Frequently used definitions describing low oxygen

Frequently used definitions describing low oxygen
Condition pO₂(mmHg) % O₂

	Normoxia (ambient)	159	21%
	Physiological hypoxia	1568	29%
	Mild hypoxia	838	15%
	Hypoxia	<8 td="">	<1 td="">
	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

	Trachea	150	19.7
	Alveoli	110	14.5
	Arterial blood	100	13.2
	Pulmonary arterial blood	40	5.3
	Brain	35	4.4
	Intestinal tissue	58	7.6
	Liver	41	5.4
	Kidney	72	9.5
	Muscle	29	3.8
	Bone marrow	49	6.4

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

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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

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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

Spatial aspects of Ca2+ signalling

Spatial aspects of Ca²⁺ signalling

a, Elementary events (red) result from the entry of external Ca²⁺ across the plasma membrane or release from internal stores in the endoplasmic or sarcoplasmic reticulum (ER/SR). They generate localized concentrations of Ca²⁺ that can activate many processes, including export of cellular material (1), opening of K⁺ channels (2) and metabolism in the mitochondria (3). The Ca²⁺ signals can also enter the nucleus (4). All of these processes respond to the very high concentrations of Ca²⁺ that build up within the sub-domain of the elementary events. b, Global Ca²⁺ signals are produced by coordinating the activity of elementary events to produce a Ca²⁺ wave that spreads throughout the cell. c, The activity of neighbouring cells within a tissue can be coordinated by an intercellular wave that spreads from one cell to the next.

Gut microbiota in health and disease

Gut microbiota in health and disease

The human gastrointestinal (GI) tract contains complex consortia of trillions of microorganisms (approximately 1 × 10¹³ to 1 × 10¹⁴, biomass > 1 kg), thousands of bacterial phylotypes, as well as hydrogen-consuming methanogenic archaea with a collective genome (also termed microbiome), the majority of which resides in the colon  As a whole, the microbiome represents more than 100 times the human genome. Thus, the human ‘metagenome’ consists of a mixture of genes embedded in the human genome (Homo sapiens) and in the genomes of our microbial partners. The microbiota and its microbiome provide us humans with additional gene products, we lack, and these serve many functions pertinent to the maintenance of our homeostasis. The human gut microbiota system may be regarded as a ‘microbial organ’ within the gut, which contributes to multiple host processes including the defense against pathogens at the gut level, immunity (mediated through a number of signal molecules and metabolites), the development of the intestinal microvilli, and the synthesis of several vitamins. Accumulating evidence indicates that the gut microbiota has a crucial role in conditions including obesity, diabetes, non-alcoholic fatty liver disease, inflammatory bowel disease (IBD) and even cancer. Gut microbial composition among healthy humans is influenced by host genotype, diet, age and sex, and it appears that organic disease and drugs can modulate microbiome composition and activities. At birth, the gut is sterile and is colonized immediately, ultimately developing into a stable community, although there are marked variations in microbial composition between individuals. Within an individual the composition is remarkably stable at different anatomical locations along the gut, but absolute number vary greatly, ranging from 10¹¹ cells g⁻¹ content in the ascending colon to 10^{7–8 in the distal ileum and 10−2–3 in the proximal ileum and jejunum.}

Gut Microbiota Host Health

Gut Microbiota Host Health

The intestinal microbiota is a complicated ecosystem that influences many aspects of host physiology (i.e. diet, disease development, drug metabolism, and regulation of the immune system). It also exhibits spatial patterning and temporal dynamics.

As the microbiota is recognized as an entirely separate organ (and containing a diversity of genes that is at least 100 times greater than the other organs

The microbiota plays important roles exerting functions essential to the maintenance of human health and well being, such as stimulation of immune system, antagonistic effects against pathogens, detoxification of carcinogenic compounds, fermentation of nondigestible food ingredients and release of a variety of metabolites involved in the crosstalk between the microbiota and the host. More than 80% of the species of the dominant intestinal microbiota cannot be cultivated by the methods available.

The catalog contains 3.3 million non-redundant genes, 150-fold more than the human genome equivalent and includes a large majority of the gut metagenomic sequences determined across three continents,

Gut microbiota epithelial function and derangements in obesity

Gut microbiota epithelial function and derangements in obesity

The gut epithelium is a barrier between the ‘outside' and ‘inside' world. The major function of the epithelium is to absorb nutrients, ions and water, yet it must balance these functions with that of protecting the ‘inside' world from potentially harmful toxins, irritants, bacteria and other pathogens that also exist in the gut lumen. The health of an individual depends upon the efficient digestion and absorption of all required nutrients from the diet. This requires sensing of meal components by gut enteroendocrine cells, activation of neural and humoral pathways to regulate gastrointestinal motor, secretory and absorptive functions, and also to regulate food intake and plasma levels of glucose. In this way, there is a balance between the delivery of food and the digestive and absorptive capacity of the intestine. Maintenance of the mucosal barrier likewise requires sensory detection of pathogens, toxins and irritants; breakdown of the epithelial barrier is associated with gut inflammation and may ultimately lead to inflammatory bowel disease. However, disruption of the barrier alone is not sufficient to cause frank inflammatory bowel disease. Several recent studies have provided compelling new evidence to suggest that changes in epithelial barrier function and inflammation are associated with and may even lead to altered regulation of body weight and glucose homeostasis. This article provides a brief review of some recent evidence to support the hypothesis that changes in the gut microbiota and alteration of gut epithelial function will perturb the homeostatic humoral and neural pathways controlling food intake and body weight.

GUT MICROBIOTA AND HOMEOSTASIS

GUT MICROBIOTA AND HOMEOSTASIS

The gastro-intestinal microbiota is a highly diverse bacterial community that performs an important digestive function and, at the same time, provides resistance against colonization by entero-pathogenic bacteria. Commensal bacteria resist pathogens thanks to resources competition, growth inhibition due to short-chain fatty acid production, killing with bacteriocins, and immune responses stimulation, external challenges such as antibiotic therapies can harm the microbiota stability and make the host susceptible to pathogen colonization

The human microbiome plays a key role in a wide range of host-related processes and has a profound effect on human health.

The human body is a complex ecosystem where microbes compete, and cooperate. These interactions can support health or promote disease, e.g. in dental plaque formation.

In nature, organisms rarely live in isolation, but instead coexist in complex ecologies with various symbiotic relationships. As defined in macroecology, observed relationships between organisms span a wide range including win-win (mutualism), win-zero (commensalism), win-lose (parasitism, predation), zero-lose (amensalism), and lose-lose (competition) situations

These interactions are also widespread in microbial communities, where microbes can exchange or compete for nutrients, signaling molecules, or immune evasion mechanisms

Gut microbiota and homeostasis and health

Gut microbiota and homeostasis and health

The gut microbiota has profound effects on the health and wellness of the host.

The human intestine is lined by epithelial cells that process nutrients and provide the first line of defense against food antigens and pathogens. Approximately one-sixth of intestinal epithelial cells are shed (exfoliated) daily.

This corresponds to the daily exfoliation of 10⁸ to 10¹⁰ cells.

 

Gut Brain Interaction in Sepsis

Gut Brain Interaction in Sepsis

The Enteric Nervous System: The Brain in the Gut

The gut has a mind of its own, the "enteric nervous system". Just like the larger brain in the head, researchers say, this system sends and receives impulses, records experiences and respond to emotions. Its nerve cells are bathed and influenced by the same neurotransmitters. The gut can upset the brain just as the brain can upset the gut.

 

The gut's brain or the "enteric nervous system" is located in the sheaths of tissue lining the esophagus, stomach, small intestine and colon. Considered a single entity, it is a network of neurons, neurotransmitters and proteins that zap messages between neurons, support cells like those found in the brain proper and a complex circuitry that enables it to act independently, learn, remember and, as the saying goes, produce gut feelings.

 

The gut's brain is reported to play a major role in human happiness and misery. Many gastrointestinal disorders like colitis and irritable bowel syndrome originate from problems within the gut's brain. Also, it is now known that most ulcers are caused by a bacterium not by hidden anger at one's mother.

 

‘Giant’ bacteria and giant virus

‘Giant’ bacteria and giant virus

It is commonly accepted that c. 80% of the bacterial species found by molecular tools in the human gut are uncultured or even unculturable

The typical diameter of the isolated bacteria ranged from 0.5 to 1.5 μm

the largest isolated bacterium, Microvirga massiliensis, reached 2.28 μm according to transmission electron microscopy, and was also shown to possess the largest genome (9.35 Mb) of any bacterium previously obtained from a human sample

The giant (194 nm in diameter) Senegalvirus isolated by amoebal co-culture is the first giant virus ever isolated from the human gut.

From prokaryotes to eukaryotes

From prokaryotes to eukaryotes

The appearance of eukaryotic cells ~2 billion years ago has been linked to the introduction of oxygen in the atmosphere and therefore aerobic metabolism. The increased presence of oxygen produces a more efficient energy source in the form of aerobic metabolism, producing 16–18 times more adenosine triphosphate (ATP) per hexose sugar than anaerobic metabolism. Since aerobic metabolism generates more energy, approximately 1000 more reactions can occur than under anaerobic metabolism.

This allowed the generation of new metabolites, for example, steroids, alkaloids and isoflavonoids

Steroids and polyunsaturated fatty acids are important elements of membranes; thus, they must have been involved in promoting organelle formation and cell compartmentalisation.

As some of the metabolites produced from respiration are involved in processes that target nuclear receptors, it has been hypothesized that higher ambient oxygen promoted these nuclear signalling systems within cells. Nuclear factors have conserved volumes and are highly hydrophobic, since they must pass through cell membranes. Experiments comparing the volume and hydrophobicity of both aerobic and anaerobic metabolites to those known for nuclear ligands indicate that aerobic metabolites are more hydrophobic and more closely match the required volumes of appropriate molecules for nuclear factors compared to the anaerobic molecules.

Since these appear important in superior eukaryotes, it has been hypothesized that such events influenced by increased oxygen levels have influenced biological evolution.

approximately 68% of transmembrane proteins in humans are high-oxygen content, whereas in most bacteria, such as E. coli, only 36% are oxygen rich. The size of the extracellular domains of transmembrane proteins increased as ambient oxygen concentration increased.

The size of the extracellular domains of transmembrane proteins increased as ambient oxygen concentration increased.

Larger and higher oxygen-containing proteins are more energy demanding than those lacking oxygen in their side chains. However, the primary hypothesis suggests that the presence of large and oxygen-rich amino acids as side chains would have resulted in weak protein structures during anoxic eras

Eukaryotes assign more communication roles to proteins than prokaryotes, allowing for more complex and variable signalling pathways. In order to achieve this, various changes in protein structure and function had to occur during evolution. The secondary structures of transmembrane proteins are more hydrophobic, and oxygen as well as nitrogen is important during the formation of hydrophilic structures. Acquisti et al. studied the oxygen content and the topology of transmembrane proteins of different organisms. The ratio of receptors to channels was higher, with a greater amount of oxygen-rich proteins, in more highly developed and ‘recent’ organisms. For example, approximately 68% of transmembrane proteins in humans are high-oxygen content, whereas in most bacteria, such as E. coli, only 36% are oxygen rich. The size of the extracellular domains of transmembrane proteins increased as ambient oxygen concentration increased. Larger and higher oxygen-containing proteins are more energy demanding than those lacking oxygen in their side chains. However, the primary hypothesis suggests that the presence of large and oxygen-rich amino acids as side chains would have resulted in weak protein structures during anoxic eras. Eukaryotes have an abundance of oxygen in the plasma membrane, as oxygen is utilized in the mitochondria. This compartmentalisation may have evolved as a mechanism to protect the transmembrane proteins, which are rich in oxygen. Through the development of complex compartmentalisation of cells, multiple processes including signalling and oxygen levels could also be controlled in different parts of the cell. In addition, there has been the emergence of multiple cell types within the same ‘greater’ organism, with over 200 different cell types in the adult human body. Multicellular organisms may have required both the accumulation of oxygen-rich amino acids in their transmembrane proteins and the allocation of respiration to specific intracellular compartments, that is, mitochondria.

Five Things Your Microbiome Can Tell You

Five Things Your Microbiome Can Tell You

1. Obesity. Ley et al (2006) and others have identified gut microbes associated with obesity, such as Eubacterium rectale. In addition, Upadhyay et al (2012) did experiments with mouse models and suggested the possibility that the microbiome could be manipulated for weight control in the near future

2. Dietary composition. Wu et al (2011) found that gut enterotypes were strongly associated with long-term diets, particularly protein and animal fat (Bacteroides) versus carbohydrates (Prevotella).

3. Antibiotics. If you have recently taken antibiotics, your gut microflora may not yet have been replenished. Dethlefsen et al (2008) found that ciprofloxacin treatment influenced the abundance of about a third of the bacterial taxa in the gut. Similarly, Jernberg et al (2007) found that long after the selection pressure from a short antibiotic exposure has been removed, there are persistent long term impacts on the human intestinal microbiota that remain for up to two years post-treatment.

4. Allergies. Is your nasal microbiome associated with the profile of chronic sinusitis? Abreu et al (2012) found that multiple, phylogenetically distinct lactic acid bacteria were depleted concomitant with an increase in the relative abundance of a single species, Corynebacterium tuberculostearicum, in patients suffering from chronic sinusitis.

5. Bacterial vaginosis. If you have a penis, your microbiome may be correlated with bacterial vaginosis in women. Price et al (2010) found that two families found in certain penis microbiomes — Clostridiales Family XI and Prevotellaceae — have been previously associated with bacterial vaginosis. This may correspond to frequent infections in your partner.

 

Features of the gut brain axis

Features of the gut brain axis

The brain and the gut are intimately connected via the gut–brain axis, which is a bidirectional communication system involving neural and humoral mechanisms. Neural connections involve the central, autonomic and enteric nervous systems. The enteric nervous system receives modulatory input from the brain and provides information to the brain via ascending neural circuits; it can also operate independently of the brain.

The effector limb of the enteric nervous system integrates physiological responses (including gut motility and secretion) and also modulates immune activity, as most immune cells possess receptors for neurotransmitters. The afferent limb comprises sensory nerves that contribute to gut reflexes and convey information to the brain. This information includes signals about noxious stimuli such as gut distension, as well as potentially dangerous signals, including the presence of bacterial endotoxins or pro-inflammatory cytokines. This information is conveyed to the brain and might result in pain, discomfort, or compensatory responses that are aimed at restoring homeostasis; these responses might involve changes in the gut physiology or immune function (for example, cytokine secretion).

The autonomic nervous system links the gut and the brain and consists of sympathetic and parasympathetic nerves. The vagus nerve is a major pathway for signals originating from the foregut and the proximal colon, whereas sacral parasympathetic nerves innervate the distal colon. The sympathetic system primarily exerts an inhibitory influence on the gut, decreasing intestinal motor function and secretion via the release of neurotransmitters such as noradrenaline. Responses to stress are conveyed via the sympathetic system and the hypothalamic–pituitary–adrenal axis.

The autonomic input from the gut is connected to the limbic system of the brain, the most important components of which are the hippocampus, the amygdala and the limbic cortex. The limbic system is responsible for a range of brain processes: the amygdala integrates responses to fear and arousal, whereas the hippocampus is responsible for memory and spatial navigation, and the limbic cortex regulates olfaction and integrates sensory and motor functions. The limbic system receives input from other brain regions that are responsible for a range of behaviours; these regions include the prefrontal cortex, the anterior cingulated gyrus, the temporal lobe and basal ganglia. Communication between the limbic and autonomic systems provides the neural circuitry underlying the strong link between behaviour and gut function in health (such as stomach 'butterflies') and disease (such as irritable bowel syndrome).

The humoral components of the gut–brain axis consist of the hypothalamic–pituitary–adrenal axis, the enteroendocrine system and the mucosal immune system. The hypothalamic–pituitary–adrenal axis is responsible for stress responses, resulting in the release of corticosterone, adrenaline and noradrenaline. Enteroendocrine cells produce hormones such as cholecystokinin and ghrelin, both of which regulate appetite, and 5-hydroxytryptamine, which has a broad range of effects on gut and brain functions.

Nature Reviews Microbiology 10, 735-742 (November 2012)