2013年9月20日 星期五

Frequently used definitions describing low oxygen

Frequently used definitions describing low oxygen
Condition pO2(mmHg) % O2
Normoxia (ambient)15921%
Physiological hypoxia156829%
Mild hypoxia83815%
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Anoxia<0 .08="" td=""><0 .1="" td="">

Physiological oxygen tensions in a selection of normal human tissue types

Physiological oxygen tensions in a selection of normal human tissue types
Organ Normal pO2(mmHg) % O2
Trachea15019.7
Alveoli11014.5
Arterial blood10013.2
Pulmonary arterial blood405.3
Brain354.4
Intestinal tissue587.6
Liver415.4
Kidney729.5
Muscle293.8
Bone marrow496.4

觀乎天文以察時變,觀乎人文以化成天下

觀乎天文以察時變,觀乎人文以化成天下
李歐梵說: 「人文這個字,最早出現在中國的《易經》,觀乎天文以察時變,觀乎人文以化成天下。這個人文是指整個人間的各種事物,用詩、書、禮、樂這些東西來教化天下。

Cancer Genetics and Epigenetics Two Sides of the Same Coin




Cancer Genetics and Epigenetics Two Sides of the Same Coin
Cancer Cell, Volume 22, Issue 1, 9-20, 10 July 2012
Epigenetic and genetic alterations have long been thought of as two separate mechanisms participating in carcinogenesis. A recent outcome of whole exome sequencing of thousands of human cancers has been the unexpected discovery of many inactivating mutations in genes that control the epigenome. These mutations have the potential to disrupt DNA methylation patterns, histone modifications, and nucleosome positioning and hence, gene expression. Genetic alteration of the epigenome therefore contributes to cancer just as epigenetic process can cause point mutations and disable DNA repair functions. This crosstalk between the genome and the epigenome offers new possibilities for therapy.
Epigenetic mechanisms help establish cellular identities, and failure of the proper preservation of epigenetic marks can result in inappropriate activation or inhibition of various cellular signaling pathways leading to cancer. It is now generally accepted that human cancer cells harbor global epigenetic abnormalities and that epigenetic alterations may be the key to initiating tumorigenesis.
The cancer epigenome is characterized by substantial changes in various epigenetic regulatory layers; herein, we introduce some important examples of epigenetic disruptions that cause mutation of key genes and/or alteration of signaling pathways in cancer development.
Promoter hypermethylation of classic tumor suppressor genes is commonly observed in cancers, a phenomenon that has been implicated with driving tumorigenesis.
The mutation of epigenetic modifiers presumably leads to profound epigenetic changes, including aberrant DNA methylation, histone modifications, and nucleosome positioning, although this remains to be demonstrated. These epigenetic alterations can lead to abnormal gene expression and genomic instability, which may predispose to cancer.
Nucleosomes, which are the basic building blocks of chromatin, contain DNA wrapped around histones.
Histones are regulators of chromatin dynamics either by changing chromatic structure by altering electrostatic charge or providing protein recognition sites by specific modifications.
Histone modifications at specific residues characterize genomic regulatory regions, such as active promoter regions which are enriched in trimethylated H3 at lysine 4 (H3K4me3), inactive promoters which are enriched in trimethylated H3 at lysine 27 (H3K27me3) or trimethylated H3 at lysine 9 (H3K9me3), and regulatory enhancers that are enriched in monomethylated H3 at lysine 4 (H3K4me1) and/or acetylated H3 at lysine 27 (H3K 27ac ).
These histone modification patterns are regulated by enzymes including histone acetyltransferases (HATs) and deacetylases (HDACs), which introduce and remove acetyl groups, respectively. Histone methyltransferases (HMTs) and demethylases (HDMs), on the other hand, introduce and remove methyl groups. During tumorigenesis, cells undergo global changes in histone modifications and in the distribution of histone variants such as H 2A .Z which may affect the recruitment of TFs and often components of the transcription machinery, thereby contributing to aberrant gene expression.
An increasing number of nucleoside analogs/small molecules are being studied as anti-cancer drugs. Inhibitiors of DNMTs 5-azacytidine (5-Aza-CR; Vidaza; azacitidine) and 5-Aza-2-deoxycytidine (5-Aza-CdR; Dacogen; decitabine) or HDACs by SAHA or Rhomidepsin have been approved for cancer treatment by the FDA and proven to have therapeutic efficacy in a variety of malignancies
The presence of multiple genetic and epigenetic aberrations within a cancer suggests that effective cancer therapies will be most beneficial when combined with epigenetic and/or other anti-cancer strategies such as standard chemotherapy.
Cancer Cell, Volume 22, Issue 1, 9-20, 10 July 2012

Cancer Epigenetics From Mechanism to Therapy





Cancer Epigenetics From Mechanism to Therapy
Cell, Volume 150, Issue 1, 12-27, 6 July 2012
DNA methylation, histone modification, nucleosome remodeling, and RNA-mediated targeting regulate many biological processes that are fundamental to the genesis of cancer.
Chromatin is the macromolecular complex of DNA and histone proteins, which provides the scaffold for the packaging of our entire genome. It contains the heritable material of eukaryotic cells. The basic functional unit of chromatin is the nucleosome. It contains 147 base pairs of DNA, which is wrapped around a histone octamer, with two each of histones H 2A , H2B, H3, and H4. In general and simple terms, chromatin can be subdivided into two major regions: (1) heterochromatin, which is highly condensed, late to replicate, and primarily contains inactive genes; and (2) euchromatin, which is relatively open and contains most of the active genes.
The term epigenetics was originally coined by Conrad Waddington to describe heritable changes in a cellular phenotype that were independent of alterations in the DNA sequence. Epigenetics is most commonly used to describe chromatin-based events that regulate DNA-templated processes.
The information conveyed by epigenetic modifications plays a critical role in the regulation of all DNA-based processes, such as transcription, DNA repair, and replication. Consequently, abnormal expression patterns or genomic alterations in chromatin regulators can have profound results and can lead to the induction and maintenance of various cancers.
DNA methylation is primarily noted within centromeres, telomeres, inactive X-chromosomes, and repeat sequences.
Although global hypomethylation is commonly observed in malignant cells, the best-studied epigenetic alterations in cancer are the methylation changes that occur within CpG islands, which are present in 70% of all mammalian promoters. CpG island methylation plays an important role in transcriptional regulation, and it is commonly altered during malignant transformation.
These have confirmed that between 5%10% of normally unmethylated CpG promoter islands become abnormally methylated in various cancer genomes. They also demonstrate that CpG hypermethylation of promoters not only affects the expression of protein coding genes but also the expression of various noncoding RNAs, some of which have a role in malignant transformation.
Understanding the cellular consequences of normal and aberrant DNA methylation remains a key area of interest, especially because hypomethylating agents are one of the few epigenetic therapies that have gained FDA approval for routine clinical use.
Although hypomethylating agents such as azacitidine and decitabine have shown mixed results in various solid malignancies, they have found a therapeutic niche in the myelodysplastic syndromes (MDS).
It is also emerging that the combinatorial use of DNMT and HDAC inhibitors may offer superior therapeutic outcomes.
early studies assessing the global distribution of this modification during embryogenesis had clearly identified an active global loss of DNA methylation in the early zygote, especially in the male pronucleus..
The N-acetylation of lysine residues is a major histone modification involved in transcription, chromatin structure, and DNA repair. Acetylation neutralizes lysine's positive charge and may consequently weaken the electrostatic interaction between histones and negatively charged DNA. For this reason, histone acetylation is often associated with a more open chromatin conformation..
Acetylation is highly dynamic and is regulated by the competing activities of two enzymatic families, the histone lysine acetyltransferases (KATs) and the histone deacetylases (HDACs). There are two major classes of KATs: (1) type-B, which are predominantly cytoplasmic and modify free histones, and (2) type-A, which are primarily nuclear and can be broadly classified into the GNAT, MYST, and CBP/p300 families.
HDACs are enzymes that reverse lysine acetylation and restore the positive charge on the side chain. There are 18 such enzymes identified, and these are subdivided into four major classes, depending on sequence homology. Class I (HDAC 1-3 and HDAC8) and class II (HDAC 4-7 and HDAC 9-10) represent the HDACs most closely related to yeast scRpd3 and scHda1, respectively, whereas class IV comprises only one enzyme, HDAC11. Class I, II, and IV HDACs share a related catalytic mechanism that requires a zinc metal ion but does not involve the use of a cofactor. In contrast, class III HDACs (sirtuin 17) are homologous to yeast scSir2 and employ a distinct catalytic mechanism that is NAD+-dependent. Analogous to the KATs, HDACs target both histone and nonhistone proteins.
Importantly, inhibitors of histone deactylases (HDAC-I) are able to reverse some of the aberrant gene repression seen in these malignancies and induce growth arrest, differentiation, and apoptosis in the malignant cells.
The best-characterized sites of histone methylation are those that occur on lysine residues and, therefore, these will be the focus of this section. Although many lysine residues on the various histones are methylated, the best studied are H3K4, H3K9, H3K27, H3K36, H3K79, and H4K20. Some of these (H3K4, H3K36, and H3K79) are often associated with active genes in euchromatin, whereas others (H3K9, H3K27, and H4K20) are associated with heterochromatic regions of the genome. monomethylation of H3K9 may be seen at active genes, trimethylation of H3K9 is associated with gene repression.
The phosphorylation of serine, threonine, and tyrosine residues has been documented on all core and most variant histones. Phosphorylation alters the charge of the protein, affecting its ionic properties and influencing the overall structure and function of the local chromatin environment. The phosphorylation of histones is integral to essential cellular processes such as mitosis, apoptosis, DNA repair, replication, and transcription. Generally speaking, the specific histone phosphorylation sites on core histones can be divided into two broad categories: (1) those involved in transcription regulation, and (2) those involved in chromatin condensation. Notably, several of these histone modifications, such as H3S10, are associated with both categories.
The high-throughput genomic platforms have established that virtually the entire genome is transcribed; however, only 2% of this is subsequently translated.
The remaining noncoding RNAs (ncRNAs) can be roughly categorized into small (under 200 nucleotides) and large ncRNAs. These RNAs are increasingly recognized to be vital for normal development and may be compromised in diseases such as cancer. The small ncRNAs include small nucleolar RNAs (snoRNAs), PIWI-interacting RNAs (piRNAs), small interfering RNAs (siRNAs), and microRNAs (miRNAs). Many of these families show a high degree of sequence conservation across species and are involved in transcriptional and posttranscriptional gene silencing through specific base pairing with their targets. In contrast, the long ncRNAs (lncRNAs) demonstrate poor cross-species sequence conservation, and their mechanism of action in transcriptional regulation is more varied. Notably, these lncRNAs appear to have a critical function at chromatin, where they may act as molecular chaperones or scaffolds for various chromatin regulators, and their function may be subverted in cancer
The principal tenet in oncologythat cancer is a disease initiated and driven by genetic anomaliesremains uncontested, but it is now clear that epigenetic pathways also play a significant role in oncogenesis.
In fact, it is now irrefutable that many of the hallmarks of cancer, such as malignant self-renewal, differentiation blockade, evasion of cell death, and tissue invasiveness are profoundly influenced by changes in the epigenome.
epigenetic regulators are targeted to these essential genes and what makes these genes solely reliant on certain epigenetic regulators..
hematopoietic malignancies are clearly more vulnerable to epigenetic interventions than solid malignancies. Thus, not all cancers are equally susceptible to epigenetic therapies..
It is likely that many of these new epigenetic drugs offer synergistic benefits, and these new therapies may also synergize with conventional chemotherapies. This strategy of combination therapy may not only increase therapeutic efficacy but also reduce the likelihood of drug resistance.
The plethora of genetic lesions in epigenetic regulators offers many possible targets for drug discovery and will no doubt attract the attention of the pharmaceutical industry.
Cell, Volume 150, Issue 1, 12-27, 6 July 2012

Cancer Epigenetics From Mechanism to Therapy











Cancer Epigenetics From Mechanism to Therapy
Cell, Volume 150, Issue 1, 12-27, 6 July 2012
DNA methylation, histone modification, nucleosome remodeling, and RNA-mediated targeting regulate many biological processes that are fundamental to the genesis of cancer.
Chromatin is the macromolecular complex of DNA and histone proteins, which provides the scaffold for the packaging of our entire genome. It contains the heritable material of eukaryotic cells. The basic functional unit of chromatin is the nucleosome. It contains 147 base pairs of DNA, which is wrapped around a histone octamer, with two each of histones H 2A , H2B, H3, and H4. In general and simple terms, chromatin can be subdivided into two major regions: (1) heterochromatin, which is highly condensed, late to replicate, and primarily contains inactive genes; and (2) euchromatin, which is relatively open and contains most of the active genes.
The term epigenetics was originally coined by Conrad Waddington to describe heritable changes in a cellular phenotype that were independent of alterations in the DNA sequence. Epigenetics is most commonly used to describe chromatin-based events that regulate DNA-templated processes.
The information conveyed by epigenetic modifications plays a critical role in the regulation of all DNA-based processes, such as transcription, DNA repair, and replication. Consequently, abnormal expression patterns or genomic alterations in chromatin regulators can have profound results and can lead to the induction and maintenance of various cancers.
DNA methylation is primarily noted within centromeres, telomeres, inactive X-chromosomes, and repeat sequences.
Although global hypomethylation is commonly observed in malignant cells, the best-studied epigenetic alterations in cancer are the methylation changes that occur within CpG islands, which are present in 70% of all mammalian promoters. CpG island methylation plays an important role in transcriptional regulation, and it is commonly altered during malignant transformation.
These have confirmed that between 5%10% of normally unmethylated CpG promoter islands become abnormally methylated in various cancer genomes. They also demonstrate that CpG hypermethylation of promoters not only affects the expression of protein coding genes but also the expression of various noncoding RNAs, some of which have a role in malignant transformation.
Understanding the cellular consequences of normal and aberrant DNA methylation remains a key area of interest, especially because hypomethylating agents are one of the few epigenetic therapies that have gained FDA approval for routine clinical use.
Although hypomethylating agents such as azacitidine and decitabine have shown mixed results in various solid malignancies, they have found a therapeutic niche in the myelodysplastic syndromes (MDS).
It is also emerging that the combinatorial use of DNMT and HDAC inhibitors may offer superior therapeutic outcomes.
early studies assessing the global distribution of this modification during embryogenesis had clearly identified an active global loss of DNA methylation in the early zygote, especially in the male pronucleus..
The N-acetylation of lysine residues is a major histone modification involved in transcription, chromatin structure, and DNA repair. Acetylation neutralizes lysine's positive charge and may consequently weaken the electrostatic interaction between histones and negatively charged DNA. For this reason, histone acetylation is often associated with a more open chromatin conformation..
Acetylation is highly dynamic and is regulated by the competing activities of two enzymatic families, the histone lysine acetyltransferases (KATs) and the histone deacetylases (HDACs). There are two major classes of KATs: (1) type-B, which are predominantly cytoplasmic and modify free histones, and (2) type-A, which are primarily nuclear and can be broadly classified into the GNAT, MYST, and CBP/p300 families.
HDACs are enzymes that reverse lysine acetylation and restore the positive charge on the side chain. There are 18 such enzymes identified, and these are subdivided into four major classes, depending on sequence homology. Class I (HDAC 1-3 and HDAC8) and class II (HDAC 4-7 and HDAC 9-10) represent the HDACs most closely related to yeast scRpd3 and scHda1, respectively, whereas class IV comprises only one enzyme, HDAC11. Class I, II, and IV HDACs share a related catalytic mechanism that requires a zinc metal ion but does not involve the use of a cofactor. In contrast, class III HDACs (sirtuin 17) are homologous to yeast scSir2 and employ a distinct catalytic mechanism that is NAD+-dependent. Analogous to the KATs, HDACs target both histone and nonhistone proteins.
Importantly, inhibitors of histone deactylases (HDAC-I) are able to reverse some of the aberrant gene repression seen in these malignancies and induce growth arrest, differentiation, and apoptosis in the malignant cells.
The best-characterized sites of histone methylation are those that occur on lysine residues and, therefore, these will be the focus of this section. Although many lysine residues on the various histones are methylated, the best studied are H3K4, H3K9, H3K27, H3K36, H3K79, and H4K20. Some of these (H3K4, H3K36, and H3K79) are often associated with active genes in euchromatin, whereas others (H3K9, H3K27, and H4K20) are associated with heterochromatic regions of the genome. monomethylation of H3K9 may be seen at active genes, trimethylation of H3K9 is associated with gene repression.
The phosphorylation of serine, threonine, and tyrosine residues has been documented on all core and most variant histones. Phosphorylation alters the charge of the protein, affecting its ionic properties and influencing the overall structure and function of the local chromatin environment. The phosphorylation of histones is integral to essential cellular processes such as mitosis, apoptosis, DNA repair, replication, and transcription. Generally speaking, the specific histone phosphorylation sites on core histones can be divided into two broad categories: (1) those involved in transcription regulation, and (2) those involved in chromatin condensation. Notably, several of these histone modifications, such as H3S10, are associated with both categories.
The high-throughput genomic platforms have established that virtually the entire genome is transcribed; however, only 2% of this is subsequently translated.
The remaining noncoding RNAs (ncRNAs) can be roughly categorized into small (under 200 nucleotides) and large ncRNAs. These RNAs are increasingly recognized to be vital for normal development and may be compromised in diseases such as cancer. The small ncRNAs include small nucleolar RNAs (snoRNAs), PIWI-interacting RNAs (piRNAs), small interfering RNAs (siRNAs), and microRNAs (miRNAs). Many of these families show a high degree of sequence conservation across species and are involved in transcriptional and posttranscriptional gene silencing through specific base pairing with their targets. In contrast, the long ncRNAs (lncRNAs) demonstrate poor cross-species sequence conservation, and their mechanism of action in transcriptional regulation is more varied. Notably, these lncRNAs appear to have a critical function at chromatin, where they may act as molecular chaperones or scaffolds for various chromatin regulators, and their function may be subverted in cancer
The principal tenet in oncologythat cancer is a disease initiated and driven by genetic anomaliesremains uncontested, but it is now clear that epigenetic pathways also play a significant role in oncogenesis.
In fact, it is now irrefutable that many of the hallmarks of cancer, such as malignant self-renewal, differentiation blockade, evasion of cell death, and tissue invasiveness are profoundly influenced by changes in the epigenome.
epigenetic regulators are targeted to these essential genes and what makes these genes solely reliant on certain epigenetic regulators..
hematopoietic malignancies are clearly more vulnerable to epigenetic interventions than solid malignancies. Thus, not all cancers are equally susceptible to epigenetic therapies..
It is likely that many of these new epigenetic drugs offer synergistic benefits, and these new therapies may also synergize with conventional chemotherapies. This strategy of combination therapy may not only increase therapeutic efficacy but also reduce the likelihood of drug resistance.
The plethora of genetic lesions in epigenetic regulators offers many possible targets for drug discovery and will no doubt attract the attention of the pharmaceutical industry.
Cell, Volume 150, Issue 1, 12-27, 6 July 2012

Osmolarity and tonicity

Osmolarity and tonicity
Osmolarity is the measure of the concentration of a solute in a solution. It is determined by the number of moles of solute particles in a given volume of fluid. Urea is a single solute. If add 10 mM urea is added to a 100 mOsM solution in a beaker, then the solution gains 10 mOsM. Please note that this question did not ask you to compare the solution to a cell.
In contrast, tonicity is a comparative term. To calculate tonicity, then then you must compare the solution to another compartment such as a cell. If you are to compare the solution to a cell then the osmolarity of the cell will be given to you. Urea does pass across the plasma membrane of all cells to equilibrate and therefore does affect the movement of water. A cell with a cytoplasm of 300 mOsM, does not shrink in a solution that is 300 mOsM NaCl nor does it shrink in a solution that has 10 mOsM urea added to it. All cells are permeable to urea.
In the medulla of the kidney there is a standing osmotic gradient of 300 mOsM to 1200 mOsM. Half of this gradient is due to urea. In this region of the kidney, the cells of the tubules and collecting duct do have transporters for urea. Red blood cells also have transporters for urea. The transporter is needed to increase the speed at which urea equilibrates across the plasma membrane of these cells. This prevents the epithelial cells from excessive shrinking due to the loss of water to the interstitial space. In addition the transporters in the collecting duct are used to remove urea from the urine and to replenish the urea in the gradient.
Water can pass across the plasma membrane in the absence of aquaporin but the transit is slow. Almost all cells of the body have aquaporin channels inserted into their plasma membranes. This means that water equilibrates essentially instantaneously across the cell membrane. Water moves in response to a gradient. The process is called osmosis.

your brain

The universe ,according to the latest reseach from the Hubble telescope ,is approximately 13 billion years old;our planet is 5 billion years old;life ,amazingly,is 4.5 billion years old;the first basic brain appeared 500 million years old;the appearance of the first homo sapiens was a mere 3 million years ago;the mordern brain evolved 50,000 years ago;civilization is,at most,on a global basis,10,000 years old;the location of the human brain in the head was confirmed only 500 years ago;and 95% of all that the human race has discovered about the internal working of its own brain has been discovered in the last 10 years.
The universe 13,000,000,000
earth 5,000,000,000
life 4,500,000,000
first brains 500,000,000
Homo sapiens 3,000,000
modern brains 50,000
civilization 10,000
location of the brain 500
95% of knowledge of the working of the brain 10
the future ?
??
???
Above from the Head Strong TONY BUZAN

THE PRINCIPLES OF BRAIN

THE BRAIN PRINCIPLE OF SYNERGY
THE BRAIN PRINCIPLE OF KNOWLEDGE
THE BRAIN PRINCIPLE OF TRUTH
THE BRAIN PRINCIPLE OF SUCCESS
THE BRAIN PRINCIPLE OF PERSISTENCE
ABOVE FROM THE HEAD STRONG TONNY BUZAN

the human superorganism

The composition and activity of the gut microbiota codevelop with the host from birth and is subject to a complex interplay that depends on the host genome, nutrition, and life-style. The gut microbiota is involved in the regulation of multiple host metabolic pathways, giving rise to interactive host-microbiota metabolic, signaling, and immune-inflammatory axes that physiologically connect the gut, liver, muscle, and brain.
Establishing and maintaining beneficial interactions between the host and its associated microbiota are key requirements for host health. Although the gut microbiota has previously been studied in the context of inflammatory diseases, it has recently become clear that this microbial community has a beneficial role during normal homeostasis, modulating the host's immune system as well as influencing host development and physiology, including organ development and morphogenesis, and host metabolism. The gut microbiota--masters of host development and physiology
More than four million gene products from the microbiome could interact with the immune system to induce a tissue metabolic infection, which is the molecular origin of the low-grade inflammation that characterizes the onset of obesity and diabetes.
Regulation of Metabolism: A Cross Talk Between Gut Microbiota and Its Human Host