Syndicate content

Archive - Apr 2017

April 22nd

Atomic-Level Motion in Proteins May Drive Bacteria's Ability to Evade Immune System Defenses

A study from Indiana University (IU) has found evidence that extremely small changes in how atoms move in bacterial proteins can play a big role in how these microorganisms function and evolve. The research, recently published online on March 27, 2017 in PNAS, is a major departure from prevailing views about the evolution of new functions in organisms, which regarded a protein's shape, or "structure," as the most important factor in controlling its activity. The PNAS article is titled “Entropy Redistribution Controls Allostery in a Metalloregulatory Protein.” "This study gives us a significant answer to the following question: How do different organisms evolve different functions with proteins whose structures all look essentially the same?" said Dr. David Giedroc (photo), Lilly Chemistry Alumni Professor in the IU Bloomington College of Arts and Sciences' Department of Chemistry, who is senior author on the study. "We've found evidence that atomic motions in proteins play a major role in impacting their function." The study also provides new insights into how microorganisms respond to their host's efforts to limit bacterial infection. Serious bacterial infections in people include severe health-care-associated infections and tuberculosis, both of which have grown increasingly common over the past decade due to rising drug resistance in bacteria. Approximately 480,000 people worldwide develop multidrug-resistant (MDR) tuberculosis each year, for example, according to the Centers for Disease Control and Prevention (CDC). "What we've shown is atomic-level motional disorder -- or entropy -- can impact gene transcription to affect the function of proteins in major ways, and that these motions can be 'tuned' evolutionarily," said Dr. Daiana A. Capdevila, a postdoctoral researcher in Dr. Giedroc's lab, who is first author on the study.

Scientists Use CRISPR Editing to Restore Visual Function in Two Mouse Models of Retinitis Pigmentosa

Using the gene-editing tool CRISPR/Cas9, researchers at University of California San Diego School of Medicine and Shiley Eye Institute at UC San Diego Health, with colleagues in China, have reprogrammed mutated rod photoreceptors to become functioning cone photoreceptors, reversing cellular degeneration and restoring visual function in two mouse models of retinitis pigmentosa. The findings are published in the April 21 advance online issue of Cell Research. Retinitis pigmentosa (RP) is a group of inherited vision disorders caused by numerous mutations in more than 60 genes. The mutations affect the eyes' photoreceptors, specialized cells in the retina that sense and convert light images into electrical signals sent to the brain. There are two types: rod cells that function for night vision and peripheral vision, and cone cells that provide central vision (visual acuity) and discern color. The human retina typically contains 120 million rod cells and 6 million cone cells. In RP, which affects approximately 100,000 Americans and 1 in 4,000 persons worldwide, rod-specific genetic mutations cause rod photoreceptor cells to dysfunction and degenerate over time. Initial symptoms are loss of peripheral and night vision, followed by diminished visual acuity and color perception as cone cells also begin to fail and die. There is no treatment for RP. The eventual result may be legal blindness. In their published research, a team led by senior author Kang Zhang, M.D., Ph.D., Chief of Ohthalmic Genetics, Founding Director of the Institute for Genomic Medicine and Co-Director of Biomaterials and Tissue Engineering at the Institute of Engineering in Medicine, both at UC San Diego School of Medicine, used CRISPR/Cas9 to deactivate a master switch gene called Nrl and a downstream transcription factor called Nr2e3.

Serendipitous Finding Leads to Promising Mouse Model for Severe Genetic Disorder Known As NGY1 Deficiency

Researchers from the RIKEN Global Research Cluster in Japan have developed a potential mouse model for the genetic disorder known as an NGLY1 deficiency. Published online on April 20, 2017 in the journal PLOS Genetics, the study describes how a complete knockout of the Ngly1 gene in mice leads to death just before birth, which can be partially rescued by a second knockout of another gene called Engase. When related genes in the mice used for making the knockouts are variable, the doubled-deletion mice survive and have symptoms that are analogous to humans with NGLY1-deficiency, indicating that these mice could be useful for testing potential therapies. NGLY1-deficiency is a relatively newly discovered genetic disorder, with the first patient identified in 2012. The symptoms are severe, and include delayed development, disordered movement, low muscle tone and strength, and the inability to produce tears. Understanding how lack of NGLY1 leads to these symptoms is critical when considering targets for therapeutic interventions, and creating useful animal models of the disease is therefore equally important. The RIKEN team has already had some success studying the consequences of Ngly1 deficiency in cultured animal cells. The Ngly1 gene codes for an enzyme that helps remove sugar chains from proteins that are scheduled for degradation. Their research showed that when Ngly1 was absent, sugars normally removed by Ngly1 were improperly removed by another enzyme called ENGase. Knocking out the ENGase gene led to normal protein degradation. The open-access PLOS Genetis article is titled “Lethality of Mice Bearing a Knockout of the Ngly1-Gene Is Partially Rescued by the Additional Deletion of the Engase Gene.”

April 20th

Circulating Serum Exosomes Have Distinct Pattern of miRNA Expression in Relapsing-Remitting Multiple Sclerosis; Pattern May Be Used As Biomarker for Identifying & Monitoring MS Relapse

Using next-generation sequencing, researcher have shown that circulating serum exosome in patients with relapsing-remitting multiple sclerosis (RRMS) exhibit a distinct pattern of micro-RNA that may be used as a biomarker to distinguish and monitor MS relapse. In an article published on April 15, 2017 in Annals of Neurology, researchers from the Medical University of Lodz in Lodz, Poland, show that, of 15 different classes of transcripts detected, 4 circulating exosomal sequences within the miRNA category were differentially expressed in RRMS patients versus healthy controls. These were hsa-miR-122-5p, hsa-miR-196b-5p, hsa-miR-301a-3p, and hsa-miR-532-5p. Serum exosomal expression of these miRNAs was significantly decreased during relapse in RRMS. These miRNAs were also decreased in patients with a gadolinium enhancement on brain magnetic resonance imaging. In vitro secretion of these miRNA by peripheral blood mononuclear cells was also significantly impaired in RRMS. Specifically, the researchers used next-generation sequencing to define the global RNA profile of serum exoxomes in 19 RRMS patients (9 in relapse, 10 in remission) and 9 healthy controls. The scientists analyzed 5 million reads and over 50,000 transcripts per sample, including a detailed analysis of microRNA (miRNA) differentially expressed in RRMS. The authors conclude that circulating exosomes have a distinct RNA profile in RRMS. Because putative targets for these miRNAs include the signal transducer and activator of transcription 3 and the cell cycle regulator aryl hydrocarbon receptor, the data suggest a disturbed cell-to-cell communication in this disease. Thus, exosomal miRNA might represent a useful biomarker to distinguish MS relapse, they conclude.

April 20th

Naked Mole Rat Struts More Stuff; Longest-Lived Rodent Shows Remarkable Ability to Withstand Oxygen Deprivation

Deprived of oxygen, naked mole-rats can survive by metabolizing fructose just as plants do, researchers report in the April 21, 2017 issue of Science. The article is titled “Fructose-Driven Glycolysis Supports Anoxia Resistance in the Naked Mole-Rat."Understanding how the animals do this could lead to treatments for patients suffering crises of oxygen deprivation, as in heart attacks and strokes. "This is just the latest remarkable discovery about the naked mole-rat -- a cold-blooded mammal that lives decades longer than other rodents, rarely gets cancer, and doesn't feel many types of pain," says Thomas Park, Ph.D., Professor of Biological Sciences at the University of Illinois at Chicago (UIC), who led an international team of researchers from UIC, the Max Delbrück Institute in Berlin, and the University of Pretoria in South Africa on the study. In humans, laboratory mice, and all other known mammals, when brain cells are starved of oxygen they run out of energy and begin to die. But naked mole-rats have a backup: their brain cells start burning fructose, which produces energy anaerobically through a metabolic pathway that is only used by plants - or so scientists thought. In the new study, the researchers exposed naked mole-rats to low oxygen conditions in the laboratory and found that they released large amounts of fructose into the bloodstream. The fructose, the scientists found, was transported into brain cells by molecular fructose pumps that in all other mammals are found only on cells of the intestine. "The naked mole-rat has simply rearranged some basic building-blocks of metabolism to make it super-tolerant to low oxygen conditions," said Dr. Park, who has studied the strange species for 18 years. At oxygen levels low enough to kill a human within minutes, naked mole-rats can survive for at least five hours, Dr.

Personalized Medicine 10.0 Discusses Recent Milestones and Future of Discovery Impacting Precision Management of Human Health and Disease on June 2 in San Francisco

Since 2008, the Personalized Medicine Conference has addressed challenging themes in genomic health through presentations and discussions among prominent scientific leaders in the biotechnology, pharmaceutical, and medical communities. In partnership with San Francisco State University’s Department of Biology, SF State Alumni, and the City of South San Francisco, the conference has showcased world-class science and striven to be the bellwether of the latest and greatest in personalized, genomic, and precision medicine. The conference has also been a valued networking opportunity for students and accomplished professionals alike, mirroring similar meetings serving the professional Biotech community. On June 2, 2017, San Francisco State University’s Department of Biology will host Personalized Medicine 10.0, a look back at the best topics and speakers over the last decade. The title for the upcoming meeting, (“Has It Changed Your Life?”) will review past conference topics, assess predictions of the past, and look to the future of personalized medicine in the coming decades. Aside from the stunning science itself, a wide variety of topics have been addressed, including clinical advances and applications, study design, business opportunities, regulatory issues, and the ethical and cultural impacts of personalized medicine. This year, the conference will revisit themes in bioinformatics, data management, oncology, epigenetics, genomics of rare diseases, nth-generation sequencing technologies, the microbiome, unprecedented developments in gene therapy and genome editing, and will project where the business and science of personalized medicine will be in the future.

Natural Experiment, Dogged Investigation, Yield Clue to Devastating Neurological Disease; Tubb4A Mutation Affects Myelin Production & Maintenance, Leads to Buildup of Microtubules in Oligodendrocytes

After a 29-year quest, Dr. Ian Duncan, a Professor of Veterinary Medicine at the University of Wisconsin-Madison, has finally pinpointed the cause of a serious neurologic disease in a colony of rats.” His new study, carried out with collaborators was published, online on April 10, 2017 in the journal Annals of Neurology, is more than the conclusion of a personal and intellectual odyssey, however. Dr. Duncan has just shown that the rat abnormality closely resembles a rare human mutation that results in severe neurologic dysfunction. The human disease can affect many parts of the brain and has been called H-ABC. Crucially, both abnormalities affect the production and maintenance of myelin -- the white, fatty insulation that nerves need to carry electrical signals. The deterioration of myelin in the brain causes the common neurologic disorder multiple sclerosis. Myelin defects are also at the root of the leukodystrophies -- genetic disorders that include H-ABC. Dr. Duncan's examination of nervous system tissue from both conditions revealed a telltale overgrowth of tiny tubes known as microtubules in oligodendrocytes, the cells that make myelin and deposit it on nerve fibers. The Annals study offers a window on a rare disease -- and also on the broader issue of myelin formation. "For a human disease, we have provided a model that did not exist before," Dr. Duncan says, "and we've shown that it's based on microtubule accumulation in oligodendrocytes. Now we've seen similar changes in the rats and the human cells." The new article is titled “A Mutation in the Tubb4a Gene Leads to Microtubule Accumulation With Hypomyelination and Demyelination." The roots of the new publication include a chance observation by two Chilean scientists, a couple of eyebrow-raising trips across the U.S.

New Weapon in Fight Against Antibiotic Resistance Discovered; ID of Key Sodium Pump in Chlamydia trachomatis and Development of Targeted Drug to Inhibit Pump Are “Tremendously Exciting,” Researcher Says

Scientists at St. Boniface Hospital Albrechtsen Research Centre and the University of Manitoba in Canada have developed a drug that combats two of the top ten "priority pathogens" recently defined by the World Health Organization (WHO) as antiobiotic-resistant bacteria requiring new interventions1. The drug, dubbed PEG-2S, has received a provisional patent, and its development is highlighted in a study published online on April 20, 2017 in the Canadian Journal of Physiology and Pharmacology (CJPP). Without affecting healthy cells, the drug prevents the proliferation of a harmful bacteria that possesses a specific type of energy supply shared by a number of other bacteria. The open-access article, entitled "Development of a Novel Rationally Designed Antibiotic to Inhibit A Nontraditional Bacterial Target,” revealed that a variety of bacteria share a unique respiratory sodium pump (NQR) that supplies energy vital to the bacteria's survival. The study showed that the drug in question, PEG-2S, inhibits the function of the NQR pump and the production and growth of Chlamydia trachomatis bacteria. The drug is highly targeted and only impacts bacterial cells with NQR pumps and is not toxic to normal, healthy cells. The list of NQR-possessing bacteria is growing steadily as genomic information becomes available. With more than 20 different pathogenic bacteria containing NQR, the possibility for this drug to avoid multidrug resistance through NQR inhibition represents a potential breakthrough in antibiotic design. Traditional targets for antibiotics are limited; no new antibiotics have been discovered since 1987. Only two antibiotics have received U.S. FDA approval since 2009. "New drugs are not being approved because they share the same target to which the bacteria are developing resistance.

April 19th

Underlying Cause of Form of Macular Degeneration Is Characterized

Named for Friedrich Best, who characterized the disease in 1905, Best disease, also known as vitelliform macular dystrophy, affects children and young adults and can cause severe declines in central vision as patients age. The disease is one in a group of conditions known as bestrophinopathies, all linked to mutations in the BEST1 gene. This gene is expressed in the retinal pigment epithelium (RPE), a layer of cells that undergirds and nourishes photoreceptor cells, the rods and cones responsible for vision. Despite the century of work on bestrophinopathies and the identification of genetic mutations responsible for the conditions, no one had identified the underlying mechanism that leads to the vision loss seen in Best disease until now.Using an animal model of Best disease in combination with biochemical and optical assays, a team of researchers at the University of Pennsylvania (Penn) has pinpointed a number of abnormalities that give rise to the impairments seen in the disease. "The genetic cause of the disease has been known for 20 years, but no one had samples of patients at the stage when the disease starts," said Karina E. Guziewicz, Research Assistant Professor of Ophthalmology in Penn's School of Veterinary Medicine (Penn Vet) and lead author on the study. But "we were now able to pinpoint this early stage and find out what factors trigger the development of lesions." The new information sets the team up for testing a gene therapy to treat the disease, as the researchers will be able to observe whether or not these structural and biochemical abnormalities have been corrected. "Now that we understand what we're seeing, it allows us to judge the success of a particular therapy," said Gustavo D. Aguirre, Professor of Medical Genetics and Ophthalmology at Penn Vet.

Cannabis-Based Medicine May Cut Seizures in Half for Those with Difficult-to-Treat Epilepsy; “It May Become an Important New Treatment Option for These Patients," Physician States

Taking cannabidiol may cut seizures in half for some children and adults with Lennox-Gastaut syndrome (LGS), a severe form of epilepsy, according to new information released today from a large-scale controlled clinical study that will be presented at the American Academy of Neurology's 69th Annual Meeting in Boston, April 22 to 28, 2017. Cannabidiol is a molecule from the cannabis plant that does not have the psychoactive properties that create a "high. “ Nearly 40 percent of people with LGS, which starts in childhood, had at least a 50 percent reduction in drop seizures when taking a liquid form of cannabidiol compared to 15 percent taking a placebo. When someone has a drop seizure, their muscle tone changes, causing them to collapse. Children and adults with LGS have multiple kinds of seizures, including drop seizures and tonic-clonic seizures, which involve loss of consciousness and full-body convulsions. The seizures are hard to control and usually do not respond well to medications. Intellectual development is usually impaired in people with LGS.Although the drop seizures of LGS are often very brief, they frequently lead to injury and trips to the hospital emergency room, so any reduction in drop seizure frequency is a benefit. "Our study found that cannabidiol shows great promise in that it may reduce seizures that are otherwise difficult to control," said study author Anup Patel, M.D., of Nationwide Children's Hospital Lisa GW and The Ohio State University College of Medicine in Columbus and a member of the American Academy of Neurology. For the randomized, double-blind, placebo-controlled study, researchers followed 225 people with an average age of 16 for 14 weeks.