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A recently published study co-authored by University of Kentucky Sanders-Brown Center on Aging researcher Justin Miller, Ph.D., identifies 11 rare candidate variants for Alzheimer’s disease. Researchers found 19 different families in Utah that suffered from Alzheimer’s disease more frequently than what is considered normal.
Miller, an assistant professor in the UK College of Medicine, was a co-first author for the study published in the journal Alzheimer’s & Dementia. The work was started at another university, however, some of the computational work was done after Miller arrived at UK in March.
For the study, genetic sequencing was conducted on two cousins from each of the 19 families. Miller says they then identified genetic variants that were shared between both cousins.
“We then used a series of filtering criteria to identify rare genetic variants that were most likely contributing to the excess Alzheimer’s disease in each family,” he said.
Researchers found 11 rare genetic variants spanning 10 genes, including previously unknown variants in two known Alzheimer’s disease risk genes.
“Identifying people with increased risk for Alzheimer’s disease before they become symptomatic may lead to earlier and more effective interventions,” Miller said. “Additionally, our methodology for analyzing high-risk pedigrees can be used to prioritize rare genetic variants that likely contribute to disease.”
Miller says while this discovery will not immediately impact patient care, they do believe identifying genetic variants associated with the disease is the first step to identifying potential drug targets that can be used to develop therapeutics.
This work was funded by the National Institutes of Health, the Huntsman Cancer Institute, Brigham Young University, University of Utah, National Cancer Institute, BrightFocus Foundation, the National Heart, Lung, and Blood Institute, and was a collaboration with Brigham Young University, the University of Utah, and the Alzheimer’s Disease Genetics Consortium.
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Materials provided by University of Kentucky. Original written by Hillary Smith. Note: Content may be edited for style and length.

In addition to chemical factors, mechanical influences play an important role in the natural growth of human organs such as kidneys, lungs and mammary glands — but also in the development of tumors. Now a research team at the Technical University of Munich (TUM) has investigated the process in detail using organoids, three-dimensional model systems of such organs which are produced in the laboratory.
Organoids are three-dimensional systems modeling various human organs. Grown in the laboratory, they exhibit properties similar to those of actual body tissue. Organoids offer science new opportunities to simulate and investigate the processes of organ growth. These processes could not be observed in the simplified two-dimensional model systems used in the past.
Using mammary gland organoids to analyze the complex interactions of cells with surrounding tissue, scientists at the Technical University of Munich, the Helmholtz Zentrum München and the Ruhr-Universität Bochum have shown, that the growth of the gland tissue in the human breast is explicitly influenced by the mechanical properties of the surrounding collagen network.
Integrated dynamic development process
The organoids grown by the team form branched glandular ducts whose structure and organization very closely resemble that of the human mammary gland. During the growth process the individual organoid branches invade into the surrounding collagen matrix.
“Starting with a single stem cell, in just 14 days these organoids form a complex, branched, three-dimensional structure consisting of several thousand cells. This is absolutely fascinating,” says Andreas Bausch, Professor for Cellular Biophysics at TU Munich and head of the research group.
The research team used temporally resolved microscopy on the growing structures over the course of several days and successfully monitored the dynamic development process in detail. They discovered that the organoid growth is substantially dictated by collective movements of the cells.
By expanding in the direction of movement and then contracting again, the cells generate forces so strong that they deform the surrounding collagen matrix, making it possible for the organoid to independently organize the direction of its own further growth.
Stable collagen ‘cage’
“This is made possible by the mechanical plasticity of the collagen,” says Benedikt Buchmann, lead author of the research team’s study. “When the individual cells move back and forth collectively they produce such tension that the cells of a branch can deform the collagen matrix.”
The overall process results in the formation of a mechanically stable collagen ‘cage’ which ultimately surrounds the growing branch. This collagen cage then controls the further generation of tension, the growth of the branches and the plastic deformation of the matrix.
These findings provide the basis for the use of this model system to investigate more complex processes such as the first steps in metastasis or mutual interaction with other cell types. Intensive current research is now on the way to determine whether this self-organization mechanism also occurs in other organs.
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Materials provided by Technical University of Munich (TUM). Note: Content may be edited for style and length.

Artificial microswimmers have received much attention in recent years. By mimicking microbes which convert their surrounding energy into swimming motions, these particles could soon be exploited for many important applications. Yet before this can happen, researchers must develop methods to better control the trajectories of individual microswimmers in complex environments. In a new study published inEPJ E, Shubhadeep Mandal at the Indian Institute of Technology Guwahati (India), and Marco Mazza at the Max Planck Institute for Dynamics and Self-Organisation in Göttingen (Germany) and Loughborough University (UK), show how this control could be achieved using exotic materials named ‘nematic liquid crystals’ (LCs) — whose viscosity and elasticity can vary depending on the direction of an applied force.

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Just as helicopter traffic reporters use their “bird’s eye view” to route drivers around roadblocks safely, radiation oncologists treating a variety of cancers can use new guidelines developed by a West Virginia University researcher to reduce mistakes in data transfer and more safely treat their patients.
Ramon Alfredo Siochi — the director of medical physics at WVU — led a task group to help ensure the accuracy of data that dictates a cancer patient’s radiation therapy. The measures he and his colleagues recommended in their new report safeguard against medical errors in a treatment that more than half of all cancer patients receive.
“The most common mistake that happens in radiation oncology is the transfer of information from one system to another,” Siochi, the associate chair for the School of Medicine’s Department of Radiation Oncology, said. “This report gives you a good, bird’s-eye view of the way data is moving around in your department.”
“How frequently do these accidents occur? I think one estimate I saw was that three out of every 100 patients might have an error, but it doesn’t necessarily harm them. Now, I don’t know what the incidence rate is of errors that are quote-unquote ‘near misses’ — when an error happens before it hits the patient — but I would imagine it is much higher.
Siochi recently chaired the Task Group of Quality Assurance on External Beam Treatment Data Transfer, a division of the American Association of Physicists in Medicine.
The group was formed in response to news coverage of radiation overdoses caused by faulty data transfer.
“In 2010, it was reported in the New York Times that a patient [in a New York City hospital] was overdosed with radiation because the data somehow didn’t transfer properly from one system to another,” Siochi said. “Long story short, the patient received a lethal dose of radiation to his head that went on for three days undetected. Now, that falls into the general class of many things happening that were not standard practice. But it could have been avoided.”
Radiation therapy is used to treat a variety of cancers, including cancers of the lung, pancreas, prostate, breast, brain and bladder. Depending on a cancer’s type or stage, radiation may cure it, shrink it or stop it from coming back.
But as the complexity of radiation therapy has grown — making it possible to target cancers that would once have been too difficult to treat — so too has the amount of data that goes into treatment machines. With more data comes more opportunity for errors.
When Siochi started practicing radiation oncology physics — in the 1990s — this data evoked a tree-lined residential street more than the six-lane highway it brings to mind today.
“It was very analog,” he said. “We’re talking maybe 20 parameters that you would need to check on a plan, and you would put it all on a paper chart. But I once did a calculation — to do an order of magnitude — and now we’re talking about 100,000 parameters. It’s just impossible for a human to check.”
The group’s report — which earned the approval of AAPM and the Science Council — makes that volume of parameters less overwhelming. It explains how data is transferred among various systems used in radiation therapy, and it suggests ways that medical physicists can test the data’s integrity throughout the process, contributing to safer treatments.
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Materials provided by West Virginia University. Note: Content may be edited for style and length.

A new University of Iowa study suggests that metabolism of plant-based dietary substances by specific gut bacteria, which are lacking in patients with multiple sclerosis (MS), may provide protection against the disease.
The study led by Ashutosh Mangalam, PhD, UI associate professor of pathology, shows that a diet rich in isoflavone, a phytoestrogen or plant-based compound that resembles estrogen, protects against multiple sclerosis-like symptoms in a mouse model of the disease. Importantly, the isoflavone diet was only protective when the mice had gut microbes capable of breaking down the isoflavones. The findings were published July 9 in Science Advances.
“Interestingly, previous human studies have demonstrated that patients with multiple sclerosis lack these bacteria compared to individuals without MS,” Mangalam says. “Our new study provides evidence that the combination of dietary isoflavones and these isoflavone metabolizing gut bacteria may serve as a potential treatment for MS.”
Isoflavones are found in soybeans, peanuts, chickpeas and other legumes. The study also found that mice fed the isoflavone diet have a microbiome that is similar to the microbiome found in healthy people and includes the bacteria which can metabolize isoflavones. Conversely, a diet lacking isoflavones promotes a microbiome in mice which is similar to one observed in patients with MS and lacks beneficial bacteria that can metabolize isoflavone.
Multiple sclerosis is an autoimmune disease of the brain and spinal cord where the immune system attacks the protective coating surrounding nerve fibers. The symptoms of this disease include muscles weakness, balance issues, and problems with vision and thinking. While there are treatments that slow down the disease, there is currently no cure for MS.
Although the exact cause of MS is unknown, a complex interaction between genetic and environmental factors are thought to initiate the disease. Recently, the gut microbiome — the trillions of gut bacteria the live inside human intestines — has emerged as a potential environmental factor that contributes to MS. In prior work, Mangalam and colleagues demonstrated that there are significant differences between the gut microbes of patients with MS and people without MS. Specifically, patients with MS lacked bacteria that are able to metabolize isoflavones. Although role of gut microbiome in human diseases such as MS is being appreciated, the mechanism through which these gut bacteria might influence the disease is poorly understood.
In the current study, Mangalam’s team, including first author Samantha Jensen, a UI graduate student in immunology, found that the bacteria that are lacking in patients with MS are able to suppress inflammation in a mouse model of MS. The team compared the effects of an isoflavone diet and an isoflavone-free diet on disease in the mouse model of MS. They found that the isoflavone diet led to disease protection. However, when the team placed the mice on the isoflavone diet but removed the isoflavone-metabolizing gut bacteria, the isoflavone diet was no longer able to protect against MS-like symptoms. When the bacteria were reintroduced, the protective effect of the isoflavone diet was restored. Furthermore, the team was able to show that a specific isoflavone metabolite called equol, which is produced by the gut bacteria from isoflavone, is also able to provide protection against disease.
“This study suggests that an isoflavone diet may be protective so long as the isoflavone metabolizing gut bacteria are present in the intestines,” say Mangalam, who also is a member of the Iowa Neuroscience institute and Holden Comprehensive Cancer Center.
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Materials provided by University of Iowa Health Care. Original written by Jennifer Brown. Note: Content may be edited for style and length.

Researchers revealed how non-alcoholic fatty liver disease can develop into a life-threatening complication. Their discovery will accelerate the search for therapeutic solutions. The study was led by Helmholtz Zentrum München in collaboration with the Heidelberg University Hospital and the German Center for Diabetes Research.
Non-alcoholic fatty liver disease is the most common liver disorder worldwide and is present in approximately 25 percent of the world’s population. Over 90 percent of obese, 60 percent of diabetic, and up to 20 percent of normal-weight people develop it. A key feature of the condition is the accumulation of fat in the liver. A liver can remain fatty without disturbing normal function; however, fat accumulations may progress into a so-called non-alcoholic steatohepatitis — an aggressive form of the non-alcoholic fatty liver disease combined with inflammation and sometimes fibrosis. Non-alcoholic steatohepatitis can lead to further complications such as liver cirrhosis, primary liver cancer and eventually death.
Liver fibrosis is a strong predictor of long-term mortality in patients with non-alcoholic fatty liver disease. The mechanisms underlying the progression from the comparatively benign fatty liver state to advanced non-alcoholic steatohepatitis and liver fibrosis are incompletely understood. “Understanding the mechanism by which this condition becomes life threatening is key in our quest for the discovery of therapeutic solutions and preventative measures,” said Stephan Herzig.
Loss of identity results in dysfunction
The researchers used comparative genomics to analyze mechanisms that control the development and specialized functions of the most abundant cell type in the liver, the hepatocyte. “Our results demonstrated that during progression to non-alcoholic steatohepatitis, hepatocytes suffer from partial identity loss, they are re-programmed,” explained Anne Loft, first co-author of the article.
The hepatocyte reprogramming is tightly controlled by a network of proteins acting as molecular switches, so-called ‘transcription factors’. Their activity results in the dysfunction of hepatocytes. The network of transcription factors that controls this process also plays a role in fibrosis progression. “These findings are important because they unravel the cellular mechanisms underlying non-alcoholic steatohepatitis. Knowing about the role of the protein networks and the identity loss of hepatocytes gives us potential intervention targets for the development of effective therapies” says Ana Alfaro, first co-author of the article.
Future work
Based on these findings, it will now be possible to develop novel approaches to effectively target certain nodes in the protein network to prevent disease progression or even revert existing fibrosis, something that is still not possible to-date.
About the people
Stephan Herzig is Director of the Helmholtz Diabetes Center at Helmholtz Zentrum München. He holds the Chair for Molecular Metabolic Control at the Technical University of Munich and an Honorary Chair at Heidelberg University. Anne Loft and Ana Alfaro are first co-authors of the study at Helmholtz Zentrum München. All are part of the German Center for Diabetes Research (DZD).
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Materials provided by Helmholtz Zentrum München – German Research Center for Environmental Health. Note: Content may be edited for style and length.

Many people react to contact allergens, but some patients develop rashes and itching much faster than others. Previously the scientists were unable to explain why, but now researchers have outlined an entire new subgroup of allergic reactions which explains these early skin reactions. The new knowledge is vital to understanding the disease mechanisms in contact allergy.
Hair dye, perfume, jewellery. Beautifying to most, but for some they are equivalent to rashes, irritation and reduced quality of life. Together with hay fever and food allergies, allergic contact dermatitis due to exposure to e.g. nickel and perfume ingredients represents the majority of allergic reactions seen among Danes.
Traditionally, researchers have distinguished between immediate and delayed allergic reactions, depending on which parts of the immune system that is responsible for the reaction. e.g., hay fever and food allergies are ‘immediate’ forms that cause immediate symptoms, whereas it can take days before the skin reacts to things like nickel and perfume. But now a new study conducted by the LEO Foundation Skin Immunology Research Center at the University of Copenhagen changes this understanding.
‘Some patients develop allergic contact dermatitis at a much earlier stage than described by text books. The aim of the study was therefore to try to determine why some react to contact allergens much faster than prescribed. It turns out that when a part of the skin is exposed to the allergen for the first time, the cells within that specific skin area will develop local memory towards the contact allergen. And then when the same area is re-exposed to the allergen at a later point in time, the patient will develop a clear reaction within only 12 hours’, explains PhD Student and first author of the study Anders Boutrup Funch.
It is the T cells in the body that are responsible for delayed allergic reactions — also known as type 4 allergic reactions. But in the new study conducted on mice the researchers have shown that the T cells are capable of building a sophisticated memory that enables them to respond much faster than previously assumed. This gives us a more complex picture of contact allergy.
‘We point to a need for clarification of this disease. Type 4 reactions should be subcategorised, giving us both the classic delayed reaction — that is, where the patient reacts 24-72 hours after exposure — and an immediate reaction, where the patient develops symptoms much faster. Based on these results, we may have to change the text books on contact allergy. At any case, we will need to add a chapter’, says the main author of the study, Professor Charlotte Menné Bonefeld.
The study also reveals that activation of the memory T cells following exposure to an allergen leads to massive recruitment of the most abundant type of white blood cells in the body — the so-called neutrophils — to the affected part of the skin. Normally, neutrophil recruitment is used to fight infections, as these cells are capable of effectively eliminating microorganisms. At the same time, they cause intense infection and local tissue damage, which is what the patients experience as a rash. Neutrophil recruitment is not seen in connection with delayed reactions to contact allergens.
The next step in the research is to test the study results on humans. Once a person has developed contact allergy, they are likely to suffer from it for the rest of their lives. Therefore, the researchers behind the study hope the new knowledge may improve contact allergy patients’ chances of getting treatment in the future.
‘First and foremost, we need to tell the world that we have new knowledge which should change our understanding of the disease’, Anders Boutrup Funch concludes.

Combining chemotherapy and BRAF oncogene inhibitors is a highly effective strategy for fighting metastatic melanoma, the leading cause of death from skin cancer in the world. This has been demonstrated in a study by researchers from the Hospital del Mar Medical Research Institute (IMIM), Hospital del Mar, and CIBER Cancer (CIBERONC), in collaboration with the Bellvitge Medical Research Institute (ICO-IDIBELL), which has just been published in the journal Oncogene.
The study, which involved the IMIM’s Stem Cells and Cancer Research Group and doctors from the Dermatology and Pathology Departments at Hospital del Mar, analysed what effect combining the two types of treatment had on malignant melanoma. In previous studies, the same researchers had already demonstrated the usefulness of blocking BRAF oncogene expression to reduce the ability of colon and rectal cancer cells to repair after chemotherapy treatment.
Low-toxicity treatment
The researchers tested the two treatments both separately and together in mice and in tumour cells in vitro. The combination of the two approaches proved to be superior in all trials after one week of treatment. Furthermore, the benefits were maintained after the end of treatment. “We have demonstrated the therapeutic potential of combining the two treatments to eradicate cancer cells. This strategy not only prevents the appearance of resistance to one of the approaches, but also offers a new therapeutic perspective for patients with mutations affecting the BRAF oncogene,” explains Dr. Lluís Espinosa, a researcher at the IMIM-Hospital del Mar and CIBERONC, and author of the study.
The study also indicates that chemotherapy administered at low doses, thereby avoiding its toxicity, combined with the standard treatment with BRAF inhibitors, can have an enormous effect on the progression of metastatic melanoma. Furthermore, because the combined treatment eliminates tumour cells rather than stopping their growth, it would also avoid lengthy treatments and the possible development of resistance. The researchers also believe that this approach could be applied to other types of cancer, including some rare subtypes of melanoma that are currently untreatable as they lack mutations in the BRAF oncogene. The authors of the study believe that this possibility is easily assessed, as the treatments already exist and are being used routinely for several types of tumours.
In this case: “The mechanism is simple: by combining low-dose chemotherapy, which has very low toxicity, with BRAF inhibitors, we damage the cell’s DNA with the chemotherapy while at the same time we prevent the cell from repairing itself thanks to the BRAF inhibitors. This not only enhances the effect of each of the treatments, but it might make the effect irreversible,” comments Dr. Fernando Gallardo, head of the dermatology department and author of the study. One of the main problems encountered with BRAF inhibitor treatment, the gold standard approach to this disease, is that the cancer cells re-grow and become resistant to this therapy, as the inhibitor only stops them, and does not eliminate them. The possibility of using this in combination with chemotherapy could eliminate the problem of certain resistance and relapse.
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Materials provided by IMIM (Hospital del Mar Medical Research Institute). Note: Content may be edited for style and length.

Sleep experts offer advice on sleeping soundly through the night.It’s normal to wake up a few times during the night, as the brain cycles through various stages of deeper and lighter sleep. Older people also often have to get out of bed to use the bathroom one or two times during the night. Waking up at night is usually harmless. Most people have no trouble falling back asleep and may not even remember their nighttime awakenings the next morning.But if you frequently wake up in the middle of the night and find yourself struggling to fall back asleep, there could be an underlying problem. If this occurs at least three times a week over a period of at least three months, it could be chronic insomnia, said Dr. Kannan Ramar, a sleep medicine specialist at the Mayo Clinic in Minnesota and former president of the American Academy of Sleep Medicine.Two of the primary drivers of insomnia are stress and anxiety. If you wake up and look at the clock and then start worrying about having to be rested for work the next day, paying your bills or other life stresses, it could activate your sympathetic nervous system, which controls what’s known as the fight-or-flight response. Levels of adrenaline, the so-called stress hormone, will rise, increasing your heart rate and leading to a state of heightened arousal, making it particularly difficult to ease back into sleep.“You might ask yourself, ‘Is this the same time I woke up last night? Why does this always happen?’” Dr. Ramar said. “Those thoughts are not helpful in terms of falling back asleep.”If you find that you’ve been awake for 25 minutes or longer, experts advise you get out of bed and do a quiet activity that calms your mind — anything to quash the stressful thoughts that were keeping you awake. Gentle stretches or breathing exercises might help, as may meditation, which has been shown in studies to help combat chronic insomnia. You might sit on the couch and knit, or read a book or magazine in dim light. Experts recommend that you avoid reading on your smartphone, since the blue light these devices emit can suppress production of melatonin, the hormone that helps make us drowsy. You might, however, pull out your phone to use a soothing app like Calm or Headspace, which are designed to help with sleep and meditation.Eventually, when you start to feel tired, get back into bed and try to doze off. Then, the next day, implement the following sleep hygiene habits to increase your odds of sleeping soundly through the night.Limit your evening alcohol intake. In small amounts, alcohol can act as a sedative, causing you to fall asleep faster. But it can also cause you to wake up in the middle of the night as your body is metabolizing it. Studies show that consuming alcohol before bed can lead to poor quality sleep.Avoid consuming any caffeine after 2 p.m. because it can linger in your system well into the evening. If you drink a cup of coffee at 3:30 p.m., about a quarter of the caffeine can still be in your system 12 hours later.Avoid napping late in the day, as this can make it harder to fall and stay asleep at night. Taking late naps will reduce what scientists call your homeostatic sleep drive, which is essentially your body’s pressure to fall sleep in the evening. If you do want to nap during the day, make sure to do it in the morning or early afternoon, and keep it short, no longer than 30 minutes. “The closer you are to bedtime or the longer the nap is, the more likely you are to run into trouble,” said Dr. Sabra Abbott, an assistant professor of neurology in sleep medicine at Northwestern University Feinberg School of Medicine in Chicago.Keep a strict sleep schedule. Waking up and going to bed at irregular times can throw off your body’s circadian rhythm, the innate 24-hour cycles that tell our bodies when to wake up and fall asleep, making it harder to sleep through the night. Try to get up at the same time each morning (aim to get at least 15 minutes of morning sunlight, which helps to shut down melatonin production) and get into bed at the same time in the evenings. Studies show that people who have irregular bedtime schedules are more likely to develop symptoms of insomnia.If you frequently get up to use the bathroom, try to limit how much water or other fluids you drink in the evening two to four hours before bedtime.If these measures don’t help, a sleep specialist can assess whether you might have a more significant underlying problem, such as sleep apnea or restless legs syndrome, that needs medical treatment. A sleep clinic could also connect you to a cognitive behavioral therapist who could help you identify and address any specific behaviors that might be causing your chronic insomnia.Do you have a health question? Ask Well