Controlling cells’ environments: A step toward building much-needed tissues and organs

Posted by Biomechanism 

With stem cells so fickle and indecisive that they make Shakespeare’s Hamlet pale by comparison, scientists today described an advance in encouraging stem cells to make decisions about their fate. The technology for doing so, reported here at the 242nd National Meeting & Exposition of the American Chemical Society (ACS), is an advance toward using stem cells in “regenerative medicine” — to grow from scratch organs for transplants and tissues for treating diseases.

Human embryonic stem cells offer the unique ability to not only renew themselves, but to also differentiate into any one of the more than 200 cell types found in the human body.

“Stem cells have great potential in regenerative medicine, in developing new drugs and in advancing biomedical research,” said Laura L. Kiessling, Ph.D., who presented the report. “To exploit that potential, we need two things: first, reproducible methods to grow human stem cells in the laboratory, and second, the ability to make stem cells grow into heart cells, brain cells or whatever kind of cell. Our technology takes a different approach to both of these problems, and the results are very encouraging.”

Biologically, so-called pluripotent human embryonic stem cells have not made up their minds about what to become. That’s essential because these cells, which are derived from embryos, have the agility to develop into the hundreds of different kinds of cells in a fully-formed human body. But controlling their differentiation has also stood as a major barrier to making the stem cell dream come true and using these all-purpose cells in medicine.

Past approaches to growing and scripting the fate of stem cells have involved adding growth-regulating and other substances to cultures of stem cells growing in the laboratory. These conditions left scientists guessing about exactly what wound up in the stem cells. Kiessling and colleagues are pioneering a new approach that involves using chemically controlled surfaces.

Kiessling previously developed chemically modified plastic and glass surfaces that take much of the guess work out of growing stem cells in laboratory cultures. In the past, scientists grew stem cells on surfaces that contained mouse cells. That left scientists with nagging questions about possible contamination of stem cells with disease-causing animal viruses — a stumbling block for using stem cells in potential medical applications. And that growth system was what scientists term “undefined.” There were variations from batch to batch of mouse cells, and scientists never really knew what the stem cells were coming into contact with and how it might be changing them. The synthetic, chemically-defined, surfaces ended that uncertainty. The approach was inexpensive, simple and a much-needed advance in producing stem cells, Kiessling explained.

With the ability to grow stem cells on the synthetic surfaces under chemically defined, or known, conditions, Kiessling’s group took an additional step in their latest research. It found that chemically defined surfaces can exert control over signaling pathways. “Signaling” is how molecules talk to one another and get things done inside a cell. It’s how an immune cell knows to fight an infection or how a pancreatic cell determines that more insulin is needed in the bloodstream, for example. By controlling how molecules inside a stem cell communicate, researchers could someday in the future nudge them to become one type of cell or tissue over another.

To see whether a new chemically defined surface could change signaling in a pilot experiment, Kiessling tested cancer cells. The research involved use of a signaling substance, transforming growth factor-beta (TGF-beta), which controls a range of activities, from cell growth to self-destruction.

“The new surfaces give scientists much more control over cells, opening up a wide range of possible future applications,” Kiessling explained. Building directly on the results of the pilot study, the surfaces could have applications in wound healing. TGF- beta can help wounds heal, but if it touches healthy skin, inflammation or even a cancerous tumor could develop. “We haven’t done this, but you could imagine a bandage that has a localized concentration of the special peptide surface that would recruit TGF-beta just to the wound site,” said Kiessling.

The surfaces also could make it easier to manufacture organs and tissues in the laboratory someday. “We think that this strategy, with different sets of peptides (building blocks of proteins) bound to the surface, could direct certain human embryonic stem cells on the surface to become one type of cell and other stem cells to become a second cell type, right next to each other. For the tissue engineering involved in growing replacement organs, you need to organize specialized cells in particular ways like this.”

Free radicals crucial to suppressing appetite

Posted by Biomechanism 

Obesity is growing at alarming rates worldwide, and the biggest culprit is overeating. In a study of brain circuits that control hunger and satiety, Yale School of Medicine researchers have found that molecular mechanisms controlling free radicals—molecules tied to aging and tissue damage—are at the heart of increased appetite in diet-induced obesity.

Caption: This image shows satiety promoting melanocortin neurons (green) in the hypothalamus, some of which are activated (red nuclei) after treatment. Credit: Tamas Horvath, Yale University

Published Aug. 28 in the advanced online issue of Nature Medicine, the study found that elevating free radical levels in the hypothalamus directly or indirectly suppresses appetite in obese mice by activating satiety-promoting melanocortin neurons. Free radicals, however, are also thought to drive the aging process.

“It’s a catch-22,” said senior author Tamas Horvath, the Jean and David W. Wallace Professor of Biomedical Research, chair of comparative medicine and director of the Yale Program on Integrative Cell Signaling and Neurobiology of Metabolism. “On one hand, you must have these critical signaling molecules to stop eating. On the other hand, if exposed to them chronically, free radicals damage cells and promote aging.”

“That’s why, in response to continuous overeating, a cellular mechanism kicks in to suppress the generation of these free radicals,” added lead author Sabrina Diano, associate professor of Ob/Gyn, neurobiology and comparative medicine. “While this free radical-suppressing mechanism—promoted by growth of intracellular organelles, called peroxisomes—protects the cells from damage, this same process will decrease the ability to feel full after eating.”

After the mice ate, the team saw that the neurons responsible for stopping overeating had high levels of free radicals. This process is driven by the hormone leptin and glucose, which signal the brain to modulate food intake. When mice eat, leptin and glucose levels go up, as does free radical levels. However, in mice with diet-induced obesity, these same neurons display impaired firing and activity (leptin resistance); in these mice, levels of free radicals were buffered by peroxisomes, preventing the activation of these neurons and thus the ability to feel sated after eating.

According to Horvath and Diano, the crucial role of free radicals in promoting satiety as well as degenerative processes associated with aging may explain why it has been difficult to develop successful therapeutic strategies for obesity without major side effects. Current studies address the question of whether, under any circumstance, satiety could be promoted without sustained elevation of free radicals in the brain and periphery.

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Other authors on the study include Zhong-Wu Liu, Jin Kwoan Jeong, Marcelo O. Dietrich, Hai-Bin Ruan, Esther Kim, Shigetomo Suyama, Kaitlin Kelly, Erika Gyengesi, Jack L. Arbiser, Denise D. Belsham, David A. Sarruf, Michael W. Schwartz, Anton M. Bennett, Marya Shanabrough, Charles V. Mobbs, Xiaoyong Yang, and Xiao-Bing Gao.

The study was supported by grants form the National Institutes of Health and the American Diabetes Association.

Citation: Nature Medicine, DOI: 10.1038/nm.2421

Nano-thermometers show first temperature response differences within living cells

Posted by Biomechanism 

Using a modern version of open-wide-and-keep-this-under-your-tongue, scientists today reported taking the temperature of individual cells in the human body, and finding for the first time that temperatures inside do not adhere to the familiar 98.6 degree Fahrenheit norm. They presented the research at the 242nd National Meeting & Exposition of the American Chemical Society (ACS), being held here this week.

Researchers are using quantum dots (shown in red) to take the temperature of living cells. Image Credit: Haw Yang, Ph.D.

Haw Yang and Liwei Lin, who collaborated on the research, did not use a familiar fever thermometer to check the temperature of cells, the 100 trillion or so microscopic packages of skin, nerve, heart, liver and other material that make up the human body. Cells are so small that almost 60,000 would fit on the head of a common pin. Yang is with Princeton University and Lin is with the University California-Berkeley.

“We used ‘nano-thermometers’,” Yang explained. “They are quantum dots, semiconductor crystals small enough to go right into an individual cell, where they change color as the temperature changes. We used quantum dots of cadmium and selenium that emit different colors (wavelengths) of light that correspond to temperature, and we can see that as a color change with our instruments.”

Yang said that information about the temperatures inside cells is important, but surprisingly lacking among the uncountable terabytes of scientific data available today.

“The inside of a cell is so complicated, and we know very little about it,” he pointed out. “When one thinks about chemistry, temperature is one of the most important physical factors that can change in a chemical reaction. So, we really wanted to know more about the chemistry inside a cell, which can tell us more about how the chemistry of life occurs.”

Scientists long have suspected that temperatures vary inside individual cells. Yang explained that thousands of biochemical reactions at the basis of life are constantly underway inside cells. Some of those reactions produce energy and heat. But some cells are more active than others, and the unused energy is discharged as heat. Parts of individual cells also may be warmer because they harbor biochemical power plants termed mitochondria for producing energy.

The researchers got that information by inserting the nano-thermometers into mouse cells growing in laboratory dishes. They found temperature differences of a few degrees Fahrenheit between one part of some cells and another, with parts of cells both warmer and cooler than others. Their temperature measurements are not yet accurate enough to give an exact numerical figure. Yang’s team also intentionally stimulated cells in ways that boosted the biochemical activity inside cells and observed temperature changes.

Yang says that those temperature changes may have body-wide impacts in determining health and disease. Increases in temperature inside a cell, for instance, may change the way that the genetic material called DNA works, and thus the way that the genes, which are made from DNA, work. Changing the temperature will also change how protein molecular machines operate. At higher temperatures, some proteins may become denatured, shutting down production.

“With these nano thermometer experiments, I believe we are the first to show that the temperature responses inside individual living cells are heterogeneous — or different,” said Yang. “This leads us to our next hypothesis, which is that cells may use differences in temperature as a way to communicate.”

Yang’s team is now conducting experiments to determine what regulates the temperature inside individual cells. One goal is to apply the information in improving prevention, diagnosis and treatment of diseases.

New skin test determines age of wild animals to help control nuisance animals

Posted by Biomechanism 

A new skin test can determine the age of wild animals while they are still alive, providing information needed to control population explosions among nuisance animals, according to a report here today at the 242nd National Meeting & Exposition of the American Chemical Society (ACS).

Tigers (and all the Order Carnivora which consists of all cats, dogs, bears, seals, weasels, stoats, pinnipeds, etc.) are descended from the family of marten-like woodland animals called the miacidae. These small omnivores evolved during the late Cretaceous period (toward the end of the age of the dinosaurs), about 70-65 million years ago.

ACS, the world largest scientific society with more than 163,000 members, is holding the meeting through Thursday at the Colorado Convention Center and downtown hotels. With 7,500 reports on new advances in science and more than 12,000 scientists and others expected in attendance, it will be one of 2011’s largest scientific gatherings.

Randal Stahl, Ph.D., said that the improved method will provide important information about the health and stability of herds, flocks and other populations of wild animals, which lack the established birthdates of prized cattle, horses, and many household pets.

“Determining the age of wild animals is important for a number of reasons,” Stahl explained. “We are in the midst of population explosions of some animals that have negative impacts on people, property and other animals. Wildlife management programs have been established to cope with the situation. Some of these programs, for instance, seek to maintain healthy numbers of breeding pairs. The new skin test will help us tell how many animals in a wild population are of breeding age.”

Stahl is a scientist with the National Wildlife Research Center (NWRC) in Fort Collins, CO. The center is the research arm of the U.S. Department of Agriculture, Animal and Plant Health Inspection Service, Wildlife Services program.

The test detects pentosidine, a biomarker for so-called advanced glycation end products (AGEs), substances that form in the body as a result of aging; the amounts can indicate an animal’s age. Those substances also form in humans, and have been linked to a range of chronic disorders, including type 2 diabetes, cancer and Alzheimer’s disease.

Tests for AGEs already exist and have been used in both animals and humans. At the ACS meeting, Stahl and colleagues described development of a more sensitive version of the animal test. That test involves taking a biopsy, or sample, of the animal’s skin. In the past, scientists needed such a large skin sample — about the size of a postage stamp — that scientists usually could do the test only on dead animals. The new version of the test requires a skin sample only the size of a pea.

“We improved the sensitivity of the pentosidine test so we can detect very small amounts of it,” Stahl said. “The advance will enable scientists to capture a few individuals, take a small skin sample without harming the animal and then release it back into the wild. With this approach, we can sample a population repeatedly over time without having an effect on the size of the population.”

Stahl’s group is currently studying double-crested cormorants, large fish-eating birds that have become a nuisance due to population explosions. Federal and state agencies in the Great Lakes region, and other areas, are trying to manage cormorant populations to reduce the birds’ adverse impacts on vegetation, other water birds, private property, fish farming, sports fishing and risks of collisions with aircraft. Those efforts involve maintaining the number of breeding pairs of cormorants at environmentally healthy levels. And the new skin test will enable scientists to gauge the number of birds that are of breeding age.

Collaborating with the NWRC field station in Mississippi, the researchers also developed a technique of handling cormorants to obtain samples with little harm to the birds. They place a small hollow metal cylinder called a biopsy punch on the bird’s skin to remove the sample and then put an adhesive on the wound to prevent infection and promote healing, just like a Band-Aid. No anesthesia is needed.

Stahl plans to use the skin analysis method to study other wild populations, such as invasive species of snakes and lizards in Florida. And because of recent coyote attacks on humans in populated areas, such as the suburbs of New York City and in California, Stahl’s team also will use the method to determine the demographics of these urban coyote populations during management activities.

Scientists develop new technologies for understanding bacterial infections

Posted by Biomechanism 

“New approach for studying molecules within their natural environment.”

Understanding how bacteria infect cells is crucial to preventing countless human diseases. In a recent breakthrough, scientists from the University of Bristol have discovered a new approach for studying molecules within their natural environment, opening the door to understanding the complexity of how bacteria infect people.

this development has enabled the research team to correlate intricate, atomic level detail of UspA1 obtained by X-ray crystallography of isolated fragments of the protein with delicate and previously unobservable physical changes of the bacterial cell as it binds to and infects its target human cells.

The research, led by a team of biochemists, microbiologists and physicists and published in the Proceedings of the National Academy of Sciences (PNAS), provides an unprecedented level of detail of the consequences of a bacterium approaching another cell, directly in situ.

Until now, traditional approaches to understanding infection have focused on either studies of the cells involved or dissection of individual molecules present within the cells. Leo Brady, Professor of Biochemistry and Mumtaz Virji, Professor of Molecular Microbiology, who led the research, have developed a novel method for bridging these, until now, separate approaches.

The team studied the common bacterium Moraxella catarrhalis, which causes middle ear infections in young children, and is a major cause of morbidity in those with heart disease. For many years, scientists approached this problem from the molecular medicine approach — through isolating and studying proteins from the Moraxella cell surface that initiate infection.

From these detailed studies the team have been able to develop an overview of one of the key proteins, called UspA1. However, as with the vast majority of molecular medicine approaches, this model has been based on studies of the UspA1 protein in isolation, rather than in its natural setting on the bacterium surface. A common worry for many biomedical scientists is how such understanding translates into the reality of these tiny molecules when they are part of a much larger cell. Understanding the increased complexity of individual molecules within the cellular mêlée is crucial to understanding why many promising drugs fail to live up to expectations.

To begin bridging this gap in our understanding, Professors Brady and Virji teamed up with Dr Massimo Antognozzi from the University’s School of Physics, whose group have been developing a novel form of atomic force microscope, termed the lateral molecular force microscope (LMFM).

Together, they have evolved the design of the LMFM microscope to optimise its ability to measure biological phenomena such as changes in UspA1 directly at the Moraxella cell surface. The LMFM differs from more conventional atomic force microscopes in tapping samples (in this case, individual cells) against an extremely fine lever, equivalent to the stylus of a record player, rather than moving the lever as is usually the case. Fabrication of extremely thin but stiff cantilevers together with exceptionally fine motor movements and a specialised visualisation system have all been combined in the device to tremendous effect. The sensitivity achieved has been further enhanced by its location within the extremely low vibration environment provided within the University’s innovative Nanoscience and Quantum Information building. The result has been a machine that can measure exquisitely fine molecular changes and forces in individual molecules directly on a living cell surface.

In the Moraxella study, this development has enabled the research team to correlate intricate, atomic level detail of UspA1 obtained by X-ray crystallography of isolated fragments of the protein with delicate and previously unobservable physical changes of the bacterial cell as it binds to and infects its target human cells.

Professor Brady said: “The findings have triggered the development of a novel technology that promises to open up a new approach for studying molecular medicine. This breakthrough will undoubtedly prove equally useful for the study of many other biological processes directly within their cellular environment, something that has long been needed in molecular medicine.”

This combined study has enabled the researchers to observe the very first responses as a bacterium binds to a human cell, hence opening the door to understanding the complexity of infection processes.
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The UspA1 LMFM studies have been funded by the Wellcome Trust and the Biotechnology and Biological Sciences Research Council (BBSRC) and are published today [29 Aug] in the journal Proceedings of the National Academy of Sciences (PNAS).

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Playing highly competitive video games may lead to aggressive behavior

 Psychology & Psychiatry 

While most research into video games and aggressive behavior has focused on violent games, competitiveness may be the main video game characteristic that influences aggression, according to new research published by the American Psychological Association.

In a series of experiments in which video games were matched on competitiveness, difficulty, and pace of action, researchers found video game violence alone did not elevate aggressive behavior. However, more competitive games produced greater levels of aggressive behavior than less competitive games, no matter how much violence was in the games, according to research published online in Psychology of Violence. The study was conducted by lead author Paul J.C. Adachi, M.A., a PhD candidate at Brock University in Canada.

In one experiment, Adachi had 42 college students (25 men, 17 women) play one of two video games, "Conan" or "Fuel," for 12 minutes. "Conan" is a violent game in which the main character battles for survival using swords and axes. "Fuel" is a nonviolent racing game. In a pilot study, both games were rated evenly in terms of competitiveness, difficulty and pace of action, but differently in terms of violence. After participants finished playing the game, they were told they were going to take part in a separate food tasting study. Participants had to make up a cup of hot sauce for a "taster" who they were told did not particularly like hot or spicy food. The participants could choose from one of four different hot sauces (from least hot to most hot) for the taster to drink. The authors found that there was no significant difference in the intensity and amount of the hot sauces prepared by the participants who played "Conan" and those who played "Fuel." The authors concluded that, in this study, video game violence alone was not sufficient to elevate aggressive behavior.

In a second experiment, Adachi had 60 college students (32 men, 28 women) play one of the following four video games: "Mortal Kombat versus DC Universe," a violent fighting game rated as highly competitive and very violent; "Left 4 Dead 2," a violent, moderately competitive first-person shooter game in which the main character battles zombies using guns; "Marble Blast Ultra," a nonviolent, noncompetitive game where players control a marble through a series of labyrinth-like mazes as quickly as possible; and "Fuel," the highly competitive, nonviolent racing game from the first study. Afterward, the students completed the same hot sauce tasting test from the first study. Electrocardiograms measured the participants' heart rates before and during video game play.

On average, students who played the highly competitive games, "Fuel" and "Mortal Kombat versus DC Universe," prepared significantly more of a hotter sauce than participants who played "Marble Blast Ultra" and "Left 4 Dead 2," the least competitive games. They also had significantly higher heart rates.

"These findings suggest that the level of competitiveness in video games is an important factor in the relation between video games and aggressive behavior, with highly competitive games leading to greater elevations in aggression than less competitive games," wrote Adachi.

More information: "The Effect of Video Game Competition and Violence on Aggressive Behavior: Which Characteristic Has the Greatest Influence?" Paul J.C. Adachi, M.A., and Teena Willoughby, PhD, Brock University, Canada; Psychology of Violence, Online First, August 17, 2011.

Provided by American Psychological Association

"Playing highly competitive video games may lead to aggressive behavior." August 29th, 2011.http://medicalxpress.com/news/2011-08-highly-competitive-video-games-aggressive.html

Comment:If you want to see real violence, try forcing your teenage son to play 'Barbie Horse Adventures' when his mates are due to drop around...

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Robert Karl Stonjek

Study links bilingual babies' vocabulary to early brain differentiation

 Psychology & Psychiatry 

This is one of the babies in the experiment wearing an EEG cap that measures brain activity. Credit: University of Texas at San Antonio

Babies and children are whizzes at learning a second language, but that ability begins to fade as early as their first birthdays.

Researchers at the University of Washington's Institute for Learning & Brain Sciences are investigating the brain mechanisms that contribute to infants' prowess at learning languages, with the hope that the findings could boost bilingualism in adults, too.

In a new study, the researchers report that the brains of babies raised in bilingual households show a longer period of being flexible to different languages, especially if they hear a lot of language at home. The researchers also show that the relative amount of each language – English and Spanish – babies were exposed to affected their vocabulary as toddlers.

The study, published online Aug. 17 in Journal of Phonetics, is the first to measure brain activity throughout infancy and relate it to language exposure and speaking ability.

"The bilingual brain is fascinating because it reflects humans' abilities for flexible thinking – bilingual babies learn that objects and events in the world have two names, and flexibly switch between these labels, giving the brain lots of good exercise," said Patricia Kuhl, co-author of the study and co-director of the UW's Institute for Learning & Brain Sciences.

Kuhl's previous studies show that between 8 and 10 months of age, monolingual babies become increasingly able to distinguish speech sounds of their native language, while at the same time their ability to distinguish sounds from a foreign language declines. For instance, between 8 and 10 months of age babies exposed to English become better at detecting the difference between "r" and "l" sounds, which are prevalent in the English language. This is the same age when Japanese babies, who are not exposed to as many "r" and "l" sounds, decline in their ability to detect them.

"The infant brain tunes itself to the sounds of the language during this sensitive period in development, and we're trying to figure out exactly how that happens," said Kuhl, who's also a UW professor of speech and hearing sciences. "But almost nothing is known about how bilingual babies do this for two languages. Knowing how experience sculpts the brain will tell us something that goes way beyond language development."

In the current study, babies from monolingual (English or Spanish) and bilingual (English and Spanish) households wore caps fitted with electrodes to measure brain activity with an electroencephalogram, or EEG, a device that records the flow of energy in the brain. Babies heard background speech sounds in one language, and then a contrasting sound in the other language occurred occasionally.

For example, a sound that is used in both Spanish and English served as the background sound and then a Spanish "da" and an English "ta" each randomly occurred 10 percent of the time as contrasting sounds. If the brain can detect the contrasting sound, there is a signature pattern called the mismatch response that can be detected with the EEG.

Monolingual babies at 6-9 months of age showed the mismatch response for both the Spanish and English contrasting sounds, indicating that they noticed the change in both languages. But at 10-12 months of age, monolingual babies only responded to the English contrasting sound.

Bilingual babies showed a different pattern. At 6-9 months, bilinguals did not show the mismatch response, but at 10-12 months they showed the mismatch for both sounds.

This suggests that the bilingual brain remains flexible to languages for a longer period of time, possibly because bilingual infants are exposed to a greater variety of speech sounds at home.

This difference in development suggests that the bilingual babies "may have a different timetable for neurally committing to a language" compared with monolingual babies, said Adrian Garcia-Sierra, lead author and a postdoctoral researcher at UW's Institute for Learning & Brain Sciences.

"When the brain is exposed to two languages rather than only one, the most adaptive response is to stay open longer before showing the perceptual narrowing that monolingual infants typically show at the end of the first year of life," Garcia-Sierra said.

To see if those brain responses at 10-12 months related to later speaking skills, the researchers followed up with the parents when the babies were about 15 months old to see how many Spanish and English words the children knew. They found that early brain responses to language could predict infants' word learning ability. That is, the size of the bilingual children's vocabulary was associated with the strength of their brain responses in discriminating languages at 10-12 months of age.

Early exposure to language also made a difference: Bilingual babies exposed to more English at home, including from their parents, other relatives and family friends, subsequently produced more words in English. The pattern held true for Spanish.

The researchers say the best way for children to learn a second language is through social interactions and daily exposure to the language.

"Learning a second language is like learning a sport," said Garcia-Sierra, who is raising his two young children as bilingual. "The more you play the better you get."

Provided by University of Washington

"Study links bilingual babies' vocabulary to early brain differentiation." August 29th, 2011.http://medicalxpress.com/news/2011-08-links-bilingual-babies-vocabulary-early.html

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Robert Karl Stonjek