groups. Recent research has also explored its interactions with other gases like nitric oxide (NO) that play important biological roles.
3) Continued study of hemoglobin seeks to further elucidate its molecular functions and implications for understanding related diseases, with the goal of developing new clinical applications and treatments. Research on hemoglobin has implications for molecular medicine broadly.
Karya tulis ilmiah ini membahas asuhan keperawatan yang diberikan kepada pasien bernama TN. S yang dirawat di ruang perawatan penyakit dalam rumah sakit TK. II Dustira Cimahi dari tanggal 10-14 Juli 2014 akibat gangguan sistem pencernaan dari hepatitis A. Tulisan ini disusun oleh Faizal Dwi Wibowo untuk memenuhi salah satu syarat program Diploma III Keperawatan di Akademi Keperawatan Rumah Sakit Dustira C
El documento describe la información que debe proporcionar un Análisis de Puestos de Trabajo (APT) sobre una ocupación. El APT debe responder preguntas sobre los requisitos del puesto, las funciones y tareas del trabajador, el lugar y forma en que se realiza el trabajo, los recursos utilizados, y las características de la profesión.
El documento describe los conceptos clave de una prueba de hipótesis estadística, incluyendo la definición de hipótesis nula y alternativa, los tipos de errores, las regiones críticas y de aceptación, y los pasos para realizar una prueba de hipótesis sobre una media cuando la varianza es conocida o desconocida. También presenta un ejemplo numérico para ilustrar cómo aplicar estos conceptos para determinar si un fabricante de cereal debe ser multado basado en el peso promedio de las cajas de cereal.
El documento describe los métodos y materiales didácticos. Explica que el objetivo final del módulo es que el profesor pueda reconocer, seleccionar y aplicar los métodos y materiales más apropiados en función de los objetivos educativos. También describe diferentes clasificaciones de métodos didácticos tradicionales versus nuevos, enfocados en el profesor versus el estudiante, e individualizados versus de socialización. Finalmente, explica que la selección de métodos y materiales debe basarse en los objetivos planteados.
Este documento describe los elementos clave de la comunicación, incluyendo el emisor, receptor, mensaje, canal y contexto. La comunicación implica codificar un mensaje por parte del emisor, transmitirlo a través de un canal y luego decodificarlo por parte del receptor.
This document discusses developing an Information Management as a Service (IMaaS) framework. It notes that information management has fundamentally changed with the rise of mobile devices and cloud computing. The document recommends taking an iterative approach to building an IMaaS using principles from Kanban, including visualizing workflows, limiting work in process, focusing on continuous flow, and driving continuous improvement. The goal is to design an information platform that meets long-term business needs by integrating storage and service strategies across on-premise and cloud-based systems.
Ortega y Gasset propone que no existe un sujeto o cosa aislados, sino que todo está relacionado. La vida de cada persona es la "realidad radical" que da sentido al mundo, y cada uno tiene su propia perspectiva sin caer en el relativismo. La vida es un proyecto en constante cambio donde se debe elegir entre circunstancias para llevar una existencia auténtica. Pensamos en el tiempo y contexto histórico en que vivimos, y la sociedad transmite normas que comparten quienes pertenecen a una generación.
The document describes an activity where students stand in a circle and each pick two other student's numbers to follow while maintaining the same distance around the circle over several minutes. The purpose is to demonstrate how everyone has an impact and influence on others, whether positively or negatively, directly or indirectly.
Виталий Колосов — «Ключевые особенности работы по СРА в арабском регионе (на ...shevchuk_conf
1. Описание стран и отличия от СНГ.
2. Какие креативы стоит использовать в различных рекламных каналах.
3. Источники трафика для арабских стран.
4. Фишки, которые работают для местных.
5. Статистика по конверсиям и выплатам.
Александр Борняков — «Как заработать на видеорекламе в США», доклад на конфер...shevchuk_conf
Рынок интернет-видеорекламы в США растет с невероятной скоростью. Все больше топовых агентств перераспределяют бюджеты в сторону увеличения доли digital видеорекламы. Поиск трафика и максимально эффективное его использование является ежедневным вызовом всех игроков рынка. Но попасть на этот рынок, даже имея высококачественный трафик, не так то просто. Александр расскажет, как устроен рынок видеорекламы в США и есть ли возможность стать частью этой монетизационной цепочки.
1. Рынок видеорекламы: основная структура и финансовые показатели.
2. Точки входа для паблишеров.
3. Верификация трафика – каким должен быть качественный паблишер.
4. Есть ли возможность стать частью американского рынка видеорекламы.
WebCamp 2016: Python. Левон Авакян: Архитектура мета игры Wargaming. Глобальн...WebCamp
В своем докладе я расскажу что такое Глобальная карта, как она устроена, какие технологии, архитектурыне решения, принципы и подходы используются. Как мы боремся с высокими нагрузками, с какими проблемами сталкиваемся, и как их решаем.
El documento presenta los diferentes tipos de evaluación en educación, incluyendo la evaluación formativa, continua, inicial, sumativa, entre otros. Explica que la evaluación formativa se realiza a lo largo de todo el proceso de aprendizaje y tiene una función de orientación, mientras que la evaluación sumativa se realiza al final para conocer los resultados obtenidos. También describe los objetivos y características de la evaluación en Formación Profesional Específica.
The four candles represent Peace, Faith, Love, and Hope. Peace, Faith, and Love's flames diminish and go out as they feel they are no longer needed. A child enters and sees the three candles unlit, beginning to cry. The fourth candle, Hope, says not to be afraid as long as it is still burning it can re-light the other candles. The child takes the candle of Hope and re-lights Peace, Faith, and Love. The message is that Hope should never go out and we can maintain Hope, Faith, Peace, and Love.
The document presents a hypothetical scenario where a person is driving a two-seater car on a stormy night and comes across a bus stop with three people waiting for help: an old lady who is dying, a doctor who previously saved the person's life, and a potential romantic partner. It questions which person the driver should give a ride to and cannot decide on the best option, before revealing a fourth option of giving the car keys to the doctor so they can drive the old lady to the hospital while the driver waits at the bus stop for their potential partner. The document ponders why no one thinks of this creative solution and suggests it may be because people are unwilling to give up any advantages they hold.
Plano de aula prosa e poesia (4° bimestre) JH COSTA
O documento resume um plano de aula sobre poesia, prosa e poesia. Inclui uma introdução aos conceitos, atividades como um sarau sobre poesia e um documentário e debate sobre prosa, e avaliações baseadas na participação dos alunos.
Rhian was born and raised in Omaha, Nebraska and earned her Bachelor's of Science in Nursing from Here. She worked as an oncology and intensive care charge nurse for 2 years before receiving an opportunity to work at Marquette Michigan, where she currently lives and works helping to mold young minds. In her spare time, Rhian pursues her dreams of earning her Doctorate of Nursing Practice and becoming a nurse practitioner, and in May 2014 she will graduate with a degree in Community Health Education, moving closer to her dreams one step at a time.
Event insurance is often overlooked upon planning things such as weddings or corporate conferences. However, it's very important as it protects you from liabilities and unforeseen mishaps. Here is the ultimate guide to event insurance from Unique Venues!
The story is about a young girl named Tsiliki who lives in a small village in Greece. One day, Tsiliki decides to go into the forest near her village to pick berries. While in the forest, she gets lost and cannot find her way back home before nightfall. She spends the night alone in the forest, scared but trying to stay brave. The next morning, some villagers find Tsiliki and lead her safely back home.
This document summarizes a study investigating the role of Set1-mediated histone H3 lysine 4 (H3K4) methylation in Saccharomyces cerevisiae survival under histidine starvation conditions. The study found that mono-methylation of H3K4 by Set1 is advantageous for optimal growth under these stressful conditions. New Set1 mutant strains, including ones capable of only mono-methylation or hyper methylation, were constructed to further examine the role of H3K4 methylation levels.
Chromatin organization involves multiple levels of DNA packaging within the cell nucleus. The basic repeating unit is the nucleosome, which consists of 146bp of DNA wrapped around an octamer of histone proteins. Nucleosomes further compact into higher order structures like the 30nm fiber. Chromatin remodeling and epigenetic modifications like DNA methylation, histone acetylation and methylation regulate gene expression by altering chromatin structure and accessibility. These heritable changes in gene expression do not involve alterations to the underlying DNA sequence.
Mugdha Rangnath's seminar topic is on epigenetics. The document defines epigenetics as heritable changes in gene expression that do not involve changes to DNA sequence. It discusses several epigenetic mechanisms including DNA methylation, histone modifications, and non-coding RNA pathways. DNA methylation involves adding methyl groups to cytosine bases and can lead to gene silencing or activation. Histone modifications like acetylation and methylation can increase or decrease gene expression. Non-coding RNAs like miRNAs regulate genes by binding to mRNA. These epigenetic changes influence gene expression and cellular differentiation.
1. Chromatin remodeling complexes use ATP hydrolysis to modify nucleosome structure and expose DNA for gene expression. The main classes are ATP-independent complexes and ATP-dependent complexes like ISWI and SWI/SNF.
2. Post-translational modifications of histone tails like acetylation, methylation, and phosphorylation can affect chromatin structure and transcription by altering DNA-histone interactions.
3. Chromatin remodeling is important for differential gene expression in specialized cell types and controlling DNA accessibility for transcription.
This document summarizes recent efforts to design small molecule epigenetic modulators that target histone acetyltransferases (HATs), histone deacetylases (HDACs), and histone methyltransferases. It describes the roles of HATs, HDACs, and histone methyltransferases in controlling gene expression through histone and DNA modifications. A handful of HAT inhibitors have been identified, including bisubstrate analogs, natural products, and synthetic small molecules. Inhibitors of HDACs and DNA methyltransferases are more established as epigenetic modulators in cancer treatment. The development of small molecule inhibitors targeting the various writers, erasers, and readers of epigenetic marks offers promise
1) The study found that OPA1, a protein responsible for mitochondrial inner membrane fusion and cristae structure, dynamically regulates cristae structure in response to changes in cellular energetic conditions.
2) When cells were starved of nutrients, cristae narrowed and OPA1 oligomerized, and these changes were rapidly reversible upon refeeding.
3) Isolated mitochondria also showed a decrease in OPA1 oligomerization and widened cristae when incubated with substrates that fuel the electron transport chain, indicating OPA1 directly senses energy substrate availability.
4) The changes in OPA1 and cristae structure were independent of mitochondrial fusion and were essential for cell survival, respiration, and
N-terminal tails of histones are the most accessible regions for modifications. These post-translational modification (PTM) of histones is a crucial step in epigenetic regulation of a gene.
The document discusses epigenetics and chromatin structure. It defines epigenetics as heritable changes in gene expression that do not involve changes to the underlying DNA sequence. This includes histone modifications and DNA methylation. It describes chromatin as being made up of nucleosomes, which consist of DNA wrapped around histone octamers. The structure of chromatin affects gene expression, with euchromatin typically being gene-rich and actively transcribed, while heterochromatin is gene-poor and transcriptionally silent. Histone modifications like acetylation and methylation also influence gene expression. DNA methylation typically silences genes and occurs most frequently at CpG islands. These epigenetic changes play important roles in development and diseases like
This document summarizes recent research on the role of epigenetic regulation in human cancers. It discusses how epigenetic mechanisms like DNA methylation and histone modifications can disrupt gene expression and lead to tumorigenesis. Specifically, it describes how hypermethylation of CpG islands can silence tumor suppressor genes, and how certain histone modifications are associated with transcriptional activation or repression. The document also reviews emerging epigenetic therapies and challenges in the field, such as a lack of predictive biomarkers and unclear mechanisms of response/resistance.
Chromatin remodeling involves modifying chromatin structure through two main classes of protein complexes: covalent histone-modifying complexes and ATP-dependent chromatin remodeling complexes. Covalent histone-modifying complexes catalyze addition or removal of elements like acetyl groups on histone tails, loosening or tightening DNA binding. ATP-dependent complexes use energy from ATP hydrolysis to move, eject, or restructure nucleosomes, exposing DNA for transcription. Chromatin remodeling plays a central role in gene expression regulation by providing dynamic access to the packaged genome.
This document summarizes different types of histone modifications. It discusses that histones help condense DNA into chromatin and are subject to post-translational modifications like acetylation, methylation, phosphorylation, ubiquitination, sumoylation, and ADP-ribosylation. These modifications affect gene expression by changing chromatin structure and recruiting other proteins. For example, acetylation loosens chromatin and methylation can either activate or repress genes depending on the amino acid modified. The document provides examples of different histone modifiers and the effects of various histone modifications.
EngenuitySC's Science Cafe - March with Dr. Patrick WosterEngenuitySC
This document discusses epigenetic modulation through inhibition of histone demethylases like LSD1. It summarizes that:
1) Polyamino(bis)guanidines and polyaminobiguanides can inhibit the histone demethylase LSD1 in vitro and in human colon cancer cells.
2) These inhibitors are non-competitive inhibitors of LSD1 and promote increased histone H3 lysine 4 dimethylation.
3) One inhibitor, verlindamycin (compound 2d), re-expresses tumor suppressor genes silenced in cancer cells and reduces tumor growth in mouse models of human colon cancer, especially in combination with 5-azacytidine.
Epigenetics involves changes in gene expression that do not involve changes to the underlying DNA sequence. Examples of epigenetics include histone modifications and DNA methylation, which regulate gene expression through alterations to chromatin structure. Histone methylation involves the addition of methyl groups to histone tails by methyltransferases and regulates gene expression by promoting or blocking the binding of transcription factors. While histone methylation does not change charge or nucleosome interactions, it creates binding sites that regulate chromatin condensation and mobility to control gene expression.
Epigenetics is the study of alterations in gene expression that occur without changes to the underlying DNA sequence. Some key mechanisms of epigenetics include DNA methylation, histone modifications, and microRNAs. DNA methylation involves the addition of methyl groups to cytosine bases and typically inhibits gene transcription. Histone modifications like acetylation and deacetylation alter chromatin structure and gene accessibility. MicroRNAs regulate gene expression through RNA interference. Epigenetic factors can be influenced by environmental exposures and differ even between identical twins, helping to explain phenotypic differences. Epigenetics also provides insights into disease development and may be modulated by nutrients.
Types of histones, histone modifications and their effectsAnuKiruthika
The document discusses histones and histone modifications. It states that histones are basic proteins that package DNA into nucleosomes, and that there are two main classes of histones - core histones and linker histones. It then describes the major types of histone modifications including acetylation, methylation, and phosphorylation, and how these modifications can impact chromatin structure and gene expression by making the chromatin more open and accessible or more condensed. Specifically, it notes that acetylation generally activates gene expression by relaxing chromatin, while methylation and phosphorylation can either activate or repress genes depending on the site of modification.
This document describes two missense mutations found in the homeodomain of the HOXD13 gene that are associated with distinctive limb phenotypes involving brachydactyly. The mutations, Ser308Cys and Ile314Leu, were identified through screening patients with congenital limb abnormalities. In vitro studies found the Ile314Leu mutation exhibited both increased and decreased binding affinity to different DNA targets, possibly due to changes in amino acid side chain interactions. The mutations were found to cause overlapping features of brachydactyly types D and E.
Epigenetics- Transcription regulation of gene expressionakash mahadev
This document provides information about epigenetics and histone modifications. It defines epigenetics as heritable changes in gene function that do not involve changes to the underlying DNA sequence. It discusses how histone modifications such as acetylation and methylation regulate gene expression by altering chromatin structure and recruiting other proteins. DNA methylation is also described as an important epigenetic modification that typically represses transcription. Several families of enzymes that establish these modifications, such as DNA methyltransferases and histone methyltransferases/acetyltransferases, are outlined.
Epigenetics mediated gene regulation in plantsSachin Ekatpure
Epigenetics mediated gene regulation in plants describes how epigenetic mechanisms like DNA methylation and histone modification can regulate gene expression without changing the underlying DNA sequence. The document discusses various epigenetic mechanisms in plants including DNA methylation, histone modifications, and RNA interference. It also outlines applications of epigenetics like improving plant stress tolerance and yield as well as evolutionary studies.
This document summarizes the effects of environmental chemical exposures on epigenetics and disease. It finds that environmental pollutants like air pollution and chemicals like arsenic and aluminum can cause epigenetic changes including DNA methylation, histone modifications, and microRNA expression. These epigenetic alterations have been linked to various diseases. The document provides a table listing specific epigenetic changes found for different environmental chemicals and the diseases studied. It concludes that while many reports link environmental exposures to epigenetic changes, most have not been directly associated with disease outcomes, and more research is still needed.
Epigenetic regulation of rice flowering and reproductionRoshan Parihar
This document summarizes a doctoral seminar on epigenetic regulation of rice flowering reproduction. It begins by defining epigenetics and epigenomics. It then discusses various epigenetic modifications in rice including DNA methylation/demethylation, histone methylation/demethylation, polycomb silencing, histone acetylation, and the role of small/long non-coding RNAs. It outlines key genes involved in these modifications and their functions. The document reviews the regulation of chromatin modifications in rice and describes networks of genetic and epigenetic control of rice flowering under different photoperiod conditions. Finally, it presents a schematic of rice reproduction structures and lists chromatin modifier genes playing roles in floral organogenesis,
Similar to Histone demethylase and it srole in cell biology review (20)
Whitepaper developed with Pharma Exec magazine on how EIM- Enterprise Information Management- can provide efficiency and kick start innovation by ensuring information flows correctly inside- and outside- the company
Healthcare products suffer from a lack of ability to control documents and non-clinical images. OpenText ApplicationXtender can solve that problem for vendors through our OEM program. This whitepaper goes through the benefits of embedding ApplicationXtender into healthcare products.
OpenText ApplicationXtender provides cost effective document management. For software vendors looking to expand or build a healthcare focused product, "AX" can be embedded to provide first class content services in without the high cost of research and development.
Automating Patient Management with ApplicationXtender WorkflowChristopher Wynder
The hardest part about managing a clinic is keeping everybody up-to-date with the right information. Whether this is simply making sure billing is alerted of a new bill or as complex as managing follow-ups after a referral. There is simply too many documents, emails and schedules for a person to manage. This is the value of workflow to a clinic or hospital- setting the rules regarding who gets to see certain types of documents and ensuring that know about the updated information.
This document discusses preparing healthcare organizations for a digital future. It explains that electronic health records and digital health information systems can improve patient care by giving providers a comprehensive digital view of a patient's health history. However, digital transformation requires new tools to securely manage both structured data and unstructured information like medical images. The document recommends that healthcare organizations implement an enterprise content management system to collect, manage, and act as a repository for both structured and unstructured patient information across departments. This will help improve efficiency, collaboration, and regulatory compliance while reducing costs.
This deck goes through the Information conundrum and how ApplicationXtender is positioned to provide the technical platform for organizations to start moving from paper to a digital future
ThinkDox talk from ECNO 2017 on using Laserfiche to manage student records and student information. We use the examples of Field trip forms and student record search to highlight the potential administrative efficiencies that can be gained.
Information Management aaS AIIM First Canadian presentationChristopher Wynder
High level talk given at AIIM Canada's breakfast event March 23, 2017.
The talk goes through the challenges of information management in the era of BYOD and cloud services. The last part of the talk is how to start with a small but impactful project to show the value of IMaaS.
ThinkDox LLC provides an information management as a service (IMaaS) solution. The document discusses developing an information management strategy and framework for long term success by implementing a service oriented approach. It also covers topics like integrating storage strategies, understanding how users work with information, generating information lifecycle models, and ensuring solutions meet organizational needs.
ECNO 2016-Using ECM to gain administrative efficiency for school boardsChristopher Wynder
Presentation from ECNO 2016. The presentation centers on embedding records management into process management. We take a IT project centric view of how to move from chaos to manage-able information access points. A key concept is how ECM and EIM technologies provide opportunities for school boards to reduce their costs and risk.
1. The document discusses different types of electronic signatures and their legal validity, including email signatures, signatures on password-protected websites, signatures validated through third parties like social media accounts, and digital signatures.
2. It analyzes four scenarios representing the different signature types to determine their ability to meet legal requirements in Canada.
3. While digital signatures provide the highest assurance, the document concludes that other electronic signatures could also be legally valid depending on the specific use case and how well they meet criteria like uniquely identifying the signer.
The document discusses improving processes for updating student records at the end of the school year. It identifies three sub-processes: 1) records change approval, 2) records change workflow, and 3) records update capture. Each sub-process is occurring outside the existing systems and causing issues. The document recommends analyzing each sub-process, addressing why they happen outside the systems, and moving the entire process to a form-based approach within a single system to optimize the process.
We are often why use a VAR- what am I paying you for? This presentation goes through the basics of how we implement Laserfiche and provide continual support above and beyond basic technical support, we make sure you understand what is possible and support you as you maximize your investment.
Laserfiche10 highlights- how the new features can benefit your mobile and wor...Christopher Wynder
Laserfiche 10 brings a lot of additional features for information management, workflow building and mobile content access. This slide deck provides the overview of how Laserfiche 10 can benefit clients looking to automate their processes.
Integrating user needs into ECM projects is key to success. Whether it is a initial implementation or a reboot or just expanding use, user needs and UX testing should be integrated into every project
The document discusses several topics related to information management within government organizations. It begins by outlining the key considerations for a Canadian government RFI on cloud services, including policy, business, technical, procurement, pricing and security. It then discusses challenges of moving to the cloud and key capabilities needed for collaboration and content management. Several graphics show examples of infrastructure layouts, the variety of locations information can be stored, and the need to define user journeys to understand how people complete tasks. It emphasizes identifying "dangerous" user groups where compliance issues are most likely to occur to prioritize support and adoption of information management systems.
Moving records management from a paper based strategy to a electronic strategy requires re-thinking what needs to be protected and where the threats to security exist.
The key is to stop focusing on the artifact (the document) and focus on the information that is important. Documents are just the storage media to move the information from person to person.
The deliverable from a consulting engagement for a hospital. The hospital needed to define the requirements for a single EIM platform. This two-day clinic allowed them to identify key issues and requirements to reduce the time to move from idea to RFP. While ensuring the that process stayed focused on hospital goals rather than just technical ease and fastest implementation.
AMCTO presentation on moving from records managment to information managementChristopher Wynder
This presentation was given to AMCTO zones 1 and 4/5. It presents how to use the records classification as the core for a faceted classification schema that can be used to enable workflow and processes across the organization.
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.
Or: Beyond linear.
Abstract: Equivariant neural networks are neural networks that incorporate symmetries. The nonlinear activation functions in these networks result in interesting nonlinear equivariant maps between simple representations, and motivate the key player of this talk: piecewise linear representation theory.
Disclaimer: No one is perfect, so please mind that there might be mistakes and typos.
dtubbenhauer@gmail.com
Corrected slides: dtubbenhauer.com/talks.html
Phenomics assisted breeding in crop improvementIshaGoswami9
As the population is increasing and will reach about 9 billion upto 2050. Also due to climate change, it is difficult to meet the food requirement of such a large population. Facing the challenges presented by resource shortages, climate
change, and increasing global population, crop yield and quality need to be improved in a sustainable way over the coming decades. Genetic improvement by breeding is the best way to increase crop productivity. With the rapid progression of functional
genomics, an increasing number of crop genomes have been sequenced and dozens of genes influencing key agronomic traits have been identified. However, current genome sequence information has not been adequately exploited for understanding
the complex characteristics of multiple gene, owing to a lack of crop phenotypic data. Efficient, automatic, and accurate technologies and platforms that can capture phenotypic data that can
be linked to genomics information for crop improvement at all growth stages have become as important as genotyping. Thus,
high-throughput phenotyping has become the major bottleneck restricting crop breeding. Plant phenomics has been defined as the high-throughput, accurate acquisition and analysis of multi-dimensional phenotypes
during crop growing stages at the organism level, including the cell, tissue, organ, individual plant, plot, and field levels. With the rapid development of novel sensors, imaging technology,
and analysis methods, numerous infrastructure platforms have been developed for phenotyping.
hematic appreciation test is a psychological assessment tool used to measure an individual's appreciation and understanding of specific themes or topics. This test helps to evaluate an individual's ability to connect different ideas and concepts within a given theme, as well as their overall comprehension and interpretation skills. The results of the test can provide valuable insights into an individual's cognitive abilities, creativity, and critical thinking skills
When I was asked to give a companion lecture in support of ‘The Philosophy of Science’ (https://shorturl.at/4pUXz) I decided not to walk through the detail of the many methodologies in order of use. Instead, I chose to employ a long standing, and ongoing, scientific development as an exemplar. And so, I chose the ever evolving story of Thermodynamics as a scientific investigation at its best.
Conducted over a period of >200 years, Thermodynamics R&D, and application, benefitted from the highest levels of professionalism, collaboration, and technical thoroughness. New layers of application, methodology, and practice were made possible by the progressive advance of technology. In turn, this has seen measurement and modelling accuracy continually improved at a micro and macro level.
Perhaps most importantly, Thermodynamics rapidly became a primary tool in the advance of applied science/engineering/technology, spanning micro-tech, to aerospace and cosmology. I can think of no better a story to illustrate the breadth of scientific methodologies and applications at their best.
Remote Sensing and Computational, Evolutionary, Supercomputing, and Intellige...University of Maribor
Slides from talk:
Aleš Zamuda: Remote Sensing and Computational, Evolutionary, Supercomputing, and Intelligent Systems.
11th International Conference on Electrical, Electronics and Computer Engineering (IcETRAN), Niš, 3-6 June 2024
Inter-Society Networking Panel GRSS/MTT-S/CIS Panel Session: Promoting Connection and Cooperation
https://www.etran.rs/2024/en/home-english/
PPT on Direct Seeded Rice presented at the three-day 'Training and Validation Workshop on Modules of Climate Smart Agriculture (CSA) Technologies in South Asia' workshop on April 22, 2024.
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
Unlocking the mysteries of reproduction: Exploring fecundity and gonadosomati...AbdullaAlAsif1
The pygmy halfbeak Dermogenys colletei, is known for its viviparous nature, this presents an intriguing case of relatively low fecundity, raising questions about potential compensatory reproductive strategies employed by this species. Our study delves into the examination of fecundity and the Gonadosomatic Index (GSI) in the Pygmy Halfbeak, D. colletei (Meisner, 2001), an intriguing viviparous fish indigenous to Sarawak, Borneo. We hypothesize that the Pygmy halfbeak, D. colletei, may exhibit unique reproductive adaptations to offset its low fecundity, thus enhancing its survival and fitness. To address this, we conducted a comprehensive study utilizing 28 mature female specimens of D. colletei, carefully measuring fecundity and GSI to shed light on the reproductive adaptations of this species. Our findings reveal that D. colletei indeed exhibits low fecundity, with a mean of 16.76 ± 2.01, and a mean GSI of 12.83 ± 1.27, providing crucial insights into the reproductive mechanisms at play in this species. These results underscore the existence of unique reproductive strategies in D. colletei, enabling its adaptation and persistence in Borneo's diverse aquatic ecosystems, and call for further ecological research to elucidate these mechanisms. This study lends to a better understanding of viviparous fish in Borneo and contributes to the broader field of aquatic ecology, enhancing our knowledge of species adaptations to unique ecological challenges.
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.
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.
ESR spectroscopy in liquid food and beverages.pptxPRIYANKA PATEL
With increasing population, people need to rely on packaged food stuffs. Packaging of food materials requires the preservation of food. There are various methods for the treatment of food to preserve them and irradiation treatment of food is one of them. It is the most common and the most harmless method for the food preservation as it does not alter the necessary micronutrients of food materials. Although irradiated food doesn’t cause any harm to the human health but still the quality assessment of food is required to provide consumers with necessary information about the food. ESR spectroscopy is the most sophisticated way to investigate the quality of the food and the free radicals induced during the processing of the food. ESR spin trapping technique is useful for the detection of highly unstable radicals in the food. The antioxidant capability of liquid food and beverages in mainly performed by spin trapping technique.
ESR spectroscopy in liquid food and beverages.pptx
Histone demethylase and it srole in cell biology review
1. Histone demethylation enzymes and dynamic cell biology
Leanne Stalker and Christopher Wynder2
Introduction
In order to maintain structure and organization within the nucleus of a eukaryotic
cell, the large DNA macromolecule is structured in to chromosomes. To provide
an additional layer of organization, these chromosomes are wrapped around
protein complexes containing proteins known as histones to form the basic unit of
chromatin, the nucleosome (Kornberg, 1974; Kornberg & Lorch, 1999). Each
nucleosome is comprised of an octameric core containing two each of Histone
H2A, H2B, H3 and H4 around which 146bp of DNA is wound. This DNA is then
secured to the core by an additional histone, histone H1(Kornberg & Lorch, 1999;
Kouzarides, 2007; Sims et al, 2003; Volkel & Angrand, 2007). This DNA/protein
complex provides a mechanism by which to conform the large DNA molecule to
the confined space of the nucleus, allows protection from DNA damage during
cell division, and plays a pertinent role in transcriptional regulation(Kooistra &
Helin, 2012; Kouzarides, 2007). Each individual histone protein contains two
highly conserved protein domains including a large globular core and an amino
terminal tail that protrudes from both the histone individually and the nucleosomal
structure as a whole(Luger et al, 1997). From a gene regulation perspective,
these N-terminal tails represent an infinite ability for the nucleosomal structure to
become modified.
2. Histone tail modifications
Due to their availability outside of the core nucleosome, many amino acid
residues on histone tails are targets of extensive post transcriptional
modifications. These occur on specific amino acid residues and include
acetylations, phosphorylations, SUMOylations, ubiquitinations and methylations.
The result of the addition of these molecular groups is varied and depends highly
on both the specific amino acid modified and the modification itself (Kouzarides,
2007). The addition of these various groups tends to result in one of two
possible consequences. First, it may change the interaction between DNA and
the histone directly leading to an alteration of the chromatin structure as a whole.
This activity is observed mostly when a posttranscriptional modification, such as
an acetylation, alters the charge of an amino acid on the histone tail. Acetylation
of a lysine (K) residue acts to neutralize its basic charge. This loosens the
interaction between the histone and DNA, increasing the accessibility of the DNA
and generally resulting in transcriptional activation(Shogren-Knaak et al, 2006;
Workman & Kingston, 1998). Acetylation is the most extensively studied of the
post-transcriptional modifications and occurs most frequently on residues K9,
K14, K18 and K56 of Histone H3. The enzymes responsible for both the addition
of the acetyl group, Histone Aceytl Transferases (HATs) and the enzymes
responsible for the removal of the acetyl group, Histone Deacetylases (HDACs)
have been increasingly popular targets for drug discovery(Khan & Khan, 2010;
Kuo & Allis, 1998).
3. The second consequence of histone modification is the alteration of non-
histone protein recruitment to histone tails. For example, histone phosphorylating
enzymes MSK1/2 and RSK2 tend to target serine residues at H3S10.
Phosphorylation of this residue is found to attract the phospho-binding protein
14-3-3, which is thought to activate NFB-regulated genes(Banerjee &
Chakravarti, 2011; Kouzarides, 2007). Greater understanding of the role of
histone phosphorylation is yet to be determined. Ubiquitylation and SUMOylation
differ from the aforementioned mechanisms because they require the addition of
large moieties(Berger, 2007). The function of ubiquitylation remains unclear but
its mechanism of action is believed to either act to recruit supplementary proteins
to histone tails or physically “wedge” chromatin open due to its size. Functional
effects of ubiquitylation appear to vary depending on the residue to which the
moiety is added. For example, ubiquitylation of H2BK123 is associated with the
activation of transcription while ubiquitylation of H2AK119 by NSPc1 has been
found to cooperate with DNA methylation correlate with the transcriptional
silencing of Hox genes.(Wright et al, 2011; Wu et al, 2008). Conversely, the
result of sumoylation is believed to be mainly transcriptionally repressive(Nathan
et al, 2006).
Histone Methylation
Recently, much interest has been placed on the regulation of histone tail
methylation. Unlike the previously mentioned modifications, methylation can
occur on both lysine and arginine (R) residues on amino terminal histone
4. tails(Shilatifard, 2006; Sims et al, 2003). This modification has also been found to
be processive, suggesting that unlike acetylation, which is either present or
absent, methylation potentially allows for an increased ability to fine tune
regulation. An arginine can become mono or dimethylated, the latter of which can
be either symmetrical or asymmetrical. Whereas a lysine can be modified in a
mono- or di- and tri-methylated form, each of which has been found to have a
differing effect (Cloos et al, 2008; Santos-Rosa et al, 2002). Methylation does
not alter the charge of the histone tail. Therefore, this modification is not thought
to play a direct role in DNA/ histone interactions. Rather, methylation can result in
a modulation of chromatin structure, altering the accessibility to chromatin to
effector proteins, or may act as a recruitment signal for regulatory factors(Cloos
et al, 2008). This results in transcriptional alterations due to changes in the
chromatin landscape as a whole (Bannister et al, 2002; Lachner et al, 2001).
Histone methylations have been found to be associated with both transcriptional
activation and repression with methylation of K4 and K36 of H3 being generally
ascribed to gene activation, whereas association with K9 and K27 of the same
histone are generally thought to be involved with transcriptional
repression(Berger, 2007). The enzymes responsible, known as lysine
methyltransferases (HMTs) are unique in the sense that they are residue
specific. For instance, the Set1/COMPASS or MLL class of histone
methyltransferases are specific for the methylation (mono-, di-, and tri-) of H3K4,
while the Su(var)3-9 family is restricted to methylation of H3K9 (Kouzarides,
2007)
5. Demethylation of the histone tail
Historically, methylation was considered to be a mark of permanence.
Without the discovery of an enzyme class capable of the removal of methylation,
it was thought that these marks were static. The discovery of the enzyme KDM1a
(also known as LSD1, BHC110) in 2004, changed this notion. KDM1a was found
to have the ability to catalyze the demethylation of histone residues by a flavin
adenine dinucleotide (FAD)-dependent amine oxidase reaction. However, the
enzymology of this demethylase requires a protonated methyl -ammonium in its
substrate. This is absent in the trimethylated version of methylation, resulting in
the conclusion that this enzyme was restricted to mono and dimethylated
modifications(Shi et al, 2004). Since then a more novel, larger protein group
named the Jumonji (JMJC) domain family has been discovered. These enzymes
catalyze the removal of methylation marks utilizing a hydroxylation reaction
through their JMJC domain. This reaction no longer requires a protonated
methyl -ammonium, allowing for the demethylation of all three methyl states. In
several cases, the trimethylated version is actually the preferred
substrate(Christensen et al, 2007; Fodor et al, 2006; Klose et al, 2006; Tsukada
et al, 2006; Whetstine et al, 2006). Historically, F-Box and Leu-rich repeat protein
11 (FBXL11) was the first enzyme discovered in this class; it has demethylase
activity towards both the mono and dimethylated versions of H3K36 (Tsukada et
al, 2006).
6. To date, JMJC enzymes of this class have been found to be active on
H3K4(Iwase et al, 2007; Klose et al, 2007; Lee et al, 2007; Secombe &
Eisenman, 2007; Seward et al, 2007; Tahiliani et al, 2007; Yamane et al, 2007) ;
H3K9(Yamane et al, 2006), H3K27(Agger et al, 2007; De Santa et al, 2007; Lan
et al, 2007), H3K36(Fodor et al, 2006) and H4K20(Liu et al, 2010). This has led
to the current understanding that methylation represents an extremely flexible
and dynamic modification state resulting in the active modulation of transcription.
Though the JMJC class of demethylases as a whole is an expansive protein
family (the human genome encodes 30 different JMJC containing proteins, 18 of
which have been proven to show demethylase acitivity on both arginine and
lysine residues(Kooistra & Helin, 2012) phylogeny has suggested that within this
family there are several clusters of proteins which appear to group together in
both structure and function. The KDM5 family of demethylases, known to target
all three methylation states of H3K4, represents one such cluster(Cloos et al,
2008)
Specific function of the KDM5 family of HDM enzymes
The KDM5 family of JMJC demethylases includes four known members:
KDM5a, KDM5b, KDM5c and KDM5d (previously known as Jarid1a, Jarid1b,
Jarid1c and Jarid1d respectively). As seen in Figure 1; these demethylases are
highly conserved structurally and are characterized by the presence of five
protein domains:JmjN and JmjC domains required for demethylation activity a
7. BRIGHT/ARID domain for A/T DNA binding, and both a C5HC2-Zinc finger
domain and several PHD (plant homeobox domains) involved in the enzymes
ability to recognize and bind methylated residues and regulate protein-protein
interactions(Cloos et al, 2008). This review will concentrate on the known roles of
KDM5 proteins in transcriptional regulation, development and disease. For a
recent review encompassing all histone demethylases, please see Kooistra et
al.(Kooistra & Helin, 2012)
H3K4 methylation: a fine balancing act
The KDM5 family of histone demethylases act specifically on H3K4
methylation marks, with a preference for trimethylated H3K4 (H3K4me3). Studies
of H3K4 methylation and its biological roles have been vast and the majority of
studies report the presence of methylated H3K4 as a sign of transcriptional
activation(Barski et al, 2007; Pokholok et al, 2005; Schubeler et al, 2004);.
H3K4me3 localized to gene promoters allows for transcriptional activation by
binding a subunit of TFIID, which then leads to the formation of the initiation
complex(Sims et al, 2003; Vermeulen et al, 2007). Though both mono- and di-
methylated versions of H3K4 span further into the transcribed protein and have
even been found at enhancer elements(Heintzman et al, 2009; Robertson et al,
2008) H3K4me3 remains strongly conserved to the transcriptional start site
(TSS)(Cloos et al, 2008; Kooistra & Helin, 2012; Santos-Rosa et al, 2002). As
8. expected due to their conserved enzymatic targets, KDM5 demethylases have
been suggested as potent transcriptional repressors through their known ability
to remove this activating mark. Recent genome studies have suggested
however, that the presence of H3K4me3 at the transcriptional start site is not
sufficient to assume active transcription (Guenther et al, 2007). Within
embryonic stem cells (ESC) for example, a very high proportion of transcriptional
start sites possess marks of both transcriptionally active, and transcriptionally
silent chromatin. These sites are said to be bivalent and represent the ability of a
non-committed cell to be poised for commitment and development(Azuara et al,
2006; Bernstein et al, 2006). This phenomenon has also been observed lower
on the evolutionary scale, with C. elegans showing H3K4me3 and H3K27me3
co-occupying promoters early in development (Wang et al, 2011).This suggests
that modification of this methyl mark may represent an ability of the cell to tweak
transcription in one direction or the other, without requiring an absolute condition
of “On” or “Off”. Studies of both KDM5a and KDM5b have suggested that these
demethylases actually co-localize with their substrate, with target genes showing
expression of both the enzyme and H3K4me3(Lopez-Bigas et al, 2008; Schmitz
et al, 2011). Though expression of H3K4me3 was generally found to be lower at
sites of demethylase recruitment, the methylation mark was not completely
absent, suggesting that these enzymes function to maintain low levels of
H3K4me3 but not to abolish the mark completely. This also suggests that
recruitment of additional factors may be required for full demethylase activity of
9. the enzyme, or that the context of the protein complex in which the KDM5
demethylase is present may alter its enzymology.
Roles for KDM5 outside of the transcriptional start site
Additional groups have suggested a role for KDM5 family members in
intragenic regions of the genome. Liefe et al. suggest that KDM5a plays a role in
Notch-mediated silencing and that demethylation at specific regulator elements
rather than entire promoter TSS regions, is sufficient to result in gene
silencing(Liefke et al, 2010) where Xie et al. have also recently suggested that
KDM5b may play a role in intragenic transcription and elongation of KDM5b
target genes, though these results are currently under debate (Schmitz et al,
2011; Xie et al, 2011). This adds an additional layer of regulation, suggesting
that the accuracy of these enzymes for transcriptional regulation is most likely
extremely pertinent to sensitive biological functions within the cell, with potentially
significant impact on processes including development and differentiation, and
that even the smallest of perturbations could wholly or in part give rise to disease
or transformation.
H3K4me3 and Cellular Identity
Previous studies in D. melanogaster have shown that the KDM5
homologue Little Imaginal Disc (LID) is required for normal development to
10. proceed through the regulation of homeotic genes (Gildea et al, 2000)
Additionally, the homologue of KDM5 in C.elegans, rbr-2, has been found to be
both an active demethylase and to play a role in the normal development of the
nematode, dependent upon this enzymology (Christensen et al, 2007). Knock
down of rbr-2 was found to result in an increase in H3K4me3 expression and
resulted in a disruption to normal vulval development. Most recently, rbr-2 has
also been implicated in regulation over C.elegans lifespan (Greer et al, 2010).
As both flies and worms only possess one copy of the KDM5 homologue, there is
no chance for functional redundancy. Within higher eukaryotes however, the role
of these proteins in development becomes increasingly complex.
Roles for KDM5 in higher order organisms
Though higher order organisms possess four KDM5 family members, their
roles appear, in many cases, to be functionally distinct. Knock out studies of
KDM5c in a zebrafish model leads to impaired neuronal development. Similar
phenomena are observed in rats where dendritic development becomes
impaired(Iwase et al, 2007). This suggests that any functional redundancy
exhibited by KDM5 family members does not include the role of KDM5c in neural
development. This is of interest considering how similar KDM5c and KDM5d, in
specific, are, and reiterates the importance of target specificity and expression
profile differences between the four family members.
11. Knock out studies in mice continue to support functionally distinct roles for
these enzymes. Though viable and possessing only mild behavioural
abnormalities, KDM5a -/- mice have been found to have altered transcription of
several cytokine genes known to be KDM5a targets. This has been shown to
lead to aberrant hematology, altered cell cycle and a resistance to apoptosis of
hematopoietic cancers(Wang et al, 2009b). Knockout of KDM5b in mice
however, in contrast to family member KDM5a, has been reported to be
embryonic lethal around E4.5(Catchpole et al, 2011). This suggests that KDM5b
is required in early embryonic development and that this role cannot be taken
over by another KDM5 family member. This early functional importance of
KDM5b is somewhat to be expected due to differences in KDM5 family member
expression profiles. Where KDM5a appears to be widely expressed through all
tissues showing high expression in the haematopoetic system(Christensen et al,
2007; Cloos et al, 2008; Klose et al, 2007; Lopez-Bigas et al, 2008) KDM5c, an X
linked gene which escapes X linked inactivation(Wu et al, 1994a; Wu et al,
1994b) appears to have more limited expression, showing neuronal expression
patterns and playing a role in neuronal development (Iwase et al, 2007). KDM5b
shows a completely different profile, widely expressed in ESCs and
undifferentiated progenitors(Dey et al, 2008), but limited in adult tissues:
restricted to the testis and differentiating mammary gland(Barrett et al, 2002; Lu
et al, 1999). Of interest however, KDM5b is highly expressed in several forms of
cancer(Barrett et al, 2002; Barrett et al, 2007; Madsen et al, 2003; Roesch et al,
2006; Roesch et al, 2010; Xiang et al, 2007). Catchpole et al. additionally report
12. the creation of a KDM5b mouse strain containing a mutation in which the ARID
domain is removed. This mutation has previously been documented to
completely obliterate the demethylase activity of KDM5b(Tan et al, 2003;
Yamane et al, 2007) though Catchpole et al. suggest that some residual activity
is a possibility (Catchpole et al, 2011). Interestingly, though these mice display
what is referred to as a “mammary phenotype” they are both viable and fertile
suggesting that the role of KDM5b in embryonic development may not hinge
completely on its enzymology (Catchpole et al, 2011). To increase the
complexity of the KDM5b knockout story, Schmitz et al. have recently suggested
that they were successful in creating a KDM5b knock out mouse that is both
viable and fertile and suggest that compensation by other family members may
rescue the knockout phenotype previously described (Schmitz et al, 2011)
KDM5; master regulators of differentiation and development
Though KDM5 family knockout mice may remain viable, distinct and
numerous defects in differentiation and development are frequently noted. This is
suggestive of a protein family involved in the regulation of differentiation control.
In 2005, Benevolenskaya et al. found the first evidence of pRB-KDM5a
complexes in cells and determined that KDM5a was a key regulator of
differentiation control by demonstrating that pRB must displace KDM5a from key
promoters in order to promote differentiation (Benevolenskaya et al, 2005). This
work was completed previous to the knowledge of KDM5a enzymology. Further
13. study in ESC suggests that during differentation the removal of KDM5a from Hox
genes correlates with increased levels of H3K4me3 (Christensen et al, 2007),
consistent with its role in cellular differentation and development. Previous work
on KDM5b has found that this family member can also repress several target
genes important to differentiation including HOXA5(Yamane et al, 2007), Brain
Factor-1 (BF-1) and Pax9 (Tan et al, 2003).
Recently, work in our laboratory has suggested that KDM5b plays a role in
mouse embryonic stem cells (mESC) to maintain a population of uncommitted
progenitors. Overexpression of KDM5b in mESC was additionally found to impair
specification, and delay or destroy neural differentiation (Dey et al, 2008). More
recent studies have supported this work, suggesting that KDM5b is required for
neural differentiation, most specifically, the generation of neural progenitors
(NPC) from ESC (Schmitz et al, 2011). KDM5b was found to occupy
developmental regulator genes in ESC, and as seen previously (Dey et al, 2008)
plays a pertinent role in gene regulation in this cell type. Their findings however,
suggest that KDM5b is dispensable for the self-renewal capacity of ESC, but
absolutely required for differentiation. Of interest, the modulation of KDM protein
expression in most cell types results in no change in global H3K4me3 levels,
including neural stem cells (NSC) (Schmitz et al, 2011) and MCF7 (Yamane et al,
2007) after the knockdown of KDM5b; and MEFs after the knockdown of KDM5a
(Klose et al, 2007). This is however different in ESC where alteration to KDM5b
levels appears to have a direct effect on global H3K4me3 levels (Dey et al, 2008;
Schmitz et al, 2011). Genome wide chromatin studies have suggested that the
14. global levels of H3K4me3 decrease from the ESC stage over the course of
differentiation (Ang et al, 2011) with bivalency being removed through
demethylation of H3K4me3 positive promoters (Bernstein et al, 2006).
H3K27me3 expression however, appears to remain present. This suggests that
the presence of H3K4me3 may be required for early development, although its
removal may also represent a required checkpoint for certain stages of
differentiation. This selective removal of H3K4me3 seems to be required for
appropriate cell fate determination to occur.
Studies in C. elegans demonstrate that the appearance of H3K4me3 is both
regulated according to cell lineage and that the deposit of this tri-methylation is
extremely dynamic (Wang et al, 2011) lending credence to the theory that both
the presence and absence of this mark may represent significant methods of
gene regulation during development. Interestingly, recent studies categorizing
the role of H3K4 methylation in fully differentiated cells such as the
cardiomyocyte adds to this work, suggesting that maintenance of H3K4me3 is
required to maintain cellular integrity even in a non dividing, fully committed cell
type (Stein et al, 2011). This also supports an ideal where though the expression
of H3K4me3 may be required to be reduced at certain developmental check-
points, that re-expression of this mark does occur at later stages of development.
All these data together paint a picture where a fine balance between methylation
and demethylation must be maintained in both a lineage and commitment
dependent manner. Slight alterations to the expression level or localization of,
15. enzymes required to maintain this balance may result in changes in levels of
H3K4me3 in either a global, or gene specific manner which, in turn, could easily
result in disease or abnormal cellular phenotypes.
Demethylation and disease; a fine balance disrupted
Known for their potent roles in development, it is of no surprise that
misregulation of several KDM5 family members has been found to play role in
several developmental diseases. Mostly targeted to the neurological system,
where several KDM5 family members have been studied as developmental
regulators, KDM5 family member involvement in diseases other than cancer has
been a target of recent study.
Past studies of KDM5c have resulted in the striking conclusion that
KDM5c regulation is pertinent to appropriate neural development. Though it is
known as an H3K4me3 demethylase, KDM5c has also been found to recognize
Histone 3 Lysine 9 trimethylation (H3K9me3) (Iwase et al, 2007), and to play a
role in RE1 silencing transcription factor (REST) mediated repression, as it has
been found to co occupy several REST target genes (Ballas & Mandel, 2005).
Loss of KDM5c causes de-repression and increases in H3K43me at key REST
targets leading to an impairment of neuronal gene regulation (Tahiliani et al,
2007). Strikingly, KDM5c has been found to be involved in several diseases of
neurodevelopment including X linked mental retardation/X linked Intellectual
16. Disability (XLMR/XLID), epilepsy, and autism spectrum disorders (ASD). Many
mutations, currently a total of more than 21, to KDM5c have been found and
continue to be found associated only with cases of XLMR (Abidi et al, 2008;
Jensen et al, 2010; Santos-Reboucas et al, 2011; Tzschach et al, 2006) several
of these mutations resulting in a decrease in the ability KDM5c to recognize
H3K9me3, or to demethylate H3K4me3; suggesting that the enzyomology of
KDM5c may be linked to pathology. One novel mutation was found to alter the
start site of KDM5C, presumably resulting in a complete lack of translation
(Ounap et al, 2012). Additionally, mutations to KDM5c have been connected to
distinct symptomology within XLMR such as memory loss (Simensen et al,
2012). This suggests that specific areas of the brain may be targeted by KDM5c
misregulation. In 2008, KDM5c was connected to another neurocognitive
phenotype when a missense mutation in exon 16 was found connected to ASD.
Though several KDM5c target genes such as BDNF and SCN2A had previously
been known to show altered expression in patients presenting with ASD, KDM5c
itself had never been implicated (Adegbola et al, 2008). KDM5c is not the only
family member with a neurodevelopmental phenotype.
KDM5b, another KDM5 family member which is a known regulator of
neurological development (Schmitz et al, 2011) has also recently been implicated
as a possible player in a congenital variant of Rett Syndrome*, a severe
neurodevelopmental disease. Molecular causes of Rett syndrome include the
persistent expression of early developmental genes (Urdinguio et al, 2008).
17. Although Rett syndrome is normally classified by a mutation in the X-linked
methyl-CpG-binding protein MeCP2 (Kramer & van Bokhoven, 2009), a
congenital variant showing FOXG1 truncation has recently been discovered
(Ariani et al, 2008; Bahi-Buisson et al, 2010; Mencarelli et al, 2009; Papa et al,
2008) Further analysis of the FOXG1 truncation shows that in both (of the two)
observed truncation events, the domain known as the JBD or the KDM5b binding
domain, is missing, suggesting that the interaction between FOXG1 and KDM5b
is pertinent to the regulation of this disease. A reduction in KDM5b binding would
result in a series of downstream effects, causing a reduction in the ability of
FOXG1 to repress transcription. This transcriptional change would, in turn, result
in a reduction of MeCP2 binding due to a delay in neural differentiation. This
may mimic what occurs when MeCP2 itself is mutated, resulting in a similar
disease phenotype.
Taken together, this data supports the conclusion that alterations to KDM5
proteins result not only in impaired development at the embryonic level, but that
these alterations and mutations may translate into long term disabilities- either
through functional deficits in the demethylase itself, or through downstream
effects on interacting proteins. This also provides additional evidence that each
KDM5 family member plays a unique role in the regional and temporal control of
chromatin structure, and that compensation by additional family members may
not be sufficient to result in phenotypic rescue. (Figure 2)
Though examples of KDM5 demethylases in disease appear limited to
diseases of a neuro-developmental decree, an increased understanding of these
18. enzymes and how they are regulated will undoubtedly uncover a wide range of
diseases in which they contribute to pathogenesis. Research efforts have, until
recently, concentrated on understanding the roles of these enzymes in various
types of cancer, as detailed below. In many cases KDM5s appear to play a role
in turning on correct genes at an incorrect time. This leads us to question
whether these enzymes may also play a role in degeneration in disorders such
as Alzheimers and Huntington’s disease, by encouraging incorrect signaling,
leading to alterations in neural regulatory networks later in life.
Demethylation and Cancer; a fine balance turned back on incorrectly?
Though they are currently know as transcriptional repressors through
their demethylase activity, several KDM5 family members first garnered the
attention of researchers long before their enzymology was discovered. KDM5a,
for example, was originally identified as an interaction partner for retinoblastoma
protein (pRB). As such, it was originally named Retinoblastoma Binding Protein
2 (RBP2) (Benevolenskaya et al, 2005). Further work on KDM5a showed that it
binds to genes known to be involved in pluripotency and is active in CD34+ and
CD105+ cell populations (known to be markers of HSCs and mesenchymal stem
cells (MSCs) respectively (Wang et al, 2009a). KDM5a target gene activation and
repression may therefore play a key role in the determination of differentiation
profiles in HSCs vs MSCs. Paired with the information gathered from KDM5a
null mice, mentioned earlier, this presents a strong case that KDM5a may play a
19. key role in the regulation of the haemotopoetic system including the modulation
of haematopoietic cell resistance to apoptosis, a hallmark of several blood
cancers. Multitudinous KDM5a target genes are preferentially expressed in
leukemia and lymphoma and interestingly, KDM5a has recently been found to be
a gene partner involved in Acute Myeloid Leukemia (Wang et al, 2009a). This
suggests that its involvement in cancer may not be limited to retinoblastoma and
that the pRB/KDM5a axis may be a pertinent player in leukemia pathogenesis as
well as a regulator of differentiation and development. Additional studies have
supported the role of KDM5a in a tumour suppressor role, including a recent
study by Liefke et al. Here they suggest that the switch that regulates Notch
target genes includes KDM5a and that through this target specific role, KDM5a
may act as a potent tumour suppressor in Notch mediated carcinogenesis (Liefke
et al, 2010).
KDM5b was additionally recognized prior to its enzymology becoming apparent.
Originally known as Plu-1, this protein was first discovered as a target up-
regulated in response to Her2/c-ErbB2 in breast cancer cell lines and primary
breast cancers (Lu et al, 1999). Of limited expression in most adult tissues,
KDM5b shows consistent up regulation in breast and prostate cancers in both
human and mice, and has been suggested as a possible oncogene in multiple
cancer types. (Barrett et al, 2002; Hayami et al, 2010; Lu et al, 1999; Roesch et
al, 2010; Xiang et al, 2007; Yamane et al, 2007) Hayami et al. draw on previous
work completed in breast (Yamane) and Prostate (Xiang) cancers and
demonstrate that KDM5b is directly involved in the proliferative rate and ability of
20. both lung and bladder cancer cells to escape apoptosis. In concordance with
other groups, they demonstrate that reduction of KDM5b level results in
alterations to the cell cycle of tumour cells, and a reduction in oncogenic potential
(Hayami et al, 2010). Delineating the exact role that KDM5b exerts in cancer has
become complex and more and more evidence points towards the theory that
cancer should be categorized as a group of diseases, rather than a single
dysfunction. KDM5b is known to be a regulator of both oncogenes and tumour
suppressors through direct interaction with their promoters, such as BRCA1 in
breast cancer (Yamane et al, 2007). It has also been associated with cell cycle
control in both an accelerating (breast cancer)(Yamane et al, 2007) and
decelerating (Melanoma) (Roesch et al, 2010) fashion and has been found to
increase the invasive potential of non invasive cell types through repression of
the tumour suppressor KAT5 (Yoshida et al, 2011). Recently, KDM5b has also
been demonstrated to promote cell cycle progression in breast cancer cells by
the epigenetic modulation of the expression of micro RNA let7e suggesting an
additional, indirect method to regulate of gene expression (Mitra et al, 2011).
In the recent years, another role of KDM5b in tumor survival has
surfaced, suggesting that KDM5b may be required for the adaptation of cells to
hypoxia. Solid tumors are considered to be highly hypoxic compared to
surrounding tissue, and adaptation to this state is pertinent for tumor survival
(Semenza, 2003). Adaptation to hypoxia is driven through Hypoxia inducible
factor-1 (HIF-1) and is largely mediated through transcriptional repression.
21. Recent screens for proteins that facilitate this adaptation noted several Jumonji
family demethylases, including KDM5b. KDM5b was found to be a direct HIF
target and shows increased expression under hypoxic conditions (Xia et al,
2009). Previous work has shown that reduced H3K4 methylation is linked to poor
prognosis in cancer patients (Seligson et al, 2005), suggesting that an ability to
demethylate H3K4 is important for tumor survival. Due to the requirement of
dioxygenases such as KDM5b, for molecular oxygen, Xia et al. propose that the
increased expression level of these enzymes may represent a compensatory
mechanism in response to decreasing oxygen availability (Xia et al, 2009).
Without this compensatory mechanism, H3K4me3 levels would be expected to
increase as tumors increase in size and oxygen levels decrease, leading to the
death of the hypoxic tumor cells. An increase in the expression level of
demethylases such as KDM5b may provide a mechanism for the tumor to
maintain low H3K4me3 levels even in situations where decreased oxygen levels
are present. This novel mechanism may allow tumors to literally skirt death and
continue to proliferate.
KDM5c, a demethylase more commonly thought to exert control
over neuronal identity, is over expressed in both prostate tumors and
seminomas, and has been shown to act as a co-repressor to Smad3. Binding of
KDM5c to Smad3 blocks its transactivation ability, thus reducing its ability to act
as an effector of the TGF-B pathway. Blockage of this pathway is apparent in
several cancer types suggesting that KDM5c may possess oncogenic potential
22. through its ability to block Smad3. Most interestingly, this appears to be
independent of its demethylase activity (Kim et al, 2008). Recently, Niu et al.
explored the role of KDM5c in clear cell renal cell carcinoma (ccRCC). A high
proportion of ccRCCs show inactivation of the tumour suppressor von Hippel-
Lindau (VHL). Additionally, VHL-/- tumours show decreased levels of H3K4me3
compared to their VHL +/+ counterparts. Interestingly, this was also shown to be
Hypoxia inducible factor- (HIF1-) dependent. Previous work, demonstrating gene
alterations in patient samples of ccRCC, had provided evidence that mutations to
KDM5c were higher than would be expected by chance in ccRCC patients
(Dalgliesh et al, 2010), suggesting a connection between KDM5c alterations and
aberrant levels of H3K4me3. Niu et al. have shown that KDM5c is responsible for
suppressing HIF response genes by removal of H3K4me3, and that mutations to
KDM5c are promote tumour growth. This tumour suppressor role of KDM5c is
specific to this family member as loss of KDM5c (but not KDM5a or KDM5b)
abolished the difference between VHL-/- and +/+ tumors (Niu et al, 2012).
Given their role in stem cell biology and development, we are left
to question whether KDM5s simply do the “right” job at the “wrong” time in
cancers; exerting control similar to non-pathogenic contexts during differentiation
and development, but with aberrant results within a fully developed tissue. The
roles of KDM5s during carcinogenesis appear to focus on helping tumour cells to
survive in contexts when appropriate cellular signaling would lead to cell death;
survival of hypoxia, escaping apoptosis, increasing potential for invasion, and
23. alterations to cell cycle leading to over proliferation and the development of
inappropriate cell types. However, information on the roles of these proteins are
often contradictory, with several being classified as proteins with both oncogenic
and tumour suppressor abilities depending on cellular context. Though, as
previously mentioned, reduced H3K4 methylation levels appear to be linked to
poor prognosis in cancer patients (Seligson et al, 2005), in the case presented
above, increased H3K4 in the context of HIF response genes in ccRCC appears
to be tumour-promoting. This again draws attention to the fine balance of
H3K4me3 expression and the regulation of the enzymes that control this
methylation, both are highly dependent upon cellular context.
KDM5s in tumour sub populations
Several groups have now suggested that KDM5 family members
exert control in specific subsets of a tumour population to maintain or promote
growth. Sharma et al. noted a population of “reversibly drug tolerant” cells within
several human cancers which maintain viability through an altered chromatin
state requiring KDM5a. These cells appear absolutely required to protect tumors
from eradication (Sharma et al, 2010). Roesch et al. show another angle of the
KDM5 cancer story, using the expression of KDM5b as a biomarker to flag a
small population of slow cycling cells within the heterogeneous population of a
melanoma (Roesch et al, 2010). These “slow” cells appear to be required for
tumour maintenance, giving rise to progeny which express low levels of KDM5b,
24. and knock down of KDM5b results in an exhaustion of tumour growth.
Interestingly the same group has also proposed that KDM5b has a tumour
suppressor role (Roesch et al, 2006; Roesch et al, 2008). It has been
suggested that the acceleration of cell cycle in these melanocytes after KDM5b
expression decrease may be due to a derepression of E2F-target genes, thus
accelerating cell cycle. Both KDM5b and KDM5a have been shown to be
members of the Rb repression complex, required for the repression of E2F target
genes during senescence (Chicas et al, 2012; Nijwening et al, 2011). Though
repression of E2F targets would generally be considered a tumour suppressive
function, mutations to Rb are common in cancer progression, allowing pro-
proliferative effects to override normal suppression and could lead to increased
oncogenic potential. Following in this theory, loss of KDM5a in a pRb defective
tumour context promotes senescence and differentiation, suggestive of an
oncogenic role in the absence of Rb (Lin et al, 2011). As noted by Chicas et al.,
this highlights the context- dependent role of these demethylases (Chicas et al,
2012). These results together suggest that though they are involved in
oncogenesis, KDM5s appear to exert their “tumourogenic potential” in different
ways, depending on cellular context and may respond differently depending on
which upstream cellular cues become activated (Figure 3).
These aspects of KDM5 demethylases, though complex, make
them potentially lucrative targets for pharmaceutical intervention. Enzymes are
known to provide excellent drug targets and KDM5b in particular, due to its low
25. expression level in most adult human tissues, may provide a potentially safe
target for pharmaceuticals. Immunotherapy approaches against KDM5b have
been investigated recently with results suggesting that KDM5b may represent a
tumour associated antigen (TAA) for breast cancer (Coleman et al, 2010).
The major question that remains for future clinical use of KDM5
targeting therapeutics is: How can we utilize this knowledge of KDM5 biology to
combat cancer and disease? Histone deacetylase inhibitors have long been the
“king” of the epigenetic pharmaceutical industry, with drugs such as Valproic
acid, Entinostat and Romadepsin showing large potential in the clinic and earning
FDA approval (Song et al, 2011). However, little has been done targeting
demethylase enzymes as possible treatment options. Recent studies have
demonstrated the release of therapeutic agents against KDM1 and studies of
agents against JMJD2 demethylases (Hamada et al, 2010), and novel assays
are being developed to screen and identify novel candidates against these
targets (Yu et al, 2012). The KDM5 family is not special in this contextual activity.
The importance of context and the flexibility that KDMs in general bring to
transcriptional control is the key to a variety of processes. Understanding how
and when the KDMs interact with both each other and the basal transcriptional
machinery will likely provide clues into a myriad of diseases.
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