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  • richardmitnick 12:13 pm on August 23, 2015 Permalink | Reply
    Tags: , , , Scripps Institute   

    From Scripps: “Hands-On Research 101: Internships Introduce Undergrads to Biomedical Science in Action” 

    Scripps

    Scripps Research Institute

    August 24, 2015
    Madeline McCurry-Schmidt

    1
    SURF Intern Joshua David says the internship at TSRI gave him new opportunities to learn about biomedicine. (Photo by Cindy Bruaer.)

    When Joshua David saw scientists from The Scripps Research Institute (TSRI) discussing Ebola virus research on the news last year, he wanted to help.

    “I discovered that Scripps is one of the top places looking at Ebola virus at the molecular level,” said David, an undergraduate chemistry major at Virginia Commonwealth University. “The scientists at Scripps are trying to help people who are suffering and dying right now.”

    David quickly got in touch with Ebola researchers at TSRI and learned about the institute’s Summer Undergraduate Research Fellows (SURF) Program, organized by the TSRI Office of Graduate Studies. The SURF Program is a 10-week internship program at TSRI that has brought 38 undergraduates to TSRI’s California and Florida campuses this year. It’s one of several outreach programs, including a summer high school internship program where another 30 students work side-by-side with researchers.

    As a SURF intern, David flew into San Diego in June and spent his summer in Associate Professor Andrew Ward’s lab.

    Learning New Techniques

    David said the internship gave him new opportunities to learn about biomedicine.

    “I’m very interested in structural biology and virology; however, these courses are not offered at my university,” David explained. “Coming here is a great opportunity because it allows me learn techniques used in these fields and gain general knowledge of each field in the process.”

    Under the guidance of C. Daniel Murin, a graduate student in the Ward lab, David learned how to build 3-D structures of proteins involved in Ebola virus attacks. The SURF program emphasizes hands-on research, so David learned to use a technique called electron microscopy (EM) to study exactly how Ebola virus interacts with antibodies.

    “I wanted to take him through that process, so he can go through it almost independently by the end of the summer,” said Murin.

    David worked with Murin on several projects, including studies involving the experimental Ebola virus treatment ZMapp, which has also been the topic of previous studies at TSRI.

    David said one challenge this summer was tackling how to use a molecular imaging program necessary for research with EM.

    “Then I just had to sit down and figure it out,” he said. “It took me about eight hours, but now I understand how to do it.”

    Helping Patients

    David hopes to bring together research and patient care in a future career as a physician-scientist. As a high school student, David interned in a hospital’s intensive care unit. He watched as patients succumbed to diseases like acute respiratory distress syndrome (ARDS)—where doctors have few treatments to offer.

    A technique like EM could give David and other scientists a better look at the proteins involved in disease—from Ebola to ARDS—and lead to new treatments.

    “You can understand how things work in cells at the atomic level, and that really interests me,” said David.

    Before David headed back to Virginia at the end of the summer, he presented a poster outlining his work to peers and supervisors at TSRI. It was chance to show what he’s learned—and why he wants to be part of the next generation of scientists.

    About the Summer Undergraduate Research Fellows (SURF) Program

    TSRI’s 10-week SURF program provides participants the opportunity to perform cutting-edge research in one of 250 laboratories side-by-side with TSRI’s world-renowned faculty. The goals of the program are to:

    Make program participants feel comfortable in a lab setting and increase their research skills
    Teach participants to think critically about the theory and application of biomedical research
    Increase the participants’ proficiency in communicating scientific concepts
    Increase the number of underrepresented and first-generation to college students who consider careers in biomedical research.

    Students can choose to apply to either the La Jolla campus in California or the Jupiter campus in Florida. Learn more at TSRI’s Education website.

    See the full article here.

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    The Scripps Research Institute (TSRI), one of the world’s largest, private, non-profit research organizations, stands at the forefront of basic biomedical science, a vital segment of medical research that seeks to comprehend the most fundamental processes of life. Over the last decades, the institute has established a lengthy track record of major contributions to the betterment of health and the human condition.

    The institute — which is located on campuses in La Jolla, California, and Jupiter, Florida — has become internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune diseases, cardiovascular diseases, virology, and synthetic vaccine development. Particularly significant is the institute’s study of the basic structure and design of biological molecules; in this arena TSRI is among a handful of the world’s leading centers.

    The institute’s educational programs are also first rate. TSRI’s Graduate Program is consistently ranked among the best in the nation in its fields of biology and chemistry.

     
  • richardmitnick 9:05 am on August 11, 2015 Permalink | Reply
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    From Scripps: “Scripps Florida Scientists Determine How Antibiotic Gains Cancer-Killing Sulfur Atoms” 

    Scripps

    Scripps Research Institute

    August 10, 2015
    Office of Communications
    Tel: 858-784-2666
    Fax: 858-784-8136
    press@scripps.edu

    1
    Ben Shen is a professor at the Florida campus of The Scripps Research Institute.

    In a discovery with implications for future drug design, scientists from the Florida campus of The Scripps Research Institute (TSRI) have shown an unprecedented mechanism for how a natural antibiotic with antitumor properties incorporates sulfur into its molecular structure, an essential ingredient of its antitumor activity.

    This new discovery could open the way to incorporating sulfur into other natural products, potentially advancing new therapies for indications beyond cancer.

    The study, which was led by TSRI Professor Ben Shen, was recently released online ahead of print by the journal Proceedings of the National Academy of Sciences, USA.

    “We found a novel mechanism to incorporate sulfur into natural products, which is unprecedented,” Shen said. “Until our study, we didn’t really know how sulfur atoms are incorporated into a natural product—now we have discovered a new family of enzymes and have a workable mechanism to account for sulfur incorporation into a larger class of natural products, known as polyketides, that include many drugs such as erythromycin (antibacterial) and lovastatin (cholesterol lowering).”

    Sulfur is critical not only to human life, but to plants and bacteria as well, and is one of the most abundant elements in the human body by weight. A number of compounds that contain sulfur have proven useful in the treatment of conditions ranging from acne and eczema to arthritis and cancer.

    The new study is focused on leinamycin (LNM), a sulfur-containing antitumor antibiotic produced by species of the soil-dwelling bacterium Streptomyces. The Shen laboratory has been studying the potential of this natural compound for development of anticancer drugs. They recently reported the discovery of LNM E1, an engineered analogue of LNM, as a “prodrug,” a medication converted through a metabolic process in the body to become an active therapy (see “Scripps Florida Scientists Show Antitumor Agent Can Be Activated by Natural Response to Cell Stress”).

    “With LNM, sulfur plays the critical role in its anticancer activity,” Shen said. “With many other natural products, sulfur could add other therapeutic properties. This is the beauty of fundamental research—it lays the foundation to create novel technologies that enable innovative translational research with implications far beyond the original discovery.”

    The study links a family of enzymes—molecules that act as biological catalysts—known as polyketide synthases (PKS) directly to a complex series of chemical reactions that ultimately add sulfur to leinamycin, a member of the polyketide family of natural products.

    “The sulfur incorporation mechanism discovered in our study revealed the novel function of a polyketide synthase, greatly expanding our understanding of its chemistry,” said TSRI’s Ming Ma, a co-first author of the study with Jeremy R. Lohman of TSRI and Tao Liu of the University of Wisconsin, current and former members of the Shen lab. “Since polyketide synthases are a large family of enzymes that have been proven amenable for polyketide structural diversity and drug discovery, it is particularly exciting that this new discovery now provides the possibilities of adding sulfur atoms to compounds similar to leinamycin or other polyketide natural products.”

    Because few sulfur-containing natural products are known, this particular enzyme and its gene could now be useful tools to probe ecological niches for the discovery of other sulfur-containing natural products.

    For more information on the study, “C-S Bond Cleavage by a Polyketide Synthase Domain,” see http://www.pnas.org/content/early/2015/07/30/1508437112.abstract?sid=ec97607b-cc2c-4d81-bf84-f1200e83f5a6

    This work was supported by the National Institutes of Health (grant CA106150).

    See the full article here.

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    The Scripps Research Institute (TSRI), one of the world’s largest, private, non-profit research organizations, stands at the forefront of basic biomedical science, a vital segment of medical research that seeks to comprehend the most fundamental processes of life. Over the last decades, the institute has established a lengthy track record of major contributions to the betterment of health and the human condition.

    The institute — which is located on campuses in La Jolla, California, and Jupiter, Florida — has become internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune diseases, cardiovascular diseases, virology, and synthetic vaccine development. Particularly significant is the institute’s study of the basic structure and design of biological molecules; in this arena TSRI is among a handful of the world’s leading centers.

    The institute’s educational programs are also first rate. TSRI’s Graduate Program is consistently ranked among the best in the nation in its fields of biology and chemistry.

     
  • richardmitnick 8:25 pm on April 9, 2015 Permalink | Reply
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    From Scripps: “Preventing Cancer Drug Failure” 

    Scripps

    Scripps Research Institute

    April 2015
    No Writer Credit

    Cancer patients fear the possibility that one day their cells might start rendering many different chemotherapy regimens ineffective. This phenomenon, called multidrug resistance, is responsible for virtually all cancer deaths among individuals who have undergone treatment.

    2
    TSRI Associate Professor Qinghai Zhang (right), shown here with Research Associate Sung Chang Lee, was a senior author of both studies.

    Now scientists at The Scripps Research Institute (TSRI) have published a pair of studies showing how the primary protein responsible for multidrug chemotherapy resistance changes shape and reacts to therapeutic drugs.

    “This information will help us design better molecules to inhibit or evade multidrug resistance,” said TSRI Associate Professor Qinghai Zhang, a senior author of both studies.

    The proteins at work in multidrug resistance are V-shaped proteins called ABC transporters. ABC transporters are found in all kingdoms of life – from bacteria to humans. In humans, an important ABC transporter is P-glycoprotein (P-gp), which catches harmful toxins in a “binding pocket” and expels them from cells.

    The problem is that in cancer patients, P-gp sometimes begins recognizing chemotherapy drugs and expelling them, too. Over time, more and more cancer cells can develop multidrug resistance, eliminating all possible treatments. A better understanding of P-gp and how it binds to molecules will help scientists develop better cancer drugs.

    For one of the new studies, researchers looked at P-gp under one of TSRI’s powerful electron microscopes. They also looked at MsbA, a similar transporter protein found in bacteria.

    The electron microscopy (EM) work – spearheaded by a postdoctoral researcher Arne Moeller, working in the laboratory of Bridget Carragher and former TSRI Professor Clint Potter – solved a major problem in transporter research.

    Until recently, researchers could only compare images of crystal structures made from transporter proteins. These crystallography images showed single snapshots of the transporter but didn’t show how the shape of the transporters could change. Using EM, however, P-pg and MsbA could be captured in action.

    The new research was also enabled by the development of new chemical tools. Previous studies were hampered by the fact that, outside the cell membranes, these transporter proteins turned into an unstructured mash.

    “They looked like tofu,” said Sung Chang Lee, a research associate in Dr. Zhang’s lab at TSRI and co-first author of the study.

    In the study, the researchers used a solution of lipids and peptides to mimic natural conditions in the cell membrane. A novel chemical called beta sheet peptide, developed by the Zhang lab, was used to stabilize the protein and provide a new perspective.

    Together with EM, this technique enabled the research team to capture a series of images showing how transporter proteins change shape in response to drug and nucleotide binding. They found that transporter proteins have an open binding pocket that constantly switches to face different sides of membranes.

    “The transporter goes through many steps – it’s like a machine,” said Dr. Zhang.

    In the second study, the researchers investigated the drug binding sites of P-gp using higher-resolution X-ray crystallography.

    Their findings show how P-gp interacts with drug-like molecules called ligands. The researchers studied crystals of the transporter bound to four different ligands to see how the transporters reacted.

    The researchers found that when certain ligands bind to P-gp, they trigger local conformational changes in the transporter. Binding also increased the rate of ATP hydrolysis, which provides mechanical energy and may be the first step in the binding pocket closing process.

    The team also found that ligands could bind to different areas of the transporter, leaving nearby slots open for other molecules. This suggested that it may be difficult to completely halt the drug expulsion process.

    Dr. Zhang said the next step in this research is to develop molecules that evade P-gp binding.

    See the full article here.

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    The Scripps Research Institute (TSRI), one of the world’s largest, private, non-profit research organizations, stands at the forefront of basic biomedical science, a vital segment of medical research that seeks to comprehend the most fundamental processes of life. Over the last decades, the institute has established a lengthy track record of major contributions to the betterment of health and the human condition.

    The institute — which is located on campuses in La Jolla, California, and Jupiter, Florida — has become internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune diseases, cardiovascular diseases, virology, and synthetic vaccine development. Particularly significant is the institute’s study of the basic structure and design of biological molecules; in this arena TSRI is among a handful of the world’s leading centers.

    The institute’s educational programs are also first rate. TSRI’s Graduate Program is consistently ranked among the best in the nation in its fields of biology and chemistry.

     
  • richardmitnick 1:28 pm on March 30, 2015 Permalink | Reply
    Tags: , Scripps Institute,   

    From Scripps: “Cells You Can See: A Profile of Art Olson” 

    Scripps

    Scripps Research Institute

    March 30, 2015
    Madeline McCurry-Schmidt

    1
    “Understanding how biology works at all levels helps us understand how to keep people well and how to cure people who are sick,” says Professor Art Olson, whose lab takes many different approaches to molecular modeling. (Photo by Cindy Brauer.)

    Click for video of Olson speaking about his work.

    Cells are bafflingly complex.

    “If you think about Manhattan—and all the people in Manhattan—and try to figure out what each person is doing and their interactions with each other at every moment… that is not as complex as a cellular environment,” said Art Olson, professor at The Scripps Research Institute (TSRI).

    To better understand this mind-boggling tangle, Olson’s lab creates models and computer programs to help scientists visualize cells, viruses and other biological players.

    If scientists can figure out how proteins and other molecules interact, they can design new drugs and therapies. Already, Olson’s work has led to advances in HIV and tuberculosis research.

    “Understanding how biology works at all levels helps us understand how to keep people well and how to cure people who are sick,” said Olson.

    Biology Becomes Art

    Olson’s strategy is to approach biological modeling from every angle possible. In his molecular graphics laboratory, researchers employ the same programs used in video game design to model colorful, richly textured biological structures.

    His lab members also use more traditional, hands-on techniques. One lab member, TSRI Associate Professor David Goodsell, paints watercolors of structures such as red blood cells and organisms such as E. coli.

    By turning scientific images into works of art, Olson’s laboratory brings biology to new audiences. In 2013, dance students at the University of Michigan set Goodsell’s images to music and turned cellular processes into choreography for a performance called Autophagy. And in 2014, two digital images created in his lab were exhibited at the San Diego International Airport as part of show, Taking Art to the Cellular Level.

    Olson was also an early adopter of 3D printing, in which layered blots of ink harden into a model. Models in hand, researchers can visualize individual atoms in an antibody, for example.

    This kind of visualization is possible with computer imaging, but Olson believes physical models have some advantages. With some of the physical models developed in the lab, one can instantly tweak the positions of molecules; one can even twist and fold proteins to see how a changing structure might affect function.

    Take the eye-catching DNA model in Olson’s office. Colorful chunks of plastic make up the ladder-rung base pairs. The Olson lab designed the double-stranded model with magnets, so it can unzip like actual DNA. Play with the model, and the magnets meet with a satisfying “snap!”

    When one of Olson’s TSRI colleagues left a few years ago to teach at the Bishop’s School in La Jolla, California, he brought models like this with him. The students loved them, and the lab has since tried designing models for use in schools. Olson is now working with an educational research institute, WestEd, in the Bay Area to test some of these models in high schools.

    “These physical models are great teaching tools,” said Olson.

    In fact, last summer TSRI Professor Erica Ollmann Saphire, a leading Ebola virus researcher and Olson’s frequent collaborator, kept one of Olson’s models on hand to show TV viewers nationwide exactly how an experimental Ebola treatment attached to the virus.

    “The Olson lab models are intuitive and clear,” said Saphire. “They allow us to immediately explain the meaning of a structure to the public and to other scientists.”

    Indeed, Olson has found that scientists like having physical models on hand. “It gives them a different view of the molecules they’re studying,” said Olson. “You can play with it in your hands, just like Watson and Crick played with their DNA model 60 years ago.”

    Modeling Fights Disease

    Olson’s inspiration to improve human health began with a plane flight.

    In the late 1960s, Olson joined the Peace Corps and was sent to teach science in a village in Ghana. The village had no phone lines, and only one store there had electricity.

    (Always a creative thinker, Olson ran power lines over the road to borrow electricity from the store for the enlarger in his photography dark room—a necessity for the village school’s photography club—which he started.)

    What really struck Olson in this new environment was the need for better public health. For example, he saw that unsafe water sources led to cholera.

    Today, Olson’s lab designs computational programs that researchers use with the goal of improving human health around the world. One useful program is Autodock, which takes the structure of a molecule and simulates how it would bind, or “dock,” with a protein. The program can test how drug molecules dock with and disable HIV, for example.

    “We now know a lot about the molecular biology of HIV. We know where the weak spots are, and we can try to target them,” said Olson. When they find a molecule “hit” that binds with the virus in Autodock, Olson’s lab alerts chemists and biologists who can test the molecule in the laboratory.

    Autodock is freely available to researchers around the world, and Olson estimates that the program has been used in at least 30,000 labs. The program is useful, but scientists can been limited by computer processing time. When Olson first started working on Autodock, it took about 20 minutes for a computer to run one docking simulation between a molecule and a disease target.

    That all changed about 10 years ago, when Olson teamed up with tech giant IBM to run Autodock on the World Community Grid, a network of more than three million* computers around the world. These are computers in homes and offices of people, not necessarily scientists, who go to worldcommunitygrid.org and volunteer their computer’s free time to run docking simulations and other programs. These programs are safe and do not interfere with the computer’s normal functions.

    WCG
    WCG Logo New

    The World Community Grid provides processing power never seen before. Today, instead of spending 20 minutes on one docking simulation, the World Community Grid can test thousands of dockings in less than a minute.

    “Now we can screen millions of molecules to look for the needle in the haystack,” said Olson.

    Olson has so far used the World Community Grid to test molecules that could fight HIV, malaria and Ebola virus.

    FAAH

    GOFIGHTAGAINSTMALARIA SCREENSAVER

    Outsmart Ebola Together

    This data sometimes points to unexpected findings. Olson’s lab recently reported that anti-malaria simulations on the World Community Grid had identified two compounds that might be used to fight drug-resistant tuberculosis.

    “It’s always a great feeling to know that what you do is actually impacting the world,” said Olson.

    See the full article here.

    [WCG runs on BOINC software from UC Berkeley. Please visit the WCG and BOINC homepages to see what is possible in Citizen Science to improve life by beating down diseases. There many other projects running BOINC software not affiliated with WCG. The current figues for all of BOINC are Active: 293,195 volunteers, 420,378 computers. 24-hour average: 8.038 PetaFLOPS. That PetaFLOP figure is very important. It is larger than what many supercomputers are running today. If BOINC was considered a supercomputer, which it is not, it would rank 5th in the all important TOP500 list of supercomputers world wide.]

    BOINCLarge

    *This figure is misleading. While it is probably a good estimate of how many people have “crunched” for WCG over time, currently the estimate is about 70,000 current crunchers.

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    The Scripps Research Institute (TSRI), one of the world’s largest, private, non-profit research organizations, stands at the forefront of basic biomedical science, a vital segment of medical research that seeks to comprehend the most fundamental processes of life. Over the last decades, the institute has established a lengthy track record of major contributions to the betterment of health and the human condition.

    The institute — which is located on campuses in La Jolla, California, and Jupiter, Florida — has become internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune diseases, cardiovascular diseases, virology, and synthetic vaccine development. Particularly significant is the institute’s study of the basic structure and design of biological molecules; in this arena TSRI is among a handful of the world’s leading centers.

    The institute’s educational programs are also first rate. TSRI’s Graduate Program is consistently ranked among the best in the nation in its fields of biology and chemistry.

     
  • richardmitnick 12:18 pm on March 28, 2015 Permalink | Reply
    Tags: , , Scripps Institute   

    From Scripps: “Team Breaks Imaging Barrier” 

    Scripps

    Scripps Research Institute

    March 30, 2015
    Madeline McCurry-Schmidt

    Advances in Electron Microscopy Could Aid Drug Design

    1
    A team from the Carragher lab has imaged a protein complex at the highest resolution ever achieved with single particle cryo-electron microscopy. The image reveals individual molecules at 2.8 Å and is, to the researchers’ knowledge, the first published research using this technique that shows individual water molecules.

    Scientists at The Scripps Research Institute (TSRI) have broken a major barrier in structural imaging. Their study, published recently in the journal eLife, shows a protein complex at the highest resolution ever achieved with a standard technique called single particle cryo-electron microscopy.

    “The instruments and software are now so good that we do not know what the barriers are any more,” said Bridget Carragher, a professor at TSRI with a joint appointment at the New York Structural Biology Center.

    With single particle cryo-electron microscopy, scientists freeze a sample and then expose it to a beam of high-energy electrons. This excites electrons in the sample, allowing scientists to capture an image.

    While the technique has many practical advantages over other structural biology methods, scientists have so far not been able to reach resolutions more detailed than 3 Angstroms (one ten-billionth of a meter, marked with the symbol Å). At this resolution, some of the details of the structure that are important for guiding drug design are not discernable.

    The new study shows that reaching resolutions greater than 3 Å is possible using single particle cryo-electron microscopy. The imaged protein complex reveals individual molecules at 2.8 Å and is, to the researchers’ knowledge, the first time a paper has been published showing individual water molecules using this technique.

    Better Imaging, Better Drugs

    The scientists used a new type of electron microscope, called the FEI Titan Krios, and a new-generation camera, called a Gatan K2 Summit, to break the 3 Å barrier.

    1
    Titan Krios

    2
    Gatan K2 Summit

    The FEI Titan Krios is housed on TSRI’s La Jolla, California, campus. It has a higher energy electron source and a more stable platform than other types of electron microscopes. It also operates with software developed at TSRI through the National Resource for Automated Molecular Microscopy to find the best parts of a sample for imaging.

    The Gatan K2 Summit camera improves imaging by directly detecting electrons, instead of losing resolution by converting electrons to light. The camera can also capture a series of images, essentially a movie, giving scientists the ability to correct for movements in the specimen and make the images as sharp as possible.

    Revealing high-resolution details in a structure helps researchers develop new drugs to treat disease. Structures seen at greater than 3 Å might show vulnerabilities in a virus where drugs could bind, for example.

    “By seeing everything in more detail, you can design more effective drugs,” said Melody Campbell, a TSRI graduate student and co-first author of the new paper with David Veesler, previously a post-doctoral fellow at TSRI and now an assistant professor at the University of Washington.

    The advances in single particle cryo-electron microscopy also allow scientists to image more kinds of structures, more quickly. For many years, scientists have relied on a high-resolution imaging technique called X-ray crystallography. Although X-ray crystallography has led to many advances in drug design, figuring out how to grow a crystal can take years and not all structures can be crystallized.

    Electron microscopy does not require a crystal, however, and many projects take only weeks or months.

    In the new study, the researchers imaged a protein complex from a microbe called Thermoplasma acidophilum. This protein complex, called a proteasome, is also found in humans and is an important target for treating many types of cancer.

    The team spent several months setting up the instruments—since the FEI Titan Krios was new to the institute—and then they captured all the raw data over a single weekend. They then used computational programs to select the clearest images and refine them over several months to build a 3D model of the proteasome.

    “It was a relief to know we had finally done it,” said Campbell. “Now we hope other people can just hop on the microscope, use similar strategies and also get high-resolution structures.”

    In addition to Carragher, Campbell and Veesler, authors of the study, “2.8 Å resolution reconstruction of the Thermoplasma acidophilum 20 S proteasome using cryo-electron microscopy,” were Anchi Cheng and Clinton S. Potter of the New York Structural Biology Center. For more information on the paper, see http://elifesciences.org/content/4/e06380.

    This research was supported by the National Institutes of Health’s National Institute of General Medical Sciences (grant GM103310), a FP7 Marie Curie IOF fellowship (273427) and an American Heart Association fellowship (14PRE18870036).

    See the full article here.

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    The Scripps Research Institute (TSRI), one of the world’s largest, private, non-profit research organizations, stands at the forefront of basic biomedical science, a vital segment of medical research that seeks to comprehend the most fundamental processes of life. Over the last decades, the institute has established a lengthy track record of major contributions to the betterment of health and the human condition.

    The institute — which is located on campuses in La Jolla, California, and Jupiter, Florida — has become internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune diseases, cardiovascular diseases, virology, and synthetic vaccine development. Particularly significant is the institute’s study of the basic structure and design of biological molecules; in this arena TSRI is among a handful of the world’s leading centers.

    The institute’s educational programs are also first rate. TSRI’s Graduate Program is consistently ranked among the best in the nation in its fields of biology and chemistry.

     
  • richardmitnick 1:42 pm on March 20, 2015 Permalink | Reply
    Tags: , , , Scripps Institute   

    From Scripps: ” Scientists Confirm Key Targets of New Anti-Cancer Drug Candidates” 

    Scripps

    Scripps Research Institute

    March 23, 2015
    Eric Sauter

    Ribosomes, ancient molecular machines that produce proteins in cells, are required for cell growth in all organisms, accomplishing strikingly complex tasks with apparent ease. But defects in the assembly process and its regulation can lead to serious biological problems, including cancer.

    Now, in a study published in the March 16 issue of The Journal of Cell Biology, scientists from the Florida campus of The Scripps Research Institute (TSRI) have confirmed the ribosome assembly process as a potentially fertile new target for anti-cancer drugs by detailing the essential function of a key component in the assembly process.

    “This study confirms that ribosome assembly is a good therapeutic target in cancer,” said Katrin Karbstein, a TSRI associate professor who led the study. “Whether or not we have pinpointed the best molecule remains to be shown, but this is a vindication of our basic research. There should be effort devoted to exploring this pathway.”

    Understanding ribosome assembly—which involves about 200 essential proteins known as “assembly factors” in addition to the four RNA molecules and 78 ribosomal proteins that are part of the mature ribosome—has become a fruitful area of research in recent years because of the importance of ribosome assembly for cell growth.

    The new study highlights the molecules Casein kinase 1δ (CK1δ) and CK1ε, which are essential for human ribosome assembly. The expression of CK1δ is elevated in several tumor types, as well as Alzheimer’s and Parkinson’s disease—and CK1δ inhibitors have shown promise in some pre-clinical animal studies.

    In the new study, Karbstein and her group—working closely with three labs across the state of Florida, including the laboratory of William Roush at Scripps Florida—used Hrr25, the yeast equivalent of Casein kinase 1δ (CK1δ) and CK1ε, as a research model.

    In biochemical experiments, the team showed that Hrr25 is necessary for ribosome assembly and that the molecule normally adds a phosphate group to an assembly factor called “Ltv1,” allowing it to separate from other subunits and mature. If Hrr25 is inactivated or a mutation blocks the release of Ltv1, the assembly process is doomed.

    “Inhibiting Hrr25 and the subsequent release of Ltv1 blocks the formation of other subunits that are required for maturation—and the subsequent production of proteins,” said Homa Ghalei, the first author of the study and a member of the Karbstein lab.

    In additional experiments on human breast cancer cells, the researchers showed that CK1δ/CK1ε inhibitors no longer induce programmed cell death (“apoptosis”) and prevent cancer cells from growing when Ltv1 is removed.

    “This clearly establishes that the anti-proliferative potency of these inhibitors is in large part due to blocking ribosome assembly,” Karbstein said.

    In addition to Karbstein and Ghalei, other authors of the study, Hrr25/CK1d-Directed Release of Ltv1 From Pre-40S Ribosomes Is Necessary For Ribosome Assembly And Cell Growth (10.1083/jcb.201409056), are Joanne R. Doherty, Yoshihiko Noguchi and William R. Roush of TSRI; Franz X. Schaub and John L. Cleveland of The Moffitt Cancer and Research Institute; and M. Elizabeth Stroupe of Florida State University. See http://jcb.rupress.org/content/208/6/745.abstract

    The work was supported by the National Institutes of Health (grants R01-GM086451, CA154739, U54MH074404 and P30-CA076292), the National Science Foundation (grant 1149763), the ThinkPink Kids Foundation, the PGA National Women’s Cancer Awareness Days and the Swiss National Foundation (P300P3-147907).

    See the full article here.

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    The Scripps Research Institute (TSRI), one of the world’s largest, private, non-profit research organizations, stands at the forefront of basic biomedical science, a vital segment of medical research that seeks to comprehend the most fundamental processes of life. Over the last decades, the institute has established a lengthy track record of major contributions to the betterment of health and the human condition.

    The institute — which is located on campuses in La Jolla, California, and Jupiter, Florida — has become internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune diseases, cardiovascular diseases, virology, and synthetic vaccine development. Particularly significant is the institute’s study of the basic structure and design of biological molecules; in this arena TSRI is among a handful of the world’s leading centers.

    The institute’s educational programs are also first rate. TSRI’s Graduate Program is consistently ranked among the best in the nation in its fields of biology and chemistry.

     
  • richardmitnick 1:30 pm on March 20, 2015 Permalink | Reply
    Tags: , , Scripps Institute   

    From Scripps: “New Compound Prevents Type 1 Diabetes in Animal Models—Before It Begins” 

    Scripps

    Scripps Research Institute

    March 23, 2015
    Eric Sauter

    Scientists from the Florida campus of The Scripps Research Institute (TSRI) have successfully tested a potent synthetic compound that prevents type 1 diabetes in animal models of the disease.

    “The animals in our study never developed high blood sugar indicative of diabetes, and beta cell damage was significantly reduced compared to animals that hadn’t been treated with our compound,” said Laura Solt, a TSRI biologist who was the lead author of the study.

    Type 1 diabetes is a consequence of the autoimmune destruction of insulin-producing beta cells in the pancreas. While standard treatment for the disease aims to replace lost insulin, the new study focuses instead on the possibility of preventing the initial devastation caused by the immune system—stopping the disease before it even gets started.

    In the study, published in the March 2015 issue of the journal Endocrinology, the scientists tested an experimental compound known as SR1001 in non-obese diabetic animal models. The compound targets a pair of “nuclear receptors” (RORα and RORg) that play critical roles in the development of a specific population (Th17) of immune cells associated with the disease.

    “Because Th17 cells have been linked to a number of autoimmune diseases, including multiple sclerosis, we thought our compound might inhibit Th17 cells in type 1 diabetes and possibly interfere with disease progression,” said Solt. “We were right.”

    The researchers found SR1001 eliminated the incidence of diabetes and minimized insulitis, which is the inflammation associated with, and destroyer of, insulin-producing cells, in the treated animals. The compound suppressed the immune response, including the production of Th17 cells, while maintaining normal insulin levels; it also increased the frequency of the expression of Foxp3 in T cells, which controls the development and function of a type of immune cell known as T regulatory cells.

    Solt notes that the study strongly suggests that Th17 cells have a pathological role in the development of type 1 diabetes and use of ROR-specific synthetic compounds targeting this cell type may have potential as a preventative therapy for type 1 diabetes. “It certainly opens the door for other areas to be looked at,” she said.

    Other authors of the study, ROR Inverse Agonist Suppresses Insulitis and Prevents Hyperglycemia in a Mouse Model of Type 1 Diabetes, include Subhashis Banerjee, Sean Campbell and Theodore M. Kamenecka of TSRI, and Thomas Burris of Saint Louis University School of Medicine. For more information on the study, see http://press.endocrine.org/doi/pdf/10.1210/en.2014-1677

    This work was supported by National Institutes of Health (grants DK080201, MH092769 and DK089984) and a National Research Service Award (DK088499).

    See the full article here.

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    The Scripps Research Institute (TSRI), one of the world’s largest, private, non-profit research organizations, stands at the forefront of basic biomedical science, a vital segment of medical research that seeks to comprehend the most fundamental processes of life. Over the last decades, the institute has established a lengthy track record of major contributions to the betterment of health and the human condition.

    The institute — which is located on campuses in La Jolla, California, and Jupiter, Florida — has become internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune diseases, cardiovascular diseases, virology, and synthetic vaccine development. Particularly significant is the institute’s study of the basic structure and design of biological molecules; in this arena TSRI is among a handful of the world’s leading centers.

    The institute’s educational programs are also first rate. TSRI’s Graduate Program is consistently ranked among the best in the nation in its fields of biology and chemistry.

     
  • richardmitnick 5:57 am on March 10, 2015 Permalink | Reply
    Tags: , , , , Scripps Institute   

    From Scripps: “TSRI Scientists Reveal Structural Secrets of Nature’s Little Locomotive” 

    Scripps

    Scripps Research Institute

    March 9, 2015
    No Writer Credit

    Findings Could Help Shed Light on Alzheimer’s, Parkinson’s, ALS and Other Diseases

    A team led by scientists at The Scripps Research Institute (TSRI) has determined the basic structural organization of a molecular motor that hauls cargoes and performs other critical functions within cells.

    1
    The new research provides the first picture of a molecular motor called the “dynein-dynactin complex,” which is critical for cell division and cargo transport. (Image courtesy of the Lander lab, The Scripps Research Institute.)

    Biologists have long wanted to know how this molecular motor—called the “dynein-dynactin complex”—works. But the complex’s large size, myriad subunits and high flexibility have until now restricted structural studies to small pieces of the whole.

    In the new research, however, TSRI biologist Gabriel C. Lander and his laboratory, in collaboration with Trina A. Schroer and her group at Johns Hopkins University, created a picture of the whole dynein-dynactin structure.

    “This work gives us critical insights into the regulation of the dynein motor and establishes a structural framework for understanding why defects in this system have been linked to diseases such as Huntington’s, Parkinson’s, and Alzheimer’s,” said Lander.

    The findings are reported in a Nature Structural & Molecular Biology advance online publication on March 9, 2015.

    Unprecedented Detail

    The proteins dynein and dynactin normally work together on microtubules for cellular activities such as cell division and intracellular transport of critical cargo such as mitochondria and mRNA. The complex also plays a key role in neuronal development and repair, and problems with the dynein-dynactin motor system have been found in brain diseases including Alzheimer’s, Parkinson’s and Huntington’s diseases, and amyotrophic lateral sclerosis (ALS). In addition, some viruses (including herpes, rabies and HIV) appear to hijack the dynein-dynactin transport system to get deep inside cells.

    “Understanding how dynein and dynactin interact and work, and how they actually look, is definitely going to have medical relevance,” said Research Associate Saikat Chowdhury, a member of the Lander lab who was first author of the study.

    To study the dynein-dynactin complex, Schroer’s laboratory first produced individual dynein and dynactin proteins, which are themselves complicated, with multiple subunits, but have been so highly conserved by evolution that they are found in almost identical form in organisms from yeast to mammals.

    Chowdhury and Lander then used electron microscopy (EM) and cutting-edge image-processing techniques to develop two-dimensional “snapshots” of dynein’s and dynactin’s basic structures. These structural data contained unprecedented detail and revealed subunits never observed before.

    Chowdhury and Lander next developed a novel strategy to purify and image dynein and dynactin in complex together on a microtubule—a railway-like structure, ubiquitous in cells, along which dynein-dynactin moves its cargoes.

    “This is the first snapshot of how the whole dynein-dynactin complex looks and how it is oriented on the microtubule,” Chowdhury said.

    Pushing the Limits

    The structural data clarify how dynein and dynactin fit together on a microtubule, how they recruit cargoes and how they manage to move those cargoes consistently in a single direction.

    Lander and Chowdhury now hope to build on the findings by producing a higher-resolution, three-dimensional image of the dynein-dynactin-microtubule complex, using an EM-related technique called electron tomography.

    “The EM facility at TSRI is the best place in the world to push the limits of imaging complicated molecular machines like these,” said Lander.

    The other co-author of the paper, Structural organization of the dynein–dynactin complex bound to microtubules, (doi:10.1038/nsmb.2996) was Stephanie A. Ketcham of the Schroer laboratory.

    The research was supported by the Damon Runyon Cancer Research Foundation (DFS-#07-13), the Pew Scholars program, the Searle Scholars program and the National Institutes of Health (DP2 EB020402-01, GM44589).

    See the full article here.

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    The Scripps Research Institute (TSRI), one of the world’s largest, private, non-profit research organizations, stands at the forefront of basic biomedical science, a vital segment of medical research that seeks to comprehend the most fundamental processes of life. Over the last decades, the institute has established a lengthy track record of major contributions to the betterment of health and the human condition.

    The institute — which is located on campuses in La Jolla, California, and Jupiter, Florida — has become internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune diseases, cardiovascular diseases, virology, and synthetic vaccine development. Particularly significant is the institute’s study of the basic structure and design of biological molecules; in this arena TSRI is among a handful of the world’s leading centers.

    The institute’s educational programs are also first rate. TSRI’s Graduate Program is consistently ranked among the best in the nation in its fields of biology and chemistry.

     
  • richardmitnick 12:26 pm on July 14, 2014 Permalink | Reply
    Tags: , , , , Scripps Institute,   

    FROM WCG: “Better tools for AIDS drug research” 

    FAAH
    FightAIDS@home

    FightAIDS@Home is a project run by the Olson Laboratory that uses distributed computing to contribute your computer’s idle resources to accelerate research into new drug therapies for HIV, the virus that causes AIDS. FightAIDS@Home made history in September 2000 when it became the first biomedical Internet-based grid computing project. FightAIDS@Home was started with Scott Kurowski, founder of Entropia. People all around the World continue to donate their home computer’s idle cycles to running our AutoDock software on HIV-1 protease inhibitor docking problems. With the generous assistance of IBM, we joined World Community Grid in late 2005, and launched FightAIDS@Home on World Community Grid on 21 November, 2005.

    How do I join the FightAIDS@Home Project?

    All you need to do is download and install the free client software. Once you have done this, your computer is then automatically put to work and you can continue using your computer as usual.


    ScienceSprings is powered by MAINGEAR computers

    24 Jun 2014

    Summary
    The Scripps research team published a paper proving the effectiveness of a method to more accurately predict bindings between protein targets and drug candidates, which could benefit FightAIDS@Home and other World Community Grid drug discovery projects.

    Paper Title:

    “Virtual screening with AutoDock Vina and the common pharmacophore engine of a low diversity library of fragments and hits against the three allosteric sites of HIV integrase: participation in the SAMPL4 protein–ligand binding challenge”

    Lay Person Abstract:

    The Olson Lab at The Scripps Institute collaborated to participate in the “SAMPL4 Challenge” which evaluated methods to predict protein target to drug candidate bindings. Olson’s lab in cooperation with Levy’s lab at Rutgers University were able to prove the utility of a method to reduce false positives and therefore potentially reduce the amount of laboratory work required to validate computational results. This should ultimately be a benefit to research projects such as FightAIDS@Home and other drug search projects on World Community Grid.

    A link to the paper is here.
    See the full article here.

    World Community Grid (WCG) brings people together from across the globe to create the largest non-profit computing grid benefiting humanity. It does this by pooling surplus computer processing power. We believe that innovation combined with visionary scientific research and large-scale volunteerism can help make the planet smarter. Our success depends on like-minded individuals – like you.”

    WCG projects run on BOINC software from UC Berkeley.

    BOINC is a leader in the field(s) of Distributed Computing, Grid Computing and Citizen Cyberscience.BOINC is more properly the Berkeley Open Infrastructure for Network Computing.

    CAN ONE PERSON MAKE A DIFFERENCE? YOU BETCHA!!

    “Download and install secure, free software that captures your computer’s spare power when it is on, but idle. You will then be a World Community Grid volunteer. It’s that simple!” You can download the software at either WCG or BOINC.

    Please visit the project pages-

    Say No to Schistosoma
    sch

    GO Fight Against Malaria
    mal

    Drug Search for Leishmaniasis
    lish

    Computing for Clean Water
    c4cw

    The Clean Energy Project
    cep2

    Discovering Dengue Drugs – Together
    dengue

    Help Cure Muscular Dystrophy
    md

    Help Fight Childhood Cancer
    hccf

    Help Conquer Cancer
    hcc

    Human Proteome Folding
    hpf

    FightAIDS@Home
    faah

    Computing for Sustainable Water

    Computing for Sustainable Water

    World Community Grid is a social initiative of IBM Corporation
    IBM Corporation
    ibm

    IBM – Smarter Planet
    sp


    ScienceSprings is powered by MAINGEAR computers

     
  • richardmitnick 4:34 pm on November 5, 2011 Permalink | Reply
    Tags: , , , , Scripps Institute,   

    FightAIDS@Home, A Public Distributed Project at WCG 

    “HIV, the virus that causes AIDS, infects over 30 million people throughout the world, and approximately 2 million new people are infected each year. HIV kills more people than any other virus on Earth. Even if/when we can eventually prevent new HIV infections, we will still need to discover new drugs that can treat the millions of people who are currently living with an HIVinfection. The need to discover new types of drugs against HIV is especially urgent, since new multi-drug-resistant mutant “superbugs” of HIV are constantly evolving and spreading throughout humanity. In addition, other scientists have recently shown that treating HIV with effective drugs also helps decrease the probability of spreading the infection to new people. When effective drugs are given to a particular patient, the number of infectious viral particles in that patient (or the “viral load”) decreases, which lowers the probability of them infecting other people. It doesn!t eliminate the possibility of spreading the infection, but it does reduce the probability.

    The FightAIDS@Home Project uses the volunteered computer power of IBM!s World CommunityGrid to test candidate compounds against the variations (or “mutants”) of HIV that can arise and cause drug resistance. We test these candidates by docking flexible models of them against 3-D, atomic-scale models of different drug targets from HIV, to predict (a) how tightly these compounds might be able to bind, (b) where these compounds prefer to bind on the protein target, and (c) what
    specific interactions are formed between the candidate and the target. That is, we use these calculations to predict the affinity/potency of the compound, the location where it binds on the molecular target, and the mode it uses to potentially disable the target. Compounds that can bind
    tightly to the right regions of particular proteins from HIV have the potential to “gum up” the viralmachinery and, thus, help advance the discovery of new types of drugs to treat HIV infections.”

    You could help in the vital work of this Public Distributed Computing project and other projects in Cancer, Dengue Fever, Clean Water, Clean Energy, and Leishmaniasis. Visit the WCG web site, download and install the BOINC software on which the projects run. Then, read about the projects and attach to those of interest.

    See the full article here.

     
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