GDF5 lends a hand to finger abnormalities

In a study appearing online on August 25 in advance of print publication of the September 1 issue of the Journal of Clinical Investigation, Petra Seemann and colleagues describe two mutations in Growth and Differentiation Factor 5 (GDF5), a signaling molecule, that result in altered binding affinities to the BMP type 1 receptors giving rise to opposing phenotypes, brachydactyly type A2 (unusually short digits) and symphalangism (fusion of the hand joints). The authors propose a model for normal joint formation.


TITLE:Activating and deactivating mutations in the receptor interaction site of GDF5 cause symphalangism or brachydactyly type A2.


AUTHOR:

Petra Seemann

Institute for Molekulare Genetik, Berlin, Germany

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Stacie Bloom

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Journal of Clinical Investigation

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Bisphenol A Exposure Increases Risk Of Abnormal Heart Rhythms In Female Rodents

The chemical bisphenol A, commonly found in many plastic household items, has been linked to yet another health problem in animals - an increased frequency of arrhythmias, or heartbeat irregularities, a new study found. The results, seen only in females, will be presented Saturday at The Endocrine Society's 91st Annual Meeting in Washington, D.C.



Past animal studies show that bisphenol A, or BPA, can have harmful effects on the reproductive, nervous and immune systems. Also, a study in humans reported last year found an increased prevalence of cardiovascular disease in people with high levels of BPA in the urine.



However, the effects of BPA on the heart are unknown, said study co-author Scott Belcher, PhD, associate professor in the University of Cincinnati's Department of Pharmacology and Cell Biophysics.



In the new study, funded by the National Institutes of Health, the University of Cincinnati researchers found that low-dose BPA and estrogen can act alone or in combination to increase harmful arrhythmias in female rats and mice. Because BPA has properties similar to the main female hormone estrogen, it is considered an "environmental estrogen."



Mice and rats in the study had normal heart rhythms at baseline, before administration of BPA or estrogen (estradiol), Belcher said. The investigators studied heart rhythms in both the working heart and in cultured heart muscle cells. In both models, exposure to BPA increased the frequency of arrhythmias, compared to baseline, in females but not in male animals, the authors found. Administration of estrogen alone also increased the frequency of arrhythmias in females.



Arrhythmias were most frequent in the female rats and mice when they received both BPA and estrogen, at levels normally found in female humans.



"We have identified a new possible risk for female heart health, caused by increased levels of estrogens in the body and exposure to the environmental estrogen BPA," Belcher said.



BPA is found in polycarbonate-plastic baby bottles, refillable water bottles and food containers as well as the linings of metal food cans. Last year the U.S. Food and Drug Administration said more research on the safety of BPA is needed.



Arrhythmias occur when the heart beats too slowly or too fast or when it skips heartbeats. These heart rhythm irregularities can cause fatigue, lightheadedness, fainting or sudden cardiac death. If a fast heart rate affects the heart's ability to pump, it can cause a heart attack.



The study's lead author, Hong-Sheng Wang, PhD, assistant professor at the University of Cincinnati, will present the results.

Battle Against Superbugs Undermined By Failing Drugs

The fight against some superbugs and other bacteria is in danger of returning to a 'pre-antibiotic era' due to increasing resistance to medicines, according to a report issued today by the Royal Society.


The report, Innovative mechanisms for tackling antibacterial resistance, criticises policies that only focus on infection control measures and restrictions on antibiotic use. It highlights the need for a sustained commitment to research and development to deliver new diagnostic tools for early identification of infections and new treatments.


David Read, Vice-president of the Royal Society said: "Much of the debate on superbugs has focussed on cleaning hospitals. This is important, but it will not deal with the fact that MRSA and other infections are increasingly resistant to the medicines we have come to rely on to treat them. We must make sure that the investment is in place to deliver the next generation of antibiotics to tackle future outbreaks of infection."


The report, based on an international symposium organised by the Royal Society, examines possible areas of research that could lead to new treatments. Barriers to the development of novel antibacterial agents are also looked at and include resistance in the pharmaceutical sector to invest in these drugs due to fact that they are currently undervalued and underpriced and thus produce less profit than other drugs.


Key improvements suggested in the report include:


- A more realistic market valuation needs to be put on antibacterials to reflect the fact that they are life-saving drugs


- The need to create regulatory conditions that will encourage venture capitalists and biotech companies as well as pharmaceutical companies to invest in antibacterials


- The need to develop more efficient diagnostic tools to enhance the rapid identification of bacteria causing an infection as well as identifying what treatments might be most effective


- The need to continue to develop traditional antibiotics, alongside the investigation of different approaches to develop antibacterial agents that act on bacteria in novel ways.


- The establishment of centres of excellence for antibacterial therapeutics. The success of such centres can be seen in the cancer sector where diverse expertise has been brought together to develop very specific targeted therapies involving partners such as patient groups and medical research charities.


1. Innovative mechanisms for tackling antibacterial resistance is based on an international symposium held at the Royal Society on 7 March 2008. The report summarises key issues raised in presentations and discussion sessions and does not necessarily represent the views of the Royal Society.


2. The Royal Society is an independent academy promoting the natural and applied sciences. Founded in 1660, the Society has three roles, as the UK academy of science, as a learned Society, and as a funding agency. It responds to individual demand with selection by merit, not by field. As we prepare for our 350th anniversary in 2010, we are working to achieve five strategic priorities to:


- Invest in future scientific leaders and in innovation

- Influence policymaking with the best scientific advice

- Invigorate science and mathematics education

- Increase access to the best science internationally

- Inspire an interest in the joy, wonder and excitement of scientific discovery


The Royal Society

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London SW1Y 5AG

United Kingdom.

Systems Characterization Of Cell Surface Receptors

Cells communicate with their environment through molecules on their surface known as receptors. Receptors bind ligands - specific companion molecules that either carry information about the outside environment or are critical cell nutrients. A variety of receptors are internalized into the cell through a process known as endocytosis. Receptors display a wide range of state-dependent endocytosis rates, but the functional significance of these patterns is not well understood.



In a paper published June 1 in the Open Access journal PLoS Computational Biology, Drs. Shankaran, Resat and Wiley from the Pacific Northwest National Laboratory employ a generalized mathematical model to comparatively explore the design principles of signal transduction and transport receptors.



The authors use a new module-based systems theory approach along with quantitative metrics for network function and robustness to show that endocytosis and other receptor/ligand properties can be described by just a few control parameters. Using mathematical analysis, the authors show that the efficiency and robustness of receptor systems are encoded by two fundamental parameters: the avidity which quantifies the ability of a receptor system to capture ligand, and the consumption which quantifies the ability to internalize bound ligand.



By examining a number of receptor systems, the authors demonstrate that the response of receptor systems can be characterized as being: i) avidity-controlled, which depends primarily on ligand capture efficiency, ii) consumption-controlled where the ability to internalize surface-bound ligand is the primary control parameter, and iii) dual-sensitive, in which both the avidity and consumption parameters are important. The location of various receptor systems in control parameter space dictates their specific function and regulation.



Most significantly, the authors argue that the evolution of a given receptor system can be understood in terms of its optimal location in avidity-consumption parameter space. For example, induced endocytosis can be shown to be an optimal solution for achieving high fidelity information transmission for signaling receptors. Overall, this study develops and applies a new strategy for quantifying the phenotype of complex systems that should be generally applicable to a wide range of problems in systems biology research.






The research was funded by the National Institutes of Health and the Biomolecular Systems Initiative at PNNL.



CITATION: Shankaran H, Resat H, Wiley HS (2007) Cell Surface Receptors for Signal Transduction and Ligand Transport: A Design Principles Study. PLoS Comput Biol 3(6): e101 doi:10.1371/journal.pcbi.0030101



CONTACT:

Haluk Resat

Pacific Northwest National Laboratory

Computational Biology and Bioinformatics

P.O. Box 999, MS: K7-90

Richland, WA 99352

United States of America



THE OPEN-ACCESS JOURNAL PLoS COMPUTATIONAL BIOLOGY (ploscompbiol/) IS THE SOURCE FOR THIS ARTICLE



PLoS Computational Biology is an open access, peer reviewed journal published weekly by the Public Library of Science (PLoS) in association with the International Society for Computational Biology (ISCB).



Contact: Johanna Dehlinger

Public Library of Science

Major Step Forward In Effort To Understand And Engineer Protein Structure

Researchers in Singapore are reporting that they have gleaned key insights into the architecture of a protein that controls iron levels in almost all organisms. Their study culminated in one of the first successful attempts to take apart a complex biological nanostructure and isolate the rules that govern its natural formation.



The Nanyang Technological University team's work on the protein ferritin, the results of which appear in this week's issue of the Journal of Biological Chemistry, is expected to have significant ramifications on the fields of drug design and nanomaterials.



"Engineering the structure of a protein is one of the ultimate dreams of structural biologists," wrote one of the journal's peer reviewers, "and approaching that dream is greatly enabled through studies aimed at finding out what governs the nanoarchitecture of the protein."



Brendan P. Orner, the assistant professor who oversaw the team's work, described the protein ferritin as a potential model for explaining complicated protein structure in general.



Across the biological kingdoms, ferritin regulates the distribution of iron, which is necessary for a number of cellular functions but also forms reactive ions that can be lethal to cells. Shaped like a spherical nanocage, ferritin is made up of 24 proteins, and it sequesters the reactive iron ions in its hollow interior. In humans, ferritin prevents iron deficiency and overload.



"The rules that govern self-assembling nanosystems, like the ferritin model, are poorly understood," Orner explained. "We systematically analyzed the interactions between the 24 ferritin units that make up the nanocage and identified the hot spots that are crucial to the cage's formation."



Their goal was to discover which amino acids are responsible for assembling the cage, and they found that it is possible to both disassemble ferritin by removing single side chains of amino acids and, surprisingly, to stabilize the structure by removing other side chains.



Understanding the assembly of the nanocage could open the door to drug design that will disrupt the structure and function of defective proteins that cause or contribute to disease. It also may aid in the creation of biological nanostructures in which scientists can grow special particles and materials with a variety of properties and applications.



"Cell biology provides many structures that are on the nanoscale and have amazing complexity and symmetry," Orner said. "The problem is that many of these structures are, like ferritin, self-assembled proteins, and, if we are going to use them for nanomaterials applications, we need to understand the fundamentals that make them form this way naturally."



Orner and his team members are particularly interested in growing nanoparticles of precise dimensions inside ferritin shells. Already, they have developed a new method to grow gold nanoparticles in them.



"Slight deviations in size or shape can radically change nanoparticles' properties, particularly in the case of metals and semiconductors," Orner said. "Our ferritin proteins are hollow, so, when we grow mineral or metal clusters inside them, the growth stops when the nanoparticles reach the limits of the protein shell."



By studying the rules that control the folding and assembly of such a protein in nature, Orner said, the investigators hope to be able to manipulate them one day to create new proteins with novel sizes and shapes and, therefore, generate nanoparticles of novel sizes and shapes inside them.



"Those nanoparticles could be used for in-vitro assays to do high-throughput drug screening of some protein-protein interactions involved in virus infection and cancer, for example," he said.



Orner's team included doctoral students Yu Zhang and Rongli Fan, undergraduate students Siti Raudah, Huihian Teo and Gwenda Teo, and scholar Xioming Sun. Their research was funded by the Singapore Ministry of Education and Nanyang Technological University.



Their resulting article has been named a "Paper of the Week" by the Journal of Biological Chemistry, putting it in the top 1 percent of papers reviewed by the editorial board in terms of significance and overall importance.



Source:

Angela Hopp


American Society for Biochemistry and Molecular Biology

Light Shed On The Molecular Basis Of Crib Death By New Research

Sudden Infant Death Syndrome (SIDS) is a condition that unexpectedly and unexplainably takes the lives of seemingly healthy babies aged between a month and a year. Now researchers of the European Molecular Biology Laboratory in Monterotondo, Italy, have developed a mouse model of the so-called crib or cot death, which remains the leading cause of death during the first year of life in developed countries. The model, published in this week's issue of Science, reveals that an imbalance of the neuronal signal serotonin in the brainstem is sufficient to cause sudden death in mice.



The brainstem, the lower part of the brain that forms the link to the spinal cord, coordinates many fundamental functions including control over cardiovascular and respiratory systems. Victims of SIDS show alterations in those brainstem neurons that communicate using the signalling molecule serotonin. Cornelius Gross and his group at the EMBL Mouse Biology Unit modified the serotonin system of mice to understand the role of this signalling molecule in the brainstem. They overexpressed an important receptor that regulates serotonin signalling, called serotonin 1A autoreceptor.



"At first sight the mice were normal. But then they suffered sporadic and unpredictable drops in heart rate and body temperature. More than half of the mice eventually died of these crises during a restricted period of early life. It was at that point that we thought it might have something to do with SIDS," says Gross.



Until now it was unclear how changes in serotonin signalling in the brainstem of SIDS infants are involved in sudden death. The findings in the mouse show that deficits in serotonin signalling in the brainstem can be sufficient to cause sudden death and strongly support the idea that a congenital serotonin defect could play a critical role in SIDS.



Serotonin neurons in the brainstem communicate to nerve cells in the spinal cord that innervate the heart and organs involved in temperature regulation such as brown fat tissue. This signalling is defective in the mouse model of SIDS. For example, when placed into a cold chamber the animals cannot properly activate brown fat tissue to produce heat. This inability to activate fundamental body systems under certain conditions is likely to explain why the mice succumb to sudden death.



While a complete block of serotonin signalling does not lead to death, upsetting its intricate balance by overexpressing serotonin 1A autoreceptor can. In response to serotonin the receptor initiates a negative feedback mechanism that reduces serotonin release and dampens down the signal to the body. The researchers caution, however, that it is unlikely that the exact same molecular mechanism leads to SIDS in humans. Nevertheless, the mouse model will help to shed light on how serotonin signalling, when dysfunctional, can be life-threatening.



"We hope the mouse model will help identify risk factors for SIDS. One open question is whether like in SIDS, the animals die during sleep and whether we can identify which mice will die by looking at their heart rate or body temperature before the crisis. Ultimately, we hope it will give new ideas to doctors about how to diagnose babies at risk for SIDS," says Enrica Audero, who carried out the research in Gross' lab.







Source: Anna-Lynn Wegener


European Molecular Biology Laboratory

Molecular Typesetting -- Proofreading Without A Proofreader

Researchers at the Universities of Leeds and Bristol (UK) have developed a model of how errors are corrected whilst proteins are being built.



Ensuring that proteins are built correctly is essential to the proper functioning of our bodies, but the 'quality assurance' mechanisms that take place during this manufacturing process are not fully understood.



"Scientists have been puzzled as to how this process makes so few mistakes", says Dr Netta Cohen, Reader at the University of Leeds' School of Computing.



To create a protein, the first step involves copying the relevant gene on our DNA onto a template, called RNA. This copying process is carried out by molecular machines called RNA polymerases.



"The RNA polymerase acts like an old fashioned newsprint typesetter, constructing newsprint by assembling letters one at a time. Similarly, RNA polymerase constructs RNA by reading the DNA and adding new letters to the RNA one at a time," explains Dr Cohen.



There's no way for the RNA polymerase to ensure that the correct letter is always incorporated at the right spot. "Statistically, we would expect to see a hundred-fold more errors than we actually do, so we know that some error correction must be happening. Otherwise, many more proteins in our bodies would malfunction," says Dr Cohen.



Biological experiments have shown that the RNA polymerase slides both forwards and backwards along the RNA sequence it has created. What's more, it has miniature scissors that can then cut out the last few letters of RNA.



So how are errors corrected? Intelligent typesetters would remove the last few letters when they spot an error. The new model suggests how the backward sliding stalls when passing an error, so wrong letters can be snipped off and copying can resume.


"The mechanism we've modelled has only recently been shown to be implicated in proofreading," says Dr Cohen. "In fact, there is more than one identified mechanism for ensuring that genetic code is copied correctly. The challenge now is to find out - through a combination of experimental biology and modelling - which mechanism is dominant."



Source:

Dr. Netta Cohen

University of Leeds