Category Archives: Genetic medicine

Using patient-derived stem cells known as induced pluripotent stem cells (iPSC) to study the genetic lung/liver disease called alpha-1 antitrypsin (AAT) deficiency, researchers have for the first time created a disease signature that may help explain how abnormal protein leads to liver disease.

The study, which appears in Stem Cell Reports, also found that liver cells derived from AAT deficient iPSCs are more sensitive to drugs that cause liver toxicity than liver cells derived from normal iPSCs. This finding may ultimately lead to new treatments for the condition.

IPSC's are derived from the donated skin or blood cells of adults and, with the reactivation of four genes, are reprogrammed back to an embryonic stem cell-like state. Like embryonic stem cells, iPSC can be differentiated toward any cell type in the body, but they do not require the use of embryos. Alpha-1 antitrypsin deficiency is a common genetic cause of both liver and lung disease affecting an estimated 3.4 million people worldwide.

Researchers from the Center for Regenerative Medicine (CReM) at Boston University and Boston Medical Center (BMC) worked for several years in collaboration with Dr. Paul Gadue and his group from Children's Hospital of Philadelphia to create iPSC from patients with and without AAT deficiency. They then exposed these cells to certain growth factors in-vitro to cause them to turn into liver-like cells, in a process that mimics embryonic development. Then the researchers studied these "iPSC-hepatic cells" and found the diseased cells secrete AAT protein more slowly than normal cells. This finding demonstrated that the iPSC model recapitulates a critical aspect of the disease as it occurs in patients. AAT deficiency is caused by a mutation of a single DNA base. Correcting this single base back to the normal sequence fixed the abnormal secretion.

"We found that these corrected cells had a normal secretion kinetic when compared with their diseased, parental cells that are otherwise genetically identical except for this single DNA base," explained lead author Andrew A. Wilson, MD, assistant professor of medicine at Boston University School of Medicine and Director of the Alpha-1 Center at Bu and BMC.

They also found the diseased (AAT deficient) iPSC-liver cells were more sensitive to certain drugs (experience increased toxicity) than those from normal individuals. "This is important because it suggests that the livers of actual patients with this disease might be more sensitive in the same way," said Wilson, who is also a physician in pulmonary, critical care and allergy medicine at BMC.

According to Wilson, while some patients are often advised by their physicians to avoid these types of drugs, these recommendations are not based on solid scientific evidence. "This approach might now be used to generate that sort of evidence to guide clinical decisions," he added.

The researchers believe that studies using patient-derived stem cells will allow them to better understand how patients with AAT deficiency develop liver disease. "We hope that the insights we gain from these studies will result in the discovery of new potential treatments for affected patients in the near future," said Wilson.

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The above story is based on materials provided by Boston University Medical Center. Note: Materials may be edited for content and length.

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iPSC model helps to better understand genetic lung/liver disease

The order in which genetic mutations are acquired determines how an individual cancer behaves, according to research from the University of Cambridge, published today in the New England Journal of Medicine.

Most of the genetic mutations that cause cancer result from environmental 'damage' (for example, through smoking or as a result of over-exposure to sunlight) or from spontaneous errors as cells divide. In a study published today, researchers at the Department of Haematology, the Cambridge Institute for Medical Research and the Wellcome Trust/Medical Research Council Stem Cell Institute show for the first time that the order in which such mutations occur can have an impact on disease severity and response to therapy.

The researchers examined genetically distinct single stem cells taken from patients with myeloproliferative neoplasms (MPNs), a group of bone marrow disorders that are characterised by the over-production of mature blood cells together with an increased risk of both blood clots and leukaemia. These disorders are identified at a much earlier stage than most cancers because the increased number of blood cells is readily detectable in blood counts taken during routine clinical check-ups for completely different problems.

Approximately one in ten of MPN patients carry mutations in both the JAK2 gene and the TET2 gene. By studying these individuals, the research team was able to determine which mutation came first and to study the effect of mutation order on the behaviour of single blood stem cells.

Using samples collected primarily from patients attending Addenbrooke's Hospital, part of the Cambridge University Hospitals, researchers showed that patients who acquire mutations in JAK2 prior to those in TET2 display aberrant blood counts over a decade earlier, are more likely to develop a more severe red blood cell disease subtype, are more likely to suffer a blood clot, and their cells respond differently to drugs that inhibit JAK2.

Dr David Kent, one of the study's lead authors, says: "This surprising finding could help us offer more accurate prognoses to MPN patients based on their mutation order and tailor potential therapies towards them. For example, our results predict that targeted JAK2 therapy would be more effective in patients with one mutation order but not the other."

Professor Tony Green, who led the study, adds: "This is the first time that mutation order has been shown to affect any cancer, and it is likely that this phenomenon occurs in many types of malignancy. These results show how study of the MPNs provides unparalleled access to the earliest stages of tumour development (inaccessible in other cancers, which usually cannot be detected until many mutations have accumulated). This should give us powerful insights into the origins of cancer."

Work in the Green Lab is supported in party by Leukaemia and Lymphoma Research and Cancer Research UK.

Dr Matt Kaiser, Head of Research at Leukaemia & Lymphoma Research, said: "We are becoming more and more aware that a cancer's genetic signature can vary from patient to patient, and we are becoming better at personalising treatment to match this. The discovery that the order in which genetic errors occur can have such a big impact on cancer progression adds an important extra layer of complexity that will help tailor treatment for patients with MPNs. The technology to do this sort of study has been available only recently and it shows once again how pioneering research into blood cancers can reveal fundamental insights into cancer in general."

Dr ine McCarthy, Science Information Officer at Cancer Research UK, says: "The methods used in this pioneering research could help improve our understanding of how cancer cells develop mutations and when they do so. This interesting study suggests that the order in which genetic faults appear can affect how patients respond to different drugs - this insight could help doctors personalise treatment to make it more effective for each patient."

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Order matters: Sequence of genetic mutations determines how cancer behaves

TWO thirds of adult cancer cases were the result of genetic bad luck rather than unhealthy living, according to groundbreaking new research from the US.

Johns Hopkins University School of Medicine scientist Dr Bert Vogelstein said random mutations in DNA were the most common cause of cancer, with the rest caused by environment or inherited genes.

But he warned the finding should not be taken as a licence to drink or smoke to excess.

"This study shows that you can add to your risk of getting cancers by smoking or other poor lifestyle factors," Dr Vogelstein said.

"However, many forms of cancer are due largely to the bad luck of acquiring a mutation in a cancer driver gene regardless of lifestyle and heredity factors."

Researchers compared the number of times organ stem cells divided with the risk of cancer in the tissues.

Those with the most divisions were generally more prone to tumours.

They found 22 of 31 cancer types were caused by random cell mutations - really just genetic misfortune which scientists could not otherwise explain.

The remainder, including smoking-related lung cancer and skin cancer, were related to heredity and environmental factors like exposure to harmful chemicals.

"Cancer-free longevity in people exposed to cancer-causing agents, such as tobacco, is often attributed to their 'good genes', but the truth is that most of them simply had good luck," Dr Vogelstein said.

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Two thirds of cancer cases were genetic of bad luck: study

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Newswise For a small percentage of cancer patients, treatment aimed at curing the disease leads to a form of leukemia with a poor prognosis. Conventional thinking goes that chemotherapy and radiation therapy induce a barrage of damaging genetic mutations that kill cancer cells yet inadvertently spur the development of acute myeloid leukemia (AML), a blood cancer.

But a new study at Washington University School of Medicine in St. Louis challenges the view that cancer treatment in itself is a direct cause of what is known as therapy-related AML.

Rather, the research suggests, mutations in a well-known cancer gene, P53, can accumulate in blood stem cells as a person ages, years before a cancer diagnosis. If and when cancer develops, these mutated cells are more resistant to treatment and multiply at an accelerated pace after exposure to chemotherapy or radiation therapy, which then can lead to AML, the study indicates.

The teams findings, reported Dec. 8 in the journal Nature, open new avenues for research to predict which patients are at risk of developing therapy-related AML and to find ways to prevent it.

About 18,000 cases of AML are diagnosed in the United States each year, with about 2,000 triggered by previous exposure to chemotherapy or radiation therapy. Therapy-related AML is almost always fatal, even with aggressive treatment.

Until now, weve really understood very little about therapy-related AML and why it is so difficult to treat, said corresponding author Daniel Link, MD, a hematologist/oncologist at Siteman Cancer Center at Washington University and Barnes-Jewish Hospital. This gives us some important clues for further studies aimed at treatment and prevention.

The researchers initially sequenced the genomes of 22 cases of therapy-related AML, finding that those patients had similar numbers and types of genetic mutations in their leukemia cells as other patients who developed AML without exposure to chemotherapy or radiation therapy, an indication that cancer treatment does not cause widespread DNA damage.

This is contrary to what physicians and scientists have long accepted as fact, said senior author Richard K. Wilson, PhD, director of The Genome Institute at Washington University. It led us to consider a novel hypothesis: P53 mutations accumulate randomly as part of the aging process and are present in blood stem cells long before a patient is diagnosed with therapy-related AML.

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Genetic Errors Linked to Aging Underlie Leukemia That Develops After Cancer Treatment

Health and Medicine for Seniors

Many Elderly Found with Puzzling Mutations Linked to Leukemia, Lymphoma

Researchers find no connection with blood cancer that seldom strikes senior citizens

Oct. 22, 2014 A surprisingly large percentage 5 percent of senior citizens over age 70 have been found to have genetic mutations linked to leukemia and lymphoma in their blood cells. The vast majority won't get blood cancer, however, as the incidence of these cancers is less than 0.1 percent among the elderly, according to the researchers at Washington University School of Medicine in St. Louis.

Mutations in the body's cells randomly accumulate as part of the aging process, and most are harmless. For some people, genetic changes in blood cells can develop in genes that play roles in initiating leukemia and lymphoma even though such people don't have the blood cancers, the scientists reported Oct. 19 in Nature Medicine.

"But it's quite striking how many people over age 70 have these mutations," said senior author Li Ding, PhD, of The Genome Institute at Washington University. "The power of this study lies in the large number of people we screened. We don't yet know whether having one of these mutations causes a higher than normal risk of developing blood cancers. More research would be required to better understand that risk."

The researchers analyzed blood samples from 3,000 people enrolled in The Cancer Genome Atlas project, a massive endeavor funded by the National Cancer Institute and the National Human Genome Research Institute at the National Institutes of Health (NIH). The effort involves cataloguing the genetic errors involved in more than 20 types of cancers.

The patients whose blood was analyzed for the current study had been diagnosed with cancer but were not known to have leukemia, lymphoma or a blood disease.

They ranged in age from 10 to 90 at the time of diagnosis and had donated blood and tumor samples before starting cancer treatment. Therefore, any mutations identified by the researchers would not have been associated with chemotherapy or radiation therapy, which can damage cells' DNA.

The researchers, including Genome Institute scientists Mingchao Xie, Charles Lu, PhD, and Jiayin Wang, PhD, zeroed in on mutations that were present in the blood but not in tumor samples from the same patients. Such genetic changes in the blood would be associated with changes in stem cells that develop into blood cells, but not to the same patient's cancer.

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Many Elderly Found with Puzzling Mutations Linked to Leukemia, Lymphoma

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Newswise At least 2 percent of people over age 40 and 5 percent of people over 70 have mutations linked to leukemia and lymphoma in their blood cells, according to new research at Washington University School of Medicine in St. Louis.

Mutations in the bodys cells randomly accumulate as part of the aging process, and most are harmless. For some people, genetic changes in blood cells can develop in genes that play roles in initiating leukemia and lymphoma even though such people dont have the blood cancers, the scientists report Oct. 19 in Nature Medicine.

The findings, based on blood samples from nearly 3,000 patients, dont mean that people with these genetic mutations are destined to develop a blood cancer. In fact, the vast majority of them wont as the incidence of blood cancers such as leukemia or lymphoma is less than 0.1 percent among the elderly.

But its quite striking how many people over age 70 have these mutations, said senior author Li Ding, PhD, of The Genome Institute at Washington University. The power of this study lies in the large number of people we screened. We dont yet know whether having one of these mutations causes a higher than normal risk of developing blood cancers. More research would be required to better understand that risk.

The researchers analyzed blood samples from people enrolled in The Cancer Genome Atlas project, a massive endeavor funded by the National Cancer Institute and the National Human Genome Research Institute at the National Institutes of Health (NIH). The effort involves cataloguing the genetic errors involved in more than 20 types of cancers.

The patients whose blood was analyzed for the current study had been diagnosed with cancer but were not known to have leukemia, lymphoma or a blood disease. They ranged in age from 10 to 90 at the time of diagnosis and had donated blood and tumor samples before starting cancer treatment. Therefore, any mutations identified by the researchers would not have been associated with chemotherapy or radiation therapy, which can damage cells DNA.

The researchers, including Genome Institute scientists Mingchao Xie, Charles Lu, PhD, and Jiayin Wang, PhD, zeroed in on mutations that were present in the blood but not in tumor samples from the same patients. Such genetic changes in the blood would be associated with changes in stem cells that develop into blood cells, but not to the same patients cancer.

They looked closely at 556 known cancer genes. In 341 patients ages 40-49, fewer than 1 percent had mutations in 19 leukemia- or lymphoma-related genes. But among 475 people ages 70-79, over 5 percent did. And over 6 percent of the 132 people ages 80-89 had mutations in these genes.

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Many Older People Have Mutations Linked to Leukemia, Lymphoma in Their Blood Cells

PUBLIC RELEASE DATE:

24-Sep-2014

Contact: Krista Conger kristac@stanford.edu 650-725-5371 Stanford University Medical Center @sumedicine

Over 500 million people worldwide carry a genetic mutation that disables a common metabolic protein called ALDH2. The mutation, which predominantly occurs in people of East Asian descent, leads to an increased risk of heart disease and poorer outcomes after a heart attack. It also causes facial flushing when carriers drink alcohol.

Now researchers at the Stanford University School of Medicine have learned for the first time specifically how the mutation affects heart health. They did so by comparing heart muscle cells made from induced pluripotent stem cells, or iPS cells, from people with the mutation versus those without the mutation. IPS cells are created in the laboratory from specialized adult cells like skin. They are "pluripotent," meaning they can be coaxed to become any cell in the body.

"This study is one of the first to show that we can use iPS cells to study ethnic-specific differences among populations," said Joseph Wu, MD, PhD, director of the Stanford Cardiovascular Institute and professor of cardiovascular medicine and of radiology.

"These findings may help us discover new therapeutic paths for heart disease for carriers of this mutation," said Wu. "In the future, I believe we will have banks of iPS cells generated from many different ethnic groups. Drug companies or clinicians can then compare how members of different ethnic groups respond to drugs or diseases, or study how one group might differ from another, or tailor specific drugs to fit particular groups."

The findings are described in a paper that will be published Sept. 24 in Science Translational Medicine. Wu and Daria Mochly-Rosen, PhD, professor of chemical and systems biology, are co-senior authors of the paper, and postdoctoral scholar Antje Ebert, PhD, is the lead author.

ALDH2 and cell death

The study showed that the ALDH2 mutation affects heart health by controlling the survival decisions cells make during times of stress. It is the first time ALDH2, which is involved in many common metabolic processes in cells of all types, has been shown to play a role in cell survival. In particular, ALDH2 activity, or the lack of it, influences whether a cell enters a state of programmed cell death called apoptosis in response to stressful growing conditions.

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Stanford scientists use stem cells to learn how common mutation in Asians affects heart health

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Newswise LOS ANGELES (July 24, 2014) Like other major research centers studying genetic causes of uncommon and poorly understood nervous system disorders, Cedars-Sinai maintains a growing collection of DNA and tissue samples donated by patients.

What sets Cedars-Sinais Repository of Neurologic and Neuromuscular Disorders apart is its special emphasis on tissue collection part of its focus on creating future individualized treatments for patients.

One of our major priorities is to advance the concept of personalized medicine. The idea is to take DNA from a patient, look at the cells derived from their tissue, and try to understand why this particular person got this disease. Then we can determine which therapy or therapies would work for each individual by first testing their cells. Many centers look at the genetics; ours is dedicated to looking at the genetics and the patients tissues, combining the two to understand how to treat the disease, said Robert H. Baloh, MD, PhD, director of neuromuscular medicine in the Department of Neurology and director of the ALS Program for research and treatment of amyotrophic lateral sclerosis, or Lou Gehrigs disease.

This individualized treatment approach depends on collaborative efforts among doctors and researchers who treat and study individual diseases and scientists at the Cedars-Sinai Regenerative Medicine Institute, one of a very few hospital-based centers devoted to stem cell research. The teams work together to discover disease-generating molecular and cellular defects, make disease-in-a-dish models and begin to fashion personalized stem cell-based research interventions.

We know that nearly every disease has some genetic component some more than others so we collect DNA for research to identify those genetic elements. But weve also expanded our focus to include the collection of skin and blood samples that can be turned into specialized stem cells. Patients are usually very willing to donate tissue to try and help us understand the causes of their neurologic or neuromuscular disease, said Baloh, a member of the Brain Program at the Regenerative Medicine Institute.

Baloh and colleagues recently showed this approach is feasible, using skin biopsies from patients with ALS. With induced pluripotent stem cells, or iPSCs, they created ALS neurons in a lab dish. Then, inserting molecules made of small stretches of genetic material, they blocked the damaging effects of a defective gene. This provided proof of concept for a new therapeutic strategy an important step in moving research findings into clinical trials.

Baloh, the repositorys principal investigator, has a particular interest in ALS and other neuromuscular disorders, but DNA, tissue and data collection is conducted for Cedars-Sinai neuroscience researchers studying virtually any disease. And its holdings can have widespread influence: Repositories of genetic material enable scientists studying similar diseases at multiple research centers to access patient data in larger quantities than any single site could provide.

We work with many other research institutions across the country to share the samples themselves as well as de-identified information about the patients what disease they have, the severity of their disease, and similar disorder-related details. This improves our ability to find new gene abnormalities, because it cant always be done with just tens or even hundreds of patients. We may need thousands of patients, especially for very rare genetic forms of disease that have very subtle genetic effects. Therefore, we study our own patients in great detail, but we also share our resources more broadly, said Baloh, adding that genetic discoveries often have implications even for patients who dont have genetic forms of disease.

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Tissue Collection Aids Search for Neurologic and Neuromuscular Disease Causes and Cures

PUBLIC RELEASE DATE:

18-Jul-2014

Contact: Charles Casey charles.casey@ucdmc.ucdavis.edu 916-734-9048 University of California - Davis Health System

(SACRAMENTO, Calif.) Researchers from UC Davis School of Medicine and Shriners Hospitals for Children Northern California have identified a group of cells in the brain that they say plays an important role in the abnormal neuron development in Down syndrome. After developing a new model for studying the syndrome using patient-derived stem cells, the scientists also found that applying an inexpensive antibiotic to the cells appears to correct many abnormalities in the interaction between the cells and developing neurons.

The findings, which focused on support cells in the brain called astroglial cells, appear online today in Nature Communications.

"We have developed a human cellular model for studying brain development in Down syndrome that allows us to carry out detailed physiological studies and screen possible new therapies," said Wenbin Deng, associate professor of biochemistry and molecular medicine and principal investigator of the study. "This model is more realistic than traditional animal models because it is derived from a patient's own cells."

Down syndrome is the most common chromosomal cause of mild to moderate intellectual disabilities in the United States, where it occurs in one in every 691 live births. It develops when a person has three copies of the 21st chromosome instead of the normal two. While mouse models have traditionally been used in studying the genetic disorder, Deng said the animal model is inadequate because the human brain is more complicated, and much of that complexity arises from astroglia cells, the star-shaped cells that play an important role in the physical structure of the brain as well as in the transmission of nerve impulses.

"Although neurons are regarded as our 'thinking cells,' the astroglia have an extremely important supportive role," said Deng. "Astroglial function is increasingly recognized as a critical factor in neuronal dysfunction in the brain, and this is the first study to show its importance in Down syndrome."

Creating a unique human cellular model

To investigate the role of astroglia in Down syndrome, the research team took skin cells from individuals with Down syndrome and transformed them into stem cells, which are known as induced pluripotent stem cells (iPSC). The cells possess the same genetic make-up as the donor and an ability to grow into different cell types. Deng and his colleagues next induced the stem cells to develop into separate pure populations of astroglial cells and neurons. This allowed them to systematically analyze factors expressed by the astroglia and then study their effects on neuron development.

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'Support' cells in brain play important role in Down syndrome

PUBLIC RELEASE DATE:

17-Jul-2014

Contact: Jeannette Spalding jeannette.spalding@case.edu 216-368-3004 Case Western Reserve University

The mysterious condition once known as "water on the brain" became just a bit less murky this week thanks to a global research group led in part by a Case Western Reserve researcher. Professor Anthony Wynshaw-Boris, MD, PhD, is the co-principal investigator on a study that illustrates how the domino effect of one genetic error can contribute to excessive cerebrospinal fluid surrounding the brains of mice a disorder known as hydrocephalus. The findings appear online July 17 in the journal Neuron.

Cerebrospinal fluid provides a cushion between the organ and the skull, eliminating waste and performing other functions essential to neurological health. Within the brain there are four spaces or ventricles where cerebrospinal fluid flows. Hydrocephalus can be damaging when excessive cerebrospinal fluid widens spaces between ventricles and creates pressure to brain tissue. In humans, hydrocephalus can cause a host of neurological ailments: impairment of balance and coordination, memory loss, headaches and blurred vision, and even damage to the brain.

"Most of the time, hydrocephalus is caused by some sort of physical blockage of the flow of cerebrospinal fluid, so called obstructive hydrocephalus. We demonstrated instead that malfunction of specific genes the Dishevelleds (Dvl genes) triggered hydrocephalus in our mouse models. These genes regulate the precise placement and alignment of cilia within ependymal cells that move cerebrospinal fluid throughout the brain," said Wynshaw-Boris, MD, PhD, James H. Jewell MD '34 Professor of Genetics and Chair, Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine. "This discovery paves the way for more focused research to determine if similar mechanisms can cause hydrocephalus in humans."

Scientists are still at the most nascent stages of understanding different causes and kinds of hydrocephalus. In some instances, the root sources are genetic; in others, the fluid accumulation is attributed to complications of premature birth. This project illuminates one way in which genetic influences contribute to the condition.

Wynshaw-Boris began this collaborative research while a professor in pediatrics at the Institute for Human Genetics and the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at the University of California at San Francisco (UCSF) before coming to Case Western Reserve in June 2013. For this hydrocephalus project, he joined fellow principal co-investigator, Arturo Alvarez-Buylla, PhD, professor of neurological surgery, and the Heather and Melanie Muss Endowed Chair, Department of Neurological Surgery, UCSF, in conducting research that proved in mice that Dvl genes regulate the placement and polarity of cilia in ependymal cells that line the ventricles of the brain.

A cilium is a slender protuberance projecting from many cells. In the ependymal cells, multiple cilia protrude from each cell as a bundle or patch, which resembles a horse's tail when beating to move cerebrospinal fluid efficiently. Each cilium must be anchored, sized and shaped correctly, properly placed and aligned in relation to other cilia within the same cell, and the alignment of cilia between cells is also necessary so that the cilia beat with precision to achieve proper movement of fluid in the right direction. It is all about excellent organization: the wrong size, shape or angle of rotation of the bundle of cilia will impede the smooth and appropriate directional flow of the cerebrospinal fluid.

The work in mice by Shinya Ohata, PhD, and Jin Nakatani, PhD, co-first authors who worked in the Alvarez-Buylla and Wynshaw-Boris labs, respectively, and their colleagues demonstrated how normal versus Dvl-deficient mice fared in terms of cilia function. They examined cilia from the ependymal cells of normal mice and found the cilia to be well organized and correctly placed within and between ependymal cells. Investigators even viewed in real time through fluorescent imaging the intricacy with which well-orchestrated cilia swayed to move fluid along in a normal fashion.

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International research team discovers genetic dysfunction connected to hydrocephalus