text:
Metabolomics/Applications/Health and Pharmaceuticals

Back to Previous Chapter: Databases Next chapter: Contributors Go to: Nutrition Go back to: Disease Research

=Heath and Pharmaceuticals=

Milk
Nutritional intake is essential for optimizing sport and exercise performance. Proper nutrition is also crucial for optimizing adaptations to training. The timing of nutritional intake is an important factor for optimizing the adaptations to any form of exercise, as well as having an important role in the recovery period after both resistance and endurance exercise.

Bovine milk products represent substantial sources of proteins, lipids, amino acids, vitamins and minerals. Low-fat milk has a number of characteristics to indicate that it is a significant recovery beverage. It contains carbohydrates in the form of lactose, casein and whey protein in a ratio that allows for slow protein absorption and sustained blood amino acid concentrations and a high concentration of electrolytes that aid in fluid recovery.

There is still developing evidence that supports the advantageous nature of consuming low-fat milk after exercise, especially for athletes who adhere to strength or endurance training regimens. The fat from free milk has proven to be as effective as, and in some cases more effective than, commercially available sports drinks when implemented to promote the recovery process after strength and endurance exercise. Milk also provides additional nutrients and vitamins that aid this recovery process and are not found in commercial sports drinks. It is in support of these details that milk has been proven to be an effective post-exercise beverage and an alternative to commercial sports drinks for lactose tolerant individuals.

Link to article:

http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=18831752

Vitamin C
Polymorphisms are involved with the xenobiotic metabolizing enzyme, GSTP1-1, in vitamin C (C) and urinary C excretion. This highlights the requirement to consider gene polymorphisms when determining the C requirements of individuals.

C intake into the blood and C excretion into the urine both occur rapidly after the oral loading of DAsA. While there may be large individual differences in the levels of C excretion, blood C levels are maintained within a relatively narrow range due to homeostasis.

Enhanced C intake is necessary for individuals that smoke. This allows smokers to maintain an in vivo C storage that is equivalent to non-smokers. This suggests that polymorphisms in enzymes that relate to xenobiotic metabolism might be related to the individual differences in urinary C excretion.

Researchers believe that it is unlikely that individual differences in C metabolism are explained solely by polymorphisms of GSTP1-1. The polymorphisms of other genes and lifestyle factors are necessary to include when considering individual C requirements and deficits. In order to further understand the variations in individual C metabolisms, investigations of the association with other polymorphisms and long-term loading experiments that involve the ingestion of DAsA are currently being performed.

Link to article:

http://www.jstage.jst.go.jp/article/jnsv/54/4/54_315/_article

Cheonggukjang
The cheonggukjang supplement leads to increased mRNA expressions of enzymes and protein that are involved in the fatty acid oxidation that occurs in the liver. As a result, this supplement reduces the accumulation of body fat and improves the serum lipids in high fat diets that have been fed to mice.

High fat diets are known to lead to overall increased body weight, energy intake and efficiency of energy storage. Cheonggukjang supplementation is expected to control the frequency of coronary heart diseases that develop as a result of poor eating habits. In turn, this should encourage the avoidance of diets that are high in fat and low in cholesterol.

Changes in the expression levels of hepatic acyl-CoA synthase (ACS) may modulate metabolic fluctuations of acyl-CoA in tissues that use fatty acids in order to generate and store energy. Cheonggukjang supplementation results in higher levels of hepatic ACS mRNA levels than those who eat normal or high fat diets.

Increased fatty acid availability with cheonggukjang supplementation induces an increased expression of hepatic carnitine palmitoyltransferase-I (CPT-I) mRNA.

Cheonggukjang supplementation up-regulates uncoupling protein 2 (UCP2) mRNA. This action may consist of cellular ATP levels and decreased metabolic efficiency. This would be in support of the resultant decrease in fat accumulation.

Cheonggukjang supplementation has evident beneficial effects on weight gain, epididymal and back fat mass, lipid profiles of serum and liver in high fat diets that are fed to mice. Cheonggukjang supplementation enhances fatty acid beta-oxidation, in the liver. These effects are believed to be attributed to cheonggukjang modulating transcriptional levels of proteins and enzymes that are associated with lipid metabolism.

Link to article:

http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=18850232

Personalized Medicine
Metabolomics: Working Toward Personalized Medicine

http://www.fda.gov/fdac/features/2005/605_metabolomics.html

Summary:

This article is sort of introducing the concept of metabolomics and its possible potentials in modern medicine to the general public. The article goes into a simplified explanation of how metabolomics came about (from the human genome project) and how exactly it relates to proteomics and genomics and details about techniques used by scientists to conduct research in this area. Currently, scientists are monitoring concentrations of metabolites in human fluid samples and are trying to figure out what the changes in metabolic profiles mean so that they can develop pharmaceuticals that are best suited for each individual person. This will save cost (if it prevents the development of an unsuccessful drug) and possibly many people’s health – as studies have shown that people who have negative reactions to certain medicines most often develop liver problems.

Definitions:

Metabolomics – the systematic study of the unique chemical fingerprints that specific cellular processes leave behind

Metabonomics - the quantitative measurement of the dynamic multiparametric metabolic response of living systems to pathophysiological stimuli or genetic modification

Toxicology – the study of adverse effects of chemicals on living organisms: symptoms, mechanisms, treatments and poisonings – especially among people

Metabolite – a product of a metabolic process (including intermediates)

NHGRI – National Human Genome Research Institute – a division of the National Institutes of Health, located in Bethesday, Maryland

Metabolome – the complete set of small molecule metabolites to be found within a living organism

Relevance:

This article relates to what we’ve learned up till now by providing a supplemental resource and real world applications. In class we’ve learned a few of the metabolic pathways and are presently learning some ways in which these pathways are regulated, but this article explains how the study of these pathways and specifically their concentrations of products and intermediates is useful in sort of genetically personalizing medicine – reducing the risk of side effects or injury and possibly enhancing the medicine’s effectiveness.

FDA
Resource: http://www.fda.gov/fdac/features/2005/605_metabolomics.html

Summary:

The main purpose of this website it to educate people about metabolomics, its potential benefits, and challenges that may be faced. It also explains the FDA’s role in metabolomics. As new drugs are being produced and tested using metabolomics, the FDA will need a new way of evaluating the data that comes in with the promise of a new drug. There must be a great understanding of this process if a drug, tested using metabolomics, is to be introduced into the general public.

Terms:

Metabolomics - study of all the molecules derived from metabolism in a living organism.

Biomarkers - substances used as indicators of a biologic state

NMR - nuclear magnetic resonance

MS - mass spectrometry

NCTR - National Center for Toxicological Research

Relevance:

In class, we have been learning about several metabolic pathways and the products they produce. Some of these metabolites are excreted from the body in urine, sweat, or pus. The focus of metabolomics is to look at the different metabolites secreted, such as glucose, and use the knowledge of how the pathway works to determine if the body is functioning properly. For example, if there is excess glucose in the urine it could mean that the person is a risk for diabetes.

Selegiline
Selegiline (L-deprenyl) is a mechanism-based inactivator of CYP2A6 inhibiting nicotine metabolism in humans and mice

http://jpet.aspetjournals.org/cgi/reprint/jpet.107.133900v1

Summary:

The other article I used was a study of the effects that Selegiline and its metabolites has on nicotine metabolism. In this article, the researchers took a look at Selegiline (L-deprenyl), which is (as of December 7, 2007) in clinical studies as a potential smoking cessation drug. In mice, Selegiline is found to be a potent nicotine inhibitor in hepatic microsomes, and its several metabolites were also found to inhibit nicotine metabolism. Hepatic microsomes were used because the liver is where nicotine is metabolized in the body, thus the effects in vitro would be similar. The study was also done in vitro with human hepatic microsomes. It appears that Selegiline is even more effective in humans than in rats because it acts both a competitive and mechanism-based inhibitor. When nicotine enters the body it binds to CNS type nicotinic receptors, which then increase dopamine levels. Selegiline in turn works as a dopamine inhibitor.

Terms:

Microsome: a small vesicle that is derived from fragmented smooth endoplasmic reticulum (SER) produced when tissues such as liver are mechanically broken

Metabolite: are the intermediates and products of metabolism, or the everyday chemical reactions that keep an organism alive, in this case the desmethylselegiline and L-methamphetamine that Selegiline is metabolized into.

Dopamine: a hormone and neurotransmitter that raises blood pressure and heart rate, and is also associated with the “pleasure system” of the brain.

Selegiline: a drug known more commonly by its several brand names (l-deprenyl, Eldepryl or Anipryl), that is used to treat early-stage Parkinsons and senile dementia. In normal clinical doses it is a selective irreversible MAO-B inhibitor, however in larger doses (>20 mg in a typical adult) it loses its specificity and also inhibits MAO-A.

Competitive Inhibitor: is a form of enzyme inhibition where binding of the inhibitor to the enzyme prevents binding of the substrate and vice versa.

Mechanism-based inhibitor: A competitive inhibitor that is converted to an irreversible inhibitor at the active site of the enzyme. (suicide inhibitor)

Relevance:

This article touches upon the various types of inhibitors that can block enzyme action that we learned about in Biochem: Conformation and Dynamics, as well as looking at how various molecules are metabolized into more useful molecules that the body can use.

Drug Development
Agilent Pharmaceuticals

http://www.chem.agilent.com/cag/Pharmanews/Pharma19/newsletter.asp?page=PN_19_F5_metabolomics.html

Summary:

The main focus of this resource is the use of metabolomics in drug development. Metabolomics can be used to eliminate the drugs that will be toxic to humans. The source also gives analytical tools to use in the identification of metabolites.

Terms:

Metabolomics- To characterize small molecules of any product of metabolism.

Metabolome- In one organism the complete set of small molecules that metabolism will produce.

Nuclear Magnetic resonance- A tool used to distinguish molecules based on their nucleus spin.

Mass Spectrometry- A tool used to measure mass to charge ratio of ions (m/z). It can be used to measure molecular weight, monitor enzyme reactions, amino acid sequencing and protein structure.

Gas Chromatography- Separates chemicals based on their volatility or how easy they evaporate into gas.

Liquid Chromatography- Separates chemical or the interactions between what is being analyzed and the chromatography column.

Relevance:

Knowing the biological and chemical process of glycolysis and gluconeogenesis. This leads to a better and rapid drug development by the characterization of the metabolites that these two pathways create.

Capsacin
In Vitro Hepatic and Skin Metabolism of Capsaicin

http://dmd.aspetjournals.org/cgi/reprint/dmd.107.019240v1

Summary:

The focus of this resource was to determine how and where the body metabolizes pure capsaicin as well as the main metabolites created during the process. The study was conducted in in vitro in human skin cells and liver cells. To compare their results, rat and dog cells were also used. The study contributed to our understanding of why capsaicin is effective as a pain treatment both topically and internally.

Terms:

Microsomes-A microsome is a small vesicle that is derived from fragmented endoplasmic reticulum (ER) produced when tissues such as liver are mechanically broken (homogenized). Microsomes contain the cell's cytochrome P450 (CYP) enzymes, involved in oxidative metabolism.

Metabolite-A substance, by-product, waste product, or endotoxin produced as the result of metabolism.

Biotransformation-The chemical conversion of substances by living organisms or enzyme preparations.

Agonist-Any molecule that improves the activity of a different molecule

Nociceptors-Nerve endings which detect and respond to painful or unpleasant stimuli.

Moiety-When referring to a molecule, a 'moiety' is a part or section of the whole.

Relevance:

This was relevant to class material because it demonstrated how different areas of the body metabolize products differently. It showed the difference between how the skin breaks down capsaicin versus how the liver utilizes the substance. It also determined/confirmed that the liver was more effective at breaking down capsaicin than was the skin.

Metabolomic data and human health
Metabolomics: Building on a Century of Biochemistry to Guide Human Health

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1457093

Summary:

The main focus of this article talks about how medical diagnosis and health issues for people utilizing metabolomic data. There are databases that contain metabolite profiles that are built, stored and indexed in accordance to metabolic and health status.

Terms:

Proteomics- large scale study of proteins with emphasis on their structure and function

Transcriptomics- global study of gene expression at the RNA level

Nuclear Magnetic Resonance- physical phenomenon based upon the quantum mechanical magnetic properties of an atom's nucleus

Macronutrient- a nutrient required or used in large quantities; examples include lipids, amino acids, simple sugars, etc

Genomics- study of an organism's entire genome

Relevance:

Every pathway that we have talked about has enzymes, cofactors, substrates, intermediates, and products. We have studied glycolysis, gluconeogenesis, and the pentose phosphate pathway and we have looked at the factors that activate and inactivate certain enzymes. As a result, since we have an idea and understanding of how the pathways work, we are able to create better foods, drugs, and agricultural chemicals that target improving health. Metabolomics has to do with metabolism so if we understand metabolism we are able to provide and figure out how to improve health sanctions and find cures for diseases. If understand the metabolite data and the metabolites function in the metabolism pathway it is easier to develop remedies to health problems.

Articles and Web Pages for Review and Inclusion
Peer-Reviewed Article #1: Vinnie Snow

Systems biology and functional genomics approaches for the identification of cellular responses to drug toxicity

'''Expert Opin Drug Metab Toxicol. 2008 November; 4(11): 1379–1389. '"

Main Focus

 * The main focus is to develop sensitive biomarkers in order to predict drug toxicity using genomic information as well as other types of omics datasets. These datasets can then be used to better understand the toxicity mechanisms of a particular biological system such as toxicity in humans.

New Terms

 * Toxicogenomics: a field of science that deals with the collection, interpretation, and storage of information about gene and protein activity within a particular cell or tissue in an organism in response to toxic substances. (source: http://en.wikipedia.org/wiki/Toxicogenomics)
 * Toxicogenetics: The study of genetic influences on the responses of organisms to toxins. (source: http://en.wiktionary.org/wiki/toxicogenetics)
 * Xenobiotics: a chemical which is found in an organism but which is not normally produced or expected to be present in it. Typically drugs such as antibiotics. (source: http://en.wikipedia.org/wiki/Xenobiotic)
 * Transcriptomics: The study of the transcriptome, the complete set of RNA transripts produced by the genome at any one time. (source: http://www.medterms.com/script/main/art.asp?articlekey=23518)
 * Pharmacogenomics: is the branch of pharmacology which deals with the influence of genetic variation on drug response in patients by correlating gene expression or single-nucleotide polymorphisms with a drug's efficacy or toxicity. (source: http://en.wikipedia.org/wiki/Pharmacogenomics)

Summary

 * This paper takes into account that testing toxicity of particular drugs on a human can be complicated. The in vivo systems are typically a rodent vector and the results don't completely correlate with that of the human body. Another method uses is human tissue culture, in vitro, in which you can learn more about specific cells but not the human body as a whole and tissues react differently in an in vitro system than they do in an in vivo system. The purpose of using toxicogenomics is to identify gene expression patterns that indicate an adverse health effect at low doses. The modern technique used to measure functional genomics is to use transcriptomic assays by microarray technology. The microarrays used enable high-throughput screening of chemicals for potential toxicity. The results are analyzed from both in vivo and in vitro systems and are coupled with data-rich output in order to build more life-like results of what would actually happen in a human system. This type of research has successfully led to important regulatory action by the FDA that allows many drugs to remain on the market due to genetic testing. This is important to both the pharmaceutical companies and the potential patients that the drugs can help. The information on genetic polymorphisms which are available through the Human Genome project has led to an major increase in research being done on genetic variation that relates to toxicity and pharmacologic phenotypes. The majority of the current research focuses on the relationship between phenotype(disease) and single nucleotide polymorphisms. So far there have been a number of publications that have shown a significant association between SNPs and disease phenotype(s). There have been few publications that have been validated that refute the original conclusion which suggests that this is a reliable method of testing toxicity.

Relevance to a Traditional Metabolism Course

 * This article relates to a traditional metabolism course in that the techniques being used evaluate the multiple pathways of metabolism as it relates to a human and in some cases rodent systems. The research uses toxicogenomics as well other omics coupled with microarrays in order to determine if a particular drug has any toxicity on a human system. The gene expression from the microarrays was used in concert with proteomic and metabolomic data which allows us to see the comprehensive picture of cellular responses when a particular drug is administered. The newer technology that is being used is the use of microarrays and the human genome project in order to see the effect on particular genes and pathways.


text: User talk:59.93.173.127

license: Creative Commons - Attribution Share-Alike - https://creativecommons.org/licenses/by-sa/4.0/

title: User talk:59.93.173.127


text:
Metabolomics/Metabolites/Lipids/Energy Storage

Back to Previous Chapter: Introduction to Metabolomics Next chapter: Hormones Back to Previous Category: Carbohydrates Next Category: Amino Acids Go to: Membrane Lipids

=Lipidomics=

L ctionality in cells extends to, but is not limited to, maintaining electrochemical gradients, subcellular partitioning, first- and second-messenger cell signaling, energy storage, protein trafficking and membrane anchoring. Physiological importance of lipids is evident when considering or observing lipid abnormalities, such as atherosclerosis, diabetes, obesity and Alzheimer's disease. Lipidomics "is a systems-based study of all lipids, the molecules with which they interact, and their function within a cell." The detection of various lipid species has been made more efficient with advances in soft-ionization mass spectrometry, combined with modern separation techniques. Lipid profiles are characterized as a mass spectrum of the composition and abundance of lipids contained from a crude lipid extract, and could be monitored over time and when responding to specific stimuli. Integrated with genomics, proteomics and metabolomics, lipidomics is expected to allow researchers to develop a better understanding of lipid functionality, in biological systems. In addition, researchers are expecting a better understanding on lipid-based disease mechanisms, for biomarker screening, and for monitoring pharmacologic therapy, as a result of lipidomic advances.

Systems biology signifies a vast impact on the future of disease treatment and prevention. The growing interest in the influence of lipids on systems biology owes largely to advances in mass spectrometry, which allow for detailed lipid profiles from minimal sample preparation. One of the developing groups involved in lipidome analysis, Lipid Metabolites and Pathways Strategy, is a consortium that has undertaken determining the complete lipidome of the mouse macrophage and its responses to a variety of stimuli, including oxidized lipids and lipopolysaccharides. Therapeutics are anticipated to advance with lipidomics as the effects of lipids on pathologic states, and influences that interfere with these effects become better understood. Integrating lipidomic data with genetic, proteomic, and metabolomic data proves to be a difficult endeavor, but will supposedly generate new modeling paradigms.

References:

http://www.jlr.org/cgi/content/full/47/10/2101

Researching differential meal fat uptake into adipose tissue depots was conducted to determine the impact of this uptake on body fat distribution. The meal fat tracer/adipose tissue biopsy approach was employed, in order to compare the effects of meal fat content on the fat uptake into visceral, upper body, and lower body subcutaneous fat depots. Fat content was monitored in premenopausal women subjects. In addition, Fatty acids intake, from normal-fat and high-fat meals, was traced with [3H]triolein.

Experimental results indicate that the proportion of dietary fat uptake into the three monitored depots was not different, between meals. Visceral fat accumulation accounted for approximately five percent of meal fat disposal, without respect to visceral fat mass. Subjects consuming normal-fat meals had an increase in meal fatty acid uptake into femoral fat, as a function of leg fat mass. This increase is identified as an increased efficiency of uptake. There was, however, an opposite pattern observed in the effects of normal-fat meals on omental fat, and high-fat meals on all monitored fat depots. Approximately forty percent of meal fat was oxidized, for both types of meals, after twenty-four hours.

Researchers concluded that greater thigh adipose tissue in women is directly associated with greater efficiency of meal fat storage, under specific energy balance conditions. However, an opposite trend was observed in visceral fat. These inferences indicate the possibility of different mechanisms that regulate fatty acid uptake, for different depots. Therefore, these differing mechanisms may also impact the distribution of body fat.

References:

http://diabetes.diabetesjournals.org/cgi/content/full/56/10/2589

Lipids In Energy Storage
Lipids are small water-insoluble biomolecules generally containing fatty acids, sterols, or isoprenoid compounds. There are a variety of lipids and each participates in different metabolism processes uniquely. Lipids are used as energy storage via fatty acids. Fatty acids are composed of carboxylic acids attached to long chains of hydrocarbons. These are carbons that can range from 4 to 36 carbons. Fatty acids can be saturated, monounsaturated or polyunsaturated depending on the number of double bonds attached at the hydrocarbon skeleton. For example, saturated Lauric (n-Dodecnoic) acid exists in the laurel plant has a 12 carbon skeleton (CH3(CH2)10COOH) with a 12:0 ratio of carbon to double bond on its hydrocarbon chain.

Unsaturated fatty acids such as Palmitoleic acid (cis-9-Hexadecenoic acid) and Oleic acid (cis-9-Octadecenic acid) has a single double bond between the 8 and 9 carbon on its hydrocarbon skeleton. Polyunsaturated fatty acids such as Arachidonic acid (cis-, cis-, cis-, cis-5,6,11,14- Icosatetraenoic acid) contained 4 double bonds on its hydrocarbon skeleton.

The most common type of fatty acid that is use for energy storage is in form of neutral fats. Neutral fats are the simplest type of lipids and are formed by three ester linkages of hydrocarbons to a glycerol otherwise known as triacylglycerols. These fats made up common foods such as butter and olive oil.

These neutral fats are efficient source energy storage because it is fully reduced and can be stored anhydrously. When it is fully reduced, these fatty acids are full of electrons which participate in a process called beta-Oxidation to produce acetyl CoA which can then integrated into the glycolysis and Citric Acid Cycle to from energy in form of ATP.

Image 2: Integration of beta-oxidation to other pathways[]

Peer-Review Articles
COORDINATED REGULATION OF HORMONE-SENSITIVE LIPASE AND LIPOPROTEIN LIPASE IN HUMAN ADIPOSE TISSUE IN VIVO: IMPLICATIONS FOR THE CONTROL OF FAT STORAGE AND FAT MOBILIZATION.[]

What is the main purpose of this article? This article implicates on the important of regulation in two different lipase enzymes for forming fatty acids.

Terms:

White adipocytes(White fat cells) - Also known as Unilocular Cells contain a large lipid droplet surrounded by a ring of cytoplasm. These fats are stored is in a semi-liquid state, and is composed primarily of triglycerides and cholesterol ester.

Function: secrete resistin, adiponectin, and leptin.

Endothelium - A layer of flat cells lining the closed internal spaces of the body such as the inside of blood vessels and lymphatic vessels (that convey the lymph, a milky fluid) and the heart.

Lipogenesis - The process by which glucose is converted to fatty acids, which are subsequently esterified to glycerol to form the triacylglycerols that are packaged in VLDL and secreted from the liver.

Lipoproteins - Any member of a group of substances containing both lipid (fat) and protein. The lipoproteins in blood plasma have been intensively studied because they are the mode of transport for cholesterol. (Online Encyclopedia Britannica)

Non-esterified fatty acids (NEFA) - The fraction of plasma fatty acids not in the form of glycerol esters. In other words, it is free fatty acids floating in the blood.

How is this article related to what we’ve learned so far in Metabolism? In our study of metabolism of fatty acids as an energy storage source, regulation and control of enzyme is crucial in the amount of energy making and energy storing. This article studied the regulation of Lipoprotein Lipase (LPL) and Hormone-Sensitive Lipase (HSL) regarding to fat deposition and mobilization of triacylglycerol in white fat cells. Control of LPL allows the activation and inactivation of fat storing and releasing in adipose tissues. Similarly the controls of HSL allow mobilization of fatty acids to other pathways for synthesis. From what we know about energy storage from fats, a fatty acid must first be activated in the cytosol in which it enters the mitochondria via carnitine shuttle. In the mitochondria, beta-oxidation of the fatty acid occurs to make acetyl coenzyme A for ATP synthesis. Insulin is also mentioned in the article as a regulator hormone. Insulin inhibits beta-oxidation in the mitochondria but allow the process of fatty acid synthesis to occur. When the body is in need of energy, or lack of glucose, the body induces Glucagon hormone to allow sugar synthesis by gluconeogenesis. The activation of Glucagon allow fatty acid to be activated in which can enter the mitochondria for acetyl CoA to be synthesize. The acetyl CoA in thus participates in ATP synthesis and storage.

INHIBITION OF MITOCHONDRIAL BETA-OXIDATION AS A MECHANISM OF HEPATOTOXICITY []

What is the purpose of this article? Integration of Information: The important of beta-oxidation in avoiding biological disfunction.

Terms:

Hepatotoxicity - The damage of liver by chemical produced in the body.

Hepatocytes - Majority of these cells are seen in the liver and mitochondria. These cells are involved in protein synthesis, protein storage and transformation of carbohydrates, synthesis of cholesterol, bile salts and phospholipids, and detoxification, modification and excretion of exogenous and endogenous substances.

Steatosis - The process describing the abnormal retention of lipids within a cell. It reflects an impairment of the normal processes of synthesis and breakdown of triglyceride fat.

Translocation - The process of moving protein by a cell to other part of cell.

Ketogenesis - The break down of fatty acid to form ketone bodies.

How is this article relate to what we’ve learned so far it Metabolism? This article discusses the severity of internal biological damages that can occur if the fatty acid beta-oxidation is inhibited. As notes, beta-oxidation is crucial in the human because ATP metabolism by fatty acid yield most of the ATP in the body. In the body, triacylglycerol is broken down via beta-oxidation in the mitochondria to yield acetyl CoA, which can go into the Citric Acid Cycle to yield energy. Acetyl CoA is an important molecule in body, not only to yield ATP but allow for other processes such as the synthesis of ketone bodies for the heart. Inhibition of beta-oxidation can be acquired by genetics precursor or through drugs. These NEFA Diethylaminoethoxyhexestrol, perhexiline maleate and amiodarone are the common harmful drugs that postpone beta-oxidation in the body. These drugs are often used for coronary heart disease treatments. With beta-oxidation inhibited problematic consequences such as Microvesicular Steatosis, Mitochondrial Cytopathies, and various inborn errors arises. Pancreatic syndrome also occurs with such inhibition.

MEDIUM CHAIN FATTY ACID METABOLISM AND ENERGY EXPENDITURE: OBESITY TREATMENT IMPLICATIONS []

What is the purpose of this article? Compare and contrast energy storage and energy expenditure of medium chain fatty acids and long chain fatty acids metabolism.

Terms:

Long chain fatty acids - Fatty acids that have 14 or more carbon attach.

Medium chain fatty acids - Fatty acids that has 8-10 carbon.

Chylomicrons - Large lipoprotein particles that are created in the small intestine. Chylomicrons transport fatty acid through the blood and to the mitochrondria.

Thermogenesis - The process of production of heat in an organism.

Omega oxidation - A process similar to beta-oxidation but the oxidation involves the  carbon from the carboxyl group of the fatty acid (wikipedia).

Peroxisomal-oxidation - The process of converting hydrogen peroxide to oxygen and water before it can decompose to form the highly reactive hydroxyl radical.

How is this article relate to what we’ve learned so far it Metabolism? In this article, medium chain fatty acids of 8-10 carbon long increases activity of lipase and thus absorb to the intestine at a much faster rate than long chain fatty acids. Study indicated that medium chain fatty acids do not need a lipoprotein for transport but can transport straight to the mitochondria via portal circulation for beta-oxidation. In this paper, other oxidative process such as omega-oxidation and peroxisomal-oxidation occurs in the liver. As seen before, long chain fatty acid need some sort of transport to other organ through the blood. Most often with long chain fatty acids, a carnitine shuttle is required to get the fatty acid into the mitochondria to do beta-oxidation. With medium chain fatty acids, a shuttle is not needed. Energy intake and stored from medium chain fatty acids metabolism is much more sufficient than long chain fatty acids. Appoximately 13% more energy intake compare to long chain fatty acids (Papamandjaris, Macdougall, Jones, p. 1209). We see than medium chain fatty acids metabolism is more efficient in which the intake and storing of energy is greater than that of long chain fatty acids. The

Web Resources
Webpage Title : Fatty Acid Oxidation

URL : http://www.dentistry.leeds.ac.uk/biochem/thcme/fatty-acid-oxidation.html

What is the purpose of this site? Integration of lipids metabolism derivatives to other pathways for energy synthesis and energy storage.

Terms:

Lipoprotein lipase - LPL uses lipoprotein lipase to hydrolyze lipids.

Hormone-sensitive lipase - It functions to hydrolyze triacylglycerols from the lipid droplet, freeing fatty acids and glycerols. (Wikipedia).

cAMP - A secondary messenger used for signal transduction.

Beta-adrenergic receptor - Any of various cell membrane receptors that can bind with epinephrine and related substances that activate or block the actions of cells containing such receptors. These cells initiate physiological responses such as increasing the rate and force of contraction of the heart as well as relaxing bronchial and vascular smooth muscle (the free dictionary).

G-Proteins - Function as "molecular switches," alternating between an inactive guanosine diphosphate (GDP) and activate guanosine triphosphate (GTP) bound state, ultimately going on to regulate downstream cell processes (wikipedia).

How is this site relate to what we’ve learn in metabolism? This is a good site on all the pathways involve in fatty acid metabolism. These include beta-oxidation, regulation of pathways, ketogenesis, and clinical significance of fatty acids. We’ve have talked about all of these process and this site really focus on the details of each process. Another pathway that is shown on this site is the mobilization of fats in adipocytes induced by hormone-sensitive lipase. This path show how fats cells are converted into glycerol.

Website Title : WKU Bio 113-Lipids

URL : http://bioweb.wku.edu/courses/BIOL115/Wyatt/Biochem/Lipid/lipid1.htm

Terms:

Saturated Fatty Acid - A fatty acid with carbon chain that has no double bond characteristics.

Unsaturated Fatty Acid (mono and poly) - A fatty acid that contain at least one double bond (monounsaturated) or many double bonds (polyunsaturated) on its carbon chain.

Hydrophillic - The polar portion of the fatty acid. This is typically the carboxyl group portion of the fatty acid.

Hydrophobic - The non-polar portion of the fatty acid. This is typically the carbon chain portion of the fatty acid.

Triglycerides - A fatty acid with a glycerol backbone connect to three fatty acid. This is often known as ‘neutral fats’ and triglycerides store energy.

How is this site relate to what we’ve learn in metabolism? This site provides good information on neutral fats that involve in energy production and storage. In metabolism, we learned that fatty acids are a good source of energy because it is fully reduced and can be stored anhydrously. This site shows the differences in saturated and unsaturated fatty acid and reasons that makes triglycerides a energy storage molecule.

Webpage Title : Mobilization and Cellular Uptake of Stored Fats (Triacylglycerols)with Animation- PharmaXChange.info

URL : http://pharmaxchange.info/press/2013/10/mobilization-and-cellular-uptake-of-stored-fats-triacylglycerols-with-animation/

What is the purpose of this site? Contains important information on the mobilization and cellular uptake of fats and fatty acids.

Terms:

Lipid Droplets Fatty acids and fats are stored in adipose tissue within lipid droplets which have a structure with a core of sterols and triacylglycerols surrounded by a layer of phospholipids. The phospholipid layer is surrounded by hydrophobic membrane proteins known as perilipins.

How is this site relate to what we’ve learn in metabolism? This is a good page covering the mobilization and cellular uptake of fatty acids and it has a useful animation which can help visualize the process.

Website Title : Pathways

URL : http://ull.chemistry.uakron.edu/Pathways/index.html

What is the purpose of this site? Provide a flow chart of fatty acid synthesis and its connection to all the metabolic pathways in the body to yield energy. This site is a good source when studying for Metabolism.

Terms:

Transamination - The reaction between an amino acid and an alpha-keto acid. The amino group is transferred from the former to the latter; this results in the amino acid being converted to the corresponding α-keto acid, while the reactant α-keto acid is converted to the corresponding amino acid (if the amino group is removed from an amino acid, an α-keto acid is left behind (wikipedia).

Deamination - The removal of the amino group on a molecule (wikipedia).

How is this site relate to what we’ve learn in metabolism? The importance of integration of pathways is crucial in learning metabolism. By integrating the pathways of fatty acid synthesis to fatty acid oxidation shows how energy is yield and stored.

 KEGG Pathway and MetaCyc

 Anabolic

Oxidative Phosphorylation : http://www.genome.ad.jp/kegg/pathway/map/map00190.html

Fatty Acid Synthesis : http://www.genome.ad.jp/kegg/pathway/map/map00061.html

Fatty acid elongation in mitochondria : http://www.genome.ad.jp/kegg/pathway/map/map00062.html

 Catabolic

Synthesis and degradation of ketone bodies : http://www.genome.ad.jp/kegg/pathway/map/map00072.html

 Metabolism

Fatty acid metabolism : http://www.genome.ad.jp/kegg/pathway/map/map00071.html

 References

[1] Nelson, L. D.; Cox, M. M., Lipids. In Lehninger Principles of Biochemistry, 4 ed.; W.H. Freeman and Company: New York, 2005. [2] Frayn, K. N.; Coppack, S. W.; Fielding, B. A.; Humphreys, S. M., Coordinated regulation of hormone-sensitive lipase and lipoprotein lipase in human adipose tissue in vivo: Implications for the control of fat storage and fat mobilization. Advances in Enzyme Regulation 1995, 35, 163-178.

[3] Fromenty, B.; Pessayre, D., Inhibition of mitochondrial beta-oxidation as a mechanism of hepatotoxicity. Pharmacology & Therapeutics 1995, 67, (1), 101-154. [4] Papamandjaris, A. A.; Macdougall, D. E.; Jones, P. J. H., Medium chain fatty acid metabolism and energy expenditure: Obesity treatment implications. Life Sciences 1998, 62, (14), 1203-1215.

=Articles and Web Pages for Review and Inclusion=


text:
Trainz/Copying Assets Between Versions And Copies Of Trainz

=Copying Content=

Introduction
This section is concerned with copying assets, i.e. Trainz data files.

All copying of assets is potentially subject to copyright considerations but this chapter does not address that issue. Nor does it address the uploading of content so as to make it available to the general public on Auran's DLS system or a third-party Trainz fansite. Uploading is covered in a separate chapter of this book.

You may wish to copy assets in situations such as the following:
 * You are upgrading to a new computer.
 * You have two or more different versions of Trainz installed on the same computer.
 * You have copies of Trainz installed on two or more computers.
 * You wish to exchange assets with a small number of friends.

Physical Copying Between Computers
{{void|1= Subject to the amount of data involved, all the normal ways of transferring files between computers can be used, such as:

Some Fundamental Concepts
Most Trainz assets have dependencies excepting scenery items and with the advent of mesh and texture libraries, between 2010 — 2014 the trend is that even former simple scenery items such as a basic house will likely have at least texture library references outside their own file folders, if not a mesh library since new assets built to v3.8 (iOS/Trainz MAC) are generating warnings when LODs are not used by content creators. A separate section of this book lists the hierarchy of assets which applies to dependencies.

 * Assets such as Driver sessions, scenarios often have a large number of dependencies and the list of dependencies in layouts (Routes) often dwarves the large number of dependencies in sessions by a factor of ten or more, even in this post-2010 day with Sessions layers keeping much of what used to be in a Map in the session as a dependency.
 * Rolling stock assets and basic industries often have a relatively low number of dependencies—unless either involve a animation (Cabin doors and windows in a Loco, passenger car doors that open, Moving assembly line, conveyors, and forklift trucks etc.).

Getting dependencies together
Assets will not work unless all their dependencies are present.
 * So in TRS2004 and before, use Tafweb's TrainzObjectz to collect which assets are to be bundled.
 * Post TRS2006-SP0 the easiest thing is to search dependencies for each session and route you mean to export.

It is possible to copy assets in two fundamentally different ways:
 * Copy the pre-installation distribution file(s). A distribution file is a file you download. On Auran's DLS system the distribution files are CDP files. On third-party Trainz fansites the distribution files can be in a variety of formats such as CDP, self-installing EXE, RAR compressed archives, or ZIP compressed archives. In general, a distribution file can contain any number of assets.
 * Copy the post-installation files.

Copying Pre-Installation Distribution Files
Distribution files can be copied between computers and installed on each. To install a CDP or EXE file, view it in Windows Explorer and double-click it. To install any other type of distribution file, refer to the instructions from the source of the file.

With Auran's DLS, by default the distribution CDP files are downloaded, run and deleted behind the scenes. This is the same concept as used by the Microsoft Update system. The distribution CDP files can be retained if they are downloaded using the FTP option, but then each asset must be downloaded separately; there is no automatic system to download dependencies with FTP.

With third-party Trainz fansites the situation varies but in most cases the default is to download the distribution files, hence retaining them naturally. }}

Copying Post-Installation Files

 * TRS2004 to TRS2004 - downloaded assets: Copy the relevant KUID folders in the C:\Program Files\Auran\TRS2004\World\Dispatcher\Downloads folder to the corresponding place on the destination computer. Then manually delete the C:\Program Files\Auran\TRS2004\Cache\world_cache_Dispatcher.chump file. It will usually be appropriate to only copy the top-level assets and then use the free third-party Trainz Objectz asset management program to list any missing dependencies.

 * TRS2004 to TRS2004 - self-created assets: Either copy the relevant folders in the C:\Program Files\Auran\TRS2004\World\Custom folder to the corresponding place on the destination computer and then manually delete the C:\Program Files\Auran\TRS2004\Cache\world_cache_Dispatcher.chump file, or (and much more preferably) use the Content Dispatcher sub-program supplied with Trainz to convert them to CDP files, which can then be installed on the recipient's computer as if they had been downloaded.

 * TRS2004 to TRS2006, to TC, to all other versions: best done via importing into other versions in a daisy chain, dealing with errors, then importing to the next higher version.

 * TRS2006 to TRS2006: (not yet written)

 * TRS2006 to TC: (not yet written; needs to include instructions for transferring those built-in assets which TC lacks)

 * Any transfers from later versions to earlier versions (eg TRS2006 to TRS2004): (not yet written; is this needed?)


text:
Chess Opening Theory/1. e4/1...Nf6/2. Nc3/2...d5/3. e5/3...Nfd7

= Alekhine's Defence =

Theory table
.

'1.e4 Nf6 2.Nc3 d5 3.e5 Nfd7'


text:
XForms/Conditional Styling

Motivation
You have a list of items that you want to display inside of a repeat loop. You want some items to have different styling based on the content of items.

Method
We will use the XForms group element to conditionally display an item inside of the repeat statement.

Sample XML Fragement
Assume your form has the following data in an instance:

Conditional Display of Items
The following text will only output element2 when element1 has a value of true.

The syntax .[a='b'] says that from the current node if the element a equals the value b then output the elements within the group.

Conditional Formatting of Items
This same strategy can be used to enclose output in different div or span elements.

In the above example all nodes with element1='true' will have a class="strong" in the output and any element with element1='false' will not have the attribute in the output.

Sample XForms Appliction
Load XForms Application

Source Code
In this example we need to display a list of synonyms for a specific term. The Synonyms are all listed and a preferred term is displayed with a bold font.

  Synonym Set (preferred term is bold) Synonyms:

Discussion
XForms 1.1 also includes the if attribute. Some XForms can conditionally use this for display of elements.

title: XForms/Conditional Styling


text:
Talk:Puzzles/Logic puzzles/Island on Fire

It should probably be added that the fire only moves to the south (because of wind).

I agree. Otherwise the small fire would just burn you. I'm going to make the change.


text:
Talk:US History/2008 Vote

Any spec u lation on the winner--205.215.119.97 (talk) 13:59, 26 February 2008 (UTC)
 * aNYONE NOW ?--205.215.119.108 (talk) 13:37, 27 October 2008 (UTC)

title: Talk:US History/2008 Vote


text:
Trumpet/Maintenance

Oiling the Valves
Equipment:
 * 1) Trumpet with sticky valves
 * 2) Valve Oil
 * 3) Oil Rag

Procedure for each valve to be oiled:
 * 1) Unscrew the top valve cap.
 * 2) Gently remove the valve from the casing. This is a very sensitive part of the instrument, any scraping or denting will impair the valve's function!
 * 3) Using the oil rag, wipe down the valve to remove any accumulated dirt/gunk and the old oil.
 * 4) Apply plenty of valve oil to the clean valve, careful not to drip extra oil on your nice clothes or good carpet.
 * 5) Gently replace the valve into the valve casing.
 * 6) Rotate the valve in the casing to make sure oil is spread evenly across the piston's surface.
 * 7) Align the valve guides with the casing (usually this means with the stamped number facing the mouthpiece). Typically they "click" when they're in the right spot.
 * 8) Thread and tighten the top valve cap.
 * 9) Repeat on the other two valves.

Cleaning the Mouthpiece
Cleaning a trumpet mouthpiece is one of the easiest steps in cleaning the instrument.

Equipment:
 * 1) Mouthpiece to be cleaned.
 * 2) Mouthpiece brush.
 * 3) Sink.
 * 4) Soap.

Procedure:
 * 1) Run the mouthpiece under warm water or let sit in warm soapy water.
 * 2) Scrub the inside of the mouthpiece with the mouthpiece brush.
 * 3) Rinse.

Cleaning the Valves
After a while valves tend to get full of gunk and need a good wash from time to time so as to not hinder your playing. Equipment:
 * Valves to be cleaned.
 * Sink.
 * Soap.
 * Small watertight container.
 * Rag.

Procedure for each valve to be cleaned:
 * 1) Unscrew the top valve cap.
 * 2) Remove the valve from the casing. Take note of which valve goes where. Most valves have a number or a mark to identify their position.
 * 3) Run the valves under warm water. Make sure that the little felt pads under the cap and the cap itself don't get wet as this can damage the valves.
 * 4) Scrub the valve holes with a brush.
 * 5) Leave inside a watertight container filled with warm soapy water for about 20 minutes. Make sure neither the felt pads or the cap get wet.
 * 6) Dry off with a rag.

title: Trumpet/Maintenance


text:
Talk:IB Theory of Knowledge

There are several factual inaccuraties on this page, thus it requires extensive editing to be acceptable.

I'm confused. By 1980 the philosophical ethics line of neo-Aristotelianism (e.g. MacIntyre) had demonstrated that ethics was not part of empirical knowledge, emotion, reason. It was assigned by MacIntyre to narrative language: but it is not a convincing answer, either, just a leftover one.

How can ethics be subsumed under epistemology, when it's clear that it's not part of it, but a separate discipline of philosophy?

FInally, the last statement is logically contradictory. If all knowing is wrong, then knowing all knowing is wrong, is wrong, and thus some knowing is correct. Are you saying the TOK class is itself logically contradictory?

Textbooks
Maybe we could add the commonly used textbooks.

Introduction to Philosophy - Louis P. Pojman Theory of Knowledge for the IB Diploma Certificate - Richard van de Lagemaat etc.

title: Talk:IB Theory of Knowledge


text:
Khepera III Toolbox/Parsing Program Output

The Khepera III Toolbox (notably the programs) uses NMEA 0183 messages as output data format. NMEA 0183 is a message-oriented communication protocol known from GPS receivers, which is about equally simple to read for humans and for computers.

NMEA 0183 Messages
NMEA 0183 is a communication standard specifying electrical characteristics as well as data format characteristics. Here, we are only using the message format of NMEA.

An NMEA message (or sentence) looks as follows: Messages always start with a $ sign, followed by a command and a list of arguments. The command as well as the arguments are separted by commas. Optionally, the message contain a trailing checksum (e.g., *4D), but none of the Khepera III programs writes this checksum.

The original NMEA specification does not allow the command to be longer than 5 characters. The Khepera III toolbox, however, does not use this restriction in favor of longer and more explicit command names.

A stream of NMEA messages can contain different types of messages, e.g. which is very handy for reporting results.

Advantages of NMEA 0183
The NMEA 0183 message format has several advantages:
 * It is human readable.
 * It is easy to parse by computers and the checksum (if any) is easy to calculate.
 * As it uses a start of message character ($) and an end of message character (CRLF), you can break a data stream apart at any point, and the parser will be able to resynchronize (i.e., read all complete messages).
 * It starts with a message type and therefore allows messages of different types to be interleaved in the same stream.
 * It optionally allows for a checksum, which is useful when the data is transmitted over lossy channels.
 * It can be converted to a CSV file with search-and-replace (see below).

Converting NMEA messages to CSV with a Text Editor
If you have a file with messages of one single type, e.g. you can use any text editor to transform it into CSV. Simply replace $SPEED, by nothing, and save the file. The resulting file can be loaded in almost any program (Matlab, Microsoft Excel, ...).

Converting NMEA messages to CSV with k3-nmea-to-csv
Instead of using a text editor, you can also use the k3-nmea-to-csv filter script to convert NMEA messages to CSV. Just pipe your file through that script, by providing the NMEA command of the messages to extract, e.g.: k3-nmea-to-csv SPEED < my_nmea_file > my_csv_file All messages that are not of type SPEED will be ignored.

Note that you can use this filter script with any program to convert its output to CSV. For example, ./infrared_proximity -r | k3-nmea-to-csv IRPROXIMITY would output the IR proximity sensor values as CSV.

Parsing NMEA with Scripts
NMEA can easily be processed with Perl, Python, Ruby or similar scripting languages. Example scripts can be found in the Examples section.

Parsing NMEA on the Robot
The modules section contains an NMEA parser (module nmea) written in C with can be used to parse NMEA messages on the robot. This can be useful to read a configuration file, for instance.


text:
Talk:System Monitoring with Xymon/User Guide

I'm sorry to say this, this page is a complete waste of time. Nagios (which is NOT spelt "Nagio") is *not* located on microsoft.com, etc.

I cleaned up that table. There was a lot of bogodata from where author had pasted from another article for formatting example but left data from that article in place. I think that table is now fixed. A lot of the other information in this article is still useful anyway, but the FAQ and HOWTO are much better than the User and Admin guides ... at least so far.


text: User talk:24.25.214.99

title: User talk:24.25.214.99


text:
US History/Keywords6

First Bush
Saddam Hussein Saddam's Insane Kuwait "19th Province" Michael Dukakis No JFK Walsh Street police shootings Buran New World Order potatoe Dodo Fires in Kwait We Three Kings "Let's Get Saddam." Cookbook:Spicy Black Beans Cookbook | Ingredients | Recipes Ingredients 2 cups canned black beans, rinsed and drained 1 tbs salt 1 tbs freshly ground black pepper 1 1/2 tbs chile oil 1/2 tbs vegetable oil 2 tsp rice vinegar 1 1/2 tsp soy sauce 1 Thai bird chile, minced

Bill Clinton
Bill Clinton pin-point attacks Land for Peace Yassir Arafat Ariel Sharon Monica Lewinsky perjury Define "is" Slobadon Milosovic ethnic Albanains World Court Operation Merlin Clinton Body Count Brittany Spears bloody glove UNAbomber cop killing nWo Stone Cold Austin 3:16 Y2K Third Way Zoë Baird Clintonomics Balloon Fetish impeachment Trump4Prez 2k16

Pre 9-11 Bush
anti-energy hanging, pregnant, dimpled chad Bush v Gore (Supreme Court decision) Ralph Nader Wikipedia.org XFL Allowing Islam on planes

Bush's First Term (2001 to 2004)
World Trade Center September 11 Daniel Pearl Danielle van Dam Osama bin Laden al Queda George W. Bush Dick Cheney Crusade Enron Keneth Lay Iraq War Jihad Watch weapons of mass destruction Democracy Now human shields Mission Acomplished Patriot Act "wet back" Harry Potter dementor manga anime Sea of Japan (East Asian Sea) A Series of Unfortunate Events DaVinci Code "Wardrobe Malfunction" Dixie Chicks John Kerry windsurfing pRESIDENT Terri Schiavo Steel Beams Jet Fuel Harambe Hillary's deleted emails Pearl Harbour Hiroshima JFK Assassination Edward Snowden should be free Bring Bake Off back to BBC

title: US History/Keywords6


text:
Metabolomics/Metabolites/Lipids/Steroids/Cholesterol

Back to Previous Chapter: Introduction to Metabolomics Next chapter: Hormones Back to Previous Category: Carbohydrates Next Category: Amino Acids Go to first subcategory: Energy Storage Go back to subcategory: Membrane Lipids

Introduction
Cholesterol is a fat-like substance that is found in the bloodstream and cells (particularly phospholipids bilayer) of humans. It is used to produce cell membranes, to create hormones and serves several other functions. It is attained through the diet and through metabolic processes in the body. In excess, it creates a problematic condition of hypercholesterolemia (high cholesterol) – a serious risk for coronary heart disease, obesity, artherosclerosis, stroke and other medical ailments.

HDL Cholesterol
High Density Lipoprotein: these are lipoproteins (combinations of fats and proteins) in the form in which they can be transported in the blood. The high-density lipoproteins transport cholesterol from the tissues of the body to the liver so it can be gotten rid of (in the bile). HDL cholesterol is therefore called the "good" cholesterol. The higher the HDL cholesterol level, the lower the risk of coronary artery disease. For each 1 mg/dl increase in HDL cholesterol there has shown to be a 2 to 4% reduction in the risk of coronary heart disease. Generally, the beginning steps to raise HDL cholesterol levels are involved in life style modification. Regular aerobic exercise, loss of excess weight (fat), and cessation of cigarette smoking cigarettes will increase HDL cholesterol levels. Moderate alcohol consumption (such as one drink a day) also raises HDL cholesterol. Some medications that are commonly used to raise HDL cholesterol include niacin, lopid, estrogen, and sometimes the statin drugs.

LDL Cholesterol
Low Density Lipoprotein - is called "bad" cholesterol, because elevated levels of LDL cholesterol are considered to be associated with an increased risk of coronary heart disease. But research shows that only oxidized LDL inflamed the epithelial cell, which makes the epithelial cell to secrete adhesive like molecule. This promotes the formation of plague, the plague not only contains LDL, but also calcium deposits and other dead cells. Therefore, only oxidized LDL lipoprotein contributes to the deposition of cholesterol on the artery walls, causing the formation of a hard, thick substance called cholesterol plaque. Over time, cholesterol plaque causes thickening of the artery walls and narrowing of the arteries, a process called atherosclerosis.

Low-density lipoprotein (LDL) receptors are typically regulated by feedback systems that depend upon intracellular cholesterol levels. Researchers have demonstrated that cytokines induce unmodified LDL accumulation in peripheral cells via disrupting cholesterol-mediated LDL receptor feedback regulation. These researchers have also investigated the regulation of cholesterol exogenous uptake via LDL receptor and its underlying mechanisms. Experiments were conducted on human hepatic cell line (HepG2) cells under physiological and inflammatory conditions.

Enzymic assay was employed to measure intracellular total cholesterol (TC), free cholesterol (FC) and cholesterol ester (CE) concentrations. Utilizing real-time quantitative PCR, LDL receptor, sterol regulatory element binding protein (SREBP)-2 and SREBP cleavage-activating protein (SCAP) mRNA levels were detected in total cellular RNA that was isolated from cells. Western blotting was used to analyze LDL receptor and SREBP-2 expression. Confocal microscopy involved with dual staining with anti-human SCAP and anti-Golgin antibodies was employed to examine the translocation of SCAP-SREBP complexes from the endoplasmic reticulum (ER) to the Golgi apparatus.

Experimental results indicated that, under physiological conditions, an increase in LDL concentration lead to an increase in intracellular cholesterol level, which in turn reduced LDL receptor mRNA presence and protein expression in HepG2 cells. By comparison, an increase of interleukin 1β (IL-1β) levels also increased intracellular levels of cholesterol, with LDL present. This was a result of increased expression of proteins and LDL receptor mRNA in HepG2. In addition, LDL was determined to reduce SREBP and SCAP mRNA levels, under these physiological conditions. Undeterred by high LDL concentration, translocation augmentation of SCAP-SREBP from the ER to the Golgi occurred via IL-1β exposure. This exposure was a result of over-expression of SREBP-2 and the disruption of the normal distribution of the SCAP-SREBP complex in HepG2.

IL-1β evidently disrupted cholesterol-mediated LDL receptor feedback regulation via augmenting SCAP-SREBP complex translocation from the ER to the Golgi. This resulted increased expression of SREBP-2 mediated LDL receptors, regardless of high LDL concentration. As a result, LDL receptor pathway produced an LDL cholesterol accumulation, in hepatic cells, under inflammatory stress.

References:

http://www.cmj.org/Periodical/paperlist.asp?id=LW20071217574113104650&linkintype=pubmed

Dietary vs. Endogenous Cholesterol
While it is easy to assume that cholesterol comes only from what you eat, surprisingly, dietary cholesterol makes up only 15% of the cholesterol in your body – the rest comes as a product of liver and cellular function (endogenous cholesterol). Although the level of cholesterol in your blood comes primarily from your body – it can be increased by high consumption of cholesterol and saturated fats in your diet

Dietary Cholesterol
Cholesterol from food is absorbed by the intestines and sent into the blood circulation. There, cholesterol is packaged in a protein coat. This cholesterol-protein coat complex is called a chylomicron. After a meal, the liver removes chylomicrons from the blood circulation. In between meals, the liver manufactures and secretes cholesterol back into the blood circulation.

•Sources include: Saturated fats, meat, poultry, fish, seafood and dairy products

Cholesterol Transport
Cholesterol is synthesized in the endoplasmic reticulum (ER), Accordingly, newly formed cholesterol goes first into the nonraft membrane but seems to become incorporated into rafts in the Golgi. From the Golgi, rafts that are formed are sent to distributed into the cell surface. Because of the high mole fraction of raft lipids in the apical membrane of epithelial cells, it has been predicted that these membranes rafts constitute the connected phase and allow for free diffusion of raft proteins over the entire membrane. Another mechanism for cholesterol transport exists in adrenal and gonadal cells utilizing cholesterol as a precursor for steroid hormone synthesis. Cholesterol is transported to the mitochondria through the cytosol (unlikely that there is a vesicular pathway connected to the mitochondria). An alternative mechanism that has been suggested involves membrane-membrane contact between the ER and mitochondria. This type of interorganelle transport has been seen in phospholipids transport and may also apply for cholesterol transfer. The key protein involved in shuttling cholesterol across the outer and inner mitochondrial membranes is the steroidogenic acute regulatory protein (StAR). Its structure has recently been determined and it has a binding pocket for cholesterol.

This figure is a schematic of cellular cholesterol distribution, processing, and trafficking. Cholesterol is synthesized in the endoplasmic reticulum (ER). Part of it is transported via the Golgi complex (1) and the trans-Golgi network (TGN) to the plasma membrane, where it is distributed either to raft (2, red) or nonraft (3, blue) microdomains. Most of the cholesterol, however, bypasses the Golgi and goes directly (4) to the cell surface. Cholesterol can be taken into the cell from the plasma membrane by endocytosis using clathrin-coated vesicles (5) or other pathways, including caveolae (small vesicles, or recesses, that have the ability to communicate with the outside of a cell and extend inward, indenting the cytoplasm and the cell membrane) (6). Rafts that have been brought into the cytosol via endocytosis can be located in endosomes specialized for sorting and recycling. From these endocytic circuits, cholesterol may be recycled to the surface (7) or transported back to the ER (8). In addition, certain routes from the Golgi complex (9) recycle cholesterol to the ER. Cholesterol is endocytosed in LDL via clathrin-coated pits (10) and transported to sorting endosomes (SE; 11). From there, it can be recycled to the surface either via a rapid route (12) or through slower routes utilizing recycling endosomes (RE; 13, 14). Cholesterol is also transported to late endocytic structures [15, late endosomes (LE) and lysosomes (LY)] that can fuse with each other (16). Sorting, recycling, and late endosomes communicate with the exocytic pathway (17 through 19), thus exchanging cholesterol between the endocytic and exocytic routes. Cholesterol esters in LDL are hydrolyzed before being released from the endocytic organelles, but cholesterol returning to the ER may become re-esterified. Cholesterol esters (CE) are deposited in cytosolic lipid droplets (20). Cholesterol can be mobilized upon ester hydrolysis from these cytosolic lipid droplets (21). Cholesterol and cholesterol esters can also be exchanged directly between circulating lipoproteins and the plasma membrane. Cholesterol can be released from cells - both from nonraft (24) and raft domains (25), the release of the raft domains may be involving caveolae (26).

Influx of Exogenous Cholesterol
Cholesterol can be taken up from lipoproteins in the circulation by mechanisms involving desorption (transfer of cholesterol from the lipoprotein to the exoplasmic leaflet of the plasma membrane bilayer) or by receptor-mediated uptake. The best understood and quantitatively the most important process is the one involving low-density lipoprotein (LDL), and its LDL-receptor. LDL is released from its receptor in the sorting endosomes and the LDL-receptor gets recycled to the cell surface. Cholesterol esters are hydrolyzed from LDL, and free cholesterol is continuously cycled to the plasma membrane. The main mechanism responsible for exit of LDL-cholesterol from late endosomes or lysosomes (membrane-bound organelles in the cytoplasm of most cells; they contain various hydrolytic enzymes that function in intracellular digestion) involves a certain protein - the NPC1 protein. This protein is defective in Niemann-Pick type C disease, a disease in which cholesterol and other lipids accumulate in vesicles derived from lysosomes. The NPC1 protein has been found in only late endocytic structures; its primary function and routes, however, have not yet been distinguished. The NPC1 protein is a multispanning membrane protein that contains a sterol-sensing domain. Mutations in this domain can result in the inactivation of the protein. Similar domains can be found in membrane proteins that regulate cholesterol synthesis. Cholesterol binding is a possible activity of this sterol-sensing domain. The NPC1 protein may also act in the removal of cholesterol from degradative endosomes by facilitating sterol transport to the Golgi or other destinations.

Cholesterol Efflux from Cells
Cellular cholesterol is continuously being lost by release of cholesterol to circulating lipoproteins. This loss can be quite rapid, up to 0.1% of total cholesterol per minute. The release from the plasma membrane can take place by desorption of cell surface cholesterol into lipoproteins. The liver and the intestine release cholesterol to the circulation mostly as esters by synthesizing and secreting lipoproteins. Another mechanism of cholesterol removal is by membrane shedding, a process that releases vesicles of membrane that may be enriched in raft lipids. Studies have shown that raft cholesterol is more slowly extracted by cyclodextrin and by HDL. Non-raft cholesterol, therefore, is the most likely source for efflux. A possible protein involved in cholesterol efflux has been identified through studies of Tangier's disease. Tangier’s disease is a genetic disease caused by the loss of function of an ATP-binding cassette transporter ABCA1 (formerly ABC1). This defect results in increased catabolism of HDL caused by a lowered efflux of cellular cholesterol. The increase in cellular cholesterol levels results in increased deposits of cholesterol esters in lipid droplets of the cytoplasm. One speculated function of ABCA1 could be to promote translocation of cholesterol from the cytoplasmic to the exoplasmic bilayer – facilitating efflux. It may also be involved in the transport of cholesterol from the Golgi to the cell surface (possibly involving rafts). This transporter may aid the formation of transport carriers by regulating lipid asymmetry. The ABCA1 protein has been determined to exist both in the plasma membrane and in the Golgi complex.

Cholesterol Homeostasis
Recent, scientific advances have shown that cholesterol completes many of its functions primarily by maintaining sphingolipid rafts in a functional state. However, how rafts contribute to cholesterol metabolism and transport is still debatable. Cellular cholesterol levels are precisely controlled by biosynthesis, efflux from cells and influx of lipoprotein cholesterol. The regulation of cholesterol homeostasis has changed perspectives and may open up more understandings of diseases caused by excess cholesterol, atherosclerosis for instance. Cells also continuously lose cholesterol to the outside circulation. Regulation of synthesis, influx and efflux keeps overall cholesterol levels controlled. The necessity of cholesterol homeostasis (and its maintenance), however, is not completely clear. Cholesterol has been thought to simply add rigidity to the plasma membrane – reducing permeability and increasing the durability of the lipid bilayer. Cholesterol was also thought to regulate the thickness of the bilayer – facilitating post-Golgi protein sorting. Cholesterol’s activities have now been expanded with the introduction of its role in lipid rafts.

Lipid Rafts of Cellular Membranes
Lipid rafts are physical bodies made up of cholesterol and sphingolipids (sphingomyelin and glycosphingolipids) in the exoplasm of the lipid bilayer. Cholesterol occupies the spaces between the saturated hydrocarbon chains of sphingolipids, thus, condensing the packing of sphingolipid molecules. This association is presumably strengthened by hydrogen bonding between the 3'-OH group of the sterol and the amide function of the sphingolipid ceramide backbone.

Removal of cholesterol from rafts (by cyclodextrin treatment, for example) dissociates the raft proteins from the lipids. Average raft size has been difficult to determine, but recent studies using photonic force microscopy have demonstrated that plasma membrane rafts usually maintain a diameter of about 50 nm, meaning about 3500 sphingomyelin molecules. Because of the small size of the raft, it can be assumed that probably not more than 10 to 30 proteins are contained in each raft. Raft size depends on the concentration of sphingolipids and cholesterol in the membrane. If the concentration of the raft lipids is increased and exceeds a critical value, the rafts would disrupt the connected phase and the liquid-disordered phase of the membrane. Such changes may play a role in regulating membrane properties both under physiological conditions and in the pathogenesis of diseases such as lipid storage disorders and atherosclerosis. Lipid rafts are dynamic assemblies that have functions in sorting and distributing lipids and proteins to the cell surface. At the cell surface, they play an important role in signal transduction and the creation of cell surface polarity. For these functions, it is crucial that not only the total cellular level of cholesterol but also its distribution are regulated.

This picture shows a lipid raft model. Lipids within the liquid-ordered phase are shown as red and in the liquid-disordered phase as blue. Cholesterol molecules, indicated by orange, arrange themselves preferentially into the liquid-ordered phase.

Factors that Influence Cholesterol Levels
•Diet: There are two factors associated with increased blood cholesterol 1.Saturated fats (in foods containing and not containing cholesterol) – they include foods with high levels of hydrogenated vegetable oils (trans fats) (palm and coconut oils), avocados and similar high fat foods of vegetable origin

2.High Cholesterol foods – only foods of animal origin actually contain cholesterol – most    common culprits include eggs, red meat, lard and shrimp

•Age: Typically as we age, blood levels of cholesterol increase due to lifestyles that have long accumulated cholesterol.

•Weight: People who are overweight are more likely to have high blood cholesterol. Also, when extra weight is centered around the abdominal region (opposed to legs and buttocks) seems to be attributable to high cholesterol

•Gender: Trends indicate that before the age of 50, men tend to have higher LDL levels and lower HDL levels than women. After the age of 50, women’s levels of LDL cholesterol usually increase (thought to be due to the post-menopausal decrease in estrogen.

•Genetics: Many people can have a predisoposal to be high in cholesterol. Also, several, minor genetic defects can result in the increased production of LDL and the decreased ability to remove them.

•Diseases: Certain diseases like diabetes can lower HDL levels, increase triglycerides and speed up the development of artherosclerosis. Hypertension (high blood pressure) can also increase blood cholesterol levels and hasten artherosclerosis

•Lifestyle: Certain lifestyle choices and environments can raise cholesterol levels including cigarette smoking, lack of exercise and stress.

•Central Obesity: Studies shows that obesity at the center is one major risk factor for the development of high blood cholesterol. People with central obesity is due to two much of fat deposites, only due to too much of calory intake than actual requirment.

Diseases and Conditions Related with high levels of Cholesterol
•	Artherosclerosis

•	Chronic Heart Disease

•	Diabetes

•	Hypercholesteremia

•	Obesity

•	Stroke


text:
User:HydraZulu

This is the page of HydraZulu. That is my name on most everything that i sign up for online. Keeping it short.

-Hydra

title: User:HydraZulu


text:
Khepera III Toolbox/The Toolbox/Modules

The Modules folder contains code libraries with functionality useful in many programs. These modules are used by the programs in the Programs folder, and can also be used in your own programs that you write for the Khepera III robot.

Module List

 * /commandline/: A simple command line parser.
 * /i2cal/: An easy-to-use interface for I2C communication.
 * /i2c stream/: An interface for I2C data streaming.
 * /khepera3/: Functions to access the sensors and actuators of the Khepera III robot. This module requires the i2cal module.
 * /measurement/: A general interface for all programs reporting sensor values.
 * /nmea/: A NMEA parser.
 * /odometry track/: Tracks the robot position (x, y, angle) by measuring the wheel rotation. This module requires the khepera3 module.
 * /odometry goto/: Drives the robot to a specific position (x, y). This module requires the odometry_track module.

title: Khepera III Toolbox/The Toolbox/Modules


text:
Khepera III Toolbox/The Toolbox/Modules/commandline

The commandline module parses command line values and provides a simple interface for accessing the values. The module expects the command line arguments to consist of
 * options with exactly one value (key-value pairs), e.g. -s 10000 or --speed 10000
 * options without value (just keys), e.g. -h or --help
 * an argument list, holding all values that were provided without a key

As an example, the command line would result in one key (--white-floor), one key-value pair (--speed 15000) and three arguments (10, 12, <tt>10</tt>).

Description
commandline_register_option registers an option with a specific type. By default (for all options that are not explicitly registered), an option is of type <tt> cCommandLine_Option_Value</tt> and "eats" the next command line argument. E.g. the command line: would be parsed as one key-value pair (<tt>--white-floor 15</tt>) by default. If <tt>--white-floor</tt> is registered as <tt>cCommandLine_Option</tt>, however, the same line will be parsed as one option (<tt>--white-floor</tt>) and one argument (<tt>15</tt>).

Once all necessary options have been registered, commandline_parse can be called to parse the command line. Subsequently, the function commandline_option_value and its _int and _float versions can be used to access option value, while commandline_option_provided returns whether the option has occurred on the command line or not. To access the arguments, commandline_argument and its _int and _float versions are available. The index must be smaller than the number returned by commandline_argument_count.

Option Hooks
Alternatively, a program can register a hook with an option: The hook function will be called each time the corresponding option appears on the command line. Note that the function will be invoked more than once if the user provides the same option multiple times.