Researchers map pathway of infection for a common, potentially life-threatening respiratory virus

Posted by Biomechanism 

“Finding ends 5-decade search.”  

Toronto—Researchers at the University of Toronto, The Hospital for Sick Children (SickKids), St. Paul’s Hospital and the University of British Columbia have identified a new treatment target for a virus that causes severe lung infections and an estimated 10% of common colds.

The virus, called human respiratory syncytial virus or RSV, is the most common reason for hospitalization of infants and children under two years of age; currently there is no effective therapy or vaccine for it.

This is the photomicrographic detection of respiratory syncytial virus (RSV) using indirect immunofluorescence technique. Photo: DigitalJournal

“This discovery provides an understanding of the mechanism through which RSV causes infection and offers a target molecule for development of new cell-based therapies,” said the study’s principal investigator Prof. Richard Hegele, Chair and Professor in U of T’s Department of Laboratory Medicine and Pathobiology who is also Chief of Paediatric Laboratory Medicine at SickKids.

The research is published in the current edition of the journal Nature Medicine.

The researchers found that RSV interacts with healthy cells by binding with a molecule located on the surface of those cells called nucleolin. By manipulating the function of nucleolin in cell culture, they were able to decrease RSV infection or increase susceptibility to it.

In mice, the researchers showed that disruption of lung nucleolin was associated with significantly reduced RSV infection, confirming that the molecule is a viable therapeutic target.

“While other factors may influence the frequency and severity of RSV infections, our results indicate that the presence of nucleolin on the cell surface is sufficient for RSV to successfully infect cells,” said Hegele. “We can now pursue strategies designed to block the interaction of RSV with cell surface nucleolin, the idea being to find approaches that will safely and effectively halt infection by preventing RSV from entering the cell in the first place.”

Researchers have been searching for a receptor for RSV for over five decades 

“This is a long-awaited and much-needed discovery that will help researchers develop new therapies for this disease, which has a large global burden, primarily affecting young children and other vulnerable populations,” said Dr. David Marchant, a research associate at UBC’s James Hogg iCAPTURE Centre at St. Paul’s Hospital, and co-lead on the study. “What is especially encouraging is that there is already a lot of ground work done in terms of understanding the biology of nucleolin to treat other ailments like cancer. The discovery of the RSV receptor combined with this knowledge could help deliver a potential therapeutic much faster.”

Increasingly, RSV is being recognized as a serious pathogen of the elderly for causing lung infections such as pneumonia. It is also a common cause of middle ear infections and can infect other organ systems, and has been implicated in the onset of asthma and allergy in children. Organ transplant recipients or other individuals whose immune systems are compromised are also at increased risk for serious RSV lung infections.

According to the World Health Organization, the global RSV disease burden is estimated at 64 million cases and 160,000 deaths each year. It is considered the single most important cause of severe respiratory illness in infants and young children.1

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The study was conducted by the following researchers: Richard G. Hegele (University of Toronto Department of Laboratory Medicine and Pathobiology, and The Hospital for Sick Children (SickKids)); Farnoosh Tayyari and David Marchant (James Hogg iCAPTURE Centre at St. Paul’s Hospital and UBC Department of Pathology and Laboratory Medicine); Theo J. Moraes (U of T and SickKids); Wenming Duan (SickKids); Peter Mastrangelo (U of T).

Study shows relationship between two mutated genes can dictate outcome of prostate cancer

Posted by Biomechanism 

“Findings from the CSHL study could yield molecular information that might be used to monitor current treatment options and classify patients for clinical trials.”

Of the 250,000 American men who will be diagnosed with prostate cancer this year, very few of them—about 1 percent—will develop lethal, metastatic disease. Finding a way to distinguish between this small cohort and the majority of patients who will develop an indolent, non-lethal form of prostate cancer is a key goal in prostate cancer research.

Prostate cancer is the most common cancer in men in the United States. Prostate cancer forms in the prostate gland, and can sometimes be felt on digital rectal examination. This is one of the purposes of the digital rectal exam. Photo: ADAM

Cold Spring Harbor Laboratory (CSHL) scientists have taken a major step towards this goal by identifying a new prostate tumor suppressor gene called PHLPP1 (pronounced FLIP or FILIP) and showing that it acts in concert with PTEN, a well-studied tumor suppressor that is mutated in roughly half of prostate cancer patients. In a study appearing in Cancer Cell on August 16, the scientists define the relationship between the two genes, showing how their individual or simultaneous loss impacts cancer progression and development of lethal disease.

PTEN’s role in prostate cancer has been relatively well characterized in mouse models that faithfully mimic human disease. These models, several of which had been previously developed by the study’s leader, CSHL Assistant Professor Lloyd Trotman, Ph.D., revealed a surprising insight about this gene. Unlike most tumor suppressor genes, which allow cancer to occur when both their copies stop working or are deleted, the loss of one copy of PTEN results in tumor formation, while paradoxically, the loss of both copies triggers cells to undergo senescence, a potent form of growth arrest that blocks development of cancer. Cells overcome this fail-safe mechanism and give rise to prostate cancer only when another gene, the “master” tumor suppressor P53, also happens to get disabled by mutations.

“This discovery, which suggests that cancer develops by navigating around such cellular roadblocks, led us to ask whether there are specific rules for prostate cancers to become lethal,” explains Trotman. “We wondered what kind of gene deletions work together with PTEN-loss to trigger cancer, or which of them trigger fail-safe mechanisms.” So his team began to examine other known components of the molecular pathway that PTEN acts on to keep prostate cancer in check.

The PTEN protein, which is a type of enzyme known as a phosphatase and works by removing phosphate molecules from its molecular targets, tempers prostate cell proliferation by preventing activation of a cancer-causing gene, or oncogene, called AKT. Focusing on another phosphatase, PHLPP1, which had been recently identified as a de-activator of AKT, the CSHL scientists showed that the PHLPP1 gene also functions as a suppressor of prostate tumors. Mice that lacked both copies of Phlpp1 developed a pre-malignant form of prostate cancer.

“We consider PHLPP1 to be a ‘druggable’ target because it has a cellular antagonist—a protein that does the exact opposite, i.e., it adds phosphates to AKT. And this agonist, a protein complex called mTORC2, can be pharmacologically inhibited,” explains Trotman. “So our study has validated the idea that specific pharmaceutical inhibitors of AKT are important in prostate cancer treatment.”

The relationship between PTEN and PHLPP1 became apparent when the scientists bred mice that were Pten-deficient and also lacked Phlpp1. The combined loss of both genes resulted in excessive Akt activity, which in turn activated the p53-driven fail-safe mechanism leading to senescence. Although this response delayed the progression of disease, the fail-safe mechanism was eventually overcome in the prostates of the mice after the spontaneous inactivation of p53.

“Breaking this p53-driven senescence was the key requirement for disease progression in the mice,” explains Trotman. To find out if and when this event actually occurs during the course of human disease, they teamed up with a group of clinical scientists led by the late Dr. William Gerald, M.D., Ph.D., and Dr. Brett Carver, M.D., at Memorial Sloan Kettering Cancer Center who had just defined the genomic landscape of more than 200 human prostate tumor samples (primary and metastatic). The collaborators found that while virtually none of the primary cancers had dual deletions of PHLPP1 and PTEN, both genes were very frequently co-deleted in metastatic tumors along with P53 and PHLPP2, a gene closely related to PHLPP1.

“The combination of mouse model and patient data point to a novel prostate cancer progression model in which the P53 senescence response acts as a barrier, not against the early initiating stages of cancer, but against life-threatening disease,” Trotman elaborates. “Without this barrier, cancer cells become metastatic more easily.”

The team has found that monitoring the transcription activity of these two genes— the extent to which they are switched “on”—following prostate surgery could predict whether a patient is on a trajectory to developing these dangerous dual deletions and relapse from hormone therapy. “This information could greatly help identify the best candidate patients for clinical trials with PI-3kinase/AKT pathway inhibitors”, says Trotman.

The team’s results may also influence which new drugs that inhibit the PI3-Kinase/AKT pathway are used as therapy and when. While drugs that inhibit mTORC2 proteins should be beneficial, the scientists have found that inhibiting the closely related mTORC1 proteins dampens the ability of the PHLPP2 protein to act as a backup to PTEN-deficiency. “So our study argues for checking a patient’s PHLPP status before giving him these drugs,” says Trotman. “We need to start assessing treatment options based on whether or not the patient’s molecular backup route is still intact.”

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“Identification of PHLPP1 as a Tumor Suppressor Reveals the Role of Feedback Activation in PTEN-Mutant Prostate Cancer Progression,” appears in Cancer Cell on August 16. The full citation is: Muhan Chen, Christopher P. Pratt, Martha E. Zeeman, Nikolaus Schultz, Barry S. Taylor, Audrey O’Neill, Mireia Castillo-Martin, Dawid G. Nowak, Adam Naguib, Danielle M. Grace, Jernej Murn, Nick Navin, Gurinder S. Atwal, Chris Sander, William L. Gerald, Carlos Cordon-Cardo, Alexandra C. Newton, Brett S. Carver, and Lloyd C. Trotman.

This work was supported by grants from the Department of the Army, the Starr Foundation, the National Institutes of Health, MSKCC Prostate SPORE, David H. Koch, and the Rita Allen Foundation. 

Haiku No. 10 - Meditative Version

Why Google Bought Motorola

Credit: Technology Review

WEB

Besides an impressive patent portfolio, Motorola will give Google greater control over the future of the mobile Web.

• BY ERICA NAONE

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Google announced today that it has agreed to acquire the smart-phone manufacturer Motorola Mobility for $12.5 billion.

In a statement, Google said the deal was largely driven by the need to acquire Motorola's patent portfolio, which it said would help it defend Android against legal threats from competitors armed with their own patents. This issue has come to the fore since a consortium of technology companies led by Apple and Microsoft purchased more than 6,000 mobile-device-related patents from Nortel Networks for about $4.5 billion, in early July. Battle lines are being drawn around patents, as companies seek to protect their interests in the competitive mobile industry through litigation as well as innovation.

However, as people increasingly access the Web via mobile devices, the acquisition could also help Google remain central to their Web experience in the years to come. As Apple has demonstrated with its wildly popular iPhone, this is far easier to achieve if a company can control the hardware, as well as the software, people carry in their pockets. Comments made by Google executives hint that Motorola could also play a role in shaping the future of the Web in other areas—for instance, in set-top boxes.

Motorola is by far Google's largest acquisition, and it takes the company into uncertain new territory. The deal is also likely to draw antitrust scrutiny because of the reach Google already has with Android, which runs on around half of all smart phones in the United States.

Motorola, which makes the Droid smart phone, went all-in with Google's Android platform in 2008, declaring that all of its devices would use the open-source mobile operating system.

Before his departure as Google CEO, Eric Schmidt had begun pressing Google employees to shift their attention to mobile. Cofounder and new CEO Larry Page seems determined to maintain this change of focus. In a conference call this morning, he told investors, "It's no secret that Web usage is increasingly shifting to mobile devices, a trend I expect to continue. With mobility continuing to take center stage in the computing revolution, the combination with Motorola is an extremely important event in Google's continuing evolution that will drive a lot of improvements in our ability to deliver great user experiences."

Motorola engineers have extensively modified Google's basic Android platform for its devices. For example, the company designed Motoblur, a user interface that pulls together Twitter, Facebook, and other social sites, into a single stream of data, and this has been a major selling point for  the company's phones.

Are Keyboards on Laptops the Next Thing to Go?

Infinitely re-configurable virtual keyboards with haptic feedback could do everything conventional input devices do -- and so much more

CHRISTOPHER MIMS

The one thing that differentiates a laptop from a tablet -- a keyboard -- could be on its way to the dustbin of history, contends long-time Mac columnist Andy Ihnatko. If you don't believe him, witness Exhibit A in the war on a technology first perfected more than a hundred and thirty years ago: The haptic display.

Apple's patent on a virtual keyboard with haptics portends a future in which physical keys lose their advantage

Apple patented their own version of a haptic display that shows -- what else -- a full-size keyboard. The general idea is that it should be possible to use tiny vibrating motors to fool fingers into thinking that they're touching a physical keyboard. Working prototypes designed for mobile phones already exist, like Immersion's TouchSense technology.

Acer's Iconia dual-screen tablet lacks haptics, but is it a reasonable facsimile of the future of laptops?

A laptop with a fully virtual keyboard would resemble what's known as a folio computer. Basically: two tablets connected with a hinge. Acer's already rolled one out, with their Iconia dual-screen tablet. Problem is, typing without a physical or a sophisticated-enough virtual keyboard remains a pain.

Acer's got at least one thing right, however: replacing a keyboard with a fully virtual interface allows you to change control modalities as easily as you switch desktop backgrounds. Imagine a future in which every application developer has the freedom to create their own custom interface metaphor: a mix of any combination of gestures, drawing tools and buttons.

Ironically, this would represent a return to exactly the sort of physical interfaces we left behind when we moved to computers in the first place. Consistent, customized interfaces that feel like the real thing -- switches, buttons, charcoal on paper, whatever -- could engage our proprioceptive sense and spatial memory in a way that current interfaces do not.

So before we lament the death of the keyboard, we should ask ourselves whether making it the primary means of engaging with the world was a good idea in the first place

Energy-Harvesting Displays

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Polarizing power: This film, which could be used in an LCD, lets through light of one polarization and can convert into electricity some of the rest.
Credit: UCLA

ENERGY

Adding solar cells to screens could prolong the battery life of many electronic gadgets.

• BY KATHERINE BOURZAC

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Adding solar cells to liquid-crystal displays could help recover a significant amount of energy that's ordinarily wasted in powering them. Two research groups have created light filters that double as photovoltaic cells, a trick that could boost the battery life of phones and laptops.

Over 90 percent of the displays sold this year will use liquid-crystal display (LCD) technology. LCDs are, however, tremendously inefficient, converting only about 5 percent of the light produced by a backlight into a viewable image. The LCD in a notebook computer consumes one-third of its power.

This type of screen remains dominant because manufacturers can make LCDs inexpensively on a huge scale. More energy-efficient kinds of displays either are too expensive to manufacture or cannot produce high-quality images. "The LCD is very inefficient, but it works," says Jennifer Colegrove, an analyst at Display Search, a market-research and consulting firm.

Two independent groups—one at the University of California, Los Angeles, the other at the University of Michigan—are tackling two of the biggest culprits of wasted light in LCDs: polarizers and color filters.

Polarizers filter out light that is incompatible with the liquid-crystal shutters in an LCD pixel, accounting for 75 percent of the total light wasted by LCD screens, and conventional color filters toss out two-thirds of the light that hits them. The two research groups have created plastic photovoltaic versions of these two display components, which convert light into electricity.

"We want to take an energy-wasting component that everybody uses and turn it into an energy-saving one," says Yang Yang, professor of materials science and engineering at UCLA. Yang's group created plastic solar cells that can act as polarizers. The researchers simply rub one layer in the solar-cell film with a cloth to align all the molecules in one direction. This alignment turns the cell into a polarizer that converts into electricity some of the light that doesn't pass through.

Yang's work is part of a three-year project being funded by Intel; in the coming year, his team plans to integrate the photovoltaic polarizer into a working display. In a paper published online in the journal Advanced Materials, the team reports that its polarizer can convert into electricity 3 or 4 percent of the light that's normally wasted by a filter. Yang expects to get this up to about 10 percent by tinkering with the materials used. 

The photovoltaic polarizers can harvest ambient light too, so they could potentially help charge a phone when it's not in use. "When the phone sits, it could work in the background, collecting energy and recycling it back to the battery," says Youssry Botros, program director at the Intel Labs Academic Research Office.

The second group, led by Jay Guo of the University of Michigan, is developing energy-harvesting color filters. Color filters are used in many types of displays, but the ones made by Guo's team are appropriate for use in reflective "electronic paper" screens. These contain arrays of sub-pixels that absorb ambient light and then reflect red, green, or blue light.

Guo and colleagues combined a common polymer solar-cell material with a kind of color filter that his group invented last year. The photovoltaic color filter converts into electricity about two percent of the light that would otherwise be wasted.

Guo estimates that full displays incorporating this photovoltaic filter could generate tens of milliwatts of power, enough to make a difference to the life of a cell phone battery. The photovoltaic color filter is described in a paper published online in the journal ACS Nano.

"It's an intriguing idea," says Gary Gibson, a scientist developing reflective color displays at HP Labs in Palo Alto, California. Low brightness is a recurring problem for color electronic paper. If the color filter proves practical, says Gibson, energy harvested from ambient light could be used to power a backlight and make the display brighter.

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Study sheds light on late phase of asthma attacks

by Biomechanics 

New research led by scientists from Imperial College London explains why around half of people with asthma experience a 'late phase' of symptoms several hours after exposure to allergens. The findings, published in the journal Thorax, could lead to better treatments for the disease. 

An estimated 300 million people suffer from asthma, and the prevalence is rising. Symptoms are commonly triggered by allergens in the environment, such as pollen and dust mites. These stimuli can cause the airways to tighten within minutes, causing breathing difficulties which range from mild to severe. Many sufferers also experience a 'late asthmatic response' three to eight hours after exposure to allergens, causing breathing difficulties which can last up to 24 hours.

In the early asthmatic response, the allergen is recognised by mast cells, which release chemical signals that cause the airways to narrow. In contrast, the mechanism behind the late phase has remained unclear. 

In research on mice and rats, the Imperial team have now found evidence that the late asthmatic response happens because the allergen triggers sensory nerves in the airways. These nerves activate reflexes which trigger other nerves that release the neurotransmitter acetylcholine, which causes the airways to narrow. If the findings translate to humans, it would mean that drugs that block acetylcholine – called anticholinergics – could be used to treat asthma patients that experience late phase responses following exposure to allergens. 

Steroids are the main treatments for asthma prescribed now, but they are not effective for all patients. A recent clinical trial involving 210 asthma patients found that the anticholinergic drug tiotropium improved symptoms when added to a steroid inhaler, but the reason for this was unexplained. 

"Many asthmatics have symptoms at night after exposure to allergens during the day, but until now we haven't understood how this late response is brought about," said Professor Maria Belvisi, from the National Heart and Lung Institute at Imperial College London, who led the research. "Our study in animals suggests that anticholinergic drugs might help to alleviate these symptoms, and this is supported by the recent clinical data. We are seeking funding to see if these findings are reproduced in proof of concept clinical studies in asthmatics." 

The researchers hypothesised that sensory nerves were involved after observing that anaesthesia prevented the late asthmatic response in mice and rats. They succeeded in blocking the late asthmatic response using drugs that block different aspects of sensory nerve cell function, adding further evidence for this idea. 

After establishing that sensory nerves detect the allergen, the researchers tested the effect of tiotropium, an anticholinergic drug that is used to treat chronic obstructive pulmonary disease. Tiotropium blocks the receptor for acetylcholine, which is released by nerves in the parasympathetic nervous system. Tiotropium also blocked the late asthmatic response, suggesting that parasympathetic nerves cause the airways to constrict. 

The study was funded by the Medical Research Council (MRC). Professor Stephen Holgate, MRC funding board chair and an expert on asthma, said: "Unravelling the complex biology of asthma is vitally important, as it is an extremely dangerous condition which exerts lifelong damaging effects. The Medical Research Council is committed to research that opens doors to improving disease resilience, particularly in conditions which attack our body over the long-term. Studies like this are making really important progress and whilst we must always be cautious when taking findings from rodents into humans, these are very interesting and potentially important results."

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 Journal reference: K. Raemdonck et al. 'A role for sensory nerves in the late asthmatic response.' Thorax, 2011. doi:10.1136/thoraxjnl-2011-200365