1.
Blood vessel
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The blood vessels are the part of the circulatory system that transports blood throughout the human body. The word vascular, meaning relating to the vessels, is derived from the Latin vas. A few structures do not contain blood vessels and are labeled, tunica media, circularly arranged elastic fiber, connective tissue, polysaccharide substances, the second and third layer are separated by another thick elastic band called external elastic lamina. The tunica media may be rich in smooth muscle, which controls the caliber of the vessel. Veins dont have the external elastic lamina, but only an internal one, tunica adventitia, entirely made of connective tissue. It also contains nerves that supply the vessel as well as nutrient capillaries in the blood vessels. Capillaries consist of more than a layer of endothelium and occasional connective tissue. When blood vessels connect to form a region of diffuse vascular supply it is called an anastomosis, anastomoses provide critical alternative routes for blood to flow in case of blockages. There is a layer of muscle surrounding the arteries and the veins which help contract and this creates enough pressure for blood to be pumped around the body. Blood vessels are part of the system, together with the heart. They are roughly grouped as arterial and venous, determined by whether the blood in it is flowing away from or toward the heart. The term arterial blood is used to indicate blood high in oxygen. This is because they are carrying the blood to and from the lungs, respectively, blood vessels do not actively engage in the transport of blood, but arteries—and veins to a degree—can regulate their inner diameter by contraction of the muscular layer. This changes the flow to downstream organs, and is determined by the autonomic nervous system. Vasodilation and vasoconstriction are also used antagonistically as methods of thermoregulation, oxygen is the most critical nutrient carried by the blood. In all arteries apart from the artery, hemoglobin is highly saturated with oxygen. In all veins apart from the vein, the hemoglobin is desaturated at about 75%. The blood pressure in blood vessels is traditionally expressed in millimetres of mercury, in the arterial system, this is usually around 120 mmHg systolic and 80 mmHg diastolic
2.
Endothelium
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It is a thin layer of simple squamous cells called endothelial cells. Endothelial cells in contact with blood are called vascular endothelial cells. Vascular endothelial cells line the entire system, from the heart to the smallest capillaries. These cells have unique functions in vascular biology and these functions include fluid filtration, such as in the glomerulus of the kidney, blood vessel tone, hemostasis, neutrophil recruitment, and hormone trafficking. Endothelium of the surfaces of the heart chambers is called endocardium. Both blood and lymphatic capillaries are composed of a layer of endothelial cells called a monolayer. In straight sections of a vessel, vascular endothelial cells typically align. Many considered the endothelium a specialized epithelial tissue, excessive or prolonged increases in permeability of the endothelial monolayer, as in cases of chronic inflammation, may lead to tissue edema/swelling. The most prevailing mechanism of endothelial dysfunction is an increase in reactive oxygen species, the signalling protein ERK5 is essential for maintaining normal endothelial cell function
3.
Embryo
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An embryo is an early stage of development of a multicellular diploid eukaryotic organism. In general, in organisms that reproduce sexually, an embryo develops from a zygote, the zygote possesses half the DNA of each of its two parents. In plants, animals, and some protists, the zygote will begin to divide by mitosis to produce a multicellular organism, the result of this process is an embryo. First attested in English in the mid-14c, the word embryon derives from Medieval Latin embryo, itself from Greek ἔμβρυον, lit. Young one, which is the neuter of ἔμβρυος, lit, growing in, from ἐν, in and βρύω, swell, be full, the proper Latinized form of the Greek term would be embryum. In animals, the development of the zygote into an embryo proceeds through specific stages of blastula, gastrula. The blastula stage typically features a fluid-filled cavity, the blastocoel, surrounded by a sphere or sheet of cells, in a placental mammal, an ovum is fertilized in a fallopian tube through which it travels into the uterus. An embryo is called a fetus at an advanced stage of development. In humans, this is from the week of gestation. During gastrulation the cells of the blastula undergo coordinated processes of cell division, invasion, in triploblastic organisms, the three germ layers are called endoderm, ectoderm, and mesoderm. The position and arrangement of the layers are highly species-specific, however. For example, in neurogenesis, a subpopulation of cells is set aside to become the brain, spinal cord. Modern developmental biology is extensively probing the molecular basis for every type of organogenesis, including angiogenesis, chondrogenesis, myogenesis, osteogenesis, and many others. In botany, a plant embryo is part of a seed, consisting of precursor tissues for the leaves, stem. Once the embryo begins to germinate — grow out from the seed — it is called a seedling, bryophytes and ferns also produce an embryo, but do not produce seeds. In these plants, the embryo begins its existence attached to the inside of the archegonium on a parental gametophyte from which the egg cell was generated, the structure and development of the rest of the embryo varies by group of plants. Once the embryo has expanded beyond the enclosing archegonium, it is no longer termed an embryo, embryos are used in various fields of research and in techniques of assisted reproductive technology. An egg may be fertilized in vitro and the embryo may be frozen for later use
4.
Wound healing
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Here wound healing is depicted and described in a discrete timeline of physical attributes comprising the posttrauma repair process. In undamaged skin, the epidermis and dermis form a barrier against the external environment. When the barrier is broken, a cascade of biochemical events is set into motion to repair the damage. This process is divided into phases, blood clotting, inflammation, tissue growth. Blood clotting may be considered to be part of the stage instead of a separate stage. Hemostasis, Within the first few minutes of injury, platelets in the begin to stick to the injured site. This activates the platelets, causing a few things to happen and they change into an amorphous shape, more suitable for clotting, and they release chemical signals to promote clotting. This results in the activation of fibrin, which forms a mesh and this makes a clot that serves to plug the break in the blood vessel, slowing/preventing further bleeding. Inflammation, During this phase, damaged and dead cells are cleared out, along with bacteria and this happens through the process of phagocytosis, where white blood cells eat debris by engulfing it. Platelet-derived growth factors are released into the wound that cause the migration and division of cells during the proliferative phase, proliferation, In this phase, angiogenesis, collagen deposition, granulation tissue formation, epithelialization, and wound contraction occur. In angiogenesis, vascular endothelial cells form new blood vessels, in fibroplasia and granulation tissue formation, fibroblasts grow and form a new, provisional extracellular matrix by excreting collagen and fibronectin. Concurrently, re-epithelialization of the epidermis occurs, in epithelial cells proliferate and crawl atop the wound bed. In wound contraction, myofibroblasts decrease the size of the wound by gripping the wound edges, when the cells roles are close to complete, unneeded cells undergo apoptosis. Maturation, During maturation and remodeling, collagen is realigned along tension lines, the wound healing process is not only complex but also fragile, and it is susceptible to interruption or failure leading to the formation of non-healing chronic wounds. Factors that contribute to non-healing chronic wounds are diabetes, venous or arterial disease, infection, Wound care encourages and speeds wound healing via cleaning and protection from reinjury or infection. Depending on each patients needs, it can range from the simplest first aid to entire nursing specialties such as wound, ostomy, timing is important to wound healing. Critically, the timing of wound reepithelialization can decide the outcome of the healing. If the epithelization of tissue over an area is slow, a scar will form over many weeks, or months, If the epithelization of a wounded area is fast
5.
Granulation tissue
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Granulation tissue is new connective tissue and microscopic blood vessels that form on the surfaces of a wound during the healing process. Granulation tissue typically grows from the base of a wound and is able to fill wounds of almost any size, examples of granulation tissue can be seen in pyogenic granulomas and pulp polyps. An excess of granulation tissue is referred to as proud flesh. The extracellular matrix of tissue is created and modified by fibroblasts. Initially, it consists of a network of collagen, a weaker form of the structural protein that can be produced rapidly. This is later replaced by the stronger, long-stranded type-I collagen, the main immune cells active in the tissue are macrophages and neutrophils, although other leukocytes are also present. These work to phagocytize old or damaged tissue, and protect the tissue from pathogenic infection. This is necessary both to aid the process and to protect against invading pathogens, as the wound often does not have an effective skin barrier to act as a first line of defense. Fibroblasts, the cells that deposit granulation tissue, depend on oxygen to proliferate. In vascularisation, also called angiogenesis, endothelial cells quickly grow into the tissue from older and these branch out in a systematic way, forming anastomoses with other vessels
6.
Angiogenesis inhibitor
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An angiogenesis inhibitor is a substance that inhibits the growth of new blood vessels. Some angiogenesis inhibitors are endogenous and a part of the bodys control. Nonetheless, inhibitors are used to treat cancer, macular degeneration in the eye. When a tumor stimulates the growth of new vessels, it is said to have undergone an angiogenic switch, the principal stimulus for this angiogenic switch appears to be oxygen deprivation, although other stimuli such as inflammation, oncogenic mutations and mechanical stress may also play a role. The angiogenic switch leads to expression of pro-angiogenic factors and increased tumor vascularization. Specifically, tumor cells release various pro-angiogenic paracrine factors (including angiogenin, vascular endothelial growth factor, fibroblast growth factor and these stimulate endothelial cell proliferation, migration and invasion resulting in new vascular structures sprouting from nearby blood vessels. Cell adhesion molecules, such as integrins, are critical to the attachment, inhibition of the VEGF pathway has become the focus of angiogenesis research as approximately 60% of malignant tumors express high concentrations of VEGF. Strategies to inhibit the VEGF pathway include antibodies directed against VEGF or VEGFR, soluble VEGFR/VEGFR hybrids, the most widely used VEGF pathway inhibitor on the market today is Bevacizumab. Bevacizumab binds to VEGF and inhibits it from binding to VEGF receptors, angiogenesis is regulated by the activity of endogenous stimulators and inhibitors. Endogenous inhibitors are found in the body naturally and involved in the process of regulating blood vessel formation. During tumor growth, the action of angiogenesis stimulators surpasses the control of angiogenesis inhibitors, allowing for unregulated or less regulated blood vessel growth, endogenous inhibitors are attractive targets for cancer therapy because they are less toxic and less likely to lead to drug resistance than some exogenous inhibitors. However, the use of endogenous inhibitors has disadvantages. In animal studies, high doses of inhibitors were required to prevent tumor growth, a target can also be added to the outside of the bacteria so that they are sent to the correct organ in the body. This method has shown to work both in vitro and in vivo in mice models, with very promising results. It is expected that this method will become commonplace for treatment of cancer types in humans in the future. Research and development in this field has been largely by the desire to find better cancer treatments. Tumors cannot grow larger than 2mm without angiogenesis, by stopping the growth of blood vessels, scientists hope to cut the means by which tumors can nourish themselves and thus metastasize. Angiogenesis inhibitors are used as treatment for the wet form of macular degeneration
7.
Perfusion
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Perfusion is the passage of fluid through the circulatory system or lymphatic system to an organ or a tissue, usually referring to the delivery of blood to a capillary bed in tissue. The word is derived from the French verb perfuser meaning to pour over or through, all animal tissues require an adequate blood supply for health and life. Poor perfusion, that is, ischemia, causes problems, as seen for example in coronary artery disease, deep vein thrombosis. Tests verifying that adequate perfusion exists are a part of an assessment process that are performed by medical or emergency personnel. The most common methods include evaluating a bodys skin color, temperature, condition, during major surgery, especially cardiothoracic surgery, perfusion must be maintained and managed by the health professionals involved, rather than left to the bodys homeostasis alone. As the lead surgeons are often too busy to handle all hemodynamic control by themselves, there are more than one hundred thousand perfusion procedures annually. In 1920, August Krogh was awarded the Nobel Prize in Physiology or Medicine for his discovering the mechanism of regulation of capillaries in skeletal muscle. Krogh was the first to describe the adaptation of blood perfusion in muscle, underperfusion is also called poor perfusion and malperfusion is any type of incorrect perfusion. Heart tissues, for example, are classified as being overperfused because they normally are receiving more blood than the rest of tissues in the organism. In the case of cells, extra blood flow in them is used for thermoregulation of a body. In equations, the symbol Q̇ often represents perfusion or, relatedly, microspheres that are labeled with radioactive isotopes have been widely used since the 1960s. Radioactively labeled particles are injected into the test subject and a detector measures radioactivity in tissues of interest. Application of this process is used to develop radionuclide angiography, a method of diagnosing heart problems, in the 1990s, methods for using fluorescent microspheres became a common substitute for radioactive particles. Perfusion of various tissues can be measured in vivo with nuclear medicine methods which are mainly positron emission tomography. The first is based on the use of an injected contrast agent that changes the magnetic susceptibility of blood, brain perfusion can be estimated with contrast-enhanced computed tomography. Perfusion can be determined by measuring the thermal diffusion and then separating it into thermal conductivity. RCBF is usually measured continuously in time and it is necessary to stop the measurement periodically to cool down and reassess the thermal conductivity
8.
Receptor (biochemistry)
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In biochemistry and pharmacology, a receptor is a protein molecule that receives chemical signals from outside a cell. When such chemical signals bind to a receptor, they cause some form of cellular/tissue response, however, sometimes in pharmacology, the term is also used to include other proteins that are drug targets, such as enzymes, transporters and ion channels. Receptor proteins can be classified by their location, transmembrane receptors include ion channel-linked receptors, G protein-linked hormone receptors, and enzyme-linked hormone receptors. Intracellular receptors are found inside the cell, and include cytoplasmic receptors. The endogenously designated -molecule for a receptor is referred to as its endogenous ligand. E. g. the endogenous ligand for the acetylcholine receptor is acetylcholine but the receptor can also be activated by nicotine. Each receptor is linked to a specific cellular biochemical pathway, while numerous receptors are found in most cells, each receptor will only bind with ligands of a particular structure, much like how locks will only accept specifically shaped keys. When a ligand binds to its receptor, it activates or inhibits the receptors associated biochemical pathway. The ligand-binding cavities are located at the interface between the subunits, type 2, G protein-coupled receptors – This is the largest family of receptors and includes the receptors for several hormones and slow transmitters e. g. dopamine, metabotropic glutamate. They are composed of seven transmembrane alpha helices, the loops connecting the alpha helices form extracellular and intracellular domains. The aforementioned receptors are coupled to different intracellular effector systems via G proteins, the insulin receptor is an example. Type 4, Nuclear receptors – While they are called nuclear receptors, they are located in the cytoplasm. They are composed of a C-terminal ligand-binding region, a core DNA-binding domain, the core region has two zinc fingers that are responsible for recognizing the DNA sequences specific to this receptor. The N terminus interacts with other transcription factors in a ligand-independent manner. Steroid and thyroid-hormone receptors are examples of such receptors, membrane receptors may be isolated from cell membranes by complex extraction procedures using solvents, detergents, and/or affinity purification. The structures and actions of receptors may be studied by using methods such as X-ray crystallography, NMR, circular dichroism. Computer simulations of the behavior of receptors have been used to gain understanding of their mechanisms of action. Ligand binding is an equilibrium process, ligands bind to receptors and dissociate from them according to the law of mass action
9.
Enzyme
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Enzymes /ˈɛnzaɪmz/ are macromolecular biological catalysts. Enzymes accelerate, or catalyze, chemical reactions, the molecules at the beginning of the process upon which enzymes may act are called substrates and the enzyme converts these into different molecules, called products. Almost all metabolic processes in the cell need enzymes in order to occur at rates fast enough to sustain life, the set of enzymes made in a cell determines which metabolic pathways occur in that cell. The study of enzymes is called enzymology, enzymes are known to catalyze more than 5,000 biochemical reaction types. Most enzymes are proteins, although a few are catalytic RNA molecules, enzymes specificity comes from their unique three-dimensional structures. Like all catalysts, enzymes increase the rate of a reaction by lowering its activation energy, some enzymes can make their conversion of substrate to product occur many millions of times faster. An extreme example is orotidine 5-phosphate decarboxylase, which allows a reaction that would take millions of years to occur in milliseconds. Chemically, enzymes are like any catalyst and are not consumed in chemical reactions, enzymes differ from most other catalysts by being much more specific. Enzyme activity can be affected by other molecules, inhibitors are molecules that decrease enzyme activity, many drugs and poisons are enzyme inhibitors. An enzymes activity decreases markedly outside its optimal temperature and pH, some enzymes are used commercially, for example, in the synthesis of antibiotics. French chemist Anselme Payen was the first to discover an enzyme, diastase and he wrote that alcoholic fermentation is an act correlated with the life and organization of the yeast cells, not with the death or putrefaction of the cells. In 1877, German physiologist Wilhelm Kühne first used the term enzyme, the word enzyme was used later to refer to nonliving substances such as pepsin, and the word ferment was used to refer to chemical activity produced by living organisms. Eduard Buchner submitted his first paper on the study of yeast extracts in 1897, in a series of experiments at the University of Berlin, he found that sugar was fermented by yeast extracts even when there were no living yeast cells in the mixture. He named the enzyme that brought about the fermentation of sucrose zymase, in 1907, he received the Nobel Prize in Chemistry for his discovery of cell-free fermentation. Following Buchners example, enzymes are usually named according to the reaction they carry out, the biochemical identity of enzymes was still unknown in the early 1900s. Sumner showed that the enzyme urease was a protein and crystallized it. These three scientists were awarded the 1946 Nobel Prize in Chemistry, the discovery that enzymes could be crystallized eventually allowed their structures to be solved by x-ray crystallography. This high-resolution structure of lysozyme marked the beginning of the field of structural biology, an enzymes name is often derived from its substrate or the chemical reaction it catalyzes, with the word ending in -ase
10.
Protease
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A protease is any enzyme that performs proteolysis, protein catabolism by hydrolysis of peptide bonds. Proteases have evolved multiple times, and different classes of protease can perform the reaction by completely different catalytic mechanisms. Proteases can be found in Animalia, Plantae, Fungi, Bacteria, Archaea, the threonine and glutamic-acid proteases were not described until 1995 and 2004 respectively. One way to make a nucleophile is by a catalytic triad, a seventh catalytic type of proteolytic enzymes, asparagine peptide lyase, was described in 2011. Its proteolytic mechanism is unusual since, rather than hydrolysis, it performs an elimination reaction, during this reaction, the catalytic asparagine forms a cyclic chemical structure that cleaves itself at asparagine residues in proteins under the right conditions. Given its fundamentally different mechanism, its inclusion as a peptidase may be debatable, an up-to-date classification of protease evolutionary superfamilies is found in the MEROPS database. In this database, proteases are classified firstly by clan based on structure, mechanism, within each clan, proteases are classified into families based on sequence similarity. Each family may contain hundreds of related proteases. Currently more than 50 clans are known, each indicating an independent evolutionary origin of proteolysis, alternatively, proteases may be classified by the optimal pH in which they are active, Acid proteases Neutral proteases involved in type 1 hypersensitivity. Here, it is released by mast cells and causes activation of complement, basic proteases Proteases are involved in digesting long protein chains into shorter fragments by splitting the peptide bonds that link amino acid residues. Some detach the terminal amino acids from the chain, others attack internal peptide bonds of a protein. Catalysis is achieved by one of two mechanisms, Aspartic, glutamic and metallo- proteases activate a water molecule performs a nucleophilic attack on the peptide bond to hydrolyse it. Serine, threonine and cysteine proteases use a nucleophilic residue and that residue performs a nucleophilic attack to covalently link the protease to the substrate protein, releasing the first half of the product. This covalent acyl-enzyme intermediate is hydrolysed by activated water to complete catalysis by releasing the second half of the product. Proteolysis can be highly promiscuous such that a range of protein substrates are hydrolysed. This is the case for digestive enzymes such as trypsin which have to be able to cleave the array of proteins ingested into smaller peptide fragments, promiscuous proteases typically bind to a single amino acid on the substrate and so only have specificity for that residue. For example, trypsin is specific for the sequences. K\, conversely some proteases are highly specific and only cleave substrates with a certain sequence. Blood clotting and viral polyprotein processing requires this level of specificity in order to achieve precise cleavage events and this is achieved by proteases having a long binding cleft or tunnel with several pockets along it which bind the specified residues
11.
Basement membrane
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The basement membrane is a thin, fibrous, extracellular matrix of tissue that separates the epithelium, mesothelium and endothelium from underlying connective tissue. As seen with electron microscope, the basement membrane is composed of two layers, the lamina and the underlying layer of reticular connective tissue. The underlying connective tissue attaches to the lamina with collagen VII anchoring fibrils. The two layers together are referred to as the basement membrane. The basal lamina layer can further be divided into two layers, the clear layer closer to the epithelium is called the lamina lucida, while the dense layer closer to the connective tissue is called the lamina densa. In addition to collagen, this supportive matrix contains intrinsic macromolecular components, the lamina densa, whose collagen IV fibers are coated with the heparan sulfate-rich proteoglycan perlecan, and the lamina lucida together make up the basal lamina. Integrins are not part of the lamina, they are part of desmosomes which are in the basement membrane. This is achieved by cell-matrix adhesions through substrate adhesion molecules, the basement membrane acts as a mechanical barrier, preventing malignant cells from invading the deeper tissues. Early stages of malignancy that are limited to the epithelial layer by the basement membrane are called carcinoma in situ. The basement membrane is essential for angiogenesis. Basement membrane proteins have been found to accelerate differentiation of endothelial cells, some diseases result from a poorly functioning basement membrane. The cause can be defects, injuries by the bodys own immune system. Genetic defects in the fibers of the basement membrane cause Alport syndrome. Non-collagenous domain basement membrane collagen type IV is autoantigen of autoantibodies in the autoimmune disease Goodpastures syndrome, a group of diseases stemming from improper function of basement membrane zone are united under the name epidermolysis bullosa. Intima Kefalides, Nicholas A. & Borel, Jacques P. eds, basement membranes, cell and molecular biology
12.
Cell growth
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The term cell growth is used in the contexts of biological cell development and cell division. When used in the context of cell division, it refers to growth of cell populations, when used in the context of cell development, the term refers to increase in cytoplasmic and organelle volume, as well as increase in genetic material following the replication during S phase. Cell populations go through a type of exponential growth called doubling. Thus, each generation of cells should be twice as numerous as the previous generation, however, the number of generations only gives a maximum figure as not all cells survive in each generation. Cell size is variable among organisms, with some algae such as Caulerpa taxifolia being a single cell several meters in length. Plant cells are larger than animal cells, and protists such as Paramecium can be 330 μm long. How these cells decide how big they should be before dividing is an open question, chemical gradients are known to be partly responsible, and it is hypothesized that mechanical stress detection by cytoskeletal structures is involved. Work on the topic generally requires an organism whose cell cycle is well-characterized, the relationship between cell size and cell division has been extensively studied in yeast. For some cells, there is a mechanism by which division is not initiated until a cell has reached a certain size. If the nutrient supply is restricted, and the rate of increase in size is slowed. Yeast cell-size mutants were isolated that begin cell division reaching a normal/regular size. Wee1 protein is a kinase that normally phosphorylates the Cdc2 cell cycle regulatory protein. Cdc2 drives entry into mitosis by phosphorylating a range of targets. This covalent modification of the structure of Cdc2 inhibits the enzymatic activity of Cdc2. Wee1 acts to keep Cdc2 inactive during early G2 when cells are still small, when cells have reached sufficient size during G2, the phosphatase Cdc25 removes the inhibitory phosphorylation, and thus activates Cdc2 to allow mitotic entry. A balance of Wee1 and Cdc25 activity with changes in size is coordinated by the mitotic entry control system. It has been shown in Wee1 mutants, cells with weakened Wee1 activity, thus, mitosis occurs before the yeast reach their normal size. This suggests that cell division may be regulated in part by dilution of Wee1 protein in cells as they grow larger, the protein kinase Cdr2 and the Cdr2-related kinase Cdr1 are localized to a band of cortical nodes in the middle of interphase cells
13.
Tandem
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Tandem is an arrangement in which a team of machines, animals or people are lined up one behind another, all facing in the same direction. The tandem harness allows additional animals to provide pulling power for a designed for a single animal. The English word tandem derives with a play from the Latin adverb tandem. Tandem seating may be used on a bicycle where it is alternative to sociable seating. Tandem can also be used generally to refer to any group of persons or objects working together. The Messerschmitt KR200 was an example of a small automobile that used tandem seating. A tandem arrangement may also be used for cars parked in a residential garage, in heavy trucks tandem refers to two closely spaced axles. Legally defined by the distance between the axles, mechanically there are many configurations, either or both axles may be powered, and often interact with each other. The two seating configurations for trainer, night and all-weather interceptor or attack aircraft are pilot and instructor side by side or in tandem, usually, the pilot is in front and the instructor behind. Attack aircraft and all-weather interceptors often use a crew member to operate avionics such as radar. Bombers such as the Convair B-58 Hustler seated three crew members in tandem, a common engineering adaptation is to lengthen the cockpit or fuselage to create a trainer with tandem seating from a single-seater aircraft. The Boeing B-47 Stratojet and Boeing XB-52 bombers used fighter-style tandem seating, the Grumman A-6 Intruder, General Dynamics F-111 Aardvark, Sukhoi Su-24 or the Sukhoi Su-34 are examples of combat aircraft that use this configuration. For training aircraft, it has the advantage that pilot and instructor can see each others actions, allowing the pilot to learn from the instructor, the tandem configuration has the advantage of being closer to the normal working environment that a fast jet pilot is likely to encounter. In some cases, such as the Northrop Grumman EA-6B Prowler, three Men In a Carriage Drawn by a Tandem Horse Team. Tandem Horse Teams Museum Victoria official site, illustration
14.
Integrin
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Integrins are transmembrane receptors that facilitate cell-extracellular matrix adhesion. The presence of integrins allow rapid and flexible responses to events at the cell surface, several types of integrins exist, and one cell may have multiple different types on its surface. Integrins are found in all animals, integrins work alongside other receptors such as cadherins, the immunoglobulin superfamily cell adhesion molecules, selectins and syndecans to mediate cell–cell and cell–matrix interaction. Ligands for integrins include fibronectin, vitronectin, collagen and laminin, integrins are obligate heterodimers, meaning that they have two subunits, α and β. Integrins in mammals have eighteen α and eight β subunits, in Drosophila five α, the α and β subunits each penetrate the plasma membrane and possess small cytoplasmic domains. Variants of some subunits are formed by differential RNA splicing, for example, through different combinations of the α and β subunits, around 24 unique integrins are generated. Integrin subunits span the membrane and have short cytoplasmic domains of 40–70 amino acids. The exception is the subunit, which has a cytoplasmic domain of 1,088 amino acids. Outside the cell membrane, the α and β chains lie close together along a length of about 23 nm and they have been compared to lobster claws, although the dont actually pinch their ligand, they chemically interact with it at the insides of the tips of their pinchers. The molecular mass of the subunits can vary from 90 kDa to 160 kDa. Beta subunits have four cysteine-rich repeated sequences, both α and β subunits bind several divalent cations. The role of divalent cations in the α subunit is unknown, the cations in the β subunits are more interesting, they are directly involved in coordinating at least some of the ligands that integrins bind. Integrins can be categorized in multiple ways, for example, some α chains have an additional structural element inserted toward the N-terminal, the alpha-A domain. Integrins carrying this domain either bind to collagens, or act as cell-cell adhesion molecules and this α-I domain is the binding site for ligands of such integrins. Those integrins that dont carry this inserted domain also have an A-domain in their binding site. In both cases, the A-domains carry up to three divalent cation binding sites, the other two sites become occupied by cations when ligands bind—at least for those ligands involving an acidic amino acid in their interaction sites. An acidic amino acid features in the site of many ECM proteins. It showed the molecule to be folded into an inverted V-shape that potentially brings the ligand-binding sites close to the cell membrane, perhaps more importantly, the crystal structure was also obtained for the same integrin bound to a small ligand containing the RGD-sequence, the drug cilengitide
15.
Neonatal
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An infant is the more formal or specialised synonym for baby, the very young offspring of a human or other animal. A newborn is, in use, an infant who is only hours, days. In medical contexts, newborn or neonate refers to an infant in the first 28 days after birth, the term applies to premature, full term, and postmature infants, before birth, the term fetus is used. The term infant is typically applied to children under one year of age, however, definitions may vary. When a human child learns to walk, the toddler may be used instead. In British English, infant is a term that can be applied to children aged between four and seven. As a legal term, infancy continues from birth until age 18, a newborns shoulders and hips are wide, the abdomen protrudes slightly, and the arms and legs are relatively long with respect to the rest of their body. In first world nations, the total body length of newborns are 35. 6–50.8 cm. The Apgar score is a measure of a transition from the uterus during the first minutes after birth. In developed countries, the birth weight of a full-term newborn is approximately 3.4 kg. After the first week, healthy term neonates should gain 10–20 grams/day, a newborns head is very large in proportion to the body, and the cranium is enormous relative to his or her face. While the adult human skull is one seventh of the total body length. Normal head circumference for an infant is 33–36 cm at birth. At birth, many regions of the skull have not yet been converted to bone. The two largest are the anterior fontanel, located at the top front portion of the head, and the smaller triangular-shaped posterior fontanel. Later in the life, these bones will fuse together in a natural process. A protein called noggin is responsible for the delay in an infants skull fusion, during labour and birth, the infants skull changes shape to fit through the birth canal, sometimes causing the child to be born with a misshapen or elongated head. It will usually return to normal on its own within a few days or weeks, special exercises sometimes advised by physicians may assist the process
16.
Endothelial
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It is a thin layer of simple squamous cells called endothelial cells. Endothelial cells in contact with blood are called vascular endothelial cells. Vascular endothelial cells line the entire system, from the heart to the smallest capillaries. These cells have unique functions in vascular biology and these functions include fluid filtration, such as in the glomerulus of the kidney, blood vessel tone, hemostasis, neutrophil recruitment, and hormone trafficking. Endothelium of the surfaces of the heart chambers is called endocardium. Both blood and lymphatic capillaries are composed of a layer of endothelial cells called a monolayer. In straight sections of a vessel, vascular endothelial cells typically align. Many considered the endothelium a specialized epithelial tissue, excessive or prolonged increases in permeability of the endothelial monolayer, as in cases of chronic inflammation, may lead to tissue edema/swelling. The most prevailing mechanism of endothelial dysfunction is an increase in reactive oxygen species, the signalling protein ERK5 is essential for maintaining normal endothelial cell function
17.
Cell junction
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A cell junction is a type of structure that exists within the tissue of some multicellular organisms, such as animals. Cell junctions consist of multiprotein complexes that provide contact between neighboring cells or between a cell and the extracellular matrix and they also build up the paracellular barrier of epithelia and control the paracellular transport. Cell junctions are especially abundant in epithelial tissues, cell junctions are especially important in enabling communication between neighboring cells via specialized proteins called communicating junctions. Cell junctions are important in reducing stress placed upon cells. In multicellular plants, the functions of cell junctions are instead provided for by cell walls. The analogues of communicative cell junctions in plants are called plasmodesmata, cells within tissues and organs must be anchored to one another and attached to components of the extracellular matrix. These junctions are most abundant in tissues that are subject to constant mechanical stress such as skin, desmosomes, also termed as maculae adherentes, can be visualized as rivets through the plasma membrane of adjacent cells. Intermediate filaments composed of keratin or desmin are attached to membrane-associated attachment proteins that form a dense plaque on the face of the membrane. Cadherin molecules form the actual anchor by attaching to the plaque, extending through the membrane. Hemidesmosomes form rivet-like links between cytoskeleton and extracellular matrix such as the basal laminae that underlie epithelia. Like desmosomes, they tie to intermediate filaments in the cytoplasm, adherens junctions share the characteristic of anchoring cells through their cytoplasmic actin filaments. Similarly to desmosomes and hemidesmosomes, their transmembrane anchors are composed of cadherins in those that anchor to other cells, there is considerable morphologic diversity among adherens junctions. Those that tie cells to one another are seen as isolated streaks or spots, the band-type of adherens junctions is associated with bundles of actin filaments that also encircle the cell just below the plasma membrane. Spot-like adherens junctions help cells adhere to extracellular matrix both in vivo and in vitro where they are called focal adhesions and this is possible due to six connexin proteins interacting to form a cylinder with a pore in the centre called a connexon. The connexon complexes stretches across the membrane and when two adjacent cell connexons interact, they form a complete gap junction channel. Connexon pores vary in size, polarity and therefore can be specific depending on the proteins that constitute each individual connexon. Gap junctions play vital roles in the body, including their role in the uniform contractile of the heart muscle. They are also relevant in signal transfers in the brain, retinal and skin cells are also dependent on gap junctions in cell differentiation and proliferation
18.
Perforation
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A perforation is a small hole in a thin material or web. There is usually more than one perforation in an organized fashion, the process of creating perforations is called perforating, which involves puncturing the workpiece with a tool. Perforations are usually used to allow separation of two sections of the material, such as allowing paper to be torn easily along the line. Packaging with perforations in paperboard or plastic film is easy for consumers to open, other purposes include filtrating fluids, sound deadening, allowing light or fluids to pass through, and to create an aesthetic design. Various applications include plastic films to allow the packages to breathe, medical films, micro perforated plate and sound, perforation can be created by pins, needles, die and punch or laser. Rotary pinned perforation rollers are precision tools that can be used to perforate a wide variety of materials, the pins or needles can be used cold or heated. Cold perforation tools include needle punches, there are a handful of manufacturers that specialize in hot and cold needle perforation tooling and equipment. In materials that have elasticity this can result in a hole that is preferred in many applications. Pinned rollers can be made from a variety of materials, including plastic, steel, in more brittle films, cold perforation can cause slitting rather than creating a round hole, which can jeopardize the materials integrity under pressure. The solution to this is often heating the pin, i. e. hot pin perforation, hot perforation melts a hole in the material, causing a reinforced ring around the hole. Hot needle perforation also assists when high density pin patterns are utilized, die and punch sets can be used for thicker materials or materials that require large holes, this process is the most common for metalworking. The workpiece is sheared by pressing the punch through the workpiece, the middle section of the workpiece is scrap, commonly known as the chad in paper and similar materials. The punch and die are shaped to produce the desired shaped hole, the clearance must be properly maintained to ensure a clean cut. Burrs are produced on the side of the workpiece that is against the die, common applications are fruit and vegetable bags, hole punching and ticket punching. Laser cutting can place many precise holes in a web, laser perforations look similar in many respects to hot needle perforations. The big advantage of laser perforation is the consistency of the hole size and this is very important in modified atmosphere packaging for fresh produce. The laser perforation is often carried out on roll slitting machines as the material is slit down to the finished roll size. Perforation frequently refers to the practice of creating a series of holes or slits so that paper or plastics can be torn more easily along a given line
19.
Pericyte
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Pericytes are contractile cells that wrap around the endothelial cells that line the capillaries and venules throughout the body. In the brain, pericytes help sustain the blood–brain barrier as well as several other homeostatic and hemostatic functions of the brain and these cells are also a key component of the neurovascular unit, which includes endothelial cells, astrocytes, and neurons. Pericytes regulate capillary blood flow, the clearance and phagocytosis of cellular debris, Pericytes stabilize and monitor the maturation of endothelial cells by means of direct communication between the cell membrane as well as through paracrine signaling. A deficiency of pericytes in the nervous system can cause the blood–brain barrier to break down. In the central system, pericytes wrap around the endothelial cells that line the inside of the capillary. Pericytes also project finger-like extensions that wrap around the capillary wall, both pericytes and endothelial cells share a basement membrane where a variety of intercellular connections are made. Many types of integrin molecules facilitate communication between pericytes and endothelial cells separated by the basement membrane, Pericytes can also form direct connections with neighboring cells by forming peg and socket arrangements in which parts of the cells interlock, similar to the gears of a clock. At these interlocking sites, gap junctions can be formed which allow the pericytes and neighboring cells to exchange ions, important molecules in these intercellular connections include N-cadherin, fibronectin, connexin and various integrins. In some regions of the basement membrane, adhesion plaques composed of fibronectin can be found and these plaques facilitate the connection of the basement membrane to the cytoskeletal structure composed of actin, and the plasma membrane of the pericytes and endothelial cells. Pericytes in the striated muscle are of two distinct populations, each with its own role. The first pericyte subtype can differentiate into fat cells while the other into muscle cells, type-1 characterized by negative expression for nestin and type-2 characterized by positive expression for nestin. The extent to which type-1 pericytes participate in fat accumulation is not known, Pericytes are also associated with allowing endothelial cells to differentiate, multiply, form vascular branches, survive apoptotic signals and travel throughout the body. Certain pericytes, known as microvascular pericytes, develop around the walls of capillaries, microvascular pericytes may not be contractile cells because they lack alpha-actin isoforms, structures that are common amongst other contractile cells. These cells communicate with cells via gap junctions and in turn cause endothelial cells to proliferate or be selectively inhibited. If this process did not occur, hyperplasia and abnormal vascular morphogenesis could occur and these types of pericyte can also phagocytose exogenous proteins. This suggests that the cell type might have derived from microglia. Pericytes regenerative capacity is affected by aging, such versatility is conducive because they actively remodel blood vessels throughout the body and can thereby blend homogeneously with the local tissue environment. Aside from creating and remodeling blood vessels in a viable fashion and it has been studied in vivo that pericytes release a hormone known as pericytic aminopeptidase N/pAPN that may help to promote angiogenesis
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Myofibroblast
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A myofibroblast is a cell that is in between a fibroblast and a smooth muscle cell in phenotype. There are many ways of myofibroblast development, Partial smooth muscle differentiation of a fibroblastic cell Activation of a stellate cell. Loss of contractile phenotype of a muscle cell. Direct myofibroblastic differentiation of a progenitor cell resident in a stromal tissue, homing and recruitment of a circulating mesenchymal precursor which can directly differentiate as above or indirectly differentiate through the other cell types as intermediates. Epithelial to mesenchymal transdifferentiation of an epithelial cell and they are positive for other smooth markers like intermediate filament type desmin in some tissues, but may be negative for desmin in some others. Similar heterogeneous positivity may exist for almost every smooth muscle marker except probably a few which are only in contractile smooth muscles like metavinculin and smoothelin. Some myofibroblasts may also be positive for GFAP, myofibroblasts are found subepithelially in many mucosal surfaces - for example, throughout almost the whole of the gastrointestinal and genitourinary tracts. Here they not only act as a regulator of the shape of the crypts and villi but also act as stem-niche cells in the intestinal crypts and they have both support as well as paracrine function in most places. In many organs like liver, lung, and kidney they are involved in fibrosis. Pericytes and renal mesangial cells are examples of modified myofibroblast-like cells. Myofibroblasts may interfere with the propagation of signals controlling heart rhythm. Ursodiol is a drug for this condition. Myofibroblasts can contract by using smooth muscle type actin-myosin complex, rich in a form of actin called alpha-smooth muscle actin and these cells are then capable of speeding wound repair by contracting the edges of the wound. More recently it has shown that fibroblasts can transform into myofibroblasts with photobiomodulation. Similarly, in wounds that fail to resolve and become keloids or hypertrophic scars, myofibroblasts may persist, rather than disappearing by apoptosis
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Collagen
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Collagen /ˈkɒlədʒᵻn/ is the main structural protein in the extracellular space in the various connective tissues in animal bodies. As the main component of tissue, it is the most abundant protein in mammals. Depending upon the degree of mineralization, collagen tissues may be rigid, compliant, Collagen, in the form of elongated fibrils, is mostly found in fibrous tissues such as tendons, ligaments and skin. It is also abundant in corneas, cartilage, bones, blood vessels, the gut, intervertebral discs, in muscle tissue, it serves as a major component of the endomysium. Collagen constitutes one to two percent of muscle tissue, and accounts for 6% of the weight of strong, tendinous muscles, the fibroblast is the most common cell that creates collagen. Gelatin, which is used in food and industry, is collagen that has been irreversibly hydrolyzed, Collagen also has many medical uses in treating complications of the bones and skin. The name collagen comes from the Greek κόλλα, meaning glue and this refers to the compounds early use in the process of boiling the skin and sinews of horses and other animals to obtain glue. Collagen occurs in places throughout the body. Over 90% of the collagen in the body, however, is type I. So far,28 types of collagen have been identified and described, type IV, forms basal lamina, the epithelium-secreted layer of the basement membrane. Type V, cell surfaces, hair and placenta The collagenous cardiac skeleton which includes the four valve rings, is histologically, elastically and uniquely bound to cardiac muscle. The cardiac skeleton also includes the separating septa of the heart chambers – the interventricular septum, Collagen contribution to the measure of cardiac performance summarily represents a continuous torsional force opposed to the fluid mechanics of blood pressure emitted from the heart. With support from collagen, atrial fibrillation should never deteriorate to ventricular fibrillation, Collagen is layered in variable densities with cardiac muscle mass. The mass, distribution, age and density of collagen all contribute to the required to move blood back. Individual cardiac valvular leaflets are folded into shape by specialized collagen under variable pressure, gradual calcium deposition within collagen occurs as a natural function of aging. Pathology of the underpinning of the heart is understood within the category of connective tissue disease. Collagen has been used in cosmetic surgery, as a healing aid for burn patients for reconstruction of bone and a wide variety of dental, orthopedic. Both human and bovine collagen is used as dermal fillers for treatment of wrinkles
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Capillary
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Capillaries are the smallest of a bodys blood vessels that make up the microcirculation. Their endothelial linings are only one layer thick. Lymph capillaries connect with larger vessels to drain lymph collected in the microcirculation. The term angiogenesis denotes the formation of new capillaries from pre-existing blood vessels, blood flows from the heart through arteries, which branch and narrow into arterioles, and then branch further into capillaries where nutrients and wastes are exchanged. The capillaries then join and widen to become venules, which in turn widen and converge to become veins, capillaries do not function on their own, but instead in a capillary bed, an interweaving network of capillaries supplying organs and tissues. The more metabolically active a cell or environment is, the capillaries are required to supply nutrients. Metarterioles are found primarily in the mesenteric microcirculation and were thought to be present in most or all capillary beds. The physiological mechanisms underlying precapillary resistance is no longer considered to be a result of precapillary sphincters outside of the mesentery organ, lymphatic capillaries are slightly larger in diameter than blood capillaries, and have closed ends. This structure permits interstitial fluid to flow into them but not out, lymph capillaries have a greater internal oncotic pressure than blood capillaries, due to the greater concentration of plasma proteins in the lymph. However lipid-soluble molecules can diffuse through the endothelial cell membranes along concentration gradients. Tight junctions can be divided into two subtypes, Those with numerous transport vesicles, which are found primarily in skeletal muscles, fingers, gonads. Those with few vesicles, which are found in the central nervous system. These capillaries are a constituent of the blood–brain barrier, fenestrated capillaries have pores in the endothelial cells that are spanned by a diaphragm of radially oriented fibrils and allow small molecules and limited amounts of protein to diffuse. In the renal glomerulus there are cells with no diaphragms, called foot processes or pedicels. Both of these types of vessels have continuous basal laminae and are primarily located in the endocrine glands, intestines, pancreas. Sinusoidal capillaries are a type of open-pore capillary, that have larger openings in the endothelium. These types of blood vessels allow red and white cells and various serum proteins to pass. These capillaries lack pinocytotic vesicles, and therefore utilize gaps present in cell junctions to permit transfer between cells, and hence across the membrane
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Microcirculation
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Microcirculation is the circulation of the blood in the smallest blood vessels, present in the vasculature embedded within organ tissues. This contrasts with macrocirculation, which is the circulation of blood to, the microcirculation is composed of terminal arterioles, capillaries, and venules that drain capillary blood. The vessels on the side of the microcirculation are called the arterioles, which are well innervated, are surrounded by smooth musclecells. Arterioles carry the blood to the capillaries, which are not innervated, have no smooth muscle, blood flows out of the capillaries into the venules, which have little smooth muscle and are 10-200 µm. The blood flows from the venules into the veins, in addition to these blood vessels, the microcirculation also includes lymphatic capillaries and collecting ducts. The main functions of the microcirculation are the delivery of oxygen and nutrients and it also serves to regulate blood flow and tissue perfusion thereby affecting blood pressure and responses to inflammation which can include edema. Most vessels of the microcirculation are lined by flattened cells of the endothelium, the endothelium provides a smooth surface for the flow of blood and regulates the movement of water and dissolved materials in the interstitial plasma between the blood and the tissues. The endothelium also produces molecules that discourage the blood from clotting unless there is a leak, pericyte cells can contract and decrease the size of the arterioles and thereby regulate blood flow and blood pressure. Microcirculation has three sectors, pre-capillary, capillary and post-capillary. In the pre-capillary sector, arterioles and precapillary sphincters participate and their function is to regulate blood flow before it enters the capillaries and venules by the contraction and relaxation of the smooth muscle found on their walls. The second sector is the sector, which is represented by the capillaries. Finally, the sector is represented by the post-capillary venules. The regulation of tissue perfusion occurs in microcirculation, there, arterioles control the flow of blood to the capillaries. Arterioles contract and relax, varying their diameter and vascular tone, distension of the vessels due to increased blood pressure is a fundamental stimulus for muscle contraction in arteriolar walls. As a consequence, microcirculation blood flow remains constant despite of changes in blood pressure. This mechanism is present in all tissues and organs of the human body, in addition, the nervous system participates in the regulation of microcirculation. The sympathetic nervous system activates the smaller arterioles, including terminals, noradrenaline and adrenaline have effects on alpha and beta adrenergic receptors. Other hormones circulate in the bloodstream and can have an effect on the microcirculation causing vasodilation or vasoconstriction, many hormones and neuropeptides are released together with classical neurotransmitters
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Fibroblast growth factor
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Fibroblast growth factors, or FGFs, are a family of growth factors, with members involved in angiogenesis, wound healing, embryonic development and various endocrine signaling pathways. The FGFs are heparin-binding proteins and interactions with cell-surface-associated heparan sulfate proteoglycans have been shown to be essential for FGF signal transduction, FGFs are key players in the processes of proliferation and differentiation of wide variety of cells and tissues. In humans,22 members of the FGF family have been identified, all of which are structurally related signaling molecules, FGF1 is also known as acidic, and FGF2 is also known as basic fibroblast growth factor. Members FGF11, FGF12, FGF13, and FGF14, also known as FGF homologous factors 1-4, have shown to have distinct functions compared to the FGFs. Although these factors possess remarkably similar sequence homology, they do not bind FGFRs and are involved in intracellular processes unrelated to the FGFs and this group is also known as iFGF. Human FGF18 is involved in development and morphogenesis in various tissues including cartilage. Human FGF20 was identified based on its homology to Xenopus FGF-20, FGF15 through FGF23 were described later and functions are still being characterized. FGF15 is the mouse ortholog of human FGF19 and, where their functions are shared, in contrast to the local activity of the other FGFs, FGF15/19, FGF21 and FGF23 have systemic effects. The mammalian fibroblast growth factor receptor family has 4 members, FGFR1, FGFR2, FGFR3, the FGFRs consist of three extracellular immunoglobulin-type domains, a single-span trans-membrane domain and an intracellular split tyrosine kinase domain. FGFs interact with the D2 and D3 domains, with the D3 interactions primarily responsible for ligand-binding specificity, heparen sulfate binding is mediated through the D3 domain. A short stretch of amino acids located between the D1 and D2 domains has auto-inhibitory functions. This acid box motif interacts with the heparan sulfate binding site to prevent receptor activation in the absence of FGFs, alternate mRNA splicing gives rise to b and c variants of FGFRs 1,2 and 3. Through this mechanism seven different signaling FGFR sub-types can be expressed at the cell surface, each FGFR binds to a specific subset of the FGFs. Similarly most FGFs can bind to several different FGFR subtypes, FGF1 is sometimes referred to as the universal ligand as it is capable of activating all 7 different FGFRs. In contrast, FGF7 binds only to FGFR2b, the signaling complex at the cell surface is believed to be a ternary complex formed between two identical FGF ligands, two identical FGFR subunits, and either one or two heparan sulfate chains. They then further fractionated the extract using acidic and basic pH and these proteins had a high degree of amino acid identity but were determined to be distinct mitogens. Human FGF2 occurs in low molecular weight and high molecular weight isoforms, LMW FGF2 is primarily cytoplasmic and functions in an autocrine manner, whereas HMW FGF2s are nuclear and exert activities through an intracrine mechanism. These proteins were found to be identical to the acidic and basic FGFs described by Gospodarowicz, FGFs are multifunctional proteins with a wide variety of effects, they are most commonly mitogens but also have regulatory, morphological, and endocrine effects
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Vascular endothelial growth factor
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Vascular endothelial growth factor, originally known as vascular permeability factor, is a signal protein produced by cells that stimulates vasculogenesis and angiogenesis. It is part of the system restores the oxygen supply to tissues when blood circulation is inadequate such as in hypoxic conditions. Serum concentration of VEGF is high in bronchial asthma and diabetes mellitus, VEGFs normal function is to create new blood vessels during embryonic development, new blood vessels after injury, muscle following exercise, and new vessels to bypass blocked vessels. When VEGF is overexpressed, it can contribute to disease, solid cancers cannot grow beyond a limited size without an adequate blood supply, cancers that can express VEGF are able to grow and metastasize. Overexpression of VEGF can cause disease in the retina of the eye. Drugs such as aflibercept, bevacizumab, and ranibizumab can inhibit VEGF, VEGF is a sub-family of growth factors, to be specific, the platelet-derived growth factor family of cystine-knot growth factors. They are important signaling proteins involved in both vasculogenesis and angiogenesis, VEGF was first identified in guinea pigs, hamsters, and mice by Senger et al. in 1983. It was purified and cloned by Ferrara and Henzel in 1989, VEGF alternative splicing was discovered by Tischer et al. in 1991. Between 1996 and 1997, Christinger and De Vos obtained the structure of VEGF, first at 2.5 Å resolution. Fms-like tyrosine kinase-1 was shown to be a VEGF receptor by Ferrara et al. in 1992, the kinase insert domain receptor was shown to be a VEGF receptor by Terman et al. in 1992 as well. In 1998, neuropilin 1 and neuropilin 2 were shown to act as VEGF receptors, the VEGF family comprises in mammals five members, VEGF-A, placenta growth factor, VEGF-B, VEGF-C and VEGF-D. The latter ones were discovered later than VEGF-A, and, before their discovery, a number of VEGF-related proteins encoded by viruses and in the venom of some snakes have also been discovered. Activity of VEGF-A, as its name implies, has been studied mostly on cells of the vascular endothelium, in vitro, VEGF-A has been shown to stimulate endothelial cell mitogenesis and cell migration. VEGF-A is also a vasodilator and increases microvascular permeability and was referred to as vascular permeability factor. There are multiple isoforms of VEGF-A that result from alternative splicing of mRNA from a single and these are classified into two groups which are referred to according to their terminal exon splice site, the proximal splice site or distal splice site. In addition, alternate splicing of exon 6 and 7 alters their heparin-binding affinity and these domains have important functional consequences for the VEGF splice variants, as the terminal splice site determines whether the proteins are pro-angiogenic or anti-angiogenic. Recently, VEGF-C has been shown to be an important inducer of neurogenesis in the subventricular zone. VEGF-A binds to VEGFR-1 and VEGFR-2, VEGFR-2 appears to mediate almost all of the known cellular responses to VEGF
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VEGF receptor
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VEGF receptors are receptors for vascular endothelial growth factor. There are three subtypes of VEGFR, numbered 1,2 and 3. Also, they may be membrane-bound or soluble, depending on alternative splicing, vascular endothelial growth factor is an important signaling protein involved in both vasculogenesis and angiogenesis. As its name implies, VEGF activity is restricted mainly to cells of the vascular endothelium, in vitro, VEGF has been shown to stimulate endothelial cell mitogenesis and cell migration. VEGF also enhances microvascular permeability and is referred to as vascular permeability factor. All members of the VEGF family stimulate cellular responses by binding to tyrosine kinase receptors on the surface, causing them to dimerize. VEGF-A binds to VEGFR-1 and VEGFR-2, VEGFR-2 appears to mediate almost all of the known cellular responses to VEGF. The function of VEGFR-1 is less defined, although it is thought to modulate VEGFR-2 signaling. Another function of VEGFR-1 is to act as a dummy/decoy receptor, in fact, an alternatively spliced form of VEGFR-1 is not a membrane bound protein but is secreted and functions primarily as a decoy. A third receptor has been discovered, however, VEGF-A is not a ligand for this receptor, vEGFR-3 mediates lymphangiogenesis in response to VEGF-C and VEGF-D. In addition to binding to VEGFRs, TACO VEGF binds to receptor complexes consisting of both neuropilins and VEGFRs and this receptor complex has increased VEGF signalling activity in endothelial cells. Neuropilins are pleitrophic receptors and therefore other molecules may interfere with the signalling of the NRP/VEGFR receptor complexes, for example, Class 3 semaphorins compete with VEGF165 for NRP binding and could therefore regulate VEGF-mediated angiogenesis. Some VEGFR antagonists are under investigation for treating various cancers, pazopanib was approved for renal cell carcinoma in 2009. Regorafenib was approved for cancer in Sept 2012
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NRP-1
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Neuropilin-1 is a protein that in humans is encoded by the NRP1 gene. In humans, the neuropilin 1 gene is located at 10p11.22 and this is one of two human neuropilins. NRP1 is a coreceptor to a tyrosine kinase receptor for both vascular endothelial growth factor and semaphorin family members. NRP1 plays versatile roles in angiogenesis, axon guidance, cell survival, migration, Neuropilin 1 has been shown to interact with Vascular endothelial growth factor A. Neuropilin 1 has been implicated in the vascularization and progression of cancers. In vitro and in mouse studies have shown membrane bound NRP1 to be proangiogenic. Elevated NRP1 expression is correlated with the invasiveness of non-small cell lung cancer both in vitro and in vivo. As a co-receptor for VEGF, NRP1 is a target for cancer therapies. A synthetic peptide, EG3287, was generated in 2005 and has shown to block NRP1 activity. EG3287 has been shown to induce apoptosis in cells with elevated NRP1 expression. A patent for EG3287 was filed in 2002 and approved in 2003, as of 2015 there were no clinical trials ongoing or completed for EG3287 as a human cancer therapy. Interestingly, soluble NRP1 has the effect of membrane bound NRP1 and has anti-VEGF activity. In vivo mouse studies have shown that injections of sNRP-1 inhibits progression of acute leukemia in mice
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Platelet-derived growth factor receptor
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Platelet-derived growth factor receptors are cell surface tyrosine kinase receptors for members of the platelet-derived growth factor family. PDGF subunits -A and -B are important factors regulating cell proliferation, cellular differentiation, cell growth, development, there are two forms of the PDGF-R, alpha and beta each encoded by a different gene. Depending on which factor is bound, PDGF-R homo- or heterodimerizes. The PDGF family consists of PDGF-A, -B, -C and -D, the four PDGFs are inactive in their monomeric forms. The PDGFs bind to the tyrosine kinase receptors PDGF receptor-α. These two receptor isoforms dimerize upon binding the PDGF dimer, leading to three possible receptor combinations, namely -αα, -ββ and -αβ, the extracellular region of the receptor consists of five immunoglobulin-like domains while the intracellular part is a tyrosine kinase domain. The ligand-binding sites of the receptors are located to the three first immunoglobulin-like domains, pDGF-CC specifically interacts with PDGFR-αα and -αβ, but not with -ββ, and thereby resembles PDGF-AB. PDGF-DD binds to PDGFR-ββ with high affinity, and to PDGFR-αβ to a lower extent and is therefore regarded as PDGFR-ββ specific. PDGF-AA binds only to PDGFR-αα, while PDGF-BB is the only PDGF that can all three receptor combinations with high affinity. Dimerization is a prerequisite for the activation of the kinase, kinase activation is visualized as tyrosine phosphorylation of the receptor molecules, which occurs between the dimerized receptor molecules. Expression of both receptors and each of the four PDGFs is under independent control, giving the PDGF/PDGFR system a high flexibility, different cell types vary greatly in the ratio of PDGF isoforms and PDGFRs expressed. Different external stimuli such as inflammation, embryonic development or differentiation modulate cellular receptor expression allowing binding of some PDGFs, additionally, some cells display only one of the PDGFR isoforms while other cells express both isoforms, simultaneously or separately. The second part of the kinase domain in the PDGFβ receptor is phosphorylated at Tyr-857. Tyr-857 has therefore been assigned a role in regulation of kinase activity. The phosphorylated tyrosine residue and in three adjacent C-terminal amino acid residues form specific binding sites for signal transduction molecules. Binding to these sites involves a common conserved stretches, denoted the Src homology 2 domain and/or Phosphotyrosine Binding Domains, in addition, reactive oxygen species -dependent STAT3 activation has been established to be a key downstream mediator of PDGFR signalling in vascular smooth muscle cells. The adaptor protein Grb2 forms a complex with Sos by the Grb2 SH3 domain, Grb2 the Grb2/Sos complex is recruited to the membrane by the Grb2 SH2 domain binding to activated PDGFR-bound SHP2, thereby allowing interaction with Ras and the exchange of GDP for GTP on Ras. Once activated, Ras interacts with proteins, namely Raf
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Smooth muscle tissue
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Smooth muscle is an involuntary non-striated muscle. It is divided into two subgroups, the single-unit and multiunit smooth muscle, within single-unit cells, the whole bundle or sheet contracts as a syncytium. Single unit smooth muscle, however, is most common and lines blood vessels, the tract. Smooth muscle is different from skeletal muscle and cardiac muscle in terms of structure, function, regulation of contraction. Smooth muscle cells known as myocytes, have a shape and, like striated muscle, can tense. However, smooth muscle tissue tends to demonstrate greater elasticity and function within a larger length-tension curve than striated muscle and this ability to stretch and still maintain contractility is important in organs like the intestines and urinary bladder. In the relaxed state, each cell is spindle-shaped, 20-500 micrometers in length, the smooth muscle is the only type of muscle without the ability to be voluntarily controlled in stressful situations. Myosin is primarily class II in smooth muscle, myosin II contains two heavy chains which constitute the head and tail domains. Each of these heavy chains contains the N-terminal head domain, while the C-terminal tails take on a coiled-coil morphology, thus, myosin II has two heads. In smooth muscle, there is a gene that codes for the heavy chains myosin II. Also, smooth muscle may contain MHC that is not involved in contraction, myosin II also contains 4 light chains, resulting in 2 per head, weighing 20 and 17 kDa. These bind the chains in the neck region between the head and tail. The MLC20 is also known as the light chain and actively participates in muscle contraction. Two MLC20 isoforms are found in muscle, and they are encoded by different genes. The MLC17 is also known as the light chain. Its exact function is unclear, but its believed that it contributes to the stability of the myosin head along with MLC20. Two variants of MLC17 exist as a result of alternate splicing at the MLC17 gene, in the uterus, a shift in myosin expression has been hypothesized to avail for changes in the directions of uterine contractions that are seen during the menstrual cycle. The thin filaments that form part of the machinery are predominantly composed of α-
. PMID 25236972.
