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News Article | August 22, 2016
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NewsScientists have discovered a new way to attack Staphylococcus aureus bacteria. The team has revealed how the bacteria regulates its salt levels. Contributed Author: Imperial College LondonTopics: Cell Biology

The basics of sexual reproduction appear to be very simple: sperm plus egg cell equals embryo. But within cells, it gets trickier: simply combining the genetic content of two cells would lead to disaster; every generation would carry twice as much DNA as its parents. To prevent this, egg and sperm cells halve their genetic content before fusing. A similar issue arises with structures called centrioles. Centrioles act as anchors for the spindle apparatus, which pulls genetic material apart during cell division. If a fertilised egg has centrioles from both the egg cell and the sperm, its genetic material will be pulled in too many directions and it will be shared unevenly between the resulting cells, which is likely to make the embryo unviable. So in animals, before an egg cell is fertilised by a sperm, its centrioles are eliminated, ensuring that the resulting embryo receives only the sperm's centrioles. When a cell is dividing, each anchor point is actually a pair of centrioles: a mature 'mother' centriole, and an immature 'daughter' centriole. "Mother centrioles are known to be very, very stable," says Péter Lénárt from EMBL, who led the work. "In the worm C.elegans, people have tagged a mother centriole in the sperm, and found it still intact in the late embryo!" To investigate how the egg cell manages to rid itself of such a resilient structure, Joana Pinto, a PhD student in the Lénárt lab, developed fluorescent tags for mother and daughter centrioles in a starfish egg cell and recorded the entire process of eliminating them. She found that the egg cell expels the two mother centrioles, jettisoning them into the two 'polar bodies' that also serve as dumps for its surplus genetic material. One daughter centriole is also dragged into a polar body, leaving the other daughter centriole alone in the egg cell. "This only happens in egg cell formation," says Lénárt. "In a normal division a single daughter centriole is never left alone." "It seems that if this daughter is alone it is unstable, and will be degraded," says Pinto. "But if we make a mother centriole stay in the cell, it doesn't get destroyed, so the fertilised egg ends up with a tripolar spindle and can't divide." Thanks to further probing aided by an electron microscopy technique developed at EMBL by Yannick Schwab's lab, the scientists found that mother centrioles are expelled into polar bodies thanks to little appendages that centrioles acquire as they mature. Their data suggests that these appendages direct mother centrioles to the cell membrane, ready for ejection. The scientists would like to probe further into how mother centrioles are transported and ejected, and investigate how and why isolated daughter centrioles break down. "Eggs are incredibly diverse - think of chickens, frogs, starfish - so I doubt that this is exactly the same in all animals," says Lénárt. "But underlying that diversity are conserved modules like the centrioles. By understanding the molecular logic of how those modules can be combined in different ways, we can begin to reconstruct how this diversity evolved." More information: Borrego-Pinto et al. Journal of Cell Biology, 21 March 2016. DOI: 10.1083/201510083

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"Cells adopt diverse shapes that are related to how they function. We wondered if cells have the ability to perceive their own shapes, specifically, the curvature of the [cell] membrane," says Drew Bridges, a Ph.D. candidate in the laboratory of Amy Gladfelter, associate professor of biological sciences at Dartmouth College and a scientist in the MBL's Whitman Center. The team focused on the septins, proteins that are usually found near micron-scaled curves in the cell membrane, such as the furrow that marks where the cell will pinch together and divide. Using live-cell imaging at the MBL, they noticed that septins in a novel model system, the fungus Ashbya gossypii, tended to congregate on fungus branches where curvature was highest. They then decided to recreate this natural phenomenon in the lab, using artificial materials they could measure more easily than living cells. Using precisely scaled glass beads coated with lipid membranes, they discovered that septin proteins preferred curves in the 1-3 micron range. They got the same result using human or fungal septins, suggesting that this phenomenon is evolutionarily conserved. "This ability of septins to sense micron-scaled cell curvature provides cells with a previously unknown mechanism for organizing themselves," Bridges says. The idea for the glass bead experiment came from "many rich intellectual discussions with other members of the MBL community," says Bridges, who has accompanied Gladfelter to the MBL each summer since 2012. "Both our collaborations and the imaging resources at MBL were central to this work." More information: Andrew A. Bridges et al, Micron-scale plasma membrane curvature is recognized by the septin cytoskeleton, The Journal of Cell Biology (2016). DOI: 10.1083/jcb.201512029

Home > Press > Are some people more likely to develop adverse reactions to nanoparticle-based medicines? Abstract: The complement system, the human body's first line of defense against blood-borne intruders, is blamed for infusion-related reactions to nanomedicines, but the conventional models used to predict the risk of cardiopulmonary side effects in response to nanopharmaceuticals might not well represent what actually occurs in humans, according to an article in Nucleic Acid Therapeutics, a peer-reviewed journal from Mary Ann Liebert, Inc., publishers. The article is available free for download on the Nucleic Acid Therapeutics website until March 1, 2016. S. Moein Moghimi, University of Copenhagen, Denmark, questions the validity of pig and sheep models to predict the risk of infusion-related reactions to nanoparticle-based medicines in humans. In the article "Complement Propriety and Conspiracy in Nanomedicine: Perspective and a Hypothesis", the author proposes that some individuals may be highly sensitive to nanoparticles due to a particular liver or lung disorder or a predisposition to liver or lung disease. Future studies should compare human lung tissue from patients with and without liver and inflammatory lung disease to explore the role of the complement system in nanopharmaceutical-related infusion reactions. In addition, a more realistic and predictive model for examining the risk of cardiopulmonary side effects associate with nanomedicines may be a rat with cirrhosis of the liver, suggests Dr. Moghimi. "We are acutely aware of the need for carefully designed and conducted clinical trials to be properly informed by the best available evidence from in vitro and in vivo models. Nucleic Acid Therapeutics encourages and welcomes opinion pieces as exemplified by Dr. Moghimi's contribution that help facilitate safe translation to the clinic," says Executive Editor Graham C. Parker, PhD, The Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine, Children's Hospital of Michigan, Detroit, MI. About Mary Ann Liebert, Inc. Mary Ann Liebert, Inc., publishers is a privately held, fully integrated media company known for establishing authoritative peer-reviewed journals in many promising areas of science and biomedical research, including Human Gene Therapy, ASSAY and Drug Development Technologies, Applied In Vitro Toxicology, and DNA and Cell Biology. Its biotechnology trade magazine, Genetic Engineering & Biotechnology News (GEN), was the first in its field and is today the industry's most widely read publication worldwide. A complete list of the firm's 80 journals, books, and newsmagazines is available on the Mary Ann Liebert, Inc., publishers website. About the Journal Nucleic Acid Therapeutics is an authoritative peer-reviewed journal published bimonthly in print and online that focuses on cutting-edge basic research, therapeutic applications, and drug development using nucleic acids or related compounds to alter gene expression. The Journal is under the editorial leadership of Editor-in-Chief Bruce A. Sullenger, PhD, Duke Translational Research Institute, Duke University Medical Center, Durham, NC, and Executive Editor Graham C. Parker, PhD. Nucleic Acid Therapeutics is the official journal of the Oligonucleotide Therapeutics Society. Complete tables of content and a sample issue may be viewed on the Nucleic Acid Therapeutics website. About the Society The Oligonucleotide Therapeutics Society is an open, non-profit forum to foster academia- and industry-based research and development of oligonucleotide therapeutics. The society brings together the expertise from different angles of oligonucleotide research to create synergies and to bring the field of oligonucleotides to its full therapeutic potential. For more information, please click If you have a comment, please us. Issuers of news releases, not 7th Wave, Inc. or Nanotechnology Now, are solely responsible for the accuracy of the content.

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Columbia University Medical Center (CUMC) and University of Iowa scientists have used a new gene-editing technology called CRISPR to repair a genetic mutation responsible for retinitis pigmentosa (RP), an inherited condition that causes the retina to degrade and leads to blindness in at least 1.5 million cases worldwide. The study was published in Scientific Reports, and marks the first time researchers have replaced a defective gene associated with a sensory disease in stem cells that were derived from a patient’s tissue. “Our vision is to develop a personalized approach to treating eye disease,” said Stephen Tsang, M.D., Ph.D., the László Z. Bitó Associate Professor of Ophthalmology and associate professor of Pathology & Cell Biology at CUMC, and one of the study’s senior authors. “We still have some way to go, but we believe that the first therapeutic use of CRISPR will be to treat an eye disease. Here we have demonstrated that the initial steps are feasible.” In the study, the researchers created stem cells from a sample of skin that was taken from a patient with retinitis pigmentosa. As the patient-derived stem cells still harbored the disease-causing mutation, the teams used CRISPR to repair the defective gene. The stem cells can potentially be transformed into healthy retinal cells and transplanted back into the same patient to treat vision loss. “The X-linked form of retinitis pigmentosa is an ideal candidate for a precision medicine approach because a common mutation accounts for 90% cases,” Tsang explains. Using CRISPR —which is easily adaptable to diverse sequences of DNA, and allows for fast and accurate editing —scientists can take a patient’s own cells and make pinpoint repairs specific to that individual’s genome. Because the corrections are made in cells derived from the patient’s own tissue, doctors can re-transplant the cells with fewer fears of rejection by the immune system. Previous clinical trials have shown that generating retinal cells from embryonic stem cells and using them for transplantation is a safe and potentially effective procedure. In this paper, the researchers targeted one of the most common variants of retinitis pigmentosa, which is caused by a single mistake in a gene called RGPR. The composition of RGPR—which contains many repeats and tight-binding nucleotide pairs—make it a difficult gene to edit. The researchers say that preliminary success with RGPR is therefore promising for treating other forms of the condition caused by mutations in other genes. The current treatment for retinitis pigmentosa recommended by the National Institutes of Health—consuming high doses of vitamin A—slows down vision loss but does not cure the disease. Other types of gene therapies for retinitis pigmentosa are currently undergoing clinical trials. Unlike CRISPR-based methods, these therapies introduce stretches of DNA that supplement some of the activity of the defective gene, but do not directly correct the original mutation. Follow-up studies have shown that any gains in vision from these gene supplementation therapies wane over time. A CRISPR-driven precision medicine approach to treating retinitis pigmentosa may improve upon current therapies and restore a patient’s vision because CRISPR, with its pinpoint accuracy, can correct the fundamental genetic defect responsible for the disease. However, CRISPR technology has not yet been approved for use in humans. Recently, another group has used CRISPR to ablate a disease-causing mutation in a rats with retinitis pigmentosa. This study hints at the promise for using CRISPR therapeutically in humans, and the CUMC and Iowa groups are now working to show that the technique does not introduce any unintended genetic modifications in human cells, and that the corrected cells are safe for transplantation. Tsang and colleagues believe that the first clinical use of CRISPR could be for treating an eye disease because compared to other body parts, the eye is easy to access for surgery, readily accepts new tissue, and can be noninvasively monitored.

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