text:
Immunoglobulin A

Immunoglobulin A (Ig A, also referred to as sIgA in its secretory form) is an antibody that plays a role in the immune function of mucous membranes. The amount of IgA produced in association with mucosal membranes is greater than all other types of antibody combined. In absolute terms, between three and five grams are secreted into the intestinal lumen each day. This represents up to 15% of total immunoglobulins produced throughout the body.

IgA has two subclasses (IgA1 and IgA2) and can be produced as a monomeric as well as a dimeric form. The IgA dimeric form is the most prevalent and, when it has bound the Secretory component, is also called secretory IgA (sIgA). sIgA is the main immunoglobulin found in mucous secretions, including tears, saliva, sweat, colostrum and secretions from the genitourinary tract, gastrointestinal tract, prostate and respiratory epithelium. It is also found in small amounts in blood. The secretory component of sIgA protects the immunoglobulin from being degraded by proteolytic enzymes; thus, sIgA can survive in the harsh gastrointestinal tract environment and provide protection against microbes that multiply in body secretions. sIgA can also inhibit inflammatory effects of other immunoglobulins. IgA is a poor activator of the complement system, and opsonizes only weakly.

IgA1 vs. IgA2
IgA exists in two isotypes, IgA1 and IgA2. They are both heavily glycosylated proteins. While IgA1 predominates in serum (~80%), IgA2 percentages are higher in secretions than in serum (~35% in secretions); the ratio of IgA1 and IgA2 secreting cells varies in the different lymphoid tissues of the human body: Both IgA1 and IgA2 have been found in external secretions like colostrum, maternal milk, tears and saliva, where IgA2 is more prominent than in the blood. Polysaccharide antigens tend to induce more IgA2 than protein antigens.
 * IgA1 is the predominant IgA subclass found in serum. Most lymphoid tissues have a predominance of IgA1-producing cells.
 * In IgA2, the heavy and light chains are not linked with disulfide, but with non-covalent bonds. In secretory lymphoid tissues (e.g., gut-associated lymphoid tissue, or GALT), the share of IgA2 production is larger than in the non-secretory lymphoid organs (e.g. spleen, peripheral lymph nodes).

Both IgA1 and IgA2 can be in membrane-bound form. (see B-cell receptor)

Serum vs. secretory IgA
It is also possible to distinguish forms of IgA based upon their location – serum IgA vs. secretory IgA.

In secretory IgA, the form found in secretions, polymers of 2–4 IgA monomers are linked by two additional chains; as such, the molecular weight of slgA is 385kD. One of these is the J chain (joining chain), which is a polypeptide of molecular mass 15kD, rich with cysteine and structurally completely different from other immunoglobulin chains. This chain is formed in the IgA-secreting cells.

The oligomeric forms of IgA in the external (mucosal) secretions also contain a polypeptide of a much larger molecular mass (70 kD) called the secretory component that is produced by epithelial cells. This molecule originates from the poly-Ig receptor (130 kD) that is responsible for the uptake and transcellular transport of oligomeric (but not monomeric) IgA across the epithelial cells and into secretions such as tears, saliva, sweat and gut fluid.

Serum IgA
In the blood, IgA interacts with an Fc receptor called FcαRI (or CD89), which is expressed on immune effector cells, to initiate inflammatory reactions. Ligation of FcαRI by IgA containing immune complexes causes antibody-dependent cell-mediated cytotoxicity (ADCC), degranulation of eosinophils and basophils, phagocytosis by monocytes, macrophages, and neutrophils, and triggering of respiratory burst activity by polymorphonuclear leukocytes.

Secretory IgA
The high prevalence of IgA in mucosal areas is a result of a cooperation between plasma cells that produce polymeric IgA (pIgA), and mucosal epithelial cells that express polymeric immunoglobulin receptor (pIgR). Polymeric IgA (mainly the secretory dimer) is produced by plasma cells in the lamina propria adjacent to mucosal surfaces. It binds to the pIgR on the basolateral surface of epithelial cells, and is taken up into the cell via endocytosis. The receptor-IgA complex passes through the cellular compartments before being secreted on the luminal surface of the epithelial cells, still attached to the receptor. Proteolysis of the receptor occurs, and the dimeric IgA molecule, along with a portion of the receptor known as the secretory component (SC), is free to diffuse throughout the lumen, with dimeric IgA and SC together forming the so-called secretory IgA (sIgA) In the gut, IgA can bind to the mucus layer covering the epithelial cells. In this way, a barrier capable of neutralizing threats before they reach the epithelial cells is formed.

Secretory IgA levels fluctuate diurnally, with the highest levels found in the small intestine and feces around ZT6, the middle of the light period. The regulation of IgA secretion is related to the microbiota, and IgA is known to control specific members of oscillating microbes through direct interactions. However, the underlying cause of the rhythmic secretion of IgA is not completely understood and may differ from one region of the body to another.

Production of sIgA against specific antigens depends on sampling of M cells and underlying dendritic cells, T cell activation, and B cell class switching in GALT, mesenteric lymph nodes, and isolated lymphoid follicles in the small intestine.

sIgA primarily acts by blockading epithelial receptors (e.g. by binding their ligands on pathogens), by sterically hindering attachment to epithelial cells, and by immune exclusion. Immune exclusion is a process of agglutinating polyvalent antigens or pathogens by crosslinking them with antibody, trapping them in the mucus layer, and/or clearing them peristaltically. The oligosaccharide chains of the component of IgA can associate with the mucus layer that sits atop epithelial cells. Since sIgA is a poor opsonin and activator of complement, simply binding a pathogen isn't necessarily enough to contain it—specific epitopes may have to be bound to sterically hinder access to the epithelium.

Clearance of IgA is mediated at least in part by asialoglycoprotein receptors, which recognizes galactose-terminating IgA N-glycans.

Genetic
Decreased or absent IgA due to an inherited inability to produce IgA is termed selective IgA deficiency and can produce a clinically significant immunodeficiency.

Anti-IgA antibodies, sometimes present in individuals with low or absent IgA, can result in serious anaphylactic reactions when transfused with blood products that incidentally contain IgA. However, most persons with suspected IgA anaphylactic reactions had experienced acute generalized reactions that were from causes other than anti-IgA transfusion.

Microbial
Neisseria species including Neisseria gonorrhoeae (which causes gonorrhea), Streptococcus pneumoniae, and Haemophilus influenzae type B all release a protease that destroys IgA. Additionally, Blastocystis species have been shown to have several subtypes that generate cysteine and aspartic protease enzymes which degrade human IgA.

Autoimmune and immune-mediated
IgA nephropathy is caused by IgA deposits in the kidneys. The pathogenesis involves the production of hypoglycosylated IgA1, which accumulates and subsequently leads to the formation of immune complexes and the production of IgA-specific IgG, further leading to tissue inflammation.

Celiac disease involves IgA pathology due to the presence of IgA antiendomysial antibodies. Additional testing has been conducted using IgA trans-glutaminase autoantibodies which has been identified as a specific and sensitive for the detection of celiac disease.

Henoch–Schönlein purpura (HSP) is a systemic vasculitis caused by deposits of IgA and complement component 3 (C3) in small blood vessels. HSP occurs usually in small children and involves the skin and connective tissues, scrotum, joints, gastrointestinal tract and kidneys. It usually follows an upper respiratory infection and resolves within a couple weeks as the liver clears out the IgA aggregates.

Linear IgA bullous dermatosis and IgA pemphigus are two examples of IgA-mediated immunobullous diseases. IgA-mediated immunobullous diseases can often be difficult to treat even with usually effective medications such as rituximab.

Drug-induced
Vancomycin can induce a linear IgA bullous dermatosis in some patients.

title: Immunoglobulin A


text:
Immunoglobulin D

Immunoglobulin D (IgD) is an antibody isotype that makes up about 1% of proteins in the plasma membranes of immature B-lymphocytes where it is usually co-expressed with another cell surface antibody called IgM. IgD is also produced in a secreted form that is found in very small amounts in blood serum, representing 0.25% of immunoglobulins in serum. The relative molecular mass and half-life of secreted IgD is 185 kDa and 2.8 days, respectively. Secreted IgD is produced as a monomeric antibody with two heavy chains of the delta (δ) class, and two Ig light chains.

Function
The function of IgD has been a puzzle in immunology since its discovery in 1964. IgD is present in species from cartilaginous fish to humans (with the possible exception of birds). This nearly ubiquitous appearance in species with an adaptive immune system demonstrates that IgD may be as ancient as IgM and suggests that IgD has important immunological functions.

In B cells, the function of IgD is to signal the B cells to be activated. By being activated, B cells are ready to take part in the defense of the body as part of the immune system. During B cell differentiation, IgM is the exclusive isotype expressed by immature B cells. IgD starts to be expressed when the B cell exits the bone marrow to populate peripheral lymphoid tissues. When a B cell reaches its mature state, it co-expresses both IgM and IgD. A 2016 study by Übelhart and colleagues found that IgD signaling is only triggered by repetitive multivalent immunogens, while IgM can be triggered either by soluble monomeric or by multivalent immunogens. Cδ knockout mice (mice that have been genetically altered so that they do not produce IgD) have no major B cell intrinsic defects. IgD may have some role in allergic reactions.

IgD was found to bind to basophils and mast cells and activate these cells to produce antimicrobial factors to participate in respiratory immune defense in humans. It also stimulates basophils to release B cell homeostatic factors. This is consistent with the reduction in the number of peripheral B cells, reduced serum IgE level and defective primary IgG1 response in IgD knockout mice.

Structural diversity
IgD has structural diversity throughout evolution of vertebrates because it is a structurally flexible locus to complement the function of IgM. One of the important features of IgD is that it can substitute for the function of IgM in the case of IgM defects. B cells may express IgD by alternative RNA splicing and class switch recombination. Alternative splicing is promoted in all jawed vertebrates but class switch recombination occurs only in higher vertebrates and increases diversification of IgD. In jawed fishes, the structure of the constant region is highly diverse with amplifications of Cδ exons. Different splice variants exist due to alternative splicing. In humans and primates, IgD has three Cδ domains and a long H region with an amino-terminal region rich in alanine and threonine residues. C-terminal regions are rich in lysine, glutamate and arginine residues modified with O-glycosylation for binding a putative IgD receptor on the surface of activated T cells. Human IgD with its H region interacts with heparin and heparan sulphate proteglycans expressed in the basophils and mast cells. Mouse IgD has a shorter H region and different amino acid composition modified with N-glycosylation.

Method of coexpression
In the human heavy chain locus, 3' of the V-D-J cassette is a series of C (for constant) genes, each conferring an Ig isotype. The Cμ (IgM) gene is 3' and closest to the V-D-J cassette, with the Cδ gene appearing 3' to Cμ.

A primary mRNA transcript will contain the transcribed V-D-J cassette, and the Cμ and Cδ genes, with introns in between them.

Alternative splicing can then occur, causing a selection of either Cμ or Cδ to appear on the functional mRNA (μ mRNA and δ mRNA respectively). Alternative splicing is thought to be possible due to two polyadenylation sites, one appearing between the Cμ and Cδ, and the other 3' of Cδ (polyadenylation in the latter site would cause Cμ to be spliced away along with the intron). The precise mechanism of how the polyadenylation site is chosen remains unclear.

The resulting functional mRNA will have the V-D-J and C regions contiguous, and its translation will generate either a μ heavy chain or δ heavy chain. The heavy chains then couple with either κ or λ light chains to create the final IgM or IgD antibody.

Zinc finger protein 318 (ZNF318) has a role in the promotion of IgD expression and controlling the alternative splicing of the long pre-mRNA. In immature B cells that mainly express the μ transcript, there is no ZFP318 expression, but in mature B cells with dual IgM and IgD expression, both δ and μ transcript is made and ZFP318 is expressed. Enders et al. (2014) found in mice that null mutations in ZFP318 resulted in no IgD expression.

Activation of immune system via IgD
Innate and adaptive Immune responses can be activated via membrane-anchored IgD that functions as a part of B-cell receptor (BCR) complexes or secreted IgD that binds to monocytes, mast cells, and basophils. Counter-intuitive to the contemporary dogmas that suggest these activated immune responses via IgD expression can potentiate autoimmune diseases and allergic inflammation, a 2010 study by Nguyen TG et al. has first demonstrated that treatments with a B-cell activating monoclonal anti-IgD antibody can attenuate disease severity in an animal model of collagen-induced arthritis. This novel therapeutic effect by anti-IgD antibody treatment was later confirmed in mouse models of epidermolysis bullosa acquisita and in chronic contact hypersensitivity. Studies have shown that levels of secreted lgD are usually elevated in patients with an autoimmune disease, and recently it has been demonstrated that IgD enhanced the activation of peripheral blood mononuclear cells in Rheumatoid Arthritis (RA) patients leading to the hypothesis that IgD could be an immunotherapeutic target for the management of RA. Activated immune responses via IgD-BCR and secreted IgD may exert suppressive effects on autoimmune diseases and allergic inflammations, suggesting a potential immune regulatory function of IgD.

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

title: Immunoglobulin D


text:
Immunoglobulin E

Immunoglobulin E (IgE) is a type of antibody (or immunoglobulin (Ig) "isotype") that has been found only in mammals. IgE is synthesised by plasma cells. Monomers of IgE consist of two heavy chains (ε chain) and two light chains, with the ε chain containing four Ig-like constant domains (Cε1–Cε4). IgE is thought to be an important part of the immune response against infection by certain parasitic worms, including Schistosoma mansoni, Trichinella spiralis, and Fasciola hepatica. IgE is also utilized during immune defense against certain protozoan parasites such as Plasmodium falciparum. IgE may have evolved as a defense to protect against venoms.

IgE also has an essential role in type I hypersensitivity, which manifests in various allergic diseases, such as allergic asthma, most types of sinusitis, allergic rhinitis, food allergies, and specific types of chronic urticaria and atopic dermatitis. IgE also plays a pivotal role in responses to allergens, such as: anaphylactic reactions to drugs, bee stings, and antigen preparations used in desensitization immunotherapy.

IgE is typically the least abundant isotype: blood serum IgE levels in a non-atopic individual are only 0.05% of the Ig concentration, compared to 75% for the IgGs at 10 mg/ml. Despite this, it is capable of triggering anaphylaxis, one of the most rapid and severe immunological reactions.

Discovery
IgE was simultaneously discovered in 1966 and 1967 by two independent groups: Kimishige Ishizaka and his wife Teruko Ishizaka at the Children's Asthma Research Institute and Hospital in Denver, Colorado, and by Gunnar Johansson and Hans Bennich in Uppsala, Sweden. Their joint paper was published in April 1969.

Receptors
IgE primes the IgE-mediated allergic response by binding to Fc receptors found on the surface of mast cells and basophils. Fc receptors are also found on eosinophils, monocytes, macrophages and platelets in humans. There are two types of Fcε receptors:
 * FcεRI (type I Fcε receptor), the high-affinity IgE receptor
 * FcεRII (type II Fcε receptor), also known as CD23, the low-affinity IgE receptor

IgE can upregulate the expression of both types of Fcε receptors. FcεRI is expressed on mast cells, basophils, and the antigen-presenting dendritic cells in both mice and humans. Binding of antigens to IgE already bound by the FcεRI on mast cells causes cross-linking of the bound IgE and the aggregation of the underlying FcεRI, leading to degranulation (the release of mediators) and the secretion of several types of type 2 cytokines like interleukin (IL)-3 and stem cell factor (SCF), which both help the mast cells survive and accumulate in tissue, and IL-4, IL-5, IL-13, and IL-33, which in turn activate group 2-innate lymphoid cells (ILC2 or natural helper cells). Basophils share a common haemopoietic progenitor with mast cells; upon the cross-linking of their surface bound IgE by antigens, also release type 2 cytokines, including IL-4 and IL-13, and other inflammatory mediators. The low-affinity receptor (FcεRII) is always expressed on B cells; but IL-4 can induce its expression on the surfaces of macrophages, eosinophils, platelets, and some T cells.

Parasite hypothesis
The IgE isotype has co-evolved with basophils and mast cells in the defence against parasites like helminths (like Schistosoma) but may be also effective in bacterial infections. Epidemiological research shows that IgE level is increased when infected by Schistosoma mansoni, Necator americanus, and nematodes in humans. It is most likely beneficial in removal of hookworms from the lung.

Toxin hypothesis of allergic disease
In 1981 Margie Profet suggested that allergic reactions have evolved as a last line of defense to protect against venoms. Although controversial at the time, new work supports some of Profet’s thoughts on the adaptive role of allergies as a defense against noxious toxins.

In 2013 it emerged that IgE-antibodies play an essential role in acquired resistance to honey bee and Russell's viper venoms. The authors concluded that "a small dose of bee venom conferred immunity to a much larger, fatal dose" and "this kind of venom-specific, IgE-associated, adaptive immune response developed, at least in evolutionary terms, to protect the host against potentially toxic amounts of venom, such as would happen if the animal encountered a whole nest of bees, or in the event of a snakebite". The major allergen of bee venom (phospholipase A2) induces a Th2 immune responses, associated with production of IgE antibodies, which may "increase the resistance of mice to challenge with potentially lethal doses".

Cancer
Although it is not yet well understood, IgE may play an important role in the immune system's recognition of cancer, in which the stimulation of a strong cytotoxic response against cells displaying only small amounts of early cancer markers would be beneficial. If this were the case, anti-IgE treatments such as omalizumab (for allergies) might have some undesirable side effects. However, a recent study, which was performed based on pooled analysis using comprehensive data from 67 phase I to IV clinical trials of omalizumab in various indications, concluded that a causal relationship between omalizumab therapy and malignancy is unlikely.

Role in disease
Atopic individuals can have up to ten times the normal level of IgE in their blood (as do sufferers of hyper-IgE syndrome). However, this may not be a requirement for symptoms to occur as has been seen in asthmatics with normal IgE levels in their blood—recent research has shown that IgE production can occur locally in the nasal mucosa.

IgE that can specifically recognise an allergen (typically this is a protein, such as dust mite Der p 1, cat Fel d 1, grass or ragweed pollen, food protein, etc.) has a unique long-lived interaction with its high-affinity receptor FcεRI so that basophils and mast cells, capable of mediating inflammatory reactions, become "primed", ready to release chemicals like histamine, leukotrienes, and certain interleukins. These chemicals cause many of the symptoms we associate with allergy, such as airway constriction in asthma, local inflammation in eczema, increased mucus secretion in allergic rhinitis, and increased vascular permeability, it is presumed, to allow other immune cells to gain access to tissues, but which can lead to a potentially fatal drop in blood pressure as in anaphylaxis.

IgE is known to be elevated in various autoimmune disorders such as SLE, rheumatoid arthritis (RA), and psoriasis, and is theorized to be of pathogenetic importance in SLE and RA by eliciting a hypersensitivity reaction.

Regulation of IgE levels through control of B cell differentiation to antibody-secreting plasma cells is thought to involve the "low-affinity" receptor FcεRII, or CD23. CD23 may also allow facilitated antigen presentation, an IgE-dependent mechanism whereby B cells expressing CD23 are able to present allergen to (and stimulate) specific T helper cells, causing the perpetuation of a Th2 response, one of the hallmarks of which is the production of more antibodies.

Role in diagnosis
Diagnosis of allergy is most often done by reviewing a person's medical history and finding a positive result for the presence of allergen specific IgE when conducting a skin or blood test. Specific IgE testing is the proven test for allergy detection; evidence does not show that indiscriminate IgE testing or testing for immunoglobulin G (IgG) can support allergy diagnosis.

Drugs targeting the IgE pathway
Currently, allergic diseases and asthma are usually treated with one or more of the following drugs: (1) antihistamines and antileukotrienes, which antagonize the inflammatory mediators histamine and leukotrienes, (2) local or systemic (oral or injectable) corticosteroids, which suppress a broad spectrum of inflammatory mechanisms, (3) short or long-acting bronchodilators, which relax smooth muscle of constricted airway in asthma, or (4) mast cell stabilizers, which inhibit the degranulation of mast cells that is normally triggered by IgE-binding at FcεRI. Long-term uses of systemic corticosteroids are known to cause many serious side effects and are advisable to avoid, if alternative therapies are available.

IgE, the IgE synthesis pathway, and the IgE-mediated allergic/inflammatory pathway are all important targets in intervening with the pathological processes of allergy, asthma, and other IgE-mediated diseases. The B lymphocyte differentiation and maturation pathway that eventually generate IgE-secreting plasma cells go through the intermediate steps of IgE-expressing B lymphoblasts and involves the interaction with IgE-expressing memory B cells. Tanox, a biotech company based in Houston, Texas, proposed in 1987 that by targeting membrane-bound IgE (mIgE) on B lymphoblast and memory B cells, those cells can be lysed or down-regulated, thus achieving the inhibition of the production of antigen-specific IgE and hence a shift of immune balance toward non-IgE mechanisms. Two approaches targeting the IgE pathway were evolved and both are in active development. In the first approach, the anti-IgE antibody drug omalizumab (trade name Xolair) recognises IgE not bound to its receptors and is used to neutralise or mop-up existing IgE and prevent it from binding to the receptors on mast cells and basophils. Xolair has been approved in many countries for treating severe, persistent allergic asthma. It has also been approved in March 2014 in the European Union and the U. S. for treating chronic spontaneous urticaria, which cannot be adequately treated with H1-antihistamines. In the second approach, antibodies specific for a domain of 52 amino acid residues, referred to as CεmX or M1’ (M1 prime), present only on human mIgE on B cells and not on free, soluble IgE, have been prepared and are under clinical development for the treatment of allergy and asthma. An anti-M1’ humanized antibody, quilizumab, is in phase IIb clinical trial.

In 2002, researchers at the Randall Division of Cell and Molecular Biophysics determined the structure of IgE. Understanding of this structure (which is atypical of other isotypes in that it is highly bent and asymmetric) and of the interaction of IgE with receptor FcεRI will enable development of a new generation of allergy drugs that seek to interfere with the IgE-receptor interaction. It may be possible to design treatments cheaper than monoclonal antibodies (for instance, small molecule drugs) that use a similar approach to inhibit binding of IgE to its receptor.

title: Immunoglobulin E


text:
Leiden University Medical Center

Leiden University Medical Center (Dutch: Leids Universitair Medisch Centrum) or LUMC is the university hospital affiliated with Leiden University, of which it forms the medical faculty. It is located in Leiden, Netherlands. LUMC is a modern university medical center for research, education and patient care. Its research practice ranges from pure fundamental medical research to applied clinical research.

Patient care
The hospital has clinical departments of all medical specialties, and acts as a tertiary referral centre for the northern part of the province of South Holland. Special units include:
 * Ophthalmology
 * Neurosurgery
 * Cardiothoracic surgery
 * Neonatal and pediatric surgery and intensive care
 * Pediatric oncology
 * Orthopedic medicine
 * Biliary surgery
 * Rheumatology
 * Level I trauma center

Research
The LUMC aims at identifying the causes of disease, improving diagnosis, prevention, and ultimately developing effective treatments. Within LUMC different specialists work together around research themes. Combining cross-border expertise may solve biomedical problems and bring answers not found when working in a stand-alone fashion. The themes are:
 * Vascular and Regenerative medicine
 * Immunity, Infection and Tolerance
 * Translational Neuroscience
 * Cancer Pathogenesis and Therapy
 * Ageing
 * Innovation in Health Strategy and Quality of Care
 * Biomedical Imaging

Education
LUMC offers a large range of education and hosts the Faculty of Medicine of Leiden University. Education is seen as a joint responsibility of students and professors and a critical scientific attitude and curiosity are valued highly. Enjoying studies and student life is also considered to be important. LUMC offers the following university courses: LUMC also offers continuing education and training for doctors, scientists and other healthcare professionals. Continuing education is organized by the departments Boerhaave Nascholing and Educatie Zorgsector.
 * Bachelor and master in Medicine
 * Bachelor and master in Biomedical Sciences
 * Bachelor in Clinical Technology (joined programme with TU Delft and Erasmus MC)
 * Master in Vitality and Ageing.
 * Master in Pharmacy
 * Electives and exchange options for international students

History of LUMC
In the very first teaching hospital in the Caeciliagasthuis in Leiden (now the Boerhaave Museum) professors gave bedside lectures – for example, Herman Boerhaave, in the 18th century. Several times, patients and professors moved to larger and better furnished premises and in 1873 the first university hospital to be built as such opened its doors on Steenstraat (it now houses the National Museum for Ethnology).

At the time, the building did justice to nursing practices and operation techniques, but after a few decades it was already obsolete. More laboratory space was needed, and safer and more comfortable conditions for patients and staff alike. The new hospital on Rijnsburgerweg, built in the early 1920s on the basis of the pavilion system, made way in the 1980s and 1990s for the present Building 1 of the LUMC.

Medicine has changed and developed beyond recognition over the centuries. After World War II, fundamental research became an increasingly important task of Leiden University's Faculty of Medicine. The Biomedical Science study programme is an expression of this. In patient care, high technology treatments have come in the place of admissions lasting weeks or months.

The many years of collaboration between the university and the teaching hospital acquired greater permanence in 1996 when the hospital and medical faculty merged to form Leiden University Medical Center, with patient care, instruction, study programmes, continuing education and research as its five core tasks.

The opening of two new buildings on 1 December 2006 was the fulfilment of a wish of long standing: all the core tasks are now under one roof. The various buildings are linked by skyways and tunnels, thus symbolising the interrelationship of the core tasks.

In 2016 Leiden University Medical Centre founded a branch at Campus The Hague, with research, teaching and a training programme for GPs.

EU Funding Fraud
In 2023 the LUMC was formally accused of fraud by the European Union in seven studies. Dean Pancras Hogendoorn stepped down because of the investigation which is currently in progress.

PREVENT-nCoV consortium
Leiden University Medical Center is part of the PREVENT-nCoV consortium comprising ExpreS2ion Biotechnologies, AdaptVac (a joint-venture between ExpreS2ion Biotechnologies and the University of Copenhagen spin-out NextGen Vaccines), the Institute for Tropical Medicine Tübingen, The Department of Immunology and Microbiology (ISIM) at the University of Copenhagen, and the Laboratory of Virology at Wageningen University and Research. In March 2020 the consortium was awarded an EU Horizon 2020 grant of €2.7million for the development of a COVID-19 vaccine candidate.

title: Leiden University Medical Center


text:
Immunoglobulin M

Immunoglobulin M (IgM) is the largest of several isotypes of antibodies (also known as immunoglobulin) that are produced by vertebrates. IgM is the first antibody to appear in the response to initial exposure to an antigen; causing it to also be called an acute phase antibody. In humans and other mammals that have been studied, plasmablasts in the spleen are the main source of specific IgM production.

History
In 1937, an antibody was observed in horses hyper-immunized with pneumococcus polysaccharide that was much larger in size than the typical rabbit γ-globulin, with a molecular weight of 990,000 daltons. In accordance with its larger size, the new antibody was originally referred to as γ-macroglobulin, and subsequently termed IgM—M for “macro”. The V domains of normal immunoglobulin are highly heterogeneous, reflecting their role in protecting against the great variety of infectious microbes, and this heterogeneity impeded detailed structural analysis of IgM. Two sources of homogeneous IgM were subsequently discovered. First, the high molecular weight protein produced by some multiple myeloma patients was recognized to be a tumor-produced γ-macroglobulin, and because the tumor is a clone, the IgM it produces is homogeneous. In the 1960s, methods were developed for inducing immunoglobulin-producing tumors (plasmacytomas) in mice, thus providing a source of homogeneous immunoglobulins of various isotypes, including IgM (reviewed in ). More recently, the expression of engineered immunoglobulin genes in tissue culture can be used to produce IgM with specific alterations and thus to identify the molecular requirements for features of interest.

Structure
Immunoglobulins are composed of light chains and heavy chains. The light chain (λ or κ) is a protein of ~220 amino acids, composed of a variable domain, VL (a segment of approximately 110 amino acids), and a constant domain, CL (also approximately 110 amino acids long). The μ heavy chain of IgM is a protein of ~576 amino acids, includes a variable domain (VH ~110 amino acids), four distinct constant region domains (Cμ1, Cμ2, Cμ3, Cμ4, each ~110 amino acids) and a "tailpiece" of ~20 amino acids. The μ heavy chain bears oligosaccharides at five asparagine residues. The oligosaccharides on mouse and human IgM have been partially characterized by a variety of techniques, including NMR, lectin binding, various chromatographic systems, and enzymatic sensitivity (reviewed in ). The structure of the oligosaccharides at each site varies in detail, and the predominant oligosaccharides—biantennary, triantennary, and high mannose—differ among the sites.

The multimeric structure of IgM is shown schematically in Figure 1. Figure 1A shows the "heterodimer" composed of one light chain, denoted L, and one heavy chain, denoted μ. The heavy and light chains are held together both by disulfide bonds (depicted as red triangles) and by non-covalent interactions.

Figure 1B shows two μL units linked by a disulfide bond in the Cμ2 domains; this (μL)2 structure is often referred to as the IgM "monomer", as it is analogous in some ways to the structure of immunoglobulin G (IgG).

On the basis of its sedimentation velocity and appearance in electron micrographs, it was inferred that IgM usually occurs as a "pentamer", i.e., a polymer composed of five “monomers” [(μL)2]5, and was originally depicted by the models in Figures 1C and 1D, with disulfide bonds between the Cμ3 domains and between the tail pieces. Also shown is that pentameric IgM includes a third protein, the J chain. J chain (J for joining) was discovered as a covalently bonded component of polymeric IgA and IgM. The J chain is a small (~137 amino acids), acidic protein. As shown, the J chain joins two μ chains via disulfide bonds involving cysteines in the tailpieces.

Molecular requirements for forming polymeric IgM
It was initially expected that the J chain would be important for forming the polymeric immunoglobulins, and indeed polymerization of IgA depends strongly (but not absolutely) on the J chain. In contrast, polymeric IgM forms efficiently in the absence of the J chain.

The predominant form of human and mouse IgM is the pentamer. By way of comparison, the structure of IgM from frogs (Xenopus) is predominantly hexameric, IgM from bony fish is predominantly tetrameric, and IgM from cartilaginous fish (mainly sharks) is predominantly pentameric. Although the pentameric form predominates in mice and humans, the hexameric form has also been observed. Subsequent studies using recombinant DNA expression systems indicated that a hexamer is a major form of mouse IgM when the IgM is produced under conditions where the incorporation of the J chain is prevented, either by producing IgM in cells that lack the J chain or by producing IgM with a μ heavy chain that lacks the cysteine in the tailpiece. In summary, hexameric IgM never contains the J chain; pentameric IgM can be formed so as to include or not include the J chain.

An important difference between the μ and γ heavy chains is the availability of cysteines for forming disulfide bonds between heavy chains. In the case of the γ heavy chain, the only inter-γ bonds are formed by cysteines in the hinge, and accordingly, each γ chain binds to only one other γ chain. By contrast, the Cμ2 and Cμ3 domains and the tailpiece each include a cysteine that form a disulfide bond with another μ chain. The cysteines in the Cμ2 domains mediate the formation of monomeric IgM (μL)2. The tailpiece along with the included cysteine is necessary and sufficient for the formation of polymeric immunoglobulins. That is, deleting the tailpiece from the μ heavy chain prevents the formation of polymeric IgM. Conversely, cells expressing a γ heavy chain that has been modified to include the tailpiece produce polymeric IgG.

The role of the cysteine in the Cμ3 domain is more subtle. Figures 1C and 1D represent possible models for pentameric IgM. In these models, each μ chain is envisaged to bind two other μ chains. However, neither model alone can fully account for the structure of polymeric IgM. For example, the model in Figure 1C predicts that the disulfide bond between the Cμ2 domains is essential for making disulfide-bonded polymeric IgM. The model in Figure 1D predicts that the disulfide bond between the Cμ3 domains is essential. Disulfide bonded, polymeric, IgM can still be made if any one of the three cysteines is absent. In the context of models in which each μ chain interacts with only two other μ chains, these results suggest that some molecules are like Figure 1C and some like Figure 1D. However, the availability of three cysteines for inter-μ chain bonding suggests that the μ chains might each bind three other μ chains, as illustrated in Figure 2. In the same spirit, Figure 2C presents a model for a J chain-containing pentamer that reflects evidence that the J chain joins μ chains that are not joined to other μ chains by the cysteines in the Cμ3 domains. These and other models, both regular and irregular are discussed elsewhere.

Pentameric IgM is typically represented as containing a single J chain per polymer, but in actuality the measurements of J chain stoichiometry have ranged from one J molecule per polymer to three J molecules per polymer. The wide range might be due to technical problems, such as incomplete radiolabeling or imprecisely quantitating an Ouchterlony line. However, the variation might also be due to heterogeneity in the IgM preparations, i.e., the various preparations might have differed substantially in their content of J-containing and J-deficient polymers.

Tertiary and quaternary structure of the μ constant region
Individual C2, C3, and C4tp domains were generated independently in E. coli and then studied using a range of approaches, including sedimentation rate, X-ray crystallography, and NMR spectroscopy, to obtain insight into the detailed three-dimensional structure of the chain. The domains of the heavy chain, like those of other immunoglobulins, have the distinctive overlaying -sheets of seven strands, which are stabilized by intra-domain disulfide linkages. Overall, the IgM constant region has a "mushroom-like" shape, with the C2-C3 domains forming a disk similar to the mushroom's head and the C4tp domains protruding like a short stem.

Function
IgM interacts with several other physiological molecules:

 * 1) IgM can bind complement component C1 and activate the classical pathway, leading to opsonization of antigens and cytolysis.
 * 2) IgM binds to the polyimmunoglobulin receptor (pIgR) in a process that brings IgM to mucosal surfaces, such as the gut lumen and into breast milk. This binding depends on the J chain.
 * 3) Two other Fc receptors that bind IgM—Fcα/μ-R and Fcμ-R -- have been detected. Fcα/μ-R, like pIgR, binds polymeric IgM and IgA. Fcα/μ-R can mediate endocytosis, and its expression in the gut suggests a role in mucosal immunity. Fcμ-R (formerly known as Toso/Faim3) binds IgM exclusively and can mediate cellular uptake of IgM-conjugated antigen. Inactivation of the corresponding genes in knock-out mice produces a phenotype, but the physiological functions of these receptors are still uncertain

Regulation of the immune response
Specific immunoglobulins that are injected into animals together with their antigen can influence the antibody response to this same antigen. Endogenous antibodies produced after a primary immunization can also affect the antibody response to a booster immunization, suggesting that similar effects occur during physiological conditions. The ”regulatory” effects can be either positive or negative. That is, depending on the type of antigen and the isotype of the antibody, the effect can be suppression or enhancement of the antibody response. Such effects are well illustrated by experiments involving immunization with xenogenic (foreign) erythrocytes (red blood cells). For example, when IgG is administered together with xenogenic erythrocytes, this combination causes almost complete suppression of the erythrocyte-specific antibody response. This effect is used clinically to prevent Rh-negative mothers from becoming immunized against fetal Rh-positive erythrocytes, and its use has dramatically decreased the incidence of hemolytic disease in newborns. In contrast to the effect of IgG, antigen-specific IgM can greatly enhance the antibody response, especially in the case of large antigens. Thus, when IgM specific for erythrocytes is injected into animals (including humans) together with erythrocytes, a much stronger antibody response to the erythrocytes is induced than when erythrocytes are administered alone. Several lines of evidence indicate that the ability of IgM to activate complement is required for its enhancing effect. That is, IgM-mediated enhancement does not occur in animals that have been depleted for complement component C3, nor in mutant animals lacking complement receptors 1 and 2. Similarly, mutant IgM that cannot activate complement does not enhance the immune response. A possible explanation for IgM-mediated enhancement is that B lymphocytes capture IgM-antigen-complement complexes and transport the complexes into areas in the spleen where efficient immune responses are generated. Because IgM is produced early in an immune response, this might be important in the initiation of antibody responses.

Synthesis
In germ-line cells (sperm and ova) the genes that will eventually encode immunoglobulins are not in a functional form (see V(D)J recombination). In the case of the heavy chain, three germ-line segments denoted V, D and J are ligated together and adjoined to the DNA encoding the μ heavy chain constant region. Early in ontogeny, B cells express both the μ and the δ heavy chains; co-expression of these two heavy chains, each bearing the same V domain depends on alternative splicing and alternative poly-A addition sites. The expression of the other isotypes (γ, ε and α) is affected by another type of DNA rearrangement, a process called Immunoglobulin class switching.

Clinical significance
IgM is the first immunoglobulin expressed in the human fetus (around 20 weeks) and phylogenetically the earliest antibody to develop.

IgM antibodies appear early in the course of an infection and usually reappear, to a lesser extent, after further exposure. IgM antibodies do not pass across the human placenta (only isotype IgG).

These two biological properties of IgM make it useful in the diagnosis of infectious diseases. Demonstrating IgM antibodies in a patient's serum indicates recent infection, or in a neonate's serum indicates intrauterine infection (e.g. congenital rubella syndrome).

The development of anti-donor IgM after organ transplantation is not associated with graft rejection but it may have a protective effect.

IgM in normal serum is often found to bind to specific antigens, even in the absence of prior immunization. For this reason, IgM has sometimes been called a "natural antibody". This phenomenon is probably due to the high avidity of IgM that allows it to bind detectably even to weakly cross-reacting antigens that are naturally occurring. For example, the IgM antibodies that bind to the red blood cell A and B antigens might be formed in early life as a result of exposure to A- and B-like substances that are present in bacteria or perhaps also in plant materials.

IgM antibodies are mainly responsible for the clumping (agglutination) of red blood cells if the recipient of a blood transfusion receives blood that is not compatible with their blood type.

A mutation of the mu chain within IgM causes autosomal recessive agammaglobulinemia.

The presence of IgM or, rarely, IgG is one of the obligate criteria for a diagnosis of Schnitzler's syndrome.

title: Immunoglobulin M


text:
Talk:Stephen Wolfram

UPE
Hello. I have just tagged this article undisclosed paid, because it was very heavily edited by a (highly likely paid) sockfarm that is focused almost exclusively on promoting Stephen Wolfram and his work. Please see this COIN thread (perma) and the related SPI for more information. The article will need a thorough review before the tag is removed. Thanks and best, Blablubbs | talk 15:12, 13 March 2021 (UTC)
 * Sounds plausible, the current text doesn't reflect the uniformly negative reception of Wolfram Physics and A New Kind of Science among the secondary WP:RS. Rolf H Nelson (talk) 04:46, 15 March 2021 (UTC)
 * Edits requiring particular scrutiny, per the master list: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31. XOR'easter (talk) 17:35, 16 March 2021 (UTC)

Evaluating: Whew! XOR'easter (talk) 21:20, 16 March 2021 (UTC)
 * 1) Nationality in infobox edit, looks OK
 * 2) Updated access-date in web reference, looks OK
 * 3) Moved text; text was bad, but moving it not a problem
 * 4) "British" to "British-American"
 * 5) Added 2 references, 1 primary
 * 6) Emphasis on "inaugural Fellow" might be puffery
 * 7) Spammy and trivial, only primary and self-published sources
 * 8) copy edit to the previous addition
 * 9) much new text, very spammy, advertorial in tone
 * 10) changed link target
 * 11) puffing up "influences" list in infobox (what are those even good for anyway?), removed initially struggled in school
 * 12) changed link target
 * 13) unsourced change of doctoral advisor
 * 14) another sock adding a source for the previous
 * 15) source for the puffery in "influences" list from edit 11
 * 16) minor tweak in citation metadata
 * 17) upgrading his grandmother from "speaker" to "expert"
 * 18) removal of test edit (thanks)
 * 19) adding empty marketing language
 * 20) hyping the "Wolfram Axiom", blatantly ignoring everyone else's contributions (see Minimal axioms for Boolean algebra)
 * 21) moved some text, hyped his SoundCloud
 * 22) unsourced BLP information about his son, early life and education material rearranged
 * 23) the dreaded "In popular culture" heading
 * 24) trivia
 * 25) addition of self-published source
 * 26) linkfarming
 * 27) more linkfarming
 * 28) added an image from Wolfram's website; claims to be CC, but the original website doesn't say so
 * 29) added his age-7 report card, same copyright concern as previous
 * 30) added paragraph about testifying before a Senate subcommittee; without a secondary source, seems WP:UNDUE
 * 31) added picture from the Senate subcommittee event; image again lifted from Wolfram's website, where no photo credit is given

Political views
In an interview with Lex Fridman, in the part 2:45:25 of the video, Wolfram mentioned the danger of giving one AI to decide on everything about society and than in 2:48:42 he said that a "market system based on choice is more liberating than a totalitarian system".

Of course its not a direct indication that he particularly supports free market economy or more specifically free market capitalism, but its possible to state that he supports a market-based system over a centralised system because of the choices it generates under "Political views" title.

--Comrade-yutyo (talk) 08:17, 11 January 2022 (UTC)

 * I don't think "centralised" and "totalitarian" are anywhere near synonyms. We shouldn't interpret primary sources like this. Guettarda (talk) 15:20, 11 January 2022 (UTC)

 * If his political views are not clear in sources, then it shouldn't be included. The context in which the comments were made is also in a hypothetical scenario and not a crisp articulation of his political views. Montesquieu1789 (talk) 00:23, 12 January 2022 (UTC)

Source for first published writing at 15
As loathe as I am to lend credibility to someone sockfarming WP, a possible source for the citation needed around his first publishing at 15 would be a link to the actual paper he published that includes the date and the name of the journal: https://content.wolfram.com/uploads/sites/34/2020/07/hadronic-electrons.pdf 172.92.181.142 (talk) 13:48, 20 March 2023 (UTC)

 * Or perhaps, same paper, but from somewhere that isn't his own website: https://www.publish.csiro.au/ph/pdf/PH750479 172.92.181.142 (talk) 13:51, 20 March 2023 (UTC)

Change scientific career fields
Change “computing” to “Computer Science” in the scientific career fields. 79.169.33.125 (talk) 21:45, 1 November 2023 (UTC)

 * This is a mistake. His computing is not computer science. I suggest a change here. Soupnero (talk) Soupnero (talk) 14:44, 6 May 2024 (UTC)

Ruthless undermining and bad habits of stealthy recording business partners
Mathematica's Wolfram sued, accused of secretly recording calls

"SWolfram has been sued by a former CEO of one of his companies who alleges he promised a stake in the firm and then reneged."

https://www.chicagobusiness.com/article/20141104/NEWS04/141109944/mathematica-s-wolfram-sued-for-allegedly-reneging-on-partnership-promise

He plays many of his business partners and associates against one another. Soupnero (talk) 14:52, 6 May 2024 (UTC)

title: Talk:Stephen Wolfram


text:
John Rowland

John Rowland may refer to:

 * Bo Rowland (1903–1964), American football player and coach, basketball player
 * John A. Rowland (1791–1873), California pioneer
 * John G. Rowland (born 1957), American (former) Governor of Connecticut
 * John Sharpe Rowland (1798–1863), 19th-century American politician
 * John Rowland (diplomat) (1925–1996), Australian diplomat
 * John Rowland (footballer, born 1936) (1936–2002), Welsh footballer
 * John Rowland (footballer, born 1941) (1941–2020), English footballer
 * John Cambrian Rowland (1819–1890), Welsh painter
 * John T. Rowland (1871–1945), American architect
 * John Rowland (MP), represented Winchelsea

Characters

 * John Rowland (Desperate Housewives), character in the U.S. television series Desperate Housewives
 * John Rowland: the main protagonist in the 1898 novella The Wreck of the Titan: Or, Futility by Morgan Robertson

title: John Rowland


text:
LaToya London

LaToya Renee London (born December 29, 1978) is an American R&B and soul singer and stage actress who was fourth-place finalist on the third season of American Idol. Her debut album, Love & Life, was released in September 2005 and spawned a number of moderate R&B chart hits. She has concentrated on stage work, including originating and performing the role of Nettie in the national tour of the Broadway musical The Color Purple from 2007 to 2010, for which she won an Ovation Award. She was the lead in the U.S. regional debut of The Bodyguard, a musical based on the 1992 film.

Early life
London was born in San Francisco, California and raised in Oakland, California, where she had her first public musical performance when, at the age of 7, she sang in her mother's wedding. Her interest in singing began when she was just 4 years old, when she frequently sang when attending Allen Temple Baptist church. As a teenager, she sang with the Oakland Youth Chorus from 1993 to 1996. In 1996, she graduated from Skyline High School (the same school actor Tom Hanks and basketball player Gary Payton attended). She also worked as a waitress and a bartender and sang in a Christian rock group. She was also a backup vocalist and did frequent guest vocals for several Bay Area artists. When she began American Idol, she was the lead vocalist in a band, All-Star Jukebox, which usually performed at weddings.

American Idol
London auditioned for the third season of American Idol in Los Angeles, California. Although she moved on through each round, she had not been featured prominently in any aired footage and was written off by many fans before the first studio performances. However, as a member of the third group of eight semifinalists, she sang Eric Carmen's "All by Myself," and received a standing ovation from celebrity judges Donna Summer, Randy Jackson and Paula Abdul. Jackson labeled her performance as "brilliant" and "what the search for a superstar is all about," Abdul called her "unbelievable" and praised her "quiet confidence," and Simon Cowell said she was "the best of the group" and that it was a "superb, outstanding performance." She was voted through to the final 12 contestants with 32.3 percent of audience votes, the largest percentage for every week of the semifinals.

In the following nine weeks, London had several high points on American Idol. Cowell called her performance of Chaka Khan's "Ain't Nobody" "amazing" and "awesome." Abdul said that she reminded her of "a young Gladys Knight" after she performed the Garth Brooks song "Ain't Goin' Down ('Til the Sun Comes Up)," Nickolas Ashford of famed soul duo Ashford & Simpson called her performance of "Ooo Baby Baby" by Smokey Robinson as "beautiful" and full of "sex appeal," Film director Quentin Tarantino called her a "powerhouse" after her performance of "Somewhere" from the musical West Side Story, and Cowell announced her as "the best singer in the competition" after she sang "All the Time" by Barry Manilow and gave her "a ten out of ten" for her performance of "Don't Rain on My Parade," which also garnered standing ovations from Abdul and Jackson.

London was central to one of the first controversies of the show. On April 21, 2004, the night after the final seven contestants performed Barry Manilow songs, London, Jennifer Hudson, and eventual winner Fantasia Barrino ended up in the bottom three with the least viewer votes. Together, these three had been dubbed "The Three Divas" for their critically acclaimed performances. London had the highest vote totals out of the three, and Hudson was ultimately eliminated. Because all three of the singers were African American and the frontrunners of the competition, music icon Elton John deemed the voting as "racist," igniting a flurry of news and speculation over the validity of the voting system. John complained at a promotional news conference that, "The three people I was really impressed with, and they just happened to be black, young female singers, and they all seem to be landing in the bottom three."

London's second controversy occurred on May 11, 2004, when the final four contestants each performed two disco songs. Simon Cowell, who previously endorsed her as the best singer in the competition, suggested that his only complaint with London was that after ten weeks he still did not know anything at all about her. Cowell also suggested that contestant Jasmine Trias would almost certainly be voted off the next day. However, on May 12, London became the ninth of the 12 finalists to be eliminated, finishing in fourth place, with Barrino also landing in the bottom two. London's farewell song was "Don't Rain on My Parade."

Performances
The songs London sang on the show follow:

Post-Idol
Immediately after being eliminated from the series, London was featured in the Norman Lear-helmed Declare Yourself voting campaign by famed photographer David LaChapelle, alongside music stars like Christina Aguilera and André 3000. Her appearance on Idol host Ryan Seacrest's daily television talk show was one of its highest-rated episodes, and Oakland Mayor Jerry Brown officially declared May 4 to be LaToya London Day; one month later, she officially received the key to the city. Her rendition of Harold Melvin & the Blue Notes "If You Don't Know Me by Now" on the top-selling compilation disc, American Idol Season 3: Greatest Soul Classics, was praised as one of the album's best. She was also heavily featured on the group track, "Ain't No Mountain High Enough."

In the summer of 2004, London performed with the other top 10 finalists in American Idol season three international tour, which crossed the United States and also visited China and Singapore. She had a guest co-hosting gig on the national entertainment news show, Access Hollywood, and she has performed for such events and galas as the Richmond/Ermet AIDS Foundation, 100 Black Men of America, and the Clear Channel holiday party. London has also performed the national anthem for numerous National Football League games, including the 2005 Super Bowl NFL Commissioner pre-game party. She has shared the stage with such icons and superstars as Elton John, Whoopi Goldberg, Barry Manilow, Gladys Knight, Nancy Wilson, Chaka Khan, Rachelle Ferrell, Goapele, and Burt Bacharach.

In November 2004, it was announced that London had been signed to jazz recording label Peak Records, an imprint of Concord Records, the final label of jazz legend Ray Charles before his death. Her first single, "Appreciate," which featured a guest rap from Black Thought of the Hip-Hop group The Roots, hit the airwaves in July, and a music video of that song followed. The CD single, "Appreciate/Every Part of Me/All By Myself" reached number eight on the Billboard Singles Sales Chart. The single sold 8,500 units.

2005–2006: Love & Life
Her debut studio album, Love & Life, was released on September 20, 2005. A mix of R&B, soul, jazz, and hip-hop, Love & Life featured songwriting by London, along with songs by well-known producers such as David Foster and Narada Michael Walden. The San Francisco Chronicle called her "impassioned and polished" with "sumptuous, wondrously elastic mezzo pipes," People magazine called it one of the best post-American Idol albums, and Apple Computer's iTunes named it one of the best albums of 2005, and her song "Non A What'cha Do" as one of the best individual recordings of the year. Love & Life sold 12,546 albums in its first week, landing at number 82 on Billboard Top 200 Albums chart and at number 27 on Billboard Top R&B/Hip-Hop Albums. To date, it has sold approximately 58,000 copies. Additionally, London has sold over 15,000 digital downloads.

London released two follow-up singles, "Every Part of Me" and "State of My Heart" in 2006, the latter of which hit number 40 on the Billboard Adult Contemporary Tracks chart and number five on the radio industry periodical Friday Morning Quarterback's Adult Contemporary spin chart.

London was also nominated for an award in the R&B category of the 2006 Bay Area Rap Scene (BARS) Awards; however, violence and disruption ended the show early before the award winners were announced. Latoya was competing against R&B star Goapele, among others.

London announced that despite having an initial three-album deal, she had parted ways from Peak Records and Concord Records. She is currently writing songs for her second album and is shopping for a new recording label.

In February 2006, she landed a lead role in Laterras R. Whitfield's touring dramatic comedy play Issues: We All Have 'Em. She sang a jazz-tinged version of "Hark! Hear the Bells" on the VH1 Soul Train Christmas television special, and sang the same song on a special edition of the 40th Anniversary A Charlie Brown Christmas album.

In late summer 2006, London made her Los Angeles professional stage debut with a starring role in the retro musical, Beehive, at the El Portal Theater in North Hollywood. London and the show earned rave reviews. That same year, the cast was nominated by the Los Angeles Drama Critics Circle for Best Ensemble Performance in their annual awards.

London was featured as a guest vocalist on Paul Taylor's new album, Ladies' Choice, released in May 2007.

London played Nettie in The Color Purple, which debuted at the Cadillac Palace Theatre for an extended run in Chicago, Illinois. London ended her run in 2010 and received a nomination for a NAACP Theatre Award in 2008 in the best supporting actress in an equity production category.

2010–present: Urban Punk
London joined with hip-hop artist H2O in 2010 to form the group Urban Punk, producing music that combines Europop melodies with hip-hop rhythms. They have released two tracks, "Around the World" and "Twisted".

In June 2013, London joined the cast of the Carolina Opry in Myrtle Beach, South Carolina.

London has starred in a number of national tours, including Redemption of a Dogg, and Tyler Perry's Madea on the Run, as well as regional productions, including Silence! The Musical and as Shug Avery in Celebration Theatre's production of The Color Purple. She was the lead in the U.S. regional debut of The Bodyguard, a musical based on the 1992 film.

Personal life
London suffered a setback when she had to pull out of the VH1 Soul Tour with Jaguar Wright and Kindred due to a "family emergency." Additionally, when Ebony magazine named her one of the hottest African American bachelorettes in America in its July 2005 issue, speculation about the state of her marriage sparked off. While she was on American Idol, she proudly stated that she was married and had stepchildren. She later confirmed that she and her husband had divorced.

Politics and endorsements
London posed for a political print advertising campaign by Declare Yourself, encouraging voter registration among youth for the 2008 United States presidential election. In the ads by photographer David LaChapelle, London has a nail through her upper and lower lips, pinning her mouth shut in a symbolic function. The ads drew national attention.

London also performed "Ain't Nobody" in Oakland on Election Day 2008 celebrating Barack Obama's historic victory.

Singles

 * Appreciate/Every Part of Me/All By Myself (August 2005)
 * Every Part of Me
 * State Of My Heart Number 40 Hot AC Tracks

Guest contributions

 * "If U Buyin'" (with C-Bo) (1999)
 * "I Know You Want Me" (with H2O from "The Mixtape Vol. 1") (2004)
 * "I Want to Show You" (with H2O from "The Mixtape Vol. 1") (2004)
 * "Konfessions" (with H2O from "The Mixtape Vol. 1") (2004)
 * With Okolo on "The "Real" Diamond N Tha Rough") (2005)
 * "Keeps Me Movin'" (with Golden Sol), from The Golden Sol EP) (August 2005)
 * "Keeps Me Movin'" (with Golden Sol from Keeps Me Movin' (Featuring Latoya London) EP) (August 2006)
 * "Keeps Me Movin' (DJ Solomon's Baltimore House Mix)" (with Golden Sol from Keeps Me Movin' (Featuring Latoya London) EP) (August 2006)
 * "Keeps Me Movin' (Ean's Disco Re-Rub)" (with Golden Sol from Keeps Me Movin' (Featuring Latoya London) EP) (August 2006)
 * "Hold Up (Wait a Minute)" (with John Payne from The Journey) (October 2006)
 * "Send My Baby Back" (with Donnie Williams and Park Place from Just Like Magic) (March 2007)
 * "Funky Times" (with Donnie Williams and Park Place from Just Like Magic) (March 2007)
 * "Just Like Magic" (with Donnie Williams and Park Place from Just Like Magic) (March 2007)
 * "I Want To Be Loved (By You)" (with Paul Taylor from "Ladies' Choice (Paul Taylor album)") (March 2007)
 * "ahh means ahh" (with aj from Worldwide) (March 2007)

Awards and nominations
Ovation Awards
 * 2012: Won the award for Featured Actress in a Musical for her role as Shug Avery in the Celebration Theatre production of "The Color Purple: The Musical"

title: LaToya London


text:
Council for New England

The Council for New England was a 17th-century English joint stock company to which King James I awarded a royal charter, with the purpose of expanding his realm over parts of North America by establishing colonial settlements.

The Council was established in November of 1620, and was disbanded (although with no apparent changes in land titles) in 1635. It provided for the establishment of the Plymouth Colony, the Province of New Hampshire, the Massachusetts Bay Colony, the New Haven Colony, and the Province of Maine.

Sir Ferdinand Gorges was a major promoter of English colonization of New England, and was a key figure in establishment and operations of the Council.

Founding
Some of the persons involved had previously received a charter in 1606 as the Plymouth Company and had founded the short-lived Popham Colony within the territory of northern Virginia (actually in present-day Maine in the United States). The company had fallen into disuse following the abandonment of the 1607 colony.

The Council was re-established, with support from Gorges, after (1) Captain John Smith had completed a thorough survey of the Atlantic side of New England (and named it such), (2) Richard Vines over-wintered in 1616, off the Maine coast and discovered that a plague was decimating Native Americans and (3) a friendly English speaking local Native American had been placed in the most likely colonization spot.

In the new 1620 charter granted by James I, the company was given rights of settlement in the area now designated as New England, which was the land previously part of the Virginia Colony north of the 40th parallel, and extending to the 48th parallel.

1620 Charter
The Charter of 1620 mentions the wish of certain settlers for English colonization of all land between degrees 34 and 45, but instead provides for colonization between degrees 40 and 48. The colonial plantation was to found settlements and commerce for Christian peoples and establish trade and commerce between these new colonies and the colonies of George Somers and Thomas Gates (Virginia Colony).

These new colonies were to be managed by Gentry from Plymouth, Exeter, and Bristol. These members of the Council were to have, in perpetuity for them and their descendants, rights and privileges extended for the governance and management of trade of the colony.

Individuals listed as beneficiaries of the charter include:
 * Ludovic Stewart, 2nd Duke of Lennox
 * George Villiers, 1st Duke of Buckingham
 * William Herbert, 3rd Earl of Pembroke
 * Thomas Howard, 14th Earl of Arundel
 * William Alexander, 1st Earl of Stirling
 * James Hamilton, 2nd Marquess of Hamilton
 * Henry Wriothesley, 3rd Earl of Southampton
 * Robert Rich, 2nd Earl of Warwick
 * John Ramsay, 1st Earl of Holderness
 * Edward la Zouche, 11th Baron Zouche
 * Edmund Sheffield, 1st Baron Sheffield
 * Baron Gorges of Dundalk
 * Robert Carr, 1st Earl of Somerset
 * Robert Mansell
 * Edward Zouch
 * Dudley Digges
 * Thomas Roe
 * Ferdinando Gorges
 * Francis Popham
 * John Brooke, 1st Baron Cobham
 * Richard Hawkins
 * Allen Apsley
 * Sir Warwick Hale
 * Sir Richard Catchmay
 * Sir John Bourchier
 * Nathaniel Rich
 * Edward Giles
 * Giles Mompesson
 * Thomas Wroth
 * Matthew Sutcliffe
 * Robert Heath
 * John Drake
 * Raleigh Gilbert
 * George Chudley
 * Thomas Hamon
 * John Argall

The Council would have full legal rights of governance and administration over the colonial plantation. The members of the Council would elect a President to oversee administrative affairs.

In 1622, the Plymouth Council issued a land grant to John Mason which ultimately evolved into the Province of New Hampshire.

1635 revocation
With the establishment of the Plymouth Colony, Massachusetts Bay Colony, Province of New Hampshire, Saybrook Colony, and New Haven Colony, the council was disbanded by royal charter.

title: Council for New England


text:
Cyanoacetylene

Cyanoacetylene is an organic compound with the formula C3HN or H\sC\tC\sC\tN. It is the simplest cyanopolyyne. Cyanoacetylene has been detected by spectroscopic methods in interstellar clouds, in the coma of comet Hale–Bopp and in the atmosphere of Saturn's moon Titan, where it sometimes forms expansive fog-like clouds.

Cyanoacetylene is one of the molecules that was produced in the Miller–Urey experiment.

title: Cyanoacetylene


text:
Renal clearance ratio

The renal clearance ratio or fractional excretion is a relative measure of the speed at which a constituent of urine passes through the kidneys. It is defined by following equation:

 * $$ clearance\ ratio\ of\ X = \frac{C_x}{C_{in}}$$

 * X is the analyte substance
 * Cx is the renal plasma clearance of X
 * Cin is the renal plasma clearance of inulin.

Creatinine is sometimes used instead of inulin as the reference substance; for example, the calcium-creatinine clearance ratio is used in an attempt to distinguish between different causes of a high plasma calcium concentration. It is easier to use creatinine rather than inulin as the comparitor as creatinine is produced by the body, whereas inulin has to be intravenously infused.

title: Renal clearance ratio


text:
Bertha Knight Landes

Bertha Ethel Knight Landes (October 19, 1868 – November 29, 1943) was the first female mayor of a major American city, serving as mayor of Seattle, Washington from 1926 to 1928. After years of civic activism, primarily with women's organizations, she was elected to the Seattle City Council in 1922 and became council president in 1924.

Early years
Landes was born in Ware, Massachusetts to Charles Sanford Knight and Cordelia Cutter. Her father, a veteran of the Union Army, moved the family to Worcester in 1873. She attended Worcester's Dix Street School and Classical High School, from which she received her diploma. At the age of 19 she moved to Bloomington, Indiana, to live with her older sister Jessie Knight, whose husband David Starr Jordan had become the president of Indiana University Bloomington. Bertha enrolled as a student at the University in the fall of 1888. She received a degree in history and political science in 1891, after which she returned to Worcester.

After three years of teaching at her alma mater, the Classical High School in Worcester, Massachusetts, she married geologist Henry Landes on January 2, 1894. Knight and Landes had met as students at Indiana University. The couple had three children, one of whom was adopted. Landes moved to Seattle in 1895 when her husband Henry became a geology professor at the fledgling University of Washington, with the help of a favorable recommendation from Jordan. Henry would go on to become Dean of the College of Sciences in 1912, the University's first.

Civic activism
In Seattle, Landes was active in women's organizations, including the Women's University Club, the Rainier Club, and the Women's Auxiliary of University Congregational Church. She was a member of the influential Women's Century Club, for which she served as the head of social services (1916-17) and then president (1918-1920). She was president of the Washington State chapter of the League of Women Voters.

From 1920-22 Bertha served as president of the Seattle Federation of Women's Clubs, which by 1923 included 245 member clubs representing thousands of women. With the Federation, in 1921 she orchestrated a weeklong Women's Educational Exhibit for Washington Manufacturers. Staffed by more than 1,000 club women and showcasing the technological innovations of 130 manufacturers, it bolstered the spirits of the business community during a period of severe recession, symbolizing for the state's business community the emergence of Seattle as a sophisticated, modern metropolis. One such manufacturer wrote to Landes after the exhibit expressing hope "that someday you will be rewarded by seeing greater prosperity in Seattle, and that you will then feel fully repaid for the untiring efforts you have put forth."

That year, Landes was appointed by the city mayor to serve on a commission studying unemployment, the only woman on the five-member commission.

In 1922, Landes organized "The Women's Civic League" (renamed the "Women's City Club" in 1923). The purpose of the club was to educate women about local, state, national and world politics, and in cooperation with other organizations, to work towards securing the welfare of the city and improving civic conditions. Within a year it had more than 500 members.

Political career

Landes and Kathryn Miracle were the first women to serve on the Seattle City Council; both were elected in 1922. Landes became council president after her reelection in 1924. She became acting mayor in 1924 when Mayor Edwin J. "Doc" Brown left town in June to attend the 1924 Democratic National Convention. Angry at what she saw as police corruption and lawless activity, Landes fired Police Chief William B. Severyns. She began her own law and order campaign, closing down illegal activities throughout the city, including lotteries, punchboards and speakeasies. Upon his return, Brown reinstated the police chief.

When Brown ran for another two-year term in 1926, Landes ran against him, on the platform that "municipal housecleaning" was needed in the Seattle government. Landes easily won the election in March, by more than 6,000 votes.

During her term, she advocated municipal ownership of utilities such as Seattle City Light and street railways. She also fought hard against bootleggers and reckless drivers, and strictly enforced regulations for dance halls and cabarets. The Civic Auditorium, later renovated as the Seattle Opera House, is one of her accomplishments. She appointed qualified professionals to head city departments, improve public transportation and parks, and put the city's finances in order.

Landes ran for a second term in 1928. Although endorsed by newspapers, the Central Labor Council, the Prohibition Party, and women's organizations, Landes was easily defeated by Frank Edwards, a political unknown, by a vote of 59,000 to 40,000, in a record turnout.

Later years
Landes became the first woman to serve as Moderator of Washington's Conference of Congregational and Christian Churches and was also elected national president of the Soroptimists, a professional women's organization. She wrote many articles for national publications, often urging women to enter politics, their "natural sphere."

During the 1930s, Landes was chair of the Sewing Room Work for the Women's Division of the Mayor's Commission for Improved Employment. She oversaw 673 women who sewed garments for women and children to "help improve the unemployment situation."

From 1933 to 1941, Landes traveled extensively. In 1933, she and her husband began to lead student groups, sponsored by the University of Washington, to the Far East. The couple also took groups of schoolteachers from across the United States to sites in Alaska, Yellowstone and Glacier National Park, among others. Henry contracted bronchitis on a trip to China in June 1936, which developed into pneumonia, leading to his death in Seattle on August 23, 1936, at the age of 68.

At the time of Henry's loss, Bertha wrote that he was "pleased and willing to have me try my wings" and that he was her "tower of strength in times of stress, and made many sacrifices without complaint that I might give my time and strength to my civic service." She added, "Life was to be lived to the fullest, always on a partnership basis and a definite sharing of different special interests. It was so lived for 40 years until the summons came for one of us, and now I have to face life and its problems alone."

Following his death, Bertha agreed to lead the tour alone in 1937. She continued her travels in 1938 aboard the ship SS Monterey, with stops in Honolulu, Pago Pago, Auckland, Sydney, and Melbourne.

During the late 1930s, Bertha began to reduce her level of civic activism. She gave fewer public speeches, focusing instead on smaller appearances and on lending endorsements and assistance to community causes such as Seattle's Women's City Club Chorus, as well as fundraising for groups like the League of Women Voters. Her health began to decline. In her private life she turned away from the traditional religious practices of the Congregational Church, of which she and Henry had been members since the late 1890s, joining instead the Unity School of Christianity.

Bertha continued to live independently at the Wilsonian Hotel in Seattle's University District until 1941, when she moved to Pacific Palisades, California, in hopes that the warmer climate would improve her health.

Death and burial
She died at her son's home in Ann Arbor, Michigan on November 29, 1943, at the age of 75. Her ashes were interred at Evergreen Washelli Memorial Park in Seattle.

Legacy
Today, the largest meeting room at Seattle City Hall is named in her honor. The tunnel boring machine used to construct the Alaskan Way Viaduct replacement tunnel under downtown Seattle was nicknamed "Bertha" after her.

A wing of Read Residence Hall at Indiana_University_Bloomington is named for her.

Marie Dressler plays a character based on her in the film Politics set in the fictional Lake City.

title: Bertha Knight Landes


text:
Tairō

Tairō (大老, "great elder") was a high-ranking official position in the Tokugawa shogunate government of Japan, roughly comparable to the office of prime minister. The tairō presided over the governing rōjū council in the event of an emergency. A tairō was nominated from among the fudai daimyōs, who worked closely with the Tokugawa traditionally. Generally, the office holder was the shogunate's chief policymaker, and provided Japan with a capable temporary leader in the absence of a shōgun, or in the event that the shōgun was incapacitated.

title: Tairō


text:
Distal convoluted tubule

The distal convoluted tubule (DCT) is a portion of kidney nephron between the loop of Henle and the collecting tubule.

Physiology
It is partly responsible for the regulation of potassium, sodium, calcium, and pH.

On its apical surface (lumen side), cells of the DCT have a thiazide-sensitive Na-Cl cotransporter and are permeable to Ca, via the TRPV5 channel. On the basolateral surface (peritubular capillary side) there is an ATP-dependent Na/K antiporter pump, a secondary active Na/Ca transporter, and an ATP dependent Ca transporter. The basolateral ATP dependent Na/K pump produces the gradient for Na to be absorbed from the apical surface via the Na/Cl symporter, and for Ca to be reclaimed into the blood by the Na/Ca basolateral antiporter.

 * It regulates pH by absorbing bicarbonate and secreting protons (H+) into the filtrate, or by absorbing protons and secreting bicarbonate into the filtrate.
 * Sodium and potassium levels are controlled by secreting K+ and absorbing Na+. Sodium absorption by the distal tubule is mediated by the hormone aldosterone. Aldosterone increases sodium reabsorption. Sodium and chloride (salt) reabsorption is also mediated by a group of kinases called WNK kinases. There are 4 different WNK kinases,, , , and.
 * It also participates in calcium regulation by reabsorbing Ca2+ in response to parathyroid hormone. PTH effect is mediated through phosphorylation of regulatory proteins and enhancing the synthesis of all transporters within the distal convoluted tubule.
 * Arginine vasopressin receptor 2 is also expressed in the DCT.

Clinical significance
Thiazide diuretics inhibit Na+/Cl− reabsorption from the DCT by blocking the thiazide-sensitive Na-Cl cotransporter.

By inhibiting the transporter, thiazide diuretics increase the gradient potential for Na. This increases the activity of the basolateral Na/Ca antiport and causes the increase in calcium reclamation associated with thiazide diuretics.

Histology
The DCT is lined with simple cuboidal cells that are shorter than those of the proximal convoluted tubule (PCT). The lumen appears larger in the PCT than the DCT lumen because the PCT has a brush border (microvilli). DCT can be recognized by its numerous mitochondria (even though it is not as much as Pct), basal enfoldings and lateral membrane interdigitations with neighboring cells.

The point where DCT contacts the cortical thick ascending limb of the loop of Henle is called macula densa. It has tightly packed columnar cells which display reversed polarity and may monitor the osmolarity of blood.

Histologically, cells of the DCT can be differentiated from cells of the proximal convoluted tubule:

title: Distal convoluted tubule


text: User talk:64.12.113.186

title: User talk:64.12.113.186


text:
U.S. Route 59

U.S. Route 59 (US 59) is a north–south United States highway (though it was signed east–west in parts of Texas). A latecomer to the U.S. numbered route system, US 59 is now a border-to-border route, part of the NAFTA Corridor Highway System. It parallels U.S. Route 75 for nearly its entire route, never much more than 100 mi away, until it veers southwest in Houston, Texas. Its number is out of place since US 59 is either concurrent with or entirely west of U.S. Route 71. The highway's northern terminus is 9 mi north of Lancaster, Minnesota, at the Lancaster–Tolstoi Border Crossing on the Canada–US border, where it continues as Manitoba Highway 59. Its southern terminus is at the Mexico–US border in Laredo, Texas, where it continues as Mexican Federal Highway 85D.

Texas
U.S. Highway 59 (US 59) in the U.S. state of Texas is named the Lloyd Bentsen Highway, after Lloyd Bentsen, former U.S. Senator from Texas. In northern Houston, US 59, co-signed with Interstate 69 (I-69), is the Eastex Freeway (from downtown Houston to the Liberty County/Montgomery County line). To the south, which is also co-signed with I-69, it is the Southwest Freeway (from Rosenberg to downtown Houston), which is one of the busiest sections of freeway in the United States with a vehicle count, as of 2006, over 330,000 vehicles per day just outside the Loop.

US 59 (overlapped by US 71) actually straddles the border between Texas and Arkansas north of I-30 near Texarkana, with the east side of the highway on the Arkansas side and the west side of the highway on the Texas side. In the past, both highways remained on the border past I-30 as State Line Avenue to downtown Texarkana; today, only US 71 does so. Nearly 90% of this route is designated to become part of I-69 in the future. Currently, 75 mph speed limits are allowed on US 59 in Duval County and portions of northern Polk County.

From the southwestern suburbs of Houston to downtown Houston, U.S. 59 is commonly referred to as the "Southwest Freeway", sometimes derisively as the "Southwest's Best Freeway." Supporting 371,000 vehicles per day, it is one of the busiest freeways in the United States. U.S. 59 is known as the "Eastex Freeway" in the north/northeast part of the Houston region. At the Mexico–US border, it ends at the World Trade International Bridge in Laredo, Texas. In Laredo, U.S. 59 is co-signed with both Interstate 69W (I-69W) and Loop 20, and has an intersection with Interstate 35 which ends at the Juarez-Lincoln International Bridge. After crossing the bridge into Mexico, Interstate 35 continues as Mexican Federal Highway 85 in Nuevo Laredo, which then runs through Mexico and Central America and ends in Panama at the Panama Canal.

Arkansas
In Arkansas, US 59 is concurrent with U.S. Route 71 from Interstate 30 at Texarkana to Acorn, and with U.S. Route 270 from Acorn to the Oklahoma state line. The Third Loop was to be extended on Interstate 49 from its original northern end to US-71 at the Texas state line opened on May 15, 2013, and was extended to State Line Road, where it intersects US-59 and US-71 in Texas.

Oklahoma
US 59 and U.S. Route 412 are co-signed for 10 mi in Delaware County, Oklahoma.

US 59 is co-signed with U.S. Route 270 from the Arkansas state line to Heavener and U.S. Route 271 from Poteau to west of Spiro. It is also co-signed with U.S. Route 64 in Sallisaw.

Kansas

U.S. 59 enters the state just south of Chetopa and runs nearly directly north across the state. It runs concurrently with U.S. 169 starting about 5 mi south of Garnett and diverges north again immediately south of Garnett. The intersection immediately south of Garnett used to be a "braided" intersection with stop and yield signs. It was identified as a high-crash location in 2001, and was rebuilt as a roundabout that opened in April 2006. The Kansas Department of Transportation is rebuilding or planning to rebuild several other rural intersections as roundabouts for increased safety. Until 2012, US 59 passed through Ottawa, Kansas, and had to be shut down or detoured every time the Marais Des Cygnes floodwall gates were closed across the highway. The highway now bypasses around Ottawa, running concurrently with Interstate 35 for 5 mi and using that highway's bridges over the Marias Des Cygnes. US 59 passes through Lawrence. The street name of US 59 in Lawrence is Iowa Street, then 6th Street as it joins U.S. 40 and jogs east to cross the Kansas River near downtown. North of the U.S. 40 and 59 Bridges, it splits with U.S. 40 as it joins U.S. 24 briefly and jogs back west before resuming a northerly course. It continues north to Nortonville, then northeast to Atchison, where it crosses the Missouri River over the Amelia Earhart Bridge.

U.S. 59 has been rebuilt and rerouted just to the east between Lawrence and Ottawa as a divided highway, as the former road was one of the most dangerous stretches of highway in the state. The project began in mid-2007, and was completed and opened to the public on October 17, 2012.

Missouri
In Missouri, US 59 roughly follows the Missouri River in the northwest corner of the state, from its entrance at Winthrop. In Saint Joseph, the highway is paired with Interstate 229 through downtown. US 59 departs from I-229 as Saint Joseph Avenue, joining with U.S. Route 71 at Interstate 29. The two highways then separate in Savannah. US 59 then follows Interstate 29 very closely until turning northward at Craig. It exits the state 10 mi north of Tarkio. This section of US 59 is immortalized in the Brewer and Shipley song "Tarkio Road".

Iowa
In Iowa, US 59 is a main north–south artery in the western part of the state. It enters Iowa south of Shenandoah and joins Interstate 80 at Avoca. It passes through the county seats of Harlan, Denison, Cherokee, and Primghar. Except for small stretches of expressway near Avoca, Denison, and Holstein, the entire length of US 59 in Iowa is an undivided two-lane road. US 59 exits the state near Hawkeye Point, the highest point in the state of Iowa.

Minnesota
US 59 enters Minnesota south of Worthington, just 1 mi east of Bigelow. It passes through rural western Minnesota for its entire length in the state. Some cities along the way include Slayton, Marshall, Clarkfield, Montevideo, and Morris. US 59 overlaps Interstate 94/U.S. Highway 52 in the Fergus Falls area. North of Fergus Falls, US 59 passes through Pelican Rapids, Detroit Lakes, and Thief River Falls before ending at the Lancaster–Tolstoi border crossing on the Canada–US border. US-59 runs for about 425 mi through Minnesota.

The Minnesota section of US 59 is legally defined as all or part of Routes 265, 16, 17, 88, 66, 144, 3, 30, and 174 in Minnesota Statutes §§ 161.115(19), (75), and (196) and 161.114(2).

History

In 1934, a coalition of government officials from Missouri, Iowa, and Minnesota agreed to sign the current US 59 as Highway 73 in an attempt to extend US 73 north from Atchison, Kansas. However, AASHO approved the route as US 59, instead.

The part in Missouri was defined in 1922 as Route 52 from Kansas to St. Joseph, Route 1 from St. Joseph to Tarkio, and Route 61 from Tarkio to Iowa. Route 61 became Route 9 in 1926, and Route 52 became part of Route 4 in 1927, and this portion became Route 18 in 1932, before being removed in favor of US 59 in the 1930s.

Historic termini
Before the 1950s, US 59 headed northwest to US 75 at Noyes, crossed the Red River of the North at St. Vincent, and terminated at US 81 in Pembina, North Dakota. A new highway and border crossing were built north of Lancaster on the present alignment in 1950. The former segment of US 59 between Lancaster and US 75 became CR 6, and the extremely short segment between US 75 and US 81 became MN 171 and ND 59. ND 59 still exists in Pembina from the state line to I-29.

From 1934 to 1935, the US 59 designation referred to a 50 mi-long route across southeastern Minnesota, from Lake City, Minnesota, to the Iowa state line just short of Chester, Iowa. That entire route is now part of US 63, and nowhere close to the present US 59, established in 1935.

In 1933, much of the present US 59 and the entirety of US 96 in Texas were originally proposed to be part of US 71. Under this plan, discussed at a meeting of the United States Good Roads Association in Beaumont, US 71 was to be diverted out of Louisiana altogether and instead rerouted from the Texarkana area southward through East Texas.

Future
A large portion of US 59 is proposed to become part of the future extension of I-69, I-69W and I-369 through Texas, allowing the current alignment and right-of-way to be upgraded without the need for government environmental studies or extensive eminent domain proceedings.

Major intersections

 * Texas
 * World Trade International Bridge at the Mexico–US border
 * in Laredo. The highways travel concurrently through the city.
 * in Laredo
 * in George West
 * east of George West
 * in Beeville
 * in Goliad
 * southwest of Victoria. I-69/US 59 will travel concurrently to Houston. US 59/US 77 travels concurrently to south-southwest of Victoria.
 * in Victoria
 * in Houston
 * in Houston
 * in Houston
 * in Houston. I-69/US 59 will travel concurrently to Tenaha.
 * in Livingston
 * in Corrigan
 * in Lufkin. The highways travel concurrently through the city.
 * in Redfield
 * in Timpson. The highways travel concurrently to Tenaha.
 * in Tenaha. I-369/US 59 will travel concurrently to Texarkana.
 * in Carthage. The highways travel concurrently to north of Carthage.
 * in Marshall
 * in Marshall
 * in Texarkana. I-369/US 59 travels concurrently to I-30.
 * in Texarkana
 * in Texarkana
 * in Texarkana. I-30/US 59 travels concurrently to the Arkansas state line.

 * Arkansas
 * in Texarkana. US 59/US 71 travels concurrently to Acorn.

 * Texas
 * north of Texarkana

 * Arkansas
 * in Lockesburg. The highways travel concurrently to De Queen.
 * in Saline Township. The highways travel concurrently to De Queen.
 * in Wickes
 * in Acorn. US 59/US 270 travels concurrently to Heavener, Oklahoma.

 * Oklahoma
 * west-northwest of Page
 * in Poteau. The highways travel concurrently to west of Spiro.
 * in Sallisaw
 * in Sallisaw. The highways travel concurrently through the city.
 * in Westville
 * in West Siloam Springs. The highways travel concurrently to Kansas.
 * east-northeast of Afton. US 59/US 60 travels concurrently for approximately 0.6 mi. US 59/US 69 travels concurrently to north of Dotyville.
 * east-northeast of Afton

 * Kansas
 * in Chetopa. The highways travel concurrently through the city.
 * in Oswego. The highways travel concurrently to the Mount Pleasant–Fairview township line.
 * in Parsons
 * in Moran
 * in Welda Township. The highways travel concurrently to Washington Township.
 * in Ottawa. The highways travel concurrently to Ottawa Township.
 * in Willow Springs Township
 * in Lawrence. The highways travel concurrently through the city.
 * in Lawrence
 * in Lawrence. US 24/US 59 travels concurrently to Williamstown.
 * in Shannon Township. The highways travel concurrently to Atchison.

 * Missouri
 * in St. Joseph. The highways travel concurrently through the city.
 * in St. Joseph
 * in Jefferson Township
 * in Nodaway Township
 * in Jackson Township. The highways travel concurrently to Nodaway Township.
 * in Hickory Township
 * in Hickory Township
 * in Union Township
 * in Tarkio Township. The highways travel concurrently to Tarkio.

 * Iowa
 * in Indian Creek Township
 * in Belknap Township. The highways travel concurrently to Oakland.
 * in Avoca
 * in Denison. The highways travel concurrently through the city.
 * on the Logan–Griggs township line. The highways travel concurrently to Holstein.
 * on the Franklin–Lincoln township line. The highways travel concurrently to Sanborn.

 * Minnesota
 * in Worthington
 * in Custer Township
 * in Camp Release Township. The highways travel concurrently to Montevideo.
 * in Moyer Township
 * on the Buse–Dane Prairie township line. The highways travel concurrently to Fergus Falls Township.
 * in Detroit Lakes
 * in Knute Township
 * at the Canada–US border on the Richardville–St. Joseph township line

title: U.S. Route 59


text:
User talk:DanielT

Name: Daniel Taylor WWW: http://www.danielt.com

title: User talk:DanielT