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MIT Scientists Identify Neural Circuit That Is Activated During “Exposure Therapy” for Phobias in Animal Model; Fear Extinction Result Is Extended in Time; Finding May Lead to Improved Treatment of Phobias and PTSD in Humans

People who are too frightened of flying to board an airplane, or too fearful of spiders to venture into the basement, can seek a kind of treatment called exposure therapy. In a safe environment, they repeatedly face cues such as photos of planes or black widows, as a way to stamp out their fearful response — a process known as extinction. Unfortunately, the effects of exposure therapy are not permanent, and many people experience a relapse. MIT scientists have now identified a way to enhance the long-term benefit of extinction in rats, offering a way to improve the therapy in people suffering from phobias and more complicated conditions such as post-traumatic stress disorder (PTSD). Work conducted in the laboratory of Ki Goosens, Ph.D., an Assistant Professor in MIT’s Department of Brain and Cognitive Sciences and a member of the McGovern Institute for Brain Research, has pinpointed a neural circuit that becomes active during exposure therapy in the rats. In a study published online on September 27, 2016 in eLife, the researchers showed that they could stretch the therapy’s benefits for at least two months by boosting the circuit’s activity during treatment. The open-access article is titled “Amygdala-Ventral Striatum Circuit Activation Decreases Long-Term Fear.” “When you give extinction training to humans or rats, and you wait long enough, you observe a phenomenon called spontaneous recovery, in which the fear that was originally learned comes back,” Dr. Goosens explains. “It’s one of the barriers to this type of therapy. You spend all this time going through it, but then it’s not a permanent fix for your problem.” According to statistics from the National Institute of Mental Health, 18 percent of U.S.

Oldest-Yet Protein Fragments Identified in 3.8-Million-Year-Old Ostrich Eggshell; Mineral Binding in Eggshell Extends Survival of Certain Protein Fragments; New Tool for Deep Evolutionary Analysis

Scientists have identified fossil proteins in a 3.8-million-year-old ostrich eggshell, suggesting that proteins could provide valuable new insights into the evolutionary tree, much farther back in time than was previously thought. The study, published online on Octber 27, 2016 in the journal eLife, suggests that survival of protein fragments in the ancient eggshell could provide genetic information almost 50 times older than any DNA record. The open-access article is titled “Protein Sequences Bound to Mineral Surfaces Persist Into Deep Time.” The findings shed new light on how animals and humans lived and interacted in the past, how some species became extinct, and why some evolved and continue to thrive today. Crucially, the research provides archaeologists with the ability to be more targeted in which fossils they submit for deeper analysis. The team at the Universities of York, Sheffield, and Copenhagen analyzed and tracked egg fossils from well-dated sites in Tanzania and South Africa, where it is expected DNA and proteins would not survive the extreme environmental conditions. Professor Matthew Collins, from the University of York’s Department of Archaeology, who led the team, said: “To date, DNA analysis from frozen sediments has been able to reach back to about 700,000 years ago, but human evolution left most of its traces in Africa and the higher temperature there takes its toll on DNA preservation.

Mitochondrial DNA Testing May Reveal Unknown Ancestry That May Influence Risk of Breast Cancer

Genetic testing of mitochondrial DNA could reveal otherwise unknown ancestry that can influence a person’s risk for certain types of breast cancer, a new study finds. University of Texas (UT) Southwestern Medical Center cancer researchers studying mitochondrial DNA (mtDNA) in a group of triple negative breast cancer patients found that 13 percent of participants were unaware of ancestry that could influence their risk of cancer. “We found 12 differences among 92 patients, a significant amount,” said lead author Dr. Roshni Rao, Director of the George N. Peters, M.D. Center for Breast Surgery at UT Southwestern. “Some patients who self-identified as Hispanic had African-American ancestry. One Hispanic woman was found to be Ashkenazi Jewish. Both African Americans and some Ashkenazi Jewish populations have a higher risk for triple negative breast cancer,” said Dr. Rao, Associate Professor of Surgery and with the Harold C. Simmons Comprehensive Cancer Center. Triple negative breast cancer is characterized by tumors that do not express receptors for estrogen, progesterone, or Her2-Neu, and accounts for about 15 to 20 percent of all breast cancer cases. This form of the disease is known to be particularly aggressive, and challenging to treat. Patients with triple negative breast cancer have a higher incidence of metastatic disease – cancer spreading to other parts of the body – and an overall higher rate of death from breast cancer, compared to patients with other types of breast cancer. “This study is the first to perform mtDNA testing for self-described African-Americans, Caucasians, and Hispanics with triple negative breast cancer and to identify unexpected mtDNA patterns,” said senior author Dr. Barbara Haley, Professor of Internal Medicine, who holds the Charles Cameron Sprague, M.D. Chair in Clinical Oncology.

Stem Cells for Chronic Myelogenous Leukemia (CML) Die in Response to Inhibition of Ezh2 Protein; Approach May Provide Additional Help to Gleevec and Gleevec-Like Drugs in Treating This Leukemia

Although targeted drugs like Gleevec have revolutionized the treatment of chronic myelogenous leukemia (CML), patients generally must take them for the rest of their lives and may cease benefiting from them over time. In new research that could suggest a road to cure, scientists at Dana-Farber Cancer Institute and Boston Children's Hospital have found that CML stem cells die in response to inhibition of a protein called Ezh2. Drugs that target the protein are currently being tested in clinical trials for other cancers. The findings, reported online on September 14, 2016 in the journal Cancer Discovery, raise the prospect that Ezh2 blockers, in combination with Gleevec and similar drugs, could eradicate the disease in some patients in relatively rapid fashion or could be an effective therapy for those who become resistant to Gleevec-like agents, the authors state.This paper is titled “Chronic Myelogenous Leukemia Initiating Cells Require Polycomb Group Protein EZH2.” In a paper published simultaneously by Cancer Discovery, a team of Scottish scientists report similar findings using a different research approach. That article is titled “Epigenetic Reprogramming Sensitizes CML Stem Cells to Combined EZH2 and Tyrosine Kinase Inhibition.” "The vast majority of patients with CML do remarkably well on imatinib [Gleevec] and similar drugs: The disease is well controlled and side effects are tolerable," says Stuart Orkin, M.D., the study's senior author and a pediatric hematologist/oncologist at Dana-Farber/Boston Children's Cancer and Blood Disorders Center. "In only 10-20 percent of patients, however, are the leukemia cells fully cleared from the body.

Long-Noncoding RNA (Chaer) May Play Key Role in Development of Heart Failure, UCLA Scientists Show

Scientists at UCLA have identified a molecule that appears to play a key role in the development of heart failure. The scientists found that blocking the molecule, known as chaer, in animal studies prevented the animals from developing heart failure. Although the research is still at an early stage, future drugs that target chaer or related signaling pathways may hold promise for treating or preventing heart failure, a condition that afflicts about 5.7 million people and is a contributing cause to roughly one in nine deaths in the United States. The results of the study were published online on September 12, 2016 in Nature Medicine. The article is titled “The long noncoding RNA Chaer defines an epigenetic checkpoint in cardiac hypertrophy.” Chaer is not a protein; it belongs to a category of RNA molecules called long non-coding RNA, or lncRNA. Non-coding RNAs have been considered part of the “dark matter” of biology because they are abundant and diverse in cells, and the DNA that encodes them accounts for most of plant and animal genomes, yet their roles have been largely unexplored. “The observation that a single lncRNA molecule can activate a broad set of heart-failure-related genes was a big surprise,” said Dr. Yibin Wang, the study’s senior author and a professor in the departments of anesthesiology, physiology and medicine at the David Geffen School of Medicine at UCLA. “The findings provide us a better understanding of the molecular processes of heart failure, which we hope eventually to target with effective therapies.” With heart failure, the muscle tissue progressively thickens and stiffens, impairing the heart’s ability to pump blood.

ASHG & Mayo Clinic Announce Collaboration for Education in Genomic Medicine

On September 22, 2016, the American Society of Human Genetics (ASHG) and Mayo Clinic Center for Individualized Medicine (CIM) announced a formal collaboration under which the two organizations will facilitate the effective use of genomics in medicine through the education of health professionals. “Genetics and genomics are evolving rapidly and reshaping significant areas of the healthcare landscape and medical education,” said Joseph D. McInerney, M.A., M.S., Executive Vice President of ASHG. “To keep pace with these developments and translate them into healthcare, learners require accurate, current, and clinically useful information conveyed through high-quality educational products and programs,” he said. “As the individuals conducting research and implementing findings in the clinic, Mayo Clinic and ASHG members are particularly well suited to advancing genetic and genomic literacy at this significant inflection point in medical history,” said Keith Stewart, M.B., Ch.B., Carlson and Nelson Endowed Director, CIM, and Vasek and Anna Maria Polak Professor of Cancer Research at the Mayo Clinic. “By combining the expertise of our organizations and leveraging our resources collaboratively, we hope to fill this need and improve health outcomes.” The first joint ASHG-CIM educational program, targeted toward obstetricians/gynecologists (OB/GYNs) and related health professionals, will address the use of prenatal cell-free DNA (cfDNA) screening in pregnant women. Analysis of cfDNA provides a method of non-invasive prenatal genetic screening by isolating DNA in a pregnant woman’s blood. “Prenatal genetics is a rapidly moving area with unique clinical and ethical challenges.

Inhibition of Key Enzyme Stimulates Differentiation of Leukemic Cells and Reduces Their Number in Mouse Model of Acute Myeloid Leukemia (AML)

A multi-institutional academic and industry research team led by investigators from Massachusetts General Hospital (MGH) and the Harvard Stem Cell Institute has identified a promising new approach to the treatment of acute myeloid leukemia (AML). In their report, published in the September 22, 2016 issue of Cell, the investigators identify a crucial dysfunction in blood cell development that underlies AML and show that inhibiting the action of a specific enzyme prompts the differentiation of leukemic cells, reducing their number and decreasing their ability to propagate the cancer. The Cell article is titled “Inhibition of Dihydroorotate Dehydrogenase Overcomes Differentiation Blockade in Acute Myeloid Leukemia.” "AML is a devastating form of cancer; the five-year survival rate is only 30 percent, and it is even worse for the older patients who have a higher risk of developing the disease," says David Scadden, M.D., Director of the MGH Center for Regenerative Medicine (MGH-CRM), Co-Director of the Harvard Stem Cell Institute (HSCI), and senior author of the Cell paper. "New therapies for AML are extremely limited -- we are still using the protocols developed back in the 1970s -- so we desperately need to find new treatments." In AML, the normal process by which myeloid stem cells differentiate into a specific group of mature white blood cells is halted, leading to the proliferation of immature, abnormal cells that crowd out and suppress the development of normal blood cells. A wide range of genetic changes occurs in AML, but the authors proposed that the effects on differentiation had to funnel through a few shared molecular events.

Small Changes in Transmission Rate of Seasonal Influenza Virus Can Lead to Rapid Evolution of New Strains, Model Shows; Results Lend Further Support to Importance of Surveillance of East, South, and Southeast Asia, and Other Densely Populated Regions

A computer model developed by scientists at the University of Chicago shows that small increases in transmission rates of the seasonal influenza A virus (H3N2) can lead to rapid evolution of new strains that spread globally through human populations. The results of this analysis, published online on September 14, 2016 in the Proceedings of the Royal Society B, reinforce the idea that surveillance for developing new, seasonal vaccines should be focused on areas of east, south, and southeast Asia where population size and community dynamics can increase transmission of endemic strains of the flu. The open-access article is titled “Explaining the Geographical Origins of Seasonal Influenza A (H3N2).” “The transmissibility is a feature of the pathogen, but it’s also a feature of the host population,” said Sarah Cobey, Ph.D., Assistant Professor of Ecology and Evolution at the University of Chicago and senior author of the study. “So a host population that potentially has more crowding, larger classroom sizes for children, or even certain types of social contact networks, potentially sustains higher transmission rates for the same virus or pathogen.” There are four influenza strains that circulate in the human population: A/H3N2, A/H1N1, and two B variants. These viruses spread seasonally each year because of a phenomenon known as antigenic drift: they evolve just enough to evade human immune systems, but not enough to develop into completely new versions of the virus. The H3N2 subtype causes the most disease each year. Genetic sequencing shows that from 2000 to 2010, 87 percent of the most successful, globally-spreading strains of H3N2 originated in east, south, and southeast Asia. Dr.

Nanoparticles with Small Interfering RNAs Target Lung Cancer Cells, While Avoiding Normal Lung Cells

Researchers with the Harold C. Simmons Comprehensive Cancer Center at the University of Texas (UT) Southwestern Medical Center successfully developed a synthetic polymer that can transport a drug into lung cancer cells without going inside of normal lung cells. Because conventional chemo drugs indiscriminately kill all rapidly dividing cells to halt the growth of cancer, these selective nanoparticles could decrease side effects by reducing drug accumulation in normal cells. “The discovery that nanoparticles can be selective to certain cells based only on their physical and chemical properties has profound implications for nanoparticle-based therapies because cell type specificity of drug carriers could alter patient outcomes in the clinic,” said corresponding author Dr. Daniel Siegwart (photo), Assistant Professor of Biochemistry at UT Southwestern Medical Center and with Simmons Cancer Center. “At the same time, a deeper understanding of nanoparticle interactions in the body opens the door to predict patient responses to existing liposome and nanoparticle therapies, and offers the potential to create future drug carriers customized according to individual genetic profiles.” The findings were published online on September 12, 2016 in PNAS. The article is titled "Functional Polyesters Enable Selective siRNA Delivery to Lung Cancer Over Matched Normal Cells." The scientists tested hundreds of polymers to make the surprising discovery that cells could respond differently to the same drug carrier, even when those cancerous and normal cells came from the lungs of the same patient.

With CRISPR-Cas Systems, Bacteria Temporally Order “Memories” of Phage, Putting Last Seen Firs. Apparently to Mount More Effective Response Against More Recent Attackers; System May Hint at Biological Approach to Information Storage

Like humans, bacteria come under attack from viruses and rely on an immune system to defend themselves. A bacterial immune system known as CRISPR helps microbes “remember” the viruses they encounter and more easily fend them off in the future. Since researchers first discovered CRISPR in the mid-2000s, they have noticed something peculiar: It records confrontations with viruses sequentially, placing the most recent attack first in a series of genetically encoded memories. Now, two researchers at The Rockefeller University have explained why microbes store their immunological memories in this particular way. Their results were published online on September 8, 2016 in Molecular Cell. The article is titled “CRISPR-Cas Systems Optimize Their Immune Response by Specifying the Site of Spacer Integration.” “Until now, no one knew if this organizational feature serves a purpose, let alone what that might be,” says senior author Luciano Marraffini, an Associate Professor and Head of the Laboratory of Bacteriology. “We found an answer: It allows the microbe to mount the strongest immune response against its most recent threat, which is likely to be the most potent one around.” Microbial CRISPR systems remember viruses by capturing genetic snippets from them and storing them like beads on a string. (CRISPR stands for clustered regularly interspaced short palindromic repeats.) Should the cell meet a particular virus again, CRISPR-associated (Cas) enzymes use these snippets, known as spacers, to recognize and cut the virus. Thanks to this precision, one such system, CRISPR-Cas9, has become a powerful tool for researchers editing genomes. Researchers have wondered for some time why CRISPR systems create a chronological record of encounters with bacteria-attacking viruses known as phage. Dr.

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