Multiple Sclerosis Scientific Molecular Map

The molecular structure, described in the February 17, 2012 issue of the journal Science, is unique as the first-ever-to-be-determined lipid G protein-coupled receptor (GPCR). Molecules of this type play important roles in everything from cancer to metabolism, and this recent success should pave the way for researchers to establish the structures of other family members.
“There’s something special about the S1P1 receptor,” said Hugh Rosen, MD, PhD, a Scripps Research chemical biologist who co-led the work with Raymond Stevens, PhD, a structural biologist also from The Scripps Research Institute. “The biological consequences of even small changes with this receptor are profound. Understanding its structure provides clues about fundamental processes important in both health and disease.”
“Being able to finally look at a lipid GPCR and the occluded cell surface binding pocket was a surprise but explains many of the issues we wondered about,” said Stevens. “It is likely that other members of this subfamily will have a similar protein architecture.”
The study is a result of decades of research by the Stevens lab to develop methods to determine the structure of GPCRs, much work in the Rosen lab on the receptor biology and chemical tools to stabilize such molecules, and a multi-disciplinary collaboration between the two labs, which Rosen notes is one of the hallmarks of research at The Scripps Research Institute. The scientists acknowledge the support of the National Institutes of Health Common Fund as making the new findings possible.
“This work promises to underscore the importance of research collaboration to accelerate scientific discovery and development of new drug therapies,” said James M. Anderson, MD, PhD, director of the Division of Program Coordination, Planning, and Strategic Initiatives that guides the NIH Common Fund. “Combining structure-based analysis with small molecule screening serves as a model for effective drug design.”
Controlling Multiple Sclerosis

The new work reveals the structure of the S1P1 receptor, a protein embedded in the membranes of various cell types. When natural ligands such as the signaling lipid sphingosine 1-phosphate or potential drugs make specific interactions deep in receptor, portions of the receptor change shape to trigger cascades of chemical reactions inside the cell important to the maintenance of health.
Researchers have long known that S1P1 receptors play critical roles in controlling multiple sclerosis and other diseases. One way these receptors do this is by regulating the flow of certain white blood cells, or lymphocytes, out of lymph nodes.

This is critical because in patients with multiple sclerosis, auto-reactive lymphocytes attack the protective sheaths of nerve cells in the brain, causing malfunctions in the way the central nervous system transmits signals through the body. The S1P1 receptors are also involved in the progressions of harmful scarring and swelling in response to lymphocyte damages in the brain.
Gilenya, the first oral drug approved to treat multiple sclerosis, reduces this lymphocyte flow out of the lymph nodes in ways first identified by Rosen’s lab about 10 years ago. Based on a screening lead from the National Institutes of Health Molecular Libraries Small Molecule Repository, Rosen and Scripps Research Chemistry Professor Ed Roberts discovered and optimized other modulators of S1P1 receptors. This led to RPC-1063, a compound in clinical trials for multiple sclerosis by Receptos, a company co-founded by Rosen and Stevens.
Rosen’s lab has also shown that modulating S1P1 receptors can protect mice from a pandemic flu virus. This shows that the receptors may also be good drug development targets for other conditions tied to immune responses.
A Shifting Binding Pocket
The new study used the technique of x-ray crystallography to reveal the high-resolution three-dimensional image of the S1P1 receptor. The results provide scientists with important new details about the receptor’s mechanism of action.
One aspect of the receptor structure that is of particular interest is the binding pocket for the natural ligand or potential drugs that activate the receptor responses. The structure revealed how the binding pocket shifts to activate signaling. Understanding how that occurs makes it easier to identify additional compounds that might have effects in controlling the receptors.
With this structural information in hand, the scientists can now advance efforts to understand the specific chemical transformations that drive the cellular responses tied to multiple sclerosis and other diseases. “Better understanding always allows you to think about applications in a variety of ways that you might not have thought about before,” said Rosen. “This is an area that will keep us busy for many years to come.”
The S1P1 receptor structure has already yielded benefits, according to Michael Hanson, a scientist and director at Receptos, and lead author of the new paper. “The structure has helped us understand the details regarding receptor-ligand interactions for this receptor and structural data can be used more routinely for drug discovery projects of other GPCRs,” he said.

From: http://ping.fm/dGq3z

San Francisco Schools 450 Job Cuts

Image by Getty Images via @daylife

Facing another year of funding cuts, the Board of Education will vote tonight on whether to issue preliminary layoff notices to 450 teachers, administrators and staff.

The board is legally obligated to notify employees of potential layoffs by March 15. In previous years, the majority of layoffs were rescinded by the time the board voted on a final budget.

School officials were hoping to reduce the tally of layoffs this year with help from The City’s rainy-day fund. But while the district could expect as much as $24 million a few years ago, in recent years that fund has been depleted.
Last year, the district also used $9.5 million in federal stimulus money to help prevent layoffs, but that money was a one-time grant.

Also tonight, the board will vote on the rules by which teachers will be laid off. While the district is required to base layoffs on seniority, it will attempt to protect the jobs of math and science teachers, teachers who are bilingual and those who focus on special education.

From: http://ping.fm/E6ox6

Researchers Gather for Shared Resources Fair and Drug Discovery Forum | Miller School of Medicine | University of Miami

The Miller Office of Research hosted two events this month at the Miller School for the research community – a Shared Resources Fair on the morning of February 17, and a Collaborative Research Exchange Forum (CREF) on drug discovery in the afternoon.

More than 200 researchers attended the third Shared Resources Fair, which featured nearly 50 posters with information about the varied core laboratories, facilities, and shared resources supporting discovery science, translational, and clinical research. Later, more than 50 faculty, staff, and students gathered at the Lois Pope LIFE Center for the forum to share information on drug discovery.

Led by Norma Sue Kenyon, Ph.D., the Martin Kleiman Professor of Surgery, Microbiology and Immunology, and Biomedical Engineering and senior associate dean for translational science, and Andrew Vinard, manager of biotechnology resources, the Core and Shared Facilities Office within the Miller Office of Research supports research excellence at the University. The fair was co-hosted by the Sylvester Comprehensive Cancer Center and the Wallace H. Coulter Center for Translational Research. Kenyon said events such as the Shared Resources Fair and the CREF reflect the University’s continuing support of its research community.

“The Miller School is committed to developing state-of-the art facilities, encouraging their use, and advancing scientific collaboration in areas of key importance to biomedical research,” said Kenyon, who is also director of the Coulter Center.

Claes Wahlestedt, M.D., Ph.D., professor of psychiatry and behavioral sciences and associate dean for therapeutic innovation, who led the drug discovery forum, added that topics like drug discovery especially benefit from an interdisciplinary team science approach.

“The Miller School has the expertise and laboratory resources needed to identify compounds that can be developed into the next generation of therapeutics,” Wahlestedt said

The CREF began with presentations and a panel discussion on:

• Chemoinformatics and drug discovery by Stephan Schürer, Ph.D., research assistant professor of molecular and cellular pharmacology and the Center for Computational Science’s lead scientist for chemoinformatics;

• Molecular oncology and drug discovery by Anthony Capobianco, Ph.D., professor of surgery and director of the Molecular Oncology Research Program, Division of Surgical Oncology;

• Cell biology and drug discovery by Glen Barber, Ph.D., chair of cell biology and anatomy, professor of medicine, and associate director of basic research at Sylvester.

Additional presentations and another panel discussion followed on these projects:

• Drug discovery at The Miami Project to Cure Paralysis by Vance Lemmon, Ph.D., the Walter G. Ross Distinguished Chair in Developmental Neuroscience and professor of neurological surgery;

• Peggy and Harold Katz Family Drug Discovery Center by Vineet Gupta, Ph.D., assistant professor of medicine, biochemistry and molecular biology, and the founding co-director of the Katz Center;

• Center for Therapeutic Innovation by Nagi Ayad, Ph.D., associate professor of psychiatry and behavioral sciences; and Shaun Brothers, Ph.D., research assistant professor of psychiatry and behavioral sciences.

From: http://ping.fm/TfYiU

Jackson Health System 1,115 Layoffs

Image by Getty Images via @daylife

Jackson Health System’s CEO announced Tuesday that his organization is laying off 920 staffers and eliminating another 195 vacant positions to give the organization the “rock-solid foundation” it needs as he right-sizes it.

Carlos Migoya said Jackson will also create about 350 new part-time jobs so it still maintains “the proper staffing levels to provide excellent medical care and customer service for our patients.”

In all the moves will save Jackson about $69 million per year, including about $55 million in benefits, Migoya estimated.

The changes are needed so Jackson can cement its foundation and then work toward “robust and sustained growth,” said Migoya, who previewed Tuesday’s layoffs at the start of this month.

Patient admissions have dropped recently at Jackson Health System, which includes six hospitals.

JHS administrators said Feb. 7 that a new three-year contract had been reached with employees represented by Service Employees International Union Local 1991 that could include up to $150 million in salary and benefit concessions, an agreement intended to help the organization “move beyond its current year-to-year survival mode.”

The president of SEIU Local 1991, Martha Baker, slammed Migoya for the “massive layoffs” in a statement Tuesday evening.

“This is what you get when you hire a billionaire banker and then cut him loose to take a chainsaw to healthcare in Miami-Dade County,” said Baker, who is a registered nurse. “It’s unbelievable that he wouldn’t consult the nurses, doctors and healthcare professionals – who have sacrificed out of their pockets to keep Jackson afloat – about how his plan to ‘right-size’ the system might harm patient care. We have no idea how Mr. Migoya thinks patient care can be maintained with such drastic cuts to frontline caregivers.”

Migoya said in a letter to members of Jackson’s Financial Recovery Board Tuesday that Jackson will have cut spending by a total of about $91 million per year, counting the new reductions and other “staffing initiatives” rolled out since last June.

“These actions will be painful for many people, including those whose positions are eliminated and those who will be working even harder to care for this great system and its patients,” Migoya wrote.

From: http://ping.fm/K6VMk

American Axle Cuts 300 Jobs

American Axle & Manufacturing Inc. has laid off 300 blue-collar workers from its manufacturing complex at I-75 and Holbrook along the Detroit–Hamtramck border.

The workers were idled Feb. 25 when the American Axle’s labor agreement with the United Auto Workers ran out. Negotiations between the company and union have stalled and the workers were left without any kind of severance package, according to former UAW official familiar with the discussions.

American Axle had announced last summer it planned to close the complex, which in the late 1970s employed as many as 8,000 workers. The company’s headquarters is still on the site but the layoffs mean no more blue-collar work is done inside the Holbrook complex.

AAM will continue to operate two smaller plants in Michigan, including one in Oxford.

In the future, however, AAM plans to depend on plants in Mexico to make components for vehicles built by customers.

The union blamed the shutdown on AAM’s unwillingness to negotiate a fair labor agreement.

“This is an indication that hard-working people are sick of constantly helping companies through concessions and back to profitability and companies refusing to share in that,” said UAW Vice President Cindy Estrada, who directs the union’s American Axle Department said last summer.

“Here is a business that started out as an American company providing good-paying jobs to 6,000 employees. As a result of the hard work of these employees, it has grown to an international company with 32 factories worldwide,” said Estrada. “All of this success was achieved off the backs of the original 6,000 hard-working Americans.”

However, American Axle has said it needs further labor concessions, including reducing the pay of active workers, to remain competitive in what has become a global market. Work done at the complex is being shifted to Mexico.

In addition, shifts in the market have reduced the demand for the axles and other heavy-duty automotive components made the company, which was spun off by General Motors Corp. in the early 1990s. GM remains AAM’s largest customer, Richard Dauch, the company’s chairman and founder, succeeded in keeping the company out of bankruptcy during the auto crisis of 2008 and 2009 and has indicated a willingness to put more work in the complex, but only if the UAW makes concessions.

From: http://ping.fm/i1kXO