Protein a Possible Key to Allergy and Asthma Control

Description

Activating a protein found on some immune cells seems to halt the cells’ typical job of spewing out substances that launch allergic reactions, a study by Johns Hopkins researchers suggests. The findings could eventually lead to new treatments for allergic reactions ranging from annoying bouts of hay fever to deadly asthma attacks.




Activating a protein found on some immune cells seems to halt the cells’ typical job of spewing out substances that launch allergic reactions, a study by Johns Hopkins researchers suggests. The findings could eventually lead to new treatments for allergic reactions ranging from annoying bouts of hay fever to deadly asthma attacks.

Previous studies by Bruce Bochner and his colleagues at the Johns Hopkins Asthma and Allergy Center had zeroed in on the protein, Siglec-8, as an important player in allergic reactions. This protein is found on the surfaces of some types of immune cells, namely eosinophils, basophils and mast cells, which have diverse but cooperative roles in normal immune function and allergic diseases. Eosinophils directly combat foreign invaders, such as parasites. Basophils and mast cells store and release substances such as histamine, prostaglandins and cytokines, which signal other immune system cells to ready for battle.

When functioning correctly, these cells are a valuable aid to keeping the body healthy and infection-free. However, in allergic reactions and asthma attacks, the cells unleash an overwhelming response that typically harms the body more than it helps.

The researchers found in previous studies that when they activated Siglec-8 on the surface of eosinophils, the cells promptly died. Expecting the same suicidal response in mast cells, the scientists tested their theory in a new study on human mast cells and mast-cell-containing tissues.

Using mast cells grown in a lab, the researchers used antibodies to activate Siglec-8. “We were surprised to see that these cells just sat there happily in their petri dishes and lived on,” says Bochner, director of the Division of Allergy and Clinical Immunology at the Johns Hopkins University School of Medicine.

With their initial theory disproven, Bochner and his colleagues suspected that Siglec-8 might be slowing down other cellular processes based on the protein’s distinctive structure. To investigate what else Siglec-8 might inhibit, the scientists activated the protein in mast cells once again with antibodies. Then, they attempted to trigger an allergic response from these cells.

Normally, mast cells respond with an outpouring of histamine, prostaglandins and other substances that spur allergic reactions in other cells. However, Bochner and his colleagues found that cells with activated Siglec-8 released less than half the typical amount of these substances.

Extending their experiment from cells to whole tissues, Bochner and his colleagues used antibodies to activate mast cells’ Siglec-8 in small pieces of human lung saved from autopsies. When the researchers triggered the cells to release their payloads-an act that typically causes airways to sharply constrict-the contractions were about 25 percent weaker than in lung tissue where the mast cells’ Siglec-8 wasn’t activated.

The researchers are still unsure exactly how Siglec-8 inhibits mast cells from releasing their immune-triggering chemicals. However, follow-up experiments suggested that activating the protein keeps calcium from moving efficiently into the cells. Mast cells need this calcium signal to release their contents.

Bochner notes that researchers might eventually use these results, published in the February Journal of Allergy and Clinical Immunology, to develop a drug with this same effect. Such a drug would have the dual effect of blocking or reducing allergic reactions by killing eosinophils and preventing mast cells from releasing their substances.

“Both of these effects could make allergic diseases and asthma less severe,” he says. “It’s an intriguing approach because there are no drugs that specifically target both these cell types.”

Though drugs exist that affect either eosinophils or mast cells, Bochner says developing a single drug that takes aim at both types of cells could be even more effective than existing therapies and may also have a reduced risk of side effects. He and his colleagues are also searching for natural molecules in the body that activate Siglec-8, which could bring researchers a step closer to developing pharmaceuticals that target this protein.

Additional Hopkins researchers who contributed to this paper include Hidenori Yokoi, M.D., Oksoon H. Choi, Ph.D., Walter Hubbard, Ph.D., Hyun-Sil Lee, Ph.D., Brendan J. Canning, Ph.D., Hyun H. Lee, M.D., Seung-Duk Ryu, Ph.D., Stephan von Gunten, Ph.D., Carol A. Bickel, M.S., Sherry A. Hudson, M.S.B., and Donald W. MacGlashan Jr., M.D., Ph.D.
(Newswise)

Fellowships offer


The Centre for Science and Technology of the Non-Aligned and Other Developing Countries is offering three Fellowship schemes aimed at supporting deserving young scientists and researchers in developing countries. Applications are invited for the year 2008.


In line with its resolute efforts to promote the South-South and North-South cooperation in science and technology, the Centre for Science and Technology of the Non-Aligned and Other Developing Countries (NAM S&T Centre; www.namstct.org) is currently executing the below-mentioned three Fellowship schemes that aim at supporting the deserving young scientists and researchers in the developing countries to upgrade their academic and research skills and invites applications from suitable candidates for the year 2008.

We request you to please forward / disseminate this information to your concerned scientist colleagues and also, if possible, display the same on your Notice Board.

I. Joint NAM S&T Centre – ZMT Bremen (Germany) Fellowship in Ecology and Biogeochemistry of Tropical Coastal Marine Systems

This is a new Fellowship scheme being started from January 2008 for affiliation of the scientists from the developing countries for a period of up to 3 months with the Centre for Tropical Marine Ecology (ZMT), Bremen, Germany [www.zmt-bremen.de] to work with its senior researchers and faculty members for upgrading research skills in the fields related to Ecology and Biogeochemistry of Tropical Coastal Marine Systems and undertaking short-term joint research projects. Depending on the research topic, the Fellows can also benefit from the ZMT’s association with the Marine Science Institute of Bremen University, Max Plank Institute for Marine Microbiology and the MARUM Research Center in Bremen. Under this scheme, the NAM S&T Centre sponsors up to five scientists in a given calendar year, one scientist only from any developing country, and covers the international airfare of the Fellows from its member countries. Applications from non-member developing countries are also welcome subject to certain conditions. ZMT provides a subsistence monthly allowance of 1000 Euros for accommodation and other expenses in Bremen. Selection is strictly on competitive basis based on the applicant’s academic and professional background, the plan of work and mutual research interests of the applicant and ZMT. Applications recommended by the parent institutions of the applicants may be submitted to the NAM S&T Centre by email and its attachments in the relevant format available at the Centre’s Website www.namstct.org, which also gives the detailed guidelines for the Fellowship. There is no last date for submitting the application, which will be considered on first-come-first basis depending upon the availability of the seats.


II. Joint NAM S&T Centre - ICCBS (Karachi, Pakistan) Fellowship in Natural Products Chemistry, Drugs and Pharmaceuticals

This Fellowship is available for affiliation of the scientists from the developing countries for a period of up to 3 months with the International Centre for Chemical and Biological Sciences (ICCBS) of the H.E.J. Research Institute of Chemistry and Dr. Panjwani Center for Molecular Medicine and Drug Research, Karachi, Pakistan [http://www.iccs.edu/] to work in the areas of Natural Products Chemistry, Herbal Medicines, Drugs, Pharmaceuticals and Neutraceuticals, Molecular Medicine, Drug Research, Clinical Research etc. in order to enhance their research skills, facilitate exchange of information and contacts and create a network between the scientists and researchers from Pakistan and other countries. Under this scheme, the NAM S&T Centre sponsors up to five scientists in a given year, one scientist only from any developing country, and covers the international airfare of the Fellows from its member countries. Applications from non-member developing countries are also welcome subject to certain conditions. The ICCBS provides free furnished accommodation and a monthly allowance of US$130 for meals and out of pocket expenses to the selected Fellows. The selection is strictly based on the professional details of the applicant, plan of work to be carried out and mutual research interests of the applicant and ICCBS. Applications recommended by the parent institutions of the applicants may be submitted to the NAM S&T Centre by email and its attachments in the relevant format available at the Centre’s Website www.namstct.org, which also gives the detailed guidelines for the Fellowship. Scientists from Pakistan are not eligible to apply for this Fellowship. There is no last date for submitting the application, which will be considered on first-come-first basis depending upon the availability of the seats.


III. NAM S&T Centre Research Fellowship in Any Scientific Field (for Scientists exclusively from the Member Countries of the NAM S&T Centre)

This Fellowship has been instituted by the NAM S&T Centre to facilitate the international travel of the scientists and researchers of its member countries to the scientific institutions located in another member country for capacity building, enhancing research skills, undertaking short-term joint scientific projects, delivering lectures and developing further linkages (not for attending workshops and conferences). All the 41 member countries of the NAM S&T Centre are listed at the Centre’s website www.namstct.org. Under this scheme, the Centre covers the expense on the international airfare of one scientist each from each of its member countries in any given year, subject to the host country providing free furnished accommodation, meals and/or a per diem allowance to the Fellow during the period of his/her affiliation with the institute(s). The selection is strictly based on the professional details of the applicant, the plan of work to be carried out and the mutual scientific and academic interests of the applicant and the host institution. A precondition for considering an application is that the applicant should first approach the host institution(s) to obtain their consent to accept him/her for working in the institution for a specified period with necessary facilities and for providing total hospitality for such period. Applications recommended by the parent institutions of the applicants may be submitted to the NAM S&T Centre by email and its attachments in the relevant format available at the Centre’s website, which also gives the detailed guidelines for the Fellowship. Up to 5 fellowships are available for award during the current year. There is no last date for submitting the application, which will be considered on first-come-first basis depending upon the availability of the seats.

For more information, please contact:
M. Bandyopadhyay
Senior Expert & Administrative Officer,
Centre for Science & Technology of Non-Aligned and Other Developing Countries
(NAM S&T Centre),
Core 6A, 2nd Floor,
India Habitat Centre, Lodhi Road,
NEW DELHI - 110 003 (INDIA)
Ph.:(+91)(11) 24645134/24644974 (O)
Fax: (+91)(11) 24644973
E-mail: namstct@gmail.com, namstct@vsnl.com

Announcement: International Conference on Biotechnology 2008

Event dates: Wednesday, 6th February 2008 09:00 AM to Friday, 8th February 2008 17:00PM

Location: Vellore, India



Vellore, India - This International Conference will be relevant and useful to the students and faculties to interact with International Scientists for their future studies and research activities.

The interaction among different sectors such as Universities, Research Institutions and Industries should help to disseminate state of the art knowledge in various fields and topics related to biotechnology. This should also serve as forum for young researchers to present their work and interact with more experienced experts in the field. This International Conference will be relevant and useful to the students and faculties to interact with International Scientists for their future studies and research activities.

The conference will encompass the following topics. However, these topics are not exclusive and papers can be submitted on current issues in allied areas in the field of Biotechnology.

Agricultural Biotechnology
Animal Biotechnology
Plant Biotechnology
Biomedical Engineering
Genetic Engineering
Microbiology & Microbial Technology
Bio-processing and Chemical Engineering
Nano-Biotechnology
Bioinformatics
Cell & Tissue Culture
Industrial & Environmental Biotechnology
Biodiversity and Bioethics
Bio-safety and Patenting

Contact Information:

School of Biotechnology
Chemical and Biomedical Engineering(SBCBE)
Vit University
Vellore-632 014
Tamilnadu
India

Email prasad@vit.ac.in

Cancer: Breast cancer goes NUMB


A protein called NUMB has a crucial role in keeping breast cancer at bay. New research shows how this protein acts to preserve the function of p53, another protein that is known to protect against cancer.

It is already known that many cases of breast cancer are characterized by the loss of the NUMB protein, which normally functions to help determine how different cell types develop. Now, researchers led by Pier Paolo Di Fiore describe how NUMB helps to stave off cancer by binding to p53 and a third protein, HDM2, which usually degrades p53 and prevents its cancer-busting activity.

By protecting p53 in this way, NUMB is itself acting as an anti-cancer protein, say the researchers, who made their discovery by studying a range of different cells in the test tube, including human breast cells. This is highlighted by the fact that cancers that feature abnormally low levels of NUMB tend to be particularly aggressive, they add.

CONTACT
Pier Paolo Di Fiore (The FIRC Institute for Molecular Oncology, Milan, Italy)
Tel: +39 02 5743 03257; E-mail: pierpaolo.difiore@ifom-ieo-campus.it

Tumour incidence: When three is better than two

People with Down’s syndrome seem to be less susceptible to cancers - an observation that may at least partly derive from their having an extra copy of the chromosome responsible for the syndrome, chromosome 21. This idea to the test in mouse models of Down’s syndrome and finds that the animals are indeed less likely to develop colon cancer.

Roger Reeves and colleagues pinpoint a gene, known as Ets2, on chromosome 21 that seems to confer protection in these mice. The authors explain their finding as a ‘dosage’ effect: having three copies of chromosome 21 instead of the normal two means that more Ets2 protein is produced. This came as a surprise, because Ets2 is generally thought to encourage tumours to grow.

The discovery could be exploited in developing a drug to promote cancer resistance, suggest the authors.

CONTACT
Roger Reeves (The Johns Hopkins University, Baltimore, MD, USA)
Tel: +1 410 955 6621; E-mail: rreeves@jhmi.edu

David Threadgill (University of North Carolina, Chapel Hill, NC, USA) N&V Author
Tel: +1 919 843 6472; E-mail: dwt@med.unc.edu

Carbon balance: Autumn warming boosts carbon loss

A warm spring in the Northern Hemisphere means that plants absorb more carbon as their growing season gets off to an early start, but what happens as autumn becomes steadily warmer as well? Not what you might expect, although a balmy autumn allows plants’ greenery to flourish for longer, carbon uptake tails off and instead escapes into the atmosphere as carbon dioxide.

Shilong Piao and colleagues found a trend over the past twenty years towards an earlier autumn-to-winter build-up of carbon dioxide in northern ecosystems, suggesting that the period of net carbon uptake is becoming shorter. They use satellite observations of vegetation greenery and biosphere modelling to explain this response to autumnal warming: although plants’ respiration (emitting carbon dioxide) and photosynthesis (storing carbon dioxide) are both stepped up, the former outstrips the latter to give a net loss of carbon.

What’s more, this loss may offset much of the increased uptake of carbon dioxide during spring. Eastern Asia and North America are both experiencing strong autumn warming, which may account for Eurasia’s larger carbon sink, suggest the authors.

CONTACT
Shilong Piao (Laboratoire des Sciences du Climat et de l'Environnement, CEA/CNRS, Paris, France)
Tel: +33 1 6908 3876; Tel: slpiao@lsce.ipsl.fr

John Miller (National Oceanic and Atmospheric Administration, Boulder, CO, USA) N&V Author
Tel: +1 303 497 7739; E-mail: john.b.miller@noaa.gov

Two Genes Are Important Key to Regulating Immune Response

Description

A research team at Weill Cornell Medical College in New York City has identified two genes that may be crucial to the production of an immune system cytokine called interleukin-10 (IL-10).




A research team at Weill Cornell Medical College in New York City has identified two genes that may be crucial to the production of an immune system cytokine called interleukin-10 (IL-10).

The discovery fills in an important "missing link" in a biochemical pathway that's long been tied to disorders ranging from lupus and Type 1 diabetes, to cancer and AIDS.

"IL-10 production has to be kept in a delicate balance for health," explains study senior researcher Dr. Xiaojing Ma, Professor of Immunology and Microbiology in the Departments of Microbiology and Immunology and Pediatrics at Weill Cornell. "Too much IL-10 can leave the body more vulnerable to killers such as viruses and cancer, and to certain antibody-driven autoimmune diseases such as lupus, while too little can lead to run-away inflammatory pathology. Therefore, a better understanding of IL-10 regulation moves us closer to understanding these illnesses and -- potentially -- how to better treat them," he says.

The findings are reported in this month's issue of Immunity (vol. 27).

Dr. Jianguo Liu, of Weill Cornell, and Dr. Elaine Y. Chung, formerly of Weill Cornell and now a post-doc at the University of Pennsylvania, were co-lead researchers on the study.

Every second, millions of the body's cells undergo naturally programmed cell death -- a process called apoptosis. In healthy individuals, these dying or dead cells are spotted and then quickly ingested and removed by immune system "scavenger" cells such as macrophages.

However, to prevent this type of clean-up from triggering a wider immune response, macrophages express the IL-10 cytokine in the presence of apoptotic cells.

IL-10 suppresses the activity of immune system T-cells that might otherwise run amuck, Dr. Ma explains.

"That can be a good thing, of course," he says. "But on the other hand, when immune system T-cell activity is weakened too much, that can help encourage AIDS in those infected with HIV. Also, excessive T-cell suppression can keep the immune system from destroying rogue cancer cells in people battling malignancy."

All of this means that "anything that we can learn about IL-10 production -- and related T-cell suppression -- is a boon to medical research," Dr. Ma explains.

Prior studies had already shown that CD36 -- a protein receptor lying on the surface of the macrophage -- was important for the recognition of apoptotic cells by macrophages. In this work, the researchers observed that CD36 also helped to trigger IL-10 production whenever apoptotic cells were around.

The team then asked a deeper question: "What signals lead to IL-10 production from CD36 present at the cell surface?"

To find out, the Weill Cornell group first exposed macrophages to apoptotic (dying) cells. They then used sensitive assays to look for key biochemical changes occurring downstream of CD36 activation.

"We found proteins in the cell nucleus that were binding to a site we knew was critical for the production of IL-10 as macrophages encountered apoptotic cells," Dr. Ma says. In subsequent biochemical experiments, the team identified the two genes responsible for the transcription (gene-directed production) of these proteins.

These genes -- pre-B transcription factor 1(Pbx-1) and Pbx-regulating protein 1 (Prep-1) -- are best known to scientists as partners for their role in embryonic development and several forms of leukemia, with Pbx playing a major part in hematopoeisis, the production of new and myriad blood cell types.

"In that sense, their presence as immune system transcription factors came as a big surprise to us," Dr. Ma says. "In fact, we still haven't figured out exactly how Pbx-1 and Prep-1 are involved in regulating IL-10 transcription. I really hope this study opens up new avenues for immunologists to find out whether there's a brand new biochemical pathway to be discovered."

The findings could also reveal exciting new information as to how aberrant IL-10 expression contributes to disease.

"Because IL-10 expression (and related T-cell suppression) are so important to the etiology of so many illnesses, discoveries like ours could point to molecular pathways that may become important new targets for drug discovery going forward," Dr. Ma explains. "It's these types of breakthroughs in the lab that -- step by step -- will end up bringing real hope to patients down the line."

This work was supported by the U.S. National Institutes of Health and the Mary Kirkland Foundation for Lupus Research.

Co-researchers include Dr. Yoichiro Homma, Yunhua Zhang, Dr. Andrea Brendolan, Dr. Matilde Saggese, Dr. Jihong Han and Dr. Licia Selleri -- all of Weill Cornell Medical College; and Dr. Roy Silverstein of the Cleveland Clinic Foundation.

Weill Cornell Medical College
Weill Cornell Medical College -- Cornell University's Medical School located in New York City -- is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Weill Cornell, which is a principal academic affiliate of NewYork-Presbyterian Hospital, offers an innovative curriculum that integrates the teaching of basic and clinical sciences, problem-based learning, office-based preceptorships, and primary care and doctoring courses. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research in such areas as stem cells, genetics and gene therapy, geriatrics, neuroscience, structural biology, cardiovascular medicine, infectious disease, obesity, cancer, psychiatry and public health -- and continue to delve ever deeper into the molecular basis of disease in an effort to unlock the mysteries behind the human body and the malfunctions that result in serious medical disorders. The Medical College -- in its commitment to global health and education -- has a strong presence in such places as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. With the historic Weill Cornell Medical College in Qatar, the Medical School is the first in the U.S. to offer its M.D. degree overseas. Weill Cornell is the birthplace of many medical advances -- from the development of the Pap test for cervical cancer to the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial for gene therapy for Parkinson's disease, the first indication of bone marrow's critical role in tumor growth, and, most recently, the world's first successful use of deep brain stimulation to treat a minimally-conscious brain-injured patient. (Newswise)

Image: Courtesy of Dr. Gray Pearson, Salk Institute for Biological Studies
The colored lines track selected cells over a time period of 12 hours in a tissue culture model that recreates the ducts of the mammary gland.


Breast Cancer Cells Have to Learn to Walk Before They Can Run


Description

Early-stage breast cancer that has not yet invaded the surrounding tissues may already contain highly motile cells, bringing the tumor one step closer to metastasis, report researchers at the Salk Institute for Biological Studies.







Early-stage breast cancer that has not yet invaded the surrounding tissues may already contain highly motile cells, bringing the tumor one step closer to metastasis, report researchers at the Salk Institute for Biological Studies.

Their study, published in the Dec. 30 issue of the Journal of Cell Biology, suggests that these cells, although not yet invasive, could wander off along milk ducts and seed new tumors within the same breast. “A lack of invasion suggested a lack of motility,” says lead author Gray Pearson, Ph.D, a postdoctoral researcher in the Molecular and Cell Biology Laboratory at the Salk, “but that’s not so.”

“This is an exciting finding because it suggests that cells might acquire migratory properties much earlier than expected,” says senior author Tony Hunter, Ph.D., a professor in the Molecular and Cell Biology Laboratory.

Due to improved screening programs, most breast tumors are discovered at an early stage when they are still small and confined. In such cases, cancer cells have not grown into the surrounding tissues and remain within the borders of a duct, the most common site where invasive breast cancer arises. These tumors are known as DCIS (ductal carcinoma in situ).

The standard treatment for DCIS is lumpectomy, the surgical removal of the tumor and surrounding tissue. Approximately 16% of DCIS patients treated with lumpectomy alone develop recurrent breast cancer growth within 5 years of treatment. One of the questions faced by oncologists and patients is whether they should add gamma radiation after undergoing surgery to catch straying tumor cells and reduce the risk of recurrent breast cancer. Currently, the decision is based solely on the size of the tumor.

“Our findings suggest that, if a DCIS contains these highly motile cells, the patient may have an increased risk for recurrent growth,” says Pearson. “Under these circumstances you would consider adding radiation treatment regardless of tumor size.”

While the presence of highly motile cells may guide treatment decisions in the future, the researchers have yet to show that wandering cells do indeed influence a patient’s outcome, cautions Pearson.

In their study, the Salk researchers used a tissue culture model that recreates the duct of the mammary gland. They embedded human cells, isolated from breast tissue, in a three-dimensional matrix that mimics their natural surroundings. These cells spontaneously develop into so called acini, hollow structures resembling tiny milk ducts.

Then they turned on the ERK1/2 MAP kinase pathway, a signaling cascade frequently activated during the development of tumors, and watched in real time as breast cancer cells learned how to walk. “We quickly realized that there was a significant cell movement, which was quite surprising,” recounts Pearson. “Within 24 hours, a large number of these spheres had lost their organization, and the cells started to dance around.” (see movie)

While dangerously invasive cells can squeeze through the basement membrane and make a run for the surrounding tissue, motile cells still could not escape the confines of the ERK-activated acini. “But the acquisition of motility prior to invasion presumably lowers the barrier for future invasive growth,” explains Pearson.

“The advent of live-cell imaging allows us to watch labeled cells move around in tissues and learn a lot about their behavior, which wouldn’t be revealed in cultured cells,” says Hunter.

With the next step, Pearson hopes to identify molecular markers for breast cancer cell motility that will help oncologists to diagnose patients who are at higher risk of metastasis.

The Salk Institute for Biological Studies in La Jolla, California, is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and the training of future generations of researchers. Jonas Salk, M.D., whose polio vaccine all but eradicated the crippling disease poliomyelitis in 1955, opened the Institute in 1965 with a gift of land from the City of San Diego and the financial support of the March of Dimes.

Cancer Stem Cells: Know Thine Enemy

Description

Stem cells -- popularly known as a source of biological rejuvenation -- may play harmful roles in the body, specifically in the growth and spread of cancer. Amongst the wildly dividing cells of a tumor, scientists have located cancer stem cells. Physician-scientists from Weill Cornell Medical College are studying these cells with hopes of combating malignant cancers in the brain.






Stem cells -- popularly known as a source of biological rejuvenation -- may play harmful roles in the body, specifically in the growth and spread of cancer. Amongst the wildly dividing cells of a tumor, scientists have located cancer stem cells. Physician-scientists from Weill Cornell Medical College are studying these cells with hopes of combating malignant cancers in the brain.

"Some patients' brain tumors respond to chemotherapy and some don't," says Dr. John A. Boockvar, the Alvina and Willis Murphy Assistant Professor of Neurological Surgery and head of the Brain Tumor Research Group at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. "We believe cancer stem cells may be the cause."

Dr. Boockvar is capturing and classifying these cancer stem cells in order to determine how they react to certain available drug therapies. Doing so will lead to more accurate and specific cancer diagnosis, allowing for tailored drug treatments. Results explaining the techniques used to harvest normal neural and brain-tumor-derived stem cells will be described in the January 2008 edition of the journal Neurosurgery.

"Cataloging brain tumor stem cells will be an enormous tool for patient diagnosis," explains Dr. Boockvar, "but it will also help to create a library of knowledge for the scientific community to understand how brain tumors form and to test and develop new drugs."

To stave off cancer stem cell growth in the brain, Dr. Boockvar is studying the use of two drugs already available for cancer treatment. Tarceva -- approved for the treatment of lung and pancreatic cancer -- works by stopping the growth and spread of cancer cells. Avastin -- approved for the treatment of colorectal cancers -- is also being studied for inhibiting cancer cell growth and works by stopping the growth of blood vessels (angiogenesis) that feed the tumor.

Preliminary results from these trials have shown that some patients' cancers are wiped out, whereas others remain resistant. Dr. Boockvar believes that these patients' drug resistance might be due to a class of stem cells resilient to available treatments. Finding biomarkers that distinguish these stem cells from those that are destroyed by known drugs might help researchers formulate new drugs.

"Determining a patient's cancer stem cell profile will take a lot of the guessing out of choosing a course of treatment," says Dr. Boockvar. "It will save money, medical resources and precious time for the patient."

NewYork-Presbyterian Hospital/Weill Cornell Medical Center

NewYork-Presbyterian Hospital/Weill Cornell Medical Center, located in New York City, is one of the leading academic medical centers in the world, comprising the teaching hospital NewYork-Presbyterian and Weill Cornell Medical College, the medical school of Cornell University. NewYork-Presbyterian/Weill Cornell provides state-of-the-art inpatient, ambulatory and preventive care in all areas of medicine, and is committed to excellence in patient care, education, research and community service. Weill Cornell physician-scientists have been responsible for many medical advances -- from the development of the Pap test for cervical cancer to the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial for gene therapy for Parkinson's disease, the first indication of bone marrow's critical role in tumor growth, and, most recently, the world's first successful use of deep brain stimulation to treat a minimally-conscious brain-injured patient. NewYork-Presbyterian, which is ranked sixth on the U.S.News & World Report list of top hospitals, also comprises NewYork-Presbyterian Hospital/Columbia University Medical Center, Morgan Stanley Children's Hospital of NewYork-Presbyterian, NewYork-Presbyterian Hospital/Westchester Division and NewYork-Presbyterian Hospital/The Allen Pavilion. Weill Cornell Medical College is the first U.S. medical college to offer a medical degree oversees and maintains a strong global presence in Austria, Brazil, Haiti, Tanzania, Turkey and Qatar. For more information, visit www.nyp.org and www.med.cornell.edu. (Newswise)

Oral Anti-Diabetic Substance Discovered

Description

Research in the Department of Biology at the University of Haifa has discovered a substance that may become an oral treatment for diabetes and its complications. The substance, which is derived from yeast, is called Glucose Tolerance Factor (GTF).



Research in the Department of Biology at the Faculty of Science and Science Education of the University of Haifa has discovered a substance that may become an oral treatment for diabetes and its complications. The substance, which is derived from yeast, is called Glucose Tolerance Factor (GTF). "The research is now at the stage where the substance has been successfully tested on diabetic rats and was found to reduce sugar and lipids in the blood of the treated animals. The next stage of the research is to evaluate GTF efficacy in humans," said Dr. Nitsa Mirsky, who is conducting the research.

Diabetes is recognized as a major global health problem. Diabetes affects 5%-10% of the population in developed countries, while in developing countries the disease has been recently declared an "epidemic". Diabetics suffer from lack of insulin or a deficiency in the body's ability to respond to insulin. Diabetes is a chronic illness with no cure and can lead to kidney failure, heart problems, strokes or blindness, as well as other complications. Approximately 50% of diabetics are treated with insulin, which has to be injected, while the rest are treated with oral medications which tend to be more difficult to regulate and often have side effects.

According to Dr. Mirsky, there are a number of problems with insulin treatment; the main one being that insulin is not always an effective treatment, due to gradual development of resistance to the hormone. An additional problem is that insulin doses are not necessarily synchronized with the patient's physical activities or eating intervals. A large dose of insulin injected before a diabetic patient eats, for example, can cause a sudden drop in blood sugar (hypoglycemia) that can result in a diabetic coma and ultimately death. In addition, the fact that insulin must be injected is in and of itself difficult for many patients.

This current research was conducted on two levels: on diabetic rats and on the molecular-cell level. The results indicate that GTF acts similarly to insulin in the rats, lowering the level of glucose, and of LDL-cholesterol, (the "bad" cholesterol), and raising the level of HDL-cholesterol (the "good" cholesterol). GTF inhibited oxidation processes that can cause atherosclerosis and result in further complications of the disease like strokes and heart attacks. Moreover, when GTF is given at early stage of the disease, it could prevent or delay renal complications. GTF also helped to prevent cataracts and retinal damage. It was also found that GTF improves the effectiveness of injected insulin. Further research is needed in order to find a combined regimen of insulin and GTF as a potential treatment for diabetes.

(Newswise)

Medicine: Looking for cancer in all the right places

Viable tumour-derived epithelial cells (also known as circulating tumour cells or CTCs) have been identified in the blood of cancer patients, and the hope is that these CTCs will enable physicians to characterize and monitor certain kinds of cancer in a non-invasive manner. A paper describes the development of a unique microfluidic platform (the ‘CTC-chip’) that can efficiently and selectively separate CTCs from peripheral blood samples.

Mehmet Toner and colleagues have used the device to identify CTCs successfully in the peripheral blood of patients with metastatic lung, prostate, pancreas, breast and colon cancer, and they have shown that they can use the CTC-chip to monitor an individual’s response to anti-cancer therapy. The approach seems to isolate more viable CTCs - and is simpler - than other methods that have been used to isolate these rare cells, so the hope is that this device could be used in clinical settings to diagnose cancer patients rapidly and monitor them while they are undergoing treatment.

CONTACT
Mehmet Toner (Harvard Medical School, Boston, MA, USA)
Tel: +1 617 724 5336; E-mail: mtoner@hms.harvard.edu

Jonathan W. Uhr (University of Texas Southwestern Medical Center, Dallas, TX, USA) N&V Author
Tel: +1 214 648 1226; E-mail: jonathan.uhr@utsouthwestern.edu

Fossil record: Terrestrial ancestors of whales


The marine mammals known as cetaceans - whales, dolphins and porpoises - originated about 50 million years ago in south Asia, but their terrestrial ancestor is something of a mystery. It is likely to have been a racoon-sized animal from India known as a raoellid, which probably took to the water in times of danger.

J Thewissen and his colleagues present evidence for a close relationship between whales and raoellids, which lived at about the same time as the earliest whales. The structures of the skull and ear region of raoellids are very similar to those of early whales, and their bone thickness and isotope evidence both indicate that these creatures spent much of their time in water. Raoellids, however, were mainly herbivorous on land, so the spur for the ancestors of whales to take to the water was probably an abundance of aquatic prey.

According to independent molecular evidence, hippos are the closest relatives of today’s whales. However, hippos don’t appear in the fossil record until some 35 million years after whales diverged from their terrestrial ancestors. Thewissen and colleagues’ raoellid Indohyus now provides the missing Eocene piece of the jigsaw.

CONTACT

J Thewissen (Northeastern Ohio Universities College of Medicine, Rootstown, OH, USA)
Tel: +1 330 325 6295; E-mail: thewisse@neoucom.edu

Neuroscience: Brain cells are smarter than you think


Individual brain cells can make a bigger contribution to behaviour and are capable of more computations than previously thought.The mammalian brain faces a serious resource problem - there aren’t enough neurons to have one responsible for every single perception, behaviour or memory. To increase its storage capacity the brain is thought to use overlapping patterns of activity across many interconnected neurons instead, but new research indicates that this underestimates the part individual cells can play.

Using a new method for stimulating neurons in the part of the mouse brain involved in whisker-touch with light, a team led by Karel Svoboda demonstrate that brief bursts of activity in a few neurons are all it takes to trigger learning and decision-making. In another study, Michael Brecht and Arthur R. Houweling managed to pin down the influence of a single cell on a rat’s ability to sense touch. By electrically stimulating neurons in the barrel cortex they found that slightly increasing a neuron’s activity directly affected whether or not rats reported a touch-like sensation. In a third technically impressive study, Karel Svoboda and Christopher D. Harvey zoomed in on the individual connections - or ‘synapses’ - between neurons. Each neuron has many synapses, scattered across its branch-like dendrites. As an animal learns, synapses become stronger or weaker, changing the pattern of connections thought to store information. Previous experiments showed that stimulating a single synapse can change its strength, but computer models predict ‘crosstalk’ between neighbouring synapses. Harvey and Svoboda confirmed this prediction, showing that the neighbours of recently strengthened connections were themselves easier to potentiate. This hints at a kind of neuronal filing system, in which connections relevant to similar kinds of behaviour might cluster together.

These papers add to our growing understanding of the complex processing that can go on within a single cell, and raise interesting questions about how widespread these effects are.

CONTACT
Karel Svoboda (Howard Hughes Medical Institute, Ashburn, VA, USA) Author papers [1] & [3]
Tel: +1 571 209 4113; E-mail: svobodak@janelia.hhmi.org

Michael Brecht (Humboldt University, Berlin, Germany) Author paper [2]
Tel: +49 30 2093 6772; E-mail: michael.brecht@bccn-berlin.de

Bernado Sabatini (Harvard Medical School, Boston, MA, USA) N&V Author
Tel: +1 617 432 5670; E-mail: bsabatini@hms.harvard.edu

Genetic risk factor for ALS

Scientists have identified a variant in the gene DPP6 that increases susceptibility to amyotrophic lateral sclerosis. Amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease) is an untreatable and fatal disorder caused by degeneration of motor neurons in the brain and spinal cord.

While mutations in genes have been found that cause rare cases of familial ALS, there has been much more limited success in identifying genetic influences on non-familial (sporadic) ALS, which accounts for more than 90% of cases.

Leonard van den Berg and colleagues carried out a genome-wide association study of more than 1,700 individuals with the disease and more than 1,900 healthy controls, sampled from three European populations, and including recently reported data from affected individuals in the United States. A single variant in DPP6 was associated with ALS in each population, increasing risk by approximately 30%. This is the first genetic risk factor identified for sporadic ALS in the context of a genome-wide study, and is the first to be found consistently in multiple populations. DPP6 encodes a dipeptidyl-peptidase-like protein, an enzyme found predominantly in the brain whose expression has been shown to be increased in rats in response to spinal cord injury.

Author contact:
Leonard van den Berg (University Medical Center, Utrecht, The Netherlands)
Tel: +31 302 506 506; E-mail: l.h.vandenberg@umcutrecht.nl



Genetic susceptibility to Kawasaki disease


A variant in a gene called ITPKC is associated with increased susceptibility to Kawasaki disease.Kawasaki disease is characterized by acute inflammation of the vascular system in infants and children, and if left untreated can lead to lethal coronary artery aneurysms.

Kawasaki disease tends to run in families, suggesting that there are genetic components to disease risk. It is also 10-20 times more common in Japan than in Western countries. Yoshihiro Onouchi and colleagues identified a region on chromosome 19 that was linked with the disease, and in particular a series of variants across four genes in the region were found more frequently in individuals with the disease than in healthy controls. The authors focused on one of these genes, ITPKC, which they regarded as the best candidate. ITPKC encodes an enzyme that is part of a signaling pathway with a critical role in certain cells of the immune system (T-cells). The authors went on to show that one of the risk variants reduces the expression of ITPKC, and that lower levels of ITPKC promote activation of T-cells. This is consistent with the marked activation of the immune system seen in Kawasaki disease.

Finally, the authors suggest that the association of ITPKC with Kawasaki disease may have immediate clinical implications. Approximately 10-20% of affected individuals are resistant to the standard treatment of intravenous immunoglobulins, but individuals with the ITPKC risk variant are 4-5 times more likely to fail to improve on the standard therapy. If these individuals could be identified with a genetic test, they could be offered alternative and more intensive therapies.

Author contact:
Yoshihiro Onouchi (SNP Research Center, RIKEN, Yokohama, Japan)
Tel: +81 45 503 9347; E-mail: onouchi@src.riken.jp

Control of EGFR in breast cancer cell invasion


A mechanism explaining how epidermal growth factor (EGF) regulates breast cancer cell invasion.The findings could contribute to the development of more specific anti-cancer drugs.

Highly proliferating, invasive breast cancer cells often express abnormally high levels of the EGF receptor (EGFR), and this is known to control both cell division and migration. In an effort to clarify the molecular pathways that are activated by EGFR specifically during cancer cell invasion ? as opposed to normal cell migration ? Hisataka Sabe and colleagues identify the protein GEP100 as a factor that directly links activated EGFR to Arf6, a protein that is often over expressed in breast cancer cells and promotes cancer cell invasion.

At high levels of GEP100, (as found in cancer cells), Arf6 was activated, allowing non-invasive cells to become invasive with stimulation of EGFR; conversely, when GEP100 was inhibited, metastasis was prevented in mice that had been injected with highly invasive breast cancer cells. Levels of GEP100 were enriched in clinical samples taken from invasive breast carcinomas, and the presence of GEP100 and EGFR correlated with tumour malignancy.

Inhibition of EGFR is an important anti-cancer treatment, although EGF also controls the growth of many normal cells. Thus, these findings could contribute to the development of more specific anti-cancer drugs that, by targeting GEP100, could efficiently block the pro-invasive activity of EGFR and inhibit the metastatic process.

Author contact:
Hisataka Sabe (Osaka Bioscience Institute, Japan)
Tel: +81 6 6872 4814; E-mail: sabe@obi.or.jp

Nuclei unplug a spin-valve

A team of scientists shows how to electrically control the polarization of nuclear spins


In any spin-based memory device—or qubit—a major challenge is preserving the spin state of an electron over reasonable times. The reason is that the electron interacts with nearby spins that cause it to ‘flip’ and lose information.

The greatest contribution to this electron ‘dephasing’ in semiconductor spin qubits is from random fluctuations of the surrounding nuclear spins. This is why a group of scientists, including Keiji Ono from the RIKEN Discovery Research Institute, Wako, and colleagues at the University of Waterloo in Canada and the University of Tokyo, are exploring a way to electrically suppress nuclear spin fluctuations. Their results are reported in the journal Physical Review Letters1.

The team built an electronic device called a vertical double quantum dot (Fig. 1) that consists of two 10 nm-thick layers of the semiconductor GaAs, separated from one another and from metallic contacts by thin layers of the semiconductor Al0.3Ga0.7As. The Al0.3Ga0.7As layers act as ‘tunnel barriers’ that confine electrons to one of the thin GaAs layers, which are therefore called ‘quantum wells’.

The team has shown previously that it can control the transport of electrons, one at a time, through the quantum wells and that this transport depends on the spin state (‘up’ or ‘down’) of the electron. In fact, under certain conditions, an electron with one particular spin state (say, ‘up’) cannot tunnel across the double-dot structure without first flipping its spin.

In their new work, the team uses this ‘spin blockade’ effect to polarize the nuclear spins in the GaAs. This superconductor contains three isotopes—71Ga, 69Ga and 75As—each of which has a large nuclear spin that interacts with an electron moving through the double dot. When the device is set to the spin-blockade mode that prevents spin ‘up’ electrons from tunneling across, the nuclear spins open the door: the interaction between the electron and nuclear spins allows the electron spin to flip from ‘up’ to ‘down’ and tunnel through the device, while the nuclear spin flips from ‘down’ to ‘up’.

The process polarizes the surrounding nuclear spins by as much as 40%. Ono notes that these measurements are the first to show that nuclear spin fluctuations can be controlled electrically and could be useful in designing spin-memory devices with longer electron spin lifetimes or based entirely on storing information in the nuclear spins themselves.
Reference

1. Baugh, J., Kitamura, Y., Ono, K. & Tarucha, S. Large nuclear Overhauser fields detected in vertically coupled quantum dots. Physical Review Letters 99, 096804 (2007).

Spin selection

RIKEN researchers are learning how to electrically control spin orientation for data storage technology

Conventional electronics depends on the electrical charges on electrons. The emerging field of spintronics aims to produce devices that also make use of the quantum spin states, or internal angular momentum, of electrons. Researchers at the University of Tokyo, the RIKEN Frontier Research System in Wako and New York University have developed a spintronic technique for accumulating ordered spin states that could have valuable applications in information storage1.

Spintronics requires ‘spin-polarized’ non-magnetic materials in which the electron spins all point in the same direction. This has previously been achieved by injecting a spin-polarized current into the material from a magnetic needle. However the direction of polarization can only be changed by rotating the needle, which is not practical at nanometer scales.

The research team has solved this problem by using two injection needles, allowing them to control the polarization direction simply by varying electrical currents. Their experimental device, called a lateral spin valve, consists of a copper strip in contact with two 80-nanometer-wide injection needles at right angles to one another, made of Permalloy—a magnetic alloy of nickel and iron (Fig. 1).

Electrons can only have spins in ‘up’ or ‘down’ states. In magnetic materials, spins can align so that when the material is observed from the ‘polarization direction’, we observe only one type of spin. “Permalloy is a strong ferromagnet that provides spin polarized electrical currents because the population[s] of up and down spins are spontaneously different,” explains RIKEN scientist YoshiChika Otani.

The researchers found that by changing the electrical currents in the Permalloy needles, they had complete control over the angle of spin polarization in the copper strip. Furthermore, the number of polarized spins accumulated in the copper strip obeyed a simple cosine relationship with the angle of polarization.

“Normally spin polarization is along the magnetization direction,” says Otani. “By combining spin polarized currents with two different quantized axes, we can rotate the resultant quantized axis.”

The technique could be used to reverse the magnetization of certain materials. “We believe that our electrical means of controlling the spin polarization is important for realizing efficient spin-injection-induced magnetization reversal,” explains Otani.

The magnetization reversal process could lead to new types of random access memory for computers. In future the researchers also hope to apply their technique to induce a quantum spin version of the Hall Effect which is exploited in several types of sensors.
Reference

1. Kimura, T., Otani, Y.-C. & Levy, P.M. Electrical control of the direction of spin accumulation. Physical Review Letters 99, 166601 (2007). | article |

Guided nerves in the embryonic brain


Japanese biologists identify a protein critical to the normal development of the embryonic brain

Early in embryonic development, nerves grow and spread through the brain. If the nerves grow in the wrong direction or are stunted, it is fatal to the embryo. Growing nerve fibers appear to be guided by an invisible cue to travel along specific pathways making the decision to change direction or branch out at particular points.

This specific directional growth of embryonic nerve fibers has been the focus of a study recently published in Nature Neuroscience1. Japanese biologists have demonstrated that a protein called OL-protocadherin (OL-pc) is crucial to the correct growth of particular nerves in the developing brain.

The team, led by Shinji Hirano and Masatoshi Takeichi of the RIKEN Center for Developmental Biology, Kobe, developed a population of mice that lack the gene for OL-pc and therefore don’t produce the protein. The team was able to show that, in these mutant mice, particular nerve fibers grew in a disorganized manner or were stunted and the embryos died within weeks. In normal mice, comparable nerve fibers grew in an orderly fashion (Fig. 1). Stained sections of brain tissue showed that the presence of OL-pc matched the regions of nerve growth. The protein was found both along the nerve fibers and at their growing tips.

Hirano and colleagues found OL-pc most abundantly in the small striatal region of the forebrain. This is the major input station of nerves associated with bodily movement. The group showed that striatal fragments transplanted outside their normal area extended nerve fibers in the normal orientation, suggesting the existence of a guidance mechanism. Also, if these striatal nerve fibers did not grow properly, the team found that non-striatal nerves travelling to other parts of the brain became tangled or misrouted, suggesting that other nerves require normal striatal nerve extension for their progression.

OL-pc molecules tend to stick to each other and so interaction between them along nerve fibers may give rise to a signal that guides growth. Alternatively, OL-pc may act as a receptor for an, as yet, unknown cue.

Although the results suggest that OL-pc is important for the growth of striatal nerve fibers, other mechanisms seem to coexist for ensuring the correct migration of these nerves. The cooperative mechanisms between these mechanisms need to be determined in the future. Further study of importance of striatal nerve fibers in guiding nerves to other brain areas and the unveiling of the signaling mechanism of OL-pc are next, says Hirano.
Reference

1. Uemura, M., Nakao, S., Suzuki, S.T., Takeichi, M. & Hirano, S. OL-protocadherin is essential for growth of striatal axons and thalamocortical projections. Nature Neuroscience 10, 1151–1159 (2007).

Nanoscale Details of Photolithography Process Revealed





Description
Scientists at the National Institute of Standards and Technology (NIST) have made the first direct measurements of the infinitesimal expansion and collapse of thin polymer films used in the manufacture of advanced semiconductor devices. It’s a matter of only a couple of nanometers, but it can be enough to affect the performance of next-generation chip manufacturing.


Scientists at the National Institute of Standards and Technology (NIST) have made the first direct measurements of the infinitesimal expansion and collapse of thin polymer films used in the manufacture of advanced semiconductor devices. It’s a matter of only a couple of nanometers, but it can be enough to affect the performance of next-generation chip manufacturing. The NIST measurements, detailed in a new paper,* offer a new insight into the complex chemistry that enables the mass production of powerful new integrated circuits.

The smallest critical features in memory or processor chips include transistor “gates.” In today’s most advanced chips, gate length is about 45 nanometers, and the industry is aiming for 32-nanometer gates. To build the nearly one billion transistors in modern microprocessors, manufacturers use photolithography, the high-tech, nanoscale version of printing technology. The semiconductor wafer is coated with a thin film of photoresist, a polymer-based formulation, and exposed with a desired pattern using masks and short wavelength light (193 nm). The light changes the solubility of the exposed portions of the resist, and a developer fluid is used to wash the resist away, leaving the pattern which is used for further processing.

Exactly what happens at the interface between the exposed and unexposed photoresist has become an important issue for the design of 32-nanometer processes. Most of the exposed areas of the photoresist swell slightly and dissolve away when washed with the developer. However this swelling can induce the polymer formulation to separate (like oil and water) and alter the unexposed portions of the resist at the edges of the pattern, roughening the edge. For a 32-nanometer feature, manufacturers want to hold this roughness to at most about two or three nanometers.

Industry models of the process have assumed a fairly simple relationship in which edge roughness in the exposed “latent” image in the photoresist transfers directly to the developed pattern, but the NIST measurements reveal a much more complicated process. By substituting deuterium-based heavy water in the chemistry, the NIST team was able to use neutrons to observe the entire process at a nanometer scale. They found that at the edges of exposed areas the photoresist components interact to allow the developer to penetrate several nanometers into the unexposed resist. This interface region swells up and remains swollen during the rinsing process, collapsing when the surface is dried. The magnitude of the swelling is significantly larger than the molecules in the resist, and the end effect can limit the ability of the photoresist to achieve the needed edge resolution. On the plus side, say the researchers, their measurements give new insight into how the resist chemistry could be modified to control the swelling to optimal levels.

The research, funded by SEMATECH, is part of a NIST-industry effort to better understand the complex chemistry of photoresists in order to meet the needs of next-generation photolithography. (Newswise)

Structural biology: A gallery of protein pumps

An international team of structural biologists has created some of the most detailed images yet of three proteins that help cells shuttle charged ions across their membranes - an important process in maintaining intracellular stores of these chemicals.

The researchers, divided into three research groups, each of which is led by Poul Nissen, have used a technique called X-ray crystallography to study the structures of three different ‘ion pumps’ with unprecedented resolution - down to the level of individual atoms within these protein complexes. The research will provide more detailed insight into the structure of these pumps, each of which break down the energy-giving molecule ATP to force ions across membranes against a concentration gradient.

In three separate research papers Nissen and colleagues unveil the structures of: the proton pump, which shuttles hydrogen ions across cell membranes in plants and fungi; the calcium pump, which moves calcium ions into cellular storage compartments and is essential for muscle function; and the sodium-potassium pump, which is important for a range of functions including transmission of nerve impulses along neurons.

The researchers report several unexpected properties of these protein complexes, including the remarkable similarity shared by the calcium and sodium-potassium pumps, which raises the question of how they manage to bind specifically to these different ions.

CONTACT
Poul Nissen (University of Aarhus, Denmark) Author papers [6], [7] & [8]
Tel: +45 8942 5025; E-mail: pn@mb.au.dk

David Gadsby (Rockefeller University, New York, NY, USA) (N&V Author)
Tel: Please check on the press site for updates
E-mail: gadsby@mail.rockefeller.edu

Climate change: Remote control of tropical cyclones


Natural climate variations, which tend to involve localized changes in sea surface temperature, may have a larger effect - per degree local warming - on tropical cyclone activity than the more uniform patterns of greenhouse-gas-induced warming.

The effect of global warming on tropical cyclone activity is widely debated. It is often assumed that warmer sea surface temperatures encourage more frequent and intense tropical cyclones, but several other factors, such as atmospheric temperature and humidity, also come into play.

Gabriel Vecchi and Brian Soden analysed climate model projections and observational reconstructions to explore the relationship between changes in sea surface temperature and tropical cyclone ‘potential intensity’ - a measure that provides an upper limit on cyclone intensity. They found that long-term changes in potential intensity are more closely related to the regional structure of warming than to local sea surface temperature change. Regions that warm more than the tropical average are characterized by increased potential intensity, and vice versa. This indicates that localized changes in sea surface temperature, such as those caused by natural climate variations, are more effective at altering potential intensity (per degree local warming) than more uniform patterns of warming, such as those expected in response to increasing greenhouse-gas concentrations.

CONTACT
Gabriel Vecchi (NOAA, Princeton, NJ, USA)
Tel: +1 609 452 6583; E-mail: Gabriel.A.Vecchi@noaa.gov

Mammals: Patterns of evolution

Mammalian evolution is less linear than previously thought, suggests a new study. The study uses the newly improved fossil record to build up a more complex picture of the evolution of key anatomical features.

Mammals are an important group for understanding life and its evolution. From the bumblebee bat to the blue whale, the group has evolved through time to display spectacular diversity and specialization. The evolution of mammals is commonly thought to involve a steady, orderly acquisition of key features from the reptile group - the ancestors from which mammals diverged. Characters such as the middle ear evolved from the reptilian jaw joint, and the ‘tribosphenic’ (crushing and biting) molar is thought to have come from the simpler, pointed teeth of reptiles.

Zhe-Xi Luo analyses a host of recently discovered fossils that alters this view radically, showing that mammal evolution was not quite so linear but more chaotic and subject to frequent changes - with many ‘dead-end’ lineages evolving. Lineage splits were accompanied by significant ecological diversification, with independent evolutionary ‘experiments’ evolving. The rapid accumulation of new data from recent finds and increasingly comprehensive ‘phylogenies’ have all contributed to this new approach of understanding how mammals evolved.

CONTACT
Zhe-Xi Luo (Carnegie Museum of Natural History, Pittsburgh, PA, USA)
Tel: +1 412 622 6578; E-mail: luoz@carnegiemnh.org

You must remember this


A part of the brain known as the basal ganglia may act to filter out irrelevant information from memory, increasing its apparent capacity. The study could help to explain why some people are better at remembering things than others.

The ability to hold information ‘online’ so that it is immediately accessible is known as working memory, and its capacity is strictly limited. These variations are not just due to having a larger or smaller memory store, but also due to differences in how effectively irrelevant items are kept out of memory.

Torkel Klingberg and colleagues find in a functional imaging study that people who can hold more items in working memory have more activity in the basal ganglia when distracting stimuli are present during a task. An auditory cue informed subjects whether an upcoming visual display would contain irrelevant distracters (along with the targets). When this cue occurred, neural activity increased in the basal ganglia and the prefrontal cortex, before the visual display appeared. This increased activity suggests readiness to filter out the upcoming distracters.

Greater activity in the globus pallidus, a subregion of the basal ganglia, correlated with less unnecessary storage in another part of the brain, the posterior parietal cortex, which is sensitive to the amount of information held in memory. Consider the posterior parietal cortex as an exclusive nightclub and the basal ganglia as the bouncer: the size of the nightclub influences its crowding, but the effectiveness of the bouncer is important too.

Author contact:
Torkel Klingberg (Karolinska Institute, Stockholm, Sweden)
Tel: +46 8 5177 6118; E-mail: Torkel.Klingberg@ki.se

Pathway to breast cancer


Scientists have identified a particular combination of mutations in hereditary breast cancers that typically have a poor prognosis. The pathway identified by the mutations.

Women with mutations in the gene BRCA1 are at very high risk of developing basal-like breast cancer, which is one of the subtypes with the worst prognosis. BRCA1 has several roles in the cell, one of which is to promote the repair of damaged DNA. While it is assumed that elevated DNA damage in the absence of normal BRCA1 function must result in additional mutations that promote the development of a tumour, there has been little progress in identifying what these ‘downstream’ mutations might be.

Based on preliminary work studying mammary cancer in mice, Ramon Parsons and colleagues searched for small chromosomal rearrangements in a known tumour suppressor gene called PTEN in a series of human BRCA1-associated breast cancer cell lines and biopsies. In a significant number of cases they found one or more of these rearrangements in PTEN, resulting in a complete loss of its expression in the tumour cells of both hereditary and non-hereditary breast cancers. This is one of the first specific and recurrent consequences of BRCA1 mutation to be identified in breast cancer, and the authors suggest that drugs targeting the PTEN pathway might be effective in treating this particular subtype. The authors also emphasize the importance of searching for structural rearrangements of this kind in other cancer genomes.

Author contact:
Ramon Parsons (Columbia University Medical Center, New York, NY, USA)
Tel: +1 212 851 5263; E-mail: rep15@columbia.edu

How protein modules fit together


Scientists have defined a new type of protein-protein interaction in tubulysin biosynthesis. This discovery will provide important guidelines for engineering cells to create new molecules and potential drugs.

Biosynthesis of small molecules is often done by a huge protein chain that can be conceptually broken down into ‘modules’ that perform specific steps in the overall synthesis. These modules have to communicate to pass along the growing small molecule, but the way in which some modules talk to each other was not known.

Kira Weissman and colleagues present a structure for one piece of a protein that directly talks to another module. They also prove that several amino acids on one side of this structure control communication to the partner protein. By switching these amino acids, then, it may be possible to mix and match modules to make brand new molecules that may be important drugs.

Author contact:
Kira Weissman (Saarland University, Saarbrücken, Germany)
Tel: +49 681 302 5497, Email: k.weissman@mx.uni-saarland.de

Silicon nanowires restore optical signals

A system for reconstructing weak or damaged optical data using tiny silicon waveguides could be incorporated into future optical chips for use in world wide communications networks.

The ability to regenerate weak and distorted optical data is vital for maximizing the performance and transmission span of modern communication systems. Unfortunately, present regenerators have to convert the optical data into electronic signals, process it and then convert it back into the optical domain for re-transmission - a costly and inconvenient approach.

Alexander Gaeta and co-workers have developed an all-optical scheme that can perform complete regeneration (amplification, retiming and reshaping of optical data bits) using silicon waveguides that have nanoscale dimensions. The team used a well-known technique in nonlinear optics called ‘four-wave mixing’ to transfer noisy and degraded data bits from an incoming light beam and convert them into high-quality, clean data bits carried on a second light beam of a different wavelength. The beauty of the approach is that it does not require any electronic circuitry and its tiny size and silicon composition potentially allow integration into optical chips of the future.

The team’s experiments took place at a wavelength of 1,550 nanometres - the region at which the world’s optical networks operate. The next challenge is to make the scheme compatible with multichannel networks that transmit many simultaneous signals, each on its own dedicated wavelength channel.

Author contact:
Alexander Gaeta (Cornell University, Ithaca, NY, USA)
Tel: +1 607 255 9983; E-mail: alg3@cornell.edu

Re-examining firefly bioluminescence



The highest quantum yield of firefly bioluminescence is less than half the previously accepted value of the past 50 years, suggests a report.

Bioluminescence - the ability to generate light in living organisms - as well as being intrinsically captivating, is of scientific interest because of its wide applications in the biological and environmental sciences, such as in gene-expression reporting and forensic investigation. In 1951, the highest quantum yield - the probability of photon emission per luciferin molecule - using firefly (Photinus pyralis) luciferase was first reported to be 88%. Although two years later it was said that a re-examination was needed, no further investigations were made.

Yoriko Ando and colleagues carried out a quantitative measurement of the firefly bioluminescence by using a total-photon-flux spectrometer they have developed. This spectrometer directly measures the quantitative luminescence spectra in the bioluminescence total flux, and hence can determine quantum yields. The team discovered that the highest quantum-yield value is actually only 41.0%.

The authors also reveal that the colour change in fireflies is mainly determined by the pH dependence of the green emission, again, totally opposing the widely accepted colour-change mechanism that is based on the chemical equilibrium of yellow-green and red emissions during pH change.

Author contact:
Yoriko Ando (Institute for Solid State Physics, University of Tokyo, Chiba, Japan)
Tel: +81 4 7136 3387; E-mail: yori@issp.u-tokyo.ac.jp

Cooling the Cretaceous greenhouse



The Earth may not have been such a hot greenhouse world during the Jurassic and Cretaceous periods, suggests a study. The research reconciles records of ancient climate and atmospheric carbon dioxide levels with our understanding of how the two are linked.

Marine data indicate a series of cold spells during the time of the dinosaurs, but these did not seem to tally with records of high carbon dioxide levels, which would suggest higher temperatures and ‘greenhouse’ conditions.

David Beerling and colleagues studied the fossilized remains of ancient liverworts and, using the isotopic composition of the fossils, they reconstructed atmospheric CO2 levels for the period between 200 and 60 million years ago. The new records show lower and more variable CO2 concentrations than previous estimates. These results suggest that carbon dioxide was in fact the main driver of long-term climate change during this period, and that the previously unexplained cold periods were tied to natural decreases in atmospheric CO2 concentration.

Author contact:
David Beerling (University of Sheffield, Sheffield, UK)
Tel: +44 114 222 4359; E-mail: D.J.beerling@Sheffield.ac.uk

Behaviour: Insects' life after sex

The molecular switch that triggers post-mating reproductive behaviour in female fruitfly is identified. Many insect females undergo a profound change in their behaviour after mating: mosquitoes seek out a blood meal; other insects prevent further mating and start laying lots of eggs. The discovery could therefore have important implications for strategies to control the reproductive and host-seeking behaviours of agricultural pests and disease carriers.

The behavioural switch had previously been attributed to a molecule from the male seminal fluid - the sex peptide. Now Barry J. Dickson and colleagues have found the receptor for this peptide and find that the neurons where it functions are implicated in other sex-related behaviours.

The authors report that this receptor, SPR, is conserved across insect species. Artificially stimulating it may result in the inhibition of both reproduction and host-seeking behaviour in target insects.

Author contact:
Barry J. Dickson (Institute of Molecular Pathology Vienna, Austria)
Tel: +43 1 797 30 3000; E-mail: dickson@imp.ac.at

Palaeoclimate: Snowball versus slushball


The reaction of the carbon cycle during rapidly cooling conditions could have prevented the Earth from completely freezing over during a critical period of its history. An increased rate of remineralization of a massive pool of dissolved organic carbon in the ocean kept atmospheric carbon dioxide levels in the past just high enough to prevent a ‘snowball Earth’; allowing photosynthesis to continue.

The snowball Earth hypothesis proposes that the Earth was fully covered with ice during a series of glaciations around 700 million years ago. Evidence from the rock record and from oxygen isotopes suggests that glaciers could have reached the Equator, with profound effects on photosynthesis and the subsequent evolution of life itself. Other theories suggest that there may have been open water in equatorial regions, but the issue remains controversial.

W. Richard Peltier and colleagues present a coupled model of the carbon cycle and climate system during the Neoproterozoic, which shows that the carbon cycle could have acted as a buffer to prevent complete snowball conditions. They find that more oxygen is taken up by a cooling ocean, which converts organic into inorganic carbon more efficiently. This creates a negative feedback loop that stabilizes low carbon dioxide levels in the atmosphere and prevents further cooling.

Many uncertainties remain and the model needs to be developed and tested further. The authors suggest that it may have been the carbon cycle and not the physical climate system that was operating in an extreme mode just before the Cambrian explosion of life.

CONTACT
W. Richard Peltier (University of Toronto, Ontario, Canada)
Tel: +1 416 978 2938; E-mail: peltier@atmosp.physics.utoronto.ca

Alan J. Kaufman (University of Maryland, College Park, MD, USA) N&V Author
Tel: +1 301 405 0395; E-mail: kaufman@geol.umd.edu

Heart disease: Transgenic cell transplants offer hope against heart-attack after attacks

Transplants of genetically engineered cells could help to reduce the risk of fatal arrhythmia in the wake of a heart attack, according to new mouse studies. The discovery could offer a way to prevent ventricular tachycardia, a type of heart arrhythmia that is currently the main cause of sudden death in patients who have previously had a heart attack.

Previously, doctors have attempted to prevent ventricular tachycardia by implanting either bone marrow cells or other cells called skeletal myoblasts into heart tissue to help it recover from the damage sustained in a heart attack. But this approach has not proven successful because the cells never develop into true heart cells.

Bernd K. Fleischmann and colleagues report that, in mice, transplantation of cells called embryonic cardiomyocytes successfully reduces the danger of ventricular tachycardia. They also deduced that the key factor in these cells is a protein called connexin 43. When they genetically engineered skeletal myoblasts, which are more readily available, to express this same protein, they discovered that these cells were now equally effective in restoring heart function, thereby avoiding the need to use cells from embryos.

CONTACT
Bernd K. Fleischmann (University of Bonn, Germany)
Tel: +49 228 688 5200; E-mail: Bernd.Fleischmann@uni-bonn.de

Michael Kotlikoff (Cornell University, Ithaca, NY, USA) Co-author
Tel: +1 607 253 3771; E-mail: mik7@cornell.edu

Looking Through the Eyes of a Mouse, Scientists Monitor Circulating Cells in Its Bloodstream

Description

A team of researchers from the Wellman Center for Photomedicine at Massachusetts General Hospital (MGH) and Harvard Medical School (HMS) have developed an optical device that allows them to peer through the eyes of a mouse and monitor the cells passing through its bloodstream.


A team of researchers from the Wellman Center for Photomedicine at Massachusetts General Hospital (MGH) and Harvard Medical School (HMS) have developed an optical device that allows them to peer through the eyes of a mouse and monitor the cells passing through its bloodstream.

In the Dec. 1 issue of the journal Optics Letters, published by the Optical Society of America, the team describes how they used the device, called a retinal flow cytometer, to non-invasively sample the blood passing through the vessels in the retinal tissue in the back of the eye. There they were able to detect circulating fluorescently labeled cells as they wound their way through the mouse.

"We could detect and count circulating cells continuously without drawing blood samples," says MGH/HMS investigator Charles Lin.

The ability to count circulating cells is important in diseases like multiple myeloma because the number of cancer cells in the bloodstream at the onset of the disease may represent only a tiny fraction of circulating cells in the bloodstream.

Though few in number, these rare cells nevertheless can be relentless. Multiple myeloma starts when cancerous immune system cells residing in the bone marrow quickly multiply out of control. Rather than forming a solid tumor, though, they spread throughout the body and crowd out other cells in the bloodstream. Multiple myeloma cells can invade bones throughout the body, eroding and weakening them and leading to fractures and sometimes paralysis because of compression of the spinal cord. Eroding the bones can also drastically increase the calcium levels in the blood, sometimes causing kidney failure. Moreover, multiple myeloma cells can crowd out the oxygen-ferrying red blood cells in the bloodstream and cause anemia.

Multiple myeloma is treatable, but the disease has a high rate of recurrence. Scientists like Lin and his collaborator Irene Ghobrial of the Dana-Farber Cancer Institute are interested in helping people with multiple myeloma by finding better drugs and treatment strategies. The new optical device may become a valuable tool because it allows them to test the effect of various experimental chemotherapy agents and therapeutic strategies in mice with multiple myeloma.

Testing the effect of new chemotherapy agents in the bloodstream of a mouse has traditionally been difficult because there was no way to monitor the blood continuously. The best scientists could do was to draw blood samples at various time points and count the number of cancer cells in these samples. But looking for rare cancer cells required drawing a lot of blood. Repeated blood sampling from a single mouse was impossible, though, because mice only have a few milliliters of blood in their body.

A few years ago Lin and his colleagues devised a way to monitor cancer cells in rodents directly. They adapted a technique called flow cytometry, which scientists have used for decades to sort cells in the laboratory. Basically it involves streaming a complex mixture of cells in liquid past the focus of a powerful microscope and looking for particular cells—distinguishable because they have particular markers that are visible under the microscope.

Lin and his colleagues developed a way to use flow cytometry in vivo and monitor a mouse’s bloodstream directly. Initially they designed a device that could focus on a vessel in the ear of a mouse. While effective, this device was limited because the one tiny vessel in the mouse’s thin external ear did not have enough flow to adequately sample the bloodstream. It was a bit like trying to sample the traffic in New York by looking at a single side street in the Bronx. A better strategy would be to monitor several avenues at once—or in vascular terms, a cluster of several vessels at the same time.

This is exactly what the researchers are doing by looking into the back of a rodent’s eye. The retinal tissue is rich with blood supply, and Lin and his colleagues were able to sample a greater number of blood vessels and a much larger volume of blood. In initial feasibility experiments, they monitored a million circulating cells in the mouse that were fluorescently labeled with a marker that allowed them to be spotted with a microscope. The cytometer allowed them to track these cells as they trafficked though the bloodstream. They could observe approximately 250 cells per minute, and over time statistically model the flow of the cells.

This new device is not designed for humans and has not been tested in clinical trials. As a laboratory tool, however, it will allow the team to observe what happens when different chemotherapy agents are given to rodents—a standard early approach for evaluating the effectiveness of new chemotherapy agents and treatment strategies for humans.

The researchers are funded by grants from the National Institutes of Health.

Paper: "Retinal Flow Cytometer," by Clemens Alt et al., Optics Letters, Vol. 32, Issue 23, December 1, pp.3450-3452; abstract at http://www.opticsinfobase.org/abstract.cfm?URI=ol-32-23-3450.

Additional Reference: "Mechanisms of regulation of CXCR4/SDF-1 (CXCL12)–dependent migration and homing in multiple myeloma," by Yazan Alsayed et al., Blood, Vol. 109, Apr 2007, pp. 2708-2717.

About OSA
Uniting more than 70,000 professionals from 134 countries, the Optical Society of America (OSA) brings together the global optics community through its programs and initiatives. Since 1916 OSA has worked to advance the common interests of the field, providing educational resources to the scientists, engineers and business leaders who work in the field by promoting the science of light and the advanced technologies made possible by optics and photonics. OSA publications, events, technical groups and programs foster optics knowledge and scientific collaboration among all those with an interest in optics and photonics. For more information, visit http://www.osa.org.

Researchers Find Mechanism for Faulty Protein Disposal

Description

A discovery by St. Jude Children’s Research Hospital scientists offers new insights into how myeloma cells dispose of defective or excess proteins and could lead to new cancer treatments.


A discovery by St. Jude Children’s Research Hospital scientists offers new insights into how myeloma cells dispose of defective or excess proteins and could lead to new cancer treatments.

The researchers identified key cellular components that carry out protein disposal, a finding that helps to explain how cancer drugs called proteasome inhibitors interfere with this process. The discovery is important because the newly identified components of the protein disposal mechanism could be targets for novel cancer drugs designed to kill the cell by blocking this mechanism. A report on this work appears in the Nov. 30 issue of “Molecular Cell.”

Myelomas are cancers of plasma cells, which are the activated form of B lymphocytes—immune system cells that respond to infection by temporarily producing extremely large amounts of proteins called antibodies that attack the target. The rapidly multiplying cancer cells continually make large numbers of new antibodies, which increases the chance for errors in the production process, resulting in the accumulation of defective proteins that must be degraded.

“Proteasome inhibitors are currently being used to treat some types of cancer including multiple myelomas, although many aspects of this cellular process remain poorly understood,” said Linda Hendershot, Ph.D., a member of the St. Jude Department of Genetics and Tumor Cell Biology, and the paper’s senior author. “Our study sheds new light on how that process works.”

The St. Jude team focused their investigation on special channels called retrotranslocons in the membrane of the cell’s protein factory. The researchers also studied a small collection of molecules that pull defective proteins out of the factory through the retrotranslocon so they can be delivered to the cell’s protein shredder—a structure called the proteasome.

The protein factory, called the endoplasmic reticulum, is somewhat like an origami workshop: In the endoplasmic reticulum, molecules called chaperones help to fold up newly made proteins into the exact shape that enables that particular protein to perform its assigned task. Successfully folded proteins are transported to the cell surface or into the blood stream where they do their job. But if the folding does not occur or is faulty, defective proteins are ejected from the endoplasmic reticulum through channels called retrotranslocons and put into the proteasome, where they get degraded. This process, called endoplasmic reticulum-associated degradation, ensures that defective proteins do not accumulate in the endoplasmic reticulum and kill the cell by disrupting the vital process of protein folding.

Previous research identified a channel out of the endoplasmic reticulum for glycosylated proteins, or proteins tagged with sugar molecules. The channel relies on the detection of the sugar molecules to identify the proteins and send them to the proteasome. However, nothing was known about the disposal of non-glycosylated proteins (proteins with few or no sugar molecules attached). The St. Jude team found that this group of proteins exits the endoplasmic reticulum through a channel that is similar to the one used for glycoproteins but that has different components. The team focused the study on non-glycosylated proteins called light chains and heavy chains, which are the building blocks for antibodies made by plasma cells.

“We wanted to determine what happens to defective heavy and light chains in plasma cells so we could get a better understanding of the molecules and channels that allow these cells to get rid of defective proteins that can’t be used to make antibodies,” Hendershot said. When plasma cells become cancerous, they multiply rapidly and continue to produce large amounts of antibodies, some of which are not folded properly. These cells depend on endoplasmic reticulum-associated degradation to dispose of unwanted proteins before they clog up the endoplasmic reticulum and eventually kill the cells.

“The class of cancer drugs called proteasome inhibitors block endoplasmic reticulum-associated degradation as well as the destruction of proteins from other parts of the cells and cause defective proteins to overload this system,” she said. “We want to fully understand how endoplasmic reticulum-associated degradation works for antibodies made by plasma cells, so we can design more specific ways to block this process in myelomas.”

The St. Jude team first demonstrated that defective light chain and heavy chain proteins in plasma cells are degraded by the proteasome after being ejected from the endoplasmic reticulum and tagged with molecules called ubiquitin—a standard way the cell flags an unwanted protein for destruction.

The researchers then examined the menagerie of molecules that collaborate to pull defective proteins out of the endoplasmic reticulum and hand it over to the proteasome. Hendershot’s team showed previously that one of those molecules, a chaperone called BiP, initially helps newly made proteins undergo folding. If the folding operation fails, however, BiP becomes a conspirator with Herp, another member of the menagerie, to send the defective protein to the proteasome. Based on a series of detailed biochemical studies, the team showed that Herp binds to both the ubiquitinated protein and the proteasome, apparently serving as a bridge to direct the protein to the shredder.

In addition to BiP and Herp, three other members of the menagerie, Derlin-1, p97 and Hrd 1 collaborate with Herp to extract defective proteins from the retrotranslocon so Herp can hand it over to the proteasome.

“Our study shows for the first time the role Herp plays at the retrotranslocon,” said Yuki Okuda-Shimizu, Ph.D. a postdoctoral fellow in Hendershot’s laboratory who contributed significantly to the project. “The study also describes how non-glycosylated proteins are removed from the endoplasmic reticulum and disposed of. This information helps to explain how the process works and how we might design ways to block it in cancer cells.”

This work was supported by the National Institutes of Health, a Cancer Center Support Grant and ALSAC.(Newswise)

St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tenn., St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fundraising organization.

How Ketamine ("Special K") Impairs Brain Circuitry


Description

Use of ketamine raising concerns by researchers at the UCSD School of Medicine who have found that ketamine leads to the impairments in brain circuitry observed in both drug abusers and schizophrenic patients by causing increased production of a toxic free radical called “superoxide.”

Scientists know that the drug ketamine – street name “Special K” – can induce schizophrenia-like symptoms in drug abusers. Ketamine is also used as an anesthetic and, more recently, as an antidepressant – raising concerns by researchers at the University of California, San Diego (UCSD) School of Medicine, who have found that ketamine leads to the impairments in brain circuitry observed in both drug abusers and schizophrenic patients by causing increased production of a toxic free radical called “superoxide.” Their findings, which could point the way to novel treatments for schizophrenia, will be published in the December 7 issue of the journal Science.

A research team led by Laura Dugan, M.D., Larry L. Hillblom Professor of Geriatrics and research scholar with the UCSD Stein Institute for Research on Aging, discovered an unexpected link between the inflammatory enzyme complex NADPH oxidase and the dysfunction of certain brain neurons exposed to ketamine. NADPH oxidase is normally found in white blood cells circulating outside the brain, where it helps kill bacterial and fungal infections by producing superoxide, a compound that can cause substantial damage to cells.

“Because of NADPH oxidase’s protective role in fighting infection, it was very surprising to find that the complex wears a second hat – it is also critical for modulating signaling in the brain,” said first author M. Margarita Behrens, Ph.D., Division of Geriatric Medicine, UCSD School of Medicine.

According to Behrens, it was known that ketamine initially impairs the inhibitory circuitry in the brain’s cortex and hippocampus by blocking the NMDA receptor, a molecule on the cell surface that controls the activity of neurons. But the UCSD researchers discovered that, as a result of blocking the receptor, ketamine also substantially increased the activity of NADPH oxidase, causing further disruption of neuronal signaling.

“Ketamine causes a ‘disinhibition’ of brain circuitry, taking the brakes off the system and causing overexcitation of the brain in response to a stimulus,” said Behrens. “This overexcitation activates NADPH oxidase, which then produces superoxide – resulting in detrimental changes in key synaptic proteins and profoundly affecting nervous system function.”

The result is impairment of the brain circuitry involved in memory, attention and other key functions related to learning. Loss of such functions sets up individuals for psychosis and deficits in information processing, resulting in symptoms such as hallucinations and delusions, as well as social withdrawal and cognitive problems, according to Behrens.

Using ketamine, Behrens and Dugan mimicked features of schizophrenia in mice, and then analyzed neurons in a region of the mouse brain that corresponds to the prefrontal cortex in humans where profound changes occur in patients with schizophrenia. The researchers found a substantial increase in the activity of NADPH oxidase, and that this activity made some neurons in this inhibitory circuitry “disappear.” When the researchers blocked the activity of NADPH oxidase with an inhibitor, or with a compound that annihilates superoxide, these neurons were protected.

“Our findings suggest that compounds that inhibit NADPH oxidase in the brain, without totally blocking its protective function of killing bacteria, could provide future therapies for schizophrenia or other diseases in humans that exhibit similar changes in neural circuitry,” said Behrens.

Additional contributors to the paper include Sameh S. Ali, Diep N. Dao, Jacinta Lucero, Grigoriy Shekhtman and Kevin L. Quick, Department of Medicine, UCSD Division of Geriatric Medicine. The research was funded in part by the Larry L. Hillblom Endowment and NARSAD.

One Mutation in Mosquito Virus Launched La Reunion Epidemic

Description
Researchers have discovered the key to how a mysterious mosquito-borne viral outbreak swept over the Indian Ocean island of La Reunion in 2005 and 2006, infecting about 266,000 people and causing at least 260 deaths — the first fatalities to be reported in connection with the virus, known as chikungunya.


Researchers have discovered the key to how a mysterious mosquito-borne viral outbreak swept over the Indian Ocean island of La Reunion in 2005 and 2006, infecting about 266,000 people and causing at least 260 deaths — the first fatalities to be reported in connection with the virus, known as chikungunya.

University of Texas Medical Branch at Galveston (UTMB) scientists proved that a single mutation in the virus glycoprotein E1 made it more infectious and facilitated its transmission by a mosquito species found on La Reunion and neighboring islands — one not previously involved in chikungunya outbreaks. The species, Aedes albopictus, is commonly known as the Asian tiger mosquito; it established itself in the United States about 20 years ago and has recently spread to southern Europe.

Chikungunya virus normally causes extreme arthritis-like joint pain, which can occasionally last for months or years. It takes its name from an African tribal word meaning “that which bends up,” a reference to the contorted, stooped posture some of its victims assume.

“Chikungunya virus had been known to be primarily carried by a different mosquito, Aedes aegypti, which is not found on La Reunion,” said UTMB professor Stephen Higgs, senior author of a paper on the discovery appearing online Dec. 7 in PloS Pathogens, a peer-reviewed open-access journal published by the Public Library of Science. “Adaptation to Aedes albopictus and introduction to a human population that had never been exposed to the virus before set everything up for this outbreak.”

Numerous tourists became infected, many of whom carried chikungunya home with them. Although the La Reunion strain of the virus did not cause a subsequent outbreak in Europe, Higgs said, it could have done so. In fact, another strain of the virus responsible for an ongoing outbreak in India has spread to Aedes albopictus mosquitoes and humans in Italy.

The UTMB researchers focused their attention on a single-amino acid change in the La Reunion chikungunya strain and found that this E1 A226V mutation led to increased virus infectivity for Aedes albopictus. To further prove the role of this mutation, lead author and graduate student Konstantin Tsetsarkin inserted that change into a chikungunya strain collected in West Africa in 1983, and then showed that it dramatically increased the virus’ ability to infect Aedes albopictus.

“After we finished with the infectivity experiments, we analyzed the ability of the virus to disseminate to mosquito salivary glands and then be transmitted by mosquitoes,” Tsetsarkin said. “Then we simultaneously infected Aedes albopictus mosquitoes with equal amounts of the mutant virus and the original strain, and we saw that the virus with the E1 A226V mutation was predominately transmitted over the other one — the mutation gave the La Reunion strain an evolutionary advantage in Aedes albopictus, enabling it to out-compete the other strain.”

The key mutation, Tsetsarkin said, was linked to the virus’ dependence on cholesterol in mosquito cell membranes, a key factor in the virus’ ability to infect those cells and spread to mosquito salivary glands. Like other mosquito-borne viruses, chikungunya spreads to humans in mosquito saliva when the insects bite people.

“This is such a simple genetic change — the equivalent of a missing comma in a six-page short story — and yet it facilitated a huge epidemic,” Higgs said. “With Aedes albopictus already present in so many countries and likely to spread to others, perhaps helped by global warming, this shows us that we need to be ready for the possibility that chikungunya will soon be spreading to other locations as well.”