Nanotechnology: The Art of Molecular Carpet-Weaving

Stable two-dimensional networks of organic molecules are important components in various nanotechnology processes. However, producing these networks, which are only one atom thick, in high quality and with the greatest possible stability currently still poses a great challenge. Scientists from the Excellence Cluster Nanosystems Initiative Munich (NIM) have now successfully created just such networks made of boron acid molecules. The current issue of the scientific journal ACSnano reports on their results. 

Scanning electron microscopy image with a superimposed molecular model [Credit: TUM]

Even the costliest oriental carpets have small mistakes. It is said that pious carpet-weavers deliberately include tiny mistakes in their fine carpets, because only God has the right to be immaculate. Molecular carpets, as the nanotechnology industry would like to have them are as yet in no danger of offending the gods. A team of physicists headed by Dr. Markus Lackinger from the Technische Universität München (TUM) und Professor Thomas Bein from the Ludwig-Maximilians-Universität München (LMU) has now developed a process by which they can build up high-quality polymer networks using boron acid components. 

The "carpets" that the physicists are working on in their laboratory in the Deutsches Museum München consist of ordered two-dimensional structures created by self-organized boron acid molecules on a graphite surface. By eliminating water, the molecules bond together in a one-atom thick network held together solely by chemical bonds -- a fact that makes this network very stable. The regular honey-comb-like arrangement of the molecules results in a nano-structured surface whose pores can be used, for instance, as stable forms for the production of metal nano-particles. 

The molecular carpets also come in nearly perfect models; however, these are not very stable, unfortunately. In these models the bonds between the molecules are very weak -- for instance hydrogen bridge bonds or van der Waals forces. The advantage of this variant is that faults in the regular structure are repaired during the self-organization process -- bad bonds are dissolved so that proper bonds can form. 

However, many applications call for molecular networks that are mechanically, thermally and/or chemically stable. Linking the molecules by means of strong chemical bonds can create such durable molecule carpets. The down side is that the unavoidable weaving mistakes can no longer be corrected due to the great bonding strength. 

Markus Lackinger and his colleagues have now found a way to create a molecular carpet with stable covalent bonds without significant weaving mistakes. The method is based on a bonding reaction that creates a molecular carpet out of individual boron acid molecules. It is a condensation reaction in which water molecules are released. If bonding takes place at temperatures of a little over 100°C with only a small amount of water present, mistakes can be corrected during weaving. The result is the sought after magic carpet: molecules in a stable and well-ordered one-layer structure. 

Markus Lackinger's laboratory is located in the Deutsches Museum München. There he is doing research at the Chair of Prof. Wolfgang Heckl (TUM School of Education, TU München). Prof. Bein holds a Chair at the Department of Chemistry at the LMU. The research was conducted in collaboration with Prof. Paul Knochel's work group (LMU) and Physical Electronics GmbH, with funding by the Excellence Cluster Nanosystems Initiative Munich (NIM) and the Bavarian Research Foundation (BFS). 

Source: Technische Universitaet Muenchen [December 29, 2011]

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Exercise cuts bowel cancer risk

Researchers at the University of Western Australia (UWA) and the Western Australian Institute for Medical Research (WAIMR) have found people who engage in vigorous physical activity may be protected against types of colorectal cancer. 

The study, published in the Cancer Causes Control journal, used a Western Australian cohort.  

Researchers examined 870 participants who had bowel cancer and a control group of 996 who did not have the disease. 

Study participants were asked to answer questions about their recreational physical activity, lifestyle, diet, medication and occupation. 

UWA PhD student Terry Boyle, also supported by the Lions Cancer Institute, says the study confirms previous research that shows the most physically active have a lower risk of bowel cancer than the least active.  

“It also gives us some clues as to what types of activity are the most effective at reducing bowel cancer risk,” Mr Boyle says.  

The study found people who performed regular vigorous physical activity over their lifetime had a 40 per cent reduced risk of cancer of the distal (lower) colon and rectum. 

“These results suggest that vigorous activity like jogging, cycling, swimming, tennis, hockey, netball and football may be the most effective physical activities to lower the risk of bowel cancer,” Mr Boyle says. 

Of the possible mechanisms linking physical activity and colon cancer, there is evidence to suggest that obesity and vitamin D may have a great effect on distal colon cancer than proximal colon cancer. 

While the link between physical activity and colon cancers remains opaque, this study supports the suggestion that lifestyle factors are more strongly tied to distal colon cancer than proximal colon cancer.  

Another finding showed physical activity performed after the age of 51 years, may be more beneficial in reducing the risk of distal colon cancer than physical activity performed earlier in life. 

“This shows that it really is never too late to start being physically active,” Mr Boyle says. 

Author: Gina Ravenscroft | Source: Science Network/Western Australia [December 20, 2011]

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Extracellular Matrix Could Lead to Advances in Regenerative Medicine

NPL scientists have created a functional model of the native extracellular matrix which provides structural support to cells to aid growth and proliferation and could lead to advances in regenerative medicine. 

Atomic Force Microscopy (AFM) image of the designed extracellular matrix [Credit: National Physical Laboratory]

The extracellular matrix (ECM) provides the physical and chemical conditions that enable the development of all biological tissues. It is a complex nano-to-microscale structure made up of protein fibres and serves as a dynamic substrate that supports tissue repair and regeneration. 

Human-made structures designed to mimic and replace the native matrix in damaged or diseased tissues are highly sought after to advance our understanding of tissue organisation and to make regenerative medicine a reality. 

Self-assembling peptide fibres that have similar properties to those of the native matrices are of particular interest. However, these near-crystalline nanostructures fail to arrange themselves into interconnected meshes at the microscopic scale, which is critical for bringing cells together and supporting tissue development. 

To solve this problem, a research team at NPL designed a small protein consisting of two complementary domains (structural units) that promote the formation of highly branched networks of fibres that span microscopic dimensions. The team showed that the created matrix is very efficient in supporting cell attachment, growth and proliferation. 

This research is part of the NPL-led international research project, 'Multiscale measurements in biophysical systems', which is jointly funded by NPL and the Scottish Universities Physics Alliance. 

Read the full article detailing this research published in Angewandte Chemie -- the premier and most authoritative publication for critical advances in chemical research. 

Source: National Physical Laboratory [December 12, 2011]

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New Synthetic Molecules Treat Autoimmune Disease in Mice

A team of Weizmann Institute scientists has turned the tables on an autoimmune disease. In such diseases, including Crohn's and rheumatoid arthritis, the immune system mistakenly attacks the body's tissues. But the scientists managed to trick the immune systems of mice into targeting one of the body's players in autoimmune processes, an enzyme known as MMP9. The results of their research recently appeared in Nature Medicine. 

Left: Natural control mechanism blocks the enzyme's zinc active site. Right: Novel antibody works as effectively as the natural control mechanism [Credit: Weizmann Institute of Science]

Prof. Irit Sagi of the Biological Regulation Department and her research group have spent years looking for ways to home in on and block members of the matrix metalloproteinase (MMP) enzyme family. These proteins cut through such support materials in our bodies as collagen, which makes them crucial for cellular mobilization, proliferation and wound healing, among other things. But when some members of the family, especially MMP9, get out of control, they can aid and abet autoimmune disease and cancer metastasis. Blocking these proteins might lead to effective treatments for a number of diseases. 

Originally, Sagi and others had designed synthetic drug molecules to directly target MMPs. But these drugs proved to be fairly crude tools that had extremely severe side effects. The body normally produces its own MMP inhibitors, known as TIMPs, as part of the tight regulation program that keeps these enzymes in line. As opposed to the synthetic drugs, these work in a highly selective manner. An arm on each TIMP is precisely constructed to reach into a cleft in the enzyme that shelters the active bit -- a metal zinc ion surrounded by three histidine peptides -- closing it off like a snug cork. "Unfortunately," says Sagi, "it is quite difficult to reproduce this precision synthetically." 

Dr. Netta Sela-Passwell began working on an alternative approach as an M.Sc. student in Sagi's lab, and continued on through her Ph.D. research. She and Sagi decided that, rather than attempting to design a synthetic molecule to directly attack MMPs, they would try coaxing the immune system into targeting MMP-9 through immunization. Just as immunization with a killed virus induces the immune system to create antibodies that then attack live viruses, an MMP immunization would trick the body into creating antibodies that block the enzyme at its active site. 

Together with Prof. Abraham Shanzer of the Organic Chemistry Department, they created an artificial version of the metal zinc-histidine complex at the heart of the MMP9 active site. They then injected these small, synthetic molecules into mice and afterward checked the mice's blood for signs of immune activity against the MMPs. The antibodies they found, which they dubbed "metallobodies," were similar but not identical to TIMPS, and a detailed analysis of their atomic structure suggested they work in a similar way -- reaching into the enzyme's cleft and blocking the active site. The metallobodies were selective for just two members of the MMP family -- MMP2 and 9 -- and they bound tightly to both the mouse versions of these enzymes and the human ones. 

As they hoped, when they had induced an inflammatory condition that mimics Crohn's disease in mice, the symptoms were prevented when mice were treated with metallobodies. "We are excited not only by the potential of this method to treat Crohn's," says Sagi, but by the potential of using this approach to explore novel treatments for many other diseases." Yeda, the technology transfer arm of the Weizmann Institute has applied for a patent for the synthetic immunization molecules as well as the generated metallobodies. 

Also participating in this research were Drs. Orly Dym, Haim Rozenberg, Rina Arad-Yellin and Tsipi Shoham, and Raanan Margalit of the Structural Biology, Immunology and Biological Regulation Departments, Raghavendra Kikkeri of the Organic Chemistry Department, Miriam Eisenstein of the Chemical Research Support Department, Ori Brenner of the Veterinary Resources Department and Tamar Danon of the Molecular Cell Biology Department. 

Prof. Irit Sagi's research is supported by the Spencer Charitable Fund; the Leona M. and Harry B. Helmsley Charitable Trust; Cynthia Adelson, Canada; Mireille Steinberg, Canada; the Leonard and Carol Berall Post Doctoral Fellowship; and the Ilse Katz Institute for Material Sciences and Magnetic Resonance Research. Prof. Sagi is the incumbent of the Maurizio Pontecorvo Professorial Chair. This work was financially supported by Merck Serono S.A., a division of Merck KGaA, Darmstadt, Germany. 

Source: Weizmann Institute of Science [December 26, 2011]

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Computers implanted in brain could help paralyzed

It sounds like science fiction, but scientists around the world are getting tantalizingly close to building the mind-controlled prosthetic arms, computer cursors and mechanical wheelchairs of the future. 

Cochlear implants work under the same premise as brain devices being developed [Credit: Kendra Luck/The Chronicle]

Researchers already have implanted devices into primate brains that let them reach for objects with robotic arms. They've made sensors that attach to a human brain and allow paralyzed people to control a cursor by thinking about it. 

In the coming decades, scientists say, the field of neural prosthetics - of inventing and building devices that harness brain activity for computerized movement - is going to revolutionize how people who have suffered major brain damage interact with their world. 

"Medicine has not taken neural prosthetics very seriously until recently," said Dr. Edward Chang, a UCSF neurosurgeon and co-director of the Center for Neural Engineering and Prostheses at UC Berkeley and UCSF. "But it's become clear in the last five to 10 years that there are some practical applications." 

Jose Carmena, a neuro-engineer at UC Berkeley and Chang's co-director, puts his thoughts more succinctly: "There's going to be an explosion in neural prosthetics." 

The joint UC Berkeley and UCSF center started a year ago to take advantage of the neurology expertise in San Francisco and the engineering skills across the bay. 

Such devices that allow the brain to control a device aren't entirely new. Aside from some small steps made at other institutions - the brain-controlled computer cursor, for example - there's the cochlear implant, the first neural prosthetic tool developed and the only one that's ever seen wide use. 

The cochlear implant, which was invented at UCSF in the 1970s, intercepts sounds as electrical signals and then sends those signals directly to the brain, bypassing the damaged nerves that caused hearing loss. The devices being developed today work under the same premise but are much more complex. 

Over the past decade, scientists have made leaps of progress in learning how to read and decode the millions of electronic impulses that fire between neurons in the brain, controlling how our bodies move and how we see, feel and relate to the world around us. 

Imagine, for example, the neural effort required just to pick up a glass of red wine, Carmena said. 

Vast amount of details 

It's not enough just to prompt the right muscles to move an arm. Millions of signals in the brain help us determine where our own arm is in relation to our body, so our hand doesn't grope wildly for the glass. Our brains sense that it's a delicate glass that must be picked up carefully, pinched between fingers. The neurons control how fast our arm moves, making sure the wine doesn't slop over the edges. 

That's an astronomical amount of communication happening, all in fractions of a second, without our even being aware of it. In fact, it's more communication than our best smart-phone technology can handle. 

"We don't have existing electronics to be able to process in real time dozens of channels from the brain," Chang said. "It turns out we need a lot of information from the brain to work." 

The neural prosthetic devices that are just in their infancy now work by connecting a device inserted into the brain directly to a computer. The signals from the brain, in the form of electrical impulses, travel through a cable to the computer, where they are decoded into instructions for some kind of action, like moving a cursor. 

But for a neural prosthetic device to actually be useful, it would have to be transplanted near or in the brain and transmit wireless signals to a device like a robotic arm. It would need to be able to last forever - or at least a lifetime - on batteries that never have to be changed and won't damage the brain. 

Scientists say the actual technology is only one problem. 

"Some of the problems are purely technical, like how do you record from hundreds and hundreds of neurons at the same time," said Philip Sabes, a neuroscientist at the Keck Center for Integrative Neuroscience at UCSF. 

Other problems are going to require an even deeper understanding of how the brain works. Scientists don't yet know what parts of the brain would be best suited for implanting a device to read electrical signals - or even whether an implanted device would work better than one that's attached to the brain's surface. 

It's possible that a surface device could collect enough information to be useful in controlling a neural prosthesis with much less risk to the patient. 

'Sense of ownership' 

But it may be that scientists need to implant a device into the brain to collect enough of the brain signals, especially for creating a prosthetic device that feels natural - a robotic arm, perhaps, that can sense hot and cold, or the difference between a wine glass and a coffee mug. 

"You want the arm to feel like it's a part of you, not this thing you're picking up," Sabes said. "It will increase the sense of ownership of the device." 

A major part of Chang's research is determining what devices would actually be useful to patients. He knows that some scientists are studying exoskeletons that may allow paralyzed people to walk someday, but he wonders if that's a truly feasible device. 

Patients may be better served by a simple computer cursor that is highly responsive to their minds and doesn't require intense, focused concentration to move, Chang said. For a person who is completely paralyzed, just being able to send and read e-mails may be life changing. 

"Controlling a robotic body, that's the dream. But it's not my dream," Chang said. "I'm not sure that kind of thing is the most useful for people. I want to find out what are the things that are going to be most useful for people, and it may be as simple as communication." 

Author: Erin Allday | Source: San Francisco Chronicle [December 27, 2011]

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Diet, nutrient levels linked to cognitive ability, brain shrinkage

New research has found that elderly people with higher levels of several vitamins and omega 3 fatty acids in their blood had better performance on mental acuity tests and less of the brain shrinkage typical of Alzheimer's disease – while "junk food" diets produced just the opposite result. 

The study was among the first of its type to specifically measure a wide range of blood nutrient levels instead of basing findings on less precise data such as food questionnaires, and found positive effects of high levels of vitamins B, C, D, E and the healthy oils most commonly found in fish. 

The research was done by scientists from the Oregon Health and Science University in Portland, Ore., and the Linus Pauling Institute at Oregon State University. It was published today in Neurology, the medical journal of the American Academy of Neurology. 

"This approach clearly shows the biological and neurological activity that's associated with actual nutrient levels, both good and bad," said Maret Traber, a principal investigator with the Linus Pauling Institute and co-author on the study. 

"The vitamins and nutrients you get from eating a wide range of fruits, vegetables and fish can be measured in blood biomarkers," Traber said. "I'm a firm believer these nutrients have strong potential to protect your brain and make it work better." 

The study was done with 104 people, at an average age of 87, with no special risk factors for memory or mental acuity. It tested 30 different nutrient biomarkers in their blood, and 42 participants also had MRI scans to measure their brain volume. 

"These findings are based on average people eating average American diets," Traber said. "If anyone right now is considering a New Year's resolution to improve their diet, this would certainly give them another reason to eat more fruits and vegetables." 

Among the findings and observations: 

• The most favorable cognitive outcomes and brain size measurements were associated with two dietary patterns – high levels of marine fatty acids, and high levels of vitamins B, C, D and E. 

• Consistently worse cognitive performance was associated with a higher intake of the type of trans-fats found in baked and fried foods, margarine, fast food and other less-healthy dietary choices. 

• The range of demographic and lifestyle habits examined included age, gender, education, smoking, drinking, blood pressure, body mass index and many others. 

• The use of blood analysis helped to eliminate issues such as people's flawed recollection of what they ate, and personal variability in nutrients absorbed. 

• Much of the variation in mental performance depended on factors such as age or education, but nutrient status accounted for 17 percent of thinking and memory scores and 37 percent of the variation in brain size. 

• Cognitive changes related to different diets may be due both to impacts on brain size and cardiovascular function. 

The epidemiology of Alzheimer's disease has suggested a role for nutrition, the researchers said in their study, but previous research using conventional analysis, and looking in isolation at single nutrients or small groups, have been disappointing. The study of 30 different blood nutrient levels done in this research reflects a wider range of nutrients and adds specificity to the findings. 

The study needs to be confirmed with further research and other variables tested, the scientists said. 

Source: Oregon State University [December 28, 2011]

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The benefits of meditation

Studies have shown that meditating regularly can help relieve symptoms in people who suffer from chronic pain, but the neural mechanisms underlying the relief were unclear. Now, MIT and Harvard researchers have found a possible explanation for this phenomenon. 

In a study published online April 21 in the journal Brain Research Bulletin, the researchers found that people trained to meditate over an eight-week period were better able to control a specific type of brain waves called alpha rhythms. 

“These activity patterns are thought to minimize distractions, to diminish the likelihood stimuli will grab your attention,” says Christopher Moore, an MIT neuroscientist and senior author of the paper. “Our data indicate that meditation training makes you better at focusing, in part by allowing you to better regulate how things that arise will impact you.” 

There are several different types of brain waves that help regulate the flow of information between brain cells, similar to the way that radio stations broadcast at specific frequencies. Alpha waves, the focus of this study, flow through cells in the brain’s cortex, where sensory information is processed. The alpha waves help suppress irrelevant or distracting sensory information. 

A 1966 study showed that a group of Buddhist monks who meditated regularly had elevated alpha rhythms across their brains. In the new study, the researchers focused on the waves’ role in a specific part of the brain — cells of the sensory cortex that process tactile information from the hands and feet. 

For this study, the researchers recruited 12 subjects who had never meditated before. Half of the participants were trained in a technique called mindfulness-based stress reduction (MBSR) over an eight-week period, while the other half were told not to meditate. 

The MBSR program calls for participants to meditate for 45 minutes per day, after an initial two-and-a-half-hour training session. The subjects listen to a CD recording that guides them through the sessions. 

The first two weeks are devoted to learning to pay close attention to body sensations. “They’re really learning to maintain and control their attention during the early part of the course. For example, they learn to focus sustained attention to the sensations of the breath; they also learn to engage and focus on body sensations in a specific area, such as the bottom of the feet, and then they practice disengaging and shifting the focus to another body area,” says Catherine Kerr, an instructor at Harvard Medical School and lead author of the paper. 

The researchers did brain scans of the subjects before the study began, three weeks into it, and at the end of eight weeks. At eight weeks, the subjects who had been trained in meditation showed larger changes in the size (amplitude) of their alpha waves when asked to pay attention to a certain body part — for example, “left foot.” These changes in wave size also occurred more rapidly in the meditators. 

The study is a “beautiful demonstration” of the effects of meditation training, and of the ability to cultivate an internal awareness of one’s own bodily sensations, says Clifford Saron, associate research scientist at the Center for Mind and Brain at the University of California at Davis, who was not involved in the research. 

Subjects in this study did not suffer from chronic pain, but the findings suggest that in pain sufferers who meditate, the beneficial effects may come from an ability to essentially turn down the volume on pain signals. “They learn to be aware of where their attention is focused and not get stuck on the painful area,” Kerr says. 

The subjects trained in meditation also reported that they felt less stress than the non-meditators. “Their objective condition might not have changed, but they’re not as reactive to their situation,” Kerr says. “They’re more able to handle stress.” 

The researchers are now planning follow-up studies in patients who suffer from chronic pain as well as cancer patients, who have also been shown to benefit from meditation. 

Author: Anne Trafton | Source: Massachusetts Institute of Technology [May 05, 2011]

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Mutation in gene critical for human development linked to arrhythmia

Arrhythmia is a potentially life-threatening problem with the rate or rhythm of the heartbeat, causing it to go too fast, too slow or to beat irregularly. Arrhythmia affects millions of people worldwide. 

The cardiac conduction system (CCS) regulates the rate and rhythm of the heart. It is a group of specialized cells in the walls of the heart. These cells control the heart rate by sending electrical signals from the sinoatrial node in the heart's right atrium (upper chamber) to the ventricles (lower chambers), causing them to contract and pump blood. 

The biologic and genetic mechanisms controlling the formation and function of the CCS are not well understood, but new research with mice shows that altered function of a gene called Tbx3 interferes with the development of the CCS and causes lethal arrhythmias. 

In a study published in the Dec. 26, 2011, Proceedings of the National Academy of Sciences early edition, researchers led by the University of Utah showed the CCS is extremely sensitive to levels of Tbx3. Mouse embryos with Tbx3 levels below a critical threshold suffered arrhythmia and couldn't survive. As the levels of Tbx3 were increased, mice survived to birth, but as adults they developed arrhythmias or had sudden death. 

Tbx3 dysfunction merits further investigation as a cause of acquired and spontaneous arrhythmias, says Anne M. Moon, M.D., Ph.D., adjunct professor of pediatrics at the U of U School of Medicine and corresponding author on the study. "The cardiac conduction system is very sensitive to Tbx3," Moon says. "Tbx3 is required for the conduction system to develop, mature, and then continue to function properly." 

The Tbx3 protein, which is a transcription factor encoded by the TBX3 gene, has been linked to heart development, but its role is not yet clearly defined. Moon and her colleagues, including first author Deborah U. Frank, M.D., Ph.D., U assistant professor of pediatrics, found that slight alterations in the structure of the Tbx3 gene alter the level of the protein in mice. When this happens, it can impair the electrical signal in the sinoatrial node and block the atrioventricular node, which conducts electrical signals from the atria to the ventricles. The result is lethal arrhythmias in embryonic and adult mice. 

This discovery has implications for the potential to regenerate functional heart tissue, according to Moon. "There's a big effort to regenerate heart muscle," she says. "But if the muscle can't conduct electrical signals, it's not going to do any good; we also need to be able to regenerate conduction tissues to regulate that muscle." 

Arrhythmia is not the first problem related to mutations in the TBX3 gene. In humans, TBX3 mutations have been shown to cause limb malformations in people with ulnar-mammary syndrome, an inherited birth disorder characterized by abnormalities of the bones in the hands and forearms and underdeveloped sweat and mammary glands. 

In her future research, Moon wants to discover specifically how Tbx3 regulates the behavior of cells in the cardiac conduction system and whether cells that don't have enough Tbx3 die or turn into some other kind of cells. 

"It turns out that Tbx3 is a lot more important in the heart than we realized," Moon says. 

Source: University of Utah Health Sciences [December 27, 2011]

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Scientists succeed in making the spinal cord transparent

In the event of the spinal cord injury, the long nerve cell filaments, the axons, may become severed. For quite some time now, scientists have been investigating whether these axons can be stimulated to regenerate. Such growth takes place on a scale of only a few millimetres. To date, changes like this could be determined only by cutting the tissue in question into wafer-thin slices and examining these under a microscope. 

A spinal cord as if made of glass: The new method enables scientists to see nerve cell in the intact cellular network Credit:© MPI of Neurobiology / Erturk]

However, the two-dimensional sections provide only an inaccurate picture of the spatial distribution and progression of the cells. Together with an international team, scientists at the Max Planck Institute for Neurobiology in Martinsried have now developed a new method by virtue of which single nerve cells can be both examined in intact tissue and portrayed in all three dimensions. 

The spinal cord is the most important pathway for relaying information from the skin, muscles and joints to the brain and back again. Damage to nerve cells in this region usually results in irreversible paralysis and loss of sensation. For many years, scientists have been doing their best to ascertain why nerve cells refuse to regenerate. They search for ways to stimulate these cells to resume their growth. 

To establish whether a single cell is growing, the cell must be visible in the first place. Up to now, the procedure has been to cut the area of the spinal cord required for examination into ultra-thin slices. These are then examined under a microscope and the position and pathway of each cell is reconstructed. In exceptional cases, scientists could go to the trouble of first digitizing each slice and then reassembling the images, one by one, to produce a virtual 3D model. 

However, this is a very time-consuming endeavour, requiring days and sometimes even weeks to process the results of just one examination. Even worse, mistakes can easily creep in and falsify the results: The appendages of individual nerve cells might get squashed during the process of slicing, and the layers might be ever so slightly misaligned when set on top of each other. 

As Frank Bradke explains: "Although this might not seem dramatic to begin with it prevents us from establishing the length and extent of growth of single cells." Bradke and his team at the Max Planck Institute of Neurobiology have investigated the regeneration of nerve cells following injuries to the spinal cord. Since July he has been working at the German Centre for Neurodegenerative Diseases (DZNE) in Bonn. "However, since changes on this crucial scale are precisely what we need to see, we worked meticulously until we came up with a better technique", he continues. 

The new technique is based on a method known as ultramicroscopy, which was developed by Hans Ulrich Dodt from the Technical University of Vienna. The Max Planck neurobiologists and an international team of colleagues have now taken this technique a step further. 

The principle is relatively straightforward. Spinal cord tissue is opaque due to the fact that the water and the proteins contained in it refract light differently. Thus, the scientists removed the water from a piece of tissue and replaced it by an emulsion that refracts light in exactly the same way as the proteins. This left them with a completely transparent piece of tissue. 

"It's the same effect as if you were to spread honey onto textured glass", Ali Erturk, the study's first author adds. The opaque pane becomes crystal clear as soon as the honey has compensated for the surface irregularities. 

The new method is a leap forward in regeneration research. By using fluorescent dyes to stain individual nerve cells, scientists can now trace their path from all angels in an otherwise transparent spinal cord section. This enables them to ascertain once and for all whether or not these nerve cells recommenced their growth following injury to the spine – an essential prerequisite for future research. 

"The really great thing is the fact that this method can also be easily applied to other kinds of tissue", Frank Bradke relates. For example, the blood capillary system or the way a tumour is embedded in tissue could be portrayed and analysed in 3D. 

Source: Max-Planck-Gesellschaft [December 25, 2011]

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Sea snails help scientists explore a possible way to enhance memory

Efforts to help people with learning impairments are being aided by a species of sea snail known as Aplysia californica. The mollusk, which is used by researchers to study the brain, has much in common with other species including humans. Research involving the snail has contributed to the understanding of learning and memory. 

At The University of Texas Health Science Center at Houston (UTHealth), neuroscientists used this animal model to test an innovative learning strategy designed to help improve the brain's memory and the results were encouraging. It could ultimately benefit people who have impairments resulting from aging, stroke, traumatic brain injury or congenital cognitive impairments. 

The proof-of-principle study was published on the Nature Neuroscience website on Dec. 25. The next steps in the research may involve tests in other animal models and eventually humans. 

The strategy was used to identify times when the brain was primed for learning, which in turn facilitated the scheduling of learning sessions during these peak periods. The result was a significant increase in memory. 

"We found that memory could be enhanced appreciably," said John H. "Jack" Byrne, Ph.D., senior author and chair of the Department of Neurobiology and Anatomy at the UTHealth Medical School. 

Building on earlier research that identified proteins linked to memory, the investigators created a mathematical model that tells researchers when the timing of the activity of these proteins is aligned for the best learning experience. 

Right now, the scheduling of learning sessions is based on trial and error and is somewhat arbitrary. If the model proves effective in follow-up studies, it could be used to identify those periods when learning potential is highest. 

"When you give a training session, you are starting several different chemical reactions. If you give another session, you get additional effects. The idea is to get the sessions in sync," Byrne said. "We have developed a way to adjust the training sessions so they are tuned to the dynamics of the biochemical processes." 

Two groups of snails received five learning sessions. One group received learning sessions at irregular intervals as predicted by a mathematical model. Another group received training sessions in regular 20-minute intervals. 

Five days after the learning sessions were completed, a significant increase in memory was detected in the group that was trained with a schedule predicted by a computer. But, no increase was detected in the group with the regular 20-minute intervals. 

The computer sorted through 10,000 different permutations in order to determine a schedule that would enhance memory. 

To confirm their findings, researchers analyzed nerve cells in the brain of snails and found greater activity in the ones receiving the enhanced training schedule, said Byrne, the June and Virgil Waggoner Chair of Neurobiology and Anatomy at UTHealth. 

"This study shows the feasibility of using computational methods to assist in the design of training schedules that enhance memory," Byrne said.  

Source: University of Texas Health Science Center at Houston [December 25, 2011]

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A new way of approaching the early detection of Alzheimer's disease

One of our genes is apolipoprotein E (APOE), which often appears with a variation which nobody would want to have: APOEε4, the main genetic risk factor for sporadic Alzheimer's disease (the most common form in which this disorder manifests itself and which is caused by a combination of hereditary and environmental factors). 

It is estimated that at least 40% of the sporadic patients affected by this disease are carriers of APOEε4, but this also means that much more still remains to be studied. The researcher at the University of the Basque Country (UPV/EHU) Xabier Elcoroaristizabal has opened up a channel for making a start by analysing candidate genes which, always in combination with APOEε4, could help to explain more cases. 

His thesis is entitled "Molecular markers in mild amnestic cognitive impairment and Alzheimer's disease" (Marcadores moleculares en deterioro cognitivo leve tipo amnesico y enfermedad de Alzheimer). An initial article on this can be read in the journal BMC Neuroscience. 

The long-term aim is to contribute towards the early detection of Alzheimer's disease by identifying signs that could be detectable in the very early phases. And, as Elcoroaristizabal explains, while there is no cure for this disorder, the alternative is to get ahead of it and delay its development: 

"Certain preventive measures involving cognitive stimulation delay its appearance. There are even new drugs that could start to be used earlier. Today there is no solution, but the more we maintain a person's correct cognitive state, the better." 

Mild amnestic, cognitive impairment 

The individuals who develop Alzheimer's go through a transition period first of all, and this could be the key moment for the effective application of preventive measures. This is mild cognitive impairment (MCI), in which slight cognitive alterations take place but do not affect everyday activities. 

Among the different types of MCI, one affects memory almost exclusively (amnestic MCI), and those people who suffer from it have a high probability of developing the disorder. The difficult and interesting part is knowing which genetic components are linked to this impairment and also in determining by what percentage the risk of developing the disease increases, a task which Elcoroaristizabal has set himself. 

"If we can identify which genes are involved and what susceptibility factors there are, preventive measures could be taken," he explains. 

So a contrast study has been carried out among a sample of patients with MCI, ones with Alzheimer's and healthy people. This can be used to observe the changes and narrow down the field for the zones to be studied, so that candidate genes can be sought there. 

Elcoroaristizabal himself notes one example among the many others identified: "It has been observed that the brain's capacity to control cholesterol levels seems to play a key role throughout the illness. So, protein encoding genes linked to this control have been analysed." 

In this quest for candidate genes, Elcoroaristizabal has confirmed that the APOEε4 genetic variation is, in fact, the main risk factor for developing Alzheimer's disease. But it does not end there; he has identified several genes which, as long as they are manifested in combination with APOEε4, could take us one step further towards the early detection of this disorder. 

"Genes that in some way are connected with neurotransmission channels, oxidative stress or the effectiveness of oestrogens seem to be linked to a greater risk for APOEε4 carriers," he explains. Specifically, the candidate genes are as follows: COMT (neurotransmission), SOD2 (oxidative stress elimination) and ESR1 and ESR2 (oestrogen action facilitators).  

Source: Basque Research [December 23, 2011]

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Scientists pioneer new method for watching proteins fold

A protein's function depends on both the chains of molecules it is made of and the way those chains are folded. And while figuring out the former is relatively easy, the latter represents a huge challenge with serious implications because many diseases are the result of misfolded proteins. Now, a team of chemists at the University of Pennsylvania has devised a way to watch proteins fold in "real-time," which could lead to a better understanding of protein folding and misfolding in general. 

The research was conducted by Feng Gai, professor in the Department of Chemistry in the School of Arts and Sciences, along with graduate students Arnaldo Serrano, also of Chemistry, and Robert Culik of the Department of Biochemistry and Molecular Biophysics at Penn's Perelman School of Medicine. They collaborated with Michelle R. Bunagan of the College of New Jersey's Department of Chemistry. 

Their research was published in the international edition of the journal Angewandte Chemie, where it was featured on the cover and bestowed VIP (very important paper) status. 

"One of the reasons that figuring out what happens when proteins fold is difficult is that we don't have the equivalent of a high-speed camera that can capture the process, " Gai said. "If the process were slow, we could take multiple 'pictures' over time and see the mechanism at work. Unfortunately, no one has this capability; the folding occurs faster than the blink of an eye." 

Gai's team uses infrared spectroscopy — a technique that measures how much light different parts of a molecule absorbs — to analyze proteins' structure and how this changes. In this case, the researchers looked at a model protein known as Trp-cage with an infrared laser setup. 

In this experiment, Gai's team used two lasers to study structural changes as a function of time. The first laser acts as the starting gun; by heating the molecule, it causes its structure to change. The second laser acts as the camera, following the motions of the protein's constituent amino acids. 

"The protein is made of different groups of atoms, and the different groups can be thought of as springs," Gai said. "Each spring has a different frequency with which it moves back and forth, which is based on the mass of the atom on either end. If the mass is bigger, the spring oscillates slower. Our 'camera' can detect the speed of that motion and we can relate it to the atoms it is made of and how that segment of the protein chain moves." 

Even in a simple protein like Trp-cage, however, there are many identical bonds, and the researchers need to be able to distinguish one from another in order to see which of them are moving while the protein folds. One strategy they used to get around this problem was to employ the molecular equivalent of a tracking device. 

"We use an amino acid with a carbon isotope marker," Culik said. "If it's incorporated into the protein correctly, we'll know where it is." 

With a single carbon atom of the Trp-cage slightly heavier than the others, the research team can use its signature to infer the position of the other atoms as they fold. The researchers could then "tune" the frequency of their laser to match different parts of the protein, allowing them to isolate them in their analyses. 

Similar isotopes could be inserted in more complicated molecules, allowing their folds to also be viewed with infrared spectroscopy. 

"This technique enhances our structural resolution. It allows us to see which part is moving," Gai said. "That would allow us to see exactly how a protein is misfolding in a disease, for example." 

Source: University of Pennsylvania [December 21, 2011]

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Understanding the mechanical biology of life's bonds

When he was 10 years old, Julio Fernandez took a correspondence course in electronics and earned a certificate for putting together a doorbell. Today, the Columbia professor of biological sciences builds and takes apart proteins, the building blocks of the body which, when they bond improperly, may cause disease. 

Traditionally, scientists study proteins in a test tube, a method that Fernandez believes does not offer an accurate enough picture of complex body biochemistry. “In a test tube how would you know what’s happening to something that requires mechanical force to extend and relax?” he says, referring to the stretching and contracting that happens to proteins when they bond with one another in the body. “You have to study proteins and biological molecules in an environment as close to their native condition as possible.” 

To that end, Fernandez has spent his career developing a new field—mechanical biology—to understand organic substances with tools from physics, engineering and computer science. His team in the Northwest Corner building builds its own equipment, engineers its own proteins and writes its own computer programs to analyze the data. Though the students each have academic specialties, many have picked up expertise on the job in other disciplines. 

In a paper published in the October edition of Nature Chemistry, Fernandez’s team made the first direct observation of how disulfide bonds reshuffle within a protein. Disulfide bonds play a central role in controlling the elasticity of tissues. They used an atomic force microscope, a device developed by physicists in the 1980s to study items such as computer chips at the nanoscale, but adapted by his team to examine biological substances. 

“Think of a protein as a rope tied up in a knot that is held together by a disulfide bond,” explains Pallav Kosuri, a Ph.D. student on Fernandez’s team. “Someone breaks the disulfide bond and the knot can now unfurl. We’re watching knots unfurl in a single protein molecule.” The team placed proteins on the examining surface of the atomic force microscope, which is fitted with a sensitive tip that is more than a thousand times sharper than the thickness of a human hair. The tip is attached to the protein, and a laser is used to record the exact position of the tip as the knot unfurls—or when the protein bonds reshuffle. 

Disulfide bonds occur in nearly 30 percent of proteins; because they’re so prevalent, scientists believe their interactions may be clues to unraveling a broad range of illnesses, from infectious disease to cancer. Viruses, for example, interact with human cells through proteins that contain disulfide bonds. Marfan Syndrome is a disorder in which fibrillin, a disulfide-bonded protein in connective tissue, malfunctions. Symptoms may include extraordinarily stretchy skin, and in heart tissue, a faulty elasticity that can affect healthy blood flow. 

As a physics student at the University of Chile, Fernandez met a group of neuroscientists from Los Angeles studying a squid native to the shores of that South American country. They lured Fernandez to the UCLA School of Medicine, where he received his Ph.D. in physiology and was a post-doctoral research fellow. Following appointments at the Max Planck Institute, the University of Pennsylvania’s School of Medicine and the Mayo Foundation, Fernandez came to Columbia in 2002. 

His lab is currently at work studying how muscle elasticity works. They’re also trying to understand the elasticity of the main receptor implicated in HIV infection—another protein with disulfide bonds. “We’re trying to revolutionize protein biochemistry from the point of view of mechanical forces,” he says. 

Author: Beth Kwon | Source: Columbia University [December 21, 2011]

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Drugs used to overcome cancer may also combat antibiotic resistance

Drugs used to overcome cancer may also combat antibiotic resistance, finds a new study led by Gerry Wright, scientific director of the Michael G. DeGroote Institute for Infectious Disease Research at McMaster University. 

"Our study found that certain proteins, called kinases, that confer antibiotic resistance are structurally related to proteins important in cancer," says Wright about the study published in Chemistry & Biology. 

"The pharmaceutical sector has made a big investment in targeting these proteins, so there are a lot of compounds and drugs out there that, although they were designed to overcome cancer, they can in fact be looked at with fresh eyes and maybe repurposed to address the problem of antibiotic resistance." 

The large-scale study involved screening 14 antibiotic resistant molecules against 80 chemically diverse protein kinase inhibitors. 

Antibiotic resistance is a problem growing in global scope, as more viruses have overcome currently available antibiotics. 

"As a result, new drugs and antibiotic strategies are urgently needed to fill the gap in infectious disease control," says Wright, adding he hopes future studies in combination therapies will provide new insight into antibiotic resistance. 

"One of the challenges facing the drug discovery community is the lack of new chemical scaffolds with antibiotic activity. This has led to the open question of whether all easily implementable antibiotic chemical scaffolds have already been exploited over the last 50 years: the so-called ''low hanging fruit''." 

Source: McMaster University [December 21, 2011]

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New insights into nanoparticles and dividing cells

What happens when living cells take up nanoparticles, those tiny entities that could offer new ways of delivering drugs into the body? A new study from researchers at UCD has tracked the progress of nanoparticles as cells divide, and their findings - which were published recently in Nature Nanotechnology - will help us better understand how different tissues in the body process a dose of nanoparticles. 

“Nanoparticles are engineered materials that we are producing, and what is very interesting about them is that they have a size that is in the nanometre range, so they are a bit bigger than proteins,” says Dr. Anna Salvati, a post-doctoral researcher at UCD School of Chemistry & Chemical Biology. “Their size allows them to interact with the cell in new ways.” 

These nano-interactions open up potential opportunities to deliver drugs in new ways into cells, so they offer one of the most promising ways to treat currently untreatable diseases, from cancers to neurodegeneration, according to Dr. Salvati: “If we learn why nanoparticles can enter so easily and what decides where they go in the cell, then we could potentially design new delivery systems and learn how to deliver medicines,” she says. 

We also need to understand bio-nano-interactions more generally from a safety perspective, she adds. “We could be exposed to nanomaterials in some cases because they are used for many applications from energy harvesting, electronics to paints. Ensuring they are safe is important.” 

Dr. Salvati works on a team with Prof Kenneth A. Dawson at the Center for BioNano Interactions, the UCD-based national platform for nanosafety, nanobiology and nanomedicine, and UCD Conway Institute for Biomolecular and Biomedical Research. 

Together with Jong Ah Kim and Dr. Christoffer Aberg, one strand of their research has been looking at the fate of nanoparticles during the life cycle of individual cells as they grow and divide. The UCD researchers introduced nanoscale polystyrene particles to human lung carcinoma cells growing in the lab, and used fluorescent markers to track the nanoparticles over space and time. What they identified was that nanoparticles could enter the cell easily and were not expelled during the cell cycle of growth, but rather got passed on to daughter cells as individual cells split into two. 

“When a cell divides, the internalised nanoparticle dose is split between the daughter cells,” explains Dr Salvati. “This means that cells in the same population can have different amounts of internalised nanoparticles, depending on the phase of their cell cycle.”  

The important observation is that a dose of nanoparticles in a cell population can be affected as cells divide, and that individual cells can end up with differing amounts of nanoparticles. 

“When you give a dose of nanoparticles and a certain exposure time, you don’t have just one simple answer where every cell behaves in the same way - we have seen that individual cells behave differently and that can affect the cell’s dose of nanoparticles,” explains Dr. Salvati. 

“The implications can be extended also for humans - inside the body the most specialised cells tend to have very slow cell division, while other cells divide very frequently. A cell that divides more frequently will dilute the amount of nanoparticles because every time it divides it dilutes the load, and a cell that divides less often potentially might accumulate more nanoparticles.” These findings will also help assure safety of nanoparticles, according to Dr. Salvati, and the UCD researchers are continuing to develop their understanding of the interactions. 

“We are looking to describe the nanoparticle accumulation and kinetics with theoretical models so they could be used to predict how nanoparticles are going to behave in cell populations,” she says. 

“It would also be interesting for us to be able to design a nanoparticle able to target cells that divide rapidly, such as cancer cells, or where we could control in which stage it enters the cell, so it might enter more easily in certain phases as the cell grows. It will open up a whole new range of options in medicine.” 

Source: University College Dublin [December 19, 2011]

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What Are Emotion Expressions For?

That cartoon scary face – wide eyes, ready to run – may have helped our primate ancestors survive in a dangerous wild, according to the authors of an article published in Current Directions in Psychological Science, a journal of the Association for Psychological Science. The authors present a way that fear and other facial expressions might have evolved and then come to signal a person’s feelings to the people around him. 

The basic idea, according to Azim F. Shariff of the University of Oregon, is that the specific facial expressions associated with each particular emotion evolved for some reason. Shariff cowrote the paper with Jessica L. Tracy of the University of British Columbia. So fear helps respond to threat, and the squinched-up nose and mouth of disgust make it harder for you to inhale anything poisonous drifting on the breeze. The outthrust chest of pride increases both testosterone production and lung capacity so you’re ready to take on anyone. Then, as social living became more important to the evolutionary success of certain species—most notably humans—the expressions evolved to serve a social role as well; so a happy face, for example, communicates a lack of threat and an ashamed face communicates your desire to appease. 

The research is based in part on work from the last several decades showing that some emotional expressions are universal—even in remote areas with no exposure to Western media, people know what a scared face and a sad face look like, Shariff says. This type of evidence makes it unlikely that expressions were social constructs, invented in Western Europe, which then spread to the rest of the world. 

And it’s not just across cultures, but across species. “We seem to share a number of similar expressions, including pride, with chimpanzees and other apes,” Shariff says. This suggests that the expressions appeared first in a common ancestor. 

The theory that emotional facial expressions evolved as a physiological part of the response to a particular situation has been somewhat controversial in psychology; another article in the same issue of Current Directions in Psychological Science argues that the evidence on how emotions evolved is not conclusive. 

Shariff and Tracy agree that more research is needed to support some of their claims, but that, “A lot of what we’re proposing here would not be all that controversial to other biologists,” Shariff says. “The specific concepts of ‘exaptation’ and ‘ritualization’ that we discuss are quite common when discussing the evolution of non-human animals.” For example, some male birds bring a tiny morsel of food to a female bird as part of an elaborate courtship display. In that case, something that might once have been biologically relevant—sharing food with another bird—has evolved over time into a signal of his excellence as a potential mate. In the same way, Shariff says, facial expressions that started as part of the body’s response to a situation may have evolved into a social signal. 

Source: Association for Psychological Science [December 22, 2011]

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How the brain cell works

University of Miami biology professor Akira Chiba is leading a multidisciplinary team to develop the first systematic survey of protein interactions within brain cells. The team is aiming to reconstruct genome-wide in situ protein-protein interaction networks (isPIN) within the neurons of a multicellular organism. Preliminary data were presented at the American Society for Cell Biology annual meeting, December 3 through 7, 2011, in Denver, Colorado. 

At the core of the new imaging technology is the phenomenon known as FRET that occurs only when two fluorescently tagged molecules come within the distance of eight nanometer or less. Detecting the FRET serves as a proxy for the two proteins X and Y associating with each other within a living cell [Credit: A. Chiba/University of Miami]

"This work brings us closer to understanding the mechanics of molecules that keep us functioning," says Chiba, principal investigator of this project. "Knowing how our cells work will improve medicine. Most importantly, we will gain a better understanding of what life is at the molecular level." 

Neurons are the cells that are mainly responsible for signaling in the brain. Like all other cells, each neuron produces millions of individual proteins that associate with one another and form a complex communication network. Until recently, observing these protein-protein interactions had not been possible due to technical difficulties. Individual proteins are small and typically less than 10 nm (nanometer) in diameter. Yet, this nano-scale distance was considered to be off-limits even with super-resolution microscopy. 

Now, Chiba and his collaborators have developed a novel methodology to examine interaction of individual proteins in the fruit fly – the model organism of choice for this project. The researchers are creating genetically engineered insects that are capable of expressing over 500 fluorescently-tagged assorted proteins, two at a time. The fluorescent tags make it possible to visualize the exact spot where a given pair of proteins associates with each other. 

The team utilizes a custom- built 3D FLIM (fluorescent lifetime imaging microscopy) system to quantify this association event within the cells of a live animal. FLIM shows the location and time of such protein interaction, providing the data that allow creation of a point-by-point map of protein-protein interactions. 

The pilot phase of this multidisciplinary project is being funded by the National Institutes of Health. It employs advanced genetics, molecular imaging technology and high-performance computation, among other fields. "Collaborating fluorescent chemistry, laser optics and artificial intelligence, my team is working in the 'jungle' of the molecules of life within the living cells," Chiba says. "This is a new kind of ecology played out at the scale of nanometers—creating a sense of deja vu 80 years after the birth of modern ecology." 

At present, the researchers still need to extrapolate from data obtained in test tubes. In the future, they will begin to visualize directly how the individual proteins interact with one another in their 'native environment,' which are the cells in our body.  

Source: University of Miami [December 21, 2011]

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