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Archive - Sep 2017

Date

September 29th

Confronted with Bacteria, Infected Cells Die Allowing Others to Live, Penn Study Finds

The immune system is constantly performing surveillance to detect foreign organisms that might do harm. But pathogens, for their part, have evolved a number of strategies to evade this detection, such as secreting proteins that hinder a host's ability to mount an immune response. In a new study, a team of researchers led by Dr. Igor E. Brodsky of the University of Pennsylvania, identified a "back-up alarm" system in host cells that responds to a pathogen's attempt to subvert the immune system. "In the context of an infection, the cells that are dying are talking to the other cells that aren't infected," said Dr. Brodsky, an Assistant Professor in the Department of Pathobiology in Penn's School of Veterinary Medicine and senior author on the study. "I don't think of it as altruistic, exactly, but it's a way for the cells that can't respond any longer to still alert their neighbors that a pathogen is present." The findings address the long-standing question of how a host can generate an immune response to something that is designed to shut off that very response. A potential future application of this new understanding may enable the cell-death pathway triggered by bacteria to be harnessed in order to target tumor cells and encourage their demise. The work was published online on August 30, 2017 in the Journal of Experimental Medicine. The article is titled “RIPK1-Dependent Apoptosis Bypasses Pathogen Blockade of Innate Signaling to Promote Immune Defense.” A major way that the immune system recognizes pathogens is by detecting patterns that are shared among microbes but are distinct from a host's own cells. Pathogens, however, don't make it easy for immune cells to destroy them. Some can inject proteins into host cells that interfere with this detection, allowing an infection to become established.

Novel Class of Lipid Mediators (Elovanoids) May Protect Brain from Stroke, Neurodegenerative Diseases

Research led by Nicolas Bazan (photo), MD, PhD, Boyd Professor and Director of the Neuroscience Center of Excellence at LSU Health New Orleans, has discovered a new class of molecules in the brain that synchronize cell-to-cell communication and neuroinflammation/immune activity in response to injury or diseases. Elovanoids (ELVs) are bioactive chemical messengers made from omega-3 very-long-chain polyunsaturated fatty acids (VLC-PUFAs, n-3). They are released on demand when cells are damaged or stressed. "Although we knew about messengers from omega-3 fatty acids such as neuroprotectin D1 (22 carbons) before, the novelty of the present discovery is that elovanoids are made of 32 to 34 carbon atoms in length," notes Dr. Bazan. "We expect that these structures will profoundly increase our understanding of cellular cross talk to sustain neuronal circuitry and particularly to restore cell equilibrium after pathological insults." Working in neuronal cell cultures from the cerebral cortex and from the hippocampus and a model of ischemic stroke, the researchers found that elovanoids not only protected neuronal cells and promoted their survival, but helped maintain their integrity and stability. The work was published online on September 27, 2017 in Science Advances. The open-access article is titled “Elovanoids Are a Novel Class of Homeostatic Lipid Mediators That Protect Neural Cell Integrity Upon Injury.” "Our findings represent a breakthrough in the understanding of how the complexity and resiliency of the brain are sustained when confronted with adversities such as stroke, Parkinson's, or Alzheimer's and neuroprotection signaling needs to be activated," says Dr. Bazan. "A key factor is how neurons communicate among themselves.

September 27th

Extracellular Vesicle (EV) ARMMs Carry Receptors That Allow Signaling Without Direct Contact Between Cells; New Research May Have “Tremendous Potential for Therapeutics and Public Health”

A newly discovered cellular messaging mechanism could lead to a new way to deliver therapeutics to tissues affected by disease, according to a new study from the Harvard T.H. Chan School of Public Health. Researchers found that a type of extracellular vesicle (EV) -- a membrane-bounded sac secreted by cells that contains proteins and RNA molecules -- known as ARMMs (ARRDC1-mediated microvesicles) also carries receptors that allow signaling without direct contact between cells. This capability may make ARMMs uniquely suited to be engineered to send therapeutics directly to affected areas of the body. "EVs are like messages in a bottle between cells," said senior author Dr. Quan Lu (photo), Associate Professor of Environmental Genetics and Pathophysiology. "We think that within the next few years, we may be able to swap the endogenous molecules in ARMMs for therapeutic cargos -- such as antibodies -- and to engineer ARMMs to home in on a particular tissue." The new study was published online on September 27, 2017 in Nature Communications. The open-access article is titled “Plasma Membrane-Derived Extracellular Microvesicles Mediate Non-Canonical Intercellular NOTCH Signaling.” There are an estimated 37 trillion cells in the human body -- and 100 times that many EVs. The EVs circulate in the blood and other bodily fluids and are involved in processes such as coagulation and the immune response. They can also be hijacked to spread cancer or viruses like HIV and Ebola. EVs are generating a great deal of interest in the biotechnology field. Researchers believe that the molecules EVs can carry include the fingerprints of disease and harmful environmental exposures. Work is already underway on developing a "liquid biopsy" to test EVs in a drop of blood.

September 26th

Researchers Identify Possible Biomarker for Diagnosing Chronic Traumatic Encephalopathy (CTE) During Life

A new biomarker (CCL11, a small cytokine) for chronic traumatic encephalopathy (CTE) has been discovered that may allow the disease to be diagnosed during life for the first time. The findings, which were published online on September26, 2017 in PLOS ONE, might also help distinguish CTE from Alzheimer's disease, which often presents with symptoms similar to CTE and also can only be diagnosed post-mortem. The ability to diagnose CTE in living individuals would allow for research into prevention and treatment of the disease. The open-access PLOS ONE article is titled “CCL11 Is Increased in the CNS in Chronic Traumatic Encephalopathy But Not in Alzheimer’s Disease.” Researchers from Boston University School of Medicine (BUSM) and the VA Boston Healthcare System (VABHS) studied the brains of 23 former college and professional football players. They compared them to the brains of 50 non-athletes with Alzheimer's disease and 18 non-athlete controls. The scientists observed that CCL11 levels were normal in the brains of the non-athlete controls and non-athletes with Alzheimer's disease, but were significantly elevated in the brains of individuals with CTE. The rsearchers then compared the degree of elevation of CCL11 to the number of years those individuals played football and found that there was a positive correlation between the CCL11 levels and the number of years played.

Pigeons Better at Multitasking Than Humans in Some Situations; Higher Density of Neurons in Brain May Be Reason

Pigeons are capable of switching between two tasks as quickly as humans – and even more quickly in certain situations. These are the findings of biopsychologists who performed the same behavioral experiments to test birds and humans. The authors hypothesize that the cause of the slight multitasking advantage in birds is their higher neuronal density. Dr. Sara Letzner and Professor Dr. Onur Güntürkün from Ruhr-Universität Bochum published the results in the September 25, 2017 issue of Current Biology, in collaboration with Professor Dr. Christian Beste from the University Hospital Carl Gustav Carus at Technische Universität Dresden. The open-access article is titled “How Birds Outperform Humans in Multi-Component Behavior.” “For a long time, scientists used to believe the mammalian cerebral cortex to be the anatomical cause of cognitive ability; it is made up of six cortical layers,” says Dr. Letzner. In birds, however, such a structure does not exist. “That means the structure of the mammalian cortex cannot be decisive for complex cognitive functions such as multitasking,” continues Dr. Letzner. The pallium of birds does not have any layers comparable to those in the human cortex; but its neurons are more densely packed than in the cerebral cortex in humans: pigeons, for example, have six times as many nerve cells as humans per cubic millimeter of brain. Consequently, the average distance between two neurons in pigeons is fifty per cent shorter than in humans. As the speed at which nerve cell signals are transmitted is the same in both birds and mammals, researchers had assumed that information is processed more quickly in avian brains than in mammalian brains.

Ascorbate Peroxidase Proximity Labeling Used to Identify Promoters of Mitochondria-Endoplasmic Reticulum Contacts; Advance Could Aid Understanding of Certain Neurodegenerative Diseases

Inside every cell is a complex infrastructure of organelles carrying out different functions. Organelles must exchange signals and materials to make the cell operate correctly. New technologies are allowing researchers to see and understand the networks that connect these organelles, allowing the scientists to build maps of the trade routes that exist within a cell. A study to be published in the September 29, 2017 issue of the Journal of Biological Chemistry, and published online on July 31, 2017, reports the use of an emerging method to identify proteins that allows two organelles, the mitochondria and the endoplasmic reticulum, to attach to each other. The open-access JBC article is titled “Ascorbate Peroxidase Proximity Labeling Coupled with Biochemical Fractionation Identifies Promoters of Endoplasmic Reticulum Mitochondrial Contacts.” "Think of [an organelle] like a ferry docking at one site, unloading and loading passengers and cars, and then going to another site and doing the same thing," said Dr. Jeffrey Golden, a professor at Brigham and Women's Hospital and Harvard Medical School who oversaw the work. "Their ability to dock, load, and unload cargo requires guides or ramps of specific width and heights that connect the boat and land or they cannot freely load and unload." Contact points between the endoplasmic reticulum (ER) and mitochondria are those "ramps" and "guides" that enable these contacts. They permit important activities like signaling, exchange of calcium and lipids, and control of mitochondrial physiology. Faulty connections between ER and mitochondria have been implicated in several neurodegenerative diseases, including Alzheimer's, Parkinson's and Huntington's disease.

Invitation to ASEMV 2017 Annual Meeting (Exosomes & Microvesicles) in Asilomar, California (October 8-12)

The American Society for Exosomes and Microvesicles (ASEMV) is inviting interested scientists to the ASEMV 2017 meeting, to be held October 8-12, 2017 at the Asilomar Conference Center in California. This center is located on the Monterrey peninsula, just south of San Francisco (www.visitasilomar.com). The meeting will cover the full breadth of the exosome field, from basic cell biology to clinical applications, and follow the ASEMV tradition of inclusion and diversity as participants learn about the latest advances in the field. ASEMV 2017 is a forum for learning the latest discoveries in the field of exosomes, microvesicles, and extracellular RNAs. Over the course of four days at the Asilomar Conference Center, ASEMV 2017 will offer presentations from leading scientists and young researchers. Topics will span the breadth of the extracellular vesicle/RNA field, including the basic sciences, disease research, translation efforts, and clinical applications. Talks will be presented in multiple sessions, beginning at 7 pm on Sunday, October 8, 2017, and concluding at 4 pm on Thursday, October 12, 2017. Poster sessions will run throughout the meeting, with ample time to get to know your colleagues in the field and explore the many opportunities in this rapidly expanding field. Please see the links below.

September 21st

Exosomes May Be Missing Link to Insulin Resistance in Diabetes

Chronic tissue inflammation resulting from obesity is an underlying cause of insulin resistance and type 2 diabetes. But the mechanism by which this occurs has remained cloaked, until now. In a paper, published in the journal Cell on September 21, 2017, University of California San Diego School of Medicine researchers identified exosomes — extremely small vesicles or sacs secreted from most cell types — as the missing link. The article is titled “Adipose Tissue Macrophage-Derived Exosomal miRNAs Can Modulate In Vivo and In Vitro Insulin Sensitivity.” “The actions induced by exosomes as they move between tissues are likely to be an underlying cause of intercellular communication causing metabolic derangements of diabetes,” said Jerrold Olefsky, MD, Professor of Medicine in the Division of Endocrinology and Metabolism at UC San Diego School of Medicine and senior author of the paper. “By fluorescently labeling cells, we could see exosomes and the microRNA they carry moving from adipose (fat) tissue through the blood and infiltrating muscle and liver tissues.” During chronic inflammation, the primary tissue to become inflamed is adipose tissue. Forty percent of adipose tissue in obesity is comprised of macrophages — specialized immune cells that promote tissue inflammation. Macrophages in turn create and secrete exosomes. When exosomes get into other tissues, they use the microRNA (miRNA) they carry to induce actions in the recipient cells. The macrophage-secreted miRNAs are on the hunt for messenger RNAs. When the miRNA finds a target in RNA, it binds to it, rendering the messenger RNA inactive. The protein that would have been encoded by the messenger RNA is no longer made. Thus, the miRNAs are a way to inhibit the production of key proteins. A team led by Dr.

Tumor-Associated Macrophages (TAMs) Promote Neuroblastoma by STAT3 Phosphorylation and Up-Regulation of c-MYC

Investigators at the Children's Center for Cancer and Blood Diseases at Children's Hospital Los Angeles have reported new findings about an immune cell - called a tumor-associated macrophage - that promotes cancer instead of fighting it. They have identified the molecular pathway, known as STAT3, as the mechanism the immune cell uses to foster neuroblastoma, a pediatric cancer, and have demonstrated use of a clinically available agent, ruxolitinib, to block the pathway. Results of the study were published online in Oncotarget on September 20, 2017. The article is titled Tumor-Associated Macrophages Promote Neuroblastoma Via STAT3 Phosphorylation and Up-Regulation of c-MYC.” Neuroblastoma is the second most common solid tumor effecting children. Individuals with high-risk disease have a mortality rate of approximately 50 percent. Certain conditions are associated with high-risk disease. High levels of some chemicals involved with inflammation and the presence of an immune cell called a tumor-associated macrophage (TAM) are associated with high-risk disease and lower survival rates. Macrophages are a type of immune cell that typically function to battle disease, not encourage it. "The macrophages are essentially co-opted by the tumor cells to help them grow," said Shahab Asgharzadeh, MD, Director of the Basic and Translational Neuroblastoma program at CHLA and lead investigator of the study. "We're trying to find out more about the mechanisms that enable TAMs to help cancer grow so that we can target the pathways they use and block their pro-tumor effect."

Discovery by Doudna Lab & Collaborators Should Help Improve Accuracy of CRISPR-Cas9 Gene Editing

Scientists at the University of California, Berkeley, and Massachusetts General Hospital have identified a key region within the Cas9 protein that governs how accurately CRISPR-Cas9 homes in on a target DNA sequence, and have tweaked it to produce a hyper-accurate gene editor with the lowest level of off-target cutting to date. The protein domain the researchers identified as a master controller of DNA cutting is an obvious target for re-engineering to improve accuracy even further, the researchers say. This approach should help scientists customize variants of Cas9 - the protein that binds and cuts DNA - to minimize the chance that CRISPR-Cas9 will edit DNA at the wrong place, a key consideration when doing gene therapy in humans. One strategy to achieve improved accuracy is to create mutations in the governing protein domain, called REC3, and see which ones improve accuracy without impacting the efficiency of on-target cutting. "We have found that even minor alterations in the REC3 domain of Cas9 affect the differential between on- and off-target editing, which suggests that this domain is an obvious candidate for in-depth mutagenesis to improve targeting specificity. As an extension of this work, one could perform a more unbiased mutagenesis within REC3 than the targeted mutations we have made," said co-first author Janice Chen, a graduate student in the lab of Dr. Jennifer Doudna, who co-invented the CRISPR-Cas9 gene-editing tool. Co-first authors Chen, Yavuz Dagdas, and Benjamin Kleinstiver, and their colleagues at UC Berkeley, Massachusetts General Hospital, and Harvard University reported their results online on September 20, 2017 in Nature. The article is titled “Enhanced Proofreading Governs CRISPR–Cas9 Targeting Accuracy.” Since 2012, when Dr.