Researchers discover molecular target for the bacterial infection brucellosis

Main Category: Infectious Diseases / Bacteria / Viruses
Article Date: 19 Aug 2013 - 1:00 PDT Current ratings for:
Researchers discover molecular target for the bacterial infection brucellosis

UC Davis scientists have uncovered a potential drug target for the development of an effective therapy against the debilitating, chronic form of the bacterial disease brucellosis, which primarily afflicts people in Mediterranean and Middle Eastern countries.

Brucellosis, which affects about 500,000 people worldwide each year, typically is caused by ingestion of unsterilized milk or close contact with body secretions from infected animals. Symptoms include intermittent or irregular fever of variable duration, headache, weakness, profuse sweating, chills, weight loss and generalized aching. It can also cause long-lasting or chronic symptoms such as recurrent fevers, joint pain and fatigue.

In a paper published online in the journal Cell Host & Microbe, the researchers reported that they have identified the cells that harbor the B. abortus bacteria during the persistent phase of the brucellosis. The cells, known as alternatively activated macrophages (AAMs), are a recently identified category of immune defense cells.

The researchers also determined that the biological pathway peroxisome proliferator activated receptor ?, abbreviated as PPAR?, is responsible for altering the metabolism of AAMs so that they supply B. abortus with the energy in the form of glucose that enables bacteria to survive and replicate and thereby sustain the chronic phase of the infectious disease. Other labs also have shown that PPAR? control a cell's metabolism.

"We found that PPAR? induces a metabolic shift in these cells that causes them to generate glucose," said Renee Tsolis, associate professor of medical microbiology and immunology at UC Davis who led the study.

"Starving the B. abortus bacteria by inhibiting the PPAR? pathway may be a new approach to eradicating the chronic, difficult-to-treat form of Brucellosis infection that usually occurs because antibiotic therapy was not used during the acute, or early, phase of the infection," said Tsolis.

Tsolis and her collaborators were the first to discover PPAR?'s role in brucellosis and to determine that AAMs harbor the bacteria during the chronic stage of the disease. The identification of the bacteria's niche is another important clue for the development of a more effective treatment, she said.

In a series of experiments, Tsolis and collaborators found that the gene encoding PPAR? is very active during chronic Brucellosis infection, but not during acute infection, and that the B. abortus bacteria did not survive in AAMs when deprived of glucose.

When the researchers inactivated the protein that normally transports glucose, the bacteria stopped reproducing, and the infection no longer was chronic, she said.

In mice infected with B. abortus, Tsolis and collaborators treated the animals with GW9662, a PPAR inhibitor. The researchers administered the inhibitor before the infection became chronic, or long lasting. The inhibitor significantly reduced the amount of AAMs and B. abortus bacteria in the mice.

"These results suggested that inhibition of PPARreduced the bacteria's survival by reducing the abundance of AAMs during chronic infection," said Tsolis.

Conversely, when the researchers treated the B. abortus-infected mice with Rosiglitazone, a drug that boosts PPAR activity, the bacteria increased by two-fold during the acute phase and four-fold during the chronic phase of infection. Rosiglitazone and other drugs that boost PPARare used to treat type 2 diabetes because they lower blood glucose by increasing cellular glucose uptake.

In other experiments, the researchers showed that AAMs, one of two categories of macrophages, are abundant in the spleen during chronic brucellosis but not during the acute, or initial, phase of the infection, which is dominated by classically activated macrophages (CAM), the second category of these immune cells.

In addition to profuse sweating, symptoms of brucellosis infection include joint and muscle pain. Among the complications of chronic infection are arthritis and endocarditis, a serious inflammation of one of the four heart valves. Brucellosis rarely occurs in the U.S., with about 100 to 200 cases reported each year, according to the U.S. Centers for Disease Control and Prevention.

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The title of the journal paper is “PPAR?-Mediated Increase in Glucose Availability Sustains Chronic Brucella abortus Infection in Alternatively Activated Macrophages.”

Authors also include: Mariana N. Xavier, Maria G. Winter, Alanna M. Spees, Andreas B. den Hartigh, Kim Nguyen, Christelle M. Roux, Vidya L. Atluri, Tobias Kerrinnes, A. Marijke Keestra and Andreas J. Baumler of UC Davis; Denise M. Monack of Stanford University, Palo Alto, CA; and Paul A. Luciw, Richard A. Eigenheer, Renato L. Santos and Teane M.A. Silva of the Universidade Federal de Minas Gerais in Brazil. Cell Host & Microbe, Volume 14, Issue 2, 159-170, 14 August 2013; 10.1016/j.chom.2013.07.009

University of California - Davis Health System

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Researchers link PRKG1 genetic mutation to thoracic aortic disease

Main Category: Heart Disease
Also Included In: Genetics
Article Date: 19 Aug 2013 - 1:00 PDT Current ratings for:
Researchers link PRKG1 genetic mutation to thoracic aortic disease

A multi-institutional team led by Dianna Milewicz, M.D., Ph.D., of The University of Texas Health Science Center at Houston (UTHealth) has found a recurrent genetic mutation that has been linked to deadly thoracic aortic dissections in family members as young as 17 years of age.

The gene known as PRKG1 makes a protein called cGMP-dependent kinase, type I. The PRKG1 mutation alters the function of the protein and causes the muscle cells in the wall of the aorta to respond incorrectly to pulsatile blood flow from the heart, and the change in this one protein ultimately causes thoracic aortic aneurysm and acute aortic dissection. The mutation was identified in four families, including three in the United States. The majority of the affected family members suffered acute aortic dissections at young ages (17 to 51 years).

"What is unique about this finding is that we identified four unrelated families from around the world and of different ethnicities who have the exact same genetic mutation, which is one altered base pair out of the 3 billion base pairs that make up our DNA," said Milewicz, senior author of the study. "The protein is normally regulated but this mutation causes the protein to be always active, almost like the brakes have gone out on a car and it cannot stop." The study was published in the online issue of the American Journal of Human Genetics. Milewicz is professor and director of the Division of Genetics at the UTHealth Medical School and holds the President George H.W. Bush Chair in Cardiovascular Research. She is also on the faculty of The University of Texas Graduate School of Biomedical Sciences and director of the John Ritter Research Program in Aortic and Vascular Disease.

For families in the study, knowing who carries the gene defect could help them make important medical decisions.

"The fact we will have a positive identification gives us a clearer picture of what to do next," said Stephen Harris of Montana, who lost one of his four daughters to the disease. "If my daughters are not carrying the gene defect, it gives them more freedom to have a baby. And they can make a decision about whether to have elective surgery sooner."

In thoracic aortic disease, the wall of the aorta, the main blood vessel leading out of the heart, weakens and forms an aneurysm that can ultimately lead to an aortic dissection and death. There are few symptoms until the aorta begins to dissect, or tear, requiring emergency surgery. Thoracic aortic aneurysms and dissections are familial in up to 20 percent of all cases. Researchers have now discovered nine different genes linked to familial thoracic aortic disease. Family members who have inherited the mutated gene will need to be monitored by a cardiologist, undergo regular imaging of the aorta and take medications to control high blood pressure and reduce the stress on the aorta. When the aorta enlarges to a certain size, elective surgery can be performed in order to avoid emergency repair to attempt to repair a catastrophic aortic dissection or rupture. . Using this management protocol, acute aortic dissections and the associated premature deaths can be prevented.

Stephen Harris' brother was the first to have symptoms of an aortic dissection when he was 51 years old and was found to have a descending thoracic aortic dissection. Cheryl Harris, Stephen's wife, said their daughter Jenny was eight months pregnant in 2006 when she began to have severe pain in her back just like her uncle but since aortic disease mostly affects older men, they didn't connect it to her. She died suddenly six days later from a dissected aorta and the baby also did not survive. In June of 2012, daughter Andra Arterbury, then 27, felt the classic symptom of extreme back pain, which radiated into her neck. She insisted on a scan at the hospital emergency room and went immediately to life-saving surgery when it showed that the aorta was dissected up into her carotid artery and down nearly to her groin.

Steve Harris traveled to Houston to consult with Milewicz and the clinical team at the Multidisciplinary Aortic and Vascular Disease Clinic. He was also found to have aortic root dilation and because of his family history of early thoracic aortic dissections at diameters smaller than 5 centimeters, he elected to have surgery. In October 2012, Anthony Estrera, M.D., associate professor of cardiovascular surgery at the UTHealth Medical School and the Memorial Hermann Heart and Vascular Institute, performed the graft replacement of his aortic root.

Wendy Amaya, 40, of Albuquerque and her family members have also suffered from the disease. Her mother, 43; brother, 35; and nephew, 23, all died from thoracic aortic dissections. Her 19-year-old son required surgery to repair a dissection in 2012 and another son has an aneurysm that is being monitored. Amaya had surgical repairs for her aorta in 2004 and 2012.

"The imaging is expensive, so it's important to find out if they have the genetic mutation. I have younger children and nieces and nephews," Amaya said. Now that the causative genetic mutation has been identified, genetic testing can identify family members who carry the familial mutation and need aortic surveillance.

Of the individuals who have the mutation, 63 percent had acute aortic dissections and 37 percent have aortic root enlargement. Of the 19 family members with dissections, five had a diagnosis of hypertension and five had evidence of damage associated with hypertension such as left ventricular hypertrophy or chronic small vessel cerebrovascular disease.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our heart disease section for the latest news on this subject.

Recurrent Gain-of-Function Mutation in PRKG1 Causes Thoracic Aortic Aneurysms and Acute Aortic Dissections

The American Journal of Human Genetics, Volume 93, Issue 2, 398-404, 01 August 2013 doi:10.1016/j.ajhg.2013.06.019

First author of the paper is Dong-chuan Guo, Ph.D., assistant professor of genetics at UTHealth. Co-authors from UTHealth are Ellen Regalado, M.S., genetic counselor and instructor; Limin Gong, assistant professor; and Guijuan Ghang, M.D., postdoctoral fellow.

Co-authors and investigators throughout world include Darren Casteel, Ph.D., of the University of California at San Diego; Guillaume Jondeau and Catherine Boileau from the Institut National de la Sante et de la Recherche Medicále of France; Jay Shendure, Mark J. Rieder, Michael J. Bamshad and Deborah Nickerson, Ph.D., from the University of Washington; Suzanne Leal, Ph.D., Regie Santos-Cortez, M.D., Ph.D., Joseph Coselli, M.D., and Choel Kim, Ph.D., from Baylor College of Medicine; Sarah Dyack and S. Gabrielle Horne, from Dalhousie University, Halifax, Nova Scotia, Canada; and the GenTAC Registry Consortium (HHSN268200648199C and HHSN268201000048C).

Funding for the research came from the National Heart, Lung and Blood Institute (NHLBI) (R01 HL62594 and P50HKL083794-01), part of the National Institutes of Health; the Vivian L. Smith Foundation; and the Tex-Gen Foundation. French and European sources provided funding for the Paris investigators. Support was also received from the NHLBI GO Exome Sequencing Project (HL-102926).

University of Texas Health Science Center at Houston

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Researchers have developed an experimental therapy that can kill human blood cancer cells in the laboratory and eradicate the disease in mice

Main Category: Lymphoma / Leukemia / Myeloma
Article Date: 15 Aug 2013 - 0:00 PDT Current ratings for:
Researchers have developed an experimental therapy that can kill human blood cancer cells in the laboratory and eradicate the disease in mice

Ottawa researchers have developed unique virus-derived particles that can kill human blood cancer cells in the laboratory and eradicate the disease in mice with few side effects. The study is published in Blood Cancer Journal by co-senior authors Drs. David Conrad and John Bell of the Ottawa Hospital Research Institute (OHRI) and the University of Ottawa (uOttawa).

While Dr. Bell and his colleagues have been investigating replicating viruses for the treatment of solid cancers for many years, with very promising results, this is the first major success they have had treating blood cancer (leukemia). It is also the first success they have had using a non-replicating virus-derived particle as opposed to a replicating virus.

"Our research indicated that a replicating virus might not be the safest or most effective approach for treating leukemia, so we decided to investigate whether we could make virus-derived particles that no longer replicate but still kill cancer," said Dr. Conrad, a hematologist conducting research in the Blood and Marrow Transplant Program at The Ottawa Hospital, and currently completing his PhD at OHRI and uOttawa in the Department of Cellular and Molecular Medicine. "We were delighted to see that this novel therapy was very safe at high doses, and worked extremely well in our laboratory leukemia models. We hope to test this in patients in the near future."

The researchers used a specific method and dose of UV light to transform regular replicating viruses into unique particles that could no longer replicate and spread, but could still enter cancer cells efficiently, kill them and stimulate a strong immune response against the cancer. These particles were able to kill multiple forms of leukemia in the laboratory, including samples taken from local patients who had failed all other therapies. Normal blood cells were not affected. This novel treatment was also successful in mouse models of leukemia. In fact, 80 per cent of the mice that received the therapy had markedly prolonged survival and 60 per cent were eventually cured, while all of the untreated mice died of their leukemia within 20 days.

"Leukemia is a devastating disease that can be very difficult to treat, and new therapies are urgently needed," said Dr. Conrad. "While we're still at the early stages of this research, I think this therapy holds a lot of promise because it appears to have a potent, long-lasting effect on leukemia without the debilitating side effects of many cancer therapies used in the clinic right now. We will likely see even better results once we optimize the dose in our preparations to advance this research into human clinical trials."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our lymphoma / leukemia / myeloma section for the latest news on this subject.

This research was funded by the Ontario Institute for Cancer Research, the Terry Fox Foundation, the Natural Sciences and Engineering Research Council of Canada, the Canadian Institutes of Health Research, Ottawa's Department of Medicine and The Ottawa Hospital Foundation.

Non-replicating rhabdovirus-derived particles (NRRPs) eradicate acute leukemia by direct cytolysis and induction of antitumor immunity. Batenchuk C, Le Boeuf F, Stubbert L, Falls T, Atkins HL, Bell JC, and Conrad DP. Blood Cancer J. 2013 Jul 12;3:e123. doi: 10.1038/bcj.2013.23.

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Cardiovascular researchers examine habits that can lead to obesity, future heart risk

Main Category: Obesity / Weight Loss / Fitness
Also Included In: Pediatrics / Children's Health;  Heart Disease
Article Date: 14 Aug 2013 - 0:00 PDT Current ratings for:
Cardiovascular researchers examine habits that can lead to obesity, future heart risk

Among middle-school children, the behaviors most often linked with obesity are school lunch consumption and two hours or more of daily TV viewing, according to a new look at the dramatic increase in childhood obesity.

The findings by the University of Michigan Frankel Cardiovascular Center will be published in the September issue of Pediatrics.

While some habits were the same for all overweight and obese children, the study found some gender differences in the habits influencing body weight.

Data from 1,714 sixth grade students enrolled in Project Healthy Schools showed girls who drank two servings of milk each day were less likely to be obese, and boys who played on a sports team were also at a healthier weight.

"Additional work is needed to help us understand the beneficial impact of improving school lunches and decreasing screen time," says cardiologist and senior study author Elizabeth Jackson, M.D., M.P.H., assistant professor of internal medicine at the University of Michigan Medical School. "Presumably playing video games, or watching TV replaces physical activity."

Students enrolled in sixth grade at 20 schools in the southeastern Michigan communinities of Detroit, Ann Arbor, Ypsilanti and Owosso were eligible for participation in this study. The median age was 11.

Obese boys and girls had poor cardiovascular profiles with lower HDL-cholesterol, higher triglycerides, higher blood pressure and higher heart rate recovery - indicating a lower level of fitness - compared to normal weight kids.

"Cardiovascular disease doesn't just start in adulthood, and there may be factors that could help us identify during youth or adolescence who might be at increased risk for developing health problems later on," Jackson says.

Other studies have linked eating school lunch with obesity, but a major issue with such studies, Jackson says, is the influence of socioeconomic status. Poor children eligible for free or reduced school lunch may already be overweight, considering the link between obesity and lower socioeconomic status.

"Although we were not able to examine the specific nutritional content of school lunches, previous research suggests school lunches include nutrient-poor and calorie-rich foods," Jackson says.

The University of Michigan study adds a new element in the fight to reduce childhood obesity by providing a real-world view of the gender differences in obesity risk factors.

Milk consumption seemed to protect girls from obesity, but made no difference for boys. A possible explanation would be a reduction in sugary drinks, which girls replaced with milk.

In the study, 61 percent of obese boys and 63 percent of obese girls reported watching television for two or more hours a day. The assumption is watching television mediates physical activity, but there were gender differences in how children spent their so-called "screen time."

When asked, obese girls were more likely than any other group to use a computer. Obese boys reported playing video games more often than normal weight boys, although the association was not as strong as in other studies.

"We did not find a significant association between time spent playing video games and obesity among boys, which has been observed in other studies," says study lead author Morgen Govindan, an investigator with the Michigan Cardiovascular Research and Reporting Program at the U-M. "Although we saw a similar trend, the association was not as strong perhaps due to our smaller sample size."

She adds: "Exploring such gender-related differences in a larger group may help in refining the interventions to promote weight loss and prevent obesity among middle school children."

The Project Healthy Schools program is designed to teach sixth graders heart-healthy lifestyles including eating more fruits and vegetables, making better beverage choices, engaging in 150 minutes of exercise per week, eating less fast food and less fatty foods, plus reducing time spent in front of computer and video game screens.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our obesity / weight loss / fitness section for the latest news on this subject.

Funding: Project Healthy Schools’ wellness efforts have been generously supported by a number of health systems, foundations, and individuals, including the University of Michigan Health System, the Thompson Foundation, the Hewlett Foundation, the Mardigian Foundation, the Memorial Healthcare Foundation, the William Beaumont Health System Foundation, the Robert C. Atkins Foundation, the Ann Arbor Area Community Foundation, the Allen Foundation, AstraZeneca HealthCare Foundation, Borders, Inc. and the Robert Beard Foundation.

Gender Differences in Physiologic Markers and Health Behaviors Associated With Childhood Obesity

Additional University of Michigan authors: Morgen Govindan; Roopa Gurm; Sathish Mohan; Eva Kline-Rogers, RN; Nicole Corriveau; Caren Goldberg, M.D.; Jean DuRussel-Weston, RN, M.P.H. and Kim A. Eagle, M.D. Pediatrics, Volume 132, Number 3, September 2013. Published online August 12, 2013. (doi: 10.1542/peds.2012-2994)

University of Michigan Health System

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Researchers compute, then combine benign viruses to fight disease

Main Category: Genetics
Article Date: 14 Aug 2013 - 0:00 PDT Current ratings for:
Researchers compute, then combine benign viruses to fight disease

Rice University researchers are making strides toward a set of rules to custom-design Lego-like viral capsid proteins for gene therapy.

A new paper by Rice scientists Junghae Suh and Jonathan Silberg and their students details their use of computational and bioengineering methods to combine pieces of very different adeno-associated viruses (AAVs) to create new, benign viruses that can deliver DNA payloads to specific cells.

The research appears this month in the American Chemical Society journal ACS Synthetic Biology.

AAVs are found in nature and commonly infect humans but cause no disease. That makes them good candidates to serve as carriers that target cells and deliver genes to treat diseases.

The team, which included graduate student and lead author Michelle Ho and undergraduates Benjamin Adler and Michael Torre, wants to define rules to design a variety of viruses that deliver therapeutic genes. They used computer models to find likely AAV candidates for recombination and then tested the model predictions by engineering 17 unique virus capsid proteins and evaluating their ability to fold and assemble into capsid-encased viruses.

Gene therapy shows promise in the treatment of not only genetic disorders but also cancer and cardiovascular diseases, said Suh, an assistant professor of bioengineering at Rice's BioScience Research Collaborative.

"But you need a mechanism to get the correct gene into the human body and to the target cells," she said. "To do that, people use gene vectors, and viruses encompass the largest category of vectors. They've naturally evolved to deliver genes into the body. Our goal is to reprogram them to target specific organs or tissues.

"The big challenge is to go about this in a rational manner," she said. "People have done a lot of work to solve the structure of viruses. We know what they look like. The question is: How can we use that information to guide the design of our viral vectors?"

The team's answer starts with the "SCHEMA" algorithm they adapted to predict how parts of very large viruses can recombine by homing in on the viral protein sequences that work well together.

Silberg, an associate professor of biochemistry and cell biology, said approaches to virus design can lean either toward brute force - "Let's make 1,000 of them and maybe we'll get lucky" - or purely computational, where a biophysicist will try to predict the role of small changes to the virus capsid.

"We're working on a hybrid approach," he said. "Instead of making a random library (of viruses) or computationally designing a single virus, which has a low frequency of working, we're trying to make smart libraries. We're learning to adapt computer programs used for small proteins with a few thousand atoms for viruses with more than 100,000 atoms."

Rather than target mutations in particular viruses, the researchers used the program to compare parts from different but related viruses to see if they would combine together to form new viruses.

"We're treating them like Legos," Silberg said. "We're taking distantly related viruses that nature might not recombine very efficiently and looking for self-contained pieces of these proteins that can be swapped."

The "parent" viruses were AAV serotype 2, which Suh said is the most commonly studied for gene therapy today, and AAV serotype 4. "They're part of the same virus family, but genetically, AAV4 is one of the most different from AAV2."

She said it has been difficult for researchers in the past to rationally make chimeras - one organism that combines parts of two or more genetically distinct elements - from these viruses using traditional techniques.

But Suh's lab confirmed the chimeric structures predicted by the computer models could be made into real hybrid viruses. Now the challenge is to make a much larger library of chimeric viruses to establish a statistically solid set of guidelines.

"We want to know how to make a more stable virus, or a virus that switches its conformation after it enters a cell," Silberg said.

"And we want to know how to make one that goes not only just to the brain, but to a specific part of the brain to target a neurodegenerative disease," Suh added. "The bottom line is that we want these rules."

Silberg said the researchers had expected to confirm that the SCHEMA algorithm could efficiently predict recombinations that could deliver cargo to cells. "But we also learned something really surprising: that you can beat these viruses up a lot more than you can small proteins, and they still assemble into large virus particles," he said. "It's really interesting that viruses fundamentally seem to tolerate the kind of mutation we're doing."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our genetics section for the latest news on this subject.

The Keck Center of the Gulf Coast Consortia Nanobiology Interdisciplinary Graduate Training Program (through a grant from the National Institute of Biomedical Imaging and Bioengineering), the Robert A. Welch Foundation and the National Science Foundation supported the research.

SCHEMA computational design of virus capsid chimeras: calibrating how genome packaging, protection, and transduction correlate with calculated structural disruption

Michelle L. Ho , Benjamin A Adler , Michael L Torre , Jonathan J. Silberg , and Junghae Suh. ACS Synth. Biol., Just Accepted Manuscript. DOI: 10.1021/sb400076r. Publication Date (Web): July 31, 2013

Rice University

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Researchers map a new metabolic pathway that controls mTORC1 activation which is involved in cell growth

Main Category: Biology / Biochemistry
Also Included In: Cancer / Oncology;  Diabetes
Article Date: 05 Aug 2013 - 1:00 PDT Current ratings for:
Researchers map a new metabolic pathway that controls mTORC1 activation which is involved in cell growth

Deciphering the body's complex molecular pathways that lead to disease when they malfunction is highly challenging. Researchers at Sanford-Burnham Medical Research Institute now have a more complete picture of one particular pathway that can lead to cancer and diabetes. In the study published by Molecular Cell, the scientists uncovered how a protein called p62 has a cascade affect in regulating cell growth in response to the presence of nutrients such as amino acids and glucose. Disrupting this chain may offer a new approach to treating disease.

The protein p62 interacts with another protein called TRAF6 to activate a protein complex called mTORC1. In fact, researchers have found that mTORC1, also known as mammalian target of rapamycin complex 1, is highly activated in cancer cells. The pathway that controls mTORC1 activation is also important for metabolic homeostasis (i.e., stability). When the pathway malfunctions, metabolic disorders such as diabetes can result and tumors can progress.

About a year ago, Maria Diaz-Meco, Ph.D., Jorge Moscat, Ph.D., and their colleagues had identified that p62 is an important player in this complex pathway. But they didn't know how. Their new study shows that p62 activates mTORC1 through TRAF6.

"The mTORC1 pathway is a major complex important not only for cancer but also for metabolic homeostasis," said Diaz-Meco. "For that reason, it's very important to unravel the mechanism that controls how mTORC1 responds to the different signals."

"mTORC1 responds to many growth signals," she added, "but the specific mechanisms that channel the activation of mTORC1 by nutrients such as amino acids and glucose are still not completely understood. Our goal was to discern the specific mechanisms that regulate this important pathway."

The researchers found that TRAF6 plays a role in activating mTORC1 by molecularly modifying it in a process called ubiquitination. TRAF6, meanwhile, itself becomes activated in the presence of amino acids. "When you have a diet high in meat, the concentration of amino acids in your blood increases, and that's a way to activate this pathway," Moscat said. This can have tremendous implications not only for diabetes, but also for cancer-cell proliferation, which needs a constant supply of nutrients to grow.

More work is needed to fully understand the pathway, but the researchers next plan is to find ways to disrupt the interaction between p62 and TRAF6, with the ultimate goal of inactivating mTORC1 and therefore controlling cancer progression. "Because mTORC1 is a highly important protein that regulates growth, therapies aimed at blocking mTORC1 activation may offer a new approach to treating disease," Diaz-Meco said.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our biology / biochemistry section for the latest news on this subject.

This work was supported by grants from the U.S. National Institutes of Health (grants R01CA132847, R01AI072581, R01DK088107, R01CA134530M).

Juan F. Linares, Sanford-Burnham; Angeles Duran, Sanford-Burnham; Tomoko Yajima, Sanford-Burnham; Manolis Pasparakis, Institute for Genetics, University of Cologne (Germany); Jorge Moscat, Sanford-Burnham; and Maria T. Diaz-Meco, Sanford-Burnham.

Sanford-Burnham Medical Research Institute

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Re-learning how to see: researchers find crucial on-off switch in visual development

Main Category: Eye Health / Blindness
Also Included In: Neurology / Neuroscience
Article Date: 05 Aug 2013 - 0:00 PDT Current ratings for:
Re-learning how to see: researchers find crucial on-off switch in visual development

A new discovery by a University of Maryland-led research team offers hope for treating "lazy eye" and other serious visual problems that are usually permanent unless they are corrected in early childhood.

Amblyopia afflicts about three percent of the population, and is a widespread cause of vision loss in children. It occurs when both eyes are structurally normal, but mismatched - either misaligned, or differently focused, or unequally receptive to visual stimuli because of an obstruction such as a cataract in one eye.

During the so-called "critical period" when a young child's brain is adapting very quickly to new experiences, the brain builds a powerful neural network connecting the stronger eye to the visual cortex. But the weaker eye gets less stimulation and develops fewer synapses, or points of connection between neurons. Over time the brain learns to ignore the weaker eye. Mild forms of amblyopia such as "lazy eye" result in problems with depth perception. In the most severe form, deprivation amblyopia, a cataract blocks light and starves the eye of visual experiences, significantly altering synaptic development and seriously impairing vision.

Because brain plasticity declines rapidly with age, early diagnosis and treatment of amblyopia is vital, said neuroscientist Elizabeth M. Quinlan, an associate professor of biology at UMD. If the underlying cause of amblyopia is resolved early enough, the child's vision can recover to normal levels. But if the treatment comes after the end of the critical period and the loss of synaptic plasticity, the brain cannot relearn to see with the weaker eye.

"If a child is born with a cataract and it is not removed very early in life, very little can be done to improve vision," Quinlan said. "The severe amblyopia that results is the most difficult to treat. For that reason, science has the most to gain by a better understanding of the underlying mechanisms."

Quinlan, who specializes in studying how communication through the brain's circuits changes over the course of a lifetime, wanted to find out what process controls the timing of the critical period of synaptic plasticity. If researchers could find the neurological on-off switch for the critical period, she reasoned, clinicians could use the information to successfully treat older children and adults.

Researchers in Quinlan's University of Maryland lab teamed up with the laboratory of Alfredo Kirkwood at Johns Hopkins University to address two questions: What are the age boundaries of the critical period for synaptic plasticity, when it comes to determining eye dominance? And what developmental processes are involved?

Experiments in rodents suggested the timing of the critical period is controlled by a specific class of inhibitory neurons, which come into play after a visual stimulus activates excitatory neurons that link the eye to the visual cortex. The inhibitory neurons act as signal controllers, affecting the interactions between excitatory neurons and synapses.

"The generally accepted view has been that as the inhibitory neurons develop, synaptic plasticity declines, which was thought to occur at about five weeks of age in rodents," roughly equivalent to five years of age in humans, Quinlan said. But in earlier experiments, Quinlan and Kirkwood found no correlation between the development of these inhibitory neurons and the loss of plasticity. In fact, they found the visual circuitry in rodents was highly adaptable at ages beyond five weeks.

In their latest research the UMD-led team looked "one synapse upstream from these inhibitory neurons," Quinlan said, studying the control of that synapse by a protein called NARP (Neuronal Activity-Regulated Pentraxin). Working with two sets of mice - one group genetically similar to wild mice and another that lacked the NARP gene - the researchers covered one eye in each animal to simulate conditions that produce amblyopia.

The mice that were genetically similar to wild mice developed amblyopia, with characteristic dominance of the normal eye over the deprived eye. But the mice that lacked NARP did not develop amblyopia, regardless of age or the length of time one eye was deprived of stimulation.

The study, published in the current issue of the peer-reviewed journal Neuron, demonstrated that only one specific class of synapses was affected by the absence of NARP. Without NARP, the mice simply had no critical period in which the brain circuitry was weakened in response to the impaired blocking vision in one eye, Quinlan said. Except for the lack of this plasticity, their vision was normal.

"It's remarkable how specific the deficit is," Quinlan said. Without the NARP protein, "these animals develop normal vision. Their brain circuitry just isn't plastic. We can completely turn off the critical period for plasticity by knocking out this protein."

Since there are indications that NARP levels vary with age, the discovery raises hope that a treatment targeting NARP levels in humans could allow correction of amblyopia late in life, without affecting other aspects of vision.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our eye health / blindness section for the latest news on this subject.

Yu Gu, Shiyong Huang, Michael G. Chang, Paul Worley, Alfredo Kirkwood, and Elizabeth M. Quinlan, “Obligatory Role for the Immediate Early Gene NARP in Critical Period Plasticity,” Neuron 79, 335-346, July 24, 2013

University of Maryland

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Researchers map a new metabolic pathway that controls mTORC1 activation which is involved in cell growth

Main Category: Biology / Biochemistry
Also Included In: Cancer / Oncology;  Diabetes
Article Date: 05 Aug 2013 - 1:00 PDT Current ratings for:
Researchers map a new metabolic pathway that controls mTORC1 activation which is involved in cell growth

Deciphering the body's complex molecular pathways that lead to disease when they malfunction is highly challenging. Researchers at Sanford-Burnham Medical Research Institute now have a more complete picture of one particular pathway that can lead to cancer and diabetes. In the study published by Molecular Cell, the scientists uncovered how a protein called p62 has a cascade affect in regulating cell growth in response to the presence of nutrients such as amino acids and glucose. Disrupting this chain may offer a new approach to treating disease.

The protein p62 interacts with another protein called TRAF6 to activate a protein complex called mTORC1. In fact, researchers have found that mTORC1, also known as mammalian target of rapamycin complex 1, is highly activated in cancer cells. The pathway that controls mTORC1 activation is also important for metabolic homeostasis (i.e., stability). When the pathway malfunctions, metabolic disorders such as diabetes can result and tumors can progress.

About a year ago, Maria Diaz-Meco, Ph.D., Jorge Moscat, Ph.D., and their colleagues had identified that p62 is an important player in this complex pathway. But they didn't know how. Their new study shows that p62 activates mTORC1 through TRAF6.

"The mTORC1 pathway is a major complex important not only for cancer but also for metabolic homeostasis," said Diaz-Meco. "For that reason, it's very important to unravel the mechanism that controls how mTORC1 responds to the different signals."

"mTORC1 responds to many growth signals," she added, "but the specific mechanisms that channel the activation of mTORC1 by nutrients such as amino acids and glucose are still not completely understood. Our goal was to discern the specific mechanisms that regulate this important pathway."

The researchers found that TRAF6 plays a role in activating mTORC1 by molecularly modifying it in a process called ubiquitination. TRAF6, meanwhile, itself becomes activated in the presence of amino acids. "When you have a diet high in meat, the concentration of amino acids in your blood increases, and that's a way to activate this pathway," Moscat said. This can have tremendous implications not only for diabetes, but also for cancer-cell proliferation, which needs a constant supply of nutrients to grow.

More work is needed to fully understand the pathway, but the researchers next plan is to find ways to disrupt the interaction between p62 and TRAF6, with the ultimate goal of inactivating mTORC1 and therefore controlling cancer progression. "Because mTORC1 is a highly important protein that regulates growth, therapies aimed at blocking mTORC1 activation may offer a new approach to treating disease," Diaz-Meco said.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our biology / biochemistry section for the latest news on this subject.

This work was supported by grants from the U.S. National Institutes of Health (grants R01CA132847, R01AI072581, R01DK088107, R01CA134530M).

Juan F. Linares, Sanford-Burnham; Angeles Duran, Sanford-Burnham; Tomoko Yajima, Sanford-Burnham; Manolis Pasparakis, Institute for Genetics, University of Cologne (Germany); Jorge Moscat, Sanford-Burnham; and Maria T. Diaz-Meco, Sanford-Burnham.

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Researchers target 'cell sleep' to lower chances of cancer recurrence and make cancer drugs more effective

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our cancer / oncology section for the latest news on this subject.

The study is a collaboration with the Dana-Farber Cancer Institute in Boston and the Catholic University in Leuven, Belgium.

Additional co-authors of this study include Sergei Boichuk, M.D., Ph.D., Joshua A. Parry, B.S., Kathleen R. Makielski, M.S., Julianne L. Baron, B.S., James P. Zewe, B.S., Keith R. Mehalek, M.S., and Danushka S. Seneviratne, B.S., all of UPCI’s Cancer Virology Program; James A. DeCaprio, M.D., and Larisa Litovchick, Ph.D., both of the Dana-Farber Cancer Institute; Patrick Schöffski, M.D., M.P.H., Maria Debiec-Rychter, M.D., Ph.D., and Agnieszka Wozniak, Ph.D., all of the Catholic University of Leuven in Belgium; and Nina Korzeniewski, Ph.D., of the University of Heidelberg School of Medicine in Germany.

This research was supported by Research Scholar Grant RSG-08-092-01-CCG from the American Cancer Society, the GIST Cancer Research Fund, The Life Raft Group and a number of private donations.

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Stem cell researchers produce new model of leukemia development

Main Category: Lymphoma / Leukemia / Myeloma
Also Included In: Stem Cell Research
Article Date: 02 Aug 2013 - 1:00 PDT Current ratings for:
Stem cell researchers produce new model of leukemia development

Eight years ago, two former Stanford University postdoctoral fellows, one of them still in California and the other at the Harvard Stem Cell Institute (HSCI) in Cambridge, began exchanging theories about why patients with leukemia stop producing healthy blood cells. What was it, they asked, that caused bone marrow to stop producing normal blood-producing cells?

And after almost a decade of bicoastal collaboration, Emmanuelle Passegué, now a professor in the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at the University of California, San Francisco, and Amy Wagers, a professor in Harvard's Department of Stem Cell and Regenerative Biology, have the answer.

They have found that cancer stem cells actively remodel the environment of the bone marrow, where blood cells are formed, so that it is hospitable only to diseased cells. This finding could influence the effectiveness of bone marrow transplants, currently the only cure for late-stage leukemia, but with a 25 percent success rate due to repopulation of residual cancer cells.

Their results, which were recently published online in Cell Stem Cell, show that leukemia cells cannot replicate in the bone marrow niche as well as healthy blood-forming stem cells can, so the cancer cells gain the advantage by triggering bone marrow-maintenance cells to deposit collagen and inflammatory proteins, leading to fibrosis - or scarring - of the bone marrow cavity.

"They remodel the microenvironment so that it is basically callous, kicking the normal stem cells out of the bone marrow and encouraging the production of even more leukemic cells," Passegué said. This model is a shift from the widely held theory that cancer cells simply crowd out the healthy cells.

Passegué and Wagers stayed in touch, despite the distance between their laboratories, via annual, two-day, "off-the-record" symposiums of junior investigators at the Harvard Stem Cell Institute and the California Institute for Regenerative Medicine (CIRM). The meetings, which began in 2005 and have continued, require all registrants to keep presentations no longer than 15 minutes and only to discuss unpublished work. "It's sort of Las Vegas rules," Wagers said.

At the second such meeting, Passegué was intrigued by Wagers' cell isolation-based approach to studying the bone marrow niche, the environment where stem cells are found. In the ensuing years, the two scientists swapped protocols, chemical reagents, mice, and even postdoctoral researchers in the pursuit of discovering what causes healthy blood cell dysfunction in leukemia. "Wagers was really involved as a creative spirit in the development of this story," Passegué said.

The observation that leukemia cells can remodel the bone marrow niche parallels work done by HSCI co-director David Scadden of the Harvard-affiliated Massachusetts General Hospital, who demonstrated that particular genetic modifications of bone-forming cells initiate changes in the marrow cavity that suppress normal blood formation and promote the emergence of leukemic cells. "So there's this bidirectional communication that's self-reinforcing, "Wagers said. "And if there's a communication loop like that, you can think about interrupting in many different ways."

Passegué wants to understand how bone-marrow support cells are manipulated to sustain leukemia cells, instead of normal blood cells, in order to design therapies that block these detrimental changes. In the short term, her work could explain why 75 percent of bone marrow transplants are unsuccessful. "A poor niche is likely a very important contributing factor for failure to engraft," she said. Her lab has shown that fibrotic bone marrow conditions can be reversed in as little as a few months by removing the bad-acting maintenance cells, and she is now investigating how to restore the healthy bone marrow environment in leukemia patients.

Passegué and Wagers believe the success of this research reflects the value of scientific partnerships. "Both HSCI and CIRM understand the importance of fostering the open communication and collaboration that drives innovation in science," Wagers said.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our lymphoma / leukemia / myeloma section for the latest news on this subject.

The 2013 HSCI/California Junior Faculty Symposium will take place Nov. 8 and 9 at the University of California, Los Angeles.

Koen Schepers, now at the University Medical Center Utrecht, was the first author on this study. The work was supported by the National Institutes of Health, CIRM, a NWO Rubicon Fellowship, and a KWF Fellowship.

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Tisch MS researchers announce breakthrough in disease monitoring

Main Category: Multiple Sclerosis
Article Date: 01 Aug 2013 - 2:00 PDT Current ratings for:
Tisch MS researchers announce breakthrough in disease monitoring

A research team lead by Violaine Harris, Ph.D., at the Tisch MS Research Center of New York, has just published findings on a new method of measuring disease activity in patients with multiple sclerosis (MS).

This important biomarker discovery is based on spinal fluid measurement of Fetuin-A levels obtained over the course of several years of clinical and pathological studies of MS patients as well as experimental models of the disease. Dr. Harris's findings are likely to change the process for making treatment decisions in MS patients.

Current MS treatment is designed to stop disease activity in the brain and spinal cord with the goal of arresting disease progression and disability. According to Dr. Saud A. Sadiq, the senior author on the study, "these findings will provide a measurable method of monitoring the effectiveness of treatment much like determining blood sugar levels are assayed for diabetic patients. Many patients with MS on treatment report 'worsening' despite stable MRI findings. Addition of Fetuin-A measurement will help better evaluate disease activity in such patients."

The Tisch MS Research Team continues to study the underlying mechanisms of elevation of spinal fluid Fetuin-A to determine its exact role in multiple sclerosis.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our multiple sclerosis section for the latest news on this subject.

Cerebrospinal fluid fetuin-A is a biomarker of active multiple sclerosis, Multiple Sclerosis Journal, Epub: 2/25/2013 doi: 10.1177/1352458513477923 ahead of print.

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posted by Dr Zinia Thomas on 1 Aug 2013 at 5:10 am

Fetuin-A levels is very much important to monitor a disease. It is important because if you can't properly monitor the disease treatment will goes wrong.

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'Tisch MS researchers announce breakthrough in disease monitoring'

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Essential clue to Huntington's disease solution found by McMaster researchers

Main Category: Huntingtons Disease
Article Date: 31 Jul 2013 - 1:00 PDT Current ratings for:
Essential clue to Huntington's disease solution found by McMaster researchers

Researchers at McMaster University have discovered a solution to a long-standing medical mystery in Huntington's disease (HD).

HD is a brain disease that can affect 1 in about 7,000 people in mid-life, causing an increasing loss of brain cells at the centre of the brain. HD researchers have known what the exact DNA change is that causes Huntington's disease since 1993, but what is typically seen in patients does not lead to disease in animal models. This has made drug discovery difficult.

In this week's issue of the science journal, the Proceedings of the National Academy of Sciences, professor Ray Truant's laboratory at McMaster University's Department of Biochemistry and Biomedical Sciences of the Michael G. DeGroote School of Medicine reveal how they developed a way to measure the shape of the huntingtin protein, inside of cell, while still alive. They then discovered was that the mutant huntingtin protein that causes disease was changing shape. This is the first time anyone has been able to see differences in normal and disease huntingtin with DNA defects that are typical in HD patients.

They went on to show that they can measure this shape change in cells derived from the skin cells of living Huntington's disease patients.

"With mouse models, we know that some drugs can stop, and even reverse Huntington's disease, but now we know exactly why," said Truant. "The huntingtin protein has to take on a precise shape, in order to do its job in the cell. In Huntington's disease, the right parts of the protein can't line up to work properly. It's like trying to use a paperclip after someone has bent it out of shape."

The research also shows that the shape of disease huntingtin protein can be changed back to normal with chemicals that are in development as drugs for HD.

"We can refold the paper clip," said Truant.

The methods they developed have been scaled up and used for large scale robotic drug screening, which is now ongoing with a pharmaceutical company. They are looking for drugs that can enter the brain more easily. Furthermore, they can tell if the shape of huntingtin has been corrected in patients undergoing drug trials, without relying on years to know if the HD is affected yet.

This research was a concerted effort from many sources: funding from the Canadian Foundation Institute and the Ontario Innovation Trust for an $11M microscopy centre at McMaster in 2006, ongoing support from the Canadian Institutes of Health Research, and important funding from the Toronto-based Krembil Foundation. The project was initiated with charity grant support from the Huntington Society of Canada, which allowed them to show this method was promising for further support.

The last piece of the puzzle was from the Huntington's disease patient community, with skin cell donations from living patients and unaffected spouses that allowed the team to look at real human disease.

There are eight other diseases that have a similar DNA defects as Huntington's disease, Truant's group is now using similar tools to develop assays to measure shape changes in those diseases, to see if this shapeshifting is common in other diseases.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our huntingtons disease section for the latest news on this subject.

Polyglutamine domain flexibility mediates the proximity between flanking sequences in huntingtin, Nicholas Stephane Caron, Carly Robyn Desmond, Jianrun Xia, and Ray Truant, doi: 10.1073/pnas.1301342110 PNAS July 29, 2013

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Researchers urge review of health system-wide pediatric injury training, triaging and prevention efforts

Main Category: Pediatrics / Children's Health
Also Included In: Health Insurance / Medical Insurance;  Public Health
Article Date: 31 Jul 2013 - 0:00 PDT Current ratings for:
Researchers urge review of health system-wide pediatric injury training, triaging and prevention efforts

New research from The Center for Injury Research and Prevention at The Children's Hospital of Philadelphia (CHOP), signals that emergency and outpatient healthcare providers may need to prepare for higher demand for treatment among younger patients with mild and moderate injuries. As federal and state policies encouraging people to be covered by health insurance go into effect, researchers estimate the potential for more than 730,000 additional medically attended injuries annually, or a 6.1 percent increase if all currently uninsured children and young adults (ages 0-26) become insured. The estimates are based on 2008 injury data from the National Health Interview Survey. The study was published in this month's Clinical Pediatrics.

"In order to assist planning efforts by healthcare systems and policymakers, we aimed to examine the impact on trauma systems of increases in young people with health insurance" says Flaura Koplin Winston, MD, PhD, lead author and Scientific Director of the Center for Injury Research and Prevention at CHOP. "This study signals a need to prepare for potential large increases in demand for care of minor and moderate pediatric and young adult injuries in both emergency department and outpatient settings."

According to the study, a significant portion of the increase will come from currently uninsured young adults (18-26 year olds), who will now be able to remain on their parents insurance until age 26 or find affordable care through exchanges. Researchers found that the causes and nature of medically attended injuries differed between insured and uninsured young adults. The uninsured sought medical care for more serious injuries like fractures when compared to other types of injury. The insured sought medical care for a wider distribution of injuries-- with the most common being sprains and strains, as well as open wounds. Of interest, among children under age 18, 11 percent of medically attended injuries among insured kids were related to overexertion, but this injury mechanism did not cause uninsured children to seek care.

Winston and her colleagues based their estimates on recent injury care data and the assumption that those new to insurance would have a probability of medically attended injury that equals that of those who already have insurance. With these assumptions, they predict that each year as many as 510,553 additional children and young adults could be seen for injury treatment in outpatient settings, nearly 195,838 in Emergency Departments or admitted to hospital, with another 30,689 being attended to through phone- only encounters. Winston cautions that the actual health system utilization rates and sites of care may vary as newly insured people may access care differently from those who are already insured.

"Health care delivery systems across the US need to have sufficient numbers of general and pediatric healthcare providers who are trained in treating moderate trauma and injury and can staff urgent carecenters, health centers, primary care practices, call centers, and emergency departments," says Dr. Winston. "In keeping with the aims of the Affordable Care Act, the goal should be that all young patients who seek care for their injuries get the appropriate care at the right time and right place."

The study authors recommend several steps health care systems can take to manage the potential increase in patients and avoid both the expensive overuse of emergency services and the long-term effects on communities of inadequately treated injury:

Train medical students and residents with relevant course content on diagnosis and treatment of concussions, musculoskeletal injury, sports medicine and open wound care. Expand programs such as Poison Control Centers and call centers, and remote medical command for triage and treatment of non-life-threatening injuries. Prevent injuries to children by allocating federal and state resources to proven injury prevention strategies. They cost less than medical care needed to treat injuries. Implement the Centers for Disease Control and Prevention's National Action Plan for Childhood Injury Prevention. Develop or expand proven off-the-job injury prevention strategies. The cost of insuring this new population of youth, the majority of whom currently live with an employed head of household, may fall to employers.

"Injury is the leading health risk for children and young adults. Proven prevention strategies and appropriate acute care will reduce fatalities and the long-term consequences that injury can have on quality of life," says Dr. Winston.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our pediatrics / children's health section for the latest news on this subject.

Dr. Winston's co-authors include Mark R. Zonfrillo, MD, MSCE of CHOP, J Felipe Garcia-Espana, PhD of Coriell Institute for Medical Research, and Ted R. Miller, PhD of the Pacific Institute for Research and Evaluation. The study was supported by National Science Foundation Center for Child Injury Prevention Studies, Pennsylvania Department of Health, and the Health Resources and Administration's Children's Safety Network.

Children's Hospital of Philadelphia

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Innovation in mouse model helps researchers distinguish disease mechanisms and biomarkers

Main Category: Urology / Nephrology
Article Date: 30 Jul 2013 - 2:00 PDT Current ratings for:
Innovation in mouse model helps researchers distinguish disease mechanisms and biomarkers

A team led by researchers at the National Institutes of Health has overcome a major biological hurdle in an effort to find improved treatments for patients with a rare disease called methylmalonic acidemia (MMA). Using genetically engineered mice created for their studies, the team identified a set of biomarkers of kidney damage - a hallmark of the disorder - and demonstrated that antioxidant therapy protected kidney function in the mice.

Researchers at the National Human Genome Research Institute (NHGRI), part of NIH, validated the same biomarkers in 46 patients with MMA seen at the NIH Clinical Center. The biomarkers offer new tools for monitoring disease progression and the effects of therapies, both of which will be valuable in the researchers' design of clinical trials for this disease.

The discovery, reported in the July 29, 2013, advance online issue of the Proceedings of the National Academy of Sciences, paves the way for use of antioxidant therapy in a clinical trial for patients with MMA. It also illustrates the mechanisms by which dysfunction of mitochondria - the power generators of the cell - affects kidney disease. Mitochondrial dysfunction is a factor not only in rare disorders, such as MMA, but also in a wide variety of common conditions, such as obesity, diabetes and cancer.

MMA affects as many as one in 67,000 children born in the United States. It can have several different causes, all involving loss of function of a metabolic pathway that moderates levels of an organic compound called methylmalonic acid. Affected children are unable to properly metabolize certain amino acids consumed in their diet, which damages a number of organs, most notably the kidneys.

"Metabolic disorders like MMA are extremely difficult to manage because they perturb the delicate balance of chemicals that our bodies need to sustain health," said Daniel Kastner, M.D., Ph.D., NHGRI scientific director. "Given that every newborn in the United States is screened for a number of inherited metabolic disorders, including MMA, there is a critical need for better understanding of the disease mechanisms and therapies to treat them."

MMA is the most common organic acid disorder and invariably impairs kidney function, which can lead to kidney failure. The most common therapy is a restrictive diet, but doctors must resort to dialysis or kidney transplantation when the disease progresses. MMA patients also suffer from severe metabolic instability, failure to thrive, intellectual and physical disabilities, pancreatitis, anemia, seizures, vision loss and strokes.

"There are no definitive treatments for the management of patients with MMA," said Charles Venditti, M.D., Ph.D., senior author and investigator in the Organic Acid Research Section of NHGRI's Genetics and Molecular Biology Branch. "This study is the culmination of collaboration with the patient community. It uses mouse modelling, coupled with innovations in genomics and biochemical analyses, to derive new insights into the causes of renal injury in MMA. Our studies have improved our understanding of the basic biology underlying MMA, created a novel animal model for testing interventions and, now, led us to the promise of a new therapy."

The researchers performed the studies using mice bred to carry gene alterations that disrupt the production of the same mitochondrial enzyme that is defective in patients with MMA. These are called transgenic mice. The enzyme, called methylmalonyl-CoA mutase (MUT), is an important component of the chemical process that metabolizes organic acids, specifically methylmalonic acid.

By measuring gene expression in the transgenic mice using DNA microarrays, researchers discovered 50 biomarkers of gene expression that each indicated declining kidney function. DNA microarrays are silicon chips with many spots to which a given molecule may bind. In this case, the DNA microarrays were used to precisely generate, with the aid of a computer program, a profile of gene expression in a kidney cell.

The researchers chose one of the biomarkers, called lipocalin-2, to test how it correlated with kidney function in 46 MMA patients. Plasma levels of this biomarker rose with kidney deterioration in patients with MMA, and may serve as a valuable indicator of MMA kidney disease progression in the clinic.

"The detection of biomarkers through microarray technology is immensely helpful in pointing to downstream pathways affected by the defective MUT activity," said Irini Manoli, M.D., Ph.D., lead author and a physician scientist and staff clinician in NHGRI's Genetics and Molecular Biology Branch. "The biomarkers provide new plasma or serum tests to follow disease progression in our patients."

Having discovered these important biomarkers of kidney function, the authors turned to kidney physiology experts on their team to explore the structural changes that occur in MMA disease. They analyzed the rate at which the kidneys filter waste from the blood. Co-author and renal physiology expert Jurgen Schnermann, M.D., and members of his laboratory at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), also part of NIH, demonstrated the early and significant decrease in this rate in MMA mice.

With further studies, the researchers identified increased production of free radicals in tissues from the mice, as well as in the MMA patients. Detection of free radicals indicates chemical instability in cells, which the researchers sought to remedy with antioxidant therapy. After treating the mice with two forms of dietary antioxidants, the researchers observed that the biomarkers of kidney damage diminished and the faltering kidney filtration rate tapered off. The findings demonstrated that readily available antioxidants can significantly affect the rate of decline of kidney function in transgenic mice, which replicate the kidney disease of MMA.

"The next step will be to translate these findings to the clinic," Dr. Venditti said. "With a progressive disorder like MMA, we are hopeful that we have achieved a laboratory success that our patients will benefit from in the near future."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our urology / nephrology section for the latest news on this subject.

Irini Manoli, Justin R. Sysol, Lingli Li, Pascal Houillier, Caterina Garone, Cindy Wang, Patricia M. Zerfas, Kristina Cusmano-Ozog, Sarah Young, Niraj S. Trivedi, Jun Cheng, Jennifer L. Sloan, Randy J. Chandler, Mones Abu-Asab, Maria Tsokos, Abdel G. Elkahloun, Seymour Rosen, Gregory M. Enns, Gerard T. Berry, Victoria Hoffmann, Salvatore DiMauro, Jurgen Schnermann, and Charles P. Venditti, "Targeting proximal tubule mitochondrial dysfunction attenuates the renal disease of methylmalonic acidemia", Published online before print July 29, 2013, doi: 10.1073/pnas.1302764110

For information about the MMA clinical trial, go to ClinicalTrials.gov and search with NCT00078078.

Learn more about the study

NIH/National Human Genome Research Institute

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Researchers uncover evolutionary pathway of monogamy in humans

Main Category: Psychology / Psychiatry
Article Date: 30 Jul 2013 - 1:00 PDT Current ratings for:
Researchers uncover evolutionary pathway of monogamy in humans

The threat of infants being killed by unrelated males is the key driver of monogamy in humans and other primates.

The study by academics from UCL, University of Manchester, University of Oxford and University of Auckland, is the first to reveal this evolutionary pathway for the emergence of pair living.

The team also found that following the emergence of monogamy males are more likely to care for their offspring. Where fathers care for young, not only can they protect infants from other males, but they can also share the burden of childcare.

Dr Kit Opie (UCL Anthropology), lead author of the study published in the journal PNAS, said: "This is the first time that the theories for the evolution of monogamy have been systematically tested, conclusively showing that infanticide is the driver of monogamy. This brings to a close the long running debate about the origin of monogamy in primates."

Infants are most vulnerable when they are fully dependent on their mother because females delay further conception while nursing slowly developing young. This leads to the threat from unrelated males, who can bring the next conception forward by killing the infant. Sharing the costs of raising young both shortens the period of infant dependency and can allow females to reproduce more quickly.

An additional benefit of sharing the burden of care is that females can then have more costly young. The considerable cognitive requirements of living in complex societies has resulted in many primate species having large, and costly, brains.

Growing a big brain is expensive and requires that offspring mature slowly. Caring fathers can help alleviate the burden of looking after young with long childhoods and may explain how large brains could evolve in humans.

Humans, uniquely among primates, have both very long childhoods and mothers that can reproduce quickly relative to other great apes. Until now, a number of hypotheses have been proposed to explain the evolution of monogamy among mammals. These include:

Paternal care, when the cost of raising offspring is high Guarding solitary females from rival males Infanticide risk, where males can provide protection against rival males

To uncover the evolutionary pathway the team gathered data across 230 primate species. These were then plotted on a family tree of the relationships between those species. Bayesian methods were used to re-run evolution millions of times across the family tree to discover whether different behaviours evolved together across time, and if so, which behaviour evolved first.

This then allowed the team to determine the timing of trait evolution and show that male infanticide is the cause of the switch from a multi-male mating system to monogamy in primates, while bi-parental care and solitary ranging by females are a result of monogamy, not the cause.

Dr Susanne Shultz, from the University of Manchester, said: "What makes this study so exciting is that it allows us to peer back into our evolutionary past to understand the factors that were important in making us human. Once fathers decide to stick around and care for young, mothers can then change their reproductive decisions and have more, brainy offspring."

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Christopher Opiea, Quentin D. Atkinson, Robin I. M. Dunbar, Susanne Shultz "Male infanticide leads to social monogamy in primates", PNAS July 29, 2013, doi: 10.1073/pnas.1307903110

University College London

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