Recently, Dr. Cheryle Séguin, a musculoskeletal researcher at the Schulich School of Medicine & Dentistry, Western University who studies spinal disc development, made a scientific breakthrough that unintentionally provided the missing link researchers needed to study the genesis of chordoma
After years of work, Dr. Séguin and her colleagues succeeded in developing a one-of-a-kind genetically engineered mouse that enables researchers to observe and manipulate an embryonic tissue called the notochord. The notochord is important because during development it gives rise to the intervertebral disc, the degeneration of which is the primary cause of back pain afflicting hundreds of millions of people worldwide. In addition to forming the discs, some notochordal cells get lodged inside the developing vertebrae, and, in about 1 in 5 people, these notochordal cells form small benign tumours inside the spine. Occasionally, these benign notochordal cell tumours turn malignant and become a cancer known as chordoma.
Little is known about what causes notochordal cells to turn into chordoma, but now Dr. Séguin’s mouse makes it possible to study that transformation. To do so, Dr. Séguin needs to isolate notochordal cells from her mouse and turn them into a cell line – a constantly dividing family of cells grown in a petri-dish. Creating a notochordal cell line will give scientists a blank slate upon which to introduce genetic changes to see which cellular pathways are activating causing the cells to become cancerous. This could shed light on the cause of chordoma, and, in turn, could point to potential therapies that address the root cause of chordoma.
The Chordoma Foundation is pleased to award Dr. Séguin a $25,000 seed grant to support her attempts to develop the world’s first notochordal cell line. This grant was made possible by funds raised through the fourth annual Purple Aster Concert, an annual music event in Calgary, Canada, held in memory of chordoma patient Alison Laird. The concert is organized by Alison’s husband, Ian, and friend, Carolyn Harley. Chordoma Foundation board member, Dr. Ed Les, also of Calgary, matched donations by concertgoers to fully sponsor the grant.
Schulich School of Medicine & Dentistry
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Wayne State University School of Medicine researchers, working with colleagues in Canada, have found that one or more substances produced by a type of immune cell in people with multiple sclerosis (MS) may play a role in the disease’s progression. The finding could lead to new targeted therapies for MS treatment.
B cells, said Robert Lisak, M.D., professor of neurology at Wayne State and lead author of the study, are a subset of lymphocytes (a type of circulating white blood cell) that mature to become plasma cells and produce immunoglobulins, proteins that serve as antibodies. The B cells appear to have other functions, including helping to regulate other lymphocytes, particularly T cells, and helping maintain normal immune function when healthy.
In patients with MS, the B cells appear to attack the brain and spinal cord, possibly because there are substances produced in the nervous system and the meninges — the covering of the brain and spinal cord — that attract them. Once within the meninges or central nervous system, Lisak said, the activated B cells secrete one or more substances that do not seem to be immunoglobulins but that damage oligodendrocytes, the cells that produce a protective substance called myelin.
The B cells appear to be more active in patients with MS, which may explain why they produce these toxic substances and, in part, why they are attracted to the meninges and the nervous system.
The brain, for the most part, can be divided into gray and white areas. Neurons are located in the gray area, and the white parts are where neurons send their axons — similar to electrical cables carrying messages — to communicate with other neurons and bring messages from the brain to the muscles. The white parts of the brain are white because oligodendrocytes make myelin, a cholesterol-rich membrane that coats the axons. The myelin’s function is to insulate the axons, akin to the plastic coating on an electrical cable. In addition, the myelin speeds communication along axons and makes that communication more reliable. When the myelin coating is attacked and degraded, impulses — messages from the brain to other parts of the body — can ‘leak’ and be derailed from their target. Oligodendrocytes also seem to engage in other activities important to nerve cells and their axons.
The researchers took B cells from the blood of seven patients with relapsing-remitting MS and from four healthy patients. They grew the cells in a medium, and after removing the cells from the culture collected material produced by the cells. After adding the material produced by the B cells, including the cells that produce myelin, to the brain cells of animal models, the scientists found significantly more oligodendrocytes from the MS group died when compared to material produced by the B cells from the healthy control group. The team also found differences in other brain cells that interact with oligodendrocytes in the brain.
‘We think this is a very significant finding, particularly for the damage to the cerebral cortex seen in patients with MS, because those areas seem to be damaged by material spreading into the brain from the meninges, which are rich in B cells adjacent to the areas of brain damage,’ Lisak said.
Wayne State University
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The possibility of an inexpensive, convenient test for Alzheimer’s disease has been on the horizon for several years, but previous research leads have been hard to duplicate.
In a study, scientists have taken a step toward developing a blood test for Alzheimer’s, finding a group of markers that hold up in statistical analyses in three independent groups of patients.
‘Reliability and failure to replicate initial results have been the biggest challenge in this field,’ says lead author William Hu, MD, PhD, assistant professor of neurology at Emory University School of Medicine. ‘We demonstrate here that it is possible to show consistent findings.’
Hu and his collaborators at the University of Pennsylvania and Washington University, St. Louis, measured the levels of 190 proteins in the blood of 600 study participants at those institutions. Study participants included healthy volunteers and those who had been diagnosed with Alzheimer’s disease or mild cognitive impairment (MCI). MCI, often considered a harbinger for Alzheimer’s disease, causes a slight but measurable decline in cognitive abilities.
A subset of the 190 protein levels (17) were significantly different in people with MCI or Alzheimer’s. When those markers were checked against data from 566 people participating in the multicenter Alzheimer’s Disease Neuroimaging Initiative, only four markers remained: apolipoprotein E, B-type natriuretic peptide, C-reactive protein and pancreatic polypeptide.
Changes in levels of these four proteins in blood also correlated with measurements from the same patients of the levels of proteins [beta-amyloid] in cerebrospinal fluid that previously have been connected with Alzheimer’s. The analysis grouped together people with MCI, who are at high risk of developing Alzheimer’s, and full Alzheimer’s.
‘We were looking for a sensitive signal,’ says Hu. ‘MCI has been hypothesised to be an early phase of AD, and sensitive markers that capture the physiological changes in both MCI and AD would be most helpful clinically.’
‘The specificity of this panel still needs to be determined, since only a small number of patients with non-AD dementias were included,’ Hu says. ‘In addition, the differing proportions of patients with MCI in each group make it more difficult to identify MCI- or AD-specific changes.’
Neurologists currently diagnose Alzheimer’s disease based mainly on clinical symptoms. Additional information can come from PET brain imaging, which tends to be expensive, or analysis of a spinal tap, which can be painful.
‘Though a blood test to identify underlying Alzheimer’s disease is not quite ready for prime time given today’s technology, we now have identified ways to make sure that a test will be reliable,’ says Hu. ‘In the meantime, the combination of a clinical exam and cerebrospinal fluid analysis remains the best tool for diagnosis in someone with mild memory or cognitive troubles.’
EurekAlert
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Investigators at Nationwide Children’s Hospital may have discovered a biological explanation for why low levels of oxygen advance spinal muscular atrophy (SMA) symptoms and why breathing treatments help SMA patients live longer.
SMA is a progressive neurodegenerative disease that causes muscle damage and weakness leading to death. Respiratory support is one of the most common treatment options for severe SMA patients since respiratory deficiencies increase as the disease progresses. Clinicians have found that successful oxygen support can allow patients with severe SMA to live longer. However, the biological relationship between SMA symptoms and low oxygen levels isn’t clear.
To better understand this relationship, investigators at Nationwide Children’s Hospital examined gene expression within a mouse model of severe SMA. ‘We questioned whether low levels of oxygen linked to biological stress is a component of SMA disease progression and whether these low oxygen levels could influence how the SMN2 gene is spliced,’ says Dawn Chandler, PhD, principal investigator in the Center for Childhood Cancer and Blood Diseases at The Research Institute at Nationwide Children’s Hospital.
SMA is caused by mutation or deletion of the SMN1 gene that leads to reduced levels of the survival motor neuron protein. Although a duplicate SMN gene exists in humans, SMN2, it only produces low levels of functional protein. This is caused by a splicing error in SMN2 in which exon 7 is predominantly skipped, lowering the amount of template used for protein construction.
Mouse models of severe SMA have shown changes in how genes are differentially spliced and expressed as the disease progresses, especially near end-stages. ‘One gene that undergoes extreme alteration is Hif3alpha,’ says Dr. Chandler. ‘This is a stress gene that responds to changes in available oxygen in the cellular environment, specifically to decreases in oxygen. This gave us a clue that low levels of oxygen might influence how the SMN2 gene is spliced.’
Upon examining mouse models of severe SMA exposed to low oxygen levels, Dr. Chandler’s team found that SMN2 exon 7 skipping increased within skeletal muscles. When the mice were treated with higher oxygen levels, exon 7 was included more often and the mice showed signs of improved motor function.
‘These data correspond with the improvements seen in SMA patients who undergo oxygen treatment,’ says Dr. Chandler. ‘Our findings suggest that respiratory assistance is beneficial in part because it helps prevent periods of low oxygenation that would otherwise increase SMN2 exon 7 skipping and reduce SMN levels.’
Dr. Chandler says daytime indicators that reveal when an SMA patient is experiencing low oxygen levels during sleep may serve as a measure to include SMA patients in earlier respiratory support and therefore improve quality of life or survival.
Nationwide Children’s Hospital
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Researchers from Boston University School of Medicine (BUSM) and Veterans Affairs (VA) Boston Healthcare System have demonstrated that the effects on white matter brain volume from long-term alcohol abuse are different for men and women. The study also suggests that with abstinence, women recover their white matter brain volume more quickly than men.
The study was led by Susan Mosher Ruiz, PhD, postdoctoral research scientist in the Laboratory for Neuropsychology at BUSM and research scientist at the VA Boston Healthcare System, and Marlene Oscar Berman, PhD, professor of psychiatry, neurology and anatomy and neurobiology at BUSM and research career scientist at the VA Boston Healthcare System.
In previous research, alcoholism has been associated with white matter pathology. White matter forms the connections between neurons, allowing communication between different areas of the brain. While previous neuroimaging studies have shown an association between alcoholism and white matter reduction, this study furthered the understanding of this effect by examining gender differences and utilising a novel region-of-interest approach.
The research team employed structural magnetic resonance imaging (MRI) to determine the effects of drinking history and gender on white matter volume. They examined brain images from 42 abstinent alcoholic men and women who drank heavily for more than five years and 42 non-alcoholic control men and women. Looking at the correlation between years of alcohol abuse and white matter volume, the researchers found that a greater number of years of alcohol abuse was associated with smaller white matter volumes in the abstinent alcoholic men and women. In the men, the decrease was observed in the corpus callosum while in women, this effect was observed in cortical white matter regions.
‘We believe that many of the cognitive and emotional deficits observed in people with chronic alcoholism, including memory problems and flat affect, are related to disconnections that result from a loss of white matter,’ said Mosher Ruiz.
The researchers also examined if the average number of drinks consumed per day was associated with reduced white matter volume. They found that the number of daily drinks did have a strong impact on alcoholic women, and the volume loss was one and a half to two percent for each additional daily drink. Additionally, there was an eight to 10 percent increase in the size of the brain ventricles, which are areas filled with cerebrospinal fluid (CSF) that play a protective role in the brain. When white matter dies, CSF produced in the ventricles fills the ventricular space.
Recovery of white matter brain volume also was examined. They found that, in men, the corpus callosum recovered at a rate of one percent per year for each additional year of abstinence. For people who abstained less than a year, the researchers found evidence of increased white matter volume and decreased ventricular volume in women, but not at all in men. However, for people in recovery for more than a year, those signs of recovery disappeared in women and became apparent in men.
‘These findings preliminarily suggest that restoration and recovery of the brain’s white matter among alcoholics occurs later in abstinence for men than for women,’ said Mosher Ruiz. ‘We hope that additional research in this area can help lead to improved treatment methods that include educating both alcoholic men and women about the harmful effects of excessive drinking and the potential for recovery with sustained abstinence.’
Boston University Medical Center
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Researchers for the first time have shown that members of a family of enzymes known as cathepsins – which are implicated in many disease processes – may attack one another instead of the bodily proteins they normally degrade. Dubbed ‘cathepsin cannibalism,’ the phenomenon may help explain problems with drugs that have been developed to inhibit the effects of these powerful proteases.
Cathepsins are involved in disease processes as varied as cancer metastasis, atherosclerosis, cardiovascular disease, osteoporosis and arthritis. Because cathepsins have harmful effects on critical proteins such as collagen and elastin, pharmaceutical companies have been developing drugs to inhibit activity of the enzymes, but so far these compounds have had too many side effects to be useful and have failed clinical trials.
Using a combination of modelling and experiments, researchers from the Georgia Institute of Technology and Emory University have shown that one type of cathepsin preferentially attacks another, reducing the enzyme’s degradation of collagen. The work could affect not only the development of drugs to inhibit cathepsin activity, but could also lead to a better understanding of how the enzymes work together.
‘These findings provide a new way of thinking about how these proteases are working with and against each other to remodel tissue – or fight against each other,’ said Manu Platt, an assistant professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. ‘There has been an assumption that these cathepsins have been inert in relationship to one another, when in actuality they have been attacking one another. We think this may have broader implications for other classes of proteases.’
Platt and student Zachary Barry made their discovery accidentally while investigating the effects of cathepsin K and cathepsin S – two of the 11-member cathepsin family. Cathepsin K degrades both collagen and elastin, and is one of the most powerful proteases. Cathepsin S degrades elastin, and does not strongly attack collagen.
When the researchers combined the two cathepsins and allowed them to attack samples of elastin, they expected to see increased degradation of the protein. What they saw, however, was not much more damage than cathepsin K did by itself.
Platt at first believed the experiment was flawed, and asked Barry – an undergraduate student in his lab who specialises in modelling – to examine what possible conditions could account for the experimental result. Barry’s modelling suggested that effects observed could occur if cathepsin S were degrading cathepsin K instead of attacking the elastin – a protein essential in arteries and the cardiovascular system.
That theoretical result led to additional experiments in which the researchers measured a direct correlation between an increase in the amount of cathepsin S added to the experiment and a reduction in the degradation of collagen. By increasing the amount of cathepsin S ten-fold over the amount used in the original experiment, Platt and Barry were able to completely block the activity of cathepsin K, preventing damage to the collagen sample.
‘We saw that the cathepsin K was going away much faster when there was cathepsin S present than when it was by itself,’ said Platt, who is also a Georgia Cancer Coalition Distinguished Scholar and a Fellow of the Keystone Symposia on Molecular and Cellular Biology. ‘We kept increasing the amount of cathepsin S until the collagen was not affected at all because all of the cathepsin K was eaten by the cathepsin S.’
The researchers used a variety of tests to determine the amount of each enzyme, including fluorogenic substrate analysis, Western blotting and multiplex cathepsin zymography – a sensitive technique developed in the Platt laboratory.
Beyond demonstrating for the first time that cathepsins can attack one another, the research also shows the complexity of the body’s enzyme system – and may suggest why drugs designed to inhibit cathepsins haven’t worked as intended.
‘The effect of the cathepsins on one another complicates the system,’ said Platt. ‘If you are targeting this system pharmaceutically, you may not have the types or quantities of cathepsins that you expect, which could cause off-
Georgia Institute of Technology Research News
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Genetics researchers have identified a key gene that, when mutated, causes the rare multisystem disorder Cornelia deLange syndrome (CdLS). By revealing how mutations in the HDAC8 gene disrupt the biology of proteins that control both gene expression and cell division, the research sheds light on this disease, which causes intellectual disability, limb deformations and other disabilities resulting from impairments in early development.
‘As we better understand how CdLS operates at the level of cell biology, we will be better able to define strategies for devising treatments for CdLS, and possibly for related disorders,’ said study leader Matthew A. Deardorff, M.D., Ph.D., a pediatric genetics clinician and scientist at The Children’s Hospital of Philadelphia. Deardorff also is in the Perelman School of Medicine at the University of Pennsylvania.
The current findings add to previous discoveries by researchers at The Children’s Hospital of Philadelphia. A group led by Ian Krantz, M.D., and Laird Jackson, M.D., announced in 2004 that mutations in the NIPBL gene are the primary cause of CdLS, accounting for roughly 60 percent of the ‘classical’ cases of the disease. In 2007, Deardorff joined them to describe mutations in two additional genes, SMC1A and SMC3. First described in 1933, CdLS affects an estimated 1 in 10,000 children.
The CdLS research team at Children’s Hospital has focused on the cohesin complex, a group of proteins that form a bracelet-like structure that encircles pairs of chromosomes, called sister chromatids. ‘Cohesin has two roles,’ said Deardorff. ‘It keeps sister chromatids together during cell division, and it allows normal transcription—the transmission of information from DNA to RNA.’
Deardorff added that mutations that perturb normal cohesin function can interfere with normal human development. Such is the case in CdLS, which exemplifies a newly recognised class of diseases called cohesinopathies.
In the current study, the scientists investigated both acetylation—how an acetyl molecule is attached to part of the cohesin complex—and deactylation, the removal of that molecule. Normally, deactylation helps recycle cohesin to make it available during successive rounds of cell division. The study team found that mutations in the HDAC8 gene threw off normal cellular recycling of cohesin.
Mutations in the gene cause loss of HDAC8 protein activity, and consequently decrease the amount of ‘recharged’ cohesin available to properly regulate gene transcription. This, in turn, the researchers suggest, impairs normal embryonic development and gives rise to CdLS.
The researchers showed in cell cultures that mutations in HDAC8 lead to a decrease in cohesin binding to genes, similar to that seen for cells deficient in the NIPBL gene. They also identified HDAC8 mutations in approximately 5 percent of patients with CdLS.
Because mothers of children with CdLS may carry mutations in the HDAC8 gene, identifying these mutations will be very useful in accurately counseling families of their recurrence risk—the likelihood of having a subsequent child with CdLS.
Furthermore, added Deardorff, by providing biological details of the underlying defect in CdLS, the current research suggests future approaches to treating the genetic disease. ‘By concentrating downstream on the biological pathway in the cohesin cycle rather than focusing on the defective gene, we may be able to eventually screen for small-molecule drugs that could be used to intervene in CdLS.’
Children’s Hospital of Philadelphia
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Researchers have identified 38 new genetic regions that are associated with glucose and insulin levels in the blood. This brings the total number of genetic regions associated with glucose and insulin levels to 53, over half of which are associated with type 2 diabetes.
The researchers used a technology that is 100 times more powerful than previous techniques used to follow-up on genome-wide association results. This technology, Metabochip, was designed as a cost-effective way to find and map genomic regions for a range of cardiovascular and metabolic characteristics on a large scale. Previous approaches were not cost effective and tested only 30-40 DNA sequence variations, but this chip allowed researchers to look at up to 200,000 DNA sequence variations for many different traits at one time. The team hoped to find new variants influencing blood glucose and insulin traits and to identify pathways involved in the regulation of insulin and glucose levels.
‘We wanted to use this improved Metabochip technology to see whether we could find additional genomic associations that may have been previously missed,’ says Dr Claudia Langenberg, co-lead author from the Medical Research Council Epidemiology Unit, Cambridge. ‘Our earlier work identified 23 genetic regions associated with blood glucose levels, highlighting important biological pathways involved in the regulation of glucose. At that stage, and before the design of the Metabochip, we were still limited by our capacity to quickly follow-up and afford parallel genotyping of promising, but unconfirmed genetic regions associated with glucose levels in many different studies across the world.’
The team combined data from new samples typed on the Metabochip with data from a previous study to discover genetic regions associated with blood glucose and insulin levels. They identified 38 previously unknown regions for three different quantitative traits associated with blood glucose levels; fasting glucose concentrations, fasting insulin concentrations and post-challenge glucose concentrations.
.’ Further analysis such as genetic mapping or ‘fine-mapping’ and functional analysis will expand and improve our understanding of the control of glucose and insulin levels in healthy persons and what goes wrong in type 2 diabetes patients. ‘
…’Our research is beginning to allow us to look at the overlap between genomic regions that influence insulin levels and other metabolic traits,’ says Dr Inga Prokopenko, co-lead author from the University of Oxford. ‘We observed some overlap between the regions we identified and genetic regions associated with abdominal obesity and various lipid levels, which are a hallmark of insulin resistance. We hope that these studies will help to find gene networks with potential key modifiers for important metabolic processes and related diseases, such as type 2 diabetes.’
The team also found many more, less significant, genetic regions that may be associated with blood glucose and insulin levels but currently don’t have the available data to definitively establish them as genome-wide significant. This supports previous evidence that there is a long tail of many other genetic regions that add up to quite small genetic effects but may increase the risk of such diseases as diabetes. Collectively, these less significant associations may represent important blood glucose and insulin level associations.
‘In addition to these top signals there is statistical evidence that many other regions that appear to be biologically plausible also influence these traits, but what’s limiting is that we don’t have large enough sample sizes to have the power to validate them,’ explains Dr Inês Barroso, co-lead author from the Wellcome Trust Sanger Institute. ‘Nevertheless, studying these functionally would be extremely beneficial if we want to fully understand the biology of blood glucose levels and the origin of diabetes.’
‘What we’ve found in this study is a number of genomic regions that influence blood glucose and insulin traits. Further analysis such as genetic mapping or ‘fine-mapping’ and functional analysis will expand and improve our understanding of the control of glucose and insulin levels in healthy persons and what goes wrong in type 2 diabetes patients.’
Wellcome Trust Sanger Institute
For the millions of people world-wide with type 1 diabetes who cannot produce sufficient insulin, the potential to transplant insulin-producing cells could offer hope for a long-term cure. The discovery of a marker to help identify and isolate stem cells that can develop into insulin-producing cells in the pancreas would be a critical step forward.
Pancreatic stem cells, the precursors of insulin-producing cells, have not yet been identified in humans or animals, and there is much debate about where they may reside. Ivka Afrikanova, Ayse Kayali, Ana Lopez, and Alberto Hayek, University of California, San Diego, CA, have identified a biochemical marker—stage-specific embryonic antigen 4 (SSEA4)—that they propose can be used to identify and purify human pancreatic stem cells. The article ‘Is Stage-Specific Embryonic Antigen 4 a Marker for Human Ductal Stem/Progenitor Cells’ reports that when grown in culture with high levels of glucose and B27, these SSEA4+ stem cells can differentiate into insulin-producing pancreatic cells.
EurekAlert
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A research team from King’s College London and the University of Exeter Medical School has identified how a genetic mutation acts during the development of nerves responsible for controlling eye muscles, resulting in movement disorders such as Duane Syndrome, a form of squint.
The findings could provide the key to reversing the condition and unlocking the causes of movement disorders in other parts of the body.
As nerves develop in the womb they respond to signals that tell them in which direction to grow. Some signals encourage them to grow to a particular part of the body, while other signals tell them to avoid certain areas.
When the system works as it should, the right type of nerve grows to the appropriate part of the body.
The surface of growing nerves includes identification receptors that respond to signals from secreted proteins. The protein mutated in Duane Syndrome acts as a switch that weighs up incoming signals from the receptors – in this way the nerve knows whether it must grow towards a part of the body or be repulsed away.
In conditions such as Duane Syndrome, the signalling breaks down and the nerve cells are unable to distinguish between a signal of attraction or repulsion. As a result, the nerves that control eye movements grow to the wrong muscles causing limited or complete loss of eye movement. If not corrected surgically, this can lead to partial blindness in later life.
This recent research has provided new insights into how this ‘switch signal’ system works and how it has failed in cases of Duane Syndrome, causing the ‘wiring up’ of the wrong muscle or ‘overshooting’ of nerve development past the correct muscle.
The findings are likely to lead to further study which will identify how the ‘switch signal’ mechanism could be harnessed to selectively change nerve cell development behaviour, how the protein could be targeted to encourage damaged cells to re-grow, and how the ‘switch’ could be manipulated to reverse damage.
EurekAlert
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Breakthrough provides surprise missing link researchers needed to study chordoma
, /in E-News /by 3wmediaRecently, Dr. Cheryle Séguin, a musculoskeletal researcher at the Schulich School of Medicine & Dentistry, Western University who studies spinal disc development, made a scientific breakthrough that unintentionally provided the missing link researchers needed to study the genesis of chordoma
After years of work, Dr. Séguin and her colleagues succeeded in developing a one-of-a-kind genetically engineered mouse that enables researchers to observe and manipulate an embryonic tissue called the notochord. The notochord is important because during development it gives rise to the intervertebral disc, the degeneration of which is the primary cause of back pain afflicting hundreds of millions of people worldwide. In addition to forming the discs, some notochordal cells get lodged inside the developing vertebrae, and, in about 1 in 5 people, these notochordal cells form small benign tumours inside the spine. Occasionally, these benign notochordal cell tumours turn malignant and become a cancer known as chordoma.
Little is known about what causes notochordal cells to turn into chordoma, but now Dr. Séguin’s mouse makes it possible to study that transformation. To do so, Dr. Séguin needs to isolate notochordal cells from her mouse and turn them into a cell line – a constantly dividing family of cells grown in a petri-dish. Creating a notochordal cell line will give scientists a blank slate upon which to introduce genetic changes to see which cellular pathways are activating causing the cells to become cancerous. This could shed light on the cause of chordoma, and, in turn, could point to potential therapies that address the root cause of chordoma.
The Chordoma Foundation is pleased to award Dr. Séguin a $25,000 seed grant to support her attempts to develop the world’s first notochordal cell line. This grant was made possible by funds raised through the fourth annual Purple Aster Concert, an annual music event in Calgary, Canada, held in memory of chordoma patient Alison Laird. The concert is organized by Alison’s husband, Ian, and friend, Carolyn Harley. Chordoma Foundation board member, Dr. Ed Les, also of Calgary, matched donations by concertgoers to fully sponsor the grant. Schulich School of Medicine & Dentistry
Wayne State research team finds possible clue to progression of MS
, /in E-News /by 3wmediaWayne State University School of Medicine researchers, working with colleagues in Canada, have found that one or more substances produced by a type of immune cell in people with multiple sclerosis (MS) may play a role in the disease’s progression. The finding could lead to new targeted therapies for MS treatment.
B cells, said Robert Lisak, M.D., professor of neurology at Wayne State and lead author of the study, are a subset of lymphocytes (a type of circulating white blood cell) that mature to become plasma cells and produce immunoglobulins, proteins that serve as antibodies. The B cells appear to have other functions, including helping to regulate other lymphocytes, particularly T cells, and helping maintain normal immune function when healthy.
In patients with MS, the B cells appear to attack the brain and spinal cord, possibly because there are substances produced in the nervous system and the meninges — the covering of the brain and spinal cord — that attract them. Once within the meninges or central nervous system, Lisak said, the activated B cells secrete one or more substances that do not seem to be immunoglobulins but that damage oligodendrocytes, the cells that produce a protective substance called myelin.
The B cells appear to be more active in patients with MS, which may explain why they produce these toxic substances and, in part, why they are attracted to the meninges and the nervous system.
The brain, for the most part, can be divided into gray and white areas. Neurons are located in the gray area, and the white parts are where neurons send their axons — similar to electrical cables carrying messages — to communicate with other neurons and bring messages from the brain to the muscles. The white parts of the brain are white because oligodendrocytes make myelin, a cholesterol-rich membrane that coats the axons. The myelin’s function is to insulate the axons, akin to the plastic coating on an electrical cable. In addition, the myelin speeds communication along axons and makes that communication more reliable. When the myelin coating is attacked and degraded, impulses — messages from the brain to other parts of the body — can ‘leak’ and be derailed from their target. Oligodendrocytes also seem to engage in other activities important to nerve cells and their axons.
The researchers took B cells from the blood of seven patients with relapsing-remitting MS and from four healthy patients. They grew the cells in a medium, and after removing the cells from the culture collected material produced by the cells. After adding the material produced by the B cells, including the cells that produce myelin, to the brain cells of animal models, the scientists found significantly more oligodendrocytes from the MS group died when compared to material produced by the B cells from the healthy control group. The team also found differences in other brain cells that interact with oligodendrocytes in the brain.
‘We think this is a very significant finding, particularly for the damage to the cerebral cortex seen in patients with MS, because those areas seem to be damaged by material spreading into the brain from the meninges, which are rich in B cells adjacent to the areas of brain damage,’ Lisak said. Wayne State University
Blood test for Alzheimer’s gaining ground
, /in E-News /by 3wmediaThe possibility of an inexpensive, convenient test for Alzheimer’s disease has been on the horizon for several years, but previous research leads have been hard to duplicate.
In a study, scientists have taken a step toward developing a blood test for Alzheimer’s, finding a group of markers that hold up in statistical analyses in three independent groups of patients.
‘Reliability and failure to replicate initial results have been the biggest challenge in this field,’ says lead author William Hu, MD, PhD, assistant professor of neurology at Emory University School of Medicine. ‘We demonstrate here that it is possible to show consistent findings.’
Hu and his collaborators at the University of Pennsylvania and Washington University, St. Louis, measured the levels of 190 proteins in the blood of 600 study participants at those institutions. Study participants included healthy volunteers and those who had been diagnosed with Alzheimer’s disease or mild cognitive impairment (MCI). MCI, often considered a harbinger for Alzheimer’s disease, causes a slight but measurable decline in cognitive abilities.
A subset of the 190 protein levels (17) were significantly different in people with MCI or Alzheimer’s. When those markers were checked against data from 566 people participating in the multicenter Alzheimer’s Disease Neuroimaging Initiative, only four markers remained: apolipoprotein E, B-type natriuretic peptide, C-reactive protein and pancreatic polypeptide.
Changes in levels of these four proteins in blood also correlated with measurements from the same patients of the levels of proteins [beta-amyloid] in cerebrospinal fluid that previously have been connected with Alzheimer’s. The analysis grouped together people with MCI, who are at high risk of developing Alzheimer’s, and full Alzheimer’s.
‘We were looking for a sensitive signal,’ says Hu. ‘MCI has been hypothesised to be an early phase of AD, and sensitive markers that capture the physiological changes in both MCI and AD would be most helpful clinically.’
‘The specificity of this panel still needs to be determined, since only a small number of patients with non-AD dementias were included,’ Hu says. ‘In addition, the differing proportions of patients with MCI in each group make it more difficult to identify MCI- or AD-specific changes.’
Neurologists currently diagnose Alzheimer’s disease based mainly on clinical symptoms. Additional information can come from PET brain imaging, which tends to be expensive, or analysis of a spinal tap, which can be painful.
‘Though a blood test to identify underlying Alzheimer’s disease is not quite ready for prime time given today’s technology, we now have identified ways to make sure that a test will be reliable,’ says Hu. ‘In the meantime, the combination of a clinical exam and cerebrospinal fluid analysis remains the best tool for diagnosis in someone with mild memory or cognitive troubles.’ EurekAlert
Low oxygen levels may decrease life-saving protein in spinal muscular atrophy
, /in E-News /by 3wmediaInvestigators at Nationwide Children’s Hospital may have discovered a biological explanation for why low levels of oxygen advance spinal muscular atrophy (SMA) symptoms and why breathing treatments help SMA patients live longer.
SMA is a progressive neurodegenerative disease that causes muscle damage and weakness leading to death. Respiratory support is one of the most common treatment options for severe SMA patients since respiratory deficiencies increase as the disease progresses. Clinicians have found that successful oxygen support can allow patients with severe SMA to live longer. However, the biological relationship between SMA symptoms and low oxygen levels isn’t clear.
To better understand this relationship, investigators at Nationwide Children’s Hospital examined gene expression within a mouse model of severe SMA. ‘We questioned whether low levels of oxygen linked to biological stress is a component of SMA disease progression and whether these low oxygen levels could influence how the SMN2 gene is spliced,’ says Dawn Chandler, PhD, principal investigator in the Center for Childhood Cancer and Blood Diseases at The Research Institute at Nationwide Children’s Hospital.
SMA is caused by mutation or deletion of the SMN1 gene that leads to reduced levels of the survival motor neuron protein. Although a duplicate SMN gene exists in humans, SMN2, it only produces low levels of functional protein. This is caused by a splicing error in SMN2 in which exon 7 is predominantly skipped, lowering the amount of template used for protein construction.
Mouse models of severe SMA have shown changes in how genes are differentially spliced and expressed as the disease progresses, especially near end-stages. ‘One gene that undergoes extreme alteration is Hif3alpha,’ says Dr. Chandler. ‘This is a stress gene that responds to changes in available oxygen in the cellular environment, specifically to decreases in oxygen. This gave us a clue that low levels of oxygen might influence how the SMN2 gene is spliced.’
Upon examining mouse models of severe SMA exposed to low oxygen levels, Dr. Chandler’s team found that SMN2 exon 7 skipping increased within skeletal muscles. When the mice were treated with higher oxygen levels, exon 7 was included more often and the mice showed signs of improved motor function.
‘These data correspond with the improvements seen in SMA patients who undergo oxygen treatment,’ says Dr. Chandler. ‘Our findings suggest that respiratory assistance is beneficial in part because it helps prevent periods of low oxygenation that would otherwise increase SMN2 exon 7 skipping and reduce SMN levels.’
Dr. Chandler says daytime indicators that reveal when an SMA patient is experiencing low oxygen levels during sleep may serve as a measure to include SMA patients in earlier respiratory support and therefore improve quality of life or survival. Nationwide Children’s Hospital
Researchers uncover gender differences in the effects of long-term alcoholism
, /in E-News /by 3wmediaResearchers from Boston University School of Medicine (BUSM) and Veterans Affairs (VA) Boston Healthcare System have demonstrated that the effects on white matter brain volume from long-term alcohol abuse are different for men and women. The study also suggests that with abstinence, women recover their white matter brain volume more quickly than men.
The study was led by Susan Mosher Ruiz, PhD, postdoctoral research scientist in the Laboratory for Neuropsychology at BUSM and research scientist at the VA Boston Healthcare System, and Marlene Oscar Berman, PhD, professor of psychiatry, neurology and anatomy and neurobiology at BUSM and research career scientist at the VA Boston Healthcare System.
In previous research, alcoholism has been associated with white matter pathology. White matter forms the connections between neurons, allowing communication between different areas of the brain. While previous neuroimaging studies have shown an association between alcoholism and white matter reduction, this study furthered the understanding of this effect by examining gender differences and utilising a novel region-of-interest approach.
The research team employed structural magnetic resonance imaging (MRI) to determine the effects of drinking history and gender on white matter volume. They examined brain images from 42 abstinent alcoholic men and women who drank heavily for more than five years and 42 non-alcoholic control men and women. Looking at the correlation between years of alcohol abuse and white matter volume, the researchers found that a greater number of years of alcohol abuse was associated with smaller white matter volumes in the abstinent alcoholic men and women. In the men, the decrease was observed in the corpus callosum while in women, this effect was observed in cortical white matter regions.
‘We believe that many of the cognitive and emotional deficits observed in people with chronic alcoholism, including memory problems and flat affect, are related to disconnections that result from a loss of white matter,’ said Mosher Ruiz.
The researchers also examined if the average number of drinks consumed per day was associated with reduced white matter volume. They found that the number of daily drinks did have a strong impact on alcoholic women, and the volume loss was one and a half to two percent for each additional daily drink. Additionally, there was an eight to 10 percent increase in the size of the brain ventricles, which are areas filled with cerebrospinal fluid (CSF) that play a protective role in the brain. When white matter dies, CSF produced in the ventricles fills the ventricular space.
Recovery of white matter brain volume also was examined. They found that, in men, the corpus callosum recovered at a rate of one percent per year for each additional year of abstinence. For people who abstained less than a year, the researchers found evidence of increased white matter volume and decreased ventricular volume in women, but not at all in men. However, for people in recovery for more than a year, those signs of recovery disappeared in women and became apparent in men.
‘These findings preliminarily suggest that restoration and recovery of the brain’s white matter among alcoholics occurs later in abstinence for men than for women,’ said Mosher Ruiz. ‘We hope that additional research in this area can help lead to improved treatment methods that include educating both alcoholic men and women about the harmful effects of excessive drinking and the potential for recovery with sustained abstinence.’ Boston University Medical Center
Enzymes implicated in disease processes attack one another instead of harming body proteins
, /in E-News /by 3wmediaResearchers for the first time have shown that members of a family of enzymes known as cathepsins – which are implicated in many disease processes – may attack one another instead of the bodily proteins they normally degrade. Dubbed ‘cathepsin cannibalism,’ the phenomenon may help explain problems with drugs that have been developed to inhibit the effects of these powerful proteases.
Cathepsins are involved in disease processes as varied as cancer metastasis, atherosclerosis, cardiovascular disease, osteoporosis and arthritis. Because cathepsins have harmful effects on critical proteins such as collagen and elastin, pharmaceutical companies have been developing drugs to inhibit activity of the enzymes, but so far these compounds have had too many side effects to be useful and have failed clinical trials.
Using a combination of modelling and experiments, researchers from the Georgia Institute of Technology and Emory University have shown that one type of cathepsin preferentially attacks another, reducing the enzyme’s degradation of collagen. The work could affect not only the development of drugs to inhibit cathepsin activity, but could also lead to a better understanding of how the enzymes work together.
‘These findings provide a new way of thinking about how these proteases are working with and against each other to remodel tissue – or fight against each other,’ said Manu Platt, an assistant professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. ‘There has been an assumption that these cathepsins have been inert in relationship to one another, when in actuality they have been attacking one another. We think this may have broader implications for other classes of proteases.’
Platt and student Zachary Barry made their discovery accidentally while investigating the effects of cathepsin K and cathepsin S – two of the 11-member cathepsin family. Cathepsin K degrades both collagen and elastin, and is one of the most powerful proteases. Cathepsin S degrades elastin, and does not strongly attack collagen.
When the researchers combined the two cathepsins and allowed them to attack samples of elastin, they expected to see increased degradation of the protein. What they saw, however, was not much more damage than cathepsin K did by itself.
Platt at first believed the experiment was flawed, and asked Barry – an undergraduate student in his lab who specialises in modelling – to examine what possible conditions could account for the experimental result. Barry’s modelling suggested that effects observed could occur if cathepsin S were degrading cathepsin K instead of attacking the elastin – a protein essential in arteries and the cardiovascular system.
That theoretical result led to additional experiments in which the researchers measured a direct correlation between an increase in the amount of cathepsin S added to the experiment and a reduction in the degradation of collagen. By increasing the amount of cathepsin S ten-fold over the amount used in the original experiment, Platt and Barry were able to completely block the activity of cathepsin K, preventing damage to the collagen sample.
‘We saw that the cathepsin K was going away much faster when there was cathepsin S present than when it was by itself,’ said Platt, who is also a Georgia Cancer Coalition Distinguished Scholar and a Fellow of the Keystone Symposia on Molecular and Cellular Biology. ‘We kept increasing the amount of cathepsin S until the collagen was not affected at all because all of the cathepsin K was eaten by the cathepsin S.’
The researchers used a variety of tests to determine the amount of each enzyme, including fluorogenic substrate analysis, Western blotting and multiplex cathepsin zymography – a sensitive technique developed in the Platt laboratory.
Beyond demonstrating for the first time that cathepsins can attack one another, the research also shows the complexity of the body’s enzyme system – and may suggest why drugs designed to inhibit cathepsins haven’t worked as intended.
‘The effect of the cathepsins on one another complicates the system,’ said Platt. ‘If you are targeting this system pharmaceutically, you may not have the types or quantities of cathepsins that you expect, which could cause off- Georgia Institute of Technology Research News
Researchers at The Children’s Hospital of Philadelphia identify new gene in Cornelia deLange syndrome
, /in E-News /by 3wmediaGenetics researchers have identified a key gene that, when mutated, causes the rare multisystem disorder Cornelia deLange syndrome (CdLS). By revealing how mutations in the HDAC8 gene disrupt the biology of proteins that control both gene expression and cell division, the research sheds light on this disease, which causes intellectual disability, limb deformations and other disabilities resulting from impairments in early development.
‘As we better understand how CdLS operates at the level of cell biology, we will be better able to define strategies for devising treatments for CdLS, and possibly for related disorders,’ said study leader Matthew A. Deardorff, M.D., Ph.D., a pediatric genetics clinician and scientist at The Children’s Hospital of Philadelphia. Deardorff also is in the Perelman School of Medicine at the University of Pennsylvania.
The current findings add to previous discoveries by researchers at The Children’s Hospital of Philadelphia. A group led by Ian Krantz, M.D., and Laird Jackson, M.D., announced in 2004 that mutations in the NIPBL gene are the primary cause of CdLS, accounting for roughly 60 percent of the ‘classical’ cases of the disease. In 2007, Deardorff joined them to describe mutations in two additional genes, SMC1A and SMC3. First described in 1933, CdLS affects an estimated 1 in 10,000 children.
The CdLS research team at Children’s Hospital has focused on the cohesin complex, a group of proteins that form a bracelet-like structure that encircles pairs of chromosomes, called sister chromatids. ‘Cohesin has two roles,’ said Deardorff. ‘It keeps sister chromatids together during cell division, and it allows normal transcription—the transmission of information from DNA to RNA.’
Deardorff added that mutations that perturb normal cohesin function can interfere with normal human development. Such is the case in CdLS, which exemplifies a newly recognised class of diseases called cohesinopathies.
In the current study, the scientists investigated both acetylation—how an acetyl molecule is attached to part of the cohesin complex—and deactylation, the removal of that molecule. Normally, deactylation helps recycle cohesin to make it available during successive rounds of cell division. The study team found that mutations in the HDAC8 gene threw off normal cellular recycling of cohesin.
Mutations in the gene cause loss of HDAC8 protein activity, and consequently decrease the amount of ‘recharged’ cohesin available to properly regulate gene transcription. This, in turn, the researchers suggest, impairs normal embryonic development and gives rise to CdLS.
The researchers showed in cell cultures that mutations in HDAC8 lead to a decrease in cohesin binding to genes, similar to that seen for cells deficient in the NIPBL gene. They also identified HDAC8 mutations in approximately 5 percent of patients with CdLS.
Because mothers of children with CdLS may carry mutations in the HDAC8 gene, identifying these mutations will be very useful in accurately counseling families of their recurrence risk—the likelihood of having a subsequent child with CdLS.
Furthermore, added Deardorff, by providing biological details of the underlying defect in CdLS, the current research suggests future approaches to treating the genetic disease. ‘By concentrating downstream on the biological pathway in the cohesin cycle rather than focusing on the defective gene, we may be able to eventually screen for small-molecule drugs that could be used to intervene in CdLS.’ Children’s Hospital of Philadelphia
Metabolic MAGIC
, /in E-News /by 3wmediaResearchers have identified 38 new genetic regions that are associated with glucose and insulin levels in the blood. This brings the total number of genetic regions associated with glucose and insulin levels to 53, over half of which are associated with type 2 diabetes.
The researchers used a technology that is 100 times more powerful than previous techniques used to follow-up on genome-wide association results. This technology, Metabochip, was designed as a cost-effective way to find and map genomic regions for a range of cardiovascular and metabolic characteristics on a large scale. Previous approaches were not cost effective and tested only 30-40 DNA sequence variations, but this chip allowed researchers to look at up to 200,000 DNA sequence variations for many different traits at one time. The team hoped to find new variants influencing blood glucose and insulin traits and to identify pathways involved in the regulation of insulin and glucose levels.
‘We wanted to use this improved Metabochip technology to see whether we could find additional genomic associations that may have been previously missed,’ says Dr Claudia Langenberg, co-lead author from the Medical Research Council Epidemiology Unit, Cambridge. ‘Our earlier work identified 23 genetic regions associated with blood glucose levels, highlighting important biological pathways involved in the regulation of glucose. At that stage, and before the design of the Metabochip, we were still limited by our capacity to quickly follow-up and afford parallel genotyping of promising, but unconfirmed genetic regions associated with glucose levels in many different studies across the world.’
The team combined data from new samples typed on the Metabochip with data from a previous study to discover genetic regions associated with blood glucose and insulin levels. They identified 38 previously unknown regions for three different quantitative traits associated with blood glucose levels; fasting glucose concentrations, fasting insulin concentrations and post-challenge glucose concentrations.
.’ Further analysis such as genetic mapping or ‘fine-mapping’ and functional analysis will expand and improve our understanding of the control of glucose and insulin levels in healthy persons and what goes wrong in type 2 diabetes patients. ‘
…’Our research is beginning to allow us to look at the overlap between genomic regions that influence insulin levels and other metabolic traits,’ says Dr Inga Prokopenko, co-lead author from the University of Oxford. ‘We observed some overlap between the regions we identified and genetic regions associated with abdominal obesity and various lipid levels, which are a hallmark of insulin resistance. We hope that these studies will help to find gene networks with potential key modifiers for important metabolic processes and related diseases, such as type 2 diabetes.’
The team also found many more, less significant, genetic regions that may be associated with blood glucose and insulin levels but currently don’t have the available data to definitively establish them as genome-wide significant. This supports previous evidence that there is a long tail of many other genetic regions that add up to quite small genetic effects but may increase the risk of such diseases as diabetes. Collectively, these less significant associations may represent important blood glucose and insulin level associations.
‘In addition to these top signals there is statistical evidence that many other regions that appear to be biologically plausible also influence these traits, but what’s limiting is that we don’t have large enough sample sizes to have the power to validate them,’ explains Dr Inês Barroso, co-lead author from the Wellcome Trust Sanger Institute. ‘Nevertheless, studying these functionally would be extremely beneficial if we want to fully understand the biology of blood glucose levels and the origin of diabetes.’
‘What we’ve found in this study is a number of genomic regions that influence blood glucose and insulin traits. Further analysis such as genetic mapping or ‘fine-mapping’ and functional analysis will expand and improve our understanding of the control of glucose and insulin levels in healthy persons and what goes wrong in type 2 diabetes patients.’ Wellcome Trust Sanger Institute
New marker for identifying precursors to insulin-producing cells in pancreas
, /in E-News /by 3wmediaFor the millions of people world-wide with type 1 diabetes who cannot produce sufficient insulin, the potential to transplant insulin-producing cells could offer hope for a long-term cure. The discovery of a marker to help identify and isolate stem cells that can develop into insulin-producing cells in the pancreas would be a critical step forward.
Pancreatic stem cells, the precursors of insulin-producing cells, have not yet been identified in humans or animals, and there is much debate about where they may reside. Ivka Afrikanova, Ayse Kayali, Ana Lopez, and Alberto Hayek, University of California, San Diego, CA, have identified a biochemical marker—stage-specific embryonic antigen 4 (SSEA4)—that they propose can be used to identify and purify human pancreatic stem cells. The article ‘Is Stage-Specific Embryonic Antigen 4 a Marker for Human Ductal Stem/Progenitor Cells’ reports that when grown in culture with high levels of glucose and B27, these SSEA4+ stem cells can differentiate into insulin-producing pancreatic cells. EurekAlert
Research identifies mechanism responsible for eye movement disorder
, /in E-News /by 3wmediaA research team from King’s College London and the University of Exeter Medical School has identified how a genetic mutation acts during the development of nerves responsible for controlling eye muscles, resulting in movement disorders such as Duane Syndrome, a form of squint.
The findings could provide the key to reversing the condition and unlocking the causes of movement disorders in other parts of the body.
As nerves develop in the womb they respond to signals that tell them in which direction to grow. Some signals encourage them to grow to a particular part of the body, while other signals tell them to avoid certain areas.
When the system works as it should, the right type of nerve grows to the appropriate part of the body.
The surface of growing nerves includes identification receptors that respond to signals from secreted proteins. The protein mutated in Duane Syndrome acts as a switch that weighs up incoming signals from the receptors – in this way the nerve knows whether it must grow towards a part of the body or be repulsed away.
In conditions such as Duane Syndrome, the signalling breaks down and the nerve cells are unable to distinguish between a signal of attraction or repulsion. As a result, the nerves that control eye movements grow to the wrong muscles causing limited or complete loss of eye movement. If not corrected surgically, this can lead to partial blindness in later life.
This recent research has provided new insights into how this ‘switch signal’ system works and how it has failed in cases of Duane Syndrome, causing the ‘wiring up’ of the wrong muscle or ‘overshooting’ of nerve development past the correct muscle.
The findings are likely to lead to further study which will identify how the ‘switch signal’ mechanism could be harnessed to selectively change nerve cell development behaviour, how the protein could be targeted to encourage damaged cells to re-grow, and how the ‘switch’ could be manipulated to reverse damage. EurekAlert