EDITOR'S CHOICE - SCIENCE INSIGHTS 2015; 12(1):367-375.


BIOLOGY, CANADA

Organisms Can Keep Gene Expression in Check

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York University researchers have learned how living beings can keep gene expression in check—which might partly explain the uncontrolled gene expression found in many cancers. "Using yeast as a model organism, we studied the Tup1 protein, a negative regulator of gene expression," says Biology Professor Emanuel Rosonina, adding, "This protein binds to some genes and blocks their expression, helping to ensure genes that shouldn't be turned on remain inactive." The current study, jointly conducted by York University and Columbia University researchers, suggests that Small Ubiquitin-like Modifier (SUMO) modifies proteins bound to active genes, in order to prevent unfettered gene over-expression that can be harmful to the organism. "One of the ways SUMO does this is by promoting the binding of Tup1 to active genes, which then acts to reduce their expression to appropriate levels," explains Rosonina, in the Faculty of Science at York U. "Sumoylation controls the timing of Tup1-mediated transcriptional deactivation" published in Nature Communications is a follow up to a previous study which found SUMO in every gene examined. "As a result of the previous study, we reported that SUMO is probably important for controlling expression of active genes because we found it on every gene we looked at, but only when they were turned on," notes Rosonina. Considering that many tumours have abnormal levels of SUMO, it will be important to examine whether inappropriate SUMO modifications in these tumours are related to the uncontrolled gene expression that is observed in most cancers, the research concludes.

Nature Communications 2015; Doi: 10.1038/ncomms7610


CELL BIOLOGY, SPAIN

The Link between Genome Packaging and Cell Pluripotency

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A study using Super-resolution microscopy reveals that our genome is not regularly packaged and links these packaging differences to stem cell state. A multidisciplinary approach allowed scientists to view and even count, for the first time, the smallest units for packaging our genome. This study has brought together biologists and physicists from the Centre for Genomic Regulation and the Institute of Photonic Sciences, both in Barcelona. In 1953 Watson and Crick first published the discovery of the double helix structure of the DNA. They were able to visualize the DNA structure by means of X-Ray diffraction. Techniques, such as electron microscopy, allowed scientists to identify nucleosomes, the first and most basic level of chromosome organisation. Until now it was known that our DNA is packaged by regular repeating units of those nucleosomes throughout the genome giving rise to chromatin. However, due to the lack of suitable techniques and instruments, the chromatin organisation inside a cell nucleus could not be observed in a non-invasive way with the sufficient resolution. Now, for the first time, a group of scientists at the CRG and ICFO in Barcelona, have been able to visualise and even count the smallest units which, packaged together, form our genome. This study was possible thanks to the use of super-resolution microscopy, a new cutting-edge optical technique that received the Nobel Prize in Chemistry in 2014. In combination with innovative quantitative approaches and numerical simulations, they were also able to define the genome architecture at the nano-scale. Most importantly, they found that the nucleosomes are assembled in irregular groups across the chromatin and nucleosome-free-DNA regions separate these groups. Biologists and physicists have been working together to take a step forward in chromatin fibre observations and studies. "By using the STORM technique, a new super-resolution microscopy method, we have been able to view and even count nucleosomes across the chromatin fibers and determine their organisation. STORM overcomes the diffraction limit that normally restricts the spatial resolution of conventional microscopes and enables us to precisely define the chromatin fibre structure", states Prof. Melike Lakadamyali, group leader at ICFO. This enabling technique allowed the researchers to go deeper and, by comparing stem cells to differentiated cells (specialised cells that have already acquired their role), they observed key differences in the chromatin fibre architectures of both cells. Pia Cosma, group leader and ICREA research professor at the CRG explains, "We found that stem cells have a different chromatin structure than somatic (specialised) cells. At the same time, this difference correlates with the level of pluripotency. The more pluripotent a cell is, the less dense is its packaging. It gives us new clues to understand the stem cells functioning and their genomic structure, which will be helpful for example, in studying cell reprogramming". What scientists have found is that DNA is not regularly packaged with nucleosomes, instead nucleosomes are assembled in groups of varying sizes, called "nucleosome clutches" -because of their similarity to egg clutches-. They found that pluripotent stem cells have, on average, clutches with less density of nucleosomes. In addition, clutch size is related to the pluripotency potential of stem cells, meaning that the more pluripotent a cell is, the less nucleosomes are included in its clutches. Even though all the cells in our body have the same genetic information, they are not expressing all the genes at the same time. So, when a cell specialises, some of the DNA regions are silenced or less accessible to the molecule that reads the genome: the RNA polymerase. Depending on the specialisation of the cells, different levels of DNA packaging will occur. This new work published in the prestigious journal Cell, establishes a new understanding of how the chromatin fibre is assembled and packaged forming a specific DNA structure in every cell. This research definitively contributes to the understanding of a novel feature of stem cells and their DNA structure, which is important for maintaining an induced pluripotent state. A joint patent has been filed by ICFO and CRG, who are now exploring business opportunities for marketing the classification of "stemness" state of cells, ie, their degree of pluripotency. This technique could determine with single cell sensitivity the pluripotency potential of stem cells, thus having the capacity of becoming a standard method of quality control of stem or pluripotent cells before their use in cell therapy or research in biomedicine.

Cell 2015; Doi: 10.1016/j.cell.2015.01.054


MEDICINE, USA

The Mysteries of Wound Healing

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Researchers at the University of Arizona have discovered what causes and regulates collective cell migration, one of the most universal but least understood biological processes in all living organisms. The findings, published in the March 13, 2015, edition of Nature Communications, shed light on the mechanisms of cell migration, particularly in the wound-healing process. The results represent a major advancement for regenerative medicine, in which biomedical engineers and other researchers manipulate cells' form and function to create new tissues, and even organs, to repair, restore or replace those damaged by injury or disease. "The results significantly increase our understanding of how tissue regeneration is regulated and advance our ability to guide these processes," said Pak Kin Wong, UA associate professor of mechanical and aerospace engineering and lead investigator of the research. "In recent years, researchers have gained a better understanding of the molecular machinery of cell migration, but not what directs it to happen in the first place," he said. "What, exactly, is orchestrating this system common to all living organisms?" The answer, it turns out, involves delicate interactions between biomechanical stress, or force, which living cells exert on one another, and biochemical signaling. The UA researchers discovered that when mechanical force disappears—for example at a wound site where cells have been destroyed, leaving empty, cell-free space—a protein molecule, known as DII4, coordinates nearby cells to migrate to a wound site and collectively cover it with new tissue. What's more, they found, this process causes identical cells to specialize into leader and follower cells. Researchers had previously assumed leader cells formed randomly. Wong's team observed that when cells collectively migrate toward a wound, leader cells expressing a form of messenger RNA, or mRNA, genetic code specific to the DII4 protein emerge at the front of the pack, or migrating tip. The leader cells, in turn, send signals to follower cells, which do not express the genetic messenger. This elaborate autoregulatory system remains activated until new tissue has covered a wound. The same migration processes for wound healing and tissue development also apply to cancer spreading, the researchers noted. The combination of mechanical force and genetic signaling stimulates cancer cells to collectively migrate and invade healthy tissue. Biologists have known of the existence of leader cells and the DII4 protein for some years and have suspected they might be important in collective cell migration. But precisely how leader cells formed, what controlled their behavior, and their genetic makeup were all mysteries—until now. "Knowing the genetic makeup of leader cells and understanding their formation and behavior gives us the ability to alter cell migration," Wong said. With this new knowledge, researchers can re-create, at the cellular and molecular levels, the chain of events that brings about the formation of human tissue. Bioengineers now have the information they need to direct normal cells to heal damaged tissue, or prevent cancer cells from invading healthy tissue. The UA team's findings have major implications for people with a variety of diseases and conditions. For example, the discoveries may lead to better treatments for non-healing diabetic wounds, the No. 1 cause of lower limb amputations in the United States; for plaque buildup in arteries, a major cause of heart disease; and for slowing or even stopping the spread of cancer, which is what makes it so deadly. The research also has the potential to speed up development of bioengineered tissues and organs that can be successfully transplanted in humans.

Nature Communications 2015; Doi: 10.1038/ncomms7556


NEUROSCIENCE, FINLAND

Classical Music Modulates Genes That are Responsible for Brain Functions

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Although listening to music is common in all societies, the biological determinants of listening to music are largely unknown. According to a latest study, listening to classical music enhanced the activity of genes involved in dopamine secretion and transport, synaptic neurotransmission, learning and memory, and down-regulated the genes mediating neurodegeneration. Several of the up-regulated genes were known to be responsible for song learning and singing in songbirds, suggesting a common evolutionary background of sound perception across species. Listening to music represents a complex cognitive function of the human brain, which is known to induce several neuronal and physiological changes. However, the molecular background underlying the effects of listening to music is largely unknown. A Finnish study group has investigated how listening to classical music affected the gene expression profiles of both musically experienced and inexperienced participants. All the participants listened to W.A. Mozart's violin concert Nr 3, G-major, K.216 that lasts 20 minutes. Listening to music enhanced the activity ofgenes involved in dopamine secretion and transport, synaptic function, learning and memory. One of the most up-regulated genes, synuclein-alpha (SNCA) is a known risk gene for Parkinson's disease that is located in the strongest linkage region of musical aptitude. SNCA is also known to contribute to song learning in songbirds. "The up-regulation of several genes that are known to be responsible for song learningand singing in songbirds suggest a shared evolutionary background of sound perception between vocalizing birds and humans", says Dr. Irma Järvelä, the leader of the study. In contrast, listening to music down-regulated genes that are associated with neurodegeneration, referring to a neuroprotective role of music. "The effect was only detectable in musically experienced participants, suggesting the importance of familiarity and experience in mediating music-induced effects", researchers remark. The findings give new information about the molecular genetic background of music perception and evolution, and may give further insights about the molecular mechanisms underlying music therapy.

PeerJ 2015; Doi: 10.7717/peerj.830


PLANT, SWITZERLAND

Antibiotics Have Unexpected Effects on Mitochondria

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An EPFL study has shown that tetracycline-based antibiotics have an unexpected effect on the development of many organisms. In addition to pointing out the issue of soil pollution by these antibiotics, which are widely administrated to livestock, the scientists call upon colleagues to explore the consequences of using them in experiments that modulate gene expression. No one assumes that antibiotics are completely harmless. But a new study shows that some of them have unexpected consequences on the development of a wide variety of organisms. Scientists have observed significant effects in concentrations similar to those found in the soils in which our food crops are grown. Since the discovery of penicillin in the first half of the 20th century, antibiotics have been a boon to medicine for their effectiveness in combating bacterial infection. Over the past few decades, the use of new generations of drugs based on specific molecules known as tetracyclines has become very widespread. They act on bacterial gene expression, weakening, stimulating, or shutting it down altogether. This ability to act directly at the level of gene expression has also led many scientists to use tetracycline antibiotics in research. But a study done at Ecole polytechnique fédérale de Lausanne (EPFL, Switzerland), published today in the scientific journal Cell Reports, calls for caution when using this family of antibiotics. The scientists, led by Norman Moullan and Laurent Mouchiroud from EPFL's Laboratory of Integrative and Systemic Physiology (Nestlé Chair in Energy Metabolism), directed by Professor Johan Auwerx, observed that these molecules have a significant effect on mitochondria, the cell's "powerhouses." "It's not that surprising, given that mitochondria are historically bacteria that evolved within our cells," says Mouchiroud. "A lot of attention has been paid to the role of antibiotics on our intestinal flora, which has ten times more cells than the rest of our bodies. However, the effects of antibiotics on our mitochondria, which themselves far outnumber the bacteria in our gut, haven't yet been studied in detail." In collaboration with two other research teams, one Swiss (Bart DePlancke) and one Dutch (Riekelt Houtkooper), the EPFL scientists revisited data from previous studies from this angle and carried out new experiments using animal and plant cells. The effects were huge. "After several days of treatment with high doses of doxycycline, mitochondrial respiration was visibly altered," explains Moullan. More surprising still, the consequences were observed all the way down the food chain, from mammals to flies to nematode worms to plants. "The worms' development was hindered. On the other hand, signs of aging appeared more slowly, something we had observed in earlier studies ." The scientists also carried out growth tests on Arabidopsis thaliana, a common plant that's frequently used in laboratory research. After growing for a week on a normal substrate, it was transplanted into soil with varying concentrations of doxycycline. "Delays in growth, some quite severe, were observed after a few days, even in soils in which the concentration of antibiotics was no stronger than is found in some agricultural soils today," says Moullan. This pollution whose consequences are just beginning to be appreciated is caused by the widespread administration of antibiotics to livestock. "Because they are give orally in feed, they are only partially digested and end up in manure, which is then spread on the fields," explains Mouchiroud. The quantities involved are huge, and the economic stakes equally sobering. In 2011, 5.6 million kg of tetracycline was administered to US livestock. A study showed that nearly half of the 210 kg of antibiotics produced in China in 2007 were tetracyclines for veterinary use. "The effects on growth of plants other than A. thaliana have not yet been studied, but our work indicates a need for caution," says Moullan. The researchers also call on their scientific colleagues to be more careful when using antibiotics in experiments for modulating gene expression. "You observe the effect you're looking for, but you lose sight of the fact that these substances have serious consequences for overall metabolic function," says

Cell Reports 2015; Doi: 10.1016/j.celrep.2015.02.034


MEDICINE, USA

Common Herpes Medication Reduces HIV-1 Levels

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Case Western Reserve researchers are part of an international team that has discovered that a common herpes drug reduces HIV-1 levels—even when patients do not have herpes. Published online in Clinical Infectious Diseases, the finding rebuts earlier scientific assumptions that Valacyclovir (brand name, Valtrex) required the presence of the other infection to benefit patients with HIV-1. The result not only means that Valacyclovir can be used effectively with a broader range of HIV-1 patients, but also suggests promising new avenues for the development of HIV-fighting drugs. This insight is particularly significant given that some forms of HIV-1 have become resistant to existing medications. "These results demonstrated that the mechanism by which Valacyclovir acts against HIV is not only through the presence of HSV-2," said senior author Benigno Rodriguez, MD, associate professor of medicine and infectious diseases, CWRU School of Medicine, co-Principal Investigator, Case Western Reserve University/University Hospitals Case Medical Center AIDS Clinical Trials Unit, and infectious disease specialist with UH Case Medical Center. Even better, Rodriguez said, studies by these groups helped illuminate exactly how the medication decreases HIV-1 levels. Valacyclovir is activated in virus-infected cells, and then blocks the ability of HIV to reproduce. The result? Reduced viral load. HIV-1 can lead to the immune deficiency known as AIDS. The herpes simplex virus 2 (HSV-2) causes periodic recurrence of genital herpes lesions, which increase the likelihood that a herpes sufferer may contract HIV through intimate contact. HSV-2 outbreaks are treated with either Acyclovir or the newer generation Valacyclovir, which requires less frequent dosing. Scientists previously thought that Valacyclovir helped reduce HIV levels and worked by decreasing the immune activation caused by HSV-2. With fewer immune cells to attack, the theory went, HIV-1 could not spread as widely. Yet Leonid Margolis, PhD, of the National Institutes of Health (NIH), believed another explanation might exist. After conducting laboratory studies with Acyclovir, an earlier sibling drug of Valacyclovir, Margolis saw that the medication clearly blocked HIV-1 reproduction, even when HSV-2 was absent. Those results helped spur clinical trials of Valacyclovir in people, and Margolis is senior author of the resulting journal article. Beginning in June, 2009, patients from UH Case Medical Center and from IMPACTA, the Civic Association for Health and Education in Lima, Peru, started participating in the trials, which lasted until July, 2012. Under its protocols, half the patients took Valacyclovir twice daily for 12 weeks, while the other half took a placebo for the same period of time. After a two-week break from any medications, the two groups switched: those previously on placebo got 12 weeks of the Valacyclovir, and those who already had taken the medication now received placebos. When study participants took Valacyclovir, their HIV viral loads went down, and when they took the placebo, their HIV viral loads went up. Ultimately, a total of 18 patients participated. "Our most recent clinical study demonstrates that acyclovir blocks HIV replication directly. The anti-HIV activity of valacyclovir does not depend on blocking the inflammation caused by herpes simplex virus 2," said Michael M. Lederman, MD, also a senior author. He is the Scott R. Inkley Professor of Medicine, Case Western Reserve University School of Medicine, and Principal Investigator of the Case Western Reserve University/University Hospitals Case Medical Center AIDS Clinical Trials Unit and infectious disease specialist with UH Case Medical Center. Lederman and Rodriguez, the two Cleveland-based members of the research team, believe that the data from this study can inform new drug development. Essentially, researchers would try to design agents based on the Valacyclovir's molecular structure - now proven to block HIV activity. "The drug might be an agent that can be used safely in some people with HIV infection who have a form of HIV that is highly resistant to other antiretroviral drugs," Lederman said. "Valacyclovir might well augment the cocktail of medications they take for reducing HIV replication. Valacyclovir is a well-tolerated drug, and it doesn't have a lot of side effects."

Clinical Infectious Diseases 2015; doi:10.1093/cid/civ172


MATERIAL, CHINA

Shape Shifting Liquid Metal Able To Propel Itself through Liquids

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A team of researchers at Tsinghua University in China has, according to a report in Newscientist, found a way to mimic, if only in a small way, the shape shifting robot in the Terminator movies. The team has published their findings in the journal Advanced Materials. As part of an effort to better understand the properties of liquid metals, the researchers were working with gallium—after adding a little bit of indium and tin they discovered that if a bit of aluminum was affixed to a single drop of the alloy (to serve as fuel) and the result was dropped into a container of sodium hydroxide (or even salt water) the drop would propel itself around the container for approximately one hour. In subsequent tests they found that if the container was shaped with channels, the drop could be made to follow a pre-designated path. What's more, they noted that if the drop encountered a part of the channel that was slimmer than it was, it could squeeze through. Surprised by the movement of the drop, the researchers took a closer look—analysis revealed that when the drop was placed in the solution, a charge imbalance occurred between the front and back of the drop, causing a pressure differential. They also found that as the aluminum reacted with the saltwater, tiny bubbles were formed which also served to push the drop forward (so long as the aluminum bit was on the back end.) The experiments by the team build on prior work by them and others (as part of an effort to make "soft" robots) that showed that with some liquid metals, an electric charge can cause both an expansion and change of shape to a drop. The researchers note that if both techniques were used, the result could be drops that not only move themselves through liquids, but change shape according to predetermined needs. They suggest their findings could conceivably pave the way for drops that are used to deliver materials via pipes or even through blood vessels.

Advanced Materials 2015; Doi: 10.1002/adma.201405438


MEDICINE, USA

Drug Restores Brain Function and Memory in Early Alzheimer's Disease

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A novel therapeutic approach for an existing drug reverses a condition in elderly patients who are at high risk for dementia due to Alzheimer's disease, researchers at Johns Hopkins University found. The drug, commonly used to treat epilepsy, calms hyperactivity in the brain of patients with amnestic mild cognitive impairment (aMCI), a clinically recognized condition in which memory impairment is greater than expected for a person's age and which greatly increases risk for Alzheimer's dementia, according to the study published this week in NeuroImage: Clinical. The findings validate the Johns Hopkins team's initial conclusions, published three years ago in the journal Neuron. They also closely match the results in animal studies performed by the team and scientists elsewhere. Next, neuroscientist Michela Gallagher, the lead investigator, hopes the therapy will be tested in a large-scale, longer-term clinical trial. Hippocampal over-activity is well-documented in patients with aMCI and its occurrence predicts further cognitive decline and progression to Alzheimer's dementia, Gallagher said. "What we've shown is that very low doses of the atypical antiepileptic levetiracetam reduces this over-activity," Gallagher said. "At the same time, it improves memory performance on a task that depends on the hippocampus." The team studied 84 subjects; 17 of them were normal healthy participants and the rest had the symptoms of pre-dementia memory loss defined as aMCI. Everyone was over 55 years old, with an average age of about 70. The subjects were given varying doses of the drug and also a placebo in a double-blind randomized trial. Researchers found low doses both improved memory performance and normalized the over-activity detected by functional magnetic resonance imaging that measures brain activity during a memory task. The ideal dosing found in this clinical study matched earlier preclinical studies in animal models. "What we want to discover now, is whether treatment over a longer time will prevent further cognitive decline and delay or stop progression to Alzheimer's dementia," Gallagher said. Other team members from Johns Hopkins included Arnold Bakker, assistant professor of psychiatry and behavioral sciences; Marilyn S. Albert, director of the Division of Cognitive Neuroscience in the Department of Neurology; professor of neurology Gregory Krauss and the clinical study coordinator, Caroline L. Speck. Gallagher, the Krieger-Eisenhower Professor of Psychology and Neuroscience, is the founder of, and a member of the scientific board of, AgeneBio, a biotechnology company focused on developing treatments for diseases that affect brain function. The company is headquartered in Baltimore. Gallagher owns AgeneBio stock, which is subject to certain restrictions under Johns Hopkins policy. She is entitled to shares of any royalties received by the university on sales of products related to her inventorship of intellectual property. The terms of these arrangements are managed by the university in accordance with its conflict-of-interest policies.

NeuroImage: Clinical 2015; Doi: 10.1016/j.nicl.2015.02.009


MATERIAL, CHINA

Graphene: A New Tool for Fighting Cavities and Gum Disease?

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Dental diseases, which are caused by the overgrowth of certain bacteria in the mouth, are among the most common health problems in the world. Now scientists have discovered that a material called graphene oxide is effective at eliminating these bacteria, some of which have developed antibiotic resistance. They report the findings in the journal ACS Applied Materials & Interfaces. Zisheng Tang and colleagues point out that dentists often prescribe traditional antibiotics to get rid of bacteria that cause tooth decay or gum disease. But with the rise in antibiotic resistance, new approaches are needed to address these problems, which can lead to tooth loss. Previous studies have demonstrated that graphene oxide—carbon nanosheets studded with oxygen groups—is a promising material in biomedical applications. It can inhibit the growth of some bacterial strains with minimal harm to mammalian cells. Tang's team wanted to see if the nanosheets would also stop the specific bacteria that cause dental diseases. In the lab, the researchers tested the material against three different species of bacteria that are linked to tooth decay and gum disease. By destroying the bacterial cell walls and membranes, graphene oxide effectively slowed the growth of the pathogens. The researchers conclude that the nanosheets could have potential uses in dental care.

ACS Appl Mater Interfaces 2015; DOI: 10.1021/acsami.5b01069


CLIMATE, CHINA, USA, UK

Asian Monsoon Rains Played a Key Role in the Evolution of Mammals

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New research has shown that the Asian monsoon rains played a key role in the evolution of mammals. And the findings, published today in the Nature journal Scientific Reports, could have implications for conserving the species living in the vast area affected by monsoon rains. A team including researchers from the University of Manchester, the University of Bristol, the Chinese Academy of Science, and Harvard University looked at the pattern of variation of the South Asian monsoon over time and compared it with the evolution of African mole rats and bamboo rats as revealed by a full analysis of their relationships coupled with studies of their distribution in space and through time and of their evolutionary rates. They found the first proof that weakening and strengthening monsoon rains played a key role in the evolution of these species. Over a period of 24 million years, the changes observed in the teeth and head shape of the rodents examined, matched the varying strength of the monsoon. Of the 38 species studied only six still exist today and the changing rains seem to have driven several species into extinction. Dr Fabien Knoll, a senior researcher at The University of Manchester, said: "It was natural to assume that a mighty climatic phenomenon like the monsoon would play a part in evolution, but until now there has never been any decisive evidence thereof. We have now found that." The monsoon is a key driver of the environment in that part of the world. When it was strong forest cover and vegetation would be a lot fuller than in periods when the rains were weaker. Dr Knoll added: "We used rodents in this study because they are the most common mammals in the fossil record, and they evolved rapidly and are very sensitive to any changes in their habitat." The researchers found that in periods when the monsoon was weaker the teeth of these rodents changed, as did other body parts they would use for digging, and they started to burrow underground. This would have provided them with resources as well as protection from predators when the forest cover was a lot thinner. The authors of this study added: "We suggest that the variations in the monsoon intensity have impacted the evolution of most, if not all, mammals living in this region, although this remains to be proved convincingly (using our methodology or others) and the pattern would probably vary from group to group."

Scientific Reports 2015; Doi: 10.1038/srep09008