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Exosomes May Contribute to Alzheimer’s; Reduction in Number May Slow Disease Progression and Protect Cognition

Vesicles, fluid-filled sacs that brain cells make to trap amyloid, a hallmark of Alzheimer's, appear to also contribute to the disease, scientists report. Reducing the production of these vesicles, called exosomes, could help reduce the amount of amyloid and lipid that accumulates, slow disease progression, and help protect cognition, scientists at the Medical College of Georgia (MCG) at Augusta University reported in the August 17, 2016 issue of The Journal of Neuroscience. The article is titled “Neutral Sphingomyelinase-2 Deficiency Ameliorates Alzheimer's Disease Pathology and Improves Cognition in the 5XFAD Mouse.” When confronted with amyloid, astrocytes (plentiful brain cells that support neurons) start making exosomes, to capture and neutralize it, said Dr. Erhard Bieberich, a neuroscientist in the MCG Department of Neuroscience and Regenerative Medicine and the study's corresponding author. "If you swarm astrocytes with amyloid, you trigger an aggressive response," he said. Happy astrocytes, on the other hand, don't make exosomes. Not unlike a landfill, the real problems begin when the biological sacs get piled too high. In such volume and close proximity to neurons, exosomes begin to interfere with communication and nutrition, neurons stop functioning well and eventually begin to die, a scenario that fits with disease progression, Dr. Bieberich said. MCG scientists followed the process in an animal model with several genetic mutations found in types of Alzheimer's that tend to run in families and produce brain plaques early in life. One mouse group also was genetically programmed to make a nonfunctional form of the enzyme neutral sphingomyelinase-2.

Mutations in Non-Coding Gene (snoRNA) Cause Severely Debilitating Disease of Brain Blood Vessels

The cause of a disease that targets blood vessels in the brain - leading to multiple debilitating symptoms and, often, to early death - has been tracked to a single mutated gene, opening up the immediate possibility of improved patient care through genetic testing, and of future treatments. The research, conducted over 12 years, was led by the teams of Professor Yanick Crow and Dr. Ray O'Keefe from The University of Manchester's Division of Evolution and Genomic Sciences, and included contributions from over 60 academics and scientists from around the world. It was published online today (August 29, 2016) in the journal Nature Genetics. The article is title “'Mutations in SNORD118 Cause the Cerebral Microangiopathy Leukoencephalopathy with Calcifications and Cysts.” This discovery involved the identification of mutations in SNORD118 - a small nucleolar RNA (snoRNA) gene - to cause leukoencephalopathy with calcification and cysts (LCC). LCC is characterized by progressive white matter degeneration in the brain. The disease can present in patients at any stage of life. Dr. Emma Jenkinson, Research Associate at The University of Manchester's Division of Evolution and Genomic Sciences, was lead laboratory researcher on this project. She said that the 12-year study unlocked greater understanding of the development of genetic disorders caused by mutations in non-coding regions of the genome. "The identification of SNORD118 as the instigator of a progressive and frequently fatal brain disease is a very significant step forward in understanding the role of non-coding RNAs in the development of certain diseases.

Telemedicine Could Improve Eye Exam Access for People with Diabetes

Electronic eye exams could become popular in the U.S. among patients who see them as an easy way to visit the eye doctor. After a nationwide telemedicine diabetic screening program in England and Wales, for example, diabetic retinopathy is no longer the leading cause of blindness there. Similar e-health programs could grow stateside, where diabetic retinopathy remains the main driver of new-onset blindness. But it hasn't been known if patients would participate. Researchers at the University of Michigan's (U-M’s) Kellogg Eye Center conducted a study of older adults to find out. If services are convenient, patients will use them, the investigation found. "Telemedicine has been shown to be a safe method to provide monitoring for diabetic eye care. If physicians plan to change the way that people get care, we must create a service that is appealing and tailored to the patients," says senior study author Maria Woodward, M.D., Assistant Professor of Ophthalmology at the Kellogg Eye Center, Early detection and treatment are key to preventing blindness from diabetic retinopathy, but fewer than 65 percent of U.S. adults with diabetes undergo screening. In underserved populations, rates can drop as low as 10 or 20 percent. Shifting screening to a telemedicine program could ease the burden on patients who face high costs of care, lack of access to care or have difficulty with transportation or getting time away from work, researchers say. Finding ways to address screening will become more important in coming decades, as the number of people with diabetes is projected to more than double to 366 million worldwide by 2030. Telemedicine allows primary care doctors to play a critical role in preventing eye damage. Retinal photographs are taken of both eyes at the doctor's office using a no-dilation retina camera.

Zika Infection May Affect Adult Brain Cells, Suggesting Risk May Not Be Limited to Pregnant Women

Concerns over the Zika virus have focused on pregnant women due to mounting evidence that it causes brain abnormalities in developing fetuses. However, new research in mice from scientists at The Rockefeller University and the La Jolla Institute for Allergy and Immunology suggests that certain adult brain cells may be vulnerable to infection as well. Among these are populations of cells that serve to replace lost or damaged neurons throughout adulthood, and are also thought to be critical to learning and memory. “This is the first study looking at the effect of Zika infection on the adult brain,” says Joseph Gleeson, Ph.D., Adjunct Professor at Rockefeller, Head of the Laboratory of Pediatric Brain Disease, and Howard Hughes Medical Institute investigator. “Based on our findings, getting infected with Zika as an adult may not be as innocuous as people think.” Although more research is needed to determine if this damage has long-term biological implications or the potential to affect behavior, the findings suggest the possibility that the Zika virus, which has become widespread in Central and South America over the past eight months, may be more harmful than previously believed. The new findings were published online in Cell Stem Cell on August 18, 2016. The open-access article is titled “Zika Virus Infects Neural Progenitors in the Adult Mouse Brain and Alters Proliferation.” “Zika can clearly enter the brain of adults and can wreak havoc,” says Sujan Shresta, Ph.D., a professor at the La Jolla Institute of Allergy and Immunology. “But it’s a complex disease—it’s catastrophic for early brain development, yet the majority of adults who are infected with Zika rarely show detectable symptoms.

Specialist Moth Takes Advantage of Defensive Compounds in Physalis Fruits

In order to survive and to repel herbivores, many plants defend themselves by producing toxic or deterrent substances. In the course of evolution, many insects have succeeded in adapting to the defensive chemistry of their host plants and thereby circumventing plants' defense mechanisms. However, the plants have also adapted their defensive system to further protect themselves against their enemies, which, in turn, generated counter-adaptations in the insects; biologists refer to this phenomenon as an "evolutionary arms race" between plants and insects. Many insects are plant pests that can be categorized as "specialists" and "generalists." Whereas generalists feed on many different plants, specialists have adapted to one or few closely related plant species as their food. The moth species Heliothis subflexa analyzed in this new study is such a host specialist. The researchers measured and compared the effects of withanolides on relative weight gains, survival rates. and the immune status in two moth species: the specialist Heliothis subflexa and the generalist Heliothis virescens. They knew from earlier studies that the specialist moth possesses a weaker immune response compared to the closely related generalist. "We were surprised to find that only Heliothis subflexa benefits from withanolides by increasing larval growth and immune system activity, but not its close relative, Heliothis virescens," says Hanna M. Heidel-Fischer, Ph.D., the leader of the study. The article was published online on August 26, 2016 in Nature Communications.

Study Targets Dynamics of CRISPR-Cas9 Complexes in Live Cells; Cas9 Stabilizes Guide RNA

A study in The Journal of Cell Biology by scientists at the University of Massachusetts Medical School reveals important new details about the inner workings of the CRISPR-Cas9 machinery in live cells that may have implications for the development of therapeutics that use the powerful gene editing tool." We don't know a lot about the details of how the CRISPR-Cas9 complex gets around the genome of a live cell and finds its target," said Thoru Pederson, Ph.D., Vitold Arnett Professor of Cell Biology and Professor of Biochemistry and Molecular Pharmacology. "What we've learned in this study about how this machinery works is important and useful for gene editors looking to develop tools for the lab and potentially the clinic." A component of the bacterial immune system that protects it from viral invasion, the CRISPR-Cas9 complex is a powerful gene editing system. More efficient and precise than previous technologies, the CRIPR-Cas9 complex is being adapted in the lab, as scientists find ways to program and deliver it quickly to selectively edit specific genetic sequences for study. In order to cut a piece of double-stranded DNA, CRISPR-Cas9 makes use of a guide RNA made of roughly 20 nucleotides to target specific regions of a genome at which the Cas9 complex then makes the cut. This allows scientists to remove or insert genetic sequences into the genome. Because the underlying dynamics of how the CRISPR/Cas9 system works inside live cells aren't well understood, some delivery systems and techniques have been more successful than others. In order to observe the actions of the CRISPR-Cas9 system at work in a live cell, Dr. Pederson and colleagues developed a technique for labeling the guide RNA and Cas9 elements with different florescent molecules so they could be tracked simultaneously.

Discovery of a Novel Wnt Inhibitor with Potential to Eradicate Colorectal Cancer Stem Cells & Impact Treatment of the Disease

A team including scients at the National Cancer Center (NCC) (Tokyo, Japan), the RIKEN Center for Life Science Technologies (CLST) (Yokohama, Japan), and Carna Biosciences Inc. (Kobe, Japan) has jointly announced the development of a novel small-molecule Wnt inhibitor named NCB-0846. Wnt signaling is a key pathway of cancer stem cell (CSC) development. The inhibitor may provide a new therapy option for patients with drug-refractory colorectal cancer. Colorectal cancer is a major cause of cancer death, accounting for approximately 700,000 deaths annually worldwide. Over 90% of colorectal cancers carry somatic mutations in Wnt signaling component genes such as the adenomatous polyposis coli (APC) tumor suppressor gene, resulting in constitutive activation of Wnt signaling. This in turn leads to the generation of CSCs, which are intrinsically resistant to conventional chemotherapy. Therefore, therapeutics that can block Wnt signaling are likely to eradicate cancer stem cells and cure the disease. However, despite a wealth of data and investment in research and development, no Wnt-inhibiting drug has yet been incorporated into clinical practice. NCC researchers have previously examined the components of the T-cell factor-4 (TCF4) and β-catenin transcription complex and identified Traf2- and Nck-interacting kinase (TNIK) as an essential regulatory component of the TCF4/β-catenin complex. TNIK regulates Wnt signaling in the most downstream part of the pathway, and its pharmacological inhibition has been anticipated to block the signal even in colorectal cancer cells with mutation of the APC gene.

Epigenetic Profiling Test Can Determine Originating Tumor in Cancers of Unknown Primary (CUP); May Enable Much-Improved Treatment

In patients with cancer, initial diagnosis most often includes the detection of the primary or original tumor and the presence or absence of metastases, i.e., cells from the original tumor that have escaped from their original location and are growing into other tissues of the patient. However, in between 5% and 10% of human tumors this process is done otherwise: metastasis is diagnosed, but the primary tumor is not detected despite various diagnostic testing. This situation is called Cancer of Unknown Primary (CUP). As the type of tumor is not known, the survival of these patients cannot be predicted and is often is very limited. Recently, work led by Dr. Manel Esteller, Director of the Epigenetics and Cancer Biology Program (PEBC) of of Bellvitge Biomedical Research Institute (IDIBELL), ICREA researcher and Professor of Genetics at the University of Barcelona in Spain, shows that it is possible to use a newly-developed epigenetic test - called EPICUP®- to deternine what type of primary tumor is responsible for the metastasis in the patient, which will allow doctors to develop more specific treatments against it. This work was published online on August 26, 2016 in The Lancet Oncology and is titled “Epigenetic Profiling to Classify Cancer of Unknown Primary: A Multicentre, Retrospective Analysis.” A commentary: “Cancer of Unknown Primary: Time to Put the Pieces of the Puzzle Together?” accompanies the research article."A few years ago, we became aware that the chemical patterns that regulate the activity of genes (the epigenome) are specific to each tissue. For example, they are different in a pancreatic cell compared to a lung cell" says Dr. Esteller. "We have analyzed these particular epigenetic signatures for each type of cancer in more than 10,000 human tumors.

Cocktail of Molecules from Mosquito Enemy (Backswimmer) and Biological Pesticide (Bti) May Offer Potent Control of Potentially Deadly Mosquitoes

Mosquitoes continue to build resistance to existing pesticides. Research has now shown that the chemical substances emitted by one of the mosquito's natural enemies - the backswimmer (photo) - makes the biological pesticide Bti more deadly. These so-called predator cues also impair the mosquito's immune system. Scientists at KU Leuven (University of Leuven), Belgium, argue that a cocktail of biological pesticides and synthetic predator cues very well be the future of mosquito control. Mosquitoes transmit quite a few deadly diseases, including West Nile virus. Around the world, therefore, the fight against these insects is high on the agenda. Existing strategies for mosquito control often involve the use of pesticides that harm the environment. These pesticides are increasingly less effective as well, as insects can become resistant to existing products relatively quickly. Biopesticides are a possible alternative. The most commonly used biological pesticide is the Bacillus thuringiensis israelensis (Bti) bacteria. Unfortunately, mosquitoes are already developing a resistance to this pesticide as well. This means the dose of Bti must be increased to kill mosquitoes, so that this biological substance, too, is beginning to harm the environment. Under the supervision of Professor Robby Stoks, KU Leuven doctoral student Lin Op de Beeck set out to find a new strategy in the fight against mosquitoes. "We already knew that chemical substances emitted by the backswimmer - a natural enemy of mosquito larvae in the water - trigger a stress response in mosquitoes. This stress response, in turn, suppresses the mosquito's immune system," says Op de Beeck. "Scientists have recently found a way to produce a synthetic version of these chemical substances known as predator cues.

Link Between Microbiome, Host Immune Response, and Healing Ability Is Demonstrated

Researchers at the Stowers Institute in Kansas City, Missouri have established a definitive link between the makeup of the microbiome, the host immune response, and an organism's ability to heal itself. The scientists showed that a dramatic shift in the microbial community of planaria robs the freshwater flatworm of its superior regenerative abilities. This same shift has been observed in human inflammatory disorders, though previous attempts to mimic it in lower organisms such as fruit flies or zebrafish have proved unsuccessful. The study, published recently in the journal eLife, provides a valuable model for uncovering the basic molecular mechanisms governing the interplay of immunity and regeneration, and could point the way toward new therapies to combat serious human ailments like chronic non-healing wounds. "This is the first animal model to link pathological shifts in endogenous bacteria with the inhibition of regeneration," says Alejandro Sánchez Alvarado, Ph.D., an investigator at the Stowers Institute and the Howard Hughes Medical Institute, and senior author of the study. "We know that some kinds of bacteria are critical to our health, and that other kinds of bacteria can make it very difficult for us to recover from illness. Now we can study how the changing nature of the microbiome - and the way the immune system responds to those changes - impacts the natural execution of regenerative processes." For a long time, researchers believed that the immune response primarily posed a barrier to effective tissue regeneration and repair. However, recent studies in a variety of different organisms have shown that it can play a central role in promoting this process as well. Still, the molecular mechanisms driving these diametrically opposed outcomes remain unclear.

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