Tag Archives: #eyes

How The 3-D Structure Of Eye-lens Proteins is Formed? (Biology)

Chemical bonds within the eye-lens protein gamma-B crystallin hold the protein together and are therefore important for the function of the protein within the lens. Contrary to previous assumptions, some of these bonds, called disulphide bridges, are already formed simultaneously with the synthesis of the protein in the cell. This is what scientists at Goethe University Frankfurt, Max Planck Institute of Biophysics  and the French Institute de Biologie Structurale in Grenoble have discovered.

The lens of the human eye gets its transparency and refractive power from the fact that certain proteins are densely packed in its cells. These are mainly crystallines. If this dense packing cannot be maintained, for example due to hereditary changes in the crystallines, the result is lens opacities, known as cataracts, which are the most common cause of vision loss worldwide.

In order for crystallins to be packed tightly in lens fibre cells, they must be folded stably and correctly. Protein folding already begins during the biosynthesis of proteins in the ribosomes, which are large protein complexes. Ribosomes help translate the genetic code into a sequence of amino acids. In the process, ribosomes form a protective tunnel around the new amino acid chain, which takes on three-dimensional structures with different elements such as helices or folded structures immediately after the tunnel’s formation. The gamma-B crystallines studied in Frankfurt and Grenoble also exhibit many bonds between two sulphur-containing amino acids, so-called disulphide bridges.

The production of these disulphide bridges is not easy for the cell, since biochemical conditions prevail in the cell environment that prevent or dissolve such disulphide bridges. In the finished gamma-B crystalline protein, the disulphide bridges are therefore shielded from the outside by other parts of the protein. However, as long as the protein is in the process of formation, this is not yet possible.

But because the ribosomal tunnel was considered too narrow, it was assumed – also on the basis of other studies – that the disulphide bridges of the gamma-B crystallins are formed only after the proteins have been completed. To test this assumption, the researchers from Frankfurt and Grenoble used genetically modified bacterial cells as a model system, stopped the synthesis of the gamma-B crystallins at different points in time and examined the intermediate products with mass spectrometric, nuclear magnetic resonance spectroscopic and electron microscopic methods, and supplemented these with theoretical simulation calculations. The result: The disulphide bridges are already formed on the not yet finished protein during the synthesis of the amino acid chain.

„We were thus able to show that disulphide bridges can already form in the ribosomal tunnel, which offers sufficient space for this and shields the disulphide bridges from the cellular milieu,“ says Prof. Harald Schwalbe from the Institute of Organic Chemistry and Chemical Biology at Goethe University. „Surprisingly, however, these are not the same disulphide bridges that are later present in the finished gamma-B crystallin. We conclude that at least some of the disulphide bridges are later dissolved again and linked differently. The reason for this probably lies in the optimal timing of protein production: the ‚preliminary‘ disulphide bridges accelerate the formation of the ‚final‘ disulphide bridges when the gamma-B crystallin is released from the ribosome.“

In further studies, the researchers now want to test whether the synthesis processes in the slightly different ribosomes of higher cells are similar to those in the bacterial model system.

Featured image: In cells, ribosomes (blue and yellow) move along mRNA molecules (red „string“) and produce proteins which are depicted here as violett strings. ©GUF


Reference: Linda Schulte, Jiafei Mao, Julian Reitz, Sridhar Sreeramulu, Denis Kudlinzki, Victor-Valentin Hodirnau, Jakob Meier-Credo, Krishna Saxena, Florian Buhr, Julian D. Langer, Martin Blackledge, Achilleas S. Frangakis, Clemens Glaubitz, Harald Schwalbe: Cysteine oxidation and disulfide formation in the ribosomal exit tunnel. Nature Communications, 2021. https://doi.org/10.1038/s41467-020-19372-x


Provided by Goethe University Frankfrut

Routine Eye Scans May Give Clues to Cognitive Decline in Diabetes (Ophthalmology / Medicine)

In older people with type 1 diabetes, damage to the retina may be linked to memory problems and other cognitive conditions.

As they age, people with diabetes are more likely to develop Alzheimer’s disease and other cognitive disorders than are people without diabetes. Scientists at Joslin Diabetes Center now have shown that routine eye imaging can identify changes in the retina that may be associated with cognitive disorders in older people with type 1 diabetes.

Ophthalmology Exam of Patient with Diabetes © Beetham Eye Institute/Joslin Diabetes Center

These results may open up a relatively easy method for early detection of cognitive decline in this population, providing better ways to understand, diagnose and ultimately treat the decline, said George L. King, MD, Joslin’s Chief Scientific Officer and senior author on a paper about the study in the Journal of Clinical Endocrinology & Metabolism.

Previous research had demonstrated an association between proliferative diabetic retinopathy (PDR, a complication of diabetes that can severely damage eyesight) and cognitive impairment in people with type 1 diabetes. “Since we knew that there were cellular changes in the retina that might reflect changes in the brain, we were interested to see whether imaging techniques that visualize those changes in the retina might be reflective of changes in cognitive functions,” said Ward Fickweiler, MD, a Joslin postdoctoral fellow and first author on the paper.

The scientists drew on eye scans routinely gathered from patients as part of normal vision care at Joslin’s Beetham Eye Institute. One set of scans was based on optical coherence tomography (OCT, a technique employing light to provide cross-sections of the retina). A second set of scans employed OCT angiography (OCTA, an extension of OCT technology that examines blood vessels in the retina). Both types of scans are non-invasive and widely available in eye clinics in the United States, and can be performed within minutes.

The study enlisted 129 participants in the Joslin Medalist Study, which examines outcomes among people who have had type 1 diabetes for 50 years or longer. These volunteers took a series of cognitive tests that included tasks probing memory function as well as psychomotor speed (assessing the time it took to arrange objects by hand).

Strikingly, the researchers found very strong associations between performance on memory tasks and structural changes in deep blood vessel networks in the retina. “Memory is the main cognitive task that is affected in Alzheimer’s disease and cognitive decline, so that was exciting,” Fickweiler said.

The Joslin team also discovered strong associations between PDR and psychomotor speed. This finding reinforced earlier outcomes that had been identified among a smaller group of Joslin Medalists, and provided details about related changes in retinal structure. Additionally, the researchers saw that PDR was associated with memory performance among the larger group of Medalists.

While these results need to be confirmed in larger clinical investigations, the routine eye exams do seem to detect the cognitive changes happening in people with diabetes, said Fickweiler.

Currently, other ways to detect conditions such as Alzheimer’s disease such as MRI scans are difficult and expensive. People typically are tested only when they’re showing symptoms of cognitive decline and treatments at that stage generally don’t offer much help.

“If you can detect the condition at an earlier stage, when they’re still asymptomatic, that may benefit patients,” Fickweiler said. Earlier detection also could aid the quest to develop better therapies for neurocognitive diseases.

The Joslin team plans to launch a larger prospective study to confirm the potential of eye imaging to pick up signs of cognitive decline over time. This research will include people with type 1 diabetes who are younger and haven’t had the disease for as long as the Medalists. The scientists also will analyze MRI brain images and postmortem brain samples donated by Medalists.

Additionally, the investigators will look for common mechanisms that may inflict damage on brain and retina tissues, which share much of their early embryonic development pathways. Likely suspects in people with diabetes include impaired blood vessels and high or low levels of blood glucose. The autoimmunity that drives type 1 diabetes also might inflict other forms of harm, King said.

Notably, Joslin Medalists often display relatively low levels of the complications that can afflict those with long-term type 1 diabetes. For instance, almost half of Medalists don’t develop advanced eye disease, and only one of the 129 Medalists in the eye-scan study may have Alzheimer’s disease. “It is possible that in the Medalists, a shared mechanism alters the progression of the early stages of retinal and brain neurodegeneration, and provides protection against both PDR and Alzheimer’s disease,” Fickweiler speculated.

In addition to follow-up work in type 1 diabetes, King and his team plan to perform a similar study for people with type 2 diabetes. PDR also is associated with cognitive decline in this much larger group of patients, who also get OCT and OCTA eye scans as part of their regular vision care.

The paper’s co-authors include Joslin’s Emily Wolfson, Samantha Paniagua, Atif Adam, Vanessa Bahnam, Konstantina Sampani, I-Hsien Wu, Gail Musen, Lloyd Aiello, Hetal Shah and Jennifer Sun. Marc Yu of Harvard Medical School also contributed.

Funding came from the Dianne Nunnally Hoppes Fund; the Beatson Pledge Fund; the National Institute of Diabetes and Digestive and Kidney Diseases; the National Eye Institute; the National Institutes of Health; JDRF; and the American Diabetes Association.

Reference: Ward Fickweiler, Emily A Wolfson, Samantha M Paniagua, Marc Gregory Yu, Atif Adam, Vanessa Bahnam, Konstantina Sampani, I-Hsien Wu, Gail Musen, Lloyd P Aiello, Hetal Shah, Jennifer K Sun, George L King, Association of Cognitive Function and Retinal Neural and Vascular Structure in Type 1 Diabetes, The Journal of Clinical Endocrinology & Metabolism, , dgaa921, https://doi.org/10.1210/clinem/dgaa921 https://academic.oup.com/jcem/advance-article-abstract/doi/10.1210/clinem/dgaa921/6055594?redirectedFrom=fulltext

Provided by Joslin Diabetes Center

About Joslin Diabetes Center

Joslin Diabetes Center is world-renowned for its deep expertise in diabetes treatment and research. Joslin is dedicated to finding a cure for diabetes and ensuring that people with diabetes live long, healthy lives.  We develop and disseminate innovative patient therapies and scientific discoveries throughout the world. Joslin is an independent, non-profit institution affiliated with Harvard Medical School, and one of only 16 NIH-designated Diabetes Research Centers in the U.S.

For more information, visit http://www.joslin.org or follow @joslindiabetes | One Joslin Place, Boston, MA 617-309-2400

How Did Life Started On The Earth? PART 21: Existence Of Consciousness Without Brain (Neuroscience)

PREVIOUSLY ON HDLSOE: PART 20, We saw how communication evolved with time. If you haven’t read that article yet. Don’t forget to visit and read it first. Today, we are going to see does consciousness exists without brain? Guys, in Neuroscience the prevailing consensus is that consciousness is an emergent property of the brain and its metabolism. i.e. When the brain dies, the mind and consciousness of the being to whom that brain belonged ceases to exist. In other words, without a brain there can be no consciousness. But what if i say, consciousness persists after death.

©Shutterstock

Yeah, it exists independently and outside of the brain as an inherent property of the universe itself like dark matter and dark energy or gravity. Thus, the brain does not create or produce consciousness; rather, it filters it. You might be thinking, I may have gone mad.. But as odd as this idea might seem at first, there are some analogies that bring this concept into sharper focus.

Let’s take an example the eye filters and interprets only a very small sliver of the electromagnetic spectrum and the ear registers only a narrow range of sonic frequencies. Similarly, the brain filters and perceives only a tiny part of the cosmos’ intrinsic ‘consciousness.” Indeed, the eye can see only the wavelengths of electromagnetic energy that correspond to visible light.

But the entire EM spectrum is vast and extends from extremely low energy, long wavelength radio waves to incredibly energetic, ultrashort-wavelength gamma rays. So, while we can’t actually “see” much of the EM spectrum, we know things like X-rays, IR exists because we have instruments for detecting them.

Similarly, our ears can register only a narrow range of sonic frequencies but we know a huge amount of others imperceptible to the human ear exist nevertheless.

When the eye dies, the EM spectrum does not vanish or cease to be; it’s just that the eye is no longer viable and therefore can no longer filter, be stimulated by, and react to light energy. But the energy it previously interacted with remains nonetheless. And so too when the ear dies, or stops transducing the sound waves, energies that the living ear normally respond to still exist.

So it is with consciousness. Just because the organ that filters, perceives, and interprets it dies does not mean the phenomenon itself ceases to exist. It only ceases to be in the now-dead brain but continues to exist independently of the brain as an external property of the universe itself. Guys, our consciousness tricks us into perceiving a false duality of self and other when in fact there is only unity.

We are not special, we are not separate from other aspects of the universe but an integral and inextricable part of them. And when we die, we transcend the human experience of consciousness, and its illusion of duality, and merge with the universe’s entire and unified property of consciousness. So, ironically, only in death can we be fully conscious.

But yes, don’t take this as joining God or a creator because the cosmic consciousness that I am talking about did not create the universe but is simply a “property” of it. So, friends for now we have to stop here.. But i will be back with LAST AND FINAL episodic part of HDLSOE very soon..

Reference: Peter Fenwick, Elizabeth Fenwick, “The Art of Dying”, Bloomsbury Academic, 2008 ISBN 0826499236, 9780826499233 Length 264 pages. https://books.google.co.in/books/about/The_Art_of_Dying.html?id=5LDkJwAACAAJ&source=kp_book_description&redir_esc=y

About the author

Dr Peter Fenwick is an internationally renowned neuropsychiatrist and a Fellow of the Royal College of Psychiatrists. He is Britain’s leading clinical authority on near-death experiences and is president of the British branch of The International Association for Near-Death Studies. He also holds appointments at the Maudsley Hospital, the John Radcliffe Hospital, and the Broadmoor Special Hospital for Violent Offenders.

Elizabeth Fenwick has written a number of books on health and family issues. She has produced books on pregnancy and child care, worked as an agony aunt advising on sexual problems on radio and in Company magazine and has been involved in sex education in two London schools. She also worked for three years as a counsellor for Childline.

© Copyright S. Aman 2020.

Research Reveals How COVID-19 Affects the Eyes (Ophthalmology / Medicine)

Sore eyes are the most significant vision-based indicator of COVID-19, according to new research published in the journal BMJ Open Ophthalmology.

Researchers at Anglia Ruskin University (ARU) asked people who had a confirmed COVID-19 diagnosis to complete a questionnaire about their symptoms, and how those compared to before they tested positive.

The study found that sore eyes was significantly more common when the participants had COVID-19, with 16% reporting the issue as one of their symptoms. Just 5% reported having had the condition beforehand.

While 18% of people reported suffering from photophobia (light sensitivity) as one of their symptoms, this was only a 5% increase from their pre-COVID-19 state.

Of the 83 respondents, 81% reported ocular issues within two weeks of other COVID-19 symptoms. Of those, 80% reported their eye problems lasted less than two weeks.

The most common reported symptoms overall were fatigue (suffered by 90% of respondents), a fever (76%) and a dry cough (66%).

Lead author Professor Shahina Pardhan, Director of the Vision and Eye Research Institute at ARU, said: “This is the first study to investigate the various eye symptoms indicative of conjunctivitis in relation to COVID-19, their time frame in relation to other well-known COVID-19 symptoms and their duration.

“While it is important that ocular symptoms are included in the list of possible COVID-19 symptoms, we argue that sore eyes should replace ‘conjunctivitis’ as it is important to differentiate from symptoms of other types of infections, such as bacterial infections, which manifest as mucous discharge or gritty eyes.

“This study is important because it helps us understand more about how COVID-19 can infect the conjunctiva and how this then allows the virus to spread through the body.”

Reference: Shahina Pardhan et al. Sore eyes as the most significant ocular symptom experienced by people with COVID-19: a comparison between pre-COVID-19 and during COVID-19 states, BMJ Open Ophthalmology (2020). DOI: 10.1136/bmjophth-2020-000632 https://bmjophth.bmj.com/content/5/1/e000632

Provided by Anglia Ruskin University

Brain Clears the Way for Binocular Vision Even Before Eyes are Open (Neuroscience)

To prepare the brain for binocular vision and depth perception, first you have to take out some of the chandeliers.

That’s the takeaway from a group of neurobiologists who studied the development of binocular vision in the mouse brain. They discovered that chandelier cells, so-named because they have many long extensions that control the firing of hundreds of excitatory pyramidal neurons and resemble a chandelier light fixture, are selectively removed from the developing mouse visual cortex even before the animal’s eyes are open by a process of programmed cell death called apoptosis.

A portion of mouse visual cortex shows where the binocular zone is located (green). Chandelier cells are stained red in this image, and the blue is a marker that helped the researchers identify the visual cortex. Chandeliers are clearly less plentiful in the binocular zone. Credit: Bor-Shuen Wang, Cold Spring Harbor Lab

This pruning of about half of the chandelier cells in the second week of development probably clears a path for certain pyramidal neurons to be more active, since chandeliers tend to have a dampening effect on their excitability, explained Josh Huang, a professor of neurobiology in the Duke University School of Medicine. He led this research at his previous position in Cold Spring Harbor Laboratory on Long Island, spearheaded by postdoctoral fellow Bor-Shuen Wang. The findings appear Dec. 7 in the journal Neuron.

“Binocular vision requires fast communication between the two visual hemispheres that receive information in the center visual field,” Huang said. “What we think is that to allow that to happen, the area that mediates this fast communication needs to have reduced inhibition,” accomplished via fewer inhibitory chandelier cells.

The binocular vision enjoyed by mammals like mice and humans is a collaboration of the physical abilities of the eyes and the interpretative abilities of the brain, Huang said. “Many animals (such as a lizard) can see with both eyes, but their processing of visual information from each eye is largely separate. Only in most mammals is there a central part of the visual world that is seen by both eyes and it is the brain that has to combine the left and right visual images into a coherent single perception.”

Some of the binocular system is laid down by genetic instructions that build the structures of the visual pathways, but the finer visual circuits are shaped by visual experience.

“The whole process of brain development is a continuous process in which genetic information plays a major role in constructing larger scaffold of the brain network,” Huang said. “But later, there are learning- and experience-dependent processes that begin to customize many of the details of the brain circuits for each individual. The phenomenon we’re talking about is right at the juncture between the genetic-instructed and use-dependent mechanisms,” Huang said.

Adding to the complexity, the brain processes binocular vision in two different and coordinated ways, Huang said. As signals travel from the left and right retina to the thalamus, some signals cross to the other side of the brain, and others don’t, but they converge in the visual cortex, thereby contributing to binocular vision. The second path is that the left and right visual cortexes, receiving information from the retina, communicate through callosal neurons via the corpus callosum, a connection between brain hemispheres. That further sharpens binocular vision.

In that second week after birth and before their eyes open, the retinas of the developing mouse generate waves of activity that help organize the visual cortex by reducing the density of the inhibitory chandelier cells. This is achieved by instructing the callosal neurons to literally kill half of the chandelier cells. The researchers showed that blocking those retinal inputs prevented chandelier cell pruning in the visual cortex.

When they experimentally prevented the chandelier pruning in some mice, those mice flunked a 3-D visual perception test, but otherwise seemed to see and behave normally. To confirm that the chandelier pruning is driven by retinal activity without any visual input, pups were raised in complete darkness. And the chandelier pruning still happened.

“Most likely, that killing of chandelier cells by callosal neurons is not random but is a step of proper binocular circuit assembly,” Huang said. As young chandelier cells begin to form connections, those that form the “wrong connections” that may slow down the callosal pathway are likely to be selectively killed, while others that contribute to other aspects of visual processing are preserved. When pruning was blocked, a significant portion of the remaining chandelier cells appeared stunted. Those, he thinks, are the ones that would have been pruned.

Reference: “Retinal and Callosal Activity-Dependent Chandelier Cell Elimination Shapes Binocularity in Primary Visual Cortex,” Bor-Shuen Wang, Maria Sol Bernardez Sarria, An Xu, Miao He, Nazia M. Alam, Glen T. Prusky, Michael C. Crair, Z. Josh Huang. Neuron (2020). DOI: 10.1016/j.neuron.2020.11.004

Provided by Duke University School of Nursing

New Technology Allows Cameras To Capture Colors Invisible To The Human Eye (Chemistry)

New research from Tel Aviv University will allow cameras to recognize colors that the human eye and even ordinary cameras are unable to perceive.

The technology makes it possible to image gases and substances such as hydrogen, carbon and sodium, each of which has a unique color in the infrared spectrum, as well as biological compounds that are found in nature but are “invisible” to the naked eye or ordinary cameras. It has groundbreaking applications in a variety of fields from computer gaming and photography as well as the disciplines of security, medicine and astronomy.

TAU breakthrough has applications in cancer detection, security and even gaming ©TAU.

The research was conducted by Dr. Michael Mrejen, Yoni Erlich, Dr. Assaf Levanon and Prof. Haim Suchowski of TAU’s Department of Physics of Condensed Material. The results of the study were published in the October 2020 issue of Laser & Photonics Reviews.

“The human eye picks up photons at wavelengths between 400 nanometers and 700 nanometers — between the wavelengths of blue and red,” explains Dr. Mrejen. “But that’s only a tiny part of the electromagnetic spectrum, which also includes radio waves, microwaves, X-rays and more. Below 400 nanometers there is ultraviolet or UV radiation, and above 700 nanometers there is infrared radiation, which itself is divided into near-, mid- and far-infrared.

“In each of these parts of the electromagnetic spectrum, there is a great deal of information on materials encoded as ‘colors’ that has until now been hidden from view.”

The researchers explain that colors in these parts of the spectrum are of great importance, since many materials have a unique signature expressed as a color, especially in the mid-infrared range. For example, cancer cells could be easily detected as they have a higher concentration of molecules of a certain type.

Existing infrared detection technologies are expensive and mostly unable to render those “colors.” In medical imaging, experiments have been performed in which infrared images are converted into visible light to identify the cancer cells by the molecules. To date, this conversion required very sophisticated and expensive cameras, which were not necessarily accessible for general use.

But in their study, TAU researchers were able to develop cheap and efficient technology that could mount on a standard camera and allows, for the first time, the conversion of photons of light from the entire mid-infrared region to the visible region, at frequencies that the human eye and the standard camera can pick up.

“We humans can see between red and blue. If we could see in the infrared realm, we would see that elements like hydrogen, carbon and sodium have a unique color,” explains Prof. Suchowski. “So an environmental monitoring satellite could ‘see’ a pollutant being emitted from a plant, or a spy satellite would see where explosives or uranium are being hidden. In addition, since every object emits heat in the infrared, all this information could be seen even at night.”

After registering a patent for their invention, the researchers are developing the technology through a grant from the Innovation Authority’s KAMIN project, and they have already met with a number of both Israel-based and international companies.

References: Mrejen, M., Erlich, Y., Levanon, A., Suchowski, H., Multicolor Time‐Resolved Upconversion Imaging by Adiabatic Sum Frequency Conversion. Laser & Photonics Reviews 2020, 14, 2000040. https://doi.org/10.1002/lpor.202000040 link: https://onlinelibrary.wiley.com/doi/10.1002/lpor.202000040

Provided by American Friends Of Tel Aviv University

Research Provides A New Understanding Of How A Model Insect Species Sees Color (Biology)

Through an effort to characterize the color receptors in the eyes of the fruit fly Drosophila melanogaster, University of Minnesota researchers discovered the spectrum of light it can see deviates significantly from what was previously recorded.

Drosophila melanogaster under green and red fluorescence used as a marker to indicate the presence of inserted genes. ©Camilla Sharkey

“The fruit fly has been, and continues to be, critical in helping scientists understand genetics, neuroscience, cancer and other areas of study across the sciences,” said Camilla Sharkey, a post-doctoral researcher in the College of Biological Sciences’ Wardill Lab. “Furthering our understanding of how the eye of the fruit fly detects different wavelengths of light will aid scientists in their research around color reception and neural processing.”

The research, led by U of M Assistant Professor Trevor Wardill, is published in Scientific Reports and is among the first research of its kind in two decades to examine Drosophila photoreceptor sensitivity in 20 years. Through their genetic work, and with the aid of technological advancements, researchers were able to target specific photoreceptors and examine their sensitivity to different wavelengths of light (or hue).

Wild-type eye colouration in Drosophila (red eyes) and those with reduced screening pigment (orange eyes). ©Camilla Sharkey

The study found:

• all receptors — those processing UV, blue and green — had significant shifts in light sensitivities compared to what was previously known;
• the most significant shift occurred in the green photoreceptor, with its light sensitivity shifting by 92 nanometers (nm) from 508 nm to 600 nm; equivalent to seeing orange rather than green best;
• a yellow carotenoid filter in the eye (derived from Vitamin A) contributes to this shift; and
• the red pigmented eyes of fruit flies have long-wavelength light leakage between photoreceptors, which could negatively impact a fly’s vision.

Researchers discovered this by reducing carotenoids in the diets of the flies with red eyes and by testing flies with reduced eye pigmentation. While fly species with black eyes, such as house flies, are able to better isolate the long-wavelength light for each pixel of their vision, flies with red eyes, such as fruit flies, likely suffer from a degraded visual image.

“The carotenoid filter, which absorbs light on the blue and violet light spectrum, also has a secondary effect,” said Sharkey. “It sharpens ultraviolet light photoreceptors, providing the flies better light wavelength discrimination, and — as a result — better color vision.”

References: http://dx.doi.org/10.1038/s41598-020-74742-1

Provided by University Of Minnesota

Researchers Identified Calcium Flares In Rods For the First Time (Neuroscience)

Thanks to refined microscopy techniques, researchers of SISSA and CNR-Iom have identified calcium flares in rods that no one had previously seen or even imagined. They raise the alarm and warn that it is necessary to carry out a replacement

Moving around in the half-light is difficult but not impossible. To help us in this undertaking we have the rods, a type of light-sensitive cells (photoreceptors) present in the retina of vertebrates, capable of detecting very low lights which allow to move about even in poorly lit cellars or caves. They are biological wonders capable of detecting even a single quantum of light, but they need continuous maintenance. They are the protagonists of the new study published in PNAS by a team of researchers of SISSA – Scuola Internazionale Superiore di Studi Avanzati and the Istituto officina dei materiali of the National research council CNR-Iom which reveals new and essential details of how the retina works and in particular photoreceptors.

©SISSA

These consist of two segments: the outer segment (OS) and the inner segment (IS). The OS of the rods is the one where the biological machine capable of capturing the light is located, while the IS is responsible for the information to be transferred to the brain. “We have understood that the outer segment is more fragile than what was thought”, comments Vincent Torre, neuroscientist of SISSA leading the team that conducted the research, adding “The OS consists of a stack of lipid discs containing the proteins responsible for phototransduction. New discs are generated at the base of the OS while used discs are removed at the tip of the OS. Traditionally, it was thought that in a stack of about 1000 discs there was almost perfect uniformity. However, our work shows that only the first 200 or 300 discs at the base of the OS are those effectively capable of detecting the single photon of light, characteristic from which comes the great sensitivity of the rods. The other discs positioned close to the tip gradually lose effectiveness and sensitivity and for this reason they must be disposed of and replaced with new discs in perfect condition”.

It was the Calcium, an ion present in large numbers in biological processes that allowed the understanding of this mechanism. Its concentration in the OS is an excellent indicator of the functionality and integrity of phototransduction, the process with which the photoreceptors convert light into nerve signals. “With new optical probes we measured the concentration and the distribution of calcium in the OS. Using advanced optical microscopy instruments, we were able to study the distribution of this metal with unprecedented resolution and accuracy.” Dan Cojoc of Cnr-Iom explains “what has emerged from the analyses is that there is greater concentration of calcium at the base of the outer segment with respect to the tip, which helps to understand the structure of the rod showing its non-homogeneity, as was thought until now.

A second and no less important result is the discovery of spontaneous calcium flares, i.e. rapid increases in calcium. These flares are not evenly distributed but located in the tips of the OS, which shows the existence of a functional gradient along the OS, a fundamental property for photoreceptor transduction of all vertebrates.” Cojoc concludes. Like a warning light, the Calcium flares indicate that the discs start to stop working at their best and need turnover. The article was also recommended to Faculty Opinions by the editor of PNAS -something reserved only for the most important contributions – for the following reasons: “This interesting article uses a new Calcium measurement method to show that light-dependent changes of Calcium in the outer segment of the rods are greater at the base than at the tip”.

Neuroscientist Gordon Fain of the University of California continues, “These differences can reflect an energy gradient that originates from the mitochondria of the inner segment. The authors of the study also make the amazing observation that Calcium increases spontaneously both at the tip and at the base (but more often at the tip), as well as more rarely in the inner segment. These increases produce sudden flares, i.e. peaks of Calcium concentration, which decrease slowly for several seconds and which remain local without propagating inside the outer segment or between the inner and outer segment.”

References: Yunzhen Li, Fabio Falleroni, Simone Mortal, Ulisse Bocchero, Dan Cojoc, Vincent Torre, “Calcium flares and compartmentalization in rod photoreceptors”, Proceedings of the National Academy of Sciences Sep 2020, 117 (35) 21701-21710; DOI: 10.1073/pnas.2004909117 link: https://www.pnas.org/content/117/35/21701/tab-article-info

Provided by SISSA

Mammals Share Gene Pathways That Allow Zebrafish To Grow New Eyes (Evolution)

Study may advance genetic therapies for blindness and other injuries to the central nervous system.

Working with fish, birds and mice, Johns Hopkins Medicine researchers report new evidence that some animals’ natural capacity to regrow neurons is not missing, but is instead inactivated in mammals. Specifically, the researchers found that some genetic pathways that allow many fish and other cold-blooded animals to repair specialized eye neurons after injury remain present in mammals as well, but are turned off, blocking regeneration and healing.

A description of the study, published online by the journal Science on Oct. 1 (science.sciencemag.org/lookup/doi/10.1126/science.abb8598), offers a better understanding of how genes that control regeneration are conserved across species, as well as how they function. This may help scientists develop ways to grow cells that are lost due to hereditary blindness and other neurodegenerative diseases.

“Our research overall indicates that the potential for regeneration is there in mammals, including humans, but some evolutionary pressure has turned it off,” says Seth Blackshaw, Ph.D., professor of neuroscience at the Johns Hopkins University School of Medicine. “In fact, regeneration seems to be the default status, and the loss of that ability happened at multiple points on the evolutionary tree,” he says.

For the study, Blackshaw’s team focused on supportive cells in the back of the eye. In zebrafish, a standard laboratory model whose genome has been well defined, these cells, known as Müller glia, respond and repair the light-sensitive retina by growing new cells in the central nervous system called neurons. In addition to regrowing eye tissue, zebrafish’s regenerative abilities extend to other body parts, including fins, tails and some internal organs.

The retina is a good testing ground for mapping genetic activity, explains Blackshaw, because it contains structures common to other cells in the nervous system. In previous studies, moreover, scientists have found that the genetic networks in the retina are well conserved across species, so comparisons among fish, birds, mice and even humans are possible.

For the new experiments, the Johns Hopkins researchers created retinal injuries in zebrafish, chickens and mice. Then they used high-powered microscopes and a previously developed gene mapping tool to observe how the supportive Müller glia cells responded.

Blackshaw said the team was surprised to find, immediately after the injury, that the cells in each of the three species behaved the same way: They entered an “active state” characterized by the activation of specific genes, some of which control inflammation.

This active state, says Blackshaw, primarily helps to contain the injury and send signals to immune system cells to combat foreign invaders such as bacteria, or to clean up broken tissue.

Beyond that step, however, the species’ responses diverged.

In zebrafish, active Müller glia began turning on a network of transcription factors that control which genes are ‘on’ and ‘off.’ In the current experiment, the NFI transcription factors activated genes that are linked to cell maturity, sending the Müller glia cells back in developmental time to a more primitive state, which then allows them to develop into many different cell types. The Müller glia then “differentiated” into new cells to replace the ones lost to injury.

In contrast, the research team saw that chickens with damaged retinas activate only some of the transcription factor ‘gene control switches’ that are turned on in zebrafish. Thus, chickens have much less capability to create new Müller glia and other neurons in the eye following injury.

Finally, the researchers looked at the injury response in mice. Mice share the vast majority of their DNA with humans, and their eyes are similar to human eyes. The researchers found that injured Müller glia in mice remained in the first “active” state for several days, much longer than the eight to 12 hours that zebrafish are in this state, and yet never acquired the ability to make new neurons.

Müller glia in all three species also express high levels of nuclear factor I (NFI) transcription factors, but rapidly turn them off following injury. In mice, however, the NFI genes are turned back on soon thereafter, and actively block the Müller glia from generating neurons.

The researchers found, to their surprise, they say, that the same genes that allowed the zebrafish cells to regenerate were “primed and ready to go” in the mouse eye, but that the “on” transcription factor was never activated. Instead, the NFI factors actively block the cells’ regenerative potential.

Blackshaw suspects that animals with a higher potential to develop disease in brain and other neurological tissue may have lost this capability over evolutionary time to help protect and stabilize other brain cells. “For example, we know that certain viruses, bacteria and even parasites can infect the brain. It could be disastrous if infected brain cells were allowed to grow and spread the infection through the nervous system,” says Blackshaw.

Now equipped with a more detailed map of the cellular response to neuronal injury and regrowth, scientists may be able to find a way to activate the regenerative capabilities hidden in human DNA, Blackshaw says.

References: Thanh Hoang, Jie Wang, Patrick Boyd, Fang Wang, Clayton Santiago, Lizhi Jiang, Sooyeon Yoo, Manuela Lahne, Levi J. Todd, Meng Jia, Cristian Saez, Casey Keuthan, Isabella Palazzo, Natalie Squires, Warren A. Campbell, Fatemeh Rajaii, Trisha Parayil, Vickie Trinh, Dong Won Kim, Guohua Wang, Leah J. Campbell, John Ash, Andy J. Fischer, David R. Hyde, Jiang Qian, Seth Blackshaw, “Gene regulatory networks controlling vertebrate retinal regeneration”, Science, Oct 2020: eabb8598 DOI: 10.1126/science.abb8598

Provided by Hopkins Medicine