Haptoglobin is the protein that in humans is encoded by the HP gene. In blood plasma, haptoglobin binds free hemoglobin released from erythrocytes with high affinity and thereby inhibits its oxidative activity; the haptoglobin-hemoglobin complex will be removed by the reticuloendothelial system. In clinical settings, the haptoglobulin assay is used to screen for and monitor intravascular hemolytic anemia. In intravascular hemolysis, free hemoglobin will be released into circulation and hence haptoglobin will bind the hemoglobin; this causes a decline in haptoglobin levels. Conversely, in extravascular hemolysis the reticuloendothelial system splenic monocytes, phagocytose the erythrocytes and hemoglobin is not released into circulation. Therefore, haptoglobin is not a reliable way to differentiate between intravascular and extravascular hemolysis; this gene encodes a preproprotein, processed to yield both alpha and beta chains, which subsequently combines as a tetramer to produce haptoglobin. Haptoglobin functions to bind free plasma hemoglobin, which allows degradative enzymes to gain access to the hemoglobin while at the same time preventing loss of iron through the kidneys and protecting the kidneys from damage by hemoglobin.
For this reason, it is referred to as the suicide protein. Haptoglobin is produced by hepatic cells but by other tissues such as skin and kidney. In addition, the haptoglobin gene is expressed in murine and human adipose tissue. Haptoglobin had been shown to be expressed in adipose tissue of cattle as well. Haptoglobin, in its simplest form, consists of two alpha and two beta chains, connected by disulfide bridges; the chains originate from a common precursor protein, proteolytically cleaved during protein synthesis. Hp exists in two allelic forms in the human population, so-called Hp1 and Hp2, the latter one having arisen due to the partial duplication of Hp1 gene. Three genotypes of Hp, are found in humans: Hp1-1, Hp2-1, Hp2-2. Hp of different genotypes have been shown to bind hemoglobin with different affinities, with Hp2-2 being the weakest binder. Hp has been found in all mammals studied so far, some birds, e.g. cormorant and ostrich but in its simpler form, in bony fish, e.g. zebrafish. Hp is absent in at least some neognathous birds.
Mutations in this gene or its regulatory regions cause hypohaptoglobinemia. This gene has been linked to diabetic nephropathy, the incidence of coronary artery disease in type 1 diabetes, Crohn's disease, inflammatory disease behavior, primary sclerosing cholangitis, susceptibility to idiopathic Parkinson's disease, a reduced incidence of Plasmodium falciparum malaria. Since the reticuloendothelial system will remove the haptoglobin-hemoglobin complex from the body, haptoglobin levels will be decreased in hemolytic anemias. In the process of binding hemoglobin, haptoglobin sequesters the iron within hemoglobin, preventing iron-utilizing bacteria from benefiting from hemolysis, it is theorized. HP has a protective influence on the hemolytic kidney; some studies associate certain haptoglobin phenotypes with the risk of developing schizophrenia. Measuring the level of haptoglobin in a patient's blood is ordered whenever a patient exhibits symptoms of anemia, such as pallor, fatigue, or shortness of breath, along with physical signs of hemolysis, such as jaundice or dark-colored urine.
The test is commonly ordered as a hemolytic anemia battery, which includes a reticulocyte count and a peripheral blood smear. It can be ordered along with a direct antiglobulin test when a patient is suspected of having a transfusion reaction or symptoms of autoimmune hemolytic anemia, it may be ordered in conjunction with a bilirubin. A decrease in haptoglobin can support a diagnosis of hemolytic anemia when correlated with a decreased red blood cell count and hematocrit, an increased reticulocyte count. If the reticulocyte count is increased, but the haptoglobin level is normal, this may indicate that cellular destruction is occurring in the spleen and liver, which may indicate a drug-induced hemolysis, or a red cell dysplasia; the spleen and liver recognize an error in the red cells, destroy the cell. This type of destruction does not release hemoglobin into the peripheral blood, so the haptoglobin cannot bind to it. Thus, the haptoglobin will stay normal. In severe extra-vascular hemolysis, haptoglobin levels can be low, when large amount of hemoglobin in the reticuloendothelial system leads to transfer of free hemoglobin into plasma.
If there are symptoms of anemia but both the reticulocyte count and the haptoglobin level are normal, the anemia is most not due to hemolysis, but instead some other error in cellular production, such as aplastic anemia Haptoglobin levels that are decreased but do not accompany signs of anemia may indicate liver damage, as the liver is not producing enough haptoglobin to begin with. As haptoglobin is indeed an acute-phase protein, any inflammatory process may increase the levels of plasma haptoglobin. Hemopexin Haptoglobin-related protein This article incorporates text from the United States National Library of Medicine, in the public domain. Haptoglobins at the US National Library of Medicine Medical Subject Headings
Advanced glycation end-product
Advanced glycation end products are proteins or lipids that become glycated as a result of exposure to sugars. They can be a factor in aging and in the development or worsening of many degenerative diseases, such as diabetes, chronic kidney disease, Alzheimer's disease. Animal-derived foods that are high in fat and protein are AGE-rich and are prone to further AGE formation during cooking. However, only low molecular weight AGEs are absorbed through diet, vegetarians have been found to have higher concentrations of overall AGEs compared to non-vegetarians; therefore it is unclear whether dietary AGEs contribute to disease and aging, or whether only endogenous AGEs matter. This does not free diet from negatively influencing AGE, but implicates dietary AGE may be less important than other aspects of diet that lead to elevated blood sugar levels and formation of AGEs. AGEs affect nearly every type of cell and molecule in the body and are thought to be one factor in aging and some age-related chronic diseases.
They are believed to play a causative role in the vascular complications of diabetes mellitus. Under certain pathologic conditions, such as oxidative stress due to hyperglycemia in patients with diabetes, hyperlipidemia, AGE formation can be increased beyond normal levels. AGEs are now known to play a role as proinflammatory mediators in gestational diabetes as well. In the context of cardiovascular disease, AGEs can induce crosslinking of collagen which can cause vascular stiffening and entrapment of low-density lipoprotein particles in the artery walls. AGEs can cause glycation of LDL which can promote its oxidation. Oxidized LDL is one of the major factors in the development of atherosclerosis. AGEs can bind to RAGE and cause oxidative stress as well as activation of inflammatory pathways in vascular endothelial cells; the formation and accumulation of advanced glycation endproducts has been implicated in the progression of age-related diseases. AGEs have been implicated in Alzheimer's Disease, cardiovascular disease, stroke.
The mechanism by which AGEs induce damage is through a process called cross-linking that causes intracellular damage and apoptosis. They form photosensitizers in the crystalline lens. Reduced muscle function is associated with AGEs. AGEs have a range of such as: Increased vascular permeability. Increased arterial stiffness Inhibition of vascular dilation by interfering with nitric oxide. Oxidizing LDL. Binding cells—including macrophage and mesangial—to induce the secretion of a variety of cytokines. Enhanced oxidative stress. Proteins are glycated through their lysine residues. In humans, histones in the cell nucleus are richest in lysine, therefore form the glycated protein N-Carboxymethyllysine. A receptor nicknamed RAGE, from receptor for advanced glycation end products, is found on many cells, including endothelial cells, smooth muscle, cells of the immune system from tissue such as lung and kidney; this receptor, when binding AGEs, contributes to age- and diabetes-related chronic inflammatory diseases such as atherosclerosis, arthritis, myocardial infarction, retinopathy and neuropathy.
The pathogenesis of this process hypothesized to activation of the nuclear factor kappa B following AGE binding. NF-κB controls several genes. In clearance, or the rate at which a substance is removed or cleared from the body, it has been found that the cellular proteolysis of AGEs—the breakdown of proteins—produces AGE peptides and "AGE free adducts"; these latter, after being released into the plasma, can be excreted in the urine. The resistance of extracellular matrix proteins to proteolysis renders their advanced glycation end products less conducive to being eliminated. While the AGE free adducts are released directly into the urine, AGE peptides are endocytosed by the epithelial cells of the proximal tubule and degraded by the endolysosomal system to produce AGE amino acids, it is thought that these acids are returned to the kidney's inside space, or lumen, for excretion. AGE free adducts are the major form through which AGEs are excreted in urine, with AGE-peptides occurring to a lesser extent but accumulating in the plasma of patients with chronic kidney failure.
Larger, extracellularly derived AGE proteins cannot pass through the basement membrane of the renal corpuscle and must first be degraded into AGE peptides and AGE free adducts. Peripheral macrophage as well as liver sinusoidal endothelial cells and Kupffer cells have been implicated in this process, although the real-life involvement of the liver has been disputed. Large AGE proteins unable to enter the Bowman's capsule are capable of binding to receptors on endothelial and mesangial cells and to the mesangial matrix. Activation of RAGE induces production of a variety of cytokines, including TNFβ, which mediates an inhibition of metalloproteinase and increases production of mesangial matrix, leading to glomerulosclerosis and decreasing kidney function in patients with unusually high AGE levels. Although the only form suitable for urinary excretion, the breakdown products of AGE—that is, peptides and free adducts—are more aggressive than the AGE proteins from which they are derived, they can perpetuate related pathology in diabetic patients after hyperglycemia has been brought under control.
Some AGEs have an innate catalytic oxidative capacity, while activation of NADH oxidase through activation of RAGE and damage to mitochondrial proteins leading to mitochondrial dysfun
Senescence or biological aging is the gradual deterioration of functional characteristics. The word senescence can refer either to senescence of the whole organism. Organismal senescence involves an increase in death rates and/or a decrease in fecundity with increasing age, at least in the part of an organism's life cycle. Senescence is the inevitable fate of all multicellular organisms with germ-soma separation, but it can be delayed; the discovery, in 1934, that calorie restriction can extend lifespan by 50% in rats, the existence of species having negligible senescence and immortal organisms such as Hydra, have motivated research into delaying senescence and thus age-related diseases. Rare human mutations can cause accelerated aging diseases. Environmental factors may affect aging, for example, overexposure to ultraviolet radiation accelerates skin aging. Different parts of the body may age at different rates. Two organisms of the same species can age at different rates, making biological aging and chronological aging distinct concepts.
There are a number of hypotheses as to. Organismal senescence is the aging of whole organisms. Actuarial senescence can be defined as an increase in mortality and/or a decrease in fecundity with age; the Gompertz–Makeham law of mortality says that that the age-dependent component of the mortality rate increases exponentially with age. In 2013, a group of scientists defined nine hallmarks of aging that are common between organisms with emphasis on mammals: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication. Aging is characterized by the declining ability to respond to stress, increased homeostatic imbalance, increased risk of aging-associated diseases including cancer and heart disease. Aging has been defined as "a progressive deterioration of physiological function, an intrinsic age-related process of loss of viability and increase in vulnerability."The environment induces damage at various levels, e.g. damage to DNA, damage to tissues and cells by oxygen radicals, some of this damage is not repaired and thus accumulates with time.
Cloning from somatic cells rather than germ cells may begin life with a higher initial load of damage. Dolly the sheep died young from a contagious lung disease, but data on an entire population of cloned individuals would be necessary to measure mortality rates and quantify aging; the evolutionary theorist George Williams wrote, "It is remarkable that after a miraculous feat of morphogenesis, a complex metazoan should be unable to perform the much simpler task of maintaining what is formed." Different speeds with which mortality increases with age correspond to different maximum life span among species. For example, a mouse is elderly at 3 years. All organisms senesce, including bacteria which have asymmetries between "mother" and "daughter" cells upon cell division, with the mother cell experiencing aging, while the daughter is rejuvenated. There is negligible senescence such as the genus Hydra. Planarian flatworms have "apparently limitless telomere regenerative capacity fueled by a population of proliferative adult stem cells."
These planarians are not biologically immortal, but rather their death rate increases with age. Some species exhibit "negative senescence", in which reproduction capability increases or is stable, mortality falls, with age, resulting from the advantages of increased body size with age. Natural selection can support lethal and harmful alleles, if their effects are felt after reproduction; the geneticist J. B. S. Haldane wondered why the dominant mutation that causes Huntington's disease remained in the population, why natural selection had not eliminated it; the onset of this neurological disease is at age 45. Haldane assumed that, in human prehistory, few survived until age 45. Since few were alive at older ages and their contribution to the next generation was therefore small relative to the large cohorts of younger age groups, the force of selection against such late-acting deleterious mutations was correspondingly small. Therefore, a genetic load of late-acting deleterious mutations could be substantial at mutation-selection balance.
This concept came to be known as the selection shadow. Peter Medawar formalised this observation in his mutation accumulation theory of aging. "The force of natural selection weakens with increasing age—even in a theoretically immortal population, provided only that it is exposed to real hazards of mortality. If a genetic disaster... happens late enough in individual life, its consequences may be unimportant". The'real hazards of mortality' such as predation and accidents, are known'extrinsic mortality', mean that a population with negligible senescence will have fewer individuals alive in older age groups. Another evolutionary theory of aging was proposed by George C. Williams and involves antagonistic pleiotropy. A single gene may affect multiple traits; some traits that increase fitness early in life may have negative effects in life. But, because many more individuals are alive at young ages than at old ages small positive effects early can be selected for, large negative effects may be weakly selected against.
Williams suggested the following example: Perhaps a gene codes for calcium deposition in bones, which promotes juvenile survival and will therefore be favored by natural selection.
Rejuvenation Research is a bimonthly peer-reviewed scientific journal published by Mary Ann Liebert that covers research on rejuvenation and biogerontology. The journal was established in 1998 and the editor-in-chief is Aubrey de Grey, it is the official journal of the European Society of Preventive and Anti-Aging Medicine as well as PYRAMED: World Federation and World Institute of Preventive & Regenerative Medicine. The journal was established in 1998 as the Journal of Anti-Aging Medicine with Michael Fossel as editor-in-chief, it obtained its current title in 2004. The journal publishes the abstracts of the biennial conferences of the SENS Research Foundation. Rejuvenation Research is abstracted and indexed in: MEDLINE Current Contents/Clinical Medicine Science Citation Index Expanded EMBASE/Excerpta Medica Scopus CAB AbstractsAccording to the Journal Citation Reports, the journal has a 2017 impact factor of 3.220. Strategies for Engineered Negligible Senescence Timeline of senescence research Official website
The Jmol applet, among other abilities, offers an alternative to the Chime plug-in, no longer under active development. While Jmol has many features that Chime lacks, it does not claim to reproduce all Chime functions, most notably, the Sculpt mode. Chime requires plug-in installation and Internet Explorer 6.0 or Firefox 2.0 on Microsoft Windows, or Netscape Communicator 4.8 on Mac OS 9. Jmol operates on a wide variety of platforms. For example, Jmol is functional in Mozilla Firefox, Internet Explorer, Google Chrome, Safari. Chemistry Development Kit Comparison of software for molecular mechanics modeling Jmol extension for MediaWiki List of molecular graphics systems Molecular graphics Molecule editor Proteopedia PyMOL SAMSON Official website Wiki with listings of websites and moodles Willighagen, Egon. "Fast and Scriptable Molecular Graphics in Web Browsers without Java3D". Doi:10.1038/npre.2007.50.1
European Chemicals Agency
The European Chemicals Agency is an agency of the European Union which manages the technical and administrative aspects of the implementation of the European Union regulation called Registration, Evaluation and Restriction of Chemicals. ECHA is the driving force among regulatory authorities in implementing the EU's chemicals legislation. ECHA helps companies to comply with the legislation, advances the safe use of chemicals, provides information on chemicals and addresses chemicals of concern, it is located in Finland. The agency headed by Executive Director Bjorn Hansen, started working on 1 June 2007; the REACH Regulation requires companies to provide information on the hazards and safe use of chemical substances that they manufacture or import. Companies register this information with ECHA and it is freely available on their website. So far, thousands of the most hazardous and the most used substances have been registered; the information is technical but gives detail on the impact of each chemical on people and the environment.
This gives European consumers the right to ask retailers whether the goods they buy contain dangerous substances. The Classification and Packaging Regulation introduces a globally harmonised system for classifying and labelling chemicals into the EU; this worldwide system makes it easier for workers and consumers to know the effects of chemicals and how to use products safely because the labels on products are now the same throughout the world. Companies need to notify ECHA of the labelling of their chemicals. So far, ECHA has received over 5 million notifications for more than 100 000 substances; the information is available on their website. Consumers can check chemicals in the products. Biocidal products include, for example, insect disinfectants used in hospitals; the Biocidal Products Regulation ensures that there is enough information about these products so that consumers can use them safely. ECHA is responsible for implementing the regulation; the law on Prior Informed Consent sets guidelines for the import of hazardous chemicals.
Through this mechanism, countries due to receive hazardous chemicals are informed in advance and have the possibility of rejecting their import. Substances that may have serious effects on human health and the environment are identified as Substances of Very High Concern 1; these are substances which cause cancer, mutation or are toxic to reproduction as well as substances which persist in the body or the environment and do not break down. Other substances considered. Companies manufacturing or importing articles containing these substances in a concentration above 0,1% weight of the article, have legal obligations, they are required to inform users about the presence of the substance and therefore how to use it safely. Consumers have the right to ask the retailer whether these substances are present in the products they buy. Once a substance has been identified in the EU as being of high concern, it will be added to a list; this list is available on ECHA's website and shows consumers and industry which chemicals are identified as SVHCs.
Substances placed on the Candidate List can move to another list. This means that, after a given date, companies will not be allowed to place the substance on the market or to use it, unless they have been given prior authorisation to do so by ECHA. One of the main aims of this listing process is to phase out SVHCs where possible. In its 2018 substance evaluation progress report, ECHA said chemical companies failed to provide “important safety information” in nearly three quarters of cases checked that year. "The numbers show a similar picture to previous years" the report said. The agency noted that member states need to develop risk management measures to control unsafe commercial use of chemicals in 71% of the substances checked. Executive Director Bjorn Hansen called non-compliance with REACH a "worry". Industry group CEFIC acknowledged the problem; the European Environmental Bureau called for faster enforcement to minimise chemical exposure. European Chemicals Bureau Official website
Simplified molecular-input line-entry system
The simplified molecular-input line-entry system is a specification in the form of a line notation for describing the structure of chemical species using short ASCII strings. SMILES strings can be imported by most molecule editors for conversion back into two-dimensional drawings or three-dimensional models of the molecules; the original SMILES specification was initiated in the 1980s. It has since been extended. In 2007, an open standard called. Other linear notations include the Wiswesser line notation, ROSDAL, SYBYL Line Notation; the original SMILES specification was initiated by David Weininger at the USEPA Mid-Continent Ecology Division Laboratory in Duluth in the 1980s. Acknowledged for their parts in the early development were "Gilman Veith and Rose Russo and Albert Leo and Corwin Hansch for supporting the work, Arthur Weininger and Jeremy Scofield for assistance in programming the system." The Environmental Protection Agency funded the initial project to develop SMILES. It has since been modified and extended by others, most notably by Daylight Chemical Information Systems.
In 2007, an open standard called "OpenSMILES" was developed by the Blue Obelisk open-source chemistry community. Other'linear' notations include the Wiswesser Line Notation, ROSDAL and SLN. In July 2006, the IUPAC introduced the InChI as a standard for formula representation. SMILES is considered to have the advantage of being more human-readable than InChI; the term SMILES refers to a line notation for encoding molecular structures and specific instances should be called SMILES strings. However, the term SMILES is commonly used to refer to both a single SMILES string and a number of SMILES strings; the terms "canonical" and "isomeric" can lead to some confusion when applied to SMILES. The terms are not mutually exclusive. A number of valid SMILES strings can be written for a molecule. For example, CCO, OCC and CC all specify the structure of ethanol. Algorithms have been developed to generate the same SMILES string for a given molecule; this SMILES is unique for each structure, although dependent on the canonicalization algorithm used to generate it, is termed the canonical SMILES.
These algorithms first convert the SMILES to an internal representation of the molecular structure. Various algorithms for generating canonical SMILES have been developed and include those by Daylight Chemical Information Systems, OpenEye Scientific Software, MEDIT, Chemical Computing Group, MolSoft LLC, the Chemistry Development Kit. A common application of canonical SMILES is indexing and ensuring uniqueness of molecules in a database; the original paper that described the CANGEN algorithm claimed to generate unique SMILES strings for graphs representing molecules, but the algorithm fails for a number of simple cases and cannot be considered a correct method for representing a graph canonically. There is no systematic comparison across commercial software to test if such flaws exist in those packages. SMILES notation allows the specification of configuration at tetrahedral centers, double bond geometry; these are structural features that cannot be specified by connectivity alone and SMILES which encode this information are termed isomeric SMILES.
A notable feature of these rules is. The term isomeric SMILES is applied to SMILES in which isotopes are specified. In terms of a graph-based computational procedure, SMILES is a string obtained by printing the symbol nodes encountered in a depth-first tree traversal of a chemical graph; the chemical graph is first trimmed to remove hydrogen atoms and cycles are broken to turn it into a spanning tree. Where cycles have been broken, numeric suffix labels are included to indicate the connected nodes. Parentheses are used to indicate points of branching on the tree; the resultant SMILES form depends on the choices: of the bonds chosen to break cycles, of the starting atom used for the depth-first traversal, of the order in which branches are listed when encountered. Atoms are represented by the standard abbreviation of the chemical elements, in square brackets, such as for gold. Brackets may be omitted in the common case of atoms which: are in the "organic subset" of B, C, N, O, P, S, F, Cl, Br, or I, have no formal charge, have the number of hydrogens attached implied by the SMILES valence model, are the normal isotopes, are not chiral centers.
All other elements must be enclosed in brackets, have charges and hydrogens shown explicitly. For instance, the SMILES for water may be written as either O or. Hydrogen may be written as a separate atom; when brackets are used, the symbol H is added if the atom in brackets is bonded to one or more hydrogen, followed by the number of hydrogen atoms if greater than 1 by the sign + for a positive charge or by - for a negative charge. For example, for ammonium. If there is more than one charge, it is written as digit.