Week in Review: Number 6

Lateral Inhibition in Pink
The optical illusion depicted illustrates an example of lateral inhibition. Lateral inhibition promotes increased contrast sensitivity through the detection of borders, as enhanced by feedback modulation of signals by horizontal cells. Horizontal cells come in three types, depending on the types of photoreceptors they synapse with, but that detail is less relevant to their function in lateral inhibition overall. Light detection is performed by the photoreceptors, which hyperpolarize in the presence of light and depolarize in the absence of light (an exception to most neuronal signaling). Depolarization leads to increased glutamate release, the neurotransmitter currency of photoreceptors, while hyperpolarization leads to decreased glutamate release. Whether the receptive field is on-center or off-center is relevant to the types of bipolar cells downstream, but is only really relevant to this discussion in the sense that the center and surround provide contrast to one another. The excitation or inhibition affects two types of bipolar cells (on-center and off-center), which then affect their corresponding retinal ganglion cells (also on-center and off-center). These cells downstream of the photoreceptors and horizontal cells are interesting in themselves, but not necessary for a discussion of lateral inhibition, which is mostly about contrast. Horizontal cells receive excitatory input from photoreceptors and send inhibitory input to all/neigboring photoreceptors. In this case (of an off-center receptive field), the surrounding horizontal cells are hyperpolarized in the presence of light. When horizontal cells are hyperpolarized, they send less inhibitory signals (recall that they send only inhibitory signals). The neighboring photoreceptor in an off/dark region is already depolarized in the absence of light, but because it receives less inhibition from its neighboring horizontal cells, it depolarizes even more and releases even more glutamate. It is this "even more" effect of modulation by horizontal cells that increases border contrast and causes shades to stand out more when placed next to one another.

Mental and Visual Distress during Pandemic Times
In a second study about Charles Bonnet Syndrome published this year, researchers at University College London seek to highlight the increased mental distress during the COVID-19 pandemic for those suffering from the condition. The study itself is small, comprising only 45 patients at one hospital. Among these patients, the researchers found that 56% experienced increased intensity and exacerbation of visual hallucinations during the interval of study between June and July 2020. The weight of the study lies in its social focus to call attention to Charles Bonnet Syndrome. The visual hallucination symptoms of this condition are frightening in themselves in ordinary times. And mental distress is unfortunately common for many during the pandemic. That the mental distress of "social isolation, loneliness, lack of exercise and exposure to distressing media over the COVID-19 lockdown" increased the symptoms of Charles Bonnet Syndrome highlights the need for awareness of the condition in particular, but also the need for social and community support for the majority of people suffering from isolation and loneliness during the pandemic.

Disulfide Bridge Formation in the Crystalline Lens
Researchers at Goethe University in Germany are taking a basic science approach to study the protein structure of the crystalline lens using a genetically modified bacterial model. In particular, they studied the disulfide bridges, bonds between two sulfur-containing amino acids, in βγ-crystallins. Where this is interesting from a molecular standpoint is that disulfide bonds are not easy for the cell to produce and maintain given a cellular environment that promotes their dissolution. In the finished βγ-crystallin protein, these bonds are shielded from the cellular environment by placement in the internal parts of the protein. But while the protein is in the process of formation, this is not yet possible. It had been previously assumed that because the ribosomal tunnel is too narrow, disulfide bridges could only form after protein formation was completed. The researchers tested this assumption on their bacterial model using various spectroscopic techniques and theoretical simulations. They found that disulfide bridges are already formed during the synthesis of the amino acid chain, that is, within the ribosomal tunnel. One of the researchers notes, "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," and that perhaps the preliminary disulfide bridges accelerate the formation of the final disulfide bridges when the protein is released from the ribosome. The focus and weight of this study in the basic sciences, and in a very restricted aspect of crystalline protein formation, limit its application in clinical settings. Nonetheless, the crystalline lens is a structure with ubiquitous impact, the transparency and power of the eye being due in large part to the packing of these crystallin proteins in the lens (with the nuance that the major refractive component of the eye is the cornea). Study of crystalline lens formation thus informs the progression of cataracts and could aid in research toward their prevention.

Protein Imbalance in Congenital Cataracts in Mice
This is another small study from Germany about the crystalline lens and cataract formation. Researchers at the Technical University of Munich used a mouse model to study hereditary forms of cataracts. The findings were not major, however, the researchers discovered that at least for the genetic conditions under study in their mouse models, clumping of normal rather than abnormal proteins was the cause of cataracts. The unstable, mutated proteins were eliminated immediately and not present. Instead, it was the "healthy" normal proteins that clumped together. One of the researchers states that the model showed that "the balance between the various proteins, or their ratios to one another, is important. When one of these components is missing, the remaining ones interact and form clumps." The proportion of hereditary, compared to age-related or other acquired, cataracts is extremely small, which limits the scope of the study. Nonetheless, as with previous studies about the crystalline lens, this study adds to the basic science knowledge base that could aid in developing drugs that help prevent or delay cataract formation. Perhaps also in a philosophical way, the study highlights the body's balance of components in maintaining optimal function.

In the News: Edition 2
As with the first EyeNet opinion piece of 2021, I generally agree with this perspective, this time about genuine representation, about publishing integrity, about the invisible hard work of editors. I agree with it more than meets the eye. Where this opinion piece is relevant to eye care is in its reference to the use of hydroxychloroquine for the treatment of COVID-19. Eye doctors are familiar with the drug by way of monitoring for adverse effects of retinal toxicity. Hydroxychloroquine (Plaquenil) was originally a drug for malaria, and also has uses in various rheumatologic and dermatologic conditions. Used for these inflammatory and skin-related conditions, hydroxychloroquine is an effective drug. One might even say that the drug design was catered for a specific disease or range of diseases. Because of hydroxychloroquine's popularity, some in the medical community sought its use as a potential treatment for the novel coronavirus. Some even imposed upon this drug the unintended use in pediatrics, which demonstrates the strength of the desire for a cure against COVID-19. Hydroxychloroquine is not FDA-approved for this form of treatment—a fact often repeated, to say the least—though the scientific curiosity and humanistic motivation to pursue this line of therapy were commendable. That being said, transparency of the scientific process was a prudent move on the part of researchers, so as to avoid false advertisement and misrepresentation while testing this therapy. That hydroxychloroquine works exceedingly well for some conditions does not mean it should be coaxed into use for other conditions. Despite hydroxychloroquine's abysmal results as a treatment for COVID-19, we can both—nay, we can all—laugh at the fact that it still appears in the news.

In Everyday News
(1) Ways to avoid COVID lockdown eye strain
(2) Free infant vision screening program
(3) The art of vision: how pets see the world
(4) Hairy corneal dermoid in a deer

Protein Imbalance in Congenital Cataracts in Mice

Article: Cloudy eyes caused by protein imbalance
Source: Technical University of Munich (Germany), via ScienceDaily
Published: February 16, 2021

Cataract-associated crystallin mutants are thermodynamically destabilized

This is another small study from Germany about the crystalline lens and cataract formation. Researchers at the Technical University of Munich used a mouse model to study hereditary forms of cataracts. The findings were not major, however, the researchers discovered that at least for the genetic conditions under study in their mouse models, clumping of normal rather than abnormal proteins was the cause of cataracts. The unstable, mutated proteins were eliminated immediately and not present. Instead, it was the "healthy" normal proteins that clumped together. One of the researchers states that the model showed that "the balance between the various proteins, or their ratios to one another, is important. When one of these components is missing, the remaining ones interact and form clumps." The proportion of hereditary, compared to age-related or other acquired, cataracts is extremely small, which limits the scope of the study. Nonetheless, as with previous studies about the crystalline lens, this study adds to the basic science knowledge base that could aid in developing drugs that help prevent or delay cataract formation. Perhaps also in a philosophical way, the study highlights the body's balance of components in maintaining optimal function.

My rating of this study: ⭐

Further reading: Understanding the molecular mechanisms underlying cataract development

Schmid PWN, Lim NCH, Peters C, et al. "Imbalances in the eye lens proteome are linked to cataract formation." Nature Structural & Molecular Biology.  28:143-151. 11 January 2021. https://doi.org/10.1038/s41594-020-00543-9

Mental and Visual Distress during Pandemic Times

Article: Visual hallucinations among blind people increase during pandemic
Source: University College London (U.K.), via Technology Networks
Published: February 12, 2021

In a second study about Charles Bonnet Syndrome published this year, researchers at University College London seek to highlight the increased mental distress during the COVID-19 pandemic for those suffering from the condition. The study itself is small, comprising only 45 patients at one hospital. Among these patients, the researchers found that 56% experienced increased intensity and exacerbation of visual hallucinations during the interval of study between June and July 2020. The weight of the study lies in its social focus to call attention to Charles Bonnet Syndrome. The visual hallucination symptoms of this condition are frightening in themselves in ordinary times. And mental distress is unfortunately common for many during the pandemic. That the mental distress of "social isolation, loneliness, lack of exercise and exposure to distressing media over the COVID-19 lockdown" increased the symptoms of Charles Bonnet Syndrome highlights the need for awareness of the condition in particular, but also the need for social and community support for the majority of people suffering from isolation and loneliness during the pandemic.

Response distributions for survey items among 45 people with Charles Bonnet syndrome

My rating of this study: ⭐🌸

See also: A Brain Mechanism underlying “Vision” in the Blind is Revealed

Jones L, Ditzel-Finn L, Potts J, et al. "Exacerbation of visual hallucinations in Charles Bonnet syndrome due to the social implications of COVID-19." BMJ Open Ophthalmology.  6:e000670. 11 February 2021. https://doi.org/10.1136/bmjophth-2020-000670

Disulfide Bridge Formation in the Crystalline Lens

Article: How the 3-D structure of eye-lens proteins is formed
Source: Goethe University (Germany), via ScienceDaily  and Technology Networks
Published: February 10, 2021

Side view of a ribosomal 50S subunit with a focus on the nascent chain

Researchers at Goethe University in Germany are taking a basic science approach to study the protein structure of the crystalline lens using a genetically modified bacterial model. In particular, they studied the disulfide bridges, bonds between two sulfur-containing amino acids, in βγ-crystallins. Where this is interesting from a molecular standpoint is that disulfide bonds are not easy for the cell to produce and maintain given a cellular environment that promotes their dissolution. In the finished βγ-crystallin protein, these bonds are shielded from the cellular environment by placement in the internal parts of the protein. But while the protein is in the process of formation, this is not yet possible. It had been previously assumed that because the ribosomal tunnel is too narrow, disulfide bridges could only form after protein formation was completed. The researchers tested this assumption on their bacterial model using various spectroscopic techniques and theoretical simulations. They found that disulfide bridges are already formed during the synthesis of the amino acid chain, that is, within the ribosomal tunnel. One of the researchers notes, "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," and that perhaps the preliminary disulfide bridges accelerate the formation of the final disulfide bridges when the protein is released from the ribosome. The focus and weight of this study in the basic sciences, and in a very restricted aspect of crystalline protein formation, limit its application in clinical settings. Nonetheless, the crystalline lens is a structure with ubiquitous impact, the transparency and power of the eye being due in large part to the packing of these crystallin proteins in the lens (with the nuance that the major refractive component of the eye is the cornea). Study of crystalline lens formation thus informs the progression of cataracts and could aid in research toward their prevention.

My rating of this study: ⭐⭐

Schulte L, Mao J, Reitz J, et al. "Cysteine oxidation and disulfide formation in the ribosomal exit tunnel." Nature Communications.  11(5569). 4 November 2020. https://doi.org/10.1038/s41467-020-19372-x

Lateral Inhibition in Pink

Article: How Many Colors in This Image? Here's The Science Behind The Illusion...
Source: ScienceAlert
Published: February 10, 2021

Center-surround receptive field,
including interaction between
photoreceptors and horizonal cells

The optical illusion depicted above illustrates an example of lateral inhibition. Lateral inhibition promotes increased contrast sensitivity through the detection of borders, as enhanced by feedback modulation of signals by horizontal cells. Horizontal cells come in three types, depending on the types of photoreceptors they synapse with, but that detail is less relevant to their function in lateral inhibition overall. Light detection is performed by the photoreceptors, which hyperpolarize in the presence of light and depolarize in the absence of light (an exception to most neuronal signaling). Depolarization leads to increased glutamate release, the neurotransmitter currency of photoreceptors, while hyperpolarization leads to decreased glutamate release. Whether the receptive field is on-center or off-center is relevant to the types of bipolar cells downstream, but is only really relevant to this discussion in the sense that the center and surround provide contrast to one another. The excitation or inhibition affects two types of bipolar cells (on-center and off-center), which then affect their corresponding retinal ganglion cells (also on-center and off-center). These cells downstream of the photoreceptors and horizontal cells are interesting in themselves, but not necessary for a discussion of lateral inhibition, which is mostly about contrast. Horizontal cells receive excitatory input from photoreceptors and send inhibitory input to all/neigboring photoreceptors. In this case (of an off-center receptive field), the surrounding horizontal cells are hyperpolarized in the presence of light. When horizontal cells are hyperpolarized, they send less inhibitory signals (recall that they send only inhibitory signals). The neighboring photoreceptor in an off/dark region is already depolarized in the absence of light, but because it receives less inhibition from its neighboring horizontal cells, it depolarizes even more and releases even more glutamate. It is this "even more" effect of modulation by horizontal cells that increases border contrast and causes shades to stand out more when placed next to one another.

My rating of this article: ⭐⭐

Further reading: Center–Surround Receptive Field

In the News: Edition 2

Article: Of Fake Scholarship and Academic Integrity
Source: EyeNet
Published: February 20, 2021

As with the first EyeNet opinion piece of 2021, I generally agree with this perspective, this time about genuine representation, about publishing integrity, about the invisible hard work of editors. I agree with it more than meets the eye. Where this opinion piece is relevant to eye care is in its reference to the use of hydroxychloroquine for the treatment of COVID-19. Eye doctors are familiar with the drug by way of monitoring for adverse effects of retinal toxicity. Hydroxychloroquine (Plaquenil) was originally a drug for malaria, and also has uses in various rheumatologic and dermatologic conditions. Used for these inflammatory and skin-related conditions, hydroxychloroquine is an effective drug. One might even say that the drug design was catered for a specific disease or range of diseases. Because of hydroxychloroquine's popularity, some in the medical community sought its use as a potential treatment for the novel coronavirus. Some even imposed upon this drug the unintended use in pediatrics, which demonstrates the strength of the desire for a cure against COVID-19. Hydroxychloroquine is not FDA-approved for this form of treatment—a fact often repeated, to say the least—though the scientific curiosity and humanistic motivation to pursue this line of therapy were commendable. That being said, transparency of the scientific process was a prudent move on the part of researchers, so as to avoid false advertisement and misrepresentation while testing this therapy. That hydroxychloroquine works exceedingly well for some conditions does not mean it should be coaxed into use for other conditions. Despite hydroxychloroquine's abysmal results as a treatment for COVID-19, we can both—nay, we can all—laugh at the fact that it still appears in the news.