New Molecular Target Identified for Treating Cerebral Malaria

                                                             Mosquito Anopheles

A drug already approved for treating other diseases may be useful as a treatment for cerebral malaria, according to researchers at Harvard T. H. Chan School of Public Health. They discovered a novel link between food intake during the early stages of infection and the outcome of the disease, identifying two molecular pathways that could serve as new targets for treatment.

“We have known for a long time that nutrition can affect the course of infectious disease, but we were surprised at how rapidly a mild reduction in food intake could improve outcome in a mouse malaria model,” said senior author James Mitchell, associate professor of genetics and complex diseases. “However, the real importance of this work is the identification of unexpected molecular pathways underlying cerebral malaria that we can now target with existing drugs.”

The study appears online January 30, 2015 in Nature Communications.

Cerebral malaria — a severe form of the disease — is the most serious consequence of infection by the parasite Plasmodium falciparum, resulting in seizures, coma, and death. Currently there is a lack of safe treatment options for cerebral malaria, particularly for use in children, who represent the majority of cases. Even patients who receive early treatment with standard antimalarial chemotherapeutic agents run a high risk of dying, despite clearance of the parasite. Moreover, around 25% of survivors develop neurological complications and cognitive impairment.

Lead authors Pedro Mejia and J. Humberto Treviño-Villarreal, both researchers at Harvard T.H. Chan School of Public Health, found that leptin—a hormone secreted from fat tissue with roles in suppressing appetite, but also in activating adaptive immune and inflammatory responses—is increased upon infection in a mouse model of cerebral malaria, and turns out to be a major bad actor in promoting neurological symptoms and death. Remarkably, Mejia, Treviño-Villarreal and colleagues showed that reducing leptin using a variety of means, either genetically, pharmacologically, or nutritionally by reducing food intake during the first two days of infection, protected against cerebral malaria.

The researchers also found that leptin acted primarily on cytotoxic T cells by turning on the well-studied mTOR protein, for which pharmacologic inhibitors are readily available. In their animal model, treating mice with the mTOR inhibitor rapamycin protected them against the neurological complications of cerebral malaria. Protection was due in part to a preservation of the blood brain barrier, which prevented the entry of blood cells carrying the parasites into the brain. As rapamycin is already FDA-approved for use in humans, trials in humans for cerebral malaria treatment with this drug may be possible, according to the researchers.

This study was the result of an ongoing collaboration between the Mitchell lab in the Department of Genetics and Complex Diseases and the labs of Manoj Duraisingh and Dyann Wirth in the Department of Immunology and Infectious Diseases. Other Harvard T.H. Chan School of Public Health authors included  Christopher Hine, Eylul Harputlugil, Samantha Lang, Ediz Calay and Rick Rogers.

This study was supported in part by grants from NIH (DK090629 and AG036712) and the Glenn Foundation for Medical Research to J.R.M.; a Harvard T.H. Chan School of Public Health Yerby postdoctoral fellowship to Mejia, and financial support from the Universidad Auto´noma de Nuevo Leo´n to Treviño-Villarreal.

Source: Harvard

Studying patterns in bacterial organization

credit to Gerard Wong, of the California NanoSystems Institute

Bacterial biofilms, at first glance, may seem to be spontaneous, random phenomena from which we have no power to protect our environment or ourselves.

They’re potentially useful as an aid to wastewater treatment, but they also cause infections that account for $6 billion a year in health care costs. Biofilms are also more resistant to antibiotic drugs, making them difficult to eradicate.

Dr. Kun Zhao, of the California NanoSystems Institute at UCLA, refuses to see biofilms as arbitrary: he emphasizes the fact that biofilms are communities of bacteria in self-produced polymeric matrices of polysaccharides, and using a biophysical approach, he studies the pattern behind their organization.

Central questions in Zhao’s research include how bacterial colonies transition from reversible to irreversible attachment, how they migrate, and how they ultimately disperse. Specifically, Zhao examines the polysaccharide Psl, which poses a positive feedback loop because it is both secreted by moving bacteria and serves as a chemo-attractant for future bacteria movement. The positive feedback creates an inherent pattern, as bacteria are more likely to visit a location they have been to before.

Zhao and colleagues have also discovered that bacterial mutants that cannot produce Psl exhibit more random and uniform movement.

To better quantify bacterial movement,Zhao has created a computer algorithm that shows the full movement history of each individual bacterium on a dish, and that provides a “search engine” allowing researchers to find every bacterium performing specific life cycle activities, like division.

Zhao has postulated a “rich get richer” mechanism for biofilms. He compares bacterial organization to Wall Street because concentrated movement ensures that some cells become extremely enriched. In the future, he hopes to model colloidal structures for biological problems, like the growth of the bacterial cell wall. Zhao currently uses colloids, which in physics are used as models for atomic systems, to observe how shapes affect self-assembly. He also would like to look at cell-substrate interactions, which are implicated in bacterial territoriality and social interactions.

by Olivia Zhu

Source: Duke University

Poison meat baits approved for use on NSW feral pigs

PHOTO: Huge feral pest pig was found on an outback property 175 kilometres north of Broken Hill in far west New South Wales. (Image: Paul Manion)

New South Wales pastoralists who are trying to reduce booming feral pig numbers on their properties could soon get some extra help.

The Australian Pesticides and Veterinary Medicines Authority has issued a permit for 1080 poison meat baits to be used on selected rangeland properties in the state.

This is the first time the authority will permit sodium fluoroacetate or 1080, to be used for feral pig control in NSW.

Western Local Land Services will run the trial, which will begin in March this year and continue until June 2016.

NSW Minister for Primary Industries, Katrina Hodgkinson, said the trial aimed to reduce the devastating impact pest pigs have on primary production.

"It's great to have that authority given to Local Land Services by the APVMA," she said.

"Feral pigs are such dreadful creatures. The farmers will tell anybody that they destroy pastures, sensors and are particularly bad for newborn lambs.

"Local Land Services will be working with landowners to make sure they're getting the best areas covered.

"They're going to be using sensor-controlled cameras to see how effective the take up is of the baits and they'll follow up with trapping, shooting and other control methods."

Ms Hodgkinson said the baits have already been used successfully for wild dog eradication.

She said efforts would be made to ensure minimal impact on non-target species.

"We want to make sure we don't impact the environment," she said.

"When you're using meat baits you'll inevitably get some native animals in there too, but I think overall the net positive is going to be very much for us using 1080 meat baits for this feral pig trial."

Source: ABC

Structure of Neuron-Connecting Synaptic Adhesion Molecules Discovered

Figure 1: Overview of the PTPd Ig1–3/Slitrk1 LRR1 complex. Copyright : Korea Advanced Institute of Science and Technology

A research team has found the three-dimensional structure of synaptic adhesion molecules, which orchestrate synaptogenesis. The research findings also propose the mechanism of synapses in its initial formation.

Some brain diseases such as obsessive compulsive disorder (OCD) or bipolar disorders arise from a malfunction of synapses. The team expects the findings to be applied in investigating pathogenesis and developing medicines for such diseases.

The research was conducted by a Master’s candidate Kee Hun Kim, Professor Ji Won Um from Yonsei University, and Professor Beom Seok Park from Eulji University under the guidance of Professor Homin Kim from the Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), and Professor Jaewon Ko from Yonsei University. Sponsored by the Ministry of Science, ICT and Future Planning and the National Research Foundation of Korea, the research findings were published online in the November 14th issue of Nature Communications.

Figure 2: Representative negative-stained electron microscopy images of Slitrk1 Full ectodomain (yellow arrows indicate the horseshoe-shaped LRR domains). The typical horseshoe-shaped structures and the randomness of the relative positions of each LRR domain can be observed from the two-dimensional class averages displayed in the orange box. Copyright : Korea Advanced Institute of Science and Technology

A protein that exists in the neuronal transmembrane, Slitrk, interacts with the presynaptic leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs) and forms a protein complex. It is involved in the development of synapses in the initial stage, and balances excitatory and inhibitory signals of neurons.

It is known that a disorder in those two proteins cause a malfunction of synapses, resulting in neuropsychosis such as autism, epilepsy, OCD, and bipolar disorders. However, because the structure as well as synaptogenic function of these proteins were not understood, the development of cures could not progress.

The research team discovered the three-dimensional structure of two synaptic adhesion molecules like Slitrk and LAR-RPTPs and identified the regions of interaction through protein crystallography and transmission electron microscopy (TEM). Furthermore, they found that the formation of the synapse is induced after the combination of two synaptic adhesion molecules develops a cluster.

Figure 3: Model of the two-step presynaptic differentiation process mediated by the biding of Slitrks to LAR-RPTPs and subsequent lateral assembly of trans-synaptic LAR-RPTPs/Slitrik complexes. Copyright : Korea Advanced Institute of Science and Technology

Professor Kim said, “The research findings will serve as a basis of understanding the pathogenesis of brain diseases which arises from a malfunction of synaptic adhesion molecules. In particular, this is a good example in which collaboration between structural biology and neurobiology has led to a fruitful result.” Professor Ko commented that “this will give new directions to synaptic formation-related-researches by revealing the molecular mechanism of synaptic adhesion molecules.”

Source: KAIST

WHO contemplates reforms after admitting missteps on Ebola

World Health Organization (WHO) Director-General Margaret Chan addresses the media during a special meeting on Ebola in Geneva on Jan. 25, 2015. Photo by Pierre Albouy/REUTERS.

In a special session on Sunday, the World Health Organization debated how to reform itself after acknowledging the organization had botched its response to the 2014 Ebola emergency. 

“The Ebola outbreak revealed some inadequacies and shortcomings in this organization’s administrative, managerial, and technical infrastructures,” WHO Director-General Margaret Chan said. At its headquarters in Geneva, Chan presented a series of proposals aimed at ending the current outbreak, as well as reinforcing preparedness globally and guaranteeing the WHO’s ability to address future large-scale outbreaks. 

She stressed the need to streamline recruitment for emergencies, as the current process is “too slow” and emphasized the need for a “one WHO” approach that employs universal operating procedures and tools for responding to emergencies. According to Chan, the current rules for reporting outbreaks – International Health Regulations (IHR) – created to prevent national health emergencies from becoming global crises, are too thin. But the largest lesson she and others at WHO learned during the outbreak fight was that well-trained, and appropriately paid health care workers, are essential to stemming the spread of disease. 

To date there have been more than 21,000 Ebola cases and over 8,400 deaths. “The volatile microbial world will always deliver surprises, Chan said. “Never again should the world be caught by surprise, unprepared.”

Source: WHO

Researchers ferret out a flu clue

Professor Michael Jennings, Deputy Director of the Institute for Glycomics. Credit: Image courtesy of Griffith University

Research that provides a new understanding as to why ferrets are similar to humans is set to have major implications for the development of novel drugs and treatment strategies.

Published in the journal Nature Communications, the research is a collaboration between Professor Michael Jennings and other researchers from the Institute for Glycomics, Griffith University and collaborators at the University of Queensland and the University of Adelaide.

The team has shown for the first time that ferrets share a mutation that was previously thought to be unique to humans, among the mammals. This helps to explain why the molecular characteristics of ferrets so uniquely mimic human susceptibility, severity and transmission of influenza A virus strains.

Professor Michael Jennings, Deputy Director of the Institute for Glycomics, says these findings open up a completely novel approach to tackling human diseases from influenza through to cancer.

"For over 80 years we've known that ferrets are uniquely susceptible to human influenza A virus, but the precise reason was unknown," Professor Jennings said.

"We have shown that ferrets have a mutation in a gene required to make a crucial sugar called sialic acid. Most animals can make two types of sialic acid. Ferrets, like humans can make only one. Different flu strains have preferences for the type of sialic acid they bind to cause infection. Because ferrets can only make the human form of this sugar, they are naturally "humanized" for the receptors recognised by human strains of the flu virus."

Source: Griffith University