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A team of researchers from Colorado State University has been studying DNA damage in living cells to learn more about how genetic abnormalities arise. It has long been known that DNA molecules in every cell get constantly damaged by things from the outside environment, like sunlight, cigarette smoke and radiation. However, more recently researchers have discovered that sources from within the cell itself can sometimes be even more damaging. DNA, or deoxyribonucleic acid, is found in the nucleus of every cell. It is the code for the traits we have as human beings, and it serves as the warehouse of information needed to make a cell work. When something goes wrong with DNA, it can lead to a mutation and changes in the cell, and can sometimes lead to disease. In a study highlighted in a recent issue of Genetics, the team -- led by J. Lucas Argueso, CSU assistant professor and Boettcher Investigator in the Department of Environmental & Radiological Health Sciences -- found that RNA, or ribonucleic acid, has a new and important part in this process. CSU researchers worked in close in collaboration with scientists from the National Institute of Environmental Health Sciences in North Carolina. RNA is a molecule that plays a central role in the function of genes. It is the "business" end of a genome. The building blocks that cells use for making RNA are knows as ribonucleotides, which was the focus of the research paper. "You don't hear as much about RNA, but cells actually have much more RNA than DNA," Argueso said. Cells also have more ribonucleotides than deoxyribonucleotides, the building blocks for making DNA. Since the two are chemically very similar, it is quite common for cells to mistakenly incorporate RNA pieces into DNA. Argueso and his team -- including Hailey Conover, Ph.D. student in Cell & Molecular Biology and lead author of the study, and Deborah Afonso Cornelio, a post-doctoral researcher -- are looking at what happens to yeast cells when they are unable to accurately remove RNA from DNA. "The same problem happens in humans, carrots, butterflies, and yeast cells, the model organism used in our lab," Argueso said. "The same yeast that is used to bake bread and to brew beer is an incredibly useful biomedical research model." Findings from this study have direct implications for children with Aicardi-Goutieres syndrome, a devastating disorder that affects the brain, the immune system and the skin. "This is a very serious disease that affects children born without a critical enzyme that removes the RNA building blocks from DNA," Argueso said. "Our model yeast cells have been engineered to have the same basic genetic defect as Aicardi-Goutieres children so that we can investigate this problem at its very core." What's next for the team? Argueso said they want to extend their work to cancer research. The team wants to determine how ribonucleotides increase chromosome abnormalities and whether those increases are asymmetric, depending on which of the two strands of DNA the ribonucleotides are introduced. Most cancers have some form of alteration in chromosomal structure, though Argueso said that breast and ovarian cancers are by far the most affected by this issue. In addition, with some forms of chemotherapy that have been used for a long time, the mechanism of action is to decrease the production of DNA building blocks. "Cancer cells reproduce quickly," Argueso said. "To do that, the cells need DNA building blocks. Chemotherapy is used to decrease the building blocks. However, when you reduce the number of DNA building blocks, you push the cancer cells into a corner, where they end up putting in more RNA building blocks into the DNA." In other words, the very thing that the chemotherapy agent is encouraging cancer cells to incorporate causes them to acquire even more mutations. This could help explain why cancers often recur in more aggressive forms after someone goes into remission. "This unintended consequence could be one of the mechanisms making that happen," Argueso said.


Proteins of the ABC-F protein family are a major source of antibiotic resistance in 'superbugs' such as Staphylococcus aureus, a group of bacteria that includes MRSA. The findings, published today in the American Society for Microbiology journal mBio, provide the first direct evidence of how this family of proteins 'protect' the bacterial ribosome, the protein makers in cells, from being blocked by antibiotics. Ordinarily, the ribosome is an ideal target for antibiotics because living bacteria cannot grow without it, but when bacteria produce ABC-F proteins many antibiotics no longer work. Until now, there has been a longstanding debate as to exactly how these proteins work. Scientists have been divided in their support for two separate ideas; that the proteins are pumps that remove antibiotics from bacterial cells, or that they interact with the bacteria's ribosomes to stop antibiotics from blocking them. Fundamental research of this type provides a better picture of the molecular basis for antibiotic resistance. It can offer valuable information that might be used in the future to design antibiotics to bypass antibiotic resistance, when scientists are able to understand more about the properties that allow drugs to enter bacterial cells. Dr Liam Sharkey, a Fellow in the School of Molecular and Cellular Biology, who carried out the research, said: "These findings provide the first direct evidence that these proteins directly protect the ribosome. As a result the goal-posts of our research have changed, we can now zoom-in and try to work out the exact details of how this protection is happening. "Our results suggest that the proteins work by removing antibiotics when they bind their targeted ribosome. It's a bit like the proteins are bouncers at a ribosome nightclub, the bouncer's job is to keep kicking out antibiotics that are trying to get in and cause trouble." This debate has been not settled until now because of the technical challenges associated with the research and much of the attention of academics in the field has been focused on the idea that these proteins are working as pumps. The research, which was funded by the Biotechnology and Biological Sciences Research Council (BBSRC), and understanding the molecular basis for antibiotic resistance is a key focus of the Astbury Centre for Structural Molecular Biology at the University of Leeds. Further progress in this area will be boosted by new state-of-the-art facilities, enabling researchers to better understand life in molecular detail. A recent £17 million investment in some of the best nuclear magnetic resonance and electron microscopy facilities in the world is now enabling scientists to remain at the forefront of research into complex proteins. The University of Leeds has played a key role in the birth of structural biology as a scientific discipline, with the development of X-ray crystallography by Nobel Laureates William and Lawrence Bragg in Leeds in 1912-13. A new academic symposium, the Astbury Conversation, is being hosted at the University of Leeds from 11 - 12 April 2016, to bring together leading researchers from across the globe to discuss the most recent innovations, new techniques and technologies in the field of structural molecular biology. Explore further: Antibiotics that only partly block protein machinery allow germs to poison themselves


New work from Princeton University researchers shows that the effectiveness of bacteria's ability to keep in touch is influenced by the physical characteristics and flow of fluid in the environments they're invading. The findings provide a better understanding of where and when in a system scientists can interfere with bacterial communication to help prevent infections and blockages. The researchers simulated real-life environments in the laboratory and found that the shape of the spaces and the flow of fluids through them affected bacterial growth and the formation of slimy surface layers called biofilms. Published in the journal Nature Microbiology, the study also found that fluid flow can determine where and when bacteria begin to act as disease-causing agents. Bacteria communicate through a chemical process called quorum sensing, in which they release molecules that serve as messages detected by nearby bacteria. Most studies of this process, however, have been done under controlled laboratory conditions, explained co-corresponding author Bonnie Bassler, Princeton's Squibb Professor of Molecular Biology and an investigator with the Howard Hughes Medical Institute. Bassler, a molecular biologist, worked with Princeton colleagues with expertise in engineering and chemistry to explore quorum sensing in settings that more accurately resemble real-world situations. "We realized that if we are going to learn how to manipulate quorum sensing on demand to find ways to treat disease, we have to know how it works in realistic settings," Bassler said. "The eventual goal of this research is to alter quorum sensing in ways that destroy harmful bacteria, and benefit desirable bacteria." In these real-world situations, fluid flow can interfere with the delivery of the chemical messengers used in quorum sensing, said co-corresponding author Howard Stone, Princeton's Donald R. Dixon '69 and Elizabeth W. Dixon Professor of Mechanical and Aerospace Engineering. "If you have sufficient flow, it can wash away a chemical before your neighbor knows it is there," Stone said. First author Minyoung Kevin Kim, a graduate student in Princeton's Department of Chemistry, built experimental devices that mimicked common environments in which bacteria are subjected to the flow of liquids such as wastewater or bodily fluids: the interior surfaces of pipes, the crevices found in the lining of the intestines, and surfaces coated with biofilms, among others. Co-author Francois Ingremeau, a former postdoctoral researcher in mechanical and aerospace engineering at Princeton who is now at the University of Grenoble in France, also conducted significant experimental and modeling work related to quorum-sensing response to fluid flow. Kim introduced a flow of fluid at speeds comparable to those found in real life. He studied two types of disease-causing bacteria, Vibrio cholerae—the infectious agent behind cholera—and Staphylococcus aureus, which can cause various infections such as abscesses and hospital infections. In each situation, the researchers found that the level and location of quorum sensing depended on the three-dimensional shape of the physical space combined with the flow conditions. In one experiment, the researchers confirmed previous observations that moving fluids can repress quorum sensing by carrying away messenger molecules. This finding helps explain why robust biofilms form under flow conditions in pipes, the researchers said. What is more, the transported quorum-sensing molecules can find their way to bacteria downstream and establish long-range communication between bacterial cells, the researchers found. This sort of communication may occur in pipes, across colonies of soil bacteria, and in the intestinal tract of animals, potentially aiding the spread of disease. In addition, quorum-sensing molecules at the base of biofilms are protected from fluid flow and can be detected by neighboring cells, the researchers observed. Cells that receive these quorum-sensing messages can then kick off a gene-expression program that enables bacteria to break free of the biofilm, travel via the flowing fluid to new sites and potentially spread infection to new sites. The researchers also investigated quorum sensing in crevices, such as pockets in the intestinal lining known as crypts. Sheltered from flow at the bottom of the crypt, quorum-sensing molecules can travel between bacteria, but molecules near the top of the crypt are carried away. This conforms to what is known about how S. aureus causes disease, Kim said. "Inside crypts, the bacteria engage in quorum sensing and activate the production of a toxin called enterotoxin B, which functions to increase the depth of the crypt," Kim said. "According to our findings, this activity further insulates S. aureus from flow, which is a mechanism that presumably enables quorum-sensing control of pathogenicity, specifically inside crypts." To explore the health consequences of quorum sensing in the crypts, the researchers introduced into the flow a molecule that acts as an antagonist to turn off quorum sensing in chambers colonized by the well-known scourge of hospitals, methicillin-resistant S. aureus, or MRSA. The researchers' antagonist molecule—synthesized by co-author Aishan Zhao, a graduate student in chemistry—diffused in the crevices and inactivated quorum sensing, which suggested that it could be used as a potential strategy for alleviating MRSA virulence. The researchers concluded that identical bacterial strains—exposed to flowing liquids and in oddly shaped spaces—can experience widely different levels of quorum sensing, leading to complex patterns of pathogenesis and colonization. "This was one of the surprising findings from the study," Kim said. Explore further: Communication breakdown: New strategy may be valid alternative to traditional antibiotics More information: The paper, "Local and global consequences of flow on bacterial quorum sensing," was published Jan. 11 in the journal Nature Microbiology.


The new theory is published along with illustrations – or "blueprints" – depicting how it applies to different vertebrate organ systems in Progress in Biophysics & Molecular Biology. According to Neo-Darwinian theory, major evolutionary changes occur as a result of the selection of random, fortuitous genetic mutations over time. However, some researchers say this theory does not satisfactorily account for the appearance of radically different life forms and their rich complexity, particularly that observed in vertebrates like humans. Embryo geometry, developed by a team from the University of San Diego, Mount Holyoke College, Evergreen State College, and Chem-Tainer Industries, Inc.. in the USA, looks at animal complexity generally and the vertebrate body in particular as more the products of mechanical forces and the laws of geometry than solely the outcome of random genetic mutation. "At the suggestion of evolutionary biologist Stephen Jay Gould, preliminary attempts at a solution to this problem were undertaken over many years. But these – as well as other, similar efforts – were met with strong opposition by supporters of the Neo-Darwinian interpretation of natural selection," commented senior author Stuart Pivar. "We hope that the theory of embryo geometry will stimulate further investigation by biologists of all stripes across a variety of fields." Anatomists have long postulated that animal complexity arises during development of the embryo – called embryogenesis – but despite detailed descriptions of the embryonic stages of all major types of animal, the evolution of organismal complexity and its expression during individual development have remained mysterious processes – until now. The researchers behind embryo geometry have shown that the vertebrate embryo could conceivably arise from mechanical deformation of the blastula, a ball of cells formed when the fertilized egg divides. As these cells proliferate, the ball increases in volume and surface area, altering its geometry. The theory posits that the blastula retains the geometry of the original eight cells produced by the first three divisions of the egg, which themselves determine the three axes of the vertebrate body. In their new paper, they present 24 schematic figures – or "blueprints" – showing how the musculoskeletal, cardiovascular, nervous, and reproductive systems form through mechanical deformation of geometric patterns. These illustrations explain how the vertebrate body might plausibly arise from a single cell, both over evolutionary time, and during individual embryogenesis. The authors have also completed a paper on the origin of the form of the flower and fruit, which they are currently submitting for publication. Explore further: New origin theory for cells that gave rise to vertebrates More information: "Origin of the vertebrate body plan in the conservation of regular geometrical patterns in the structure of the blastula," Progress in Biophysics & Molecular Biology DOI: 10.1016/j.pbiomolbio..2016.06.007


Plants use energy from the Sun to convert carbon dioxide and water into carbohydrates that act as the building blocks and energy sources for life. Oxygen is produced as a by-product of photosynthesis. However, this also causes secondary reactions that slow photosynthesis. "Photosynthesis has developed in conditions where the atmosphere's oxygen content was low and its carbon dioxide content high. When photosynthetic organisms became the dominant life form around the world, the atmosphere's oxygen content rose, after which its secondary reactions have become a problem for photosynthesis," says University Lecturer of Molecular Plant Biology Mikko Tikkanen from the University of Turku. Tikkanen also works in the Academy of Finland's Centre of Excellence in Molecular Biology of Primary Producers. Despite having developed safety mechanisms against secondary reactions, plants cannot avoid damage completely. An intriguing observation was that the damage alters the function of photosystem I. Instead of forwarding electrons from water splitting photosystem II, a damaged photosystem I begins to dissipate excess excitation energy as heat and stops producing NADPH molecules, which is its normal function. "We proved that altering the function is a way to protect the photosynthetic apparatus from more extensive damage. Damage initiates a series of changes, where the direction of light energy is turned towards damaged photosystem I centres. This reduces the risk of damage to photosystem II and curtails the electron flow towards photosystem I, which stops the damage, Tikkanen explains. In photosynthesis, photosystem II oxidises water into electrons, hydrogen protons and oxygen, whereas photosystem I uses electrons to produce high energy NADPH. The damage referred to as photoinhibition has been thought to be a detrimental reaction that should be avoided. It was thought, among other things, to reduce profits from crops. "It was previously believed that photosystem II and photosystem I worked in series but rather independently in converting light energy into chemical form. Our new research demonstrates that photosystems form a functional pair in that damage to one protects the other from more extensive damage," Tikkanen says. An understanding of the roles of photosynthesis' different photosystems is important with regard to understanding the evolution of the photosynthesis mechanism. "When the roles are recognised, we will no longer use the wrong methods in an effort to increase the effectiveness of photosynthesis. New data helps us see the problem points for the development of artificial photosynthesis," Tikkanen says. Explore further: Researchers find a way to improve FELs approach used to study Photosystem II in plants More information: Arjun Tiwari et al. Photodamage of iron–sulphur clusters in photosystem I induces non-photochemical energy dissipation, Nature Plants (2016). DOI: 10.1038/nplants.2016.35

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