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Lawrence B. Salkoff

Lawrence B. Salkoff is an American neuroscientist and a professor of Neuroscience and Genetics at Washington University School of Medicine Salkoff received his Bachelor of Arts degree in Economics in 1967 from University of California-Los Angeles. After graduation he volunteered in the United States Peace Corps working in Colombia, South America from 1967-1970. Upon Salkoff's return to the United States he studied at the University of California, where he received his PhD in Neurogenetics in 1979. Subsequently, Salkoff trained as a Postdoctoral Associate in Neurogenetics at Yale University, in the laboratory of Professor Robert Wyman with consultation and aid from Professor Charles F. Stevens. Salkoff's career began in 1978 before much detail was known about ion channel structure using Drosophila as a model system; as a graduate student he worked on the shibire mutant and characterized its defects in synaptic transmission. Cloning of the extended family of potassium channel genes; the structure of potassium channels which shape the electrical activity in the nervous system was unknown when Salkoff was a graduate student.

It was believed that one way to obtain the protein structure of a potassium channel was to identify a gene encoding the channel protein in a genetically tractable organism, combine newly developed tools in biophysics, molecular genetics, DNA sequencing in eukaryotes, molecular cloning, to clone and sequence the gene and functionally express the encoded channel in a heterologous expression system. To this end, as a postdoctoral researcher, Salkoff adapted the voltage clamp technique to the fruit fly Drosophila, used by Alan Lloyd Hodgkin and Andrew Huxley to reveal the ionic basis of the nerve action potential; this enabled the direct observation of ion currents in a genetically tractable organism. This technique was used to show that the Drosophila Shaker gene was the structural gene for a potassium channel, a claim, based on several genetic criteria and confirmed by biophysical analysis of the expected ion channel current phenotype. Thus, mutations of a structural gene should produce loss of function mutations where the gene product is absent or non-functional, gain of function mutations where the functional properties of the gene product is changed, position effect mutations where a breakpoint near the gene reduces expression of a normal gene product.

All three classes of mutations were characterized by Salkoff, e.g. 1. Loss-of-function mutant. 2. Gain-of-function mutant (which changed the inactivation kinetics of the current, 3. Position effect conferred by the W32 X-chromosome breakpoint. Salkoff combined voltage-clamp technique with genetic analysis to reveal the location of the Shaker gene on the Drosophilia polytene chromosome map; these studies validated the Shaker gene as the structural locus of a potassium channel and guided a chromosomal “walking” strategy to the physical location of the Shaker locus. It had the effect of directing great attention to Drosophila as a model system combining molecular genetics with biophysical tools and enabled the study of ion channel biology using a comprehensive approach not possible in other systems. Salkoff found; this study showing the location of the Shaker gene on the physical chromosome map facilitated the cloning of the Shaker potassium channel. Based on these findings Salkoff began a genomic DNA "walk" along the chromosome to clone the Shaker gene in conjunction with Patrick H. O'Farrell and Lily Jan but moved to Washington University before the project was finished.

The project was completed by several laboratories. The cloning and functional expression of a family of voltage-gated K+ channels conserved in all animals brought order to the field of electrophysiology, validated the use of simple animal models in the field of membrane excitability. After the initial cloning of the Shaker gene by several laboratories. Salkoff's laboratory used the Shaker cDNA as a stepping stone with which to clone and functionally characterize the extended gene family of voltage-dependent potassium channels which in addition to Shaker, was designated Shab and Shal; the Salkoff lab showed that all families were conserved in mammals and were independent current systems (that did not form heteromultimers between families One or more of these genes expressing voltage-dependent potassium currents are expressed in all vertebrate and invertebrate neurons. Salkoff's studies showed that an “essential set” of ion channels was conserved throughout the animal kingdom and was present in primitive metazoan forms such as jellyfish, thus proving that the electrical properties of the nervous system developed early in evolution.

This work contributed to one of the fundamental revelations of modern biology, that the basic genes and proteins that form complex animal life are conserved, having evolved only once, present in LUCA, the Last universal common ancestor to all current metazoan life. In addition to the cloning and characterization of voltage-dependent potassium channels, Salkoff's lab cloned and functionally characterized the “SLO” family of high conductance potassium channels; the discovery of a high conductance sperm¬specific potassium channel turned out to be the key to understanding membrane potential changes that occur during sperm capacitation. Salkoff was the recipient of the “John Belling Prize in Genetics” and was a Research Fe

Collina d'Oro

Collina d'Oro is a municipality in the district of Lugano in the canton of Ticino in Switzerland. It was formed from the 2004 union of the villages of Agra and Montagnola. On 1 April 2012, it incorporated the independent municipality of Carabietta. Gentilino is first mentioned in 1210 as Gentarino. Montagnola is first mentioned in 1226 as Montegnola'; the hamlet of Bigogno, part of Agra, is first mentioned in 1270 in an inventory of the lands of the monastery of S. Abbondio in Como in the Valle di Lugano; the inventory of Como Cathedral mentions their allodial titles and episcopal loans in Agra as well as possessions of the Disentis Abbey. The same document mentions the church of S. Tommaso in Agra; the church belonged to the parish of S. Pietro in Pambio and became an under-parish in 1591; the Chapel of S. Assunta in Bigogno was completed before 1609. In the statutes of Como from 1335, the Concilium or Vicinanza of Agra and Premona or Barbengo is first mentioned. In addition to agriculture, the village was once famous for training and sending artisans to Russia along with other European nations.

In 1912 a regional sanatorium opened in the village. It was a residence to for many German-speaking and intellectuals, they published the monthly magazine Die Terrasse from the sanatorium. It fell into disrepair. In the Early Middle Ages Gentilino belonged to the royal court of Agnuzzo, donated in 818 by Emperor Louis the Pious to the clergy of Como. During the 11th Century it belonged to the monastery of S. Abbondio in Como; the union of the monastic estates in 1335 led to the creation of the Concilium Sancti Abundii which included Gentilino and Viglio as well as Montagnola and the surrounding villages. In the early 18th Century, the village wanted to buy the monastery's rights to the village. However, this triggered a long-running dispute, in which the Canton was involved, it is believed that the church of S. Abbondio was the center of a medieval parish, which became a sub-parish in the 11th Century. However, the first written record of the church dates from 1140; the current appearance is due to an enlargement in the 17th Century.

In the past centuries, the population lived from agriculture, but there were a large exodus of builders. It has grown into a bedroom community for the nearby city of Lugano; the merger of several separate properties of the monastery of S. Abbondio in Como in 1535, led to the establishment of the Concilium Sancti Abundii which covered not only Gentilino but the village of Montagnola with the hamlets of Vigilio, Arasio, Poprino and Scairolo. An inventory of the monastery mentioned the presence of a fortress at Arasio. Montagnola belongs to the parish of S. Abbondio at Gentilino; the chapels in S. Silvestro in Arasio and SS Nazaro in Celso were first mentioned in 1270 and 1442 respectively; the local economy was based on agriculture as well as emigration of architects and builders from the Gilardi, Lucchini and Camuzzi families into various European countries Russia. Several of these builders were able to create major works in these foreign cities and rise to great fame; the pleasant climate and attractive location of the village attracted many illustrious personalities from abroad, including the writer Hermann Hesse.

A museum to the writer opened in 1997. Between 1923-27 it was the seat of the prestigious Officina Bodoni, the printing shop of Hans Mardersteig. Since 1956, Montagnola is home to an international school, The American School In Switzerland. Due to its proximity to Lugano, Montagnola is now a kind of residential suburb of the city. Carabietta is first mentioned in 1335 as Carabio. In 1375 it was mentioned as La Carabieta. At the end of the 14th Century it belonged to the Pieve of Agno, in the 15th-16th Centuries to the Pieve of Lugano, it became a dependent of the parish church of Morcote. Between 1803-16, Carabietta belonged to the political municipality of Morcote. During the Middle Ages and under the Swiss Confederation, the village was granted the status as an imperial cassina or a village, exempt from taxes; the church of San Bernardo was built in 1634, stands on the foundations of a late-medieval church. The residents of the village supplemented their income from agriculture through money sent back by emigrants.

Carabietta was one of the smallest municipalities of Ticino. It was developing into a small commuter town. Collina d'Oro has an area, as of 1997, of 6.15 km2. Of this area, 11.8 % is used for agricultural purposes. Of the rest of the land, or 36.2% is settled and 0.05 km2 or 0.5% is unproductive land. Lago di Muzzano is shared with the neighboring municipalities; the village of Agra is located at an elevation of 570 m at the foot of Monte Crocione. Until the merger, the village of Gentilino included the north side of the Collina d'Oro valley, the settlement of Viglio; the former municipality of Montagnola stretched over the central portion of the Collina d'Oro valley from the Bay of Agno to Pian Scairolo, included a number of villages. Carabietta was located on the Agno arm of Lake Lugano. Collina d'Oro has a population of 4,895; as of 2008, 28.5% of the population are resident foreign nationals. Over the last 10 years the population has changed at a rate of 21.1%. Most of the population speaks Italian, with German being second most common and English being third

Multi-Mission Effects Vehicle

The Multi-Mission Effects Vehicle was a dual-purpose short range surface-to-air and anti-tank platform intended for use by the Canadian Forces. It was based on Air Defense Anti-Tank System technology, integrated onto an 8×8 wheeled LAV III; the MMEV project was canceled in November 2006. In late September 2005, the DND announced a $750M project for 30 MMEVs. Prime contractor for the first, $100M phase of the project was to be Oerlikon Contraves Canada; the Canadian Forces worked with Defence Research and Development Canada and Canadian industry through the Technology Demonstration Program to develop fire control systems and ergonomics that would directly contribute to the development of the MMEV. Oerlikon Contraves Canada was selected for the MMEV project since it owns the intellectual property rights to the ADATS technology, the cornerstone of the new MMEV system; the MMEV was designed to engage fixed wing aircraft and helicopters at low to medium altitudes, land-based targets at up to 8 km.

The MMEV was designed with a full ISTAR platform, enabling it to communicate with NATO and Tri-Services of the Canadian Forces. The MMEV was to integrate the latest technology, such the Oerlikon Contraves search-and-acquisition X-Tar 3D radar providing a high detection probability, covering a range of 25 kilometres. A resistance to electronic and electro-optical systems built by Oerlikon / Rheinmetall. Rheinmetall Defence - Multi-Mission Effects Vehicle Rheinmetall Defence - Canada has announced its intent to acquire MMEV CASR Background — CF Multi-Mission Effects Vehicle Project Multi-Mission Effects Vehicle Army to keep aging tanks

Regulatory B cell

Regulatory B cells represent a small population of B cells which participates in immunomodulations and in suppression of immune responses. These cells regulate the immune system by different mechanisms; the main mechanism is a production of anti-inflammatory cytokine interleukin 10. The regulatory effects of Bregs were described in various models of inflammation, autoimmune diseases, transplantation reactions and in anti-tumor immunity. In the 1970s it was noticed that Bregs could suppress immune reaction independently of antibody production. In 1996 Janeway´s group observed an immunomodulation of experimental autoimmune encephalomyelitis by B cells. Similar results were shown in a model of chronic colitis one year later. A role of Bregs was found in many mouse models of autoimmune diseases as rheumatoid arthritis or systemic lupus erythematosus. Bregs can develop from different subsets of B cells. Whether Breg cells uniquely derive from a specific progenitor or originate within conventional B cell subsets is still an open question.

Bregs shared. Mouse Bregs were CD5 and CD1d positive in model of EAE or after exposition of Leishmania major. By contrast mouse Bregs in model of collagen-induced arthritis were CD21 and CD23 positive. Breg were found in human, too. Markers of peripheral blood Bregs were molecules CD24 and CD38. However, peripheral blood Bregs were CD24 and CD27 positive after cultivation with anti-CD40 antibody and CpG bacterial DNA, they were positive for CD25, CD71 and PD-L1 after stimulation by CpG bacterial DNA and through TLR9. There are several mechanisms of Breg action; the most examined mechanism is production of IL-10. IL-10 has strong anti-inflammatory effects, and it inhibits or suppresses inflammatory reactions mediated by T cells Th1 type immune reactions. This was shown for example in CIA or contact hypersensitivity. Regulatory B cell subsets have been demonstrated to inhibit Th1 responses through IL-10 production during chronic infectious diseases such as visceral leishmaniasis. Next suppressive Breg mechanism is production of transforming growth factor, another anti-inflammatory cytokine.

Role of Bregs producing TGF-β was found in mouse of models of diabetes. Another mechanism of Breg acting involves surface molecules, for example FasL or PD-L1, which cause death of target cells. Resting B lymphocytes do not produce cytokines. After lipopolysaccharide stimulation are produced TNFα, IL-1β, IL-10 and IL-6; this indicates. There are two types of signals to activate Breg, namely signals generated by external pathogens and endogenous signals produced by the action of body cells. Structures characteristic of pathogenic microorganisms recognize the TLR receptors that trigger a signal cascade at the end of, the production of effector cytokines; the main endogenous signal is the stimulation of the surface molecule CD40. In autoimmune diseases, many models of Breg involvement are described in the suppression or alleviation of autoimmune pathology; the most well-known mechanism of action of Bregs is the production of anti-inflammatory cytokines, most IL-10. This mechanism was described in the EAE model, but in lupus erythematodes.

Another cytokine produced with an anti-inflammatory effect is TGF-β, which has a role in the suppression of T lymphocytes, for example in diabete. Not just cytokines can cause an anti-inflammatory state. There is the second option to do it. There are surface molecules, which after binding to the target cell receptor, causes cell apoptosis. An increase in expression of this molecule has been described in the CIA model. In order to suppress immune responses, it is possible that cancerous proliferation uses Breg for its leakage from the immune system. Leukemia B cells spontaneously produce large amounts of IL-10. Secretion of TNF-α B cells promotes the development of skin carcinoma. However, the positive effect of Breg on the treatment of cancer is described. In patients with metastatic cancer, those with a higher number of CD20 positive B lymphocytes in the lymph nodes are more to survive; the immunosuppressive properties of Breg play an essential role in allotransplants. It is necessary to cushion the immune response against the transplant and Breg can do it.

For other types of transplants, B cells can participate both in tolerance and more in transplant rejection, depending on the origin of Breg subpopulations

Han Tha Myint

Han Tha Myint is a Burmese politician. He serves on the National League for Democracy's Central Executive Committee and is a party spokesman. Han Tha Myint won the seat in the Pyithu Hluttaw to represent the Budalin Township Constituency No. 1 during the 1990 Burmese general election, winning about 81% of the votes. The Union Election Commission announced his forced resignation from the post on 11 June 1996, he was born to Khin Khin Kyi on 7 May 1948 in Rangoon, Burma. His father Thein Pe Myint was a prominent Anti-Fascist People's Freedom League leader and a close friend of General Aung San. Han Tha Myint obtained a Bachelor of Engineering degree from the Rangoon Institute of Technology in 1970