Simple technique appears to be safe and effective, review suggests
By Robert Preidt
MONDAY, Oct. 15 (HealthDay News) -- A technique called the "mother's kiss" is a safe and effective way to remove foreign objects from the nostrils of young children, according to British researchers.
In the mother's kiss, a child's mother or other trusted adult covers the child's mouth with their mouth to form a seal, blocks the clear nostril with their finger, and then blows into the child's mouth. The pressure from the breath may expel the object in the blocked nostril.
Before using it, the adult should explain the technique to the child so that he or she is not frightened. If the first attempt is unsuccessful, the technique can be tried several times, according to a review published in the current issue of the CMAJ (Canadian Medical Association Journal).
For their report, researchers in Australia and the United Kingdom examined eight case studies in which the mother's kiss was used on children aged 1 to 8 years.
"The mother's kiss appears to be a safe and effective technique for first-line treatment in the removal of a foreign body from the nasal cavity," Dr. Stephanie Cook, of the Buxted Medical Centre in England, and colleagues concluded. "In addition, it may prevent the need for general anesthesia in some cases."
Further research is needed to compare various positive-pressure techniques and test how effective they are in different situations where objects are in various locations and have spent different lengths of time in the nasal passages, the researchers noted in a journal news release.
The U.S. National Library of Medicine has more about foreign objects in the nose.
SOURCE: CMAJ (Canadian Medical Association Journal), news release, Oct. 15, 2012
Copyright © 2012 HealthDay. All rights reserved. URL:http://www.healthscout.com/template.asp?id=669525


Some unknown terrible person shot a defenseless pilot whale last month, leaving it to swim the Atlantic in agony for weeks before it finally beached itself on the New Jersey shore and died. Authorities are still looking for the shooter. The bullet wound caused a fulminant infection in the whale’s jaw that prevented it from eating, so it basically starved to death. This was determined during a necropsy, an autopsy for animals.
Along with sympathy for the poor creature, this debacle aroused an interesting question: How does one autopsy a whale? With four-ton meat hooks, whaling knives and bone saws, actually. Michael Moore, a veterinarian and whale biologist at the Woods Hole Oceanographic Institution, does it all the time.
Moore spends much of his time studying North Atlantic right whales, an endangered species whose name derives from whalers’ adage that these were the “right whales” to hunt, because they’re easy to spot and float when they die. They’re no longer hunted for their oil, but they are entangled in fishing lines and injured in ship collisions, often suffering for a great while and also succumbing to starvation. “It’s the most egregious animal welfare issue globally at this time,” in Moore’s words. But protecting them requires understanding how they died, and to do this Moore must take them apart, studying their broken bones and lobster net-tangled flukes to determine their exact causes of death.In partnership with the National Oceanic and Atmospheric Administration, Moore deploys on-call, toting a case full of knives to examine right whales that have beached or are floating in the open ocean. Right whales are baleen whales and at least two orders of magnitude bigger than the toothed pilot whale that was shot, so in most cases, they must be examined right where they‘re found — that means on the beach. They either beach themselves and die there, or they’re towed to shore once they have been located at sea.
Moore and other rubber-suited biologists work amid 120,000 pounds of slick black-and-red whale flesh, clambering over and through the carcass to find out what went wrong. Time is of the essence, because the longer they wait, the more the animal’s internal organs break down, making it difficult to determine how it died.
Moore uses a Japanese whaling hook, which is useful for pulling back sheets of blubber to get at the animal’s internal organs. He carries a bone saw — formerly his mother’s — to get through jaws and vertebrae to find the location of a fatal injury. He’s even visited indigenous Alaskan tribes to study their ancestral whale processing techniques.
The pilot whale that died was small, so it was trucked to a necropsy facility at the the Marine Mammal Stranding Center in Brigantine, N.J., down the shore north of Atlantic City. It weighed about 740 pounds when it beached, quite gaunt for an animal that should normally weigh more than a ton. Researchers knew something was seriously wrong, but they had to perform a necropsy to determine what it was.
The creatures are brought in on trucks and hoisted into the facility on chains rigged to the ceiling, attached to four-ton-rated meat hooks. They lay on negative-pressure steel tables, the same types used in human autopsy procedures, which suck out odors and pathogens as the biologists get to work. The lab also contains deep freezers for stringing up deceased animals; it harbors an overwhelming odor of chemical and organic substances. (It’s somewhat legendary at WHOI that Moore lost his sense of smell while in veterinary school, which he says enables him to get literally inside a rotting animal carcass without losing his lunch or his cool.)
The 11-foot-long pilot whale died shortly after authorities reached its side on the beach on Sept. 24. But it wasn’t until a necropsy a couple weeks later that they knew what happened. The bullet entered near its blow hole, but the wound had closed and faded a bit, suggesting it had been shot about a month prior. The .30-caliber round lodged in its jaw, causing the infection.
“This poor animal literally starved to death,” said Bob Schoelkopf, co-director of the Marine Mammal Stranding Center, in an interview with the AP. “It was wandering around and slowly starving to death because of the infection. Who would do that to an innocent animal?”
That question is now in the hands of the authorities. For biologists like Moore and Schoelkopf, necropsies can at least answer the question of how. Why, of course, is something else entirely.
Five amazing, clean technologies that will set us free, in this month's energy-focused issue. Also: how to build a better bomb detector, the robotic toys that are raising your children, a human catapult, the world's smallest arcade, and much more.


Narrator: This is Science Today. A new air sampler, which can effectively trap and evaluate fine particle pollutants in both their solid and gas phases has been developed by scientist Lara Gundel of the Lawrence Berkeley National Laboratory. This sampler can greatly impact future EPA air quality standards and lead to a definitive understanding of how pollutants such as polycyclic aromatic hydrocarbons and pesticides, affect our health.
Gundel: I guess the innovations we made were a way to separate the gases and particles accurately and then to be able to collective measure particles and the gases separately and accurately.
Narrator: Gundel achieved this by coating an inner tube of roughened glass inside the filter with sticky resin beads, which were finely ground up until their pores were small enough to trap gas particles.
Gundel: We quickly decided that this new technology that we had, these new kinds of sampler designs, could be used in outdoor air, in general atmospheric questions.
Narrator: Gundel is currently collaborating with other scientists and the EPA to test this sampler at various sites across the country. For Science Today, I'm Larissa Branin.


The atlas of climate change: mapping the world's greatest challenge
University of California Press
, 2007 - Science
- 112 pages
Today's headlines and recent events reflect the gravity of climate change. Heat waves, droughts, and floods are bringing death to vulnerable populations, destroying livelihoods, and driving people from their homes.
Rigorous in its science and insightful in its message, this atlas examines the causes of climate change and considers its possible impact on subsistence, water resources, ecosystems, biodiversity, health, coastal megacities, and cultural treasures. It reviews historical contributions to greenhouse gas levels, progress in meeting international commitments, and local efforts to meet the challenge of climate change.
With more than 50 full-color maps and graphics, this is an essential resource for policy makers, environmentalists, students, and everyone concerned with this pressing subject.
The Atlas covers a wide range of topics, including:
* Warning signs
* Future scenarios
* Vulnerable populations
* Renewable energy
* Emissions reduction
* Personal and public action
Copub: Myriad Editions


Classroom Strategies for Students with Disabilities
This information is intended as a guide to assist students with disabilities in understanding and coping with their particular disability and its characteristics. Because every person and disability is unique, it is important to keep individual qualities and characteristics in mind when evaluating the usefulness of this information for a particular person in a particular circumstance. For additional information regarding these topics, please contact the Counselor/Coordinator of Student Accommodations.
Difficulty paying attention or concentrating on one task for an extended period of time
Difficulty hearing or processing/understanding what is heard.
Total loss of sight
Total loss of hearing
Difficulty expressing oneself in spoken or written form
Difficulty controlling hand, eye or other muscles that aid in the perception and expression of information
Difficulty understanding/interpreting what one hears or reads
Difficulty remembering information
Difficulty seeing or processing/understanding what is seen
For additional information please contact the Counselor/Coordinator of Student Accommodations at 217/234-5259 or email Jordan Hicks at email@example.com


Sustainability and Renewable Merino
Wool runs on grass
The primary inputs for wool production are water, sunshine and fertile soils to grow grass – the primary diet of sheep.
As such merino production inherently has the potential of being fully sustainable providing it is operated within the carrying capacity of the ecosystem.
They must operate, or be in the process of implementing, a grazing management strategy based on long term sustainability.
The management system must embrace holistic farming principals with the goal of developing a resilient ecosystem that can regenerate, withstand stress and rebuild itself when necessary.
This goal should be to aim for 100% ground cover all year, with a focus on perennial grasses to regenerate the ecology and increase biodiversity.
Holistic farming principles include:
- Clear goals for the people involved
– Clear goals for the land in use
– Clear goals for the business
- Clear goals for the management of livestock
The management process should involve:
- Reviewing these strategies regularly
– Making decision with these goals in mind
– Monitoring the health of your land, your business and the people involved


ingredients & lore
blended with decaf ceylon tea, natural peach flavor, marigold flowers, apple pieces and apricots
Cultivation of peaches began in China as early as 2000BC. The winds of trade brought peaches to Greece and Persia, where they were instantly accepted. The juicy fruit was also a big hit with the Romans, who cultivated it throughout the empire. From Italy, peaches made the leap across the Atlantic, where early settlers planted them throughout the East Coast. Soon they were so plentiful, local botanists thought of them as native fruits.


OFF THE CHARTS
Oil supply rising, but demand may more than keep pace
Published: Saturday, November 24, 2012 at 4:36 p.m.
Last Modified: Saturday, November 24, 2012 at 4:36 p.m.
It used to be taken for granted that as economies grew, they would use more oil. That was a major reason cited in warnings that the world would run out of oil, particularly if standards of living rose in developing countries.
Well, standards of living are improving in developing countries, but the dire forecasts now appear to be wrong. In part that is because new discoveries and improving technologies have increased the amount of oil that can be produced. It also reflects conservation, in part, as cars become more efficient and as other steps are taken to reduce oil use.
The International Energy Agency, in its 2012 World Energy Outlook, released last week, forecast that U.S. oil production, which began to rise in 2009 after decades of decline, would continue rising through at least 2020, when it could be about as high as it was in 1970, the year of peak production.
At the same time it forecast that by 2035, U.S. oil consumption, which peaked in 2005, could decline to levels not seen since the 1960s, depending on how much conservation is encouraged.
The IEA report also forecast that by around 2020, the United States could surpass Saudi Arabia as the world's largest oil producer, and that while the country was not likely to become a net exporter of oil, the North American continent as a whole could be by around 2030.
But despite declining demand in some countries that historically were heavy users of oil, the world demand for oil seems likely to continue to rise. The IEA forecast that global energy demand – including demand for energy produced by other sources – is likely to rise by 35 percent by 2035, with a large part of the increase coming from China and India.
In 1969, the United States consumed a third of the oil used in the world, while China used less than 1 percent. Last year the U.S. share was less than 22 percent, while the Chinese accounted for 11 percent. The IEA forecasts that by 2030, the U.S. share could be less than the Chinese one.
By 2035, U.S. consumption of oil is expected to be as much as one-third less than it was last year. In China, oil consumption is expected to be up as much as two-thirds from the 2011 level, and India's is predicted to more than double.
Reader comments posted to this article may be published in our print edition. All rights reserved. This copyrighted material may not be re-published without permission. Links are encouraged.


Aswan High Dam on the Nile River
Aswan-- On 15 January 1971, Egypt celebrated the completion of the High Dam, whose funding was the center of a Cold War dispute that led to the 1956 Suez War. Located on the Upper Nile, around 1000km downstream from Cairo, the gigantic mountain of concrete and steel is among the 20th century's most elaborate engineering work. Aswan High Dam on the Nile River is located at the north end of Lake Nasser.
The construction of the High Dam began in 1960, and it was officially inaugurated ten years later, at a cost of US$1 billion, much of which was provided by the former Soviet Union. The dam stores 160 billion cubic meters of water, and the reservoir behind it, named Lake Nasser, stretches some 350km into Egypt and 150km into Sudan. It is a symbol for Egyptians patience and challenge.
The Suez Crisis began on 26 July 1956 when Egyptian President Gamal Abdel Nasser nationalised the Suez Canal. The move was in response to a decision by the United States and Britain to withdraw finance for the Aswan High Dam - a massive project to bring water to the Nile valley and electricity to develop Egypt's industry - because of Egypt's political and military ties to the Soviet Union.
The world-famous High Dam was an engineering miracle when it was built in the 1960s. Today it provides irrigation and electricity for the whole of Egypt and, together with the old Aswan Dam, 6km downriver, wonderful views for visitors. From the top of the two mile-long High Dam you can gaze across Lake Nasser, the huge reservoir created when it was built to Kalabsha temple in the south and the huge power station to the north.
The story of the High Dam was a tale of a nation, hikayit sha‘b, as Abdel Halim Hafiz chanted in an iconic song from the Nasserist period.
This nation lived under the yoke of British colonialism for over 70 years. After gaining independence, Egypt's revolutionary president, Colonel Gamal Abdel Nasser, approached the World Bank to finance the construction of a dam on the Nile, a vital step towards economic development. The World Bank refused. In an audacious challenge to old and new imperialism, Nasser nationalized the Suez Canal in 1956 to acquire funding for the project. The struggling nation heroically endured subsequent military assaults and a trade embargo. The dam was eventually built.
The story of the High Dam at Aswan is indeed the tale of this nation. The stages of its history chronicle critical transformations in Egyptian history at large. During the last half century, the dam moved from being a celebrated monument to Egyptian independence to a forgotten barrage deep in the country's south. It was a state-engineered tool of anti-imperialist propaganda, whose splendor faded away with the downfall and fundamental reversion of the anti-imperial project.
In other words Egypt had monopoly of the waters. On behalf of its colonial possessions - Sudan, Kenya, Tanzania and Uganda - Britain, which was primarily concerned with the Suez Canal and the passage to India, signed away their most precious resource.
Egypt had the right to veto any project along the Nile and full rights of inspection.
In 1959, this deal was overtaken by a new agreement between Egypt and Sudan splitting the waters 75 per cent to 25 per cent and guaranteeing Cairo "full control of the river".
The results of this control are nowhere more clearly seen than at Lake Nasser, a man-made reservoir 550km-long, created when Egypt completed the Aswan high dam. The country's largest engineering project took six years to build and another five years to fill.
Some 55.5 billion cu m of water gush from the Aswan dam into Egypt annually. It has enabled Cairo to regulate the life-giving annual flood, to irrigate its otherwise parched landscape, and at the point it was finished supplied half the country's electricity needs.
Nasser was in need of a success, a success to rival that of the Suez Canal, which is a 190 km-long man-made waterway linking the Mediterranean with the Red Sea. The French dug the Suez Canal 97 years before Nasser took the decision to nationalize it. Nasser took the decision to nationalize the Suez Canal just two years before it was supposed to revert back to Egyptian control. This was used as justification by three countries [Britain, France and Israel] to launch a tripartite strike against Egypt. The President's decision to cancel the contract just two years before its expiry date made it seem like Nasser was seeking a popular confrontation.
The difference is that the Aswan High Dam is a success story, whereas the Suez Canal was a story of conflict. The High Dam is a witness of the history of Egypt's relationship with the Soviet Union, which continued throughout Nasser's rule. The Aswan High Dam is considered to be the most important construction of the Nasser regime.
Abu Simbel, Egypt — In the 1960s, rising waters from a new dam threatened to submerge the temples and monuments of Nubia, the ancient home of black pharaohs in Egypt's far south. To preserve them, the antiquities were dismantled, moved and reconstructed. Today, most of the surviving monuments can be seen only from the lake created by the waters that nearly destroyed them.
A short flight from Aswan is Abu Simbel and the Great Temple of Ramses II, and the gods of creation and light, Ptah, Amen and Heru-khuti is the most iconic Ancient Egyptian sight after the Pyramids. The temple has four massive statues of Ramses II and the gods Ra-Horakhty, Amun and Ptah at its entrance. Beyond lie two pillared halls and the sacred sanctuary. Every wall and ceiling is a storybook art gallery of this extraordinary pharaoh's life. (He lived to 90 and is said to have fathered more than 200 children).
Know more details about Visiting Temples of Ramses II at Abu Simbel, Aswan
Construction of the high dam was an enormous national project that every Egyptian contributed to. Nubians in particular sacrificed their possessions, including 45 Nubian villages lying on 300 square kilometers of land and one million palm trees. They were moved from a paradise on the banks of the Nile. These treasures are all submerged under water now. Along with the loss of the land, there was also the loss of heritage, values, memories and lifestyle, and, above all proximity to the water, the primary source of life.
For More Information Visit: Aswan Tourism and Tourist Information
Cruise ships on Egypt's Lake Nasser visit the ancient temples of Nubia's black pharaohs:
The Aswan High Dam: A Political Witness: http://aawsat.com/english/news.asp?section=2&id=19640
Memories of a high dam: http://www.almasryalyoum.com/en/news/memories-dam-high-dam%E2%80%A6
Suez Crisis: Key players: http://news.bbc.co.uk/2/hi/5195582.stm
Nile deal brings countries to boiling point over water: http://www.nzherald.co.nz/world/news/article.cfm?c_id=2&objectid=10648772


|Met proto-oncogene (hepatocyte growth factor receptor)|
Crystallographic structure of MET. PDB rendering based on 1r0p.
|External IDs||ChEMBL: GeneCards:|
|RNA expression pattern|
c-Met (MET or MNNG HOS Transforming gene) is a proto-oncogene that encodes a protein known as hepatocyte growth factor receptor (HGFR). The hepatocyte growth factor receptor protein possesses tyrosine-kinase activity. The primary single chain precursor protein is post-translationally cleaved to produce the alpha and beta subunits, which are disulfide linked to form the mature receptor.
MET is a membrane receptor that is essential for embryonic development and wound healing. Hepatocyte growth factor (HGF) is the only known ligand of the MET receptor. MET is normally expressed by cells of epithelial origin, while expression of HGF is restricted to cells of mesenchymal origin. Upon HGF stimulation, MET induces several biological responses that collectively give rise to a program known as invasive growth.
Abnormal MET activation in cancer correlates with poor prognosis, where aberrantly active MET triggers tumor growth, formation of new blood vessels (angiogenesis) that supply the tumor with nutrients, and cancer spread to other organs (metastasis). MET is deregulated in many types of human malignancies, including cancers of kidney, liver, stomach, breast, and brain. Normally, only stem cells and progenitor cells express MET, which allows these cells to grow invasively in order to generate new tissues in an embryo or regenerate damaged tissues in an adult. However, cancer stem cells are thought to hijack the ability of normal stem cells to express MET, and thus become the cause of cancer persistence and spread to other sites in the body.
MET proto-oncogene (GeneID: 4233) has a total length of 125,982 bp, and it is located in the 7q31 locus of chromosome 7. MET is transcribed into a 6,641 bp mature mRNA, which is then translated into a 1,390 amino-acid MET protein.
MET is a receptor tyrosine kinase (RTK) that is produced as a single-chain precursor. The precursor is proteolytically cleaved at a furin site to yield a highly glycosylated extracellular α-subunit and a transmembrane β-subunit, which are linked together by a disulfide bridge.
- Region of homology to semaphorins (Sema domain), which includes the full α-chain and the N-terminal part of the β-chain
- Cysteine-rich MET-related sequence (MRS domain)
- Glycine-proline-rich repeats (G-P repeats)
- Four immunoglobulin-like structures (Ig domains), a typical protein-protein interaction region.
A Juxtamembrane segment that contains:
- a serine residue (Ser 985), which inhibits the receptor kinase activity upon phosphorylation
- a tyrosine (Tyr 1003), which is responsible for MET polyubiquitination, endocytosis, and degradation upon interaction with the ubiquitin ligase CBL
- Tyrosine kinase domain, which mediates MET biological activity. Following MET activation, transphosphorylation occurs on Tyr 1234 and Tyr 1235
- C-terminal region contains two crucial tyrosines (Tyr 1349 and Tyr 1356), which are inserted into the multisubstrate docking site, capable of recruiting downstream adapter proteins with Src homology-2 (SH2) domains. The two tyrosines of the docking site have been reported to be necessary and sufficient for the signal transduction both in vitro.
MET signaling pathway
MET activation by its ligand HGF induces MET kinase catalytic activity, which triggers transphosphorylation of the tyrosines Tyr 1234 and Tyr 1235. These two tyrosines engage various signal transducers, thus initiating a whole spectrum of biological activities driven by MET, collectively known as the invasive growth program. The transducers interact with the intracellular multisubstrate docking site of MET either directly, such as GRB2, SHC, SRC, and the p85 regulatory subunit of phosphatidylinositol-3 kinase (PI3K), or indirectly through the scaffolding protein Gab1
Tyr 1349 and Tyr 1356 of the multisubstrate docking site are both involved in the interaction with GAB1, SRC, and SHC, while only Tyr 1356 is involved in the recruitment of GRB2, phospholipase C γ (PLC-γ), p85, and SHP2.
GAB1 is a key coordinator of the cellular responses to MET and binds the MET intracellular region with high avidity, but low affinity. Upon interaction with MET, GAB1 becomes phosphorylated on several tyrosine residues which, in turn, recruit a number of signalling effectors, including PI3K, SHP2, and PLC-γ. GAB1 phosphorylation by MET results in a sustained signal that mediates most of the downstream signaling pathways.
Activation of signal transduction
MET engagement activates multiple signal transduction pathways:
- The RAS pathway mediates HGF-induced scattering and proliferation signals, which lead to branching morphogenesis. Of note, HGF, differently from most mitogens, induces sustained RAS activation, and thus prolonged MAPK activity.
- The PI3K pathway is activated in two ways: PI3K can be either downstream of RAS, or it can be recruited directly through the multifunctional docking site. Activation of the PI3K pathway is currently associated with cell motility through remodeling of adhesion to the extracellular matrix as well as localized recruitment of transducers involved in cytoskeletal reorganization, such as RAC1 and PAK. PI3K activation also triggers a survival signal due to activation of the AKT pathway.
- The STAT pathway, together with the sustained MAPK activation, is necessary for the HGF-induced branching morphogenesis. MET activates the STAT3 transcription factor directly, through an SH2 domain.
- The beta-catenin pathway, a key component of the Wnt signaling pathway, translocates into the nucleus following MET activation and participates in transcriptional regulation of numerous genes.
Role in development
During embryonic development, transformation of the flat, two-layer germinal disc into a three-dimensional body depends on transition of some cells from an epithelial phenotype to spindle-shaped cells with motile behaviour, a mesenchymal phenotype. This process is referred to as epithelial-mesenchymal transition (EMT). Later in embryonic development, MET is crucial for gastrulation, angiogenesis, myoblast migration, bone remodeling, and nerve sprouting among others. MET is essential for embryogenesis, because MET -/- mice die in utero due to severe defects in placental development. Furthermore, MET is required for such critical processes as liver regeneration and wound healing during adulthood.
Tissue distribution
MET is normally expressed by epithelial cells. However, MET is also found on endothelial cells, neurons, hepatocytes, hematopoietic cells, and melanocytes. HGF expression is restricted to cells of mesenchymal origin.
Transcriptional control
MET transcription is activated by HGF and several growth factors. MET promoter has four putative binding sites for Ets, a family of transcription factors that control several invasive growth genes. ETS1 activates MET transcription in vitro. MET transcription is activated by hypoxia-inducible factor 1 (HIF1), which is activated by low concentration of intracellular oxygen. HIF1 can bind to one of the several hypoxia response elements (HREs) in the MET promoter. Hypoxia also activates transcription factor AP-1, which is involved in MET transcription.
Role in cancer
MET pathway plays an important role in the development of cancer through:
- angiogenesis (sprouting of new blood vessels from pre-existing ones to supply a tumor with nutrients);
- scatter (cells dissociation due to metalloprotease production), which often leads to metastasis.
Coordinated down-regulation of both MET and its downstream effector extracellular signal-regulated kinase 2 (ERK2) by miR-199a* may be effective in inhibiting not only cell proliferation but also motility and invasive capabilities of tumor cells.
Interaction with tumour suppressor genes
PTEN (phosphatase and tensin homolog) is a tumor suppressor gene encoding a protein PTEN, which possesses lipid and protein phosphatase-dependent as well as phosphatase-independent activities. PTEN protein phosphatase is able to interfere with MET signaling by dephosphorylating either PIP3 generated by PI3K, or the p52 isoform of SHC. SHC dephosphorylation inhibits recruitment of the GRB2 adapter to activated MET.
Cancer therapies targeting HGF/MET
Since tumor invasion and metastasis are the main cause of death in cancer patients, interfering with MET signaling appears to be a promising therapeutic approach. A comprehensive list of HGF and MET targeted experimental therapeutics for oncology now in human clinical trials can be found here.
MET kinase inhibitors
Kinase inhibitors are low molecular weight molecules that prevent ATP binding to MET, thus inhibiting receptor transphosphorylation and recruitment of the downstream effectors. The limitations of kinase inhibitors include the facts that they only inhibit kinase-dependent MET activation, and that none of them is fully specific for MET.
- K252a (Fermentek Biotechnology) is a staurosporine analogue isolated from Nocardiopsis sp. soil fungi, and it is a potent inhibitor of all receptor tyrosine kinases (RTKs). At nanomolar concentrations, K252a inhibits both the wild type and the mutant (M1268T) MET function.
- SU11274 (SUGEN) specifically inhibits MET kinase activity and its subsequent signaling. SU11274 is also an effective inhibitor of the M1268T and H1112Y MET mutants, but not the L1213V and Y1248H mutants. SU11274 has been demonstrated to inhibit HGF-induced motility and invasion of epithelial and carcinoma cells.
- PHA-665752 (Pfizer) specifically inhibits MET kinase activity, and it has been demonstrated to represses both HGF-dependent and constitutive MET phosphorylation. Furthermore, some tumors harboring MET amplifications are highly sensitive to treatment with PHA-665752.
- ARQ197 (ArQule) is a promising selective inhibitor of MET, which entered a phase 2 clinical trial in 2008.
- Foretinib (XL880, Exelixis) targets multiple receptor tyrosine kinases (RTKs) with growth-promoting and angiogenic properties. The primary targets of foretinib are MET, VEGFR2, and KDR. Foretinib has completed a phase 2 clinical trials with indications for papillary renal cell carcinoma, gastric cancer, and head and neck cancer.
- SGX523 (SGX Pharmaceuticals) specifically inhibits MET at low nanomolar concentrations.
- MP470 (SuperGen) is a novel inhibitor of c-KIT, MET, PDGFR, Flt3, and AXL. Phase I clinical trial of MP470 had been announced in 2007.
HGF inhibitors
Since HGF is the only known ligand of MET, formation of a HGF:MET complex blocks MET biological activity. For this purpose, truncated HGF, anti-HGF neutralizing antibodies, and an uncleavable form of HGF have been utilized so far. The major limitation of HGF inhibitors is that they block only HGF-dependent MET activation.
- NK4 competes with HGF as it binds MET without inducing receptor activation, thus behaving as a full antagonist. NK4 is a molecule bearing the N-terminal hairpin and the four kringle domains of HGF. Moreover, NK4 is structurally similar to angiostatins, which is why it possesses anti-angiogenic activity.
- Neutralizing anti-HGF antibodies were initially tested in combination, and it was shown that at least three antibodies, acting on different HGF epitopes, are necessary to prevent MET tyrosine kinase activation. More recently, it has been demonstrated that fully human monoclonal antibodies can individually bind and neutralize human HGF, leading to regression of tumors in mouse models. Two anti-HGF antibodies are currently available: the humanized AV299 (AVEO), and the fully human AMG102 (Amgen).
- Uncleavable HGF is an engineered form of pro-HGF carrying a single amino-acid substitution, which prevents the maturation of the molecule. Uncleavable HGF is capable of blocking MET-induced biological responses by binding MET with high affinity and displacing mature HGF. Moreover, uncleavable HGF competes with the wild-type endogenous pro-HGF for the catalytic domain of proteases that cleave HGF precursors. Local and systemic expression of uncleavable HGF inhibits tumor growth and, more importantly, prevents metastasis.
Decoy MET
Decoy MET refers to a soluble truncated MET receptor. Decoys are able to inhibit MET activation mediated by both HGF-dependent and independent mechanisms, as decoys prevent both the ligand binding and the MET receptor homodimerization. CGEN241 (Compugen) is a decoy MET that is highly efficient in inhibiting tumor growth and preventing metastasis in animal models.
Immunotherapy targeting MET
Drugs used for immunotherapy can act either passively by enhancing the immunologic response to MET-expressing tumor cells, or actively by stimulating immune cells and altering differentiation/growth of tumor cells.
Passive immunotherapy
Administering monoclonal antibodies (mAbs) is a form of passive immunotherapy. MAbs facilitate destruction of tumor cells by complement-dependent cytotoxicity (CDC) and cell-mediated cytotoxicity (ADCC). In CDC, mAbs bind to specific antigen, leading to activation of the complement cascade, which in turn leads to formation of pores in tumor cells. In ADCC, the Fab domain of a mAb binds to a tumor antigen, and Fc domain binds to Fc receptors present on effector cells (phagocytes and NK cells), thus forming a bridge between an effector and a target cells. This induces the effector cell activation, leading to phagocytosis of the tumor cell by neutrophils and macrophages. Furthermore, NK cells release cytotoxic molecules, which lyse tumor cells.
- DN30 is monoclonal anti-MET antibody that recognizes the extracellular portion of MET. DN30 induces both shedding of the MET ectodomain as well as cleavage of the intracellular domain, which is successively degraded by proteasome machinery. As a consequence, on one side MET is inactivated, and on the other side the shed portion of extracellular MET hampers activation of other MET receptors, acting as a decoy. DN30 inhibits tumour growth and prevents metastasis in animal models.
- OA-5D5 is one-armed monoclonal anti-MET antibody that was demonstrated to inhibit orthotopic pancreatic and glioblastoma tumor growth and to improve survival in tumor xenograft models. OA-5D5 is produced as a recombinant protein in Escherichia coli. It is composed of murine variable domains for the heavy and light chains with human IgG1 constant domains. The antibody blocks HGF binding to MET in a competitive fashion.
Active immunotherapy
Active immunotherapy to MET-expressing tumors can be achieved by administering cytokines, such as interferons (IFNs) and interleukins (IL-2), which triggers non-specific stimulation of numerous immune cells. IFNs have been tested as therapies for many types of cancers and have demonstrated therapeutic benefits. IL-2 has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of renal cell carcinoma and metastatic melanoma, which often have deregulated MET activity.
See also
- Bottaro DP, Rubin JS, Faletto DL, Chan AM, Kmiecik TE, Vande Woude GF, Aaronson SA (February 1991). "Identification of the hepatocyte growth factor receptor as the met proto-oncogene product". Science 251 (4995): 802–4. doi:10.1126/science.1846706. PMID 1846706.
- Galland F, Stefanova M, Lafage M, Birnbaum D (1992). "Localization of the 5' end of the MCF2 oncogene to human chromosome 15q15----q23". Cytogenet. Cell Genet. 60 (2): 114–6. doi:10.1159/000133316. PMID 1611909.
- Cooper CS (January 1992). "The met oncogene: from detection by transfection to transmembrane receptor for hepatocyte growth factor". Oncogene 7 (1): 3–7. PMID 1531516.
- "Entrez Gene: MET met proto-oncogene (hepatocyte growth factor receptor)".
- Gentile A, Trusolino L, Comoglio PM (March 2008). "The Met tyrosine kinase receptor in development and cancer". Cancer Metastasis Rev. 27 (1): 85–94. doi:10.1007/s10555-007-9107-6. PMID 18175071.
- Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF (December 2003). "Met, metastasis, motility and more". Nat. Rev. Mol. Cell Biol. 4 (12): 915–25. doi:10.1038/nrm1261. PMID 14685170.
- Gandino L, Longati P, Medico E, Prat M, Comoglio PM (January 1994). "Phosphorylation of serine 985 negatively regulates the hepatocyte growth factor receptor kinase". J. Biol. Chem. 269 (3): 1815–20. PMID 8294430.
- Peschard P, Fournier TM, Lamorte L, Naujokas MA, Band H, Langdon WY, Park M (November 2001). "Mutation of the c-Cbl TKB domain binding site on the Met receptor tyrosine kinase converts it into a transforming protein". Mol. Cell 8 (5): 995–1004. doi:10.1016/S1097-2765(01)00378-1. PMID 11741535.
- Ponzetto C, Bardelli A, Zhen Z, Maina F, dalla Zonca P, Giordano S, Graziani A, Panayotou G, Comoglio PM (April 1994). "A multifunctional docking site mediates signaling and transformation by the hepatocyte growth factor/scatter factor receptor family". Cell 77 (2): 261–71. doi:10.1016/0092-8674(94)90318-2. PMID 7513258.
- Maina F, Casagranda F, Audero E, Simeone A, Comoglio PM, Klein R, Ponzetto C (November 1996). "Uncoupling of Grb2 from the Met receptor in vivo reveals complex roles in muscle development". Cell 87 (3): 531–42. doi:10.1016/S0092-8674(00)81372-0. PMID 8898205.
- Abounader R, Reznik T, Colantuoni C, Martinez-Murillo F, Rosen EM, Laterra J (December 2004). "Regulation of c-Met-dependent gene expression by PTEN". Oncogene 23 (57): 9173–82. doi:10.1038/sj.onc.1208146. PMID 15516982.
- Pelicci G, Giordano S, Zhen Z, Salcini AE, Lanfrancone L, Bardelli A, Panayotou G, Waterfield MD, Ponzetto C, Pelicci PG (April 1995). "The motogenic and mitogenic responses to HGF are amplified by the Shc adaptor protein". Oncogene 10 (8): 1631–8. PMID 7731718.
- Weidner KM, Di Cesare S, Sachs M, Brinkmann V, Behrens J, Birchmeier W (November 1996). "Interaction between Gab1 and the c-Met receptor tyrosine kinase is responsible for epithelial morphogenesis". Nature 384 (6605): 173–6. doi:10.1038/384173a0. PMID 8906793.
- Furge KA, Zhang YW, Vande Woude GF (November 2000). "Met receptor tyrosine kinase: enhanced signaling through adapter proteins". Oncogene 19 (49): 5582–9. doi:10.1038/sj.onc.1203859. PMID 11114738.
- Gual P, Giordano S, Anguissola S, Parker PJ, Comoglio PM (January 2001). "Gab1 phosphorylation: a novel mechanism for negative regulation of HGF receptor signaling". Oncogene 20 (2): 156–66. doi:10.1038/sj.onc.1204047. PMID 11313945.
- Gual P, Giordano S, Williams TA, Rocchi S, Van Obberghen E, Comoglio PM (March 2000). "Sustained recruitment of phospholipase C-gamma to Gab1 is required for HGF-induced branching tubulogenesis". Oncogene 19 (12): 1509–18. doi:10.1038/sj.onc.1203514. PMID 10734310.
- O'Brien LE, Tang K, Kats ES, Schutz-Geschwender A, Lipschutz JH, Mostov KE (July 2004). "ERK and MMPs sequentially regulate distinct stages of epithelial tubule development". Dev. Cell 7 (1): 21–32. doi:10.1016/j.devcel.2004.06.001. PMID 15239951.
- Marshall CJ (January 1995). "Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation". Cell 80 (2): 179–85. doi:10.1016/0092-8674(95)90401-8. PMID 7834738.
- Graziani A, Gramaglia D, Cantley LC, Comoglio PM (November 1991). "The tyrosine-phosphorylated hepatocyte growth factor/scatter factor receptor associates with phosphatidylinositol 3-kinase". J. Biol. Chem. 266 (33): 22087–90. PMID 1718989.
- Boccaccio C, Andò M, Tamagnone L, Bardelli A, Michieli P, Battistini C, Comoglio PM (January 1998). "Induction of epithelial tubules by growth factor HGF depends on the STAT pathway". Nature 391 (6664): 285–8. doi:10.1038/34657. PMID 9440692.
- Monga SP, Mars WM, Pediaditakis P, Bell A, Mulé K, Bowen WC, Wang X, Zarnegar R, Michalopoulos GK (April 2002). "Hepatocyte growth factor induces Wnt-independent nuclear translocation of beta-catenin after Met-beta-catenin dissociation in hepatocytes". Cancer Res 7 (62): 2064–71. ISSN 0008-5472. PMID 11929826.
- Gude NA, Emmanuel G, Wu W, Cottage CT, Fischer K, Quijada P, Muraski JA, Alvarez R, Rubio M, Schaefer E, Sussman MA (May 2008). "Activation of Notch-mediated protective signaling in the myocardium". Circ. Res. 102 (9): 1025–35. doi:10.1161/CIRCRESAHA.107.164749. PMID 18369158.
- "he fields of HGF/c-Met involvement". HealthValue. Retrieved 2009-06-13.
- Boccaccio C, Comoglio PM (August 2006). "Invasive growth: a MET-driven genetic programme for cancer and stem cells". Nat. Rev. Cancer 6 (8): 637–45. doi:10.1038/nrc1912. PMID 16862193.
- Birchmeier C, Gherardi E (October 1998). "Developmental roles of HGF/SF and its receptor, the c-Met tyrosine kinase". Trends Cell Biol. 8 (10): 404–10. doi:10.1016/S0962-8924(98)01359-2. PMID 9789329.
- Uehara Y, Minowa O, Mori C, Shiota K, Kuno J, Noda T, Kitamura N (February 1995). "Placental defect and embryonic lethality in mice lacking hepatocyte growth factor/scatter factor". Nature 373 (6516): 702–5. doi:10.1038/373702a0. PMID 7854453.
- Shirasaki F, Makhluf HA, LeRoy C, Watson DK, Trojanowska M (December 1999). "Ets transcription factors cooperate with Sp1 to activate the human tenascin-C promoter". Oncogene 18 (54): 7755–64. doi:10.1038/sj.onc.1203360. PMID 10618716.
- Gambarotta G, Boccaccio C, Giordano S, Andŏ M, Stella MC, Comoglio PM (November 1996). "Ets up-regulates MET transcription". Oncogene 13 (9): 1911–7. PMID 8934537.
- Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio PM (April 2003). "Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene". Cancer Cell 3 (4): 347–61. doi:10.1016/S1535-6108(03)00085-0. PMID 12726861.
- "HGF/c-Met and cancer". HealthValue. Retrieved 2009-06-13.
- Kim S, Lee UJ, Kim MN, et al. (June 2008). "MicroRNA miR-199a* regulates the MET proto-oncogene and the downstream extracellular signal-regulated kinase 2 (ERK2)". J. Biol. Chem. 283 (26): 18158–66. doi:10.1074/jbc.M800186200. PMID 18456660.
- Maehama T, Dixon JE (May 1998). "The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate". J. Biol. Chem. 273 (22): 13375–8. doi:10.1074/jbc.273.22.13375. PMID 9593664.
- Morris MR, Gentle D, Abdulrahman M, Maina EN, Gupta K, Banks RE, Wiesener MS, Kishida T, Yao M, Teh B, Latif F, Maher ER (June 2005). "Tumor suppressor activity and epigenetic inactivation of hepatocyte growth factor activator inhibitor type 2/SPINT2 in papillary and clear cell renal cell carcinoma". Cancer Res. 65 (11): 4598–606. doi:10.1158/0008-5472.CAN-04-3371. PMID 15930277.
- Morotti A, Mila S, Accornero P, Tagliabue E, Ponzetto C (July 2002). "K252a inhibits the oncogenic properties of Met, the HGF receptor". Oncogene 21 (32): 4885–93. doi:10.1038/sj.onc.1205622. PMID 12118367.
- Berthou S, Aebersold DM, Schmidt LS, Stroka D, Heigl C, Streit B, Stalder D, Gruber G, Liang C, Howlett AR, Candinas D, Greiner RH, Lipson KE, Zimmer Y (July 2004). "The Met kinase inhibitor SU11274 exhibits a selective inhibition pattern toward different receptor mutated variants". Oncogene 23 (31): 5387–93. doi:10.1038/sj.onc.1207691. PMID 15064724.
- Wang X, Le P, Liang C, Chan J, Kiewlich D, Miller T, Harris D, Sun L, Rice A, Vasile S, Blake RA, Howlett AR, Patel N, McMahon G, Lipson KE (November 2003). "Potent and selective inhibitors of the Met [hepatocyte growth factor/scatter factor (HGF/SF) receptor] tyrosine kinase block HGF/SF-induced tumor cell growth and invasion". Mol. Cancer Ther. 2 (11): 1085–92. PMID 14617781.
- Christensen JG, Schreck R, Burrows J, Kuruganti P, Chan E, Le P, Chen J, Wang X, Ruslim L, Blake R, Lipson KE, Ramphal J, Do S, Cui JJ, Cherrington JM, Mendel DB (November 2003). "A selective small molecule inhibitor of c-Met kinase inhibits c-Met-dependent phenotypes in vitro and exhibits cytoreductive antitumor activity in vivo". Cancer Res. 63 (21): 7345–55. PMID 14612533.
- Smolen GA, Sordella R, Muir B, Mohapatra G, Barmettler A, Archibald H, Kim WJ, Okimoto RA, Bell DW, Sgroi DC, Christensen JG, Settleman J, Haber DA (February 2006). "Amplification of MET may identify a subset of cancers with extreme sensitivity to the selective tyrosine kinase inhibitor PHA-665752". Proc. Natl. Acad. Sci. U.S.A. 103 (7): 2316–21. doi:10.1073/pnas.0508776103. PMC 1413705. PMID 16461907.
- Matsumoto K, Nakamura T (April 2003). "NK4 (HGF-antagonist/angiogenesis inhibitor) in cancer biology and therapeutics". Cancer Sci. 94 (4): 321–7. doi:10.1111/j.1349-7006.2003.tb01440.x. PMID 12824898.
- Cao B, Su Y, Oskarsson M, Zhao P, Kort EJ, Fisher RJ, Wang LM, Vande Woude GF (June 2001). "Neutralizing monoclonal antibodies to hepatocyte growth factor/scatter factor (HGF/SF) display antitumor activity in animal models". Proc. Natl. Acad. Sci. U.S.A. 98 (13): 7443–8. doi:10.1073/pnas.131200498. PMC 34688. PMID 11416216.
- Burgess T, Coxon A, Meyer S, Sun J, Rex K, Tsuruda T, Chen Q, Ho SY, Li L, Kaufman S, McDorman K, Cattley RC, Sun J, Elliott G, Zhang K, Feng X, Jia XC, Green L, Radinsky R, Kendall R (February 2006). "Fully human monoclonal antibodies to hepatocyte growth factor with therapeutic potential against hepatocyte growth factor/c-Met-dependent human tumors". Cancer Res. 66 (3): 1721–9. doi:10.1158/0008-5472.CAN-05-3329. PMID 16452232.
- Mazzone M, Basilico C, Cavassa S, Pennacchietti S, Risio M, Naldini L, Comoglio PM, Michieli P (November 2004). "An uncleavable form of pro–scatter factor suppresses tumor growth and dissemination in mice". J. Clin. Invest. 114 (10): 1418–32. doi:10.1172/JCI22235. PMC 525743. PMID 15545993.
- Michieli P, Mazzone M, Basilico C, Cavassa S, Sottile A, Naldini L, Comoglio PM (July 2004). "Targeting the tumor and its microenvironment by a dual-function decoy Met receptor". Cancer Cell 6 (1): 61–73. doi:10.1016/j.ccr.2004.05.032. PMID 15261142.
- Reang P, Gupta M, Kohli K (2006). "Biological Response Modifiers in Cancer". MedGenMed 8 (4): 33. PMC 1868326. PMID 17415315.
- Petrelli A, Circosta P, Granziero L, Mazzone M, Pisacane A, Fenoglio S, Comoglio PM, Giordano S (March 2006). "Ab-induced ectodomain shedding mediates hepatocyte growth factor receptor down-regulation and hampers biological activity". Proc. Natl. Acad. Sci. U.S.A. 103 (13): 5090–5. doi:10.1073/pnas.0508156103. PMC 1458799. PMID 16547140.
- Jin H, Yang R, Zheng Z, Romero M, Ross J, Bou-Reslan H, Carano RA, Kasman I, Mai E, Young J, Zha J, Zhang Z, Ross S, Schwall R, Colbern G, Merchant M (June 2008). "MetMAb, the one-armed 5D5 anti-c-Met antibody, inhibits orthotopic pancreatic tumor growth and improves survival". Cancer Res. 68 (11): 4360–8. doi:10.1158/0008-5472.CAN-07-5960. PMID 18519697.
- Martens T, Schmidt NO, Eckerich C, Fillbrandt R, Merchant M, Schwall R, Westphal M, Lamszus K (October 2006). "A novel one-armed anti-c-Met antibody inhibits glioblastoma growth in vivo". Clin. Cancer Res. 12 (20 Pt 1): 6144–52. doi:10.1158/1078-0432.CCR-05-1418. PMID 17062691.
- Comoglio, P M (1993). "Structure, biosynthesis and biochemical properties of the HGF receptor in normal and malignant cells". EXS (SWITZERLAND) 65: 131–65. ISSN 1023-294X. PMID 8380735.
- Naldini, L; Weidner K M, Vigna E, Gaudino G, Bardelli A, Ponzetto C, Narsimhan R P, Hartmann G, Zarnegar R, Michalopoulos G K (Oct. 1991). "Scatter factor and hepatocyte growth factor are indistinguishable ligands for the MET receptor". EMBO J. (ENGLAND) 10 (10): 2867–78. ISSN 0261-4189. PMC 452997. PMID 1655405.
- Petrelli, Annalisa; Gilestro Giorgio F, Lanzardo Stefania, Comoglio Paolo M, Migone Nicola, Giordano Silvia (Mar. 2002). "The endophilin-CIN85-Cbl complex mediates ligand-dependent downregulation of c-Met". Nature (England) 416 (6877): 187–90. doi:10.1038/416187a. ISSN 0028-0836. PMID 11894096.
- Ng, Cherlyn; Jackson Rebecca A, Buschdorf Jan P, Sun Qingxiang, Guy Graeme R, Sivaraman J (Mar. 2008). "Structural basis for a novel intrapeptidyl H-bond and reverse binding of c-Cbl-TKB domain substrates". EMBO J. (England) 27 (5): 804–16. doi:10.1038/emboj.2008.18. PMC 2265755. PMID 18273061.
- Grisendi, S; Chambraud B, Gout I, Comoglio P M, Crepaldi T (Dec. 2001). "Ligand-regulated binding of FAP68 to the hepatocyte growth factor receptor". J. Biol. Chem. (United States) 276 (49): 46632–8. doi:10.1074/jbc.M104323200. ISSN 0021-9258. PMID 11571281.
- Davies, G; Jiang W G, Mason M D (Apr. 2001). "HGF/SF modifies the interaction between its receptor c-Met, and the E-cadherin/catenin complex in prostate cancer cells". Int. J. Mol. Med. (Greece) 7 (4): 385–8. ISSN 1107-3756. PMID 11254878.
- Ponzetto, C; Zhen Z, Audero E, Maina F, Bardelli A, Basile M L, Giordano S, Narsimhan R, Comoglio P (Jun. 1996). "Specific uncoupling of GRB2 from the Met receptor. Differential effects on transformation and motility". J. Biol. Chem. (UNITED STATES) 271 (24): 14119–23. doi:10.1074/jbc.271.24.14119. ISSN 0021-9258. PMID 8662889.
- Liang, Q; Mohan R R, Chen L, Wilson S E (Jul. 1998). "Signaling by HGF and KGF in corneal epithelial cells: Ras/MAP kinase and Jak-STAT pathways". Invest. Ophthalmol. Vis. Sci. (UNITED STATES) 39 (8): 1329–38. ISSN 0146-0404. PMID 9660480.
- Wang, Dakun; Li Zaibo, Messing Edward M, Wu Guan (Sep. 2002). "Activation of Ras/Erk pathway by a novel MET-interacting protein RanBPM". J. Biol. Chem. (United States) 277 (39): 36216–22. doi:10.1074/jbc.M205111200. ISSN 0021-9258. PMID 12147692.
- Hiscox S, Jiang WG (1999). "Association of the HGF/SF receptor, c-met, with the cell-surface adhesion molecule, E-cadherin, and catenins in human tumor cells.". Biochem Biophys Res Commun 261 (2): 406–11. doi:10.1006/bbrc.1999.1002. PMID 10425198.
Further reading
- Peruzzi B, Bottaro DP (2006). "Targeting the c-Met signaling pathway in cancer". Clin. Cancer Res. 12 (12): 3657–60. doi:10.1158/1078-0432.CCR-06-0818. PMID 16778093.
- Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF (December 2003). "Met, metastasis, motility and more". Nat. Rev. Mol. Cell Biol. 4 (12): 915–25. doi:10.1038/nrm1261. PMID 14685170.
- Zhang YW, Vande Woude GF (February 2003). "HGF/SF-met signaling in the control of branching morphogenesis and invasion". J. Cell. Biochem. 88 (2): 408–17. doi:10.1002/jcb.10358. PMID 12520544.
- Paumelle R, Tulasne D, Kherrouche Z, Plaza S, Leroy C, Reveneau S, Vandenbunder B, Fafeur V, Tulashe D, Reveneau S (April 2002). "Hepatocyte growth factor/scatter factor activates the ETS1 transcription factor by a RAS-RAF-MEK-ERK signaling pathway". Oncogene 21 (15): 2309–19. doi:10.1038/sj.onc.1205297. PMID 11948414.
- Comoglio PM (1993). "Structure, biosynthesis and biochemical properties of the HGF receptor in normal and malignant cells". EXS 65: 131–65. PMID 8380735.
- Maulik G, Shrikhande A, Kijima T, et al. (2002). "Role of the hepatocyte growth factor receptor, c-Met, in oncogenesis and potential for therapeutic inhibition". Cytokine Growth Factor Rev. 13 (1): 41–59. doi:10.1016/S1359-6101(01)00029-6. PMID 11750879.
- Ma PC, Maulik G, Christensen J, Salgia R (2004). "c-Met: structure, functions and potential for therapeutic inhibition". Cancer Metastasis Rev. 22 (4): 309–25. doi:10.1023/A:1023768811842. PMID 12884908.
- Knudsen BS, Edlund M (2004). "Prostate cancer and the met hepatocyte growth factor receptor". Adv. Cancer Res. Advances in Cancer Research 91: 31–67. doi:10.1016/S0065-230X(04)91002-0. ISBN 978-0-12-006691-9. PMID 15327888.
- Dharmawardana PG, Giubellino A, Bottaro DP (2005). "Hereditary papillary renal carcinoma type I". Curr. Mol. Med. 4 (8): 855–68. doi:10.2174/1566524043359674. PMID 15579033.
- Kemp LE, Mulloy B, Gherardi E (2006). "Signalling by HGF/SF and Met: the role of heparan sulphate co-receptors". Biochem. Soc. Trans. 34 (Pt 3): 414–7. doi:10.1042/BST0340414. PMID 16709175.
- Proto-Oncogene Proteins c-met at the US National Library of Medicine Medical Subject Headings (MeSH)
- UniProtKB/Swiss-Prot entry P08581: MET_HUMAN, ExPASy (Expert Protein Analysis System) proteomics server of the Swiss Institute of Bioinformatics (SIB)
- A table with references to significant roles of MET in cancer


A transportation study by engineering researchers reveals that different speed limits for cars and large trucks on rural, interstate highways can compromise safety.
“We found that speed variation and vehicle interactions have a direct impact on highway safety,” said Steven Johnson, professor of industrial engineering with the Mack Blackwell Transportation Center. “Data from previous studies and simple logic say that a higher number of interactions among vehicles increases the chances that accidents will occur.”
Johnson reported this finding in Cost-Benefit Evaluation of Heavy Truck-Automobile Speed Differentials on Rural Interstate Highways, a study of speed limits and car-versus-large-truck speed differentials on rural, interstate highways. Sponsored by the U.S. Department of Transportation, commercial trucking companies and private fleets, the study will help regulatory agencies and trucking-company decision-makers establish policies regarding speed limits and differentials for both heavy trucks and automobiles.
After examining existing literature on speed limits, Johnson and graduate student Naveen Pawar measured the speeds of heavy trucks and automobiles in five states. Speed-limit configurations ranged from a uniform 75 mph for cars and heavy trucks to 65 mph for automobiles and 55 mph for trucks. The researchers also analyzed speed, accident and maintenance data and interviewed truck drivers, safety and maintenance managers of commercial trucking companies and original equipment manufacturers of trucks, tires and engines.
There is a caveat to their findings: vehicle dynamics, such as braking and maneuvering, improve on slower-moving trucks.
“People argue that heavy trucks require longer braking distances for any given speed, and lower truck speeds help equalize the stopping distance,” Johnson said. “On the other hand, opponents of lower truck speed limits have suggested that the differential speeds increase speed variance and therefore have a negative impact on highway safety. Our research demonstrates that it is likely that both of these arguments are correct.”
See Johnson’s report at www.mackblackwell.org/web/research/final-reports.htm.


Aleutian lowArticle Free Pass
Aleutian low, large atmospheric low-pressure (cyclonic) centre that frequently exists over the Aleutian Islands region in winter and that shifts northward and almost disappears in summer. Although the Aleutian low is associated with smaller eastward-moving low- and high-pressure centres, the region’s average pressure is low. It is the source region of the maritime polar air masses that influence the climate of the western U.S. The low-pressure centres that persist in the higher latitudes of the Northern Hemisphere consist of the Aleutian low and the Icelandic low.
What made you want to look up "Aleutian low"? Please share what surprised you most...


Mersen, Treaty of
Mersen, Treaty of, 870, redivision of the Carolingian empire by the sons of Louis I, Charles the Bald (later Charles II) of the West Franks (France) and Louis the German of the East Franks (Germany), signed at Mersen (Dutch Meersen ), now in the Netherlands. The treaty superseded the tripartite division of the empire in 843 (see Verdun, Treaty of). It divided the kingdom of Lotharingia between Charles and Louis, following the death (869) of their nephew, Lothair, king of Lotharingia. France obtained the territories roughly corresponding to the modern Netherlands, Belgium, and Lorraine and Germany received Alsace and the left bank of the Lower Rhine. The borders established did not last long.
The Columbia Electronic Encyclopedia, 6th ed. Copyright © 2012, Columbia University Press. All rights reserved.
More on Treaty of Mersen from Infoplease:
See more Encyclopedia articles on: German History


05/10/2012 - Americans love economic mobility. It’s kind of a founding myth for us: We see ourselves as having broken free from rigid, aristocratic Europe to form a meritocracy that guaranteed a chance to move up in the world. Though there has been much talk lately about rising income inequality in the United States, what has worried pundits on both the left and the right has been recent reports that Americans aren’t as economically mobile as citizens in other Western nations.
The Pew Economic Mobility Project has been studying this phenomenon, and is out with a new report examining which regions in America are the most and least mobile. Researchers looked at Americans ages 35 to 39 and then examined their incomes ten years later. The study covered the time period between 1978 and 2007, and tackled three different measures of income mobility: absolute mobility (as measured by inflation-adjusted income growth over time), and relative upward and downward mobility — i.e. movement up or down the socio-economic ladder. In other words, are Americans born poor becoming rich and vice-versa?
Interestingly enough, geographic mobility doesn’t appear have a large effect on economic mobility. That is, it doesn’t matter if you’re born in Maryland or you move there – you’re more likely move up the economic ladder either way. According to Erin Currier, Project Manager of the Pew Economic Mobility Project, individuals who do move states do have better economic mobility, but more than two-thirds of Americans stay in their birth state for the remainder of their lives. Therefore, “Geographic mobility might help an individuals’ economic mobility, [but] it’s not really driving state-level findings as a whole.”
So why are some states more economically mobile than others? This study doesn’t seek to specifically address the causes of relative mobility between states, but there are some important factors that the Economic Mobility Project has found are essential to promoting economic mobility overall, and these include things like like “educational attainment, savings and asset building, and neighborhood poverty during childhood,” according to Currier.
Read the full article, Which States Have the Most Economic Mobility?, on Time's website.


Subfertility, a condition in which a person is less fertile than average but still capable of contributing to a pregnency, affects about one in 20 men. Up to 80 percent of subfertility could be due to sperm damage caused by oxidative stress or harmful particles produced by a person's own body.
While infertility has historically been seen as a woman's problem, male infertility is present in up to half of infertile couples.
Varicocele, a condition in which a man has varicose veins in the scrotum, is the most common cause of male subfertility. Other causes include hormonal disorders, problems with quantity and motility of sperm, infections, obesity, drug use and exposure to radiation and chemotherapy. Depending on the condition, male infertility and subfertility can be treated with surgery, hormone therapy and assisted reproductive technologies.
While, as we've seen, some doctors dismissed the link between antioxidants and fertility, others said they were not surprised by the results because healthy nutrition and lifestyle are already recommended for couples planning to conceive.
Dr. Jeanne O'Brien, associate professor of urology at University of Rochester Medical Center, is one of those doctors. O'Brien said she routinely suggests that her patients take antioxidants if they want a baby. She also recommends decreasing alcohol consumption, smoking cessation, exercising and stress reduction.
"I tell them the antioxidants may help and certainly don't harm them at the recommended dosages," said O'Brien. "I believe it is the lifestyle changes and increased health awareness that accompanies antioxidant consumption that may make a difference in terms of increased fertility."
O'Brien said antioxidants are never her sole recommendations. "There are always additional factors, testing, medication or alternatives offered in conjunction with them," O'Brien said.
"I use antioxidants for select men with impaired semen quality and demonstration of elevated oxidative stress, which is manifest by increased levels of reactive oxygen species," said Kim. "However, I do not assess for oxidative stress if identifiable causes of male infertility are present. In clinical practice, improvements in pregnancy and live birth rates are certainly not as robust as suggested by the Cochrane review."
And Kim warns that, despite the hype around antioxidant supplements, they should not be consumed without a watchful eye. For example, excessive consumption of Vitamin E, or more than 400 units per day, has been shown to have possible negative cardiac and vascular effects.
"Although generally considered safe in moderation, numerous large-scale studies have indicated that many supplemental antioxidants can actually be detrimental to overall health, said Kim. "With an understanding of these caveats, an assessment of the severity of male factor infertility, and very modest expectations of possible benefit, a man could try antioxidants before attempting assisted reproduction."


Technology in the Classroom
Assistive Word Processing
Assistive technology to support writing includes special software as well as inexpensive word processors.
Using a Pen Scanner
Pen scanners, handheld scanner and Iris Pens
Effective Use of Switches
Augmentative or Alternative Communication
Augmentative or Alternative Communication or AAC. Picture symbol systems, symbol boards, voice output etc.
Word Q - Predictive Software Application
This application makes Dyslexic students want to write! Find out what all the excitement is when language delayed or impaired students use Word Q.
An extensive search database for those people looking for information on assistive products for people with disabilities.
Assistive Technology Solutions
This site offers a list of solutions and devices that make accessing the computer easier for students with disabilities.
Assisitive Technology Tools
A great site dedicated to enhancing the lives of children and adults with disabilities using the latest assistive technology.
Communicating with Technology
Find out about synthetic speech systems, speech to text and screen readers. Great for the visually or hearing impaired student.
A Language Arts Lesson Plan on Summarizing Text
A lesson plan for teachers to use technology and students' interest in texting to reinforce summarizing skills and to increase reading comprehension. This lesson plan is aimed toward high school students.
Tips for Using a Smart Board in the Special Education Classroom
Smart Boards are fun tools for children with disabilities, working like giant touch screens.
IEPgoals.net Is a New Site Offering Support for Goal Writing
IEPgoals.net, a new website, provides goal writing guidance, especially useful for early intervention and children on the autistic spectrum disorder.


In the summer of 2007, shoppers at some food co-ops in the upper Midwest encountered a new label on their produce: “Local Fair Trade.” Seasonal staples such as cucumbers, squash, and broccoli were the first to don the label, a large, hard-to-miss sticker symbolizing the union of two approaches to sustainable food: eating food grown locally, and purchasing food traded fairly.
We’ve gotten used to a variety of labels on our food. There’s “organic,” which used to connote ideas like “pure” and “natural” but these days technically means food certified as organic by the USDA (if domestically produced) or by the food’s country of origin. “Local” usually means food grown or produced within a few hundred miles of its selling location. And “fair trade” is seen most commonly on popular imports such as coffee and chocolate; the label means that the food’s growers or producers were paid a decent wage.
So what does “local fair trade” mean? According to Erik Esse, the director of the Minneapolis-based Local Fair Trade Network, the label is an attempt to answer a question: “How can the principles of fair trade, which have effectively moved many farmers and workers in the developing world out of poverty and towards self-sufficiency, work here in the U.S., where our farmworkers are having some of the same problems?”
At the heart of the local or “domestic fair trade” label is the idea of fair and equitable relationships. The label can be applied to food grown in the U.S. under a set of guidelines, including a living wage and an emphasis on fair and healthy living conditions. The product of nearly a decade of careful planning, the domestic fair-trade label is an effort to incorporate social-justice awareness into our burgeoning efforts to eat foods that have been cleanly and sustainably produced.
As the fair-trade movement (both international and domestic) wants everyone to understand, the local people behind the food we eat deserve sustainability, too. The USDA’s national organic standards guarantee that organically certified food is not genetically modified and is grown without petroleum-based fertilizers or synthetic chemicals. But the standards have nothing to say about the people who produce the food. This fact appalls those who work closely with farmworkers, including Richard Mandelbaum of El Comité de Apoyo a los Trabajadores Agrícolas (CATA), a migrant-farmworker organization based in New Jersey.
“Organic standards include all sorts of rules about how livestock needs to be treated, but absolutely none for the human beings that are on the farm,” says Mandelbaum.
The Local Fair Trade Network’s Esse isn’t sure that enough consumers are paying attention to those human beings, either. “The way stores like to put up pictures of happy farmers these days — that’s in some ways great, in that it’s identifying that there’s a person growing their food,” he says. “But in some ways, those smiles mask the fact of how little money they get paid and how hard their lives are.”
Although some organic farms in the U.S. opt to pay their workers a living wage, as well as provide vacation days and access to health care, many do none of those things. Small-scale organic farmers, who often live hand-to-mouth themselves, rarely have the budget to do so. And most large, industrial-sized organic farms rely on hundreds if not thousands of underpaid migrant workers, in much the same way that conventional farms and food processors do.
According to a 2005 survey report from the University of California, Davis, the majority of the 188 California organic farms surveyed did not pay a living wage or provide medical or retirement plans. And despite the nationwide boom in organic food — the industry was worth more than $17 billion by the end of 2006 — the wealth has not trickled down. While the absence of synthetic pesticides (and the health impacts that accompany them) can be a draw to some workers, most employees on organic farms earn no more than those on conventional ones.
Across the country, three to five million people labor every year on farms and in factories, planting, cultivating, harvesting, and processing fresh produce and other agricultural products. Their lives are anything but easy. According to the National Agricultural Workers Survey, 61 percent of farmworkers live in poverty. In recent years, their median income has not kept up with inflation: for individual farmworkers, the median annual income is now $7,500, while for farmworker households, the median annual income is less than $10,000. (The overall U.S. median household income, according to the U.S. Census Bureau, is more than $48,000.) It is also estimated that between 72 and 78 percent of farmworker households have no health insurance.
Today’s domestic fair-trade movement dates back as far as 1999, when CATA, along with Rural Advancement Foundation International-USA (RAFI-USA) and several other partners, argued for an inclusion of labor issues in the federal organic standards.
“When it became clear that the issues of social justice and fairness would not be incorporated into the federal [organic standards],” says RAFI’s Michael Sligh, “that really triggered our work to look at opportunities to make that additional claim to the marketplace.”
The result was something called the Agricultural Justice Project (AJP), a group that set to work devising a separate set of standards that would cover both equity for the small-scale farmer as well as fair working conditions for farmworker. But not everyone was convinced.
“When we first started out, it wasn’t uncommon to get a shrug from those in the organic/sustainable community, with responses like, ‘I’m not sure why you’re focused on this,’” says CATA’s Mandelbaum. “But in the last two years, we’ve seen that consumers are increasingly dissatisfied with anonymous products, and really want to know how their food is made — environmentally of course, but also increasingly socially.”
In 2005, the Agricultural Justice Project, along with the international fair-trade organization Equal Exchange and several domestic farmer cooperatives, held the first meeting of the Domestic Fair Trade Working Group (now renamed the Domestic Fair Trade Association). By 2006, it became clear that the best place to pilot a domestic fair-trade label was the Minnesota/Wisconsin area.
According to Erik Esse, whose Local Fair Trade Network is the Minneapolis-based arm of the movement, there are around 40 food co-ops in Minnesota and more than 25 in Wisconsin. “The fact that consumer cooperatives are so key to the area,” he says, “as opposed to the corporate natural-food-store model, means we have a background that lends to embracing fair trade. [The customers] already believe in democracy and in consumer activism.”
By early 2007, four small farms in the upper Midwest had been chosen to participate in the Domestic Fair Trade Working Group’s pilot project, along with two food co-ops in the Minneapolis area. All the farms involved were closely audited, including their business practices and employee policies. And they pledged to, among other things, “1) Respect workers’ freedom of association and right to collective bargaining, 2) Provide adequate health and safety protections, including access to adequate medical care, information on potential hazards, and using the least toxic methods available, and 3) Pay a living wage.”
Esse points out that although small-scale farmers and farmworkers are often in similar financial situations, there is still some tension between the two groups. “Farmers don’t always want to stir the pot,” he says. “We often hear, ‘Things are going fine; why would I want to bring this up?’”
Rufus Hauke, of Keewaydin Farms in Viola, Wisconsin, does want to stir the pot. He’s a produce farmer participating in the pilot project who, along with his brother, decided to remake the family farm according to a vision for what he calls “the next evolution of food.” Although he has only a few employees, Hauke was excited to offer them the paperwork and training necessary to help get the first Keewaydin Fair Trade growing season off the ground.
Culinate’s features address the practical challenges and joys of food.
Want more? Comb the archives.
Flatbreads from around the continent
Beyond a supporting role
The great Sicilian-Neapolitan kitchen rivalry
Five ideas each month for eating better


Subscribe Free! to the DigiFreq Pro Audio and Music Technology Newsletter
Numerous studies, including one released last month by University of Louisville researchers, indicate that learning to play the piano as a preschooler sets a child up for later academic success. And now "Piano For Preschoolers" has introduced a new way for parents to teach their children the piano - complete with a Casio(R) keyboard.
Developed by Angie Crellin, a mother of two who has studied the piano for over 30 years, "Piano For Preschoolers" uses color-coded notes printed on a traditional musical staff to teach songs preschoolers already love, like "Twinkle, Twinkle, Little Star." A corresponding color strip sits behind the piano's keys and guides the child to the correct key for each note.
Crellin came up with the "Piano For Preschoolers" concept when her son, a preschooler at the time, expressed interest in playing the piano. Crellin's daughter had done the same several years before, but she had quickly lost interest once Crellin introduced popular beginning piano books to the lessons. Not wanting the same thing to happen with her son, Crellin decided to create a program that was fun for children and easy for parents to teach. Hundreds of hours of research later, she had "Piano For Preschoolers."
"The results were amazing," said Crellin. "My son loved playing real songs he recognized and couldn't wait to learn more. But the truly remarkable thing was that my preschool son started helping my second-grade daughter with her math homework."
Crellin's results correspond to those obtained by Dr. Frances Rauscher of the University of Wisconsin and Dr. Gordon Shaw of the University of California. The researchers, who have long studied the connection between math and music, compared the effects of musical and nonmusical training on preschoolers' intellectual development. They found that preschoolers who received piano or keyboard training performed 34% higher on tests measuring spatial-temporal ability than did other preschoolers. Those who received piano or keyboard training could think in pictures and see the pictures moving or changing shape over time - a crucial skill for later success in mathematics, science and engineering.
But the pint-sized students of "Piano For Preschoolers" don't care about all that. Most are just having fun playing for rapt audiences of parents and grandparents.
"The 'Piano For Preschoolers' program really seems to be boosting children's self-confidence," said Crellin. "Customers report their preschoolers are practicing the piano with no prompting from the parents. And that's really the key. No four-year-old will stay motivated to learn if she isn't having fun."
The entire "Piano For Preschoolers" system is $129.95 plus shipping. It includes: a music book of 17 familiar songs written in color-coded notes; the durable color strip to set behind the piano keys; a parent/teacher guide with step-by-step instructions for each lesson; and a free Casio(R) SA-75 electronic keyboard.
For more information: www.pianoforpreschoolers.com


Big Leap Forward in Understanding Genetics Underlying Prevalent Diseases
The Wellcome Trust Case Control Consortium (WTCCC), a collaboration of 24 leading human geneticists analyzing thousands of DNA samples from patients suffering prevalent human diseases, have announced breakthrough research findings. Hailed as a "...new chapter in medical science...", genetic variants have been found for:
- Crohn's disease
- coronary heart disease
- rheumatoid arthritis
- Type I and Type II diabetes
Some of the fascinating findings:
- Type I Diabetes and Crohn's disease share a common gene, suggesting similar biological pathways!
- An obesity gene as well as three new genes linked to Type II Diabetes
- The WTCCC used gene chip technology, which is not unlike microchip technology, enabling scientists to scan hundreds of thousands of DNA markers at once.
Thank you jurvetson for use of photo Playing with DNA featuring James Watson!
Recent Blog Posts


A view can become a page or a block. There is no difference in work between a page and a block. A page needs a path to display the page. A block is assigned to a region to display the page. There might be a few seconds different to set them up. After that, you can blocks in far more ways than usually shown in tutorials.
Blocks have their uses including constructing complex pages. The content of a page is usually the content of a node in the content region. A view replaces the node to display a list or some other small variation of content.
Next you are asked to make the view more complicated. You scratch your head. What you really need is a collection of views displaying different content. You could use panels and a bunch of other complex approaches. Think about the format again.
If you want a list of different views. You can make each one a block then place them one after the other down the page. Consider a shop.
A shop might list the top selling product in each category with a view sorted by category. The marketing manager then asks for the categories in a different order. The CEO wants some categories to list the top three. The product manager wants one category to list only one product but all the colours for the product.
You could make each category a separate view with each view in a block. Each view can have different criteria. You can give your CEO, sales manager, and marketing manager access to the block admin page and let them fight over the sequence of the blocks.
What method do you use to determine when to use multiple views?
Use the one view when you list data one set of data. Use multiple views when people want different data selection. For example, some product categories have colours but not all product categories. Some product categories have multiple packs but not all product categories.
If the one list has to be by category then colour or pack size and all the products use the same content type, you could use one view to sort by category then colour then pack size. There will be no overlap or conflict or missing data.
The same list becomes more complicated when each product category has a different content type and each content type has a different set of attributes. You might be able to product one list in one view but it will be sensitive to change and management will want change. Start with two views or more views stacked as blocks to form one list.
Another example is a book shop where novels have different descriptions and content types compared to other books. Cook books may have a special content type to allow listing by food type, country, major ingredients, and the reality television show paying for the cook book.
If the data is exactly the same for each view but the display is different, consider multiple displays on one view. The technique is described in another page. you make the first view a page to list the data and validate your data selection. You then add some displays to create the blocks. Each display might vary by as little as selecting a different content type.
Top ten lists are popular and soon take up too much space. People start talking about variations. Perhaps the top three items, including teasers, followed by the next seven without teasers.


As a developmental pathway towards autonomy and dexterity in robot in-hand manipulation, HANDLE is a Large Scale IP project coordinated by the university Pierre and Marie Curie of Paris and include a consortium formed by nine partners from six EU countries: France, UK, Spain, Portugal, Sweden, and Germany.
The TACO project aims at enhancing the abilities of service robots by improving the sensing system with real 3D foveation properties and to increase their ability to interact with their natural environment in a more natural and human-like way.
The PV-Servitor project focuses on concepts for a fully autonomous cleaning robot for ground mounted large scale photovoltaic power plants consisting of 100 kW and over.
STIFF-FLOP is researching how to take some of the new capabilities in soft robotics and apply them to the development of tools for endoscopic surgery. This project takes inspiration from octopus tentacles for the design of flexible soft robots.
DEXDEB is researching meat deboning. Taking apart an animal carcass to produce high-quality pieces of meat is a skilled but unpleasant and dangerous task. In DEXDEB we are looking at two designs of robotic hand and using them as the “left hand” that pulls at the meat, while a human operator slices the meat with a knife held in their right hand. This will provide DEXDEB with a baseline for doing more complex human-robot interaction work later.
HYFLAM is investigating the role of robotics in biosafety level 3 and 4 laboratories. Working with a UK Government lab and Hamburg University, HYFLAM is looking at a range of skilled tasks and investigating whether a robotic hand can perform them, and how well it performs them when working with software like that developed in HANDLE. This could lead to a new generation of robotic systems for hazardous lab work.


Is it scientific fact that acid stabilizes meringue or is this a fallacy? If so does anyone know actually why and are there any other substances that do this well also?
Acids allow more air to be beaten into a meringue. In order to make meringue, the proteins in egg white must be denatured. In their natural state, the proteins are curled up into tightly packed balls. When the egg is beaten, they uncoil into long strands.
These strands then begin to coagulate, or join together, with the help of the sugar you add. The air you whisk in gets trapped between these joining strands, giving the meringue its characteristic light texture.
Acid delays coagulation, which means that there is more time for air to get trapped in amongst the proteins, resulting in a lighter meringue.
The acids usually added to meringue are white wine vinegar, lemon juice, or cream of tartar. Fresh eggs are more acidic than old ones, so these help too.
Some cooks use copper bowls to make meringue, because copper ions from the bowl bind to a particular protein (conalbumin) and strengthen it.
|show 3 more comments|
I have made two separate meringue mixtures side by side: one with vinegar and one without. In my experience it makes no difference to the final outcome provided that you add the sugar really slowly (a tablespoon at a time) and not too early. If this is done correctly then there is no need to add an acid.


International Women’s Day (IWD) was founded in 1910 in order to confront the great inequalities women faced in the labor force and society as a whole. Unfortunately, one hundred years later, women still make up a majority of the world’s poor.
Women’s wages in the U.S. are only 76% of men’s, but the disparity of long-term earnings between men and women is far worse. A study comparing total earnings between 1983 and 1998 showed women averaging just 38% of men’s wages (Institute for Women’s Policy Research, 2004).
In large part, this is because 80% of American women under 40 are mothers, according to the U.S. census. Without adequate paid maternity leave, mothers are frequently forced to quit stable jobs and disrupt career plans. Add to that $611 in average monthly childcare costs (U.S. Department of Labor), which is more than two weeks pay at the federal minimum wage.
Eighty-seven percent of single parent households are headed by women and of those 37% are in poverty (Association for Women’s Rights and Development). Once a family falls into poverty it is astoundingly hard for them to escape. Sixty percent of families that are in the bottom fifth of income remain there a decade later (Association for Women’s Rights and Development).
The impact of the financial crisis, however, is worldwide. Of the 1.5 million people living on a dollar or less per day, 70% are women (UN.org). Forced into the factories with the worst working conditions, women make up 90% of the world’s sweatshop labor (Women Thrive Worldwide). Often being laid off, these women are accustomed to making 13 cents to one dollar per hour (Powell and Skarbek 2004). Forced to work, women are less likely to attend school or leave the home before marriage. Seventy-seven million girls of primary school age worldwide are out of school, compared to only 55 million boys (The World Bank).
Women around the world are bound together by discrimination and economic servitude created by capitalism. Their work is devalued down to pennies, and often the largest use of their time - household labor - goes unpaid. IWD is a chance to remember and celebrate the struggles of women, which have won huge improvements in our lives. If women united internationally and with the wider struggles of working people to fight for equal rights, better working conditions, wages and stronger social services such as health care, child care and food support, we could collectively improve conditions for all.


Chile's economy is based on the export of minerals, which account for about half of the total value of exports. Copper is the nation's most valuable resource, and Chile is the world's largest producer. Agriculture is the main occupation of about 15% of the population; it accounts for about 6% of the national wealth, and produces less than half of the domestic needs. The Vale of Chile is the country's primary agricultural area; its vineyards are the basis of Chile's wine industry. Grapes, apples, pears, onions, wheat, corn, oats, peaches, garlic, asparagus, and beans are the chief crops. Livestock production includes beef and poultry. Sheep raising is the chief pastoral occupation, providing wool and meat for domestic use and for export. Fishing and lumbering are also important economic activities. Chile's industries largely process its raw materials and manufacture various consumer goods. The major products are copper and other minerals, processed food, fish meal, iron and steel, wood and wood products, transportation equipment, and textiles.
The dependence of the economy on copper prices and the production of an adequate food supply are two of Chile's major economic problems. Chile's main imports are petroleum and petroleum products, chemicals, electrical and telecommunications equipment, industrial machinery, vehicles, and natural gas. In addition to minerals, it also exports fruit, fish and fish products, paper and pulp, chemicals, and wine. The chief trading partners are the United States, China, Brazil, Argentina, and South Korea.
The Columbia Electronic Encyclopedia, 6th ed. Copyright © 2012, Columbia University Press. All rights reserved.
More on Chile Economy from Fact Monster:
See more Encyclopedia articles on: South American Political Geography


| ||Minding Your Mind || |
When Striving for Perfection Is a Problem
Last Reviewed by Faculty of Harvard Medical School on May 4, 2012
By Howard LeWine, M.D.
Harvard Medical School
Some people can't live with the slightest imperfection. Their need to appear or be perfect perfectionism is so intense that it's exhausting if not painful.
But striving for perfection, while accepting that perfection rarely can be achieved, can lead to growth and development and a feeling of satisfaction. It can be a powerful motivator as long as it is based on reasonable standards and expectation. For example, the desire to have a perfect golf swing or tennis stroke can enhance the pleasure you take in these pursuits, whether you are an amateur or professional.
Perfectionism is unproductive, however, when it is linked to excessively high standards and is driven by a fear of failure.
Back to top
Types of Perfectionism
Perfectionism comes in many forms:
- Obsessive concern over mistakes
- Setting excessively high personal standards
- Perceiving parents as overly critical
- Unreasonable doubts about ability to perform tasks
- An over-emphasis on organization
- Trying to live up to high expectations you're convinced other people, such as parents, have of you
- Having high expectations of other people
But whatever form it takes, perfectionism can rob you of life's pleasures.
Back to top
The Roots of Perfectionism
It may not be so easy to figure out where perfectionism comes from. For some, it is a part of their inborn temperament like perfect skin and teeth. Researchers have linked perfectionism to anxiety, depression and eating disorders. The trait of perfectionism is common among people with obsessive-compulsive disorders. Or it could be a response to having parents who expected too much from you. Maybe they never let you off the hook, even if you got 98 out of 100 on an exam.
Back to top
The Role of Indirect Aggression
What goes on outside the home is also a big factor in the development of perfectionism. For some women, perfectionism is a way to cope with indirect aggression, a term for the socially manipulative behaviors of the stereotypical "mean girls" that they may have experienced.
A recent study published in the journal Aggressive Behavior supports the idea that perfectionism may develop in a social group and suggests that indirect aggression triggers it. The "aggressor" talks behind a person's back, gives someone the "silent treatment," tells secrets, or is nice in private but rejecting in public to hide her hostility toward another.
Girls and women tend to resort to this kind of social bullying because they are not encouraged or taught how to express aggressive or competitive feelings directly. They become aggressive in ways that can be easily concealed or denied.
For the study, researchers at McMaster University asked two groups of college-age women to fill out surveys about what types of verbal abuse, physical abuse and indirect aggression they had experienced in grades 3 through 12. They also asked the women to answer questions to gauge whether they were perfectionists.
The women who recalled experiencing indirect aggression in childhood were more likely to become perfectionists by the time they reached college. Verbal and physical abuse apparently was not linked to perfectionism.
The authors acknowledge that the study asked subjects to report on old experiences and that women who are perfectionistic might be more likely to recall past events in a negative way, no matter how they were treated in reality.
Even so, the authors say that a victim of indirect aggression may without knowing it come to feel that being "perfect" is the only way to assert herself in social situations or maintain control. Thus, perfectionism becomes a way to cope with a threatening environment.
Back to top
Making Perfectionism Work for You
There is a fine line between the positive aspects of striving to be perfect and perfectionism that can be detrimental. Striving to be perfect can be very positive as long as it:
- Is realistic
- Moves you forward
- Helps you feel stronger
- Gives you the satisfaction you deserve after all that hard work.
Perfectionism becomes a problem when it makes you feel worse instead of better, or when your inability to be satisfied unless you are perfect realizing that it will always be out of reach causes suffering.
You can make perfectionism work for you. Here's how:
- Look at and change unrealistic and self-destructive thought patterns with cognitive behavior therapy.
- Understand how you became perfectionistic and ease up on unwarranted self-criticism. Psychodynamic therapy can help you do this.
- If you do have one of the underlying disorders linked to perfectionism (obsessive-compulsive disorder, anxiety or depression), then a medication or psychotherapy may help by targeting the pressure coming from that source.
Consult a mental health professional as a first step. The goal is to let go of the excessively high standards and find ways to cope with fears of failure. At the same time, you want to hold on to the positive force of striving for perfection.
Back to top
Howard LeWine, M.D. is chief editor of Internet Publishing, Harvard Health Publications. He is a clinical instructor of medicine at Harvard Medical School and Brigham and Women's Hospital. Dr. LeWine has been a primary care internist and teacher of internal medicine since 1978.


GNU Octave is a high-level language, primarily intended for numerical computations. It provides a convenient command line interface for solving linear and nonlinear problems numerically, and for performing other numerical experiments. It may also be used as a batch-oriented language. Octave has extensive tools for solving common numerical linear algebra problems, finding the roots of nonlinear equations, functions written in Octave's own language, or by using dynamically loaded modules written in C, C++, Fortran, or other languages.
Donations to support the software can be made at https://my.fsf.org/donate/working-together/octave.
DocumentationUser manual included; User FAQ included; Printed and online user manual available from http://www.network-theory.co.uk/octave/manual/
- PARI GP
- Octave-data smoothing
- Octave-information theory
- Octave-linear algebra
- GNU Oflox
This is a GNU package:octave
released on 31 May 2012
|License||Verified by||Verified on||Notes|
|GPLv2||Kelly Hopkins||6 December 2011|
|GPLv3orlater||Kelly Hopkins||29 January 2010|
Leaders and contributors
|John W. Eaton||Maintainer|
Resources and communication
|Developer||VCS Repository Webview||http://www.octave.org/hg/octave|
|Required to build||GNU make|
|Required to build||a recent version of g++|
|Required to build||libstdc++|
|Required to build||fortran|
This entry (in part or in whole) was last reviewed on 4 February 2012.
Permission is granted to copy, distribute and/or modify this document under the terms of the GNU Free Documentation License, Version 1.3 or any later version published by the Free Software Foundation; with no Invariant Sections, no Front-Cover Texts, and no Back-Cover Texts. A copy of the license is included in the page “GNU Free Documentation License”.
The copyright and license notices on this page only apply to the text on this page. Any software described in this text has its own copyright notice and license, which can usually be found in the distribution itself.


Individual differences |
Methods | Statistics | Clinical | Educational | Industrial | Professional items | World psychology |
Developmental Psychology: Cognitive development · Development of the self · Emotional development · Language development · Moral development · Perceptual development · Personality development · Psychosocial development · Social development · Developmental measures
BSID-III is the current version and is a standard series of measurements used primarily to assess the motor (fine and gross), language (receptive and expressive), and cognitive development of infants and toddlers, ages 0-3. This measure consists of a series of developmental play tasks and takes between 45 - 60 minutes to administer. Raw scores of successfully completed items are converted to scale scores and to composite scores. These scores are used to determine the child's performance compared with norms taken from typically developing children of their age (in months). The assessment is often used in conjunction with the Social-Emotional Adaptive Behavior Questionnaire. Completed by the parent or caregiver, this questionniare establishes the range of adaptive behaviors that the child can currently achieve and enables comparison with age norms.
- Essentials of Bayley Scales of Infant Development II Assessment Maureen M. Black, Kathleen Matula. New York: John Wily, 1999. ISBN: 978-0-471-32651-9
- "Scales of Infant Development and Play-Based Assessment in Two-Year Old At-Risk Children" Lisa Kelly-Vance, Howard Needelman, Kim Troia, Brigette Oliver Ryalls, University of Nebraska-Omaha, USA Developmental Disabilities Bulletin, Vol. 27 (1), 1999
- "Poor predictive validity of the Bayley Scales of Infant Development for cognitive function of extremely low birth weight children at school age." Hack M, Taylor HG, Drotar D, Schluchter M, Cartar L, Wilson-Costello D, Klein N, Friedman H, Mercuri-Minich N, Morrow M. Pediatrics. 2005 Aug;116(2):333-41.


Science Fair Project Encyclopedia
|President of the|
Historically, Landes was part of Gascony. It was one of the original 83 departments created during the French Revolution on March 4, 1790. It was created from parts of the provinces of Guyenne and Gascony.
- Prefecture website (in French)
- Conseil Général website (in French)
Landes is also the name of a commune in the Charente-Maritime département, in France.
The contents of this article is licensed from www.wikipedia.org under the GNU Free Documentation License. Click here to see the transparent copy and copyright details