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Archive - Aug 2013

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August 24th

BT-R3 Receptor Mediates Killing of the Malaria Vector Anopheles gambiae by Bacillus thuringiensis

Researchers at The University of Texas at Dallas (UTD), led by Dr. Lee Bulla, have demonstrated for the first time the selective cytotoxicity of the Bacillus thuringiensis subsp. israelensis Cry4B toxin is mediated by BT-R3. The Cry toxins produced by Bacillus thuringiensis exert their insecticidal activity by binding with high affinity to their cognate cadherin receptors located on the surface of epithelial cells that line the midgut of susceptible insects. In the case of Anopheles gambiae, binding of the Cry4B toxin by BT-R3, in turn, triggers an internal signaling event that turns on a cell death pathway. The novelty of the research done by the UTD scientists is that they were able to establish the direct involvement of the BT-R3 receptor, cloned from Anopheles gambiae, in mediating toxicity of the Cry4B toxin in living cells. This research is reported in an article published in the July 2013 issue of Experimental Biology and Medicine and is a culmination of proteomics, genomics, and bioinformatics strategies developed in the Bulla laboratory. Validation of BT-R3 as a functional receptor for Cry4B exemplifies the power of proteomics, genomics, and bioinformatics to identify target proteins such as the BT-R3 receptor. The process of target selection starts with data mining of archived protein sequences available in various genome and proteome databases, and results in the selection and annotation of candidate proteins based on their potential to mediate insecticidal action. It brings together genome- and proteome-based target identification and target-directed screening for validating the action of insecticidal proteins such as the Cry4B toxin—engineered or otherwise.

August 23rd

New Approach Provides Unprecedented Control of Genome Editing in Flies; Promises Insight into Human Development, Disease

In an era of widespread genetic sequencing, the ability to edit and alter an organism's DNA is a powerful way to explore the information within and how it guides biological function. A paper from the University of Wisconsin–Madison (UW-Madison) published as an open-access article in the August 2013 issue of the journal GENETICS takes genome editing to a new level in fruit flies, demonstrating a remarkable level of fine control and, importantly, the transmission of those engineered genetic changes through generations. Both features are key for driving the utility and spread of an approach that promises to give researchers new insights into the basic workings of biological systems, including embryonic development, nervous system function, and the understanding of human disease. "Genome engineering allows you to change gene function in a very targeted way, so you can probe function at a level of detail" that wasn't previously possible, says Dr. Melissa Harrison, an assistant professor of biomolecular chemistry in the UW–Madison School of Medicine and Public Health and one of the three senior authors of the new study. Disrupting individual genes has long been used as a way to study their roles in biological function and disease. The new approach, based on molecules that drive a type of bacterial immune response, provides a technical advance that allows scientists to readily engineer genetic sequences in very detailed ways, including adding or removing short bits of DNA in chosen locations, introducing specific mutations, adding trackable tags, or changing the sequences that regulate when or where a gene is active. The approach used in the new study, called the CRISPR RNA/Cas9 system, has developed unusually quickly.

Gold Standard for Damage-Free Delivery of Drugs or Biosensors to Cell Interior

Cells are very good at protecting their precious contents — and, as a result, it’s very difficult to penetrate their membrane walls to deliver drugs, nutrients, or biosensors without damaging or destroying the cell. One effective way of doing so, discovered in 2008, is to use nanoparticles of pure gold, coated with a thin layer of a special polymer. But nobody knew exactly why this combination worked so well, or how it made it through the cell wall. Now, researchers at MIT and the Ecole Polytechnique de Lausanne in Switzerland have figured out how the process works, and the limits on the sizes of particles that can be used. Their analysis was published online on August 5, 2013 in the journal Nano Letters, in a paper by graduate students Reid Van Lehn, Prabhani Atukorale, Yu-Sang Yang, and Randy Carney, and professors Alfredo Alexander-Katz, Darrell Irvine, and Francesco Stellacci. Until now, says Van Lehn, the paper’s lead author, “the mechanism was unknown. … In this work, we wanted to simplify the process and understand the forces” that allow gold nanoparticles to penetrate cell walls without permanently damaging the membranes or rupturing the cells. The researchers did so through a combination of lab experiments and computer simulations. The team demonstrated that the crucial first step in the process is for coated gold nanoparticles to fuse with the lipids — a category of natural fats, waxes, and vitamins — that form the cell wall. The scientists also demonstrated an upper limit on the size of such particles that can penetrate the cell wall — a limit that depends on the composition of the particle’s coating. The coating applied to the gold particles consists of a mix of hydrophobic and hydrophilic components that form a monolayer — a layer just one molecule thick — on the particle’s surface.

August 22nd

Brain Scan May Help Diagnose Dyslexia

Approximately 10 percent of the U.S. population suffers from dyslexia, a condition that makes learning to read difficult. Dyslexia is usually diagnosed around second grade, but the results of a new study from MIT suggest that it might be possible to identify those children before they even begin reading, so they can be given extra help earlier. The study, done with researchers at Boston Children’s Hospital, found a correlation between poor pre-reading skills in kindergarteners and the size of a brain structure that connects two language-processing areas. Previous studies have shown that in adults with poor reading skills, this structure, known as the arcuate fasciculus, is smaller and less organized than in adults who read normally. However, it was unknown if these differences cause reading difficulties or result from lack of reading experience. “We were very interested in looking at children prior to reading instruction and whether you would see these kinds of differences,” says Dr. John Gabrieli, the Grover M. Hermann Professor of Health Sciences and Technology, professor of brain and cognitive sciences and a member of MIT’s McGovern Institute for Brain Research. Dr. Gabrieli and Dr. Nadine Gaab, an assistant professor of pediatrics at Boston Children’s Hospital, are the senior authors of a paper describing the study results in the August 14, 2013 issue of the Journal of Neuroscience. Lead authors of the paper are MIT postdocs Zeynep Saygin and Elizabeth Norton. The new study is part of a larger effort involving approximately 1,000 children at schools throughout Massachusetts and Rhode Island. At the beginning of kindergarten, children whose parents give permission to participate are assessed for pre-reading skills, such as being able to put words together from sounds.

Protein-Based Urine Test Predicts Kidney Transplant Outcomes

Levels of a protein in the urine of kidney transplant recipients can distinguish those at low risk of developing kidney injury from those at high risk, a study suggests. The results also suggest that low levels of this protein, called CXCL9, can rule out rejection as a cause of kidney injury. The study was published online on August 22, 2013 in the American Journal of Transplantation. The work was funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. To prevent rejection, kidney transplant recipients typically take immunosuppressive drugs every day. However, these drugs can cause kidney damage and lead to other serious side effects such as cancer, infection, and infertility. Even with immunosuppressive therapy, 10 to 15 percent of kidney recipients experience rejection during the first year after transplantation. Currently, the only definitive way to distinguish rejection from other causes of kidney injury is by performing a biopsy, in which doctors remove a small piece of kidney tissue to look for rejection-associated damage. Although this procedure is generally considered safe, it carries some minor risks for the patient and does not always provide an accurate impression of the overall state of the kidney. "A noninvasive urine test to accurately monitor the risk of kidney rejection could dramatically reduce the need for biopsies and possibly enable doctors to safely reduce immunosuppressive therapy in some patients," said NIAID Director Anthony S. Fauci, M.D.

Fetal Stem Cell Transplantation Favorably Impacts Radiation-Induced Cognitive Dysfunction

Patients receiving cranial irradiation treatment for brain cancer may find the treatment life-saving, but often suffer progressive and debilitating cognitive detriments, including spatial learning and memory deficits. The cognitive deficits are a contributing factor to the often significant adverse impacts on the surviving patients' quality of life after radiation therapy. In an effort to improve post-irradiation cognitive impairment, scientists at the University of California, Irvine, and colleagues at Neuralstem, Inc. (Rockville, MD), have transplanted fetal stem cells into laboratory animals with radiation-induced cognitive impairments and found that this led to a number of cognitive improvements. The study was published online on July 17, 2013 as an early e-publication for the journal Cell Transplantation. "Multiple mechanisms contribute to disrupted cognition following irradiation for patients with central nervous system malignancies. These include the depletion of radiosensitive populations of stem and progenitor cells in the hippocampus," said study co-author Dr. Charles L. Limoli of the Department of Radiation Oncology at the University of California, Irvine. "Interventions to combat long-term brain damage resulting from toxic radiation and chemotherapies therapies have yet to be developed. However, stem cell replacement strategies may provide a much needed intervention." The researchers explored the potential beneficial impact of intra-hippocampal transplantation of fetal-derived human neural stem cells by transplanting the cells into laboratory rats a month after the animals were subjected to cranial irradiation with resulting cognitive deficits. The stem cells were FDA-approved human, fetal-derived neural stem cells provided by Neuralstem, Inc.

Study Shows How SARS Virus Hijacks Host Cells

University of California-Irvine (UC-Irvine) infectious disease researchers and a colleague from the UK have uncovered components of the SARS coronavirus – which triggered a major outbreak of severe acute respiratory syndrome in 2002-2003 – that allow the virus to take over host cells in order to replicate. This insight is critical for a full understanding of any outbreaks caused by such viruses and may prove beneficial in the development of therapies, not only for human coronavirus infections, but for other pathogenic illnesses as well. Study results were published online on August 13, 2013 in the July/August issue of the open-access journal mBio. Megan Angelini, a graduate student in Professor Michael Buchmeier’s laboratory in the Department of Molecular Biology & Biochemistry at UC-Irvine, and colleagues found that three proteins of the SARS coronavirus – nsp3, nsp4, and nsp6 – have the ability to hijack a host cell’s internal membranes and utilize them to make more virus. “Understanding how the virus uses the host cell to reproduce itself could lead to potential therapies for these kinds of pathogens,” said Dr. Buchmeier, who is also deputy director of the Pacific Southwest Regional Center of Excellence for Biodefense & Emerging Infectious Diseases at UC-Irvine. Additionally, he said, because membrane rearrangement is a tactic employed by all known positive-sense, single-stranded RNA viruses, including those responsible for polio and dengue fever, this work adds to that body of knowledge. Although the majority of infections caused by coronaviruses in humans are relatively mild, the SARS outbreak of 2002 and 2003 and the emergence last fall of the Middle East respiratory syndrome (MERS) coronavirus highlight their ability to potentially infect millions around the globe.

A Mother’s Mitochondrial Genes Influence Her Child’s Aging

As we grow older, not only the function of organs slows down. Also, on a cellular level, more and more damage occurs. One reason is that DNA errors accumulate which cause defective cells. Now a team of researchers led by Dr. Nils-Göran Larsson at the Max Planck Institute for Biology of Ageing in Cologne has shown that aging is determined not only by the accumulation of DNA damage that occurs during lifetime but also by damage that we acquire from our mothers. In a study in mice, the researchers have shown that mutations of maternally inherited mitochondrial DNA influence the offspring’s aging process starting from birth. The results were published online in Nature on August 21, 2013. Aging is a complex process, in the course of which more and more damage accumulates within the body’s tissues, cells, and molecules – with serious consequences: organs lose their function and mortality risk increases. Why some people age faster than others has many reasons that are still unsolved. However, damage that occurs within the mitochondria – the cell’s powerhouses – seems to be of particular importance for aging. “The mitochondrion contains its own DNA, the so-called mitochondrial DNA or mtDNA, which changes faster than the DNA in the nucleus, and this has a significant impact on the aging process,” says Dr. Larsson, Director at the Max Planck Institute for Biology of Aging in Cologne and scientist at the Karolinska Institute in Stockholm. Together with Dr. Lars Olson, also a scientist at the Karolinska Institute, he led the study. “Many mutations in the mitochondria gradually disable the cell’s energy production.” Contrary to previous findings, not only mutations that accumulate during lifetime play a role: “Surprisingly, we discovered that our mother’s mitochondrial DNA seems to influence our own aging,” says Dr.

Genetic Signatures of DNA-Damaging Processes That Lead to Cancer

Researchers from the Wellcome Trust Sanger Institute and collaborating institutions have provided the first comprehensive compendium of mutational processes that drive tumor development. Together, these mutational processes explain most mutations found in 30 of the most common cancer types. This new understanding of cancer development could help in the treatment and prevention of a wide range of cancers. The results of this seminal work were published online in Nature on August 14, 2013. Each mutational process leaves a particular pattern of mutations, an imprint or signature, in the genomes of cancers it has caused. By studying 7,042 genomes of people with the most common forms of cancer, the research team uncovered more than 20 signatures of processes that mutate DNA. For many of the signatures, they also identified the underlying biological process responsible. All cancers are caused by mutations in DNA occurring in cells of the body during a person's lifetime. Although we know that chemicals in tobacco smoke cause mutations in lung cells that lead to lung cancers and ultraviolet light causes mutations in skin cells that lead to skin cancers, we have remarkably little understanding of the biological processes that cause the mutations which are responsible for the development of most cancers. "We have identified the majority of the mutational signatures that explain the genetic development and history of cancers in patients," says Dr. Ludmil Alexandrov first author from the Wellcome Trust Sanger Institute. "We are now beginning to understand the complicated biological processes that occur over time and leave these residual mutational signatures on cancer genomes." All of the cancers contained two or more signatures, reflecting the variety of processes that work together during the development of cancer.

August 21st

MERS Virus Discovered in Bat Near Site of Human Outbreak in Saudi Arabia

A 100% genetic match for Middle East Respiratory Syndrome (MERS) virus has been discovered in an insect-eating bat in close proximity to the first known case of the disease in Saudi Arabia. The discovery points to the likely animal origin for the disease, although researchers say that an intermediary animal is likely also involved. Led by a team of investigators from the Center for Infection and Immunity (CII) at Columbia University's Mailman School of Public Health, EcoHealth Alliance, and the Ministry of Health of the Kingdom of Saudi Arabia, the study is the first to search for an animal reservoir for MERS in Saudi Arabia, and the first to identify such a reservoir by finding a genetic match in an animal. The results appear online in the November 2013 issue of Emerging Infectious Diseases, a journal of the U.S. Centers for Disease Control and Prevention. "There have been several reports of finding MERS-like viruses in animals. None were a genetic match. In this case, we have a virus in an animal that is identical in sequence to the virus found in the first human case. Importantly, it's coming from the vicinity of that first case," says W. Ian Lipkin, M.D., director of the Center for Infection and Immunity and a co-author of the study. MERS was first described in September 2012 and continues to spread. Close to 100 cases have been reported worldwide, 70 of them from Saudi Arabia. The causative agent, a new type of coronavirus, has been determined; however, the origin of the virus has been unknown until now. Over a six-week period during field expeditions in October 2012 and April 2013, the researchers collected more than 1,000 samples from seven bat species in regions where cases of MERS were identified in Bisha, Unaizah, and Riyadh.