Sequencing of Malaria Genomes Reveals Challenges, Opportunities in Battle Against Parasite

Mosquitoes transmit malaria. Genetic variability revealed in malaria genomes newly sequenced by two multi-national research teams points to new challenges in efforts to eradicate the parasite, but also offers a clearer and more detailed picture of its genetic composition, providing an initial roadmap in the development of pharmaceuticals and vaccines to combat malaria. (Credit: © Kletr / Fotolia)                                       Science Daily  — Genetic variability revealed in malaria genomes newly sequenced by two multi-national research teams points to new challenges in efforts to eradicate the parasite, but also offers a clearer and more detailed picture of its genetic composition, providing an initial roadmap in the development of pharmaceuticals and vaccines to combat malaria.

The research appears in two studies published in the latest issue of the journal Nature Genetics. They focus on Plasmodium vivax (P. vivax), a species of malaria that afflicts humans and the most prevalent human malaria parasite outside Africa, and Plasmodium cynomolgi(P. cynomolgi), a close relative that infects Asian Old World monkeys.

"The bad news is there is significantly more genetic variation inP. vivax than we'd thought, which could make it quite adept at evading whatever arsenal of drugs and vaccines we throw at it," said Professor Jane Carlton, senior author on both studies and part of New York University's Center for Genomics and Systems Biology. "However, now that we have a better understanding of the challenges we face, we can move forward with a deeper analysis of its genomic variation in pursuing more effective remedies."

In one study, the researchers examined P. vivax strains from different geographic locations in West Africa, South America, and Asia, providing the researchers with the first genome-wide perspective of global variability within this species. Their analysis showed thatP. vivax has twice as much genetic diversity as the world-widePlasmodium falciparum (P. falciparum) strains, revealing an unexpected ability to evolve and, therefore, presenting new challenges in the search for treatments.

The second study, performed jointly with Professor Kazuyuki Tanabe at Osaka University, Japan, sequenced three genomes of P. cynomolgi. The researchers compared its genetic make-up to P. vivax and to Plasmodium knowlesi (P. knowlesi), a previously sequenced malaria parasite that affects both monkeys and humans in parts of Southeast Asia.

Their work marked the first time P. cynomolgi genomes have been sequenced, allowing researchers to identify genetic diversity in this parasite. Its similarity to P. vivax means that their results will also benefit future efforts to understand and fight against forms of malaria that afflict humans.

"We have generated a genetic map of P. cynomolgi, the sister species to P. vivax, so we can now push forward in creating a robust model system to study P. vivax," explained Tanabe. "This is important because we can't grow P. vivax in the lab, and researchers desperately need a model system to circumvent this."

Much of the work occurred under a seven-year grant from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. The funding has established 10 International Centers of Excellence for Malaria Research (ICEMR). Carlton is heading an ICEMR based in India, where malaria -- and P. vivax in particular -- is a significant public health burden. A particular aim of this Center of Excellence is to support and help train scientists in India who can then work to combat infectious diseases, such as malaria, where they are most prominent. The P. vivaxsequencing was funded by NIAID as part of the NIAID funded Genomic Sequencing Center for Infectious Diseases at the Broad Institute under Contract No. HHSN272200900018C. The Burroughs Wellcome Fund was instrumental in providing pilot funds for the P. cynomolgi sequencing.

Researchers at the following institutions were also part of theP. vivax sequencing: The Broad Institute, the National Institute of Malaria Research in India, Arizona State University, and the Centers for Disease Control and Prevention.

Researchers at the following institutions were also part of the work on P. cynomolgi: Osaka University, Dokkyo Medical University, Japan's Corporation for Production and Research of Laboratory Primates, Nagasaki University, Juntendo University's School of Medicine, the University of Tokyo, the National Institute of Biomedical Innovation, the Centers for Disease Control and Prevention, and Arizona State University.

Turning White Fat Into Energy-Burning Brown Fat: Hope for New Obesity and Diabetes Treatments

Science Daily   — Columbia University Medical Center (CUMC) researchers have identified a mechanism that can give energy-storing white fat some of the beneficial characteristics of energy-burning brown fat. The findings, based on studies of mice and of human fat tissue, could lead to new strategies for treating obesity and type 2 diabetes. The study was published August 2 in the online edition of the journal Cell.

"Turning white fat into brown fat is an appealing therapeutic approach to staunching the obesity epidemic, but it has been difficult to do so in a safe and effective way," said study leader Domenico Accili, MD, professor of Medicine and the Russell Berrie Foundation Professor at CUMC.Humans have two types of fat tissue: white fat, which stores excess energy in the form of triglycerides, and brown fat, which is highly efficient at dissipating stored energy as heat. Newborns have a relative abundance of brown fat, as protection against exposure to cold temperatures. In adults, however, almost all excess energy is stored as white fat.

White fat can be "browned" with a class of drugs called thiazolidazines (TZDs), which increase the body's sensitivity to insulin. However, TZDs have many adverse effects -- including liver toxicity, bone loss, and, ironically, weight gain -- which have limited the use of these drugs.

The current study was undertaken to learn more about the function of TZDs, with the ultimate goal of developing better ways to promote the browning of white fat.

Scientists have known that TZDs promote the browning of white fat by activating a cell receptor called peroxisome proliferator-activated receptor-gamma (ppar-gamma), but the exact mechanism was not clear. To learn more, Dr. Accili and his colleagues studied a group of enzymes called sirtuins, which are thought to affect various biological processes, including metabolism.

The researchers had previously shown in mice that when sirtuin activity increases, so does metabolic activity. In the present study, they found that sirtuins boost metabolism by promoting the browning of white fat. "When we sought to identify how sirtuins promote browning, we observed many similarities between the effect of sirtuins and that of TZDs," said lead author Li Qiang, PhD, associate research scientist in Medicine at CUMC.

Sirtuins work by severing the chemical bonds between acetyl groups and proteins, a process known as deacetylation. "So the next question was whether sirtuins remove acetyl groups from ppar-gamma and, indeed, that was what we found," said Dr. Qiang.

To confirm that the deacetylation of ppar-gamma is crucial to the browning of fat, the researchers created a mutant version of ppar-gamma, in effect mimicking the actions of sirtuins. The mutation promoted the development of brown fat-like qualities in white fat.

"Our findings have two important implications," said Dr. Accili. "First, they suggest that TZDs may not be so bad -- if you can find a way to tweak their activity. Second, one way to tweak their activity is by using sirtuin agonists -- that is, drugs that promote sirtuin activity."

"The truth is, making sirtuin agonists has proved to be a real bear -- more promise than fact," he continued. "But now, for the first time, we have a biomarker for good sirtuin activity: the deacetylation of ppar-gamma. In other words, any substance that deacetylates ppar-gamma should in turn promote the browning of white fat and have a beneficial metabolic effect."

Dr. Accili's paper is titled, "Brown Remodeling of White Adipose Tissue by SirT1-Dependent Deacetylation of Ppar-gamma." The other contributors are Ning Kon (CUMC), Wenhui Zhao (CUMC), Sangkyu Lee (University of Chicago, Chicago, Illinois), Yiying Zhang (CUMC), Michael Rosenbaum (CUMC), Yingming Zhao (University of Chicago), Wei Gu (CUMC), and Stephen R. Farmer (Boston University School of Medicine, Boston, Mass.)

This research was supported by grants from the National Institutes of Health (HL087123, DK58282, DK64773, DK063608, and RR024156).

Pranams at the feet of Shri Raghavendra

Shri Raghavendra Swami Araadhana 2012 starts today with Poorva Aradhana. Shri Raghavendra Swami Ji was a Great Saint of India and went into Jeeva Samadhi 341 years ago. The Samadhi day for 2102 falls on 4th August and is observed with due veneration and prayers all over the world by devotees.

Sri Raghavendra Swami attained Jeeva Samadhi on Dwitiya Day of Sravana Krishna Paksha in 1671. This date is celebrated each year as Sri Raghavendra Swamy Aradhana at Brindavans all over the world. The Raghavendra Swami Mutt in Mantralayam housing his Brindavan is visited by thousands of devotees every year.