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Corena-McLeod M.,Neuropsycopharmacology Laboratory | Walss-Bass C.,University of Texas Health Science Center at San Antonio | Oliveros A.,Neuropsycopharmacology Laboratory | Gordillo Villegas A.,University of Florida | And 7 more authors.
PLoS ONE | Year: 2013

Background:Mitochondrial short and long-range movements are necessary to generate the energy needed for synaptic signaling and plasticity. Therefore, an effective mechanism to transport and anchor mitochondria to pre- and post-synaptic terminals is as important as functional mitochondria in neuronal firing. Mitochondrial movement range is regulated by phosphorylation of cytoskeletal and motor proteins in addition to changes in mitochondrial membrane potential. Movement direction is regulated by serotonin and dopamine levels. However, data on mitochondrial movement defects and their involvement in defective signaling and neuroplasticity in relationship with mood disorders is scarce. We have previously reported the effects of lithium, valproate and a new antipsychotic, paliperidone on protein expression levels at the synaptic level.Hypothesis:Mitochondrial function defects have recently been implicated in schizophrenia and bipolar disorder. We postulate that mood stabilizer treatment has a profound effect on mitochondrial function, synaptic plasticity, mitochondrial migration and direction of movement.Methods:Synaptoneurosomal preparations from rat pre-frontal cortex were obtained after 28 daily intraperitoneal injections of lithium, valproate and paliperidone. Phosphorylated proteins were identified using 2D-DIGE and nano LC-ESI tandem mass spectrometry.Results:Lithium, valproate and paliperidone had a substantial and common effect on the phosphorylation state of specific actin, tubulin and myosin isoforms as well as other proteins associated with neurofilaments. Furthermore, different subunits from complex III and V of the electron transfer chain were heavily phosphorylated by treatment with these drugs indicating selective phosphorylation.Conclusions:Mood stabilizers have an effect on mitochondrial function, mitochondrial movement and the direction of this movement. The implications of these findings will contribute to novel insights regarding clinical treatment and the mode of action of these drugs. © 2013 Corena-McLeod et al.

Yet predicting how a chess game will progress is one of the most challenging modeling problems in the world. Simply by making the first move, the white player sets the game down a certain path; with the following move, the black player veers off down another. The number of possible games of chess has been estimated in excess of 10,000,000. And in all these games, not a single move is made in isolation: every move is a result of the input—the feedback—from the previous move, which was also a result of every move that came before. This system of feedback loops is what makes chess so difficult to model and predict, but also makes an excellent analogy for a major area of research at Yale: systems biology. "This is, in some sense, the essence of a systems approach," says Andre Levchenko, John C. Malone Professor of Biomedical Engineering and Director of the Systems Biology Institute at Yale's West Campus. "We are very, very interested in interactions, and put interactions at the center of the analysis—not the components themselves necessarily, but just the interactions." In Levchenko's Institute, individual cells stand in for rooks, knights and pawns, and the game is much larger: studying (and predicting) the behavior of huge systems of cell networks, whether it's to determine the likely progression of a cancerous tumor or study the development of diabetes. "Cells are exquisitely sensitive to a variety of different cues, chemical cues and mechanical ones," says Levchenko. "In fact that's the key to their survival, or to their proper function. If you think about what we call disease, that's the inability of cells to mount the response to cues that would be adequate. For example, instead of dying or staying put, cells may start dividing; that's in response to their own state, but also to certain cues they see in the environment. It's misinterpretation of these cues that may lead to cancer, for example." In the past, cell studies have been limited to looking at individual pieces of the puzzle: a small group of cells at one time responding to one input, or even a single cell responding to a single input. In a chess game, it would be the equivalent of examining how the white player might move his rook if the black player puts it in jeopardy. This remains a common approach in drug research: cells are exposed to different doses of a drug and the exposure is held constant for a period of time. Researchers study how the cells respond to the various dosages, and hope that the results will be instructive in deciding which candidate drugs to promote for further studies and which to abandon as they are unlikely to be helpful. But this is only looking at one piece of the system. In the chess game, the white player might not move the rook at all, but sacrifice it to save the queen that is in jeopardy from the same prior move. If you were only looking at the rook, you wouldn't predict that outcome. Similarly, in a living human, many more factors may contribute to how a given drug would affect cells, and actual results could be very different from what you would see with the narrow focus on dosage. Instead of looking at just one small piece of the larger picture, Levchenko and his Institute go several steps further. "What we're trying to do is circumvent some of those limitations of current research," he says. "We're trying to be mindful that reality can be complex." Here Levchenko, who comes from an engineering background, draws a parallel. "To understand a system that someone else, or even we, have designed, that's reverse engineering," he says. "When you grow up in an engineering community, you develop appreciation for the complexity of systems, because when you try to build systems—to engineer them—you do it by design, but also by tweaks and tinkering and trying to figure out what works and doesn't work. "Biology is very much engineering in that sense—an engineering science, because that's what we do all the time," says Levchenko. It's no surprise, then, that among the many Yale researchers collaborating with Levchenko's Institute are several faculty members from SEAS, including Kathryn Miller-Jensen, Rong Fan, and recent hire Michael Murrell. Fan's research will be familiar to readers of Yale Engineering (see "The Translator," 2013-2014 issue). The associate professor of biomedical engineering was a chemist by training, but insists he was always an engineer at heart. "My early training was more toward technology development, and my role in systems biology research was to develop better tools," says Fan. Among Fan's primary interests is how cells communicate. Cells can respond to their environment based on several different cues, including mechanical forces and chemical signals. Given his background in chemistry, Fan has focused on cells' chemical signaling. "Cells talk to each other, but it's unfortunate they don't understand English," laughs Fan. "They talk, but it's in a different language—they secrete proteins and bring those proteins throughout the cells and to the surface of the neighboring cells. "The proteins secreted by one cell can mediate another cell," says Fan. "It's essentially a conversation. I think once we can measure a large protein panel, you'll be able to get an understanding of what they talk about. Then you know what they are going to do." But the need for these kinds of large-scale measurements brings back the chess analogy: looking at just a piece of the board doesn't tell you how the game is going to progress. "If you look at one or two proteins, that will not give you a systems-level view of a whole biological mechanism," says Fan. "In my lab, we develop a kind of microchip technology that we can use to interrogate individual cells, but also very large protein panels." Fan has shared the device he developed for this purpose with Miller-Jensen, associate professor of biomedical engineering and molecular, cellular, and developmental biology, who studies the way that cells communicate to mount an immune response in the face of viral infections. Viruses can hijack cell signaling for their own benefit, allowing them to evade immune response and replicate. Among many avenues of exploration, Miller-Jensen's group uses single-cell analysis to reverse engineer the signals sent during an immune response—work for which Miller-Jensen won an NSF CAREER Award earlier this year. Feedback from Miller-Jensen's group, in turn, is used to further develop Fan's device. "It's a mutual scientific exchange," says Fan. "It's a way of developing a tool by testing the device on cells. Sometimes we'll see something weird and then analyze the data in depth, and realize we need to take out a protein or replace it, improving the device. So that's a mutually beneficial process, I think." This is a critical element of modeling efforts in systems biology, as Levchenko sees it. "The most interesting times are the times where we see that a model doesn't work, doesn't give us a correct prediction," he says. "That's an opportunity for us to learn how these systems work, because there's clearly something we don't yet understand—something we haven't taken into account. Frequently it's just the telltale sign that we can find something new and different, and that's a great thing for us." This kind of research calls for a wide range of expertise. In addition to the aforementioned SEAS researchers, key faculty at the Institute include Farren Isaacs, assistant professor of molecular, cellular, and developmental biology; Gunter Wagner, the Alison Richard Professor of Ecology and Evolutionary Biology; Murat Acar, assistant professor of molecular, cellular, and developmental biology and of physics; and Jesse Rinehart, assistant professor of cellular and molecular physiology. Together, the researchers' efforts have wide-ranging translational applications. In diabetes, for example, multiple types of cells are involved, including pancreas and liver cells. Many studies focus solely on the pancreas, guaranteeing from the start that they will never get a full picture of the system. Similarly, cell signaling is critical in the development of cancer; when signaling is interrupted or altered, cells can begin multiplying wildly, leading to the development of tumors. This has become an important focus of the Institute, particularly for aggressive types of cancer cells, and complements the cutting-edge cancer initiatives currently led by Joseph Schlessinger at the Cancer Biology Institute at Yale's West Campus. Given the current state of systems biology, it's natural that SEAS research would relate to work being done at the Systems Biology Institute, and Levchenko sees it as an expected evolution. "For a very long time, biology was just cataloging parts science," says Levchenko. "Cells are very complicated; let's take this protein, categorize this protein, take another protein, categorize that protein, and so on. That was an important, necessary step in the development of our new approaches to biology. "Systems biology now is a step beyond that," he says. "It's thinking about how parts interact with each other—very much an engineering approach, because in engineering—yes parts are important—but how do we build something that performs as we want? How do we understand something that's been built before?" "It's exceptionally easy for a systems biologist to talk to an engineer," says Levchenko, "because we share the appreciation for the importance of complexity for proper function. It's a synergy of philosophy; it's a synergy of techniques." Explore further: A novel method for identifying the body's 'noisiest' networks

Vencappa S.,Cancer Biology | Donaldson L.F.,University of Nottingham | Hulse R.P.,Cancer Biology
American Journal of Translational Research | Year: 2015

Increased patient survival is a mark of modern anti-cancer therapy success. Unfortunately treatment sideeffects such as neurotoxicity are a major long term concern. Sensory neuropathy is one of the common toxicities that can arise during platinum based chemotherapy. In many cases the current poor understanding of the neurological degeneration and lack of suitable analgesia has led to high incidences of patient drop out of treatment. VEGF-A is a prominent neuroprotective agent thus it was hypothesised to prevent cisplatin induced neuropathy. Systemic cisplatin treatment (lasting 3 weeks biweekly) resulted in mechanical allodynia and heat hyperalgesia in mice when compared to vehicle control. PGP9.5 sensory nerve fibre innervation was reduced in the plantar skin in the cisplatin treated group versus vehicle control mice. The cisplatin induced sensory neurodegeneration was associated with increased cleaved caspase 3 expression as well as a reduction in Activating Transcription Factor 3 and pan VEGFA expression in sensory neurons. VEGF-A165b expression was unaltered between vehicle and cisplatin treatment. rhVEGF-A165a and rhVEGF-A165b both prevented cisplatin induced sensory neurodegeneration. Cisplatin exposure blunts the regenerative properties of sensory neurons thus leading to sensory neuropathy. However, here it is identified that administration of VEGF-A isoform subtypes induce regeneration and prevent cell death and are therefore a possible adjunct therapy for chemotherapy induced neuropathy. © 2015 E-Century Publishing Corporation. All rights reserved.

Liu Y.,Sloan Kettering Cancer Center | Raheja R.,Sloan Kettering Cancer Center | Yeh N.,Sloan Kettering Cancer Center | Ciznadija D.,Sloan Kettering Cancer Center | And 9 more authors.
Oncogene | Year: 2014

The TRIM family of genes is largely studied because of their roles in development, differentiation and host cell antiviral defenses; however, roles in cancer biology are emerging. Loss of heterozygosity of the TRIM3 locus in ∼20% of human glioblastomas raised the possibility that this NHL-domain containing member of the TRIM gene family might be a mammalian tumor suppressor. Consistent with this, reducing TRIM3 expression increased the incidence of and accelerated the development of platelet-derived growth factor-induced glioma in mice. Furthermore, TRIM3 can bind to the cdk inhibitor p21 WAF1/CIP1. Thus, we conclude that TRIM3 is a tumor suppressor mapping to chromosome 11p15.5 and that it might block tumor growth by sequestering p21 and preventing it from facilitating the accumulation of cyclin D1-cdk4. © 2014 Macmillan Publishers Limited.

News Article
Site: www.nature.com

From climate change to gene-editing ethics, researchers tackled many thorny issues this year. They also made important discoveries — including ice mountains on Pluto, evidence of quantum weirdness and details about the molecular machines inside cells. The world got serious this year about climate change. With the United Nations climate summit in Paris looming in December, both industrialized and developing nations pledged for the first time to control or reduce their greenhouse-gas emissions. As the number of pledges grew during the year — to 184 by the time of the conference — so did optimism that the Paris talks would be a historic turning point in efforts to curb global warming. The meeting, which took place under heightened security because of the Paris terrorist attacks in November, yielded a landmark agreement on 12 December that was approved by 195 countries. It commits most countries to reduce emissions and keep warming to ‘well below’ 2 °C. Nations will assess their progress in 2018 and must revisit their climate pledges every five years starting in 2020. Climate negotiators were treated to some surprising good news in early December, when researchers at the Global Carbon Project reported that global carbon emissions could drop by 0.6% in 2015. China and the United States, the world’s biggest carbon emitters, helped to build momentum in the run-up to Paris. China announced that it would launch an emissions cap-and-trade system. And after years of indecision, US President Barack Obama made the symbolic move of saying no to the Keystone XL pipeline that would have transported oil from Canada to US refineries. Even Pope Francis weighed in. He released an encyclical on the environment in June and gave speeches during his visit to North America in September that warned of the dangers of climate change and the urgent need to curb it. Two surveys of people in the United States that were conducted after the Pope’s visit suggested that he helped to boost the acceptance of climate change as an important problem. But nations’ climate pledges will probably not keep warming to within 2 °C above pre-industrial levels, and past that point, many scientists think that the world will see warming-related ecological and economic disruptions. The average global surface temperature is now already 1 °C above pre-industrial levels, and 2015 will probably be the warmest year on record. In Solar System exploration, dwarf planets ruled. The tiny worlds of Pluto and Ceres — the latter in the heart of the asteroid belt between Mars and Jupiter — received their first-ever spacecraft visits in 2015, producing many breathtaking images. Pluto grabbed the spotlight when the New Horizons spacecraft flew past it on 14 July. The world revealed itself as a geological wonderland of ice mountains, nitrogen glaciers and smooth, frigid plains. The sheer complexity of Pluto’s surface astounded planetary scientists, including principal investigator Alan Stern, and raised major questions about what could be fuelling the geological activity that created it. Ceres made a much more gradual appearance beginning in March, when its gravitational pull tugged NASA’s Dawn spacecraft into orbit. The dark, water-rich body turns out to hold a number of its own mysteries, including a pyramid-shaped mountain, bright spots of reflective salt and an enigmatic haze that fills some of its craters in the morning sunlight. The European Space Agency’s Rosetta craft continued its spectacular orbit around Comet 67P/Churyumov–Gerasimenko. Its Philae lander, presumed lost after a bumpy landing in November 2014, phoned home in June before falling silent, perhaps permanently, the following month. Researchers analysing Rosetta data reported this year that oxygen is streaming out of the comet, and that its rubber-duck shape was probably a result of a low-speed collision between two smaller comets. NASA’s MAVEN (Mars Atmosphere and Volatile Evolution) mission delivered its first detailed measurements of how the solar wind strips away Mars’s atmosphere over time, leading to the mostly airless world that Mars is today. And 11 years after arriving at the Saturn system, NASA’s Cassini spacecraft confirmed that the buried ocean beneath the surface of the moon Enceladus stretches around the entire globe — making it a tempting place to hunt for extraterrestrial life. Rarely has a method roared onto the scene as quickly as the accurate, easy-to-use yet controversial CRISPR–Cas9 genome-editing system. In April, scientists in China reported use of the technique to edit non-viable human embryos, which spurred researchers and bioethicists to debate in editorials and meetings whether the technology should ever be used in human embryos, even for basic research. The debate culminated in the International Summit on Human Gene Editing in early December in Washington DC, which brought together nearly 500 ethicists, scientists and legal experts from more than 20 countries. The organizers wrapped up the event with a statement: the tools are not yet ready to be used to edit the genomes of human embryos intended for pregnancy. But they did not call for an outright ban of this work for basic research. Over the past three years, CRISPR has become the tool of choice for scientists seeking to enhance animals and crops, and to cure human disease (see ‘CRISPR craze’). In October, researchers set a record by editing the genomes of pig embryos in 62 places at once — a move that could help to revitalize the field of xenotransplantation. The genetic tinkering could lower the risk of exposure to potentially dangerous pig viruses when people receive human-like organs grown in swine. Dogs, goats and sheep have also had their DNA modified with the low-cost technology. CRISPR could target human diseases as well. With that aim in mind, in August, Google and other investors pumped US$120 million into the genome-editing start-up Editas Medicine in Cambridge, Massachusetts. The firm plans to use CRISPR in clinical trials in 2017 to correct a genetic mutation in some people who are visually impaired. Other, more mature genome-editing technologies are already entering the clinic. In November, researchers in the United Kingdom announced that they had used a different system — enzymes called TALENs — to edit human immune cells and transplant them into a one-year-old with leukaemia, possibly saving her life. And in December, scientists from Sangamo Biosciences in Richmond, California, announced that in 2016 they will begin a human trial to test DNA-snipping zinc-finger nucleases that correct a gene defect for haemo­philia. Edward Jenner, who tested the first vaccine more than 200 years ago, would have been proud of the progress in 2015. After being fast-tracked into human trials this April, the rVSV-ZEBOV Ebola vaccine was found to offer near-total protection to people who received it soon after exposure to the disease, according to preliminary analysis of an ongoing clinical trial in Guinea. The vaccine consists of a weakened livestock virus that has been engineered to produce an Ebola protein, and it was the result of an accelerated development programme that experts say could be emulated to combat other emerging diseases. But rVSV-ZEBOV arrived too late to have much impact on the Ebola epidemic, which has killed more than 11,000 people across West Africa. The disease is on the wane, but it made a surprising comeback in Liberia recently; after twice saying that it had rid itself of the virus, the country announced three new cases in November, including one death. Nearly 30 years in the making, the world’s first malaria vaccine won a lukewarm endorsement from a global vaccine advisory group in October. Researchers reported in April that the vaccine achieved a modest 30% protection rate in a clinical trial involving more than 15,000 children in Africa. The panel recommended pilot tests of the vaccine, called RTS,S, in up to 1 million children before it is widely distributed. Polio vaccines brought the debilitating disease nearer than ever to global eradication: this year, just 66 wild-poliovirus cases were recorded as of 9 December. In July, Nigeria — one of three countries, along with Pakistan and Afghanistan, that have never interrupted the spread of the virus — cele­brated a full year without a new wild-poliovirus infection for the first time, prompting the World Health Organization to remove the country from its list of polio-endemic nations in September. This paves the way for Africa to be declared polio-free as early as 2017. Finally, Mexico approved the first ever vaccine against dengue virus. The vaccine’s maker, Paris-based Sanofi, now hopes to secure approval in other countries in Latin America and Asia. Physicists celebrated the 100th anniversary of Albert Einstein’s general theory of relativity in November with special conferences, books and collections of his papers. Einstein also made headlines in August when physicists presented the most convincing proof yet that two objects, such as subatomic particles, could be linked, or ‘entangled’. This would allow one particle to influence the behaviour of another, even if the two are widely separated. Researchers showed that they could produce a robust entanglement between two electrons placed 1.3 kilometres from each other. Einstein famously despised this phenomenon, which he called ‘spooky action at a distance’, because it seemingly broke the universal rule that nothing can travel faster than the speed of light. Despite Einstein’s misgivings, the approach could one day be used to build a highly secure quantum Internet that is immune to hackers. Oil and gas exploration and other human activities are thought to have triggered earthquakes worldwide, from Switzerland to India and China, but nowhere have scientists scrambled to understand and respond to the quakes as much as in Oklahoma. The state began recording an increase in seismicity in 2009, and this year experienced the most yet — it now has more quakes of magnitude 3 and above each year than California. In April, officials finally acknowledged the probable role of the energy industry. The Oklahoma Geological Survey announced that oil and gas wells that pump wastewater deep into the ground are probably to blame: the injection of tens of millions of litres of liquid shifts fault stresses and increases the likelihood of quakes. In response, the Oklahoma Corporation Commission, which regulates oil and gas exploration, cut back on the number of wastewater disposal wells allowed in the areas with the most seismic activity — a remarkable move given how powerful the energy industry is in state politics. Debate about how to boost the reproducibility of research results shifted from handwringing to analysis and action in 2015. Researchers in an array of fields struggle to independently reproduce published results for many reasons, ranging from poorly described methods to flawed data analysis. In December, the US-based Reproducibility Project: Cancer Biology announced that it had scaled back its attempts to reproduce high-profile papers in cancer biology, from 50 papers to 37, because of the excessive cost and time required. Efforts to quantify the problem bore fruit this year. In April, another Reproducibility Project team showed that some two-thirds of attempts to replicate published psychology studies ended in failure. And a controversial analysis estimated that US$28 billion a year is spent on biomedical studies that are not reproducible, often because of poor documentation and flawed materials. Funders have responded. Key biomedical institutes in the United Kingdom, including the Wellcome Trust, released a report this year sketching out strategies to improve reproducibility, such as standardizing experimental practices. The US National Institutes of Health (NIH) released reproducibility guidelines in October. These asked grant reviewers to look for flaws in experimental design that might introduce bias and requested that grant applicants describe how they will authenticate reagents. Some scientific societies pushed back this year on another set of NIH guidelines from 2014 that required authors to describe their experiments more fully. The societies said that the rules would make the preparation and reviewing of papers too burdensome. Publishers are also getting involved: around a dozen journals this year began asking their authors to use unique identifiers for their reagents as part of a push by the Resource Identification Initiative. The discussion about sexism grew more public this year, driven by several incidents that highlighted how chauvinism still permeates science. In April, evolutionary geneticist Fiona Ingleby of the University of Sussex in Brighton, UK, revealed on Twitter that PLoS ONE had rejected a paper that she wrote with a female colleague, after a reviewer said that adding “one or two” male co-authors would improve the analysis. The journal removed the reviewer from its database and asked the academic editor handling the paper to step down from its editorial board. In June, Nobel-prizewinning biologist Tim Hunt drew widespread criticism when he spoke of his “trouble with girls” in laboratories. “You fall in love with them, they fall in love with you, and when you criticize them, they cry,” he said at an international science-journalism conference in Seoul. Hunt, who two days later resigned from his post as an honorary professor at University College London, said that he had meant to be light-hearted and that he had been “hung out to dry”, but the university did not reinstate him. October brought the biggest story of all: the revelation that renowned exoplanet hunter Geoffrey Marcy had sexually harassed multiple students over at least a decade. Marcy resigned from his post at the University of California, Berkeley, amid public outrage from colleagues at the university and in astronomy more widely. The case has prompted soul-searching among scientific societies, and several are developing or re-evaluating policies intended to prevent sexual harassment at meetings and other events. Structural biologists uncovered unprecedented detail on life’s molecular machinery this year, thanks to advances in a technique called cryo-electron microscopy (cryo-EM). Researchers can determine structures of cellular proteins by flash-freezing them, then photographing them at near-atomic resolution using an electron microscope. Cryo-EM has usurped X-ray crystallo­graphy in the past three years because it doesn’t require proteins to be crystallized first, allowing researchers to analyse many more molecules. Using the technique, biologists have mapped well over 100 molecular structures in detail this year, including the proteasome, which recycles damaged or unwanted proteins, and the spliceosome, which chops out pieces of messenger RNA before the sequence is translated into protein. This year also saw the sharpest cryo-EM structure so far — that of a bacterial enzyme involved in sugar breakdown — and researchers hope to bring this level of detail to medically important molecules. Tailoring treatments to individual patients has long been a goal in biomedicine, but US President Barack Obama gave this effort a big boost with his announcement in January of the Precision Medicine Initiative (PMI). As part of the US$215-million programme, which will award its first grants next year, the NIH and partner organizations will recruit one million people across the country, collecting genetic information, health records and even data from electronic health-monitoring devices. Researchers will use the information to look for links between disease risk and genetic and environmental factors. The PMI inspired other governments to bet on giant longitudinal studies of their own. Soon after Obama’s speech, California announced a $3-million initiative. And China is expected to launch its own large-scale project next year, which will take advantage of the country’s considerable genomic-sequencing capacity. Iceland showed this year what is possible with large numbers of human-genome sequences. In March, the Icelandic firm deCODE genetics in Reykjavik published four papers on its analysis of more than 2,600 full genomic sequences from Icelanders — the largest collection of human genomes from a single population. It described mutations linked to Alzheimer’s disease and mutation rates in the Y chromosome.

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