Labslink Research News

Target Meeting’s 2nd World Molecular & Cell Biology Online Conference Held on February 5-8, 2013: Join for Free

Tue, 22 Jan 2013 15:34:12 PDT

A Free Virtual Molecular & Cell Biology Conference at Targetmeeting.com featuring 80+ live presentations (17 sessions) from academic and industry experts around the world. Computer and internet connection are required. Do not need any special equipment or software. All the attendees just connect to the online conference's server to participate in real time with their distinguished counterparts from across the globe. They can participate from their home or office depending on their convenience, which will save them the trouble of traveling and in utilizing their time optimally. Furthermore, attendees can earn the free Certificates of Attendance. It is a great opportunity to learn about recent advances in the field of molecular & cell biology without travel and money cost.

Major sessions (17 sessions) include
Cell signaling pathways
Cell death
RNA biology
Stem cells
GPCR structure & function
Protein structure & modification
Animal model
Cancer biology & therapy
Cell adhesion & migration
Neuron biology & neurological diseases
And many more…

Keynote & Featured Speakers (80+) include
Devyn M. Smith, Chief Operating Officer, Neusentis Research Unit at Pfizer, USA.
Richard G. Pestell, Chairman & Associate Dean, Thomas Jefferson University, USA.
Rolf D Hubmayr, Walter and LeonoreAnnenberg Professor, Mayo Clinic, USA.
Rakesh Srivastava, Tyler Endowed Professor, University of Kansas Medical Center, USA.
Min Du, Professor & Chair, University of Wyoming, USA.
Leif Hertz, Professor, University of Saskatchewan, SK, Canada.
David Hecht, Professor, Chemistry, Southwestern College, USA.
Jacek Jawien, Professor & Chair, Jagiellonian University School of Medicine, Poland.
Steven Stacker, Head, PeterMacCallum Cancer Centre, Australia.
Dan Tulpan, Professor, University of Moncton, Canada.
Romano Maria Fiammetta, Professor, Federico II University of Naples, Italy.
Farid Menaa, Director R&D, Fluorotronics, Inc. USA.
Kathleen L. Hefferon, Professor& Director, Cornell University, USA.
Yin-Yuan Mo, Professor, Southern Illinois University School of Medicine, USA.
Ming Pei, Director, West Virginia University, USA.
View all speaker profiles, visit www.targetmeeting.com

Researchers, medical professionals, and other related people can enjoy many benefits by participating in the 2nd World Molecular & Cell Biology Online Conference. They can know, learn and follow up on major developments taking place in the areas of interest. You can have the rare privilege of meeting the best international speakers and world-renowned researchers in real time. You can have that much-needed opportunity of networking and exchanging views with the target audience directly. Participants get a worldwide platform to express their opinions and ideas. With their experience and expertise, they can build a solid reputation and create a tremendous and lasting impact on the community. The 2nd World Molecular & Cell Biology Online Conference can create new opportunities for the leading life science professionals and can help them establish new associations with fellow researchers. According to Target Meeting, all presentations and discussions happen in real time. Importantly, they save the participants the hassle of travel; help them use their valuable time effectively and save money. Participants can ask questions, discuss problems, and exchange their ideas on the online platform. The conference presents them the ultimate opportunity to discuss their proposals and initiatives with global experts, something that perhaps would not have been possible using other methods of communication or correspondence. Target Meeting is a leading online life science conference organizer. Thousands of international speakers and ten thousands of attendees participated in the online symposiums and conferences at Target Meeting. With the persistent efforts, Target Meeting has achieved a well-respected reputation among the attendees and within life science communities, based on the quality of organizers, speakers and scientific programs, as well as excellent attendee experience. They have a solid record of having created outstanding opportunities for scientists and clinicians to share their latest research and in inspiring breakthrough ideas. The conferences are a great way to establish and maintain professional relationships with the best brains in medical science. Sign up early (free) to secure your seat, please visit http://www.targetmeeting.com. Upcoming Free Online Conferences at Target Meeting
• February 5-8, 2013, TM’s 2nd world molecular & cell biology online conference.
• March 19-21, 2013, TM’s 2nd world immunology online conference.
• April 16-18, 2013, TM’s 2nd world virology & microbiology online conference.
• May 21-23, 2013, TM’s 2nd world genetics & genomics online conference.
• June 18-20, 2013, TM’s 2nd world neuroscience online conference.
And many more… Contact: William Smith Target Meeting Williams @ targetmeeting dot com
Address: Belliare, TX, 77401, USA

great tool to find conference and courses

Sat, 28 Apr 2012 02:36:59 PDT

Hey guys

Some people working at the NKI (Netherlands Cancer Institute) have setup a
search engine for scientific meetings. check the description and the website
as well, if interested...
This website, called biomeeter (www.biomeeter.com) is really well done as it
gives a nice overview of the upcoming meetings organized, and the search can
be done by field or keyword, or even by location (as it's always possible to
combine business with pleasure ;-)).
Another great characteristic of Biomeeter is that you can add yourself
meetings to the website and share the info. And last but not least: you can
get informed with an email alert about upcoming meetings in your field.
So, check it out and if you like it, spread the word in your lab and
institute!

World Molecular & Cell Biology Online Conference Held on February 16-18, 2012

Wed, 08 Feb 2012 16:52:52 PDT

Target Meeting (www.targetmeeting.com) is a leading life science conference organizer. They specialize in organizing conferences, symposiums and workshops, which brings together the known researchers, professors and life science suppliers from across the world to debate over the latest developments in biomedical research.

The 2012 World Molecular & Cell Biology Online Conference scheduled to be held on February 16 - 18, 2012. The 14 sessions, which will be spread over three days will discuss cell signaling pathways, neuron biology and neurological diseases, DNA / protein structure & function, stem cell biology, microbiology and immunology, receptor structure & function, gene expression & regulation, cell adhesion & migration, cancer biology / therapy and many more. More than 60 leading professors and researchers will give oral presentations at the online conference.

All the attendees just have to connect to the online conference's servers to participate in real time with their distinguished counterparts from across the globe. They can participate from their home or office depending on their convenience, which will save them the trouble of traveling and in utilizing their time optimally. According to Target Meeting, you don't need to have any fancy and special equipment to participate and exchange views. A good Internet connection and a headphone is all that is required.

Researchers and medical professionals can enjoy many benefits by participating in this World Molecular & Cell Biology Online Conference. They can know, learn and follow up on major developments taking place in the areas of interest. You can have the rare privilege of meeting the best international speakers and world-renowned researchers in real time. You can have that much-needed opportunity of networking and exchanging views with the target audience directly.

Participants get a worldwide platform to express their opinions and ideas. With their experience and expertise, they can build a solid reputation and create a tremendous and lasting impact on the community. The 2012 World Molecular & Cell Biology Online Conference can create new opportunities for the leading professionals and can help them establish new associations with fellow researchers.

According to Target Meeting, all presentations and discussions happen in real time. Importantly, they save the participants the hassle of travel; help them use their valuable time effectively and save money. Participants can ask questions, discuss problems, and exchange their ideas using an online platform. The conference presents them the ultimate opportunity to discuss their proposals and initiatives with global experts, something that perhaps would not have been possible using other methods of communication or correspondence.

The organizers have an impeccable reputation of having organized many such online conferences covering various aspects of life science. They have a solid record of having created outstanding opportunities for scientists to share their latest research and in inspiring breakthrough ideas. The conferences are a great way to establish and maintain professional relationships with the best brains in life science.

Target Meeting is organizing 80+ symposiums and 10+ conferences in 2012. For more information about symposiums and conferences, please visit www.targetmeeting.com. Sign up early to secure your seat.

Dyslexia-linked genetic variant decreases midline crossing of auditory pathways

Wed, 01 Feb 2012 17:17:16 PDT

Finnish scientists have found that a rare dyslexia-linked genetic variant of the ROBO1 gene decreases normal crossing of auditory pathways in the human brain. The weaker the expression of the gene is, the more abnormal is the midline cross........> Full story

Scripps Research team proves plausibility of new pathway to life's chemical building blocks

Tue, 31 Jan 2012 19:36:05 PDT

For decades, chemists considered a chemical pathway known as the formose reaction the only route for producing sugars essential for life to begin, but more recent research has called into question the plausibility of such thinking.......> Full story

Cell signaling key to stopping growth and migration of brain cancer cells

Tue, 17 Jan 2012 17:13:10 PDT

Brain cancer is hard to treat: it’s not only strong enough to resist most chemotherapies, but also nimble enough to migrate away from radiation or surgery to regrow elsewhere........> Full story

Scripps Research scientists define cellular pathway essential to removing damaged mitochondria

Tue, 23 Aug 2011 17:46:33 PDT

In a joint research effort with researchers at St. Jude Children’s Research Hospital, and with help from scientists at The University of Pennsylvania, The University of Minnesota, and the National Institutes of Health, investigators from the Florida campus of The Scripps Research Institute have defined a specific protein complex that allows cells to rid themselves of damaged mitochondria, which are the energy producing machines of the cell........> Full story

New component of a plant steroid-activated pathway discovered

Thu, 18 Aug 2011 16:28:40 PDT

Plant biologists have been working for years to nail down the series of chemical signals that one class of plant hormones, called brassinosteroids, send from a protein on the surface of a plant cell to the cell's nucleus. New research from Carnegie scientists Tae-Wuk Kim and Zhiyong Wang, with contributions from the University of California San Francisco, isolated another link in this chain. Fully understanding the brassinosteroid pathway could help scientists better understand plant growth and help improve food and energy crop production. Brassinosteroids are found throughout the plant kingdom and regulate many aspects of growth and development, as well as resistance to external stresses. Mutant plants that are deficient in brassinosteroids show defects at many phases of the plant life cycle including reduced seed germination, irregular growth in the absence of light, dwarfism, and sterility. The series of proteins involved in a plant cell detecting the presence of brassinosteroids and using this information to respond to the plant's environment is one of the best-studied aspects of plant cellular physiology and biochemistry. Previous research had identified a pathway of chemical signals that starts when a brassinosteroid binds to a receptor on the surface of a plant cell and activates a cascade of activity that consists of adding and removing phosphates from a series of proteins. The research team was able to identify a new aspect of this pathway, a protein called Constitutive Differential Growth1, or CDG1. Their work will be published in Molecular Cell on August 19. Using an extensive array of research techniques, they determined that when activated by the brassinosteroid receptor, CDG1 adds a phosphate to another protein called BSU1. It was already known that the BSU1 protein in turns deactivates a third protein called BIN2. When BIN2 is active it inhibits two other proteins called BZR1 and BZR2, which are part of a special class called transcription factors. When they are inactive, they are unable to enter the plant cell's nucleus. But once BIN2 is deactivated by BSU1, they are able to bind directly to DNA molecules inside the nucleus and promote a wide variety of gene activity. "Together with our previous work, these results provide the detailed mechanisms of brassinosteroid signaling," Wang said. "Because this system of brassinosteroid-activated proteins is one of the best-understood chemical pathways in plant physiology, these results could help scientists understand many other plant cell systems."

Pitt team finds molecular pathway that leads to inflammation in asthma

Mon, 08 Aug 2011 19:06:23 PDT

Researchers at the University of Pittsburgh School of Medicine have identified a molecular pathway that helps explain how an enzyme elevated in asthma patients can lead to increased mucus production and inflammation that is characteristic of the lung condition. Their findings, reported online in this week's Proceedings of the National Academy of Sciences, reveal unique interactions between biological molecules that could be targeted to develop new asthma treatments. An enzyme called epithelial 15-lipoxygenase 1 (15LO1) metabolizes fatty acids to produce an eicosanoid known as 15 hydroxyeicosaetetranoic acid (15 HETE) and is elevated in the cells that line the lungs of asthma patients, explained Sally E. Wenzel, M.D., professor of medicine, Pitt School of Medicine, and director of the Asthma Institute at UPMC and Pitt School of Medicine. Her team showed in 2009 that the enzyme plays a role in mucus production. "In this project, we found out 15 HETE is conjugated to a common phospholipid," she said. "That complex, called 15HETE-PE, and 15LO1 behave as signaling molecules that appear to have a powerful influence on airway inflammation." By examining lung cells obtained by bronchoscopy from 65 people with asthma, the researchers found that both 15LO1 and 15HETE-PE displace an inhibitory protein called PEBP1 from its bond with another protein called Raf-1, which when freed can lead to activation of extracellular signal-regulated kinase(ERK). Activated ERK is commonly observed in the epithelial, or lung lining, cells in asthma, but until now the reason for that was not understood. "This is an important study as it directly explores the important role of 15-lipoxygenase 1 in the airway epithelial cells of patients with asthma, which immediately establishes the relevance to human disease," said Mark T. Gladwin, M.D., chief, Division of Pulmonary, Allergy and Critical Care Medicine, UPSOM. Other experiments showed that knocking down 15LO1 decreased the dissociation of Raf-1 from PEBP1, which in turn reduced ERK activation. The pathway ultimately influences the production of factors involved in inflammation and mucus production. "These results show us on both a molecular and mechanistic level and as mirrored by fresh cells from the patients themselves that the epithelial cells of people with asthma are very different from those that don't have it," Dr. Wenzel said. "It also gives us a potential treatment strategy: If we can prevent Raf-1 displacement, we might have a way of stopping the downstream consequences that lead to asthma."

Signaling pathways point to vulnerability in breast cancer stem cells

Fri, 10 Jun 2011 20:52:07 PDT

Whitehead Institute researchers have identified signals from breast epithelial cells that can induce those cells to transition to and maintain a mesenchymal and stem cell-like cell state that imbues both normal and cancer cells with a greater ability to migrate and self-renew. Interrupting these signals strips the cells of the migratory, invasive and self-renewal abilities used by cancer stem cells to seed new tumors. "Stem cells are important in both cancers and normal tissues. On the one hand we'd like to know what creates so-called cancer stem cells in tumors and on the other hand we'd like to know what creates normal stem cells in normal epithelial tissues," says Whitehead Founding Member Robert Weinberg. "We have reason to believe that these two dynamics are orchestrated by a common regulatory machinery. So this work may be applicable for understanding both breast cancer cells and normal epithelial cells, such as the normal cells in the normal mammary ducts." During an epithelial-to-mesenchymal transition (EMT), epithelial cells acquire the traits of mesenchymal cells. Unlike the tightly-packed epithelial cells that stick to one another, mesenchymal cells are loose and free to move around a tissue. The attributes of mesenchymal cells are beneficial during development, but when hijacked by cancer cells, confer the ability to migrate to distant sites. In addition, the passage through an EMT enables adult cancer cells to seed new tumors with high efficiency, the hallmark trait of cancer stem cells. Although passage through an EMT is recognized as an important step in the formation of cancer stem cells, scientists have been unable to clearly identify the cues in a cell's microenvironment that induce an EMT. By studying human breast epithelial cells, Christina Scheel, a postdoctoral researcher in the Weinberg lab, pinpointed three signaling pathways (TGF-beta, non-canonical Wnts, and canonical Wnts) that work together to maintain migratory and self-renewing traits of both normal breast epithelial and breast cancer cells. These pathways are continuously activated in the stem cells by autocrine signals; that is, signals produced by the cells themselves. Studying how these autocrine signals function in breast epithelial cells allowed Scheel to specify the signals that allow these cells to pass through an EMT and enter into a mesenchymal and stem cell-like state in the first place. Her findings are published in the June 10 issue of Cell. Interestingly, Scheel discovered that epithelial cells are kept in their differentiation state via inhibition of the three signaling pathways, that is, normal epithelial cells naturally produce proteins that block these signaling proteins. To push normal breast epithelial cells through an EMT in vitro, she removed these endogenous inhibitors by administering a cocktail of neutralizing antibodies and added growth factors that stimulate the three pathways, thereby mimicking the autocrine signaling found in mesenchymal cells. By applying the resulting EMT-inducing cocktail continuously, Scheel pushed the cells into a mesenchymal and stem cell-like state, with associated increased migratory ability and stem cell-like characteristics. Eventually, the former epithelial cells stabilized this state through autocrine signaling and were no longer dependent on the EMT cocktail. To see the effects of blocking this autocrine signaling in an animal model, Scheel implanted into mice human breast cancer epithelial cells that had passed through an EMT. She then injected the implantation site with proteins that block the three pathways. The injected mice had one-tenth the number of tumors found in mice that did not receive the inhibitory proteins. In addition, breast cancer cells that were pre-treated in vitro with these proteins displayed a greatly reduced ability to metastasize when subsequently implanted into mice. Scheel notes that these experiments show how cancer cells' knack for usurping normal cell functions could ultimately lead to their downfall. "These autocrine signals are not something breast cancer cells invent anew, but derive instead an activation of normal stem cell programs," says Scheel. "Breast cancer stem cells rely on these signals to maintain themselves, so they remain susceptible to blocking this autocrine signaling. It might be a terrific way to target breast cancer stem cells. In addition, our gain in understanding how both migratory and self-renewal traits are activated in normal breast epithelial cells might further our understanding of normal tissue homeostasis and might be of great utility in the area of regenerative medicine, where it would be highly desirable to create great numbers of epithelial stem cells without resorting to genetic intervention." Although Scheel's research gives new insight into how both cancer and normal breast cells transition to and maintain a mesenchymal cell state, she and Weinberg caution that the same signals and signaling pathways may not apply for non-breast cells. "Are the same agents signaling the EMT in non-mammary tissues – the skin, liver, the gut, pancreas and so forth? We don't know the generalizability of Scheel's findings yet, although I can imagine that there are many commonalities," says Weinberg, who is also a professor of biology at MIT and the Director of the MIT/Ludwig Center for Molecular Oncology. "Secondly, we don't know if these three signaling pathways are ultimately those that are critically important for activating the EMT in non-mammary cell types. Alternatively, there may be other contextual signals besides these three that play an equally important role in triggering an EMT in non-mammary cells? Whether these signaling pathways turn out to have a degree of universality, we just don't know."

Buenos 'notch-es': Universal signaling pathway found to regulate sleep

Thu, 05 May 2011 19:48:40 PDT

Sleeping worms have much to teach people, a notion famously applied by the children's show "Sesame Street," in which Oscar the Grouch often reads bedtime stories to his pet worm Slimy. Based on research with their own worms, a team of neurobiologists at Brown University and several other institutions has now found that "Notch," a fundamental signaling pathway found in all animals, is directly involved in sleep in the nematode C. elegans. "This pathway is a major player in development across all animal species," said Anne Hart, associate professor of neuroscience at Brown. "The fact that this highly conserved pathway regulates how much these little animals sleep strongly suggests that it's going to play a critical role in other animals, including humans. The genes in this pathway are expressed in the human brain." The work, to be published May 24 in the journal Current Biology, offers new insights into what controls sleep. The lead authors are Komudi Singh, a postdoctoral fellow in the Department of Neuroscience at Brown University, and Michael Chao, a previous member of the Hart laboratory, who is now an associate professor at California State University–San Bernardino. "We understand sleep as little as we understand consciousness," said Hart, the paper's senior author. "We're not clear why sleep is required, how animals enter into a sleep state, how sleep is maintained, or how animals wake up. We're still trying to figure out what is critical at the cellular level and the molecular level." Ultimately, Hart added, researchers could use that knowledge to develop more precise and safer sleep aids. "We only have some really blunt tools that we can use to change sleep patterns," she said. "But there are definite side effects to manipulating sleep the way we do now." Mysterious napping Hart first realized that Notch pathway genes might be important for sleep when her group was investigating an entirely different behavior. She was studying the effect of this pathway on the nematodes' revulsion to an odious-smelling substance called octanol. What she found, and also reports in the Current Biology paper, is that adult nematodes without Notch pathway genes (like osm-11) have their Notch receptors turned off and, therefore, they do not avoid octanol as normal worms do. But she was shocked to find that the adult nematodes in which the osm-11 gene was overexpressed were doing something quite bizarre. "Normally, adult nematodes spend all of their time moving" she said. "But, these animals suddenly start taking spontaneous 'naps.' It was the oddest thing I'd seen in my career." Nematode sleep is not exactly the same as sleep in larger animals, but these worms do go into a quiescent sleep-like state when molting. The worms with too much osm-11 were dozing when they were not supposed to. Other experiments showed that worms lacking osm-11 and the related osm-7 genes were hyperactive, exhibiting twice as many body bends each minute as normal nematodes. The story became clear. The more Notch signaling was turned on, the sleepier the worms would be. When it is suppressed, they go into overdrive and become too active. In humans, the gene that is most similar to osm-11 is called Deltalike1 (abbreviated DLK1). It is expressed in regions of the brain associated with the sleep-wake cycle. Beyond Notch That result alone is not enough to lead directly to the development of a new sleep drug, even for worms. Notch signaling is implicated in a lot of different activities in the body, Hart said, some of which should not be encouraged. "Too much Notch signaling can cause cancer, so we would have to be very targeted in how we manipulate it," she said. "One of the next steps we're going to take is to look at the specific steps in Notch signaling that are pertinent to arousal and quiescence." Focusing on those steps could minimize side effects, Hart said.

Experimental drug inhibits cell signaling pathway and slows ovarian cancer growth

Sun, 17 Apr 2011 20:51:36 PDT

An experimental drug that blocks two points of a crucial cancer cell signaling pathway inhibits the growth of ovarian cancer cells and significantly increases survival in an ovarian cancer mouse model, a study at UCLA's Jonsson Comprehensive Cancer Center has found. The drug, called NVP-BEZ235, also inhibits growth of ovarian cancer cells that have become resistant to the conventional treatment with platinum chemotherapy, and helps to re-sensitize the cancer cells to the therapy. It also enhances the effect of platinum chemotherapy on ovarian cancer cells that are still responding to the therapy, said Dr. Oliver Dorigo, an assistant professor of obstetrics and gynecology, a Jonsson Cancer Center researchers and senior author of the study. "Platinum-based chemotherapy drugs are effective in treating ovarian cancers as long as the cancer cells remain sensitive to platinum," Dorigo said. "But once the tumor becomes resistant, treating the cancer becomes very challenging. This is a significant clinical problem, since the majority of ovarian cancer patients develop resistance at some point during treatment. Breaking chemotherapy resistance is a difficult challenge, but crucial if we want to improve long-term survival for our patients." The study, performed on cells lines and mouse models, appears in the April 15, 2011 issue of the journal Clinical Cancer Research. Dorigo has been working in his laboratory over the last several years in an effort to develop new therapies for ovarian cancer. About 22,000 American women are diagnosed with ovarian cancer, and more than 14,000 deaths are attributed to this disease every year. Dorigo has focused his research efforts on a pathway called PI3Kinase/Akt/mTOR, which once activated promotes ovarian cancer growth. The activated pathway also makes the cancer more aggressive and more likely to spread to other organs, Dorigo said, so targeting it offers great promise for more effective therapies for the disease. In this two-year study, Dorigo and postdoctoral fellow Chintda Santiskulvong found that inhibiting two checkpoints of the pathway - PI3Kinase and mTOR - with NVP-BEZ235 decreased cancer growth, both in cell culture dishes and in mice with ovarian cancer. It also significantly increased survival in the mice, he said. More importantly, NVP-BEZ235 slowed growth of the ovarian cancer cells that had become resistant to platinum and helped to break that resistance. "We were very encouraged to find that NPV-BEZ235 could re-sensitize the ovarian cancer cells to standard platinum treatment," Dorigo said. "In addition, we found this drug to be more effective in inhibiting ovarian cancer cell growth than other drugs that target only one checkpoint, mTOR, in this pathway. We believe that NVP-BEZ235 has superior efficacy because of the dual effect on PI3Kinase and mTOR." The experimental drug is being tested as a single agent at the Jonsson Cancer Center in human clinical trials against other solid tumors. Researchers involved with those studies have said early results are encouraging. "This is clearly a promising agent with activity in humans," said Dr. John Glaspy, a professor of hematology/oncology and a Jonsson Cancer Center scientist involved with the studies. "We are still assessing its tolerability in patients." Dorigo said he hopes to initiate a clinical trial for women with ovarian cancer that tests the combination of NVP-BEZ235 with platinum chemotherapy, as he believes that the combination might be more effective than each drug alone.

Scripps Research scientists identify mechanism of long-term memory

Wed, 13 Apr 2011 19:12:22 PDT

Using advanced imaging technology, scientists from the Florida campus of The Scripps Research Institute have identified a change in chemical influx into a specific set of neurons in the common fruit fly that is fundamental to long-term memory. The study was published in the April 13, 2011 issue of The Journal of Neuroscience. "In studying fruit flies' learning and long-term memory storage, we observed an increase in calcium influx into a specific set of brain neurons in normal fruit flies that was absent in 26 different mutants known to impair long-term memory,," said Ron Davis, chair of the Scripps Research Department of Neuroscience, who led the study. "This logical conclusion is that this increase, which we call a memory trace, is a signature component of long-term memory." The memory trace in question is an increased influx of calcium into a set of neurons after long-term memory forms in a part of the insect brain known as mushroom bodies, a pair of oversized lobes known to mediate learning and memory, particularly the memories of smell. They have been compared to the hippocampus, a site of memory formation in humans. Increases in calcium influx also occur with learning in other animal models, Davis said, and it seems highly likely a similar correlation exists in humans. Measuring Memory Traces To measure the changes in the Drosophila neurons, Davis and his colleagues used functional optical imaging, an advanced technology that his laboratory helped pioneer for the study of learning and memory. Using protein sensors that become fluorescent when calcium levels are increased, the team was able to highlight changes in the levels of calcium influx into the mushroom body neurons in response to odor learning. These observed memory traces occur in parallel with behavioral changes. Interestingly, these memory traces occur only with spaced conditioning – where the insects receive multiple episodes of learning but with periods of rest between each episode. Spaced conditioning is required for long-term memories to form. In an earlier study last December, also published in The Journal of Neuroscience, Davis found not only that fruit flies receiving spaced conditioning exhibited a long-term memory trace, but also that their memories lasted between four and seven days. In flies that were given a single episode of learning, memory formation lasted only a day and the long-term memory trace failed to form. These two studies are the newest in a series of six studies on the topic, including those published in the journal Neuron in 2004 and 2006, Cell in 2005, and Nature Neuroscience in 2008. Davis reviewed all of his studies of memory traces in the most recent issue of Neuron. "The phenomenon of spaced conditioning is conserved across all species," Davis said. "No one really knows why it's important to long-term memory formation but there appears to be something magical about that rest period during learning."

Combining MEK and PI3K inhibitors appears encouraging in a safety study with early signs of anti-tumor activity

Sat, 02 Apr 2011 10:49:21 PDT

The combination of two compounds that inhibit two of the most frequently mutated cancer pathways is showing promise in an ongoing Phase I trial, according to data presented at the AACR 102nd Annual Meeting 2011, held here April 2-6. The research, presented by Johanna Bendell, M.D., tests a combination of GDC-0973, which inhibits MEK1/2 and GDC-0941, which inhibits PI3K. Bendell, director of Gastrointestinal Oncology Research and associate director of the drug development unit at the Sarah Cannon Research Institute in Nashville, said the RAS/RAF/MEK and PI3K pathways are altered in most tumors. "Combining agents that block multiple pathways in tumor cells is likely the future of targeted therapy in cancer medicine. Blocking two pathways that interact with each other has the potential to have more anti-cancer activity than blocking either pathway alone," says Bendell. The researchers enrolled 27 patients who received the combination of different doses of GDC-0973 and GDC-0941 on a daily 21 day on/7 day off schedule. The most common side effects seen were diarrhea, fatigue, rash, nausea, vomiting, decreased appetite and taste changes. Most of these side effects were mild. Several patients have demonstrated decreases in tumor size, including two patients with melanoma, one with prostate cancer, two with non-small cell lung cancer. One patient with lung cancer and two patients with melanoma had stable disease over six months. The study is ongoing. "We are very encouraged by this early data. We are able to give these agents together safely and we are seeing early signs of anti-cancer activity," said Bendell.

Getting organized: Berkeley Lab study shows how breast cell communities organize into breast tissue

Mon, 14 Mar 2011 03:24:18 PDT

In biology, the key to a healthy life is organization. Cells that properly organize themselves into communities live long and prosper, whereas disorganized cells can become cancerous. A study by researchers with the Lawrence Berkeley National Laboratory (Berkeley Lab) of the different types of cells that make up the human breast shows that not only do cells possess an innate ability to self-organize into communities, but these communities of different types of cells can also organize themselves with respect to one another to form and maintain healthy tissue.........> Full story

Researchers in France and Austria find novel role for calcium channels in pacemaker cell function

Thu, 10 Mar 2011 03:27:31 PDT

Pacemaker cells in the sinoatrial node control heart rate, but what controls the ticking of these pacemaker cells? New research by Angelo Torrente and his colleagues of the M.E. Mangoni group's, reveals, for the first time, a critical functional interaction between Cav1.3 calcium ion (Ca2+) channels and ryanodine-receptor (RyR) mediated Ca2+ signaling. The study also sheds light on a long-standing debate regarding the relative contributions of the 'funny current' generated by ion channels and the RyR dependent spontaneous diastolic Ca2+ release theory in determining heart rate. The investigation by the research team compared pacemaker cells in normal mice with mutants that lacked the L-type Cav1.3 channels to contrast how they handled calcium. They found that the absence of Cav1.3 channels in sinoatrial node (SAN) cells reduced the frequency of Ca2+ transients, which determine the rate of cardiac muscle contraction. The Cav1.3 channels were also found to be important regulators of ryanodine-receptor dependent local calcium release in the diastolic pacemaker phase. Overall, their results show that local calcium release in SAN cells is tightly controlled by the Cav1.3 channels. Defects in calcium channels controlling heart muscle function are known to cause heart failure, and this study reveals that Cav1.3 mutant mice also suffer from bradycardia and other cardiac arrhythmias. "Our results clarify the role of Cav1.3 channels in pacemaker generation, and are a step towards using it as a target for drug therapy to treat heart dysfunction related to the sinoatrial node", says A. Torrente of CNRS in Montpellier, France, who was the lead author on the study. Not only Cav1.3 channels are critical to the heart pacemaker cell function, they appear to be important to several other cellular mechanisms as well. In both humans and mice, Cav1.3 mutations have been linked to sinoatrial node dysfunction and deafness (or SANDD) syndrome. Cav1.3 channels are believed to play a role in pancreatic β-cell stimulation, and they may also serve as pacemaker channels in the central nervous system, playing a pathophysiological role in Parkinson's disease. "A better understanding of these channels in SAN could help us to comprehend the mechanism of calcium release in many other tissues and disease conditions as well", says Torrente.

Ohio State study: Targeted ovarian cancer therapy not cost-effective

Tue, 08 Mar 2011 03:23:35 PDT

An analysis conducted by Ohio State University cancer researchers has found that adding the targeted therapy bevacizumab to the treatment of patients with advanced ovarian cancer is not cost effective. The findings comparing the relative value of various clinical strategies will be published online March 7 in the Journal of Clinical Oncology. The researchers performed a cost-effectiveness analysis looking at a clinical trial conducted by the Gynecologic Oncology Group (GOG) studying the use of bevacizumab along with standard chemotherapy for patients with advanced ovarian cancer, said first author Dr. David E. Cohn, a gynecologic surgical oncologist and researcher at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James). Bevacizumab is a novel targeted therapy designed to inhibit angiogenesis, the process by which new blood vessels develop and carry vital nutrients to a tumor. Although a discussion regarding cost-effectiveness of a potentially life-extending intervention invariably suggests the rationing of limited health care resources, the intent of this study was to provide a framework with which to evaluate the pending results of a clinical trial of three different interventions for ovarian cancer, said Cohn. "We do not suggest that bevacizumab, also known by the brand name Avastin, should be withheld from a patient with ovarian cancer, but rather argue that studies evaluating the effectiveness of new treatments should also be interpreted with consideration of the expense," says Cohn, who collaborated with Dr. J. Michael Straughn Jr., an associate professor of obstetrics and gynecology at the University of Alabama at Birmingham. The results of the randomized phase III GOG clinical trial demonstrated an additional 3.8 months of progression-free survival when maintenance bevacizumab was added for about one year following treatment with standard chemotherapy drugs carboplatin and paclitaxel along with bevacizumab. "We put together a model looking at the variety of treatment arms on this clinical trial, each of which included 600 patients," said Cohn. "Given the fact that the addition of the drug was associated with 3.8 months of additional survival without cancer, we set out to determine whether or not that benefit of survival was justified by the expense of the drug." The model showed that standard chemotherapy for patients in the clinical trial would cost $2.5 million, compared to $78.3 million for patients who were treated with standard chemotherapy and bevacizumab, plus additional maintenance treatments of bevacizumab for almost one year. Bevacizumab has been used in the treatment of recurrent ovarian cancer, and the U.S. Food and Drug Administration has approved it for the treatment of colorectal, lung, breast, brain (glioblastoma) and renal cell cancers. Typically each treatment with bevacizumab costs $5,000, with most of those costs directly attributable to the cost of the drug, Cohn said. Effectiveness was defined as months of progression-free survival, and costs were calculated as total costs per strategy. Cost-effectiveness strategies were defined as the cost per year of progression-free survival. Incremental cost-effectiveness ratio was defined as the costs per progression-free life-year saved. "Ultimately, we found that if you reduced the drug cost to 25 percent of the baseline, it does become cost effective to treat patients with bevacizumab," said Cohn. "Or, if the survival could be substantially increased above the 3.8 months of progression-free survival, that could lead to cost-effective treatment for patients with advanced ovarian cancer." Ovarian cancer is the most lethal gynecologic cancer, with almost 14,000 women expected to die from the disease this year, according to the American Cancer Society. "It is anticipated that in the future, there will be increased scrutiny regarding the individual and societal costs of an effective medication," said Cohn. "We hope that future clinical trials will incorporate the prospective collection of cost, toxicity and quality-of-life data to allow for a fully informed interpretation of the results."

UCSF researchers uncover hormone pathway to fatty liver disease

Wed, 02 Mar 2011 03:20:04 PDT

Scientists at the UCSF Cardiovascular Research Institute have discovered how a change in growth hormone activity in mice leads to fatty liver disease, a condition whose human counterpart is of rising concern worldwide. Disruption of a key protein in the pathway that responds to growth hormone could explain how fatty liver disease develops, the researchers said, but may also offer insights into how our bodies regulate fat in general. The team's findings and the first reports of a mouse model to study the pathway will appear in the April issue of the Journal of Clinical Investigation and online March 1 at www.jci.org. Until recently, the growth of fat deposits in the liver that characterizes fatty-liver disease was mainly considered a result of alcoholism. Over the last decade, though, scientists have been baffled by the rising incidence of the non-alcoholic version of the disease, which now affects as many as one in four people worldwide, according to UCSF cardiologist Ethan Weiss, MD, senior author of the paper. Known risk factors for the condition include obesity, diabetes and malnutrition, among many others, but its precise mechanism had eluded researchers. "Fatty liver disease is an increasingly prevalent condition that is poorly understood," Weiss said. "We knew that growth hormone had been linked to fatty liver, but previous reports showed that it both causes and cures the condition. We set out to figure out why that happens." The team focused on a protein in the liver known as JAK2. While better known as being linked to cancers such as blood cancers, this protein is also a key player in an important chemical pathway in the liver. Normally, the pituitary gland secretes growth hormone, which communicates with JAK2 and sets off a series of steps to produce insulin-like growth factor 1 (IGF-1), an important mediator of growth and other effects. It was common knowledge that disrupting this pathway would halt IGF-1 production, but in their analysis, Weiss and his team found that disrupting the pathway also caused fatty liver disease. The team engineered a mouse model in which the gene producing JAK2 had been removed solely in the liver, disrupting the pathway that produces the insulin-like growth factor. As expected, the levels of growth factor in these mice were low or nonexistent and the mice developed early and severe fatty-liver disease. Further analysis showed that another protein, called CD36, was working in the liver to draw in the fat in the JAK2-deficient mice. The amount of growth hormone secreted by the pituitary gland also was dramatically elevated. The team realized that low IGF-1 levels were sending the pituitary gland into overdrive, secreting more growth hormone in order to jumpstart the growth factor's production. But without JAK2, the signaling pathway was broken and IGF-1 production was at a standstill. That explained the low growth factor levels, but not the fatty livers. The team then took advantage of a second set of mice with no capability of producing growth hormone, which is known to activate energy from fat stores. When crossing the JAK2-deficient mice with the growth hormone-deficient "little" mice, the researchers noticed a huge difference in the offspring. "We saw a complete disappearance of the fatty liver in these offspring," he said. "It was just gone." The team concluded that the growth hormone signaling pathway is not only essential in producing IGF-1 and mobilizing fat, but in regulating how fat is taken up by the liver. This newfound understanding has huge implications for understanding and treating fatty liver disease in humans, Weiss said, such as the possibility of developing a therapeutic drug that works within this pathway.

Scientists find a new way insulin-producing cells die

Sun, 27 Feb 2011 17:36:43 PDT

The death of insulin-producing beta cells in the pancreas is a core defect in diabetes. Scientists in Italy and Texas now have discovered a new way that these cells die — by toxic imbalance of a molecule secreted by other pancreatic cells. "Our study shows that neighboring cells called alpha cells can behave like adversaries for beta cells. This was an unexpected finding," said Franco Folli, M.D., Ph.D., professor of medicine/diabetes at The University of Texas Health Science Center at San Antonio. He is co-lead author on the study with Carla Perego, Ph.D., assistant professor of physiology at the University of Milan. Balance needed to control sugars Alpha and beta cells are grouped in areas of the pancreas called the islets of Langerhans. Alpha cells make glucagon, the hormone that raises blood sugar during fasting. In the same environment the beta cells make insulin, the hormone that lowers sugars after a meal. Imbalance ultimately leads to diabetes. "We found that glutamate, a major signaling molecule in the brain and pancreas, is secreted together with glucagon by alpha cells and affects beta cell integrity," Dr. Folli said. "In a situation where there is an imbalance toward more alpha cells and fewer beta cells, as in Type 1 and Type 2 diabetes, this could result in further beta cell destruction." Role of alpha cells Glutamate toxicity is a new mechanism of beta cell destruction not previously known, Drs. Perego and Folli said. It has not been typically thought that alpha cells could themselves be a cause of beta cell damage, they said. The study also found a protection for beta cells, namely, a protein called GLT1 that controls glutamate levels outside the beta cells. "GLT1 is like a thermostat controlling the microenvironment of beta cells with respect to glutamate concentration," Dr. Perego said. Early warning A diagnostic test for glutamate toxicity in the islets of Langerhans is being developed by the authors, Dr. Folli said. Eventually an intervention to slow the process could follow. Glutamate poisoning is a new candidate mechanism for beta cell destruction in diabetes. Others are high glucose, buildup of a protein called amyloid, and free fatty acids, which are found in patients with type 2 diabetes. "The vicious cycle in diabetes is that there are several substances that have been shown, also by us, to be toxic to beta cells," Dr. Folli said. "And now we have found a new one, glutamate."

Collisions of protein machines cause DNA replication derailment

Fri, 25 Feb 2011 03:26:49 PDT

DNA damage, if not kept in check, can lead to many problems including cancers. Researchers, funded by the Biotechnology and Biological Sciences Research Council (BBSRC) and the Wellcome Trust and working at The University of Nottingham, have shown that the process of replication is even riskier than originally thought. This new information is published tomorrow (24 February) in the journal Nature......> Full story

La Jolla Institute-led team illuminates cell pathway key to insulin resistance in Type 2 diabetes

Thu, 24 Feb 2011 03:13:19 PDT

A research team, led by La Jolla Institute scientist Joel Linden, Ph.D., has shed new light on the problem of insulin resistance, and identified the key participants in a molecular pathway that holds therapeutic promise for reducing the severity of type 2 diabetes. The researchers looked at the role of adenosine, an immune system signaling molecule, in triggering inflammation, which significantly contributes to insulin resistance. Insulin resistance keeps the body from properly handling sugar and is one of the key factors underlying type 2 diabetes. Diabetes now affects nearly 26 million Americans and is the seventh leading cause of death in the U.S., according to the Centers for Disease Control. "Several previous studies have shown that if you block adenosine signaling, insulin resistance is diminished," said Dr. Linden. "However, it wasn't known exactly how the process worked or which cells were directly involved." Dr. Linden's team identified the primary cellular players in the adenosine-fueled inflammation cascade that contributes to insulin resistance. Their study, in animal models, also tested the effectiveness of a recently synthesized adenosine receptor blocker. "We found that if you use this molecule to selectively block one of the adenosine receptors, insulin resistance is decreased and diabetes gets better," said Dr. Linden, one of the world's leading authorities on adenosine. Eugene Barrett, Ph.D., a past president of the American Diabetes Association, praised the study's findings as important. "There is a great need for new approaches to lessen the disease burden caused by insulin resistance," said Dr. Barrett, a professor of medicine and director of the University of Virginia's Diabetes Center, which was not involved in the study. "The work of Dr. Linden and his collaborators opens a new avenue to explore with possibly important therapeutic implications." The findings were published in a paper entitled "Links Between Insulin Resistance, Adenosine A2B Receptors, and Inflammatory Markers in Mice and Humans" in the February issue of the scientific journal Diabetes. Dr. Linden was senior author on the study, which involved scientists from Pennsylvania State University, the University of Virginia, the La Jolla Institute for Allergy & Immunology and Clinical Data, Inc., a pharmaceutical company examining possible therapeutic applications targeting adenosine receptors. Robert A. Figler, Ph.D., of Clinical Data Inc. was first author on the paper. "Our study clarifies the molecular steps triggered by adenosine, which leads to inflammation linked not only to type 2 diabetes but to other inflammatory diseases," Dr. Figler said. Clinical Data has an ongoing development program in A2B receptor antagonists, he added, and is pursuing the therapeutic potential of these agents in diabetes as well as asthma. Clinical Data plans to soon begin a clinical trial for patients with asthma. In type 2 diabetes, Dr. Linden explained, the ability of insulin to stimulate glucose uptake by the tissues is reduced, an occurrence known as insulin resistance. "Insulin's job is to move glucose out of the blood stream and into other body tissues, where it can be used," he said. "If insulin can't do its job because the body's tissues aren't responding to it sufficiently, then you end up with a buildup of sugar in the blood." "So we asked ourselves the question," Dr. Linden continued, 'why don't the tissues respond?'" Recently, said Dr. Linden, the scientific community has learned that type 2 diabetes is associated with chronic low-grade inflammation. "We believe, as do many scientists, that insulin resistance involves macrophages, which are cells of the body that contribute to inflammation," he explained. "We discovered that adenosine stimulates macrophages. The macrophages then release chemicals called cytokines, which are molecules that rev up the immune system. We believe it is the cytokines that cause tissues to become less sensitive to insulin." By using an adenosine receptor blocker, the team prevented the adenosine from activating the macrophages, said Dr. Linden. "So the downstream effect of releasing cytokines does not occur." The result? The tissues began to better respond to insulin, which reduces blood sugar levels in diabetic animals. While sensitivity to insulin was significantly improved, Dr. Linden said insulin resistance was not completely reversed. "We will be studying this further to better understand the details of insulin resistance," he said.

Sleeping Trojan horse to aid imaging of diseased cells

Fri, 18 Feb 2011 03:17:00 PDT

A unique strategy developed by researchers at Cardiff University is opening up new possibilities for improving medical imaging. Medical imaging often requires getting unnatural materials such as metal ions into cells, a process which is a major challenge across a range of biomedical disciplines. One technique currently used is called the 'Trojan Horse' in which the drug or imaging agent is attached to something naturally taken up by cells. The Cardiff team, made of researchers from the Schools of Chemistry and Biosciences, has taken the technique one step further with the development of a 'sleeping Trojan horse'. The first example of its kind, this is delivery system resolves some of the current difficulties involved in transporting metal ions into cells. It is not itself taken up by cells so does not interfere with natural functions until it is 'woken' by the addition of the metal ions. This minimises the unwanted uptake and need for time-consuming purification associated with the common 'Trojan Horse' technique. The research was led by Dr Mike Coogan, Senior Lecturer in Synthetic Chemistry, along with the paper's first author, Flora Thorp-Greenwood. Dr Coogan said: "The sleeping Trojan horse process happens rapidly, and the vessel is capable of carrying metals which have positron-emitting isotopes, so it has potential for use in bimodal fluorescence and PET imaging. Combined agents for these types of imaging are known but rare, so this is a significant development in the field. "There is also additional potential for use in radiotherapy as the metal-bearing form not only enters cells but also localises in the nucleolus. In principle, the concept could also be used to improve delivery of a huge range of drugs and imaging agents into cells or the body." The study A 'Sleeping Trojan Horse' which transports metal ions into cells, localises in nucleoli, and has potential for bimodal fluorescence/PET imaging is published in the advanced article section of Chemical Communications. Published by the Royal Society of Chemistry, this is the leading weekly journal for the publication of important developments in the chemical sciences.

Scientists discover gene regulation mechanism unique to primates

Thu, 10 Feb 2011 03:37:31 PDT

Scientists have discovered a new way genes are regulated that is unique to primates, including humans and monkeys. Though the human genome – all the genes that an individual possesses – was sequenced 10 years ago, greater understanding of how genes function and are regulated is needed to make advances in medicine, including changing the way we diagnose, treat and prevent a wide range of diseases. "It's extremely valuable that we've sequenced a large bulk of the human genome, but sequence without function doesn't get us very far, which is why our finding is so important," said Lynne E. Maquat, Ph.D., lead author of the new study published today in the journal Nature. When our genes go awry, many diseases, such as cancer, Alzheimer's and cystic fibrosis can result. The study introduces a unique regulatory mechanism that could prove to be a valuable treatment target as researchers seek to manipulate gene expression – the conversion of genetic information into proteins that make up the body and perform most life functions – to improve human health. The newly identified mechanism involves Alu elements, repetitive DNA elements that spread throughout the genome as primates evolved. While scientists have known about the existence of Alu elements for many years, their function, if any, was largely unknown. Maquat discovered that Alu elements team up with molecules called long noncoding RNAs (lncRNAs) to regulate protein production. They do this by ensuring messenger RNAs (mRNAs), which take genetic instructions from DNA and use it to create proteins, stay on track and create the right number of proteins. If left unchecked, protein production can spiral out of control, leading to the proliferation or multiplication of cells, which is characteristic of diseases such as cancer. "Previously, no one knew what Alu elements and long noncoding RNAs did, whether they were junk or if they had any purpose. Now, we've shown that they actually have important roles in regulating protein production," said Maquat, the J. Lowell Orbison Chair, professor of Biochemistry and Biophysics and director of the Center for RNA Biology at the University of Rochester Medical Center. The expression of genes that call for the development of proteins involves numerous steps, all of which are required to occur in a precise order to achieve the appropriate timing and amount of protein production. Each of these steps is regulated, and the pathway discovered is one of only a few pathways known to regulate mRNAs directly in the midst of the protein production process. Regulating mRNAs is one of several ways cells control gene expression, and researchers from institutions and companies around the world are honing in on this regulatory landscape in search of new ways to manage and treat disease. According to Maquat, "This new mechanism is really a surprise. We continue to be amazed by all the different ways mRNAs can be regulated." Maquat and the study's first author, Chenguang Gong, a graduate student in the Department of Biochemistry and Biophysics at the Medical Center, found that long noncoding RNAs and Alu elements work together to trigger a process known as SMD (Staufen 1-mediated mRNA decay). SMD conditionally destroys mRNAs after they orchestrate the production of a certain amount of proteins, preventing the creation of excessive, unwanted proteins in the body that can disrupt normal processes and initiate disease. Specifically, long noncoding RNAs and Alu elements recruit the protein Staufen-1 to bind to numerous mRNAs. Once an mRNA finishes directing a round of protein production, Staufen-1 works with another regulatory protein previously identified by Maquat, UPF1, to initiate the degradation or decay of the mRNA so that it cannot create any more proteins. While the research fills in a piece of the puzzle as to how our genes operate, it also accentuates the overwhelming complexity of how our DNA shapes us and the many known and unknown players involved. Maquat and Gong plan on exploring the newly identified pathway in future research.

A second pathway for antidepressants

Tue, 08 Feb 2011 03:29:34 PDT

Using a unique and relatively simple cell-based fluorescent assay they developed, scientists with the U.S. Department of Energy (DOE)’s Lawrence Berkeley National Laboratory (Berkeley Lab) and the University of California (UC), Berkeley have identified a means by which fluoxetine, the active ingredient in Prozac, suppresses the activity of the TREK1 potassium channel. TREK1 activity has been implicated in mood regulation and could be an important target for fluoxetine and other antidepressant drugs........> Full story

Dynamic systems in living cells break the rules

Wed, 26 Jan 2011 03:27:26 PDT

There is considerable interest in understanding transport and information pathways in living cells. It is crucial for both the transport of, for example, medicine into cells, the regulation of cell life processes and their signalling with their environment. New research in biophysics at the Niels Bohr Institute shows surprisingly that the transport mechanisms do not follow the expected pattern. The results have been published in the scientific journal Physical Review Letters. The researchers studied fat molecules which are naturally occurring in cells. Using a special state-of-the-art instrument, an optical tweezer, they were able to hold onto the small fat molecules inside living yeast cells using an extremely focused laser light. By measuring the movement of the fat molecules over several hours they could observe that they were not behaving as expected. The laws of physics for motion In the world of physics, there is something called Brownian motion. Ordinary Brownian motion describes how a substance passively spreads in a liquid. For example, when you pour a spoonful of sugar into a glass of water the sugar will distribute itself evenly after a while. Would fat molecules behave 'ordinarily' and simple distribute itself evenly in the cell fluid? In any case, the researchers had expected that the Ergodicity theorem (tenet), which is a generally recognized law of nature, would be adhered to. The Ergodicity theorem predicts that statistically, the result of throwing 10 dice once would have the same average distribution as throwing one die 10 times. The Ergodicity theorem is expected to apply for anomalous transport processes in unorganized materials, for example, biological systems. The researchers expected therefore, that if you observe the transport of fat molecules in many cells at once, then you would get the same result as by looking a single cell repeatedly over a long period of time. You expect a pattern. Breaks common wisdom "But neither the one nor the other common wisdom held true. It turned out the fat molecules broke with all the patterns. Our analysis of the spreading of liquid fat granules in living yeast cells showed that not only was the distribution abnormal, but that the movement in the relevant time period was also in conflict with the statistics for ergodicity. They almost have their own will", explains Lene Oddershede, associate professor in the biophysics group, Optical Tweezers at the Niels Bohr Institute at the University of Copenhagen. The experimental studies were performed here, while researchers from DTU as well as Germany and Israel have worked with the theoretical calculations. The conclusion is that controlling living systems is more complicated than previously thought and that the basic concepts in statistical physics must be replaced when analysing certain aspects of biomolecular dynamics in cells. "We have gained very important knowledge. What we thought would apply, did not hold up at all, so now we need to find a completely new law for the physics in living organisms. Our goal is to discover how the cell signals and how it communicates both internally and with its environment", explains Lene Oddershede.

Research provides new kidney cancer clues

Thu, 20 Jan 2011 03:17:26 PDT

In a collaborative project involving scientists from three continents, researchers have identified a gene that is mutated in one in three patients with the most common form of renal cancer. The gene – called PBRM1 – was found to be mutated in 88 cases out of 257 clear cell renal cell carcinomas (ccRCC) analysed, making it the most prevalent to be identified in renal cancer in 20 years. The identification of a frequently mutated gene provides new insights into the biology of the disease, which will be critical in the continued effort to improve treatment for renal cancer. The study, published today in the journal Nature, was carried out by researchers from the Wellcome Trust Sanger Institute (UK), the National Cancer Centre of Singapore, and Van Andel Research Institute (VARI) of Grand Rapids, Michigan. Renal cancer is among the 10 most common cancers in both men and women in the United States, striking nearly 60,000 Americans in 2010, and killing more than 13,000, according to the National Cancer Institute. Renal cell carcinoma (RCC) accounts for 9 out of 10 kidney cancers, and ccRCC is the most common subtype, accounting for 8 out of 10 RCC cases. Survival rates for early-detected ccRCC tumors can be as high as 95 percent, but that prognosis falls over time as tumors develop. Diagnosis is complicated by the fact that tumors can grow in the kidney for some time without presenting symptoms. For many years, the main genetic determinant known to be involved in the development of renal carcinoma was mutation of the VHL gene on chromosome 3. "Until recently, when we talked about the genetics of renal carcinoma we would inevitably be talking about VHL – a gene mutated in eight out of ten patients," said Dr. Andy Futreal, Head of Cancer Genetics and Genomics and co-Head of the Cancer Genome Project at the Wellcome Trust Sanger Institute. "But we knew this was likely not to be the full story – so the question we have sought to answer is which genes are conspiring with VHL to cause the disease we see in patients?" "Over the last year or so, we have started to assemble that puzzle – this research provides a new and critical piece." The team's recent work had previously identified three mutated genes associated with renal cancer. These genes are all involved in altering part of the scaffold – known as chromatin – that holds the DNA together in our cells and can influence gene activity. "Our understanding of how kidney cancer develops had already markedly improved through identification of three new mutated cancer genes, each of which makes a small contribution to the disease" said Professor Mike Stratton, Director of the Sanger Institute and co-Head of the Cancer Genome Project. "Now, our discovery of PBRM1 mutations in one in three kidney cancers is a major advance. We think we may have an almost complete understanding of the set of abnormal genes that drive this cancer and our understanding of the disease has been transformed by the realisation that most of these genes are involved in providing the structure that encases DNA in the cell and that regulates its function. This insight will provide us with many new therapeutic directions for this cancer." Much of the story, the researchers suggest, seems to be locked into a small region of chromosome 3. The study finds that PBRM1(also known as Baf180) is tied together with two previously identified renal cancer genes – including the well-established VHL cancer gene and the recently identified gene SETD2 – on a small region of chromosome 3. The team suggests that the fact that the genes are linked in their location allows cancer to exploit our biology – by reducing the number of genetic events needed to hit and inactivate all three genes. The team found a significant level of overlap, with many patients carrying mutations in two, if not all three of the genes in this region. "This study has begun to unlock the way these latest gene discoveries contribute to cancer," said Professor Bin Tean Teh, M.D., Ph.D., Head of the Van Andel Research Institute Laboratory for Cancer Genetics and the NCSS-VARI Translational Research Laboratory at the National Cancer Centre of Singapore. "And it is to the cancer's advantage that they sit together. The challenge for the future will be to build a picture of the processes the genes control. That will mean looking beyond the linear DNA code to the chemical interactions that take place at the structural level – at the level of the chromosome." Importantly, the newly discovered gene, PBRM1, functions as part of a protein complex called SWI-SNF, which also acts to alter the structure of chromatin – further pointing to the importance of genome regulation in renal cancer. "Our work provides evidence that PBRM1 may affect the processes of cell division in renal cells. Therefore, a defect in this gene could lead to abnormal cellular growth," said Kyle Furge, Ph.D., Head of VARI's Laboratory of Computational Biology. "For researchers, this discovery is exciting because PBRM1 is a protein that modifies the DNA in the cell. This study is one of the first to show that proteins that modify DNA are frequently mutated in cancer." The mutations all appear to inactivate a protein that plays a role in remodelling the structure of the genetic material, allowing access of the DNA code to other proteins that can repair damage, control cell growth and turn other genes on and off. In addition to the PBRM1 mutations, the team also found mutations in a gene called ARID1A in some ccRCC cases. The same gene was identified just weeks ago in clear cell ovarian cancer. The researchers suggest that further larger-scale research will be needed to understand what role this second gene plays in renal cancer.

Roundworm unlocks pancreatic cancer pathway

Thu, 20 Jan 2011 03:15:58 PDT

The National Cancer Institute estimates that more than 43,000 Americans were diagnosed with pancreatic cancer last year and more than 36,000 died from the disease. Despite advances in genetic science showing that the Ras oncogene is mutated in virtually all pancreatic cancers, scientists have been frustrated by the complexity of the signaling pathways in humans, which make it difficult to pinpoint potential therapeutic targets. In a study published today in the Cell Press journal Developmental Cell, a team of researchers led by Channing Der, PhD, Distinguished Professor of Pharmacology at UNC-Chapel Hill, took a step back to a simpler organism – a common roundworm – and made a discovery about how the Ras oncogene chooses a signaling pathway and how the consequences of that choice play out in cellular development – a key issue in cancer, which is characterized by uncontrolled cell growth. Der, who is also a member of UNC Lineberger Comprehensive Cancer Center, explains, "In humans the cell signaling pathways are very complex; there are more than 20 different downstream partners beyond the two proteins we study – Raf and RalGEF – that Ras can choose to interact with. In C. elegans, there is only one of each protein. That made it easier for us to identify how Ras chooses a partner to 'dance' with and what are the critical events in the subsequent cell development that promote cancer." "We found an elegant mechanism by which Ras switches partners and showed that the choice leads to very different fates for the cell. Now we can go back to the human pancreatic cancer cell and ask whether similar mechanisms are at work in determining how Ras causes pancreatic cancer," he adds. Scientists often study simpler organisms to tease out genetic and cellular activity that might be almost impossible to map in humans. "Worms' cells actually share a great deal of functional overlap with human cells. However, while there may be one mechanism in a simple organism like a worm, there are multiple mechanisms at work in humans. It's a great thing for us as people, because there is a great deal of redundancy in our biological systems that helps them self-repair and function better, but it makes it a lot harder to study what's going on at a basic level," Der notes. "If this signaling works in a similar way in humans, the C. elegans model may be very powerful for helping us find new therapeutic targets for pancreatic cancer," he concludes.

New tool for cell research may help unravel secrets of disease

Fri, 14 Jan 2011 03:27:21 PDT

Advancements in understanding rotational motion in living cells may help researchers shed light on the causes of deadly diseases, such as Alzheimer’s, according to Ning Fang, an associate scientist at the U.S. Department of Energy’s Ames Laboratory and faculty member at Iowa State University. In an article entitled “Resolving Rotational Motions of Nano-objects in Engineered Environments and Live Cells with Gold Nanorods and Differential Interference Contrast Microscopy” published in the November 2 issue of the Journal of the American Chemical Society, and an article in press in ACS Nano, Fang and his research team write about the influence of differential interference contrast Microscopy on revealing nanoparticle movement in living cells.......> Full story

Researchers create 'scoring system' for PTEN mutation testing

Tue, 11 Jan 2011 03:32:28 PDT

Researchers have discovered a method for more precise identification of individuals who should undergo testing for genetic mutations of the tumor suppressor gene PTEN, which associates with a variety of conditions including several types of cancers. The research has created a diagnostic scoring system that improves on established criteria. Led by Charis Eng, M.D., Ph.D., Chair of the Genomic Medicine Institute at the Lerner Research Institute of Cleveland Clinic, the study – the largest clinical study to date on the identification of PTEN – involved 3,042 participants, including both adults and children. Dr. Eng and her team established a semi-quantitative diagnostic score as an evidence-based improvement over the existing National Comprehensive Cancer Network (NCCN) 2010 diagnostic criteria, resulting in more accurate diagnoses and, theoretically, better outcomes. These results contribute to clinical practice recommendations. "The new criteria give non-genetics healthcare providers a guide of who should be referred to genetics evaluation, which includes genetic counseling," said Dr. Eng. "Knowing one's PTEN gene status will lead to personalized cancer screening, resulting in catching cancers earlier or even preventing them from coming at all." In addition to the association between mutant PTEN and disease, the study's novel scoring system also incorporates the amount of PTEN protein as it relates to disease. A higher diagnostic score correlates with lower PTEN protein, substantiating previous laboratory studies that show lower PTEN levels associate with carcinogenesis. "This is the first human evidence of a causal relationship between PTEN protein deficiency and disease manifestation, which had only been previously been shown in the laboratory dish or animal model," Eng remarked. Researchers studied an international group of 290 patients who carry disease-causing PTEN mutations, which exceeds the total number of such patients reported in all published medical literature by 37 percent. The study also hails higher stringency, as only probands (the first family member to be affected by the disease) were included. This increases the study's ability to assess each disease feature, such as macrocephaly (larger-than-normal head size), various cancers and age at onset, as well as skin, neurologic, and gastrointestinal complications, without bias. For the first time, the scoring system provides criteria for addressing important differences in assessing pediatric versus adult patients. Furthermore, autism, which was first linked to mutant PTEN by Dr. Eng and her team, is included in the clinical criteria. Although vascular malformations (altered blood vessels) have long been reported in adults with Cowden syndrome, the malformations are not part of NCCN criteria. In contrast, the newly discovered criteria specifically recommend these patients undergo further genetic testing for early diagnosis of other lurking complications, such as cancers, so that more careful screening can occur.

Wildflower colors tell butterflies how to do their jobs

Mon, 10 Jan 2011 03:20:23 PDT

The recipe for making one species into two requires time and some kind of separation, like being on different islands or something else that discourages gene flow between the two budding species. In the case of common Texas wildflowers that share meadows and roadside ditches, color-coding apparently does the trick. Duke University graduate student Robin Hopkins has found the first evidence of a specific genetic change that helps two closely related wildflowers avoid creating costly hybrids. It results in one of the normally light blue flowers being tagged with a reddish color to appear less appetizing to the pollinating butterflies which prefer blue. "There are big questions about evolution that are addressed by flower color," said Hopkins, who successfully defended her doctoral dissertation just weeks before seeing the same work appear in the prestigious journal Nature. What Hopkins found, with her thesis adviser, Duke biology professor Mark Rausher, is the first clear genetic evidence for something called reinforcement in plants. Reinforcement keeps two similar proto-species moving apart by discouraging hybrid matings. Flower color had been expected to aid reinforcement, but the genes had not been found. In animals or insects, reinforcement might be accomplished by a small difference in scent, plumage or mating rituals. But plants don't dance or choose their mates. So they apparently exert some choice by using color to discourage the butterflies from mingling their pollen, Hopkins said. Where Phlox drummondii lives by itself, it has a periwinkle blue blossom. But where its range overlaps with Phlox cuspidata, which is also light blue, drummondii flowers appear darker and more red. Some individual butterflies prefer light blue blossoms and will go from blue to blue, avoiding the dark reds. Other individual butterflies prefer the reds and will stick with those. This "constancy" prevents hybrid crosses. Hybrid offspring between drummondii and cuspidata turn out to be nearly sterile, making the next generation a genetic dead-end. The persistent force of natural selection tends to push the plants toward avoiding those less fruitful crosses, and encourages breeding true to type. In this case, selection apparently worked upon floral color. Hopkins was able to find the genes involved in the color change by crossing a light blue drummondii with the red in greenhouse experiments. She found the offspring occurred in four different colors in the exact 9-to-3-to-3-to-1 ratios of classical Mendelian inheritance. "It was 2 in the morning when I figured this out," she said. "I almost woke up my adviser." From there, she did standard genetics to find the exact genes. The change to red is caused by a recessive gene that knocks out the production of the plant's one blue pigment while allowing for the continued production of two red pigments. Even where the red flowers are present, about 11 percent of each generation will be the nearly-sterile hybrids. But without color-coding, that figure would be more like 28 percent, Hopkins said. Why and how the butterflies make the distinction has yet to be discovered. Hopkins will be continuing her research as a visiting scientist at the University of Texas, and the clear message from all of her advisers is "follow the butterflies. Everyone wants to know more about the butterflies!"

Link between signaling molecules could point way to therapies for epilepsy, stroke, other diseases

Sat, 08 Jan 2011 17:37:04 PDT

In the Old West, camps sent smoke signals across distances to share key developments or strategy. Likewise, two important signaling molecules communicate across nerve cells to regulate electrical and chemical activity, neuroscientists from the UT Health Science Center San Antonio reported today.

The findings in rodent models have implications for potential future treatment of epilepsy, stroke and other problems, the researchers said.

“We now have novel targets for therapeutic intervention for a range of neurological and cardiovascular diseases, including stroke, epilepsy, dementia, hypertension, mental illness and others,” said senior author Mark S. Shapiro, Ph.D., professor of physiology at the Health Science Center. “This study should guide clinicians and pharmaceutical companies in developing new therapies against mental, neurological, cardiovascular or cerebrovascular diseases that afflict many millions of people.”......> Full story

New research reveals unexpected biological pathway in glaucoma

Tue, 04 Jan 2011 03:19:21 PDT

In a study published today in the Proceedings of the National Academy of Sciences (Early Edition ahead of print), a team of researchers from the Kennedy Krieger Institute and four collaborating institutions, identified a new and unexpected biological pathway that appears to contribute to the development of glaucoma and its resulting vision loss. Prior research has suggested that the optic nerve head, the point where the cables that carry information from the eye to the brain first exit the eye, plays a role in glaucoma. In this study, researchers report a series of findings that offer novel insights into cellular and molecular mechanisms operating at the optic nerve head in two mouse models of glaucoma. Most notably, they discovered that at a specific location within the optic nerve head, there is a unique class of cells called astrocytes that demonstrate properties that appear to make them a critical factor in the visual blinding that occurs in glaucoma. Further, at this same site, researchers found abnormal forms of a protein called gamma synuclein that is similar to abnormal forms of alpha synuclein, a related protein known for its key role in cell loss in Parkinson's disease. The findings suggest that a biological process similar to Parkinson's disease unfolds in glaucoma at the specific anatomical location pinpointed in this study for the first time. Finally, researchers discovered that at this anatomical location, there is a surprising process whereby astrocytes remove the debris of neurons, the cells that die in neurodegenerative disorders such as glaucoma. It is likely that this newly discovered process involving removal of the debris of one cell by a neighboring cell is important not only in glaucoma and Parkinson's disease, but also for many neurodegenerative diseases. "These findings are very exciting because they give us several novel targets for future interventions," said Dr. Nicholas Marsh-Armstrong, senior study author and a research scientist at Kennedy Krieger Institute. "I believe these findings put us on the cusp of discovering a treatment for glaucoma that may also have relevance for a number of other neurodegenerative diseases." Future studies will examine this novel pathway and molecular/cellular mechanism to understand precisely what steps go awry in glaucoma and what can be controlled pharmacologically to identify interventions that slow the disease progression. Dr. Marsh-Armstrong and other scientists at Kennedy Krieger Institute collaborated on this study with colleagues at the Johns Hopkins University School of Medicine, University of California at San Diego, Cardiff University in England, and the University of Murcia in Spain.

Carnegie Mellon researchers discover mechanism for signaling receptor recycling

Thu, 23 Dec 2010 03:31:23 PDT

An international team of researchers led by Carnegie Mellon University's Manojkumar Puthenveedu has discovered the mechanism by which signaling receptors recycle, a critical piece in understanding signaling receptor function. Writing in the journal Cell, the team for the first time describes how a signaling receptor travels back to the cell membrane after it has been activated and internalized. Signaling receptors live on the cell membrane waiting to be matched with their associated protein ligand. When they meet, the two join together like a lock and key, turning on and off critical functions within the cell. Many of these functions play a role in human health, and each new discovery about how these complex receptors work provides a potential therapeutic target for conditions including heart, lung and inflammatory disease.......> Full story

Mammalian aging process linked to overactive cellular pathway

Thu, 23 Dec 2010 03:27:55 PDT

Whitehead Institute researchers have linked hyperactivity in the mechanistic target of rapamycin complex 1 (mTORC1) cellular pathway, to reduced ketone production, which is a well-defined physiological trait of aging in mice. Their results are reported in the December 23 edition of the journal Nature. "This is the first paper that genetically shows that the mTORC1 pathway in mammals affects an aging phenotype," says Whitehead Institute Member David Sabatini. "It provides us with a molecular framework to study an aging-related process in deeper detail." When we think of aging, sagging skin, dimmed vision, and fragile bones come to mind. But Sabatini's lab is more interested in the cellular changes that occur as organisms age. One cellular pathway, the mTORC1 pathway, is known to coordinate cell growth with nutrient availability and other growth factors. Previous research has shown that when this pathway is inhibited, a variety of animals, including worms, flies, and mice tend to live longer. Although an increased lifespan suggests that mTORC1 is involved in aging, it fails to clarify mTORC1's precise role in the process. In fact, lifespan is a poor proxy for studying aging, as it is not always a cause of death. One well-defined trait of aging is a decrease in ketogenesis, or the ability to produce ketones. During sleep or other times of low carbohydrate intake, the liver converts fatty acids to ketones, which are vital sources of energy during fasting, especially for the heart and brain. As animals age, their ability to produce ketones as a response to fasting declines. The cause of this phenomenon remains unknown. To determine whether mTORC1 mediates ketogenesis in mice, Shomit Sengupta, a former graduate student in Sabatini's lab and first author on the Nature paper, studied the effects of induced hyperactivity in the mTORC1 pathway in the livers of fasting mice. He found that while most blood and liver metabolite levels did not change significantly, ketone levels fell. After establishing that activating the mTORC1 pathway decreases ketogenesis, Sengupta tried to find exactly where mTORC1 was acting. Knowing that peroxisome proliferator-activated receptor alpha (PPAR-alpha) is an activator of liver ketogenesis, Sengupta attempted to jumpstart the process by stimulating PPAR-alpha. Interestingly, ketone levels failed to increase—a clear indication that that mTORC1 was thwarting PPAR-alpha. "That now places mTORC1 as the master regulator of ketogenesis," says Sengupta, who is now a Research Fellow at Harvard Medical School. "It could be one of many inputs for PPAR alpha – that's unclear right now. But mTORC1 is sufficient and necessary to suppress PPAR-alpha and ketogenesis." Connecting mTORC1 to the aging-related decline in ketogenesis was the next step. If mTORC1 activation is responsible for lower ketone levels caused by aging, turning on mTORC1 in older mice should not affect their already low ketone levels – it would be like trying to turn off a light switch that is already off. So Sengupta compared the ketone production of old and young mice during fasting. While turning on the mTORC1 pathway during fasting reduced ketone production in the young mice, the old mice maintained the same, low ketone levels. And when the mTORC1 pathway was turned off in very young mice that were subsequently aged, these older mice did not experience the decline in ketogenesis found in normal mice. Their ketogenesis levels were similar to younger mice, confirming that continual inhibition of the mTORC1 pathway prevented the aging-induced decline in ketone production. It might follow that suppressing mTORC1 could slow aging, and indeed, some have suggested that the drug rapamycin, an mTOR inhibitor used to treat cancer and to prevent organ transplant rejection, might have anti-aging properties. "Rapamycin definitely has lots of anti-aging hype," says Sabatini, who is also a professor of biology at MIT and a Howard Hughes Medical Institute (HHMI) investigator. "Having worked with that molecule a lot, I'm not sure I would take it for long periods of time, just for slowing down aging." Instead Sabatini is focused on a host of more practical questions, including why ketogenesis is suppressed by aging and how aging serves to activate mTORC1. "We know enough of what's upstream of mTORC1 that I think now we can test different components and ask which one is sort of acting funny in its aged state," says Sabatini.

Ion channel responsible for pain identified by UB neuroscientists

Mon, 20 Dec 2010 03:26:05 PDT

University at Buffalo neuroscience researchers conducting basic research on ion channels have demonstrated a process that could have a profound therapeutic impact on pain. Targeting these ion channels pharmacologically would offer effective pain relief without generating the side effects of typical painkilling drugs, according to their paper, published in a recent issue of The Journal of Neuroscience. "Pain is the most common symptom of injuries and diseases, and pain remains the primary reason a person visits the doctor," says Arin Bhattacharjee, PhD, UB assistant professor of pharmacology and toxicology in the School of Medicine and Biological Sciences, director of the Program in Neuroscience and senior author on the paper. "Fifty million Americans suffer from chronic pain, costing between $100-200 billion a year in medical expenses, lost wages and other costs," says Bhattacharjee. "The need to understand pain mechanisms remains paramount for human health and for society." Inflammatory pain can result from penetration wounds, burns, extreme cold, fractures, arthritis, autoimmune conditions, excessive stretching, infections and vasoconstriction. "There are efficacious treatments for inflammatory pain, such as corticosteroids and non-steroidal anti-inflammatory drugs," says Bhattacharjee, "but the adverse side effects associated with these drugs limit their long-term use and compromise patient compliance. As a result, there is a great need to understand the cellular processes involved in inflammatory pain to create less toxic, less addictive, analgesic drugs." Pain-responsive nerve cells, known as nociceptors, are electrical cells that normally respond to pain stimuli. Nociceptors then relay information to the central nervous system, indicating the location, nature and intensity of the ensuing pain. Nociceptors are sensitized during inflammation, their ionic properties are altered and their firing characteristics changes. This sensitization causes a state of "hyperalgesia," or increased sensitivity to pain. "Merely touching the inflamed area can be very painful," notes Bhattacharjee. "The ionic mechanisms that are chiefly responsible for this inflammatory-mediated change in nociceptive firing had not been clearly identified. "We were able to demonstrate that a certain class of potassium channels is removed from the surface of nociceptive cells during inflammatory signaling. The removal of these ion channels is linked to the hypersensitivity of these nerve cells. We demonstrated that reducing the expression of these channels by gene interference techniques produced a similar nociceptor hyperexcitability. " Bhattacharjee says his team plans to extend their ion channel "trafficking" studies to in vivo models, using peptide inhibitors to try to prevent the removal of the potassium channels from the surface of nociceptors during inflammation. "We expect to show that maintaining these channels at the surface during inflammation will be effective for pain relief. Successful completion of our studies will provide the impetus for direct human clinical trials. Megan O. Nuwer, PhD, and Kelly E. Picchione, PhD, both in the neuroscience program, are co-authors on the paper.

Ovarian cancer clue: Methylation-mediated suppression of a key pathway is found

Tue, 14 Dec 2010 03:23:53 PDT

Ovarian cancer is the leading cause of death among gynecological cancers. To better understand the disease and improve therapies, researchers are investigating how deregulation of genes across the genome could be contributing to malignancy. In a study published online today in Genome Research (www.genome.org), scientists have identified age-related gene-specific accumulation of DNA methylation that suppresses a critical cellular pathway contributing to ovarian carcinogenesis, information that will be crucial for future translational research. Epigenetic silencing of genes by a chemical modification called DNA methylation is known to play a role in the development of malignancies such as ovarian cancer by turning off genes that normally suppress tumor growth. Yet the scope of DNA methylation across the entire cancer genome is not well understood, hindering efforts to understand the biological basis of the disease. In this study, an international team of researchers from the United States and Japan performed a genome-wide analysis of gene expression in ovarian cancer by transcriptome profiling, looking for genes silenced by DNA methylation that might be involved in the disease. The research group analyzed gene expression in established ovarian cancer cell lines and primary cultured ovarian cancer cells that were either mock treated, or treated with a chemical agent that blocks DNA methylation. This strategy identified 378 candidate methylated genes in ovarian cancers. When the group began investigating the functions of the genes subject to methylation in the malignancies, an intriguing clue to the biology of ovarian cancer arose from the list. "While we hoped to identify a substantial group of candidate methylated genes," said researcher Susan Murphy of Duke University Medical Center and senior author of the study, "we did not anticipate that we would find methylation-mediated deregulation of many genes involved in a specific functional pathway, the TGF-beta pathway." The TGF-beta pathway is a cellular signaling network that controls cell growth and differentiation, normally curbing tumor growth, but can promote cancer when disrupted. This work reports for the first time that methylation of genes in the TGF-beta superfamily suppresses the TGF-beta pathway in ovarian cancer. Murphy and colleagues also observed that methylation increased with patient age, suggesting that gene-specific methylation accumulates over time. Murphy added that the methylated genes identified in this study will aid in the design of new strategies to treat the disease. "Knowing the identity of these genes provides for the ability to carry out focused studies to understand their specific role in ovarian cancer," Murphy explained, "and may present opportunities for targeted therapeutic interventions."

SRC-1 controls liver's 'sweet spot' for glucose production

Wed, 01 Dec 2010 03:32:18 PDT

SRC-1 (steroid receptor coactivator) orchestrates glucose production in the liver, regulating the activity of a cascade of enzymes that turns sugar production on and off in the liver, said Baylor College of Medicine (www.bcm.edu) and Duke University Medical Center (www.dukehealth.org) researchers in a report that appears in the current issue of Cell Metabolism (http://www.cell.com/cell-metabolism/). "As we achieve a better understanding of gluconeogenesis (production of glucose) in the liver, we can look for new ways to treat metabolic diseases such as type 2 diabetes," said Dr. Jean-Francois Louet, instructor in molecular and cellular biology at BCM and a first author of the report. Dr. Atul R. Chopra, a resident physician at BCM, is the other first author. SRC-1 is a member of a family of steroid receptor coactivators that control important processes in the body. Dr. Bert O'Malley (http://www.bcm.edu/mcb/index.cfm?pmid=7694), chair of molecular and cellular biology at BCM and a senior author of the report, discovered SRC-1 and has been a pioneer in uncovering the role of these molecules as cellular master regulators. "For some years, cell and animal studies have indicated a 'missing control protein' in gluconeogenesis," said O'Malley. "In this study, we identify SRC-1 as this missing factor. Our identification of the coactivator SRC-1 as a 'master actor' in this tight control provides a possible therapeutic target for regulating liver glucose production." The liver plays an important role in gluconeogenesis – the production of glucose (from non-sugar source) in response to need, as when you fast. It keeps glucose levels in balance – increasing the levels when needed and turning off that "spigot" when you eat and the levels of glucose increase. "Ninety percent of endogenous (within the body) glucose production is in the liver," said Louet. He and his colleagues showed that mice that lack SRC-1 have hypoglycemia (too little sugar in their blood) when they have just eaten and when they are fasting. "Without SRC-1, glucose production is impaired in the animals," he said. When he and his colleagues restored the SRC-1 to the liver tissues in the animal, glucose levels in the blood became normal. In collaboration with members of the laboratory of Dr. Christopher B. Newgard (http://pharmacology.mc.duke.edu/faculty/newgard.htm) (another senior author of the report) at Duke, the team used metabolomics to see what was happening in the tissue and blood from the mice that lacked SRC-1. Metabolomics is the study of a complete collection of metabolites present in a cell or tissue under a particular set of conditions. The collection is called the metabolome. "We found something we had never seen before. There was strong disorganization of the production of some metabolites that are important for regulating gluconeogenesis," said Louet. As the group collaborated, it found that SRC-1 controls a gene for a transcription factor called C/EBP alpha that in turn targets a gene for an enzyme called pyruvate carboxylase, which is crucial to beginning the process of gluconeogenesis. (A transcription factor regulates the copying of specific genes [DNA] into a form of RNA the cell's machinery uses to build a protein.) Mice born lacking C/EBP alpha die soon after birth, an indication of the importance of this gene. SRC-1 keeps these genes in tight control, insuring that the production of glucose in the liver goes up and down as the body needs.

New imaging technique accurately finds cancer cells, fast

Thu, 25 Nov 2010 06:43:02 PDT

The long, anxious wait for biopsy results could soon be over, thanks to a tissue-imaging technique developed at the University of Illinois. The research team demonstrated the novel microscopy technique, called nonlinear interferometric vibrational imaging (NIVI), on rat breast-cancer cells and tissues. It produced easy-to-read, color-coded images of tissue, outlining clear tumor boundaries, with more than 99 percent confidence – in less than five minutes. Led by professor and physician Stephen A. Boppart, who holds appointments in electrical and computer engineering, bioengineering and medicine, the Illinois researchers will publish their findings on the cover of the Dec. 1 issue of the journal Cancer Research. In addition to taking a day or more for results, current diagnostic methods are subjective, based on visual interpretations of cell shape and structure. A small sample of suspect tissue is taken from a patient, and a stain is added to make certain features of the cells easier to see. A pathologist looks at the sample under a microscope to see if the cells look unusual, often consulting other pathologists to confirm a diagnosis. “The diagnosis is made based on very subjective interpretation – how the cells are laid out, the structure, the morphology,” said Boppart, who is also affiliated with the university’s Beckman Institute for Advanced Science and Technology. “This is what we call the gold standard for diagnosis. We want to make the process of medical diagnostics more quantitative and more rapid.” Rather than focus on cell and tissue structure, NIVI assesses and constructs images based on molecular composition. Normal cells have high concentrations of lipids, but cancerous cells produce more protein. By identifying cells with abnormally high protein concentrations, the researchers could accurately differentiate between tumors and healthy tissue – without waiting for stain to set in. Each type of molecule has a unique vibrational state of energy in its bonds. When the resonance of that vibration is enhanced, it can produce a signal that can be used to identify cells with high concentrations of that molecule. NIVI uses two beams of light to excite molecules in a tissue sample. “The analogy is like pushing someone on a swing. If you push at the right time point, the person on the swing will go higher and higher. If you don’t push at the right point in the swing, the person stops,” Boppart said. “If we use the right optical frequencies to excite these vibrational states, we can enhance the resonance and the signal.” One of NIVI’s two beams of light acts as a reference, so that combining that beam with the signal produced by the excited sample cancels out background noise and isolates the molecular signal. Statistical analysis of the resulting spectrum produces a color-coded image at each point in the tissue: blue for normal cells, red for cancer. Another advantage of the NIVI technique is more exact mapping of tumor boundaries, a murky area for many pathologists. The margin of uncertainty in visual diagnosis can be a wide area of tissue as pathologists struggle to discern where a tumor ends and normal tissue begins. The red-blue color coding shows an uncertain boundary zone of about 100 microns – merely a cell or two. “Sometimes it’s very hard to tell visually whether a cell is normal or abnormal,” Boppart said. “But molecularly, there are fairly clear signatures.” The researchers are working to improve and broaden the application of their technique. By tuning the frequency of the laser beams, they could test for other types of molecules. They are working to make it faster, for real-time imaging, and exploring new laser sources to make NIVI more compact or even portable. They also are developing new light delivery systems, such as catheters, probes or needles that can test tissue without removing samples. “As we get better spectral resolution and broader spectral range, we can have more flexibility in identifying different molecules,” Boppart said. “Once you get to that point, we think it will have many different applications for cancer diagnostics, for optical biopsies and other types of diagnostics.” The National Cancer Institute of the National Institutes of Health sponsored the study. Other co-authors were Beckman Institute researchers Praveen Chowdary, Zhi Jiang, Eric Chaney, Wladimir Benalcazar and Daniel Marks, and professor of chemistry and physics Martin Gruebele.

AgriLife scientist: Functional amino acids regulate key metabolic pathways

Mon, 22 Nov 2010 03:21:28 PDT

Functional amino acids play a critical role in the development of both animals and humans, according to a Texas AgriLife Research scientist. In a journal article appearing in the American Society for Nutrition (Advances in Nutrition 1:31-37, 2010), Dr. Guoyao Wu, AgriLife Research animal nutritionist and senior faculty fellow in the department of animal science at Texas A&M University, calls for scientists to "think out of the box” and place more emphasis on this area of study. "We need to move forward and capitalize on the potential of functional amino acids in improving health and animal production," he said. A functional amino acid is an amino acid that can regulate key metabolic pathways to improve health, growth, development and reproduction of animals and humans, Wu said. "This involves cell signaling through amino acids and their metabolites, and the metabolic pathways may include protein synthesis, antioxidative reactions and oxidation of energy substrates," he said. "A functional amino acid can be either a 'nonessential' or an 'essential' amino acid." Past research emphasis has focused primarily on essential amino acids. However, Wu says both essential amino acids and non-essential amino acids should be taken into consideration. "This is important when formulating balanced diets to maximize growth performance in livestock species, poultry and fish," he said. "It is also recommended that nonessential amino acids be provided to humans to prevent growth retardation and chronic diseases." Wu's previous research discovered that arginine, an amino acid, contributes many positive benefits in growth and embryo development in pigs, sheep and rats. Arginine also aids in fighting obesity. Wu has identified this as an important area for expanded research on new amino acids and health. "Currently in the U.S., more than 60 percent of adults are overweight or obese," he said. "Globally, more than 300 million adults are obese and more than 1 billion are overweight. Also, a large number of children in the U.S. and other countries are overweight or obese. The most urgent needs of new research in amino acids and health are the roles of functional amino acids in the treatment and prevention of obesity and its associated cardiovascular dysfunction." Wu also said that dietary supplementation with arginine can help improve meat quality in pigs prior to slaughter. The two top scientific discoveries in the field of amino acids and health over the past two decades are nitric oxide synthesis from arginine and the role of amino acids in cell signaling. "An important area of research in the next few years may be to study the molecular and cellular mechanisms whereby some amino acids (e.g., arginine) can regulate metabolic pathways in animals and humans," he said. "An example is how arginine reduces obesity and ameliorates the metabolic syndrome, and how elevated levels of leucine may contribute to mitochondrial dysfunction and insulin resistance (including vascular resistance) in obese subjects." He said "unquestionably" recent advances in understanding functional amino acids are "expanding our basic knowledge of protein metabolism and transforming practices of nutrition worldwide." Though nutritional studies conducted on animals have benefited human health, Wu suggests that caution should be taken to "extrapolate animal data to humans" as dietary requirements differ from one species to another. Wu said that humans need diets with balanced portions of amino acids for cardiovascular and reproductive health.

Rare disease reveals new path for creating stem cells

Mon, 22 Nov 2010 03:19:57 PDT

As debilitating as disease can be, sometimes it acts as a teacher. Researchers at Harvard Medical School and the Harvard School of Dental Medicine have found that by mimicking a rare genetic disorder in a dish, they can rewind the internal clock of a mature cell and drive it back into an adult stem-cell stage. This new "stem cell" can then branch out into a variety of differentiated cell types, both in culture and in animal models. "This certainly has implications for personalized medicine, especially in the area of tissue engineering," says Bjorn Olsen, the Hersey Professor of Cell Biology at Harvard Medical School and Dean of Research at the Harvard School of Dental Medicine. These findings appear November 21, online in Nature Medicine. Fibrodysplasia Ossificans Progressiva (FOP), which affect fewer than 1,000 people worldwide, is a horrific genetic disease in which acute inflammation causes soft tissue to morph into cartilage and bone. Over the course of a few decades, patients gradually become thoroughly ossified, as though parts of their body have turned to stone. There is no cure or treatment. Damian Medici, an instructor of medicine at Harvard Medical School and Beth Israel Deaconess Medical Center, found that, unlike normal skeletal tissue, the pathological cartilage and bone cells from these patients contained biomarkers specific for endothelial cells—cells that line the interior of blood vessels. This led him to question whether or not the cartilage and bone growing in soft tissues of FOP patients had an endothelial origin. Medici and his colleagues transferred the mutated gene that causes FOP into normal endothelial cells. Unexpectedly, the endothelial cells converted into a cell type nearly identical to what are called mesenchymal stem cells, or adult stem cells that can differentiate into bone, cartilage, muscle, fat, and even nerve cells. (Embryonic stem cells have the potential to become any type of cell, whereas adult stem cells are limited.) What's more, through further experiments the researchers found that instead of using the mutated gene to induce the transformation, they could incubate endothelial cells with either one of two specific proteins (growth factors TGF-beta2 and BMP4) whose cellular interactions mimicked the effects of the mutated gene, providing a more efficient way to reprogram the cells. Afterwards, Medici was able to take these reprogrammed cells and, in both culture dishes and animal models, coax them into developing into a group of related tissue types. "It's important to clarify that these new cells are not exactly the same as mesenchymal stem cells from bone marrow," says Medici. "There are some important differences. However, they appear to have all the potential and plasticity of mesenchymal stem cells." "The power of this system is that we are simply repeating and honing a process that occurs in nature," says Olsen. "In that sense, it's less artificial than other current methods for reprogramming cells." According to study collaborator Frederick Kaplan, Isaac & Rose Nassau Professor of Orthopaedic Molecular Medicine at the University of Pennsylvania School of Medicine and a world expert on FOP, "While we want to use this knowledge to stop the renegade bone formation of FOP, these new findings provide the first glimpse of how to recruit and harness the process to build extra bone for those who desperately need it." Medici and Olsen echo this, stating that the most direct application for these findings is the field of tissue engineering and personalized medicine. It is conceivable that transplant patients may one day have some of their own endothelial cells extracted, reprogrammed, and then grown into the desired tissue type for implantation. Host rejection would not be an issue.

Scientists ferret out a key pathway for aging

Fri, 19 Nov 2010 03:27:44 PDT

For decades, scientists have been searching for the fundamental biological secrets of how eating less extends lifespan. It has been well documented in species ranging from spiders to monkeys that a diet with consistently fewer calories can dramatically slow the process of aging and improve health in old age. But how a reduced diet acts at the most basic level to influence metabolism and physiology to blunt the age-related decline of tissues and cells has remained, for the most part, a mystery. Now, writing in the current online issue (Nov. 18) of the journal Cell, a team of scientists from the University of Wisconsin-Madison and their colleagues describe a molecular pathway that is a key determinant of the aging process. The finding not only helps explain the cascade of events that contributes to aging, but also provides a rational basis for devising interventions, drugs that may retard aging and contribute to better health in old age. "We're getting closer and closer to a good understanding of how caloric restriction works," says Tomas A. Prolla, a UW-Madison professor of genetics and a senior author of the new Cell study. "This study is the first direct proof for a mechanism underlying the anti-aging effects we observe under caloric restriction." The Wisconsin study focuses on an enzyme known as Sirt3, one of a family of enzymes known as sirtuins, which have been implicated in previous studies in the aging process, gene transcription, programmed cell death and stress resistance under reduced calorie conditions. In mammals, including humans, there are seven sirtuins that seem to have wide-ranging influence on cell fate and physiology. Sirt3 has been less studied than other members of the sirtuin family, but the new study provides "the first clear evidence that sirtuins have anti-aging effects in mammals," according to John M. Denu of UW-Madison's Wisconsin Institute for Discovery and a senior author of the report. The Sirt3 enzyme, Denu explains, acts on mitochondria, structures inside cells that produce energy and that are the sources of highly reactive forms of oxygen known as free radicals, which damage cells and promote the effects of aging. Under reduced-calorie conditions, levels of Sirt3 amp up, altering metabolism and resulting in fewer free radicals produced by mitochondria. "This is the strongest and most direct link that caloric restriction acts through mitochondria," says Prolla, who has studied the effects of reduced calorie diets on aging and health for more than a decade. "Sirt3 is playing a surprisingly important role in reprogramming mitochondria to deal with an altered metabolic state under caloric restriction." The lead authors of the new study are postdoctoral fellows Shinichi Someya, of UW-Madison and the University of Tokyo, and Wei Yu of UW-Madison. The work involved a mouse model that exhibits age-related hearing loss, a phenomenon associated with free radical damage to the cells of the cochlea, a structure in the inner ear that converts sound vibrations to nerve impulses. Age-related hearing loss is common in humans, and is newly exemplified by such things as ultrasonic cell phone ring tones that only the very young can hear as the cells that capture the highest frequencies are the first to go. "Hearing loss is associated with the loss of specific cell types in the cochlea," notes Prolla, whose previous work established a genetic link to cell death and age-related hearing loss. "And hearing loss is prevented through caloric restriction." In companion experiments in cultured cells and detailed in the Cell report, the Wisconsin team and their colleagues show that elevated levels of Sirt3 protect cells from cell stress and death caused by free radicals. "Sirt3 is sufficient to provide protection against oxidative damage," says Denu. Although sirtuins have been studied extensively and are believed by many scientists to play a role in aging, the new study is the first to conclusively link the enzymes to slowing the aging process in mammals. According to Denu, who is also a professor of biomolecular chemistry in the UW School of Medicine and Public Health, knowing the molecular basis of how the sirtuin enzymes work may ultimately lead to the rational development of drugs that activate the pathways of enzymes like Sirt3 to slow down the process of aging.

Scripps Research scientists identify new mechanism regulating daily biological rhythms

Fri, 12 Nov 2010 03:23:29 PDT

For Immediate Release – Scientists from the Florida campus of The Scripps Research Institute have identified for the first time a novel mechanism that regulates circadian rhythm, the master clock that controls the body's natural 24-hour physiological cycle. These new findings could provide a new target not only for jet lag, shift work, and sleep disturbances, but also for disorders that result from circadian rhythm disruption, including diabetes and obesity as well as some types of cancer. The study is published in the November 12, 2010 edition (Volume 285, Number 45) of the Journal of Biological Chemistry. "It's well known that the nuclear receptors RORα and REV-ERBα regulate expression of the gene BMAL1, which is vital to virtually every aspect of human physiology and a core component of the circadian clock," said Tom Burris, a professor in the Department of Molecular Therapeutics at Scripps Florida who led the study. "BMAL1 functions as an obligate heterodimer (only working as a dimer with a partner) with either CLOCK or NPAS2 so it was unclear how RORa and REV-ERBa could control this complex. In this study, we show that both partners are targets. As we understand more about the relationship between these receptors and their gene targets, we can consider the possibility of modulating the body's core clock, especially as we continue to develop synthetic ligands targeting these two nuclear receptors." Circadian rhythms are conserved across a wide variety of organisms, from Drosophila (fruit flies) to humans. In mammals, these rhythms respond to light signals and are controlled by the "master clock" in the brain. In the periphery, semi-autonomous clocks can respond to signals from the brain and from other cues including nutrient status. Disorders linked to dysfunctional circadian rhythms can be severe and potentially deadly, Burris said. "When you're dealing with circadian rhythm, the most obvious disease target is sleep – for people who do shift work, critical jobs like police work, fire fighting, and medicine," he said. "If circadian rhythm is disrupted, you're prone to metabolic disorders like diabetes and obesity and even breast cancer – because the core clock is closely linked to the cell cycle. If your clock goes awry, you run the risk of your cell cycle going awry as well." The Role of Nuclear Receptors Nuclear receptors are proteins that recognize and regulate hormones as well as other molecules. As a result, they control an organism's metabolism by activating gene expression. The study found that oscillations in the expression of RORα and REV-ERBα not only influence the pattern of circadian expression of BMAL1, but also of NPAS2, a protein that is part of the circadian clock. The fact that NPAS2 is a target of both receptors suggests that there is a specific mechanism that coordinates the relative levels of each receptor to maintain correct circadian function.. "Based on the fact that BMAL1 and NPAS2 work together within the circadian clock, it seems highly unlikely that these two nuclear receptors would only regulate one of them," Burris said. "Our study shows for the first time that, like BMAL1, NPAS2 is also a direct target for RORα and REV-ERBα. This discovery makes this complex a very good therapeutic target." The expression of RORα and REV-ERBα follows a 24-hour circadian pattern (with opposing phases) leading to the correct circadian pattern of gene expression of BMAL1 and NPAS2. "We think it's something of a competition between these two receptors for binding to promoters of these genes that triggers either the activation (RORα) or repression (REV-ERBα) of the gene," Burris said. Nuclear receptors make tempting drug targets because they can bind directly to DNA and activate genes through specific ligands—molecules that affect receptor behavior—such as the sex hormones, vitamins A and D, and glucocorticoids, which modulate the body's response to stress. Nuclear receptors have been implicated in a number of cancers, including prostate, breast, and colon cancers, and other diseases as well, including type 2 diabetes, atherosclerosis, and metabolic syndrome. The other important aspect of nuclear receptors is their practicality. Scientists can design small molecule therapeutics to force them to change their ways. Burris said that he has already identified several new synthetic ligands (drug like molecules) for both receptors.

Stem cell transplants in mice produce lifelong enhancement of muscle mass

Thu, 11 Nov 2010 03:35:27 PDT

A University of Colorado at Boulder-led study shows that specific types of stem cells transplanted into the leg muscles of mice prevented the loss of muscle function and mass that normally occurs with aging, a finding with potential uses in treating humans with chronic, degenerative muscle diseases. The experiments showed that when young host mice with limb muscle injuries were injected with muscle stem cells from young donor mice, the cells not only repaired the injury within days, they caused the treated muscle to double in mass and sustain itself through the lifetime of the transplanted mice. "This was a very exciting and unexpected result," said Professor Bradley Olwin of CU-Boulder's molecular, cellular and developmental biology department, the study's corresponding author. Muscle stem cells are found within populations of "satellite" cells located between muscle fibers and surrounding connective tissue and are responsible for the repair and maintenance of skeletal muscles, said Olwin. The researchers transplanted between 10 and 50 stem cells along with attached myofibers -- which are individual skeletal muscle cells -- from the donor mice into the host mice. "We found that the transplanted stem cells are permanently altered and reduce the aging of the transplanted muscle, maintaining strength and mass," said Olwin. A paper on the subject was published in the Nov. 10 issue of Science Translational Medicine. Co-authors on the study included former CU-Boulder postdoctoral fellow John K. Hall, now at the University of Washington Medical School in Seattle, as well as Glen Banks and Jeffrey Chamberlain of the University of Washington Medical School. Olwin said the new findings, while intriguing, are only the first in discovering how such research might someday be applicable to human health. "With further research we may one day be able to greatly resist the loss of muscle mass, size and strength in humans that accompanies aging, as well as chronic degenerative diseases like muscular dystrophy." Stem cells are distinguished by their ability to renew themselves through cell division and differentiate into specialized cell types. In healthy skeletal muscle tissue, the population of satellite stem cells is constantly maintained, said Olwin. "In this study, the hallmarks we see with the aging of muscles just weren't occurring," said Olwin. "The transplanted material seemed to kick the stem cells to a high gear for self-renewal, essentially taking over the production of muscle cells. But the team found that when transplanted stem cells and associated myofibers were injected to healthy mouse limb muscles, there was no discernable evidence for muscle mass growth. "The environment that the stem cells are injected into is very important, because when it tells the cells there is an injury, they respond in a unique way," he said. "We don't yet know why the cells we transplanted are not responding to the environment around them in the way that the cells that are already there respond. It's fascinating, and something we need to understand." At the onset of the experiments the research team thought the increase in muscle mass of the transplanted mice with injured legs would dissipate within a few months. Instead, the cells underwent a 50 percent increase in mass and a 170 percent increase in size and remained elevated through the lifetime of the mice -- roughly two years, said Olwin. In the experiments, stem cells and myofibers were removed from three-month-old mice, briefly cultured and then transplanted into three-month-old mice that had temporarily induced leg muscle injuries produced by barium chloride injections. "When the muscles were examined two years later, we found the procedure permanently changed the transplanted cells, making them resistant to the aging process in the muscle," he said. "This suggests a tremendous expansion of those stem cells after transplantation," Olwin said. Fortunately, the research team saw no increase in tumors in the transplanted mice despite the rapid, increased growth and production of muscle stem cells. As part of the research effort, the team used green fluorescent protein -- which glows under ultraviolet light -- to flag donor cells in the injected mice. The experiment indicated many of the transplanted cells were repeatedly fused to myofibers, and that there was a large increase in the number of satellite cells in the host mice. "We expected the cells to go in, repopulate and repair damaged muscle and to dissipate," Olwin said. "It was quite surprising when they did not. "It is our hope that we can someday identify small molecules or combinations of small molecules that could be applied to endogenous muscle stem cells of humans to mimic the behavior of transplanted cells," Olwin said. "This would remove the need for cell transplants altogether, reducing the risk and complexity of treatments." But Olwin said it is important to remember that the team did not transplant young cells into old muscles, but rather transplanted young cells into young muscles. The research has implications for a number of human diseases, Olwin said. In muscular dystrophy, for example, there is a loss of a protein called dystrophin that causes the muscle to literally tear itself apart and cannot be repaired without cell-based intervention. Although injected cells will repair the muscle fibers, maintaining the muscle fibers requires additional cell injections, he said. "Progressive muscle loss occurs in a number of neuromuscular diseases and in muscular dystrophies," he said. "Augmenting a patient's muscle regenerative process could have a significant impact on aging and diseases, improving the quality of life and possibly improving mobility." Olwin said the research team is beginning experiments to see if transplanting muscle stem cells from humans or large animals into mice will have the same effects as those observed in the recent mouse experiments. "If those experiments produce positive results, it would suggest that transplanting human muscle stem cells is feasible," he said.

Inhibitory neurons key to understanding neuropsychiatric disorders

Thu, 11 Nov 2010 03:32:10 PDT

The brain works because 100 billion of its special nerve cells called neurons regulate trillions of connections that carry and process information. The behavior of each neuron is precisely determined by the proper function of many genes. In 1999, Baylor College of Medicine (www.bcm.edu) researcher Dr. Huda Zoghbi (http://www.bcm.edu/genetics/index.cfm?pmid=11053), and her colleagues identified mutations in one of these genes called MECP2 as the culprit in a devastating neurological disorder called Rett syndrome (http://www.nichd.nih.gov/health/topics/rett_syndrome.cfm). In new research in mice published in the current issue of the journal Nature (www.nature.com), Zoghbi and her colleagues demonstrate that the loss of the protein MeCP2 in a special group of inhibitory nerve cells in the brain reproduces nearly all Rett syndrome features. Children, mostly girls, born with Rett syndrome, appear normal at first, but stop or slow intellectual and motor development between three months and three years of age, losing speech, developing learning and gait problems. Some of their symptoms resemble those of autism. These inhibitory (gamma-amino-butyric-acid [GABA]-ergic) neurons make up only 15 to 20 percent of the total number of neurons in the brain. Loss of MeCP2 causes a 30 to 40 percent reduction in the amount of GABA, the specific signaling chemical made by these neurons. This loss impairs how these neurons communicate with other neurons in the brain. These inhibitory neurons keep the brakes on the communication system, enabling proper transfer of information. "In effect, the lack of MeCP2 impairs the GABAergic neurons that are key regulators governing the transfer of information in the brain", said Dr. Hsiao-Tuan Chao (http://www.bcm.edu/labs/zoghbi/Lab_members_info/chao.html), an M.D./Ph.D student in Zoghbi's laboratory and first author of the report. Chao made the discovery by developing a powerful new tool or mouse model that allowed researchers to remove MeCP2 from only the GABAergic neurons. "We did this study thinking that perhaps all we would see was a few symptoms of Rett syndrome," said Chao. "Strikingly, we saw that removing MeCP2 solely from GABAergic neurons reproduced almost all the features of Rett syndrome, including cognitive deficits, breathing difficulties, compulsive behavior, and repetitive stereotyped movements. The study tells us that MeCP2 is a key protein for the function of these neurons." Once the authors determined that the key problem rested with the GABAergic neurons, they sought to find out how the lack of MeCP2 disturbed the function of these neurons. Chao discovered that losing MeCP2 caused the GABAergic neurons to release less of the neurotransmitter, GABA. This occurs because losing MeCP2 reduces the amount of the enzymes required for the production of GABA. Intriguingly, prior studies showed that expression of these enzymes is also reduced in some patients with autism, schizophrenia and bipolar disorder, said Chao. "This tells us a lot about what is going on in the brains of people with Rett syndrome, autism or even schizophrenia," said Chao. "A child is born healthy. She starts to grow and then begins to lose developmental milestones. Communication between neurons is impaired, in part due to reduced signals from GABAergic neurons." "This study taught us that an alteration in the signal from GABAergic neurons is sufficient to produce features of autism and other neuropsychiatric disorders," said Zoghbi, a Howard Hughes Medical Institute investigator and director of the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital.

Scripps Research team 'watches' formation of cells' protein factories for first time

Sat, 30 Oct 2010 04:44:23 PDT

For Immediate Release – A team from The Scripps Research Institute has revealed the first-ever pictures of the formation of cells' "protein factories." In addition to being a major technical feat on its own, the work could open new pathways for development of antibiotics and treatments for diseases tied to errors in ribosome formation. In addition, the techniques developed in the study can now be applied to other complex challenges in the understanding of cellular processes. Identifying and observing the molecules that form ribosomes—the cellular factories that build the proteins essential for life—has for decades been a key goal for biologists but one that had seemed nearly unattainable. But the new Scripps Research study, which appears in the October 29, 2010 issue of the journal Science, yielded pictures of the chemical intermediate steps in ribosome creation. "For me it was a dream experiment," said project leader James Williamson, Ph.D., professor, member of the Skaggs Institute for Chemical Biology, and dean of graduate and postgraduate studies at Scripps Research, who credits collaborators at the Scripps Research National Resource for Automated Molecular Microscopy (NRAMM) facility for making it possible. "We have great colleagues at Scripps to collaborate with who are willing to try some crazy experiments, and when they work it's just beautiful." Past studies of the intermediate molecules that combine to form ribosomes and other cellular components have been severely limited by imaging technologies. Electron microscopy has for many years made it possible to create pictures of such tiny molecules, but this typically requires purification of the molecules. To purify, you must first identify, meaning researchers had to infer what the intermediates were ahead of time rather than being able to watch the real process. "My lab has been working on ribosome assembly intensively for about 15 years," said Williamson. "The basic steps were mapped out 30 years ago. What nobody really understood was how it happens inside cells." Creating a New View The NRAMM group, led by Scripps Research Associate Professors Clinton Potter and Bridget Carragher and working with Scripps Research Kellogg School of Science and Technology graduate students Anke Mulder and Craig Yoshioka, developed a new technique, described in the Science paper and dubbed discovery single-particle profiling, which dodges the purification problem by allowing successful imaging of unpurified samples. An automated data capture and processing system of the team's design enables them to decipher an otherwise impossibly complex hodgepodge of data that results. For this project, second author Andrea Beck, a research assistant in the Williamson laboratory, purified ribosome components from cells of the common research bacterium Escherichia Coli. She then chemically broke these apart to create a solution of the components that form ribosomes. The components were mixed together and then were rapidly stained and imaged using electron microscopy. "We went in with 'dirty' samples that contained horribly complex mixtures of all different particles," said Williamson. Mulder, who is first author on the paper, collected and analyzed the particles that were formed during the ribosome assembly reaction. Using the team's advanced algorithms, they were able to process more than a million data points from the electron microscope to ultimately produce molecular pictures. The Pieces Fit The team produced images that the scientists were able to match like puzzle pieces to parts of ribosomes, offering strong confirmation that they had indeed imaged and identified actual chemical intermediates in the path to ribosome production. "We always saw the same thing no matter how we processed the data, and this led us to believe this was real," said Williamson. Further confirmation came as the researchers imaged components from different timeframes. After breaking down ribosome components, the scientists prepared samples at various stages allowing enough time for the molecular mix to begin combining as they do during ribosome creation in cells. Imaging this time series, the team was able to show higher concentrations of larger, more complex molecules and fewer smaller molecules as time elapsed. These results fit with the limited information that was already available about the timing of formation steps, providing further confirmation of the team's success. Interestingly, this work also confirmed that there are more than one possible paths in ribosome formation, a phenomenon known as parallel assembly that been suggested by prior research but never definitively confirmed. Long-Term Potential Williamson says that with the information now at hand, they will be able to move forward with studies of which additional molecules might be present in cells and essential for ribosome formation. Such data could offer exciting medical potential. All bacteria contain and are dependent on ribosomes. Identification of molecules required for ribosome assembly could offer new targets for antibiotic drugs aimed at killing bacteria. "If we can figure out how to inhibit assembly, that would be a very important therapeutic avenue," said Williamson. There are also indications that some diseases such as Diamond Blackfan Anemia might be caused, at least in some cases, by errors in ribosome production. Better understanding of that production could also reveal ways such errors might be repaired to cure or prevent disease. At the more basic level, this successful project has also proven techniques that Scripps Research scientists and other researchers can apply to allow similar imaging and understanding of other complex but critical cellular processes.

Study details molecular structure of major cell signaling pathway

Fri, 22 Oct 2010 03:26:53 PDT

Scientists at the University of North Carolina at Chapel Hill School of Medicine have reported the exact molecular structure and mechanisms of a major cell signaling pathway that serves a broad range of functions in humans. Up to half of drugs approved by the US Food and Drug Administration directly or indirectly target G protein-coupled receptors. These receptors, which are proteins that live in the outer membranes of cells, take molecular signals from outside the cell and convert them into responses within – and those responses help control behaviors as wide-ranging as cell growth, muscle contraction, platelet aggregation, sight, and smell. Many G protein-coupled receptors engage two partners: the G protein, Gq, and an enzyme called phospholipase C, or PLC, to pass signals into the cell. Until now, it's been a mystery how this transfer of information occurs. "We thought that to really understand how this signaling complex works, we had to go to the atomic level," said co-senior investigator Kendall Harden, PhD, Kenan Professor in the department of pharmacology at UNC. The detailed atomic structure, to be published by the journal Science, within the Science Express web site, on Thursday October 21st 2010 , "is the culmination of 15 years of work, collaboration and a small but crucial bit of educated serendipity," Harden said. For years, the group had been trying to understand how the G protein bound to PLC. The main challenge of solving any atomic structure is to get enough of the highly purified proteins. Then, it's a matter of setting up the right conditions — a trial-and-error process of tweaking the pH of the solution, the salts and numerous other variables — to get the proteins to form a crystal that can withstand the imaging process. Robots produce thousands of slightly different chemical conditions, each produced in volumes smaller than a pinhead, and automated imaging captures each reaction. UNC research analyst Gary Waldo, the lead author of the paper, rifled through thousands of these imaged droplets before he found one that showed the PLC bound to Gq. Enzymes had eaten away part of the PLC molecule, and this missing piece allowed the PLC to properly crystallize with its partner. The group then created the PLC with the exact same portion missing. It bound to the G protein and formed crystals overnight, said co-investigator John Sondek, PhD, co-senior investigator and professor of pharmacology and biochemistry and biophysics at UNC. Sondek and Harden are members of the UNC Lineberger Comprehensive Cancer Center. Once they had the structure, the researchers were able to alter parts of the complex to see exactly how they interact and how the complex works to both turn on and turn off the signal. For example, three different areas of the PLC molecule come into contact with the G protein. To better help understand the importance of the interaction, the researchers introduced a small mutation in part of the PLC molecule they hypothesized was important to shut off the signal at the cell membrane. Expressing this mutation in the PLC of eyes of flies, the group found that the signaling pathway in eyes exposed to light stay stuck in the 'on' position. "The flies can't see because they can't refresh the signal," Sondek said. The group plans to carry more of the molecular work into mice and other animals. "It's already well known how important the signaling pathway is, Harden said. "but our new knowledge helps us see how G proteins and PLC work together to regulate, for example, the proliferation of cells, and how certain genetic mutations in these molecules may contribute to cancer." The new findings will also allow scientists to understand how this signaling complex interacts with other molecules. The group will eventually be able to visualize this complex interaction in real time, and to disrupt it using small compounds. Of course, new science generates many more questions, which Harden and Sondek will pursue. "You can't be anything other than ecstatic," Harden said.

Shock tactics: Bioelectrical therapy for cancer and birth defects?

Tue, 19 Oct 2010 03:29:07 PDT

Stem cell therapies hold increasing promise as a cure for multiple diseases. But the massive potential of a healthy stem cell has a flip side, as faulty regulation of stem cells leads to a huge range of human diseases. Even before birth, mistakes made by the stem cells of the foetus are a major cause of congenital defects, and cancer is also caused by the body losing control of stem cell function. Guiding stem cells along the correct pathways and, where necessary, reversing their mistakes is the goal of everyone in this field. Now, Michael Levin (http://www.drmichaellevin.org/) and colleagues from Tufts University (http://www.tufts.edu/), Medford, MA, have identified a novel and readily modifiable signal by which an organism can control the behaviour of stem cell offspring. Their work is published in Disease Models & Mechanisms on October 19th, 2010, at http://dmm.biologists.org/. Levin's laboratory works on an intriguing phenomenon: bioelectrical signalling. There is always a difference in voltage, called the transmembrane potential, between the inside and outside of all cells, and controlling exactly what this difference is turns out to be vitally important. Specialised protein checkpoints sited in a cell's outer membrane regulate ion flow in and out of the cell, producing voltage gradients. These, combined with more conventional protein-based signalling systems, can specify cell destiny. Levin's team already knew from collaborative work with David Kaplan's lab, also at Tufts, that the properties of human stem cells growing in artificial culture could be drastically altered by changing their transmembrane potential. Now they have taken this work one important step further, by asking whether tampering with the transmembrane potential of one kind of cell can have a domino effect in a whole organism, altering the destiny of other cell types. To do this, they focused on the development of neural crest stem cells, which are responsible for directing development of the face and heart, but which also generate melanocytes, the pigment cells of the skin. Using frog tadpoles and melanocytes as a model system, they showed that tweaking the transmembrane potential of a tiny population of 'instructor' cells sends a signal to developing melanocytes that causes them to overgrow and start to resemble metastatic cancer cells. Most excitingly, they found that the signal can travel over long distances in the tadpole, and that the messenger carrying it is serotonin – an important neurotransmitter involved in mood regulation and many other aspects of nervous system function. This novel bioelectrical method of changing stem cell behaviour has huge implications. It is very likely that there are similar 'instructor' cells that direct other important cell populations, and changing their voltage gradients would be relatively easy (Levin's lab simply used an anti-parasitic drug already available on prescription). The resulting bioelectrical therapy could potentially be harnessed to improve regenerative repair after injury, repair birth defects and detect and prevent cancer.

Research team identifies new mechanism with suspected role in cancer

Tue, 19 Oct 2010 03:26:12 PDT

If women had no prolactin receptors on cells in their mammary glands, they would not produce milk when they were nursing. Prolactin receptors are also found in other organs including the lung and the colon. The only problem is that these receptors are sort of like cellular wiring, and when the wrong conditions bring them together, the resulting short circuit can produce cancer. In new research published online Oct. 18, 2010, in the Proceedings of the National Academy of Science, a team led by researcheres at Brown University and Rhode Island Hospital has identified a key chemical process by which cells with prolactin receptors can sometimes take that turn for the worse. That key step is called "acetylation" — a chemical reaction inside the cell, triggered by the binding of the arrival of the prolactin hormone at the receptor. That process can draw prolactin receptors together into a structure called a "dimer." Like a pair of chopsticks, this dimer structure is just right to pick up growth factors in the body that can lead to cancerous growth, said Y. Eugene Chin, associate professor of surgery (research) in the Warren Alpert Medical School of Brown University, based at Rhode Island Hospital. "Our findings may provide an important clue about how to develop drugs to break down receptor dimers in breast cancer therapy," said Chin, a senior author on the paper that also involved researchers from Zhejiang University School of Medicine in China and the University of Rochester in Rochester, N.Y. Normally, a shared positive electrical charge and the resulting mutual repulsion keeps prolactin receptors from coming together. In their experiments, the team found that when prolactin binds to the receptors outside the cells, the acetylation neutralizes that charge on the receptors inside the cells, allowing the receptor molecules to come together, Chin said. The more prolactin receptors a cell has, the more susceptible it is to this problem occurring, Chin said. Overexpression of prolactin receptors in patients has been linked to cancer in the past. Chin, who has been investigating the molecular basis of cancer for years, said he is encouraged about uncovering this new step. He points to drugs, such as Herceptin, that target receptors to combat cancer. "This will be extremely important for breast cancer and other cancer therapy by targeting receptors," he said. One possibility will be developing monoclonal antibodies to target the prolactin receptors directly, he said. But artificial compounds could also be developed to block the receptors from joining as dimers.

Breakthrough: With a chaperone, copper breaks through

Tue, 19 Oct 2010 03:20:47 PDT

Information on proteins is critical for understanding how cells function in health and disease. But while regular proteins are easy to extract and study, it is far more difficult to gather information about membrane proteins, which are responsible for exchanging elements essential to our health, like copper, between a cell and its surrounding tissues.

Now Prof. Nir Ben-Tal and his graduate students Maya Schushan and Yariv Barkan of Tel Aviv University's Department of Biochemistry and Molecular Biology have investigated how a type of membrane protein transfers essential copper ions throughout the body. This mechanism, Schushan says, could also be responsible for how the body absorbs Cisplatin, a common chemotherapy drug used to fight cancer. In the future, this new knowledge may allow scientists to improve the way the drug is transferred throughout the body, she continues.

Their breakthrough discovery was detailed in a recent issue of PNAS (Proceedings of the National Academy of Sciences).

Cellular gatekeepers and chaperones

Most proteins are water soluble, which allows for easy treatment and study. But membrane proteins reside in the greasy membrane that surrounds a cell. If researchers attempt to study them with normal technology of solubilization in water, they are destroyed — and can't be studied.

Copper, which is absorbed into the body through a membrane protein, is necessary to the healthy functioning of the human body. A deficiency can give rise to disease, while loss of regulation is toxic. Therefore, the cell handles copper ions with special care. One chaperone molecule delivers the copper ion to an "entrance gate" outside the cell; another chaperone then picks it up and carries it to various destinations inside the cell.

The researchers suggest that this delicate system is maintained by passing one copper ion at a time by the copper transporter, allowing for maximum control of the copper ions. "This way, there is no risk of bringing several copper ions into the protein at the same time, which ultimately prevents harmful chemical reactions between the ions and the abundant chemical reagents within the cell," explains Prof. Ben-Tal. Once the ion has passed through the transporter into the cell, the transporter is ready to receive another copper ion if necessary.

Improving cancer drugs — and more

The mechanism which transfers copper throughout the body may also be responsible for the transfer of the common chemotherapy drug Cisplatin. By studying how copper is transferred throughout the body, researchers may also gain a better understanding of how this medication and others are transferred into the cell.

With this information, says Prof. Ben-Tal, scientists could improve the transfer of the drug throughout the body, or develop a more effective chemotherapy drug. And that's not the only pharmaceutical dependent on the functioning of membrane proteins. "Sixty percent of drugs target membrane proteins," he explains, "so it's critical to learn how they function." This work was done in collaboration with Prof. Turkan Haliloglu from Bogazici University, Istanbul.

Bioelectrical signals turn stem cells' progeny cancerous

Tue, 19 Oct 2010 03:16:33 PDT

Biologists at Tufts University School of Arts and Sciences have discovered that a change in membrane voltage in newly identified "instructor cells" can cause stem cells' descendants to trigger melanoma-like growth in pigment cells. The Tufts team also found that this metastatic transformation is due to changes in serotonin transport. The discovery could aid in the prevention and treatment of diseases like cancer and vitiligo as well as birth defects. The research is reported in the October 19, 2010, issue of Disease Models and Mechanisms. "Discovering this novel bioelectric signal and new cell type could be very important in efforts to understand the mechanisms that coordinate stem cell function within the host organism and prevent tumor growth. Ultimately it could enable us to guide cell behaviors toward regenerative medicine applications," said research leader and senior author Michael Levin, Ph.D., professor of biology and director of the Center for Regenerative and Developmental Biology at Tufts. Co-authors on the paper were Tufts Postdoctoral Associate Douglas Blackiston, Research Associate Professor Dany S. Adams, Research Associate Joan M. Lemire and doctoral student Maria Lobikin. Misregulation of stem cells is a known factor in cancers and birth defects. Recent studies have shown that stem cells exhibit unique electrophysiological profiles and that ionic currents controlled by ion channel proteins play important roles during stem cell differentiation. However, while many genetic and biochemical signaling pathways play a part in regulating the interplay between cells and the host organism, the role of bioelectric signals remains poorly understood, particularly when looking beyond artificial cultures to entire living organisms. "One of the things we need to know is how cells know what to do in order to participate in the complex pattern of a host organism. The body normally tells cells 'don't become cancerous and go off on your own; instead, participate in keeping up the normal shape of all the tissues and organs, as individual cells age and die,'" said Levin. To determine how changes in membrane voltage regulate cell behavior in vivo, the Tufts researchers looked at a group of stem cells in Xenopus laevis frog embryos called the neural crest. Neural crest stem cells migrate throughout the body in vertebrates, including humans. They give rise to many cell types, including pigmentation cells called melancocytes, and contribute to structures such as the heart, face and skin. Congenital malformations of the neural crest are known to affect their descendent cells and cause birth defects. The Tufts biologists manipulated the electrical properties of a special, sparse cell population present throughout the embryo by using the common anti-parasitic drug ivermectin to open the glycine gated chloride channel (GlyCl). The GlyCl channel is one of the many ion channels that control cellular membrane voltage and is a marker of this unique "instructor cell" population. Changing the chloride ion level to hyperpolarize or depolarize the cells in turn triggered abnormal growth in distant melanocytes derived from the neural crest. These pigment cells not only grew in greater numbers but also formed long, branch-like shapes and thoroughly invaded neural tissues, blood vessels and gut. This pattern is typical of metastasis. The ability of these GlyCl-expressing cells to radically change the shape, position, and quantity of a different cell type (melanocytes) revealed a new and potentially highly important cell type -- an instructor capability that can change the behavior of other cells a considerable distance away. The researchers achieved similar results when they used a variety of different methods to manipulate transmembrane potential. Therefore, they concluded that the impact was triggered by the voltage change itself and was not intrinsically dependant on ivermectin, chloride flow or the GlyCl channel. Testing of human epidermal melanocytes in a depolarizing medium also showed a shape change similar to that found in the Xenopus tadpoles. The researchers also addressed the question of how cells sensed depolarization and converted this biophysical signal into changes in distant cells' behavior. After testing three potential mechanisms, they found that transport of serotonin (a neurotransmitter that can be modulated to regulate mood, appetite and other functions) across the cell surface was the likely messenger. The Tufts researchers note that analysis of other ion channels might reveal other instructor cells that can signal and change the behavior of various important cells in the body. Learning to identify and manipulate such cell types may reveal additional roles for ion flows and establish a new model for control of cell behavior in regenerative medicine and oncology. Levin and his colleagues are already pursuing avenues for early, non-invasive cancer detection using voltage-sensitive dyes and exploring techniques to normalize cancer by repolarizing abnormal cells and instructor cells.