<![CDATA[Dr. Michael Mullan - Alzheimers Blog]]>Sat, 16 Dec 2017 12:20:27 -0500Weebly<![CDATA[Genetic Mutations In ADAM10 May Lead to Alzheimer's]]>Thu, 26 Sep 2013 21:19:55 GMThttp://michaelmullan.org/1/post/2013/09/genetic-mutations-in-adam10-may-lead-to-alzheimers.htmlPicture
    Researchers at Massachussets General Hospital have found two gene mutations that may cause common form of Alzheimer's, which manifests after age sixty.  The mutations are in a gene called ADAM10, an enzyme previously linked to the amyloid precursor protein processing.
    The report, which will be published October 16th in Neuron, explores how the mutations affect the growth and toxicity of amyloid in a mouse model.  The research also shows that these mutations affect the hippocampus's ability to create new neural cells, which are imperative to learning and memory.  Dr. Rudolph Tanzi, director of Genetics and Aging Research at Massachussets General, says that their pinpointing of the pathological gene mutations add to the only previous discovery of other mutations.  Tanzi also says the study's result show that lowered ADAM10 activity can cause Alzheimer's.
    Amyloid beta forms its characteristic plaques when the amyloid precursor protein (APP) is shortened by enzymes called secretases.  APP is progressively processed by beta-secretase and subsequently gamma-secretases resulting in amyloid beta peptide that may oligomerize resulting in toxic species.  ADAM10 is the alpha-secretase that can alternatively process APP that prevents processing by Beta-secretase resulting in into peptides that stimulate neural growth.  
    Tanzi's team went about studying how mutations in ADAM10, a helpful molecule, could heighten the likelihood of developing Alzheimer's disease.  Transgenic mice experiments showed the scientists four things; mutations lowered the brain's release of beneficial proteins, reduced ADAM10 activity caused increased generation of amyloid beta, a mutation-caused reduction in ADAM10 impaired the ability of the hippocampus to generate new neurons, and the mutations achieve these destructive powers by changing the correct folding of ADAM10 to interfere with its normal funcntions.  Scientists belive that this new research regarding the importance of ADAM10 and alpha-secretase in Alzheimer's disease will allow for new treatment options and research.     
Source:
1) Massechussets General Hospital (September 24, 2013). Rare Mutations Increase Risk of Late-Onset Alzheimer's Disease.  Science Daily.  Retrieved September 26, 2013, from http://www.sciencedaily.com/releases/2013/09/130924113454.htm
Keywords: Alzheimer's, ADAM10, alpha-secretase

By Emma Henson

Roskamp Institute is a non-profit research institute located at Sarasota, FL. The mission of the institute is identify cure for Brain related disorders. Dr. Michael Mullan is the head of the institute. He discovered Swedish mutation in APP gene.

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<![CDATA[Alzheimer’s disease: Molecular Chain Reaction Found?]]>Thu, 26 Sep 2013 20:59:43 GMThttp://michaelmullan.org/1/post/2013/09/september-26th-2013.htmlPicture
Researchers at Lund University in Sweden headed by Professor Singerup Linse and Erik Helistrand have recently identified a molecular mechanism behind the crucial step in Alzheimer’s that leads to the death of brain cells.
The neurological disease is associated, as a general statement, with memory loss and changes in personality.  The research at Lund helps identify on a molecular level the chemical reactions which cause plaque, a major benchmark in the progression of the disease, to form.   Amyloid beta in its soluble form, found naturally within the brain, acts as a building block and turns into plaque called amyloid fibrils, though the exact pathways of these reactions remain unclear.  An early section of the process of formation of fibrils is two small protein fragments of amyloid beta coming together within a nucleus of a cell to form a fibril.  Lund University’s study suggests that fibrils have a catalytic surface, allowing reactions to happen quicker while touching them, creating new nuclei which in turn aid the proliferation of more fibrils, causing exponential growth in plaque formation.  After a small but crucial amount of amyloid fibrils are created, more immediately surface to begin a self-perpetuating process key to understanding Alzheimer’s.  These findings dash what was previously believed; that fibrils formed in single nuclei reactions as a uniform process.  More profound perhaps than the catalytic surface is the discovery that this aggregation of amyloid fibrils creates toxic oligomers, small groups of proteins.  These oligomers have been identified as neurotoxins that play a significant part in cell-death.
It is the hope of Professor Linse that new medicines targeted at shutting down the catalyzation of amyloid fibrils and the resultant neurotoxins can slow or even stop the progression of the disease. For now, it is heartening that ongoing Alzheimer’s research is yielding new information about the degenerative disease and possible ways to fight its progression.

References:
1)  S. I. A. Cohen, S. Linse, L. M. Luheshi, E. Hellstrand, D. A. White, L. Rajah, D. E.  Otzen, M. Vendruscolo, C. M. Dobson, T. P. J. Knowles. Proliferation of amyloid- 42 aggregates occurs through a secondary nucleation mechanism. Proceedings of the National Academy of Sciences, 2013; DOI: 10.1073/pnas.1218402110
2) Lund University (2013, May 29). Molecular chain reaction in Alzheimer’s disease. ScienceDaily. Retrieved May 30, 2013, from http://www.sciencedaily.com /releases/2013/05/

Keywords: Alzheimer’s disease, Amyloid Beta Protein

Article By: Lauren Horne (edited by Emma Henson)

Roskamp Institute is devoted to find cure for brain related disorders. Its a non-profit research institute located at Sarasota, Florida. Dr. Michael Mullan is the head and CEO of the Roskamp Institute.


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<![CDATA[Traumatic Brain Injury and Increased Risk for Alzheimer's Disease]]>Thu, 29 Aug 2013 16:29:46 GMThttp://michaelmullan.org/1/post/2013/08/traumatic-brain-injury-sci-brain-alzheimers-risk-michael-mullan.htmlPicture
Recently, there has been increasing interest in the role of sports head injuries and subsequent cognitive decline. For instance, American football players are being scrutinized more closely because of new research suggesting close links between repeated concussion and decline in cognitive abilities.

Complaints by professional players are now being taken seriously, as associations all over the country begin to take action.

“I’ve had times where I walked up to the line, where I know the play, but don’t know what to do.” – Oakland Raiders tight end Tony Stewart

“I’ve known of players hiding concussions..Sometimes players aren’t real sure.  They hit their head, they get a little cuckoo for a little while.  It happens all the time.” – Kansas City Chiefs center Rudy Niswanger

Over the last three decades, there has been much work on the relationship between head injury (usually single head injury) and Alzheimer's disease (AD) and other dementias. Many well designed, population based studies have suggested a link between head injury and the development of AD and other dementias. However, there are many discrepancies between these studies and the risk attributed to head injury has varied widely between them. Several key factors are often examined in these studies to try to understand better the relationship between traumatic brain injury (TBI) and AD.

The following areas have been studied extensively:

1.      The Gender Effect:  Despite the many case control and cohort studies, none have shown an increased risk for AD after TBI for women. Although many TBI studies focus on the male population who are more at risk (for instance, in contact sports or in the military) the finding that women are at no increased risk of AD after TBI suggests that there may be a protective effect of female hormones against the development of AD after head injury.

2.      The degree of injury and subsequent development of AD or related disorders: Few studies have adequately assessed the degree of injury and so information in this area is limited but, the studies that have, in general, suggest that more moderate or severe injuries predispose to dementia later in life. For instance, one study divided TBI into mild, moderate, and severe categories:  injuries with loss of consciousness (LOC) or post-traumatic amnesia (PTA) of less than 30 minutes (mild); of more than 30 minutes but less than 24 hours (moderate); and of more than 24 hours (severe). Most studies suggested moderate and severe disease is more related to AD and that full recovery of cognitive loss can be regained after mild TBI.

3.      Time of injury to the development of subsequent dementia:  This relationship has been studied in large populations and there are good data to suggest that TBI in old age is associated with worsening of outcome compared to TBI at a younger age. Nevertheless, even individuals that have TBI in early adulthood (if the injury is severe enough) are at increased risk of AD and other dementias as many as five decades later.



One key question is how the brain "remembers" the injury for so many years and why there may be no signs of cognitive impairment soon after the injury for many decades until AD onsets. The question of the molecular underpinnings of TBI and how the brain continues to register that an injury has occurred is an area of intense study.

One such candidate for molecular memory is amyloid.  The amyloid molecule is increased in the brains of AD sufferers and occurs early in the pathological sequence that leads to full-blown AD. Most studies show that only about one-third of TBI victims have amyloid at autopsy.  Although amyloid is produced acutely after TBI, much of that amyloid does not stay in the brain but is degraded in the weeks and months following injury.

Another pathological molecule central to the AD process is tau.  Tau protein is formed when neurons die.  Although tau has been implicated in TBI, again, there are inconsistent data between studies -- some showing no increased involvement of tau while others show hyperphosphorylation and/or aggregation of tau. More recently in repetitive head injury (for instance, those occurring in American football) tau has been implicated as it has been seen particularly around blood vessels in the brain.

Whatever the ultimate underlying cause of the link between TBI and the subsequent development of AD, we can expect that once those links are fully uncovered, they will become new targets for the prevention of AD following TBI.

One other area that deserves attention is the genetic risk for poor recovery after TBI and subsequent risk for AD. Although it is generally accepted that APOE4 is a risk factor for AD, some studies of head injury have been equivocal in demonstrating that APOE4 acts synergistically with TBI to increase risk for AD.

However, given the plethora of data on the negative roles of APOE4 in the brain after TBI, it is safe to assume that individuals who carry the E4 are most probably at greater risk for developing AD than those who do not. It has been advocated that those individuals carrying an APOE4 allele should not engage in professions or pastimes with increased risk of TBI.

Much more work is needed in this area; but, at this stage, as a precaution, this is probably a position that can be easily endorsed.

Dr. Michael Mullan is the president of Sci-Brain. A company providing personalized program to reduce risk of Alzheimer's disease and improve your Brain Health.


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<![CDATA[Alzheimer’s in Mice: Drug-reversible?]]>Fri, 31 May 2013 20:30:50 GMThttp://michaelmullan.org/1/post/2013/05/alzheimers-in-mice-drug-reversible.htmlWithin the journal Science, University of Pittsburgh Graduate School of Public Health scientists confirm that a study which was performed on a mouse model with Alzheimer’s disease, when treated with an anti-cancer drug, significantly improved its brain function and memory capabilities. The cancer drug, known as bexarotene, which was previously studied and used for cullaneous T-cell Lymphoma, was shown to drastically improve the level of cognitive deficits within the brains of mice that were expressing gene mutations that were linked to human Alzheimer’s disease, but the study could not confirm the effect it had on amyloids plaque, the build-up of toxic proteins in the brain that effectively leads to a number of brain-damaging diseases, including Alzheimer’s.
    Dr. Rada Koldamova, M.D and Ph.D., senior author and associate professor at Pitt Public said with confidence that the continual study of bexarotene for therapeutic treatment of Alzheimer’s disease. For this study, Dr. Koldamova and her team studied mice that expressed human Apoliopoprotein E4 (APOE4), otherwise known as the only genetic risk factor for Alzheimer’s disease. Bexarotene is chemically related to vitamin A and activates Retinoic X Receptors (RXR) all over the body, and once activated, they bind to DNA, and regulate gene expression of many biological processes, with a consequence of increased levels of APOE4, thanks to RXR activation by bexarotene.
    Results of the study showed that male and female mice responded equally, and that after ten days of beginning the testing with bexarotene, mice that genetically expressed human Alzheimer’s APOE3 or APOE4 were able to perform as well in cognitive testing as their non-Alzheimer’s counterpart mice. The drug testing did not affect the mice’s overall weight or behavior, merely their level of cognition and memory retention.

Sources:
University of Pittsburgh Schools of the Health Sciences (2013, May 23). Drug reverses Alzheimer's disease deficits in mice.

By Lauren Horne
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<![CDATA[Alzheimer’s disease: Molecular Trigger Found?]]>Fri, 31 May 2013 20:29:04 GMThttp://michaelmullan.org/1/post/2013/05/alzheimers-disease-molecular-trigger-found.htmlScientists at Cambridge’s Department of Chemistry have been able to construct a detailed map that shows how the formation of proteins in the brain can lead to a build-up so massive that it can lead to the development of numerous brain-damaging diseases, chief among them is Alzheimer’s. In 2010, the Alzheimer’s Research Trust found that with dementia alone, it cost the UK economy E23 billion, way more than cancer and heart disease combined cost.
    Normally, proteins are made up of chemical building blocks known as amino acids, which are joined together in a code ordered by our DNA. New proteins appear as long, thin strips, which are then intricately folded to properly carry out their designated biological function. However, there are points at which the protein can ‘misfold,’ or unfold and get tangled together with other newly-made proteins. The tangles stick to one another until they number in the millions, known as amyloid fibrils, and they start the huge deposits of proteins known as plaque, which are so huge that they are insoluble.  
    When the level of plaque in the brain reaches a critical level, a chain reaction is set off, and new focal points of tendrils form. From these tendrils, a smaller number of proteins, known as toxic oligomers, can easily diffuse through membranes, effectively killing neurons, causing memory loss, and other dementia symptoms.
    This new groundbreaking information required scientists to come together, using kinetic experiments with a framework of theory. Master equations, more commonly used in the fields of chemistry and physics, aided researchers in their efforts to better understand a disease such as Alzheimer’s, and how better to fight it.

By Lauren Horne

Sources:
    University of Cambridge (2013, May 20). Molecular trigger for Alzheimer's disease identified. ScienceDaily. Retrieved May 22, 2013,
    Samuel I. A. Cohen, Sara Linse, Leila M. Luheshi, Erik Hellstrand, Duncan A. White, Luke Rajah, Daniel E. Otzen, Michele Vendruscolo, Christopher M. Dobson, and Tuomas P. J. Knowles. Proliferation of amyloid-β42 aggregates occurs through a secondary nucleation mechanism. Proceedings of the National Academy of Sciences, 2013; DOI: 10.1073/pnas.1218402110]]>
<![CDATA[Genetic Sequencing of Human Diseases: the Largest Study ]]>Fri, 31 May 2013 20:26:41 GMThttp://michaelmullan.org/1/post/2013/05/genetic-sequencing-of-human-diseases-the-largest-study.html
    At Queen Mary University in London, researchers have conducted the largest study of genetic sequencing of human diseases known to date, identifying the genetic basis of six different diseases: autoimmune thyroid disease, celiac disease, Crohn’s disease, psoriasis, multiple sclerosis, and type 1 diabetes. For these diseases, the exact cause is not known, but according to the study, it was believed that the diseases were a complex combination of both genetic and environmental factors. For each disease, there was only a small portion of hereditability is explained by genetic variants.
    In past studies and experiments, genetic variants were only identified as weak-effect. For this study, global scientists used highly throughput sequencing techniques in order to identify new variants, along with rarer and higher risk variants. In a previous experiment that contained twenty-five risk genes, the risk genes were found in a sample of nearly 42,000 individuals, 24,892 of the individuals with autoimmune disease, and 17,019 individuals were controls.
    Within the May 2013 edition of the journal Nature, scientists suggest that the overall genetic risk of these diseases more than likely involves a complex combination of weak-effect variants which are common in the overall human population. David van Heel, Professor of Gastrointestinal Genetics at Barts and Queen Mary University, led the study, saying that there is a lesser risk of autoimmune disease from a few high-risk genetic variations, and a greater risk of random selection from the common genetic variants, each having a weak effect. Heel goes on to say that the genetic risk likely comes from inheriting a large amount of common variants from both parents. This would mean that it would be nearly impossible to test individually for such diseases. However, scientists are started to grasp the biological basis for the conditions that cause these diseases, opening a pathway for researchers to follow, hopefully leading to new drug avenues and possible treatment options.

By Lauren Horne
Sources:
    Queen Mary, University of London (2013, May 22). Largest genetic sequencing study of human disease. ScienceDaily. Retrieved May 23, 2013,]]>
<![CDATA[Toxic Brain Protein: Stopped by Cancer Drug]]>Fri, 31 May 2013 20:24:43 GMThttp://michaelmullan.org/1/post/2013/05/toxic-brain-protein-stopped-by-cancer-drug.html    At Georgetown University Medical Center, tiny, almost meniscal dosage amounts of a Leukemia-inhibiting drug known as nilotinib, were being administered to lab mice in a clinical trial to see the effects of the drug on inhibiting the formation of certain proteins in the brain, which if allowed to proceed unchecked, would build up and cause any number of diseases, from Parkinson’s disease and even Alzheimer’s disease, to a lesser known disease known as Lewry body disease.
    Neurologist and senior investigator for this study, Charbel E-H Moussa, MB and PhD, head of the dementia laboratory at Georgetown University stated that when this utilized drug, nilotinib, is used to treat CML, or chronic myelogenous leukemia. When used in high enough and safe doses, it causes the cancer cells to go into a state of autophagy, pushing them to cannibalize their own organelles, which leads to the death of tumor cells.
    In the study that was performed, for the first time, cancer drugs were being utilized for a different cause. Mice in the lab that over-expressed a specific protein, known as alpha-Symuclein, were given one Milligram of nilotinib every two days. Previous testing of the drug concluded that it would get rid of the toxic protein found in the brain, the cells would go into a state of autophagy and within a matter of treatments, the lab mice treated with the drug had drastically better movement and functionality than the untreated mice.
    At the end of the experiment, Moussa hypothesized that in order for therapy of these neurological diseases to be effective, it must happen as soon as possible. Later usage may result in retardation of further extracellular formation, as well as the accumulation of intracellular proteins such as Lewy bodies, which was the whole point of using the Leukemia drug in the first place.
Sources:
    Michaeline L. Hebron, Irina Lonskaya, and Charbel E.-H. Moussa. Nilotinib reverses loss of dopamine neurons and improves motor behavior via autophagic degradation of α-synuclein in Parkinson's disease models. Hum. Mol. Genet., May 10, 2013 DOI: 10.1093/hmg/ddt192
    Georgetown University Medical Center (2013, May 10). Cancer drug prevents build-up of toxic brain protein. ScienceDaily.]]>
<![CDATA[Risk of Cancer vs Alzheimer’s disease]]>Fri, 31 May 2013 20:22:15 GMThttp://michaelmullan.org/1/post/2013/05/risk-of-cancer-vs-alzheimers-disease.htmlFrom a recently published artilce in the May 2013 online issue of Neurology, a leading medical journal of the American Academy of Neurology, researchers in Minneapolis reported a study where 1,102 participants with average age of 79 years, were followed for the span of 3.7 years, were tested to see if ever they developed dementia. At the start of the study, 109 of the patients admitted to having skin cancer in the past. During the study trials, 32 people developed skin cancer, and 125 people developed dementia, including 100 people with Alzheimer’s dementia.
    At the end of the testing period, of the 141 participants who developed skin cancer, only two of them also developed Alzheimer’s dementia. Resulting statistics showed that participants who developed skin cancer were around 80 percent less likely to develop Alzheimer’s disease versus those who did not develop skin cancer. There was no link found between Melanoma, a less common but powerful form of skin cancer, and Alzheimer’s disease. Nor was there a link with any other forms of dementia. The links were limited only to Alzheimer’s dementia and weaker forms of skin cancer.
    Reviewing commentary of study author Richard B Lipton, MD, of Albert Einstein College of Medicine in Bronx, New York,  stated that the protective effects of skin cancer were still unknown. However, there was a strong tendency to link physical activity protecting against dementia, and outdoor activities leading to a higher UV exposure from the sun, leading to a greater chance of skin cancer. Further insight guided Lipton to suggest genetic factors as a possible link between the two diseases, as the study showed that physical activity alone did not reduce the risk levels of Alzheimer’s to a meaningful level. More testing is surely needed, but this is a promising step in the right direction.

By Lauren Horne

Sources:    
    R. S. White, R. B. Lipton, C. B. Hall, J. R. Steinerman. Nonmelanoma skin cancer is associated with reduced Alzheimer disease risk. Neurology, 2013; 80 (21): 1966 DOI: 10.1212/WNL.0b013e3182941990
    American Academy of Neurology (AAN) (2013, May 15). Skin cancer may be linked to lower risk of Alzheimer's disease. ScienceDaily.
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<![CDATA[New study underscores the role of brain NF-kB in Aging]]>Fri, 10 May 2013 18:02:55 GMThttp://michaelmullan.org/1/post/2013/05/nfkb-anatabine-michaelmullan.htmlA new study by researchers at the Albert Einstein School of Medicine dramatically underscores the potential role of the NF-kB protein in aging. NF-kB is a master protein which controls many inflammatory chemicals throughout the body. Researchers at the Roskamp Institute have studied NF-kB for many years as a potential way of controlling chronic inflammation which accompanies aging and underlies conditions such as Alzheimer’s disease. This new study points to a part of the brain as regulating the aging process. The current view of aging generally suggests that enzymes, DNA, proteins and other constituents of the body essentially “wear out” with age, accumulating damage due to environmental insults until they no longer function properly. This new study suggests something quite different, namely that a part of the brain called the Hypothalamus deliberately induces aging throughout the body. It has been suggested that one reason why the brain might take such drastic action is to inhibit reproduction past a certain age. This suggestion is highly speculative at this stage, but the data offered by the Albert Einstein researchers suggests that, with age, increased NF-kB activity triggers degeneration in both the brain and other areas of the body. The researchers showed that as mice aged, they increasingly expressed NF-kB in the part of the brain that is normally responsible for the production of reproductive and growth hormones. The researchers artificially manipulated NF-kB activity using genetic techniques and showed that reducing NF-kB activity was associated with better performance in cognitive tests, greater muscle strength and greater bone mass and skin thickness. Conversely, exacerbation of NF-kB activity increased all of these peripheral signs of aging, as well as reducing cognitive abilities. Furthermore the research suggested that microglia (the inflammatory cells resident in the brain) are the originators of the NF-kB activity and this spreads to nearby neurons, including those responsible for growth and reproductive hormones. These findings are of direct significance to work at the Roskamp Institute as researchers there have shown that increased NF-kB collates strongly with Alzheimer’s pathology and pathology of other central nervous system disorders. Moreover, they have worked extensively on ways to reduce NF-kB activation, particularly using the naturally occurring compound Anatabine.  Roskamp Institute researchers have shown in multiple preclinical studies of neuroinflammation (such as Alzheimer's, traumatic brain injury and Multiple Sclerosis) that Anatabine (supplied by RockCreek Pharmaceuticals) has potent anti-inflammatory properties. This new finding suggests that NFKB inhibitors might also have a role in decelerating aging. In fact,  preliminary studies at the Roskamp Institute suggest that mortality in mice with Alzheimer pathology is reduced by Anatabine treatment. Additional studies are needed to clarify whether Anatabine might reduce the Hypothalamic inflammation and increase the release of hormones that oppose aging.

Dr. Michael Mullan M.D., Ph.D
President & CEO
Roskamp Institute]]>
<![CDATA[SCI-BRAIN: Empowering individuals with the knowledge they need to change their lifestyle to reduce risk of Alzheimer's Disease]]>Wed, 13 Feb 2013 22:18:23 GMThttp://michaelmullan.org/1/post/2013/02/sci-brain-empowering-individuals-with-the-knowledge-they-need-to-change-their-lifestyle-to-reduce-risk-of-alzheimers-disease.htmlPicture
Although the main thrust of many  Alzheimer's Disease research establishments around the world has been to find new medicinal treatments for the condition, it has become clear especially over the last decade that certain lifestyle choices have a very significant impact on our risk for Alzheimer's Disease. In particular, we now know that diet, physical exercise and the use of our brains in mental tasks all alter our risk for the disease. In some cases these factors have a very  dramatic that on whether we will develop the disease in a specific time frame or not. In addition, we know that certain medical conditions adversely  impact our risk for the disease and controlling these conditions reduces or removes that increased risk. Dr. Michael Mullan at the Roskamp Institute has therefore partnered with Nicci Kobritz who has been providing quality home health care in the Sarasota area for many years to form a new company, Sci-Brain, specifically to deliver the benefits of our knowledge to residents of Sarasota and surrounding areas. Sci-Brain has developed a proprietary method to assess an individual's risk for developing Alzheimer's Disease or related disorders. The risk evaluation is based on lifestyle factors which are modifiable and are known to correlate with lower risk if they are changed. The Sci-Brain program therefore offers a way to lower risk for Alzheimer's Disease and related disorders by empowering individuals with the knowledge they need to change their lifestyle choices.

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