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Archive - Mar 2017

March 8th

“Jumping Genes” May Set Stage for Brain Cell Death in Alzheimer's & Other Neurodegenerative Diseases—“Alu Neurodegeneration Hypothesis” Expounded

The latest round of failed drug trials for Alzheimer's has researchers questioning the reigning approach to battling the disease, which focuses on preventing a sticky protein called amyloid from building up in the brain. Duke University scientists have identified a mechanism in the molecular machinery of the cell that could help explain how neurons begin to falter in the initial stages of Alzheimer's, even before amyloid clumps appear. This rethinking of the Alzheimer's process centers on human genes critical for the healthy functioning of mitochondria, the energy factories of the cell, which are riddled with mobile chunks of DNA called Alu elements. If these "jumping genes" lose their normal controls as a person ages, they could start to wreak havoc on the machinery that supplies energy to brain cells -- leading to a loss of neurons and ultimately dementia, the researchers say. And if this "Alu Neurodegeneration Hypothesis" holds up, it could help identify people at risk sooner, before they develop symptoms, or point to new ways to delay onset or slow progression of the disease, said study co-author Peter Larsen, Ph.D., Senior Research Scientist in co-author Biology Professor Anne Yoder's lab at Duke. The researchers describe the Alu neurodegeneration hypothesis in a paper published online on March 8, 2017 in Alzheimer's & Dementia: The Journal of the Alzheimer's Association. The open-access article is titled “The Alu Neurodegeneration Hypothesis: A Primate-Specific Mechanism for Neuronal Transcription Noise, Mitochondrial Dysfunction, and Manifestation of Neurodegenerative Disease.” The dominant idea guiding Alzheimer's research for 25 years has been that the disease results from the abnormal buildup of hard, waxy amyloid plaques in the parts of the brain that control memory.

Exploring New Complication from an Emergent Tickborne Parasite—Asplenic Patients at Increased Risk of WAHA After Treatment for Babesiosis

Babesiosis is a rare, but increasingly common, disease spread by ticks. After a bite from an infected tick, microscopic malaria-like parasites are transmitted into the host where they can infect and destroy red blood cells, causing nonimmune hemolytic anemia. Treatment with antimicrobials usually clears the parasite and resolves the anemia. However, sporadic cases of warm-antibody autoimmune hemolytic anemia (WAHA) have been observed in patients after treatments for babesiosis. This autoimmune form of anemia occurs when the body attacks its own red blood cells, eliminating these cells from circulation. To better understand this complication, Brigham and Women’s Hospital (BWH) researchers led by Ann Wolley, M.D., and Francisco Marty, M.D., of the Division for Infectious Diseases at BWH conducted a retrospective analysis of patients who had been cared for at BWH from January 2009 through June 2016. Of 86 patients diagnosed with babesiosis during that time, six developed WAHA two to four weeks later, after the parasitic infection had been resolved. These six cases are presented in a study published online in the New England Journal of Medicine on March 9, 2017. The NEJM article is titled “Post-Babesiosis Warm Autoimmune Hemolytic Anemia.” In general, people who have weakened immune systems and those who have undergone splenectomy are at higher risk for severe and relapsing babesiosis, but WAHA after babesiosis in patients without history of autoimmune diseases had not been defined previously. All six babesiosis patients with WAHA were asplenic, meaning that their spleens had previously been removed. The researchers found that WAHA was much more common among asplenic patients with babesiosis, affecting as many as one in three of these patients. Many of these patients needed to receive immunosuppressive treatment to address WAHA.

New Centrifugal Microfluidic Platform (Exodisc) Enables Rapid, Size-Selective, and Efficient Isolation and Analysis of Nanoscale Extracellular Vesicles (EVs) from Raw Biological Samples; Utility in Cancer Diagnostics Seen

A team of researchers, led by Professor Yoon-Kyoung Cho of the School of Life Sciences at UNIST (Ulsan National Institute of Science and Technology in the Republic of Korea) has recently developed a new technique that effectively identifies cancer-causing substances in the urine or blood. In the study, Professor Cho, a group leader at the Institute for Basic Science (IBS) Research Center for Soft and Living Matter (CSLM) in the Republic of Korea, presented an integrated centrifugal microfluidic platform (Exodisc), a device that isolates extracellular vesicles (EVs) from urine. The results of the study were published (online on January 9, 2017) in the February 2017 issue of ACS Nano. The article is titled “Exodisc for Rapid, Size-Selective, and Efficient Isolation and Analysis of Nanoscale Extracellular Vesicles from Biological Samples.” The research team expects that this may be potentially useful in clinical settings to test urinary EV-based biomarkers for cancer diagnostics. Extracellular vesicles (EVs) are cell-derived nanovesicles (40-1,000 nm in size), present in almost all types of body fluids, which play a vital role in intercellular communication and are involved in the transport of biological signals for regulating diverse cellular functions. Despite the increasing clinical importance of EVs as potential biomarkers in the diagnosis and prognosis of various diseases, current methods of EV isolation and analysis suffer from complicated procedures with long processing times. For instance, even ultracentrifugation (UC), the most commonly used method for EV isolation, requires time-consuming steps involving centrifugation and acquisition of large sample volumes, and the results suffer from low yield and purity.

CRISPR-Cas9 Successfully Used to Modify Archaeal Species for First Time; Technique Allows Much More Rapid Generation of Mutants for Study; Utility Seen for Global Climate Change Studies

A new study by Dr. Bill Metcalfe, G. William Arends Professor of Microbiology at the University of Illinois, and his postdoctoral Fellow Dr. Dipti Nayak, has documented the use of CRISPR-Cas9-mediated genome editing in the third domain of life, Archaea, for the first time. The ground-breaking work, reported online on March 6, 2017 in PNAS, has the potential to vastly accelerate future studies of these organisms, with implications for research including global climate change. Dr. Metcalf and Dr. Nayak are members of the Carl R. Woese Institute for Genomic Biology at Illinois. The PNAS article is titled “Cas9-Mediated Genome Editing in the Methanogenic Archaeon Methanosarcina acetivorans.” "Under most circumstances, our model archaeon, Methanosarcina acetivorans, has a doubling time of 8 to 10 hours, as compared to E. coli, which can double in about 30 minutes. What that means is that doing genetics, getting a mutant, can take months--the same thing would take three days in E. coli," explains Dr. Nayak. "What CRISPR-Cas9 enables us to do, at a very basic level, is speed up the whole process. It removes a major bottleneck... in doing genetics research with this archaeon.” "Even more," continues Dr. Nayak, "with our previous techniques, mutations had to be introduced one step at a time. Using this new technology, we can introduce multiple mutations at the same time. We can scale up the process of mutant generation exponentially with CRISPR." CRISPR, short for Clustered Regularly Interspaced Short Palindromic Repeats, began as an immune defense system in archaea and bacteria. By identifying and storing short fragments of foreign DNA, Cas (CRISPR-associated system) proteins are able to quickly identify that DNA in the future, so that it can then quickly be destroyed, protecting the organism from viral invasion.

American Society of Human Genetics (ASHG) Opposes H.R.1313 “Preserving Employee Wellness Programs Act”--Bill Would Undermine Genetic Privacy Protections, ASHG Maintains

In a March 8, 2017 press release, the American Society of Human Genetics (ASHG) announced that it opposes H.R.1313, the Preserving Employee Wellness Programs Act, introduced on March 2,2017 and scheduled for markup by the House Education and the Workforce Committee on March 8, 2017. If enacted, this bill would fundamentally undermine the privacy provisions of the Genetic Information Nondiscrimination Act (GINA) and the Americans with Disabilities Act (ADA), the ASHG maintains. “We urge the Committee not to move forward with consideration of this bill,” said ASHG President Nancy J. Cox, Ph.D. “As longtime advocates of genetic privacy, we instead encourage the Committee to pursue ways to foster workplace wellness and employee health without infringing upon the civil rights afforded by ADA and GINA.” According to the ASHG, a key component of the ADA and GINA Acts is that they prevent workers and their families from being coerced into sharing sensitive medical or genetic information with their employer. For GINA, genetic information encompasses not only employees’ genetic test results, but also their family medical histories. H.R.1313 would effectively repeal these protections by allowing employers to ask employees invasive questions about their and their families’ health, including genetic tests they, their spouses, and their children may have undergone, the ASHG maintains. GINA’s requirement that employees’ genetic information collected through a workplace wellness program only be shared with health care professionals would no longer apply. The ASHG said that the bill would also allow employers to impose financial penalties of up to 30 percent of the total cost the employee’s health insurance on employees who choose to keep such information private.

Study Finds 63 Alterations in Human Genome That Modestly Increase Risk of Premature Male-Pattern Baldness; Short Stature Among Associations Implicated; Link with Prostate Cancer Confirmed

Short men may have an increased risk of becoming bald prematurely. An international genetic study under the leadership of the University of Bonn at least points in this direction. During the study, the scientists investigated the genetic material of more than 20,000 men. Their data show that premature hair loss is linked to a range of various physical characteristics and illnesses. The work was published online on March 8, 2017 in Nature Communications. The open-access article is titled “Meta-Analysis Identifies Novel Risk Loci and Yields Systematic Insights into the Biology of Male-Pattern Baldness.” It has already long been known that men with premature hair loss suffer from heart diseases and prostate cancer somewhat more often. The new genetic data now confirm suspicions that there are further connections to other characteristics and illnesses. In their study, the researchers analyzed genetic data from approximately 11,000 men with premature baldness. Approximately12,000 men with no hair loss served as a control. The participants came from seven different countries. “We were thus able to identify 63 alterations in the human genome that increase the risk of premature hair loss,” explains Dr. Stefanie Heilmann-Heimbach. The human geneticist at the University of Bonn is one of the lead authors of the international study. “Some of these alterations were also found in connection with other characteristics and illnesses, such as reduced body size, earlier occurrence of puberty, and various cancers.” The genetic findings also confirm the link between hair loss and an increased risk of prostate cancer. The link with heart disease is much more complicated. Genes that reduce the risk were found along with genes that increase the risk.

March 7th

Exosome-Based Breakthrough May Make Non-Invasive Blood Test Feasible for Detecting Cancer; Breast Cancer Study Reveals Phosphoproteins Isolated from ECVs As Potential Biomarkers; Earlier Detection and More Facile Monitoring May Be Enabled

Doctors may soon be able to detect and monitor a patient’s cancer with a simple blood test, reducing or eliminating the need for more invasive procedures, according to the results of new research by Purdue University scientists and colleagues. W. Andy Tao, Ph.D., a Professor of Biochemistry and member of the Purdue University Center for Cancer Research, and collaborators identified a series of proteins, isolated from extracellular vesicles (ECVs) in blood plasma, that, when elevated, signify that the patient has cancer. The findings were published online on March 7, 2017 in PNAS. The article is titled “Phosphoproteins in Extracellular Vesicles As Candidate Markers for Breast Cancer.” Dr. Tao’s work was done with samples from breast cancer patients, but it is possible the method could work for any type of cancer and other types of diseases. The work relies on analysis of sub-cellular vesicles (ECVs known as “microvesicles” and “exosomes”) in blood plasma. Protein phosphorylation, the addition of a phosphate group to a protein can lead to cancer cell formation. So, phosphorylated proteins, known as phosphoproteins, have been seen as prime candidates for cancer biomarkers. Until now, however, scientists weren’t sure identification of phosphoproteins in blood was possible because the liver releases phosphatase into the bloodstream, which dephosphorylates proteins. “There are so many types of cancer, even multiple forms for different types of cancer, that finding biomarkers has been discouraging,” Dr. Tao said. “This is definitely a breakthrough, showing the feasibility of using phosphoproteins in blood for detecting and monitoring diseases.” Dr. Tao and his colleagues found nearly 2,400 phosphoproteins in a blood sample and identified 144 that were significantly elevated in cancer patients.

Study Reveals Association Between Type 2 Diabetes and Risk of Death from Cancer in East and South Asians

A new study published online on March 7, 2017 in Diabetologia (the journal of the European Association for the Study of Diabetes [EASD]) reveals that type 2 diabetes (T2D) is associated with a 26% increase in the risk of death from cancer in Asians, as well as increases in the risk of death from site-specific cancers that can be even greater. The research conducted by Dr. Yu Chen (Associate Professor of Epidemiology at the Department of Population Health at New York University School of Medicine) and colleagues, as well as researchers from institutes across America and Asia, looked into the relationship between T2D and cancer deaths across cohort studies conducted in seven Asian countries. There is increasing evidence of an association between T2D and an individual's risk of developing cancer or dying from the disease. Most of the studies into this relationship have looked only at Western populations, but with diabetes becoming increasingly prevalent throughout Asia, it is important to understand whether the risk of developing cancer in Asians with T2D is similar to that seen in the West, or whether they face different, and possibly greater risks than white western populations. Earlier research had suggested that at any given body mass index (BMI), Asians are more susceptible to developing insulin resistance, and go on to have a higher prevalence of T2D in comparison with people of European extraction. Although there have been previous studies of diabetes and site-specific cancer risk in East Asian populations, the authors note that the majority only considered one or a few cancer types, included only a small number of patients with diabetes, or didn't control for other important risk factors such as obesity.

Zone in with Zon: “Evolving Polymerases to Do the Impossible”

In his March 7, 2017 Zone-in-with-Zon blog post, “Evolving Polymerases to Do the Impossible” (http://zon.trilinkbiotech.com/), Dr. Jerry Zon describes recent work (http://www.nature.com/nchem/journal/v8/n6/full/nchem.2493.html) of Professor Floyd Romesberg of the Scripps Research Institute Department of Chemistry, and his team, as “a tour de force of experimental methodology” that has evolved nucleic acid polymerases into mutant polymerases that can do what previously seemed impossible. Romesberg’s lab has, Dr. Zon writes, “successfully achieved what I think of as ‘multiple molecular moonshots,’ wherein a Taq polymerase (which normally reads and writes DNA during PCR), was evolved by novel selection (SELEX) methods into mutant polymerases that are able to transcribe DNA into 2’-O-methyl (2’-OMe) RNA, and reverse-transcribe 2’-OMe RNA into DNA for PCR/sequencing…This was exemplified using a 60-mer DNA template and 18-mer 2’-OMe RNA primer to produce a fully-modified 48-mer 2’-OMe RNA by means of an evolved mPol and all four A, G, C and U 2’-OMe NTPs, which I am proud to say were purchased from TriLink BioTechnologies! This type of molecular evolution of a polymerase has no precedent.” With regard to the significance of this achievement, Dr. Zon said the following. “The present study is the first to evolve an mPol for reverse transcription of fully modified 2’-OMe RNA into DNA, which can then be amplified by PCR and/or sequenced, thereby opening the door for a variety of new analytical methods. Most importantly, the molecular mechanism by which these remarkable mPol activities were evolved, namely, the stabilization of an interaction between the ‘thumb and fingers domains,’ may be general and thus useful for the optimization of other Pols.

Detailed Chemical Structure of P22 Virus Resolved

Scientists at Baylor College of Medicine, the Lawrence Berkeley National Laboratory, Massachusetts Institute of Technology, and Purdue University have completed a model of unprecedented near-atomic resolution of the chemical structure of the P22 virus. The study was published online on March 7, 2017 in PNAS. The open-access article is titled “Accurate Model Annotation of a Near-Atomic Resolution Cryo-EM Map.” For nearly 30 years, the laboratory of Dr. Wah Chiu, Distinguished Service Professor and Alvin Romansky Professor of Biochemistry and Molecular Biology at Baylor and senior author of the paper, has been applying electron cryomicroscopy and computer reconstruction techniques to determine the 3-D structures of biological nanomachines, such as the P22 virus. This virus is a bacteriophage -- a type that infects bacteria, in this case Salmonella -and has been extensively studied through genetics, biochemistry, and biophysics. Nevertheless, its precise chemical structure has remained unresolved. "In 2011, we published a structure of the P22 virus that allowed us to trace out a majority of the protein backbone with certainty, but we could not visualize the fine details, such as individual, small side chains," said co-first author Corey Hryc, a graduate student in the Chiu lab. "Since then, the technology in the microscopes has improved; we have new detectors that allow us to record better- and higher-contrast images to improve the resolution of our data. In addition, we have new processing algorithms that allow us to increase our ability to resolve the structure." "The novelty of this work is that we took more than 20,000 two-dimensional individual images of the P22 virus with the electron cryomicroscope and combined them using computational protocols to produce a 3-D map with unprecedented detail," Dr. Chiu said.