A Telescope for Your Eye: New Contact Lens Design May Improve Sight of Patients With Macular Degeneration

A Telescope for Your Eye: New Contact Lens Design May Improve Sight of Patients With Macular Degeneration

  9:04:00 PM    Science Lover

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Contact lenses correct many people's eyesight but do nothing to improve the blurry vision of those suffering from age-related macular degeneration (AMD), the leading cause of blindness among older adults in the western world. That's because simply correcting the eye's focus cannot restore the central vision lost from a retina damaged by AMD. Now a team of researchers from the United States and Switzerland led by University of California San Diego Professor Joseph Ford has created a slim, telescopic contact lens that can switch between normal and magnified vision. With refinements, the system could offer AMD patients a relatively unobtrusive way to enhance their vision.

This image shows five views of the switchable telescopic contact lens. a) From front. b) From back. c) On the mechanical model eye. d) With liquid crystal glasses. Here, the glasses block the unmagnified central portion of the lens. e) With liquid crystal glasses. Here, the central portion is not blocked. (Credit: Optics Express)

The team reports its work in the Optical Society's (OSA) open-access journal Optics Express.

Visual aids that magnify incoming light help AMD patients see by spreading light around to undamaged parts of the retina. These optical magnifiers can assist patients with a variety of important everyday tasks such as reading, identification of faces, and self-care. But these aids have not gained widespread acceptance because they either use bulky spectacle-mounted telescopes that interfere with social interactions, or micro-telescopes that require surgery to implant into the patient's eye.

"For a visual aid to be accepted it needs to be highly convenient and unobtrusive," says co-author Eric Tremblay of the École Polytechnique Fédérale de Lausanne (EPFL) in Switzerland. A contact lens is an "attractive compromise" between the head-mounted telescopes and surgically implanted micro-telescopes, Tremblay says.

The new lens system developed by Ford's team uses tightly fitting mirror surfaces to make a telescope that has been integrated into a contact lens just over a millimeter thick. The lens has a dual modality: the center of the lens provides unmagnified vision, while the ring-shaped telescope located at the periphery of the regular contact lens magnifies the view 2.8 times.

To switch back and forth between the magnified view and normal vision, users would wear a pair of liquid crystal glasses originally made for viewing 3-D televisions. These glasses selectively block either the magnifying portion of the contact lens or its unmagnified center. The liquid crystals in the glasses electrically change the orientation of polarized light, allowing light with one orientation or the other to pass through the glasses to the contact lens.

The team tested their design both with computer modeling and by fabricating the lens. They also created a life-sized model eye that they used to capture images through their contact lens-eyeglasses system. In constructing the lens, researchers relied on a robust material commonly used in early contact lenses called polymethyl methacrylate (PMMA). The team needed that robustness because they had to place tiny grooves in the lens to correct for aberrant color caused by the lens' shape, which is designed to conform to the human eye.

Tests showed that the magnified image quality through the contact lens was clear and provided a much larger field of view than other magnification approaches, but refinements are necessary before this proof-of-concept system could be used by consumers. The researchers report that the grooves used to correct color had the side effect of degrading image quality and contrast. These grooves also made the lens unwearable unless it is surrounded by a smooth, soft "skirt," something commonly used with rigid contact lenses today. Finally, the robust material they used, PMMA, is not ideal for contact lenses because it is gas-impermeable and limits wear to short periods of time.

The team is currently pursuing a similar design that will still be switchable from normal to telescopic vision, but that will use gas-permeable materials and will correct aberrant color without the need for grooves to bend the light. They say they hope their design will offer improved performance and better sight for people with macular degeneration, at least until a more permanent remedy for AMD is available.

"In the future, it will hopefully be possible to go after the core of the problem with effective treatments or retinal prosthetics," Tremblay says. "The ideal is really for magnifiers to become unnecessary. Until we get there, however, contact lenses may provide a way to make AMD a little less debilitating."

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Dark Matter of the Genome Revealed

Dark Matter of the Genome Revealed

  10:29:00 AM    Science Lover

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6MK9UNF4B2AX
An international team of researchers has discovered the vast majority of the so-called "dark matter" in the human genome, by means of a sweeping comparison of 29 mammalian genomes. The team, led by scientists from the Broad Institute, has pinpointed the parts of the human genome that control when and where genes are turned on. This map is a critical step in interpreting the thousands of genetic changes that have been linked to human disease.

Rendering of DNA. Researchers have discovered the vast majority of the so-called "dark matter" in the human genome, by means of a sweeping comparison of 29 mammalian genomes. (Credit: iStockphoto/Martin McCarthy)

Their findings appear online October 12 in the journal Nature.

Early comparison studies of the human and mouse genomes led to the surprising discovery that the regulatory information that controls genes dwarfs the information in the genes themselves. But, these studies were indirect: they could infer the existence of these regulatory sequences, but could find only a small fraction of them. These mysterious sequences have been referred to as the dark matter of the genome, analogous to the unseen matter and energy that make up most of the universe.

This new study enlisted a menagerie of mammals -- including rabbit, bat, elephant, and more -- to reveal these mysterious genomic elements.

Over the last five years, the Broad Institute, the Genome Institute at Washington University, and the Baylor College of Medicine Human Genome Sequencing Center have sequenced the genomes of 29 placental mammals. The research team compared all of these genomes, 20 of which are first reported in this paper, looking for regions that remained largely unchanged across species.

"With just a few species, we didn't have the power to pinpoint individual regions of regulatory control," said Manolis Kellis, last author of the study and associate professor of computer science at MIT. "This new map reveals almost 3 million previously undetectable elements in non-coding regions that have been carefully preserved across all mammals, and whose disruptions appear to be associated with human disease."

These findings could yield a deeper understanding of disease-focused studies, which look for genetic variants closely tied to disease.

"Most of the genetic variants associated with common diseases occur in non-protein coding regions of the genome. In these regions, it is often difficult to find the causal mutation," said first author Kerstin Lindblad-Toh, scientific director of vertebrate genome biology at the Broad and a professor in comparative genomics at Uppsala University, Sweden. "This catalog will make it easier to decipher the function of disease-related variation in the human genome."

This new map helps pinpoint those mutations that are likely responsible for disease, as they have been preserved across millions of years of evolution, but are commonly disrupted in individuals that suffer from a given disease. Knowing the causal mutations and their likely functions can then help uncover the underlying disease mechanisms and reveal potential drug targets.

The scientists were able to suggest possible functions for more than half of the 360 million DNA letters contained in the conserved elements, revealing the hidden meaning behind the As, Cs, Ts, and Gs. These revealed:

• Almost 4,000 previously undetected exons, or segments of DNA that code for protein
• 10,000 highly conserved elements that may be involved in how proteins are made
• More than 1,000 new families of RNA secondary structures with diverse roles in gene regulation
• 2.7 million predicted targets of transcription factors, proteins that control gene expression

"We can use this treasure trove of new elements to revisit disease association studies, focusing on those that disrupt conserved elements and trying to discern their likely functions," said Kellis. "Using a single genome, the language of DNA seems cryptic. When studied through the lens of evolution, words light up and gain meaning."

The researchers were also able to harness this collection of genomes to look back in time, across more than 100 million years of evolution, to uncover the fundamental changes that shaped mammalian adaptation to different environments and lifestyles. The researchers revealed specific proteins under rapid evolution, including some related to the immune system, taste perception, and cell division. They also uncovered hundreds of protein domains within genes that are evolving rapidly, some of which are related to bone remodeling and retinal functions.

"The comparison of mammalian genomes reveals the regulatory controls that are common across all mammals," said Eric Lander, director of the Broad Institute and the third corresponding author of the paper. "These evolutionary innovations were devised more than 100 million years ago and are still at work in the human population today."

In addition to finding the DNA controls that are common across all mammals, the comparison highlighted areas that have been changing rapidly only in the human and primate genomes. Researchers had previously uncovered two hundred of these regions, some of which are linked to brain and limb development. The expanded list -- which now includes more than 1,000 regions -- will give scientists new starting points for understanding human evolution.

The comparison of many complete genomes is beginning to offer a clear view of once indiscernible genomic regions, and with additional genomes, that resolution will only increase. "The power of this resource is that it continues to improve with the inclusion of more species," said Lindblad-Toh. "It's a very systematic and unbiased approach that will only become more powerful with the inclusion of additional genomes."

Other Broad researchers who contributed to this work include Manuel Garber, Or Zuk, Michael F. Lin, Pouya Kheradpour, Jason Ernst, Evan Mauceli, Lucas D. Ward, Michele Clamp, Sante Gnerre, Jessica Alföldi, Jean Chang, Federica Di Palma, Mitchell Guttman, David B. Jaffe, Irwin Jungreis, Marcia Lara, Jim Robinson, Xiaohui Xie, Michael C. Zody, and members of the Broad Institute Sequencing Platform and Whole Genome Assembly Team.

This project was supported by the National Human Genome Research Institute, National Institute for General Medicine, the European Science Foundation, National Science Foundation, the Sloan Foundation, an Erwin Schrödinger Fellowship, the Gates Cambridge Trust, Novo Nordisk Foundation, University of Copenhagen, the David and Lucile Packard Foundation, the Danish Council for Independent Research Medical Sciences, and The Lundbeck Foundation.

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Non-coding RNA has role in inherited neurological disorder -- and maybe other brain diseases too

Non-coding RNA has role in inherited neurological disorder -- and maybe other brain diseases too

  1:26:00 AM    Science Lover

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A team of scientists, led by researchers at the University of California, San Diego School of Medicine, have uncovered a novel mechanism regulating gene expression and transcription linked to Spinocerebellar ataxia 7, an inherited neurological disorder. The discovery promises to have broad ramifications, suggesting that abundant non-coding transcripts of ribonucleic acid (RNA) may be key players in neurological development and function, and could be powerful targets for future clinical therapies.

Researchers have discovered that expression
of the ataxin‑7 gene - the cause of the
neurological disorder spinocerebellar
ataxia type 7 - has two regulators: a highly
conserved, multi‑tasking protein called
CTCF and, surprisingly, an adjacent promoter
containing non‑coding RNA.
Credit: Illustration courtesy of Christina
Takamatsu‑Butler, UC San Diego.

The research, headed by Albert La Spada, MD, PhD, chief of the division of genetics in the UCSD department of pediatrics, and professor of cellular and molecular medicine, neurosciences and biological sciences, is published in the June 22 issue of the journal Neuron.

"Our paper highlights a number of important emerging themes in our understanding of gene regulation in the brain," said La Spada, who is also associate director of the UCSD Institute for Genomic Medicine.

"With the advent of new technologies, science has learned that the vast majority of our transcripts are non-coding," said La Spada. "The challenge going forward is to determine what they do do, and if they have specific functions. It now seems increasingly likely that a multitude of these non-coding RNAs help finely tune transcription regulation in the brain, and perturbation of their work is linked to disease. If we can figure out exactly how, we should be able to gain new insights into how the brain is so precisely regulated – knowledge that may help us better understand how the brain works."



Spinocerebellar ataxia 7 is one of several types of spinocerebellar ataxia (SCA), genetic degenerative disorders characterized by atrophy in the cerebellum of the brain, progressive loss of physical coordination – and in the case of type 7 – retinal degeneration that can result in blindness. There is currently no known cure.

Many SCAs are classified as polyglutamine diseases, caused when a protein associated with the disease contains too many repeats of the amino acid glutamine. Polyglutamine diseases are also known as "CAG Triplet Repeat Disorders" because CAG is the sequence of nucleic acids that codes for glutamine.

La Spada and colleagues have long studied SCA. In 2001, they were the first to demonstrate that SCA7 retinal degeneration was the result of transcription dysregulation of ataxin-7, the protein associated with SCA7. Following up, they decided to learn how the gene that expresses ataxin-7 is itself regulated.

The researchers found not one, but two, regulators. The first is called CTCF, a highly conserved protein that regulates a variety of transcriptional processes, most notable establishing insulator domains and controlling genomic imprinting. But they also discovered an adjacent, alternative promoter dubbed intron 2 promoter (P2A) and a transcribed antisense, non-coding RNA, which they labeled SpinoCerebellarAtaxia-AntisenseNoncodingTranscript1 or SCAANT1.

Antisense RNA is single-stranded ribonucleic acid whose primary function appears to be as an inhibitor or suppressor of a gene, though sometimes it can promote gene expression instead. Most antisense RNAs are non-coding, meaning that their sequences do not provide information for making proteins. Even though non-coding RNAs do not provide instructions for the production of vital proteins, they comprise the bulk of the human genome. A major challenge for biomedical research in the 21st century is to figure what they do, and how they do it.

In their Neuron paper, La Spada and colleagues highlight one function, at least for SCAANT1. When they investigated how CTCF regulated ataxin-7 gene expression in transgenic mice, they discovered that CTCF promotes the production of SCAANT1 which in turn represses the newly discovered ataxin-7 sense promoter P2A. In mice lacking SCAANT1, sense promoter P2A is de-repressed, allowing a mutant ataxin-7 gene to be expressed, resulting in mice with a version of SCA7. The scientists found a similar lack of antisense SCAANT1 in the fibroblasts and white blood cells taken from human patients with SCA7, implicating deregulation of this pathway in the disease process.

As many inherited neurological disorders are now known to exhibit such overlapping "bidirectional" transcription, the findings in SCA7 could shed light on similar abnormalities with non-coding RNA function in a number of brain diseases.

Provided by University of California - San Diego

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Early Light Refines Brain's Circuitry for Vision: Studies Show Importance of Visual Stimulation in Wiring Up Species' Brains to See

Early Light Refines Brain's Circuitry for Vision: Studies Show Importance of Visual Stimulation in Wiring Up Species' Brains to See

  10:08:00 AM    Science Lover

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Any parent knows that newborns still have a lot of neurological work to do to attain fully acute vision. In a wide variety of nascent animals, genes provide them with only a rough wiring plan and then leave it to the developing nervous system to do its own finish work. Two studies by Brown University researchers provide new evidence of a role for exposure to light in the environment as mouse pups and tadpoles organize and refine the circuitry of their vision systems.

Light and sight: connected at the beginning Because 
the retinal layer of rods and cones is not connected 
early in mice, neuroscientists had no reason to suspect 
that light helps develop neural connections for vision. 
David Berson, right, with Jordan Renna, has shown 
that photosensitive cells he discovered a decade ago are 
connected and do help with neural development. 
(Credit: Mike Cohea/Brown University)

"Through a combination of light-independent and light-dependent processes, the visual system is getting tuned up over time," said David Berson, professor of neuroscience.

His new work, published in advance online June 5 in Nature Neuroscience, offers the surprising result that light exposure can enhance how well mice can organize the nerve endings from their left eye and their right eye in an area of the brain where they start out somewhat jumbled. Neuroscientists had thought that mammals were unable to see at this stage, but a new type of light-sensitive cell that Berson discovered a decade ago turns out to let in the light.

Meanwhile, Berson's colleague Carlos Aizenman, assistant professor of neuroscience, co-authored a paper online May 31 in the Journal of Neuroscience showing that newborn tadpoles depend on light to coordinate and improve the response speed, strength and reliability of a network of neurons in a vision-processing region of their brains.

"This is how activity is allowing visual circuits to refine and sort themselves out," said Aizenman. "Activity is fine-tuning all these connections. It's making the circuit function in a much more efficient, synchronous way."

Not completely blind mice
Berson, postdoctoral scholar Jordan Renna, and former postdoctoral researcher Shijun Weng conducted several experiments in newborn mice to see whether light influences the process by which the mice rewire to distinguish between their eyes.

"For certain functions, the brain wants to keep track of which eye is which," Berson said. Among those functions are the perception of depth and distance.

At a circuit level, the brain keeps signals from the two eyes distinct by segregating their nerve endings into separate regions in the dorsal lateral geniculate nucleus (dLGN), a key waystation on the path to the visual cortex and conscious visual perception. Scientists have long known this sorting-out process depends on waves of activity that spontaneously excite cells in the inner retina. They did not know until now that the waves are influenced by a light-sensitive type of cell called intrinsically photosensitive retinal ganglion cells (ipRGCs).

About a decade ago, a team Berson led at Brown discovered the ipRGCs, which are the first light-sensitive cells to develop in the eye. They reside in the inner retina, the home of retinal cells that send visual information directly to the brain. The outer retina is where the more familiar rods and cones sense light. Early in life, when the brain is segregating nerve endings into distinct regions in the dLGN, the two retinal layers are not connected, so until ipRGCs were discovered there was no reason to believe that light would affect the sorting process.

The new research doesn't say anything definitive about the consequences of light exposure at this stage for eyesight in adults, especially given that some mammals (such as monkeys) experience this developmental stage in utero.

"Whether different animals in nature are exposed to enough light to induce a change in segregation patterns is unclear," Renna said.

But the research shows that light exposure does improve how well the sorting goes, Berson said, and the work advances neuroscientists' understanding of the eye-distinction process, which is widely studied as a model of "activity-driven" neural development.

To assess the effect of light on retinal waves, Renna used electrodes to record the activity of cells in the inner retinas of newborn mice, first recording in the dark, then in the light, and then again in the dark. In every case retinas experienced waves, but when the retinas were exposed to light, the waves lasted about 50 percent longer.

Renna then tested whether the light-sensitive cells were really creating this wave-lengthening effect by repeating the study in "knock-out" mice in which the ability of the ipRGCs to sense light had been genetically abolished. With the cells disabled, exposure to light no longer made any difference in the duration of the waves.

Finally, to assess the effect of light on the left-right sorting process in the dLGN, Renna examined the tissues from normal mice and the mice whose ipRGCs couldn't sense light. In each case he fluorescently labeled the nerve endings from one eye red and the other green. A computer comparison of the tissues showed that the normal mice developed a higher degree of segregation between red and green than the knockout mice. In other words, the ability of ipRGCs to sense light improved sorting out one eye from another in the dLGN.

Twinkling tadpoles

In his study, Aizenman collaborated with Arto Nurmikko, professor of engineering and physics, to investigate the function of in the optic tectum of tadpole brains. They flooded the tectal neurons in live tadpoles with a molecule that makes calcium ions fluoresce. As whole networks of neurons became active, they'd take in the ions and glow. The researchers recorded the tadpoles with a high-resolution, high-speed camera that could capture the millisecond-to-millisecond activity of the neurons.

Led in the lab by engineering graduate student Heng Xu, the lead author, and postdoctoral researcher Arseny Khakhalin, the team reared some young tadpoles under normal conditions of 12 hours of light and 12 hours of darkness during the crucial days of development when the tectum is developing. They reared others in the dark, and still others with a chemical that blocks the activity of NMDA receptors, a subtype of receptor to the neurotransmitter glutamate, that is known to promote neural rewiring.

Then they exposed all the tadpoles, however they were reared, to blue LED light flashes delivered via a fiber optic cable mounted next to the eye.

What they found over the course of several experiments was that the neural networks in the tectums of tadpoles reared under normal conditions developed a faster, more cohesive, and stronger response (in terms of the number of neurons) to light.

The tectal neural networks of tadpoles kept in the dark during development failed to progress at all. Those whose NMDA receptors were blocked occupied a middle ground, showing more progress than dark-reared tadpoles but less than normal tadpoles. Tadpoles, they found, train their brains with the light they see.

Aizenman said he hopes the calcium ion imaging technique will prove useful in a wide variety of other neuroscience experiments, including studying how tadpoles neurally encode behaviors such as fleeing when they see certain stimuli.

In the meantime, his team and Berson's have added to the understanding scientists have been building of how creatures turn the somewhat mushy approximations of their brains at birth into high-functioning animal minds.

"That's what everybody is after," Aizenman said. "How do you get this fine-tuned, finely wired brain in the first place?"

Berson and Renna's work was funded by the National Institutes of Health. Aizemnan and Nurmikko's research received support from the National Science Foundation, the NIH's National Eye Institute, and the Whitehall Foundation.

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Sections of Retinas Regenerated and Visual Function Increased With Stem Cells from Skin

Sections of Retinas Regenerated and Visual Function Increased With Stem Cells from Skin

  1:02:00 PM    Science Lover

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Scientists from Schepens Eye Research Institute are the first to regenerate large areas of damaged retinas and improve visual function using IPS cells (induced pluripotent stem cells) derived from skin. The results of their study, which is published in PLoS ONE this month, hold great promise for future treatments and cures for diseases such as age-related macular degeneration, retinitis pigmentosa, diabetic retinopathy and other retinal diseases that affect millions worldwide.

Histological staining of a teratoma containing Rho-/- eye
at 21 days post-injection of a heterogeneous population of
SSEA1-containing D33 differentiated cells. (Credit: Tucker
et al.,DOI: 10.1371/journal.pone.0018992)

"We are very excited about these results," says Dr. Budd A. Tucker, the study's first author. "While other researchers have been successful in converting skin cells into induced pluripotent stem cells (iPSCs) and subsequently into retinal neurons, we believe that this is the first time that this degree of retinal reconstruction and restoration of visual function has been detected," he adds. Tucker, who is currently an Assistant Professor of Ophthalmology at the University of Iowa, Carver College of Medicine, completed the study at Schepens Eye Research Institute in collaboration with Dr. Michael J. Young, the principle investigator of the study, who heads the Institute's regenerative medicine center.

Today, diseases such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD) are the leading causes of incurable blindness in the western world. In these diseases, retinal cells, also known as photoreceptors, begin to die and with them the eye's ability to capture light and transmit this information to the brain. Once destroyed, retinal cells, like other cells of the central nervous system have limited capacity for endogenous regeneration.

"Stem cell regeneration of this precious tissue is our best hope for treating and someday curing these disorders," says Young, who has been at the forefront of vision stem cell research for more than a decade.

While Tucker, Young and other scientists were beginning to tap the potential of embryonic and adult stem cells early in the decade, the discovery that skin cells could be transformed into "pluripotent" cells, nearly identical to embryonic cells, stirred excitement in the vision research community. Since 2006 when researchers in Japan first used a set of four "transcription factors" to signal skin cells to become iPSCs, vision scientists have been exploring ways to use this new technology. Like embryonic stem cells, iPSCs have ¬the ability to become any other cell in the body, but are not fraught with the ethical, emotional and political issues associated with the use of tissue from human embryos.

Tucker and Young harvested skin cells from the tails of red fluorescent mice. They used red mice, because the red tissue would be easy to track when transplanted in the eyes of non-fluorescent diseased mice.

By forcing these cells to express the four Yamanaka transcription factors (named for their discoverer) the group generated red fluorescent IPSCs, and, with additional chemical coaxing, precursors of retinal cells. Precursor cells are immature photoreceptors that only mature in their natural habitat -- the eye.

Within 33 days the cells were ready to be transplanted and were introduced into the eyes of a mouse model of retina degenerative disease. Due to a genetic mutation, the retinas of these recipient mice quickly degenerate, the photoreceptor cells die and at the time of transplant electrical activity, as detected by ERG (electroretinography), is absent.

Within four to six weeks, the researchers observed that the transplanted "red" cells had taken up residence in the appropriate retinal area (photoreceptor layer) of the eye and had begun to integrate and assemble into healthily looking retinal tissue.

The team then retested the mice with ERG and found a significant increase in electrical activity in the newly reconstructed retinal tissue. In fact, the amount of electrical activity was approximately half of what would be expected in a normal retina. They also conducted a dark adaption test to see if connections were being made between the new photoreceptor cells and the rest of the retina. In brief, the group found that by stimulating the newly integrated photoreceptor cells with light they could detect a signal in the downstream neurons, which was absent in the other untreated eye.

Based on the results of their study, Tucker and Young believe that harvesting skin cells for use in retinal regeneration is and will continue to be a promising resource for the future.

The two scientists say their next step will be to take this technology into large animal models of retinal degenerative disease and eventually toward human clinical trials.

Other scientists involved in the PLoS ONE study include In-Hyun Park, Sara D. Qi, Henry J. Klassen, Caihui Jiang, Jing Yao, Stephen Redenti, and George Q. Daley.

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Why the Eye Is Better Than a Camera at Capturing Contrast and Faint Detail Simultaneously

Why the Eye Is Better Than a Camera at Capturing Contrast and Faint Detail Simultaneously

  8:52:00 AM    Science Lover

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The human eye long ago solved a problem common to both digital and film cameras: how to get good contrast in an image while also capturing faint detail.

Cones normally release the neurotransmitter glutamate 
in the dark, while light decreases glutamate release. This 
graph of neurotransmitter release shows what 
happens when cone cells are exposed to a dark spot in a 
light background (top) under various scenarios, including 
no feedback (green trace) and only negative feedback 
from horizontal cells (red trace). Negative feedback to 
many cones enhances edges, but would decrease 
detail in dark areas were it not for newly discovered 
positive feedback that is localized to only a few cone
cells (blue trace). (Credit: Richard Kramer lab, UC Berkeley)

Nearly 50 years ago, physiologists described the retina's tricks for improving contrast and sharpening edges, but new experiments by University of California, Berkeley, neurobiologists show how the eye achieves this without sacrificing shadow detail.

"One of the big success stories, and the first example of information processing by the nervous system, was the discovery that the nerve cells in the eye inhibit their neighbors, which allows the eye to accentuate edges," said Richard Kramer, UC Berkeley professor of molecular and cell biology. "This is great if you only care about edges. But we also want to know about the insides of objects, especially in dim light."

Kramer and former graduate student Skyler L. Jackman, now a post-doctoral fellow at Harvard University, discovered that while light-sensitive nerve cells in the retina inhibit dozens of their close neighbors, they also boost the response of the nearest one or two nerve cells.

That extra boost preserves the information in individual light detecting cells -- the rods and cones -- thereby retaining faint detail while accentuating edges, Kramer said. The rods and cones thus get both positive and negative feedback from their neighbors.

"By locally offsetting negative feedback, positive feedback boosts the photoreceptor signal while preserving contrast enhancement," he said.

Jackman, Kramer and their colleagues at the University of Nebraska Medical Center in Omaha report their findings May 3 in the journal PLoS Biology. Kramer also will report the findings at the 2011 annual meeting of the Association for Research in Vision and Ophthalmology in Ft. Lauderdale, Fla.

From horseshoe crabs to humans

The fact that retinal cells inhibit their neighbors, an activity known as "lateral inhibition," was first observed in horseshoe crabs by physiologist H. Keffer Hartline. That discovery earned him a share of the 1967 Nobel Prize in Physiology or Medicine. This form of negative feedback was later shown to take place in the vertebrate eye, including the human eye, and has since been found in many sensory systems as a way, for example, to sharpen the discrimination of pitch or touch.

Lateral inhibition fails, however, to account for the eye's ability to detect faint detail near edges, including the fact that we can see small, faint spots that ought to be invisible if their detection is inhibited by encircling retinal cells.

Kramer noted that the details of lateral inhibition are still a mystery half a century after Hartline's discovery. Neurobiologists still debate whether the negative feedback involves an electrical signal, a chemical neurotransmitter, or protons that change the acidity around the cell.

"The field is at an impasse," Kramer said. "And we were surprised to find this fundamental new phenomenon, despite the fact that the anatomy of the retina has been known for more than 40 years."

The retina in vertebrates is lined with a sheet of photoreceptor cells: the cones for day vision and the rods for night vision. The lens of the eye focuses images onto this sheet, and like the pixels in a digital camera, each photoreceptor generates an electrical response proportional to the intensity of the light falling on it. The signal releases a chemical neurotransmitter (glutamate) that affects neurons downstream, ultimately reaching the brain.

Unlike the pixels of a digital camera, however, photoreceptors affect the photoreceptors around them through so-called horizontal cells, which underlie and touch as many as 100 individual photoreceptors. The horizontal cells integrate signals from all these photoreceptors and provide broad inhibitory feedback. This feedback is thought to underlie lateral inhibition, a process that sharpens our perception of contrast and color, Kramer said.

The new study shows that the horizontal cells also send positive feedback to the photoreceptors that have detected light, and perhaps to one or two neighboring photoreceptors.

"Positive feedback is local, whereas negative feedback extends laterally, enhancing contrast between center and surround," Kramer said.

Electrical vs. chemical signals

The two types of feedback work by different mechanisms, the researchers found. The horizontal cells undergo an electrical change when they receive neurotransmitter signals from the photoreceptors, and this voltage change quickly propagates throughout the cell, affecting dozens of nearby photoreceptors to lower their release of the glutamate neurotransmitter.

The positive feedback, however, involves chemical signaling. When a horizontal cell receives glutamate from a photoreceptor, calcium ions flow into the horizontal cell. These ions trigger the horizontal cell to "talk back" to the photoreceptor, Kramer said. Because calcium doesn't spread very far within the horizontal cell, the positive feedback signal stays local, affecting only one or two nearby photoreceptors.

The discovery of a new and unsuspected feedback mechanism in a very well-studied organ is probably related to how the eye is studied, Kramer said. Electrodes are typically stuck into the retina to both change the voltage in cells and record changes in voltage. Because the new signal is chemical, not electrical, it would have been easily missed.

Jackman and Kramer found the same positive feedback in the cones of a zebrafish, lizard, salamander, anole (whose retina contains only cones) and rabbit, proving that "this is not just some weird thing that happens in lizards; it seems to be true across all vertebrates and presumably humans," Kramer said.

The research was supported by the National Institutes of Health and the organization Research to Prevent Blindness.

Coauthors with Kramer and Jackman are Norbert Babai and Wallace B. Thoreson of the Department of Ophthalmology at the University of Nebraska Medical Center and James J. Chambers of the Department of Chemistry at the University of Massachusetts, Amherst.

Source:Science Daily

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New Light-Sensing Mechanism Found in Neurons

New Light-Sensing Mechanism Found in Neurons

  1:06:00 AM    Science Lover

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A UC Irvine research team led by Todd C. Holmes has discovered a second form of phototransduction light sensing in cells that is derived from vitamin B2. This discovery may reveal new information about cellular processes controlled by light.

This image shows blue-light sensing arousal neurons. (Credit: UCI)

For more than 100 years, it had been believed that the phototransduction process was solely based on a chemical derived from vitamin A called retinal. Phototransduction is the conversion of light signals into electrical signals in photoreceptive neurons and underlies both image-forming and non-image-forming light sensing.
In discovering this new light-sensing phototransduction mechanism, the UCI scientists found that phototransduction can also be mediated by a protein called cryptochrome, which uses a B2 vitamin chemical derivative for light sensing. Cryptochromes are blue-light photoreceptors found in circadian and arousal neurons that regulate slow biochemical processes, but this is the first time they have been linked to rapid phototransduction.

Their work appears March 3 on online Express site for the journal Science.

"This is totally novel mechanism that does not depend on retinal," said Holmes, a professor of physiology & biophysics. "This discovery opens whole new technology opportunities for adapting light-sensing proteins to drive medically relevant cellular activities."

This basic science breakthrough -- "which literally and figuratively came 'out of the blue,'" Holmes said -- has implications in the fast-growing field of optogenetics. Optogenetics combines optical and genetic research techniques to probe neural circuits at the high speeds needed to understand brain information processing. In one area, it is being used to understand how treatments such as deep brain massage can aid people with neurodegenerative diseases.

Holmes' team found that cryptochrome mediates phototransduction directly in fruit fly circadian and arousal neurons in response to blue-light wavelengths. The researchers also found that they could genetically express cryptochrome in neurons that are not ordinarily electrically responsive to light to make them light responsive.

Keri Fogel, Kelly Parson and Nicole Dahm of UCI contributed to the study, which received National Institutes of Health support.

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No Wrong Side To This Bad

No Wrong Side To This Bad

  10:28:00 AM    Science Lover

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US researchers have created a smart hospital bed that is aware of its surrounding. The intelligent bed will make important decisions regarding the patients' healthcare which will involve both improving and saving precious lives.

A prototype of the smart bed that is being tested at the University of New Hampshire could revolutionise health care In the future

John LaCourse, professor at the University of New Hampshire, is currently negotiating with hospital bed manufacturers

to adopt his prograq~.med algorithm, which could become the basis for computerised hospital beds.

These smart hospital beds would communicate with and respond to medical devices that monitor a patient's condition.

"Perhaps a sleeping patient moves, causing a drop in blood pressure. The blood pressure monitor would communicate

this change to the bed and the bed, in turn, would move up or down until the patients' blood pressure is stabilised," he says.

IMPROVED POST-SURGERY CARE

Post-surgical needs may also be met with this bed. "Procedures such as retinal surgery require exact blood pressure levels," says LaCourse. "A smart hospital bed would adjust itself to maintain these levels for patients."

Even quality-of-life conditions such as bed sores could be addressed. "Instead of requiring hospital staff to move the patient, monitors could send signals to the bed to roll the patient to his left or right to avoid bed sores," says LaCourse.

"Microprocessors installed into the bed can also sense respiration patterns to determine when breathing has ceased, the bed moves in such a way that the breathing resumes," said Jonathan Waters, who is working on modifying the bed for sleep apnoea.

PLUG AND PLAY

The ultimate success of LaCourse's project rests with the plug-and-play component. Plug-and-play means that medical devices – everything from blood pressure monitors to breathing machines- "can talk to each other and share patient information which greatly reduces care errors," explains LaCourse.

To realise plug-and-play capability, however, LaCourse's technology must become the industry standard for hospital bed manufacturers. 1n this way, medical devices could seamlessly connect to and exchange patient data.

LaCourse is hopeful that, within two to three years, his technology may be accepted by most if not all hospital bed companies.

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From Eye to Brain: Researchers Map Functional Connections Between Retinal Neurons at Single-Cell Resolution

From Eye to Brain: Researchers Map Functional Connections Between Retinal Neurons at Single-Cell Resolution

  10:00:00 AM    Science Lover

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By comparing a clearly defined visual input with the electrical output of the retina, researchers at the Salk Institute for Biological Studies were able to trace for the first time the neuronal circuitry that connects individual photoreceptors with retinal ganglion cells, the neurons that carry visuals signals from the eye to the brain.

A unique neural recording system developed by an 
international team of high energy physicists, which 
is able to record simultaneously the tiny electrical 
signals generated by hundreds of the retinal output 
neurons, is one of the essential elements of the study. 
Recording electrodes are shown in the foreground 
and retinal ganglion cells in the background. 
(Credit: Image: Courtesy of Dr. E.J. Chichilnisky, 
Salk Institute for Biological Studies)

Their measurements, published in the Oct. 7, 2010, issue of the journal Nature, not only reveal computations in a neural circuit at the elementary resolution of individual neurons but also shed light on the neural code used by the retina to relay color information to the brain.

"Nobody has ever seen the entire input-output transformation performed by complete circuits in the retina at single-cell resolution," says senior author E.J. Chichilnisky, Ph.D., an associate professor in the Systems Neurobiology Laboratories. "We think these data will allow us to more deeply understand neuronal computations in the visual system and ultimately may help us construct better retinal implants."

One of the essential elements that made the experiments possible was the unique neural recording system developed by an international team of high-energy physicists from the University of California, Santa Cruz; the AGH University of Science and Technology, Krakow, Poland; and the University of Glasgow, UK. This system is able to record simultaneously the tiny electrical signals generated by hundreds of the retinal output neurons that transmit information about the outside visual world to the brain. These recordings are made at high-speed (over ten million samples each second) and with fine spatial detail, sufficient to detect even a locally complete population of the tiny and densely spaced output cells known as "midget" retinal ganglion cells.

Retinal ganglion cells are classified based on their size, the connections they form, and their responses to visual stimulation, which can vary widely. Despite their differences, they all have one thing in common-a long axon that extends into the brain and forms part of the optic nerve.

Visual processing begins when photons entering the eye strike one or more of the 125 million light-sensitive nerve cells in the retina. This first layer of cells, which are known as rods and cones, converts the information into electrical signals and sends them to an intermediate layer, which in turn relays signals to the 20 or so distinct types of retinal ganglion cells.

In an earlier study, Chichilnisky and his team found that each type of retinal ganglion cells forms a seamless lattice covering visual space that transmits a complete visual image to the brain. In the current study, postdoctoral researcher and co-first author Greg D. Field, Ph.D., and his collaborators zoomed in on the pattern of connectivity between these layers of retinal ganglion cells and the full lattice of cone receptors.

The Salk researchers simultaneously recorded hundreds of retinal ganglion cells, and based on density and light response properties, identified five cell types: ON and OFF midget cells, ON and OFF parasol cells, and small bistratified cells, which collectively account for approximately 75 percent of all retinal ganglion cells.

To resolve the fine structure of receptive fields-the small, irregularly shaped windows through which neurons in retina view the world-the authors used stimuli with tenfold smaller pixels. "Instead of a diffuse region of light sensitivity, we detected punctate islands of light sensitivity separated by regions of no light sensitivity," he says.

When combined with information on spectral sensitivities of individual cones, maps of these punctate islands not only allowed the researchers to recreate the full cone mosaic found in the retina, but also to conclude which cone fed information to which retinal ganglion cell.

"Just by stimulating input cells and taking a high density recording from output cells, we can identify all individual input and output cells and find out who is connected to whom," says Chichilnisky.

Chichilnisky and his team discovered that populations of ON and OFF midget and parasol cells each sampled the complete population of cones sensitive to red or green light, with midget cells sampling these cones in a surprisingly non-random fashion. Only OFF midget cells frequently received strong input from cones sensitive to blue light.

The research was funded in part by the Helen Hay Whitney Foundation, the German Research Foundation, the National Institutes of Health, the Chapman Foundation, the Miller Institute for Basic Research in Science, the Polish Ministry of Science and Higher Education, the Burroughs Wellcome Trust, the McKnight Foundation, the National Science Foundation, the Sloan Foundation, the Engineering and Physical Sciences Research Council and The Royal Society of Edinburgh.

Researchers who also contributed to the work include co-first author Jeffrey L. Gauthier, Ph.D., Martin Greschner, Timothy A. Machado, Lauren H. Jepson, and Jonathon Shlens in the Systems Neurobiology Laboratory at the Salk Institute, co-first author Alexander Sher and Alan Litke at the Santa Cruz Institute for Particle Physics at the University of California, Santa Cruz, Deborah E. Gunning and Keith Mathieson in the Department of Physics and Astronomy at the University of Glasgow, Wladyslaw Dabrowski at the Faculty of Physics and Applied Computer Science at the AGH University of Science and Technology in Krakow, and Liam Paninski in the Department of Statistics and Center for Theoretical Neuroscience at Columbia University, New York.

Editor's Note: This article is not intended to provide medical advice, diagnosis or treatment.

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Blind Mice Can 'See' Thanks to Special Retinal Cells

Blind Mice Can 'See' Thanks to Special Retinal Cells

  9:36:00 AM    Science Lover

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It would make the perfect question for the popular television show "Are You Smarter than a 5th Grader:" What parts of the eye allow us to see?

Mice without rods and cones function can still see -- 
and not just light, but also patterns and images -- 
thanks to a third kind of photosensitive cell in the 
retina, according to new research. 
(Credit: iStockphoto/Steven Maltby)

The conventional wisdom: rods and cones. The human retina contains about 120 million rods, which detect light and darkness, shape and movement, and about 7 million cones, which in addition detect color. Without them, or so we are taught, our eyesight simply would not exist.

But that might not be true, according to a study -- published July 15 in the journal Neuron -- that provides new hope to people who have severe vision impairments or who are blind.

A team led by biologist Samer Hattar of The Johns Hopkins University's Krieger School of Arts and Sciences found that mice that didn't have any rods and cones function could still see -- and not just light, but also patterns and images -- courtesy of special photosensitive cells in the rodents' retinas. Until now, it was presumed that those cells, called intrinsically photosensitive Retinal Ganglion Cells, (or ipRGCs), didn't play a role in image formation, but instead served other functions, such as dictating when the animals went to sleep or woke up. (All mammals, including humans, have ipRGCs, as well as rods and cones.)

"Up until now, it was assumed that rods and cones were the only cells capable of detecting light to allow us to form images," said Hattar, who as an assistant professor in the Department of Biology, studies mammals' sleep-wake cycles, also called "circadian rhythms." "But our study shows that even mice which were blind could form low-acuity yet measurable images, using ipRGCs. The exciting thing is that, in theory at least, this means that a blind person could be trained to use his or her ipRGCs to perform simple tasks that require low visual acuity."

"Visual acuity" refers to the sharpness or clarity of a person's (or animal's) vision. Someone with so-called "20/20 vision" can see clearly at a distance of 20 feet what the "average" human being can see at that distance. In contrast, a person with "20/100" vision would have to stand 20 feet away from, for instance, an eye chart that the average person could read from 100 feet away. People with very low visual acuity (worse than "20/100" with corrective lenses) are considered "legally blind."

In addition to providing hope for people with serious vision problems, Hattar's findings hint that, in the past, mammals may have used their ipRGCs for sight/image formation, but during the course of evolution, that function was somehow taken over by rods and cones.

The study also concludes that, far from being homogenous, ipRGCs come in five different subtypes, with the possibility that each may have different light-detecting physiological functions.

To conduct the study, the team used a special system to genetically label cells and then "trace" them to the rodents' brains before subjecting the mice to a number of vision tests. In one, mice followed the movements of a rotating drum, a test that assessed the animals' ability to track moving objects. In another, the rodents were placed within a "Y"-shaped maze and challenged to escape by selecting the lever that would let them out. That lever was associated with a certain visual pattern. The mice that were blind -- they lacked rods, cones and ipRGCs -- couldn't find that lever. But those with only ipRGCs could.

"These studies are extremely exciting to me, because they show that even a simple light-detecting system like ipRGCs has incredible diversity and may support low-acuity vision, allowing us to peer into evolution to understand how simple vision may have originally evolved before the introduction of the fancy photoreceptors rods and cones," Hattar said.

Hattar's team worked on this study in collaboration with groups led by David Berson of Brown University and Glen Prusky of Weill Cornell Medical College. It was supported by grants from the National Institutes of Health, the David and Lucile Packard Foundation and the Alfred P. Sloan Foundation.

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