From: Journal of Human Hypertension Alert <journal_of_human_hypertension@ealert.nature.com>
Date: Fri, Nov 20, 2009 at 10:13 PM
Subject: Journal of Human Hypertension - Table of Contents alert Volume 23 Issue 12
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Thursday, November 26, 2009
Fwd: Journal of Human Hypertension - Table of Contents alert Volume 23 Issue 12
From: Journal of Human Hypertension Alert <journal_of_human_hypertension@ealert.nature.com>
Date: Fri, Nov 20, 2009 at 10:13 PM
Subject: Journal of Human Hypertension - Table of Contents alert Volume 23 Issue 12
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Fwd: Targeting Cancer Invasion and Metastasis- THE MIAMI 2010 WINTER SYMPOSIUM
From: Nature Publishing Group <Nature.Publishing.Group@ealert.nature.com>
Date: Fri, Nov 20, 2009 at 11:50 PM
Subject: Targeting Cancer Invasion and Metastasis- THE MIAMI 2010 WINTER SYMPOSIUM
To: support4bt@gmail.com
| The University of Miami, Nature Publishing Group and Scripps Florida present |  | ||
| THE MIAMI 2010 WINTER SYMPOSIUM | |||
| Targeting Cancer Invasion and Metastasis | |||
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Abstract submission deadline: December 4, 2009 Rapid progress is being made in elucidating the biology of primary tumors, but the mechanisms of metastasis and invasion remain only partially understood. This meeting will focus on recent advances in our knowledge of basic molecular pathways of invasion, migration and immune surveillance and how that knowledge can be translated into new clinical concepts for diagnosis and therapy. SYMPOSIUM AWARDEES SPEAKERS For more information and to register visit: www.nature.com/natureconferences/miami/mws2010 |
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As a registered user of Nature Publishing Group's Web sites, our database indicates that you have opted-in to receive product information and special offers. If you no longer wish to receive these e-mails or to discontinue all e-mail services from Nature Publishing Group please update your online account. Modify My Account (You will need to log in to be recognised as a Nature.com registrant) For further technical assistance, please contact our registration department For print subscription enquiries, please contact our subscriptions department For other enquiries, please contact our customer feedback department Nature Publishing Group | 75 Varick St Fl 9 | New York | NY 10013-1917 | USA Nature Publishing Group's offices: Principal offices: London • New York Worldwide offices: Basingstoke • Boston • Buenos Aires • Delhi • Hong Kong • Madrid • Melbourne • Munich • Paris • San Francisco • Tokyo • Washington DC Macmillan Publishers Limited is a company incorporated in England and Wales under company number 785998 and whose registered office is located at Brunel Road, Houndmills, Basingstoke, Hampshire RG21 6XS. © 2009 Nature Publishing Group, a division of Macmillan Publishers Limited. All rights reserved |
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Inefficient Selection: New Evolutionary Mechanism Accounts For Some Of Human Biological Complexity
We have found a specific evolutionary mechanism to account for a portion of the intricate biological complexity of our species," said Ariel Fernandez, professor of bioengineering at Rice University. "It is a coping mechanism, a process that enables us to deal with the fitness consequences of inefficient selection. It enables some of our proteins to become more specialized over time, and in turn makes us more complex."
Fernandez is the lead author of a paper slated to appear in the December issue of the journalGenome Research. The research is available online now.
Fernandez said the study drew from previous findings by his own research group and from seminal work of Michael Lynch, Distinguished Professor of Biology at Indiana University and a recently elected a fellow of the National Academy of Science. Lynch's work has shown that natural selection is less efficient in humans as compared with simpler creatures like bacteria. This "selection inefficiency" arises from the smaller population size of humans as compared with unicellular organisms.
"In all organisms, genes get duplicated every so often, for reasons we don't fully understand," Fernandez said. "When working efficiently, natural selection eliminates many of these duplicates, which are called 'paralogs.' In our earlier work, we saw that an unusual number of gene duplicates had survived in the human genome, which makes sense given selection inefficiency in humans."
In prior research on protein structure, Fernandez's team found that some proteins are packaged more poorly than others. Moreover, they found that the least-efficiently packed proteins are structurally stable only when they bind with partner proteins to form complexes.
"These poorly packed proteins are potential troublemakers when gene duplication occurs," Fernandez said. "The paralog encodes more copies of the protein than the body needs. This is called a 'dosage imbalance,' and it can make us sick. For instance, dosage imbalance has been implicated in Alzheimer's and other diseases."
Given selection inefficiency, Fernandez knew that paralogs encoding poorly packed proteins could remain in the human genome for quite a while. So he and graduate student Jianpeng Chen decided to examine whether gene duplicates had remained in the genome long enough for random genetic mutations to affect the paralogs dissimilarly. Fernandez and Chen, now a senior researcher in Beijing, China, cross-analyzed databases on genomics, protein structure, microRNA regulation and protein expression in such troublesome paralogs.
"The longer these duplicate genes stick around due to inefficient selection, the more likely they are to suffer a random mutation," Fernandez said. "Portions of every gene act to regulate protein expression -- by binding with microRNA, for example. We found numerous instances where random mutations had caused paralogs to be expressed dissimilarly, in ways that removed detrimental dosage imbalances."
Lynch said one aspect of Fernandez's research that is potentially groundbreaking is the observed tendency of proteins to evolve a more open structure in complex organisms.
"This observation fits with the general theory that large organisms with relatively small population sizes -- compared to microbes -- are subject to the vagaries of random genetic drift and hence the accumulation of very mildly deleterious mutations," Lynch said.
In principle, he said, the accumulation of such mutations may encourage a slight breakdown in protein stability. This, in turn, opens the door to interactions with other proteins that can return a measure of that lost stability.
"These are the potential roots for the emergence of novel protein-protein interactions, which are the hallmark of evolution in complex, multicellular species," Lynch said. "In other words, the origins of some key aspects of the evolution of complexity may have their origins in completely nonadaptive processes."
Fernandez said the research reveals how increasingly specialized proteins can evolve. He drew an analogy to a business that hires two delivery drivers that initially cover the same parts of town but eventually specialize to deliver only to specific neighborhoods.
"Eventually, even if times become tough, you cannot lay off either of them because they each became so specialized that your company needs them both," he said.
The more simple a creature is, the fewer specialized proteins it possesses. Humans and other higher-order mammals need many specialized proteins to build the specialized tissues in their skin, skeleton and organs. Even more specialized proteins are needed to maintain and regulate them. This complexity requires that the duplicates of the original jack-of-all-trades gene be retained, but this does not happen unless selection is inefficient. This is frequently a point of contention between proponents of evolution and intelligent design.
Fernandez and Chen looked at duplicate genes across the human genome and found that the more poorly packed a protein was, the more likely it was to be distinguished through paralog specialization.
"This supports the case for evolution because it shows that you can drive complexity with random mutations in duplicate genes," Fernandez said. "But this also implies that random drift must prevail over Darwinian selection. In other words, if Darwinian selection were ruthlessly efficient in humans -- as it is in bacteria and unicellular eukaryotes -- then our level of complexity would not be possible."
The research is supported by the National Institutes of Health.
Protein p53 plays three cancer-fighting roles
A new study shows this cancer-controlling protein, p53, does not one, not two, but three different jobs, all in one convenient package.
Previous studies have demonstrated that p53 stops cancer from developing by sensing stress, such as DNA damage, and turning on genes that keep cells from dividing until the damage is repaired. The protein, which is a normal component of cells, also teams up with other molecules to trigger apoptosis, a type of cellular suicide, in over-stressed cells.
And now, researchers from University of Tokyo and their colleagues report in the July 23 Nature that p53 helps slice long pieces of RNA into small regulatory molecules called microRNAs. These microRNAs help control production of proteins, including some involved in cell proliferation, which can lead to cancer if unchecked.
This newly discovered function for p53 is "really surprising," says Franck Toledo, a geneticist at the Curie Institute's research center in Paris. Toledo and others have studied p53's other two roles, but no one previously suspected the protein might also participate in the slicing and dicing of RNAs.
All three of the cancer-related functions require a part of the protein that latches on to specific DNA sequences. Most cancers have some disruption in p53's action, either a mutation or inactivation of the protein, Toledo says. In many tumors, the mutation lies in the portion of p53 called the DNA-binding domain.
Scientists thought that p53 could direct the production of long RNAs, called primary transcripts, which eventually are broken up into microRNAs. Previous work has shown that the protein turns on production of a long RNA molecule that gets chopped into a microRNA called miR-34.
Mutations in the protein would disrupt production of the primary transcripts, ultimately leading to lower levels of microRNAs. But the Japanese team found that primary transcripts of several microRNAs associated with cancer are made as usual in DNA-damaged cells, indicating that p53 doesn't play a role in their production. But it was still possible that p53 mutations might disrupt the machinery that chops RNA into microRNA, says Kohei Miyazono, a molecular biologist at the University of Tokyo.
In the new study, Miyazono and colleagues also show that p53's DNA-binding domain interacts with Drosha and p68, proteins in an assemblage responsible for snipping primary transcripts into hairpin-shaped molecules. Another group of proteins, which includes the protein Dicer, chops the hairpins into the final, mature microRNAs. Levels of both the hairpin-shaped intermediates and mature microRNAs were lower in cells in which p53 was mutated, the team found.
Some of the affected microRNAs that the researchers examined control production of proteins involved in cell proliferation. Having too little of these microRNAs could allow too much of these growth-promoting proteins to be made, leading to uncontrolled growth and cancer.
The normal form of p53 serves as a molecular matchmaker, bringing Drosha and p68 together slightly more efficiently than the two proteins find each other on their own, the researchers showed. But altered forms of p53 spirit away p68, interrupting its interaction with Drosha.
People who have low levels of p53 develop cancer earlier and have poorer prognoses after treatment, Toledo says. It is possible that other variations in the protein may affect the ability to process microRNAs, which could make some people more vulnerable to cancer, he says. The new "findings suggest that, in human cancers, mutations that affect the DNA-binding domain of p53 essentially perform a hat trick by hitting three tumor-suppressive functions at once," Toledo and colleague Boris Bardot, also at the Curie Institute, write in a commentary published in the same issue of Nature.
Miyazono says p53 is clearly important in cancer cells, but might not be as crucial for microRNA processing in normal cells. The protein's function might be performed by other proteins in normal cells, he suggests. His group is working on different components of the microRNA-processing machinery, so other researchers will have to figure out p53's normal role in making microRNAs.
Still, he thinks the findings could have clinical applications if researchers can find ways to restore mutated or inactivated p53 to normal function.
Original report was modified by Jakub Málek.
Source: www.sciencenews.org
Slicing chromosomes leads to new insights into cell division
By using ultrafast laser pulses to slice off pieces of chromosomes and observe how the chromosomes behave, biomedical engineers at the University of Michigan have gained pivotal insights into mitosis, the process of cell division.
Their findings could help scientists better understand genetic diseases, agingand cancer.
Hunt’s group hypothesized that polar ejection forces should be proportional to the chromosome’s size, and therefore could be predictably changed by altering the size of the chromosomes. Using newts as a model organism, they cut off pieces of the chromosomes’ arms.
More on www.ns.umich.edu