Article: Cell-replacement Therapies for Visual System Disorders
Source: Vanderbilt University Medical Center, via NEI
Published: July 30, 2021
 |
| Neurons (green) and their supporting astrocytes (violet), created in a petri dish from stem cells |
Article: Scientists uncover how decisions about what we see are relayed back through the brain
Source: National Institutes of Health, via NEI and ScienceDaily
Published: July 27, 2021
Researchers studying how decisions based on visual information is made, in both forward and backward pathways, is broadcast widely to neurons in the visual system. Feedback, such as visual information about color or shape, help the brain to focus on visual information relevant to decision-making. When a decision is based on what we see, information about expectation (such as a pedestrian on a crosswalk) or attention (like the color of a shirt) is relayed to brain regions involved in visual processing, raising the activity of neurons involved in that object or event. Such feedback might help the brain to focus on difficult-to-see features or help stabilize the decision being made. Some scientists have wondered what happens when two different types of information are relevant to a decision at the same time. To test the question of whether feedback is specific to each type of information, and selective for each decision, the researchers trained monkeys to distinguish whether an object on a screen in a particular location
looked concave or convex, while ignoring objects in irrelevant locations. The researchers measured the monkeys' neuronal activity involved in processing visual information while the animals were performing the task. They then tested whether decision-related feedback was selective for both location and depth. According to the news article, "Similar to previous studies, they found that location feedback is
selective, but location feedback didn’t vary depending on the decision
the animal made, it was only associated the location that the animal was
paying attention to. Conversely, feedback related to the object’s depth
was associated with the decision, but was spatially unselective,
meaning that even depth-sensing neurons that couldn’t possibly be used
to make the decision got extra decision-related feedback anyway."
My rating of this study:
Quinn KR, Seillier L, Butts DA, et al. “Decision-related
feedback in visual cortex lacks spatial selectivity.” Nature Communications. 22 July
2021. https://doi.org/10.1038/s41467-021-24629-0
Corneal Confocal Microscopy Identifies Corneal Nerve Fiber Loss in Patients with Long COVID
Long COVID is defined as "signs and symptoms that develop during or
following an infection
consistent with COVID-19 and which continue for more than 4 weeks and
are not explained by an alternative diagnosis," according to the
National Institute for Health and Care Excellence (NICE) in England.
Long COVID affects at least 10% of individuals who have recovered from
acute SARS-CoV-2 infection, with symptoms ranging from headaches and
"brain fog" to numbness and neuropathic pain. The presence of neurologic
symptoms prompted researchers to investigate whether an imaging
technique called corneal confocal microscopy (CCM) can be used to
identify underlying nerve damage in patients with long COVID. A quick
and non-invasive technique for real-time imaging of corneal nerve
fibers, corneal confocal microscopy is useful in identifying tell-tale
signs of corneal nerve damage in neurodegenerative diseases such as
diabetic neuropathy and multiple sclerosis, and now long COVID, as
indicators of nerve damage elsewhere in the body. The present study
examined 40 patients who had recovered from COVID-19 three to four
months previously, and compared them with 30 healthy control
participants who never had the disease. They found evidence of both
nerve damage and increased dendritic cells (a type of immune cell) in
the corneas of individuals with long COVID, with the severity of nerve
damage correlated with the severity of
disease at presentation. Based on their findings, the authors argue that
CCM has the potential to be a valuable diagnostic tool to diagnose and
assess cases of long COVID. One of the researchers adds, "The
identification of underlying nerve damage also allows us to think
about this condition as a neurodegenerative disease, which may be
amenable to treatment.”
CaMKII Gene Therapy Preserves RGC Axons & Somas
Some conditions, such as excitotoxicity and retinal ischemia, injure the
retinal ganglion cell (RGC) soma, while damage to the retinal ganglion
cell axon can result from optic nerve transection, compression,
intracranial hypertension, and glaucoma. A neuroprotective therapy that
preserves both RGC axons and somas would therefore have wide-ranging
benefit. Researchers are investigating the potential of calcium /
calmodulin-dependent protein kinase II (CaMKII) as a target for gene
therapy to protect RGCs from diverse pathological insults and ultimately
preserve vision. Studies in small animal models indicate that damage to
RGC somas or optic nerve axons led to inactivation of CaMKII and its
downstream signaling target, cAMP response element binding protein
(CREB). However, reactivation of CaMKII and CREB provided robust
protection for retinal ganglion cells. For example, experiments wherein
CaMKII was delivered via adeno-associated viral vector to mice just
prior to the toxic insult or just after optic nerve crush led to
increased CaMKII activity and robust protection of retinal ganglion
cells. In particular, the gene therapy introduced a more active version
of CaMKII with a modified amino acid to boost their activity in RGCs.
The researchers then tested the modified enzyme in a range of injury and
disease animal models, including two models of glaucoma for both high
and normal intraocular pressure. The results indicated that among gene
therapy-treated mice, 77% of
retinal ganglion cells survived 12 months after the toxic insult
compared with 8% in control mice, and six months following optic nerve
crush, 77% of retinal ganglion cells had survived versus 7% in controls.
The mice treated with CaMKII gene therapy also showed preserved
function for visually-guided behavior such as finding a submerged
platform, depth perception, and avoiding overhead shadows (simulated
predators). Further research in larger animal models is warranted to
better characterize the precise role of CaMKII, which might vary
depending on different conditions, before starting clinical trials.
Nonetheless, as one of the researchers highlights, the fact that gene
therapy with CaMKII would involve a one-time transfer
of a single gene adds to its vast potential to treat many retinal
and optic nerve conditions.
Wearable Collision-Warning Device for Blind and Visually Impaired People
For individuals with visual impairment or blindness, collisions and
falls are a common risk in independent daily life. The use of mobility
aids such long canes and guide dogs can offer benefits, but also come
with limitations. For example, a long cane primarily detects hazards on
the ground, often missing hazards above ground level. The range of long
cane sweeping is also limited and not always appropriate in busy
settings with many pedestrians. Guide dogs are highly effective but can
be cost-prohibitive, as training a guide dog typically costs
$45,000-$60,000. Vision rehabilitation researchers at Harvard developed
and tested a wearable collision-warning device as an added safety
measure to reduce collisions, for use along with the conventional long
cane. The device uses a chest-mounted wide-angle camera connected to a
processing unit that records video and analyzes
collision risk based on the relative movement of incoming and
surrounding objects in the camera’s field of view. This information is
relayed to two Bluetooth-connected wristbands worn by the user, which
vibrate on either or both wrists depending on the location of the
imminent object, with both wristbands vibrating to indicate an object
directly ahead. Notably, this device analyzes relative
motion, warning only of approaching obstacles that pose a collision
risk and ignoring objects that are not on a collision course. The
researchers then conducted a randomized-controlled trial involving 31
blind or severely visually impaired adults who, after training, were
instructed to use the device at home for 4 weeks, in conjunction with
their existing mobility aids. The device was randomized (double-masked)
to switch between active and silent modes, with silent mode replicating
the placebo condition, only recording but not alerting the user. The
results showed that the collision frequency in active mode was 37% less
than that in silent mode, demonstrating the potential benefit of the
device, especially as a more affordable option than a guide dog. One of
the authors adds that the video recordings from the device can also
provide rich data about daily mobility life and challenges for people
with visual impairment to improve mobility aid training. The researchers
plan on ongoing technical improvements in device processing power and
cosmesis.
Progress in SD-OCT Algorithms to Detect Early Biomarkers of Diabetic Retinopathy
Researchers conducted a study of spectral-domain ocular coherence
tomography (SD-OCT) algorithms to detect early biomarkers in diabetic
retinas. One of the study authors argues, "Many algorithms use any image
information that differs between diabetic
patients and controls, which can identify which individuals might have
diabetes, but these can be nonspecific... Our method can be
combined with the other AI methods to provide early information
localized to specific retinal layers or types of tissues, which allows
inclusion of information not analyzed in the other algorithms." In
particular, they compared the SD-OCT images of 33 diabetic patients
(without diabetic macular edema) with 33 age-matched control
participants. According to their results, "Diabetic retinas, although
not thicker than controls, had subtle but
quantifiable pattern changes in SD-OCT images particularly in deeper
fundus layers. The size range and distribution of this pattern in
diabetic eyes were consistent with small blood vessel abnormalities and
leakage of lipid and fluid. Feature-based biomarkers may augment retinal
thickness criteria for management of diabetic eye complications, and
may detect early changes."
Hippocampus Needed to Recognize Image Sequences
While the mammalian brain stores images in the visual cortex, new research shows that the
ability to recognize a sequence of images depends on the hippocampus, a
brain structure associated with memory. The hippocampus essentially
influences how the images are stored in the cortex if they have a
sequential relationship, but does not affect the encoding of simple
visual stimuli in the cortex. In their experiments, the researchers
trained mice with two forms of visual recognition memory: (1) stimulus
selective response plasticity (SRP), which involves
learning to recognize a non-rewarding, non-threatening single visual
stimulus after it has been presented over and over, eventually leading
to disinterest, and (2) visual sequence plasticity, which involves learning to recognize and predict a sequence of images. Visual sequence plasticity also evokes an elevated electrical response if the stimulus is novel. This response is much
greater than what is observed if the same stimuli are presented in
reverse order or at a different speed. To test the role of the
hippocampus, the researchers chemically removed large portions of the structure in mice and examined the tell-tale electrical response each kind of recognition memory should evoke. Mice
with or without a hippocampus performed equally well in learning SRP,
suggesting that the hippocampus was not needed to form that kind of
memory. However, mice lacking an intact hippocampus did not perform well
in visual sequence plasticity, showing no elevated electrical response to the
sequences, no ability to recognize them in reverse or when
delayed and no inclination to "fill in the blank" when one was missing. The experiments reveal there is a "division of labor" for many
different forms of memory, in this case between simple recognition of images and the more complex recognition of image sequence, only
the latter of which involves the hippocampus. Because SRP and visual
sequence plasticity involve different brain circuits, the researchers
next plan to explore whether those differences can help to diagnose
neurodegenerative diseases such as dementia.
In Other News
(1) Motor control and eye tracking in autism spectrum disorder
(2) A patient's story about his experience with low vision
(3) More to pictures than meets the eye
Article: Brain’s “memory center” is needed to recognize image sequences, but not single sights
Source: Picower Institute for Learning and Memory at MIT, via ScienceDaily
Published: July 26, 2021
While the mammalian brain stores images in the visual cortex, new research shows that the ability to recognize a sequence of images depends on the hippocampus, a brain structure associated with memory. The hippocampus essentially influences how the images are stored in the cortex if they have a sequential relationship, but does not affect the encoding of simple visual stimuli in the cortex. In their experiments, the researchers trained mice with two forms of visual recognition memory: (1) stimulus selective response plasticity (SRP), which involves learning to recognize a non-rewarding, non-threatening single visual stimulus after it has been presented over and over, eventually leading to disinterest, and (2) visual sequence plasticity, which involves learning to recognize and predict a sequence of images. Visual sequence plasticity also evokes an elevated electrical response if the stimulus is novel. This response is much greater than what is observed if the same stimuli are presented in reverse order or at a different speed. To test the role of the hippocampus, the researchers chemically removed large portions of the structure in mice and examined the tell-tale electrical response each kind of recognition memory should evoke. Mice with or without a hippocampus performed equally well in learning SRP, suggesting that the hippocampus was not needed to form that kind of memory. However, mice lacking an intact hippocampus did not perform well in visual sequence plasticity, showing no elevated electrical response to the
sequences, no ability to recognize them in reverse or when
delayed and no inclination to "fill in the blank" when one was missing. The experiments reveal there is a "division of labor" for many
different forms of memory, in this case between simple recognition of images and the more complex recognition of image sequence, only the latter of which involves the hippocampus. Because SRP and visual sequence plasticity involve different brain circuits, the researchers next plan to explore whether those differences can help to diagnose neurodegenerative diseases such as dementia.
My rating of this study:
.
"The spatiotemporal organization of experience dictates hippocampal involvement in primary visual cortical plasticity." Current Biology. 26 July 2021. https://doi.org/10.1016/j.cub.2021.06.079
Article: New biomarkers may detect early eye changes that can lead to diabetes-related blindness
Source: Indiana University School of Optometry, via ScienceDaily and NEI
Published: July 26, 2021
Article: Something in Patients' Eyes Could Reveal The Presence of 'Long COVID'
Source: ScienceAlert
Published: July 26, 2021
Article: ...researchers use pioneering eye exam to identify nerve damage in long COVID patients
Source: Weill Cornell Medicine-Qatar (Qatar)
Published: August 9, 2021
 |
| CCM images in a healthy patient (A), a patient with long COVID (B), and a patient with COVID-19 (C) |
My rating of this study:
.
"Corneal confocal microscopy identifies corneal nerve fibre loss and increased dendritic cells in patients with long COVID." British Journal of Ophthalmology. 26 July 2021. https://doi.org/10.1136/bjophthalmol-2021-319450
Article: Gene Therapy May Preserve Vision in Retinal Disease and Serious Retinal Injury
Source: Icahn School of Medicine at Mount Sinai
Published: July 22, 2021
Article: Scientists discover gene therapy provides neuroprotection to prevent glaucoma vision loss
Source: National Eye Institute
Published: July 22, 2021
Article: Gene Therapy Protects Optic Nerve Cells and Vision in Mice with Retinal Injury and Glaucoma
Source: Genetic Engineering & Biotechnology News
Published: July 23, 2021
 |
| Graphical abstract |
Article: Wearable Devices Can Reduce Collision Risk in Blind and Visually Impaired People
Source: Massachusetts Eye and Ear Infirmary, via ScienceDaily
Published: July 22, 2021
For individuals with visual impairment or blindness, collisions and falls are a common risk in independent daily life. The use of mobility aids such long canes and guide dogs can offer benefits, but also come with limitations. For example, a long cane primarily detects hazards on the ground, often missing hazards above ground level. The range of long cane sweeping is also limited and not always appropriate in busy settings with many pedestrians. Guide dogs are highly effective but can be cost-prohibitive, as training a guide dog typically costs $45,000-$60,000. Vision rehabilitation researchers at Harvard developed and tested a wearable collision-warning device as an added safety measure to reduce collisions, for use along with the conventional long cane. The device uses a chest-mounted wide-angle camera connected to a processing unit that records video and analyzes
collision risk based on the relative movement of incoming and
surrounding objects in the camera’s field of view. This information is relayed to two Bluetooth-connected wristbands worn by the user, which vibrate on either or both wrists depending on the location of the imminent object, with both wristbands vibrating to indicate an object directly ahead. Notably, this device analyzes relative
motion, warning only of approaching obstacles that pose a collision
risk and ignoring objects that are not on a collision course. The researchers then conducted a randomized-controlled trial involving 31 blind or severely visually impaired adults who, after training, were instructed to use the device at home for 4 weeks, in conjunction with their existing mobility aids. The device was randomized (double-masked) to switch between active and silent modes, with silent mode replicating the placebo condition, only recording but not alerting the user. The results showed that the collision frequency in active mode was 37% less than that in silent mode, demonstrating the potential benefit of the device, especially as a more affordable option than a guide dog. One of the authors adds that the video recordings from the device can also provide rich data about daily mobility life and challenges for people with visual impairment to improve mobility aid training. The researchers plan on ongoing technical improvements in device processing power and cosmesis.
My rating of this study: 🌸
.
"Home-Use Evaluation of a Wearable Collision Warning Device for Individuals With Severe Vision Impairments: A Randomized Clinical Trial." JAMA Ophthalmology. 22 July 2021.
Article: Larger pupils? You might just have gained someone’s trust
Source: Leiden University (Netherlands)
Published: March 2, 2021
As part of a PhD dissertation, a junior researcher in the Netherlands conducted several experiments exploring synchrony of physiological responses, such as pupil size, and aspects of social interaction like trust. Known as autonomic mimicry, we humans can align our physiological responses with one another through involuntary non-verbal signals. Prior studies had investigated larger movements, such as facial expressions and body language in synchrony of social interaction. Advances in technology to measure eye movements and pupil diameter allowed for studies of more subtle responses. The researcher in this case conducted an experiment in which human participants played a "trust game" with a computer simulation while their pupil diameter was measured. According to the news article, "The results showed
that in social interactions where the computer simulations’ pupils were
larger, the subject trusted the simulation more and mimicked the pupil
diameter of the simulation. In an interaction where the simulations’
pupils were smaller, the subjects seemed to trust the simulation
significantly less." The now post-doc also explored whether partially blocking sight influenced the response, but cautions that such research is still in development. For more information about the topic, see her blog post from 2018 and the corresponding journal article.
My rating of this study:
New Genetic Test Improves Detection of Glaucoma Risk
Often called the silent thief of sight, glaucoma is a complex eye
disease that results from irreversible damage to the optic nerve. Early
screening and detection well before vision loss can inform clinical
decisions and thereby potentially improve quality of life for patients.
This early diagnosis of glaucoma often comes from clinical assessments;
however, researchers in Australia are exploring genetic variation as a promising indicator of disease risk stratification. As tested in a sample of 2,507 individuals with open-angle glaucoma from the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG), along with clinical and genetic data from 411,337 individuals in cross-sectional cohort studies from the UK Biobank (between 2006 and 2010),
the researchers report that their new genetic test can identify high
polygenic risk of glaucoma (top 5% of the population) comparable to
heterozygous monogenic risk (specifically for the MYOC p.Gln368Ter
variant, the most common single-gene variant known to cause primary
open-angle glaucoma), but is more than 15 times more prevalent in the
general population (and more than 6 times more common in ANZRAG). The
study concludes, "Monogenic and high polygenic risk were each associated with a more
than 2.5-fold increased odds of developing glaucoma and an equivalent
mean age at glaucoma diagnosis, with high polygenic risk more than 15
times more common in the general population." In other words,
while both monogenic risk and high polygenic risk for open-angle
glaucoma are equal, polygenic risk is much more prevalent, and their new
genetic test can detect that risk from the contribution of multiple
genes. The senior author of the study comments, “Genetic testing is not
currently a routine part of glaucoma diagnosis
and care, but this test has the potential to change that. We’re now in a
strong position to start testing this in clinical trials” to begin in
2022.
Elevated Complement Factor H-Related Proteins is Associated with Increased Risk of AMD
Researchers in the U.K. and Germany conducted a genome-wide association
study to investigate genetic variants that determine increased risk of
AMD. From 604 blood plasma samples, they identified five proteins,
Complement Factor H-Related 1 to 5 (CFHR-1 to CFHR-5), as being higher
in individuals with age-related macular degeneration (AMD) than those
without the disease. These FHR proteins are part of the complement
pathway of the innate immune system. In AMD, the complement pathway is
over-activated in the back of the eye, specifically in the
intercapillary septa of the retinal pigment epithelium/Bruch's
membrane/choriocapillaris (RPE/BrM/CC) complex, leading to a damaging
inflammatory response. The findings are novel in the sense that they
expand upon earlier information pointing to only Complement Factor H and
its protein FH as being implicated in AMD pathogenesis. The study also
employed technological advances in mass spectrometry to measure the
levels of these proteins, which are usually present at low levels in the
blood and are very similar to each other. The researchers emphasize
that the study demonstrates association and that research of studies
over time would be needed to predict risk. However, the results are the
first step toward developing tests to predict risk of AMD and potential
treatments. While elevated levels of each of the five FHR proteins is
associated with AMD risk, the inflammation pathway is not the only
driver of AMD. Therefore, being able to measure levels of these proteins
would help to identify patients who would best benefit from FHR-targeting therapies.
HtrA1 Augmentation as Potential Therapy for AMD
Age-related macular degeneration (AMD) is the leading cause of
irreversible blindness in individuals over the age of 55. Fifteen years
of research identified HtrA1 protein, a serine protease enzyme encoded
by the HTRA1 gene, as normally increasing with age in the retinal
pigmented epithelium (RPE)-Bruch’s membrane interface, and helps to
maintain normal RPE function to deliver nutrients and remove waste from
the eye's photoreceptors. The present research shows that individuals
with AMD-associated risk variants located on chromosome 10 have impaired
expression of the HTRA1 gene, resulting in approximately 50% reduction
in HtrA1 protein levels at the RPE-Bruch’s membrane interface during
aging. The resulting dysfunction leads to abnormal deposits and blood
vessels characteristic of AMD. The team found that reduced HTRA1 mRNA
was only a risk factor in the RPE, and not in the neural retina or the choroid.
According to the lead author of the study, seeing HtaA1 as protective
in maintaining the RPE-Bruch's membrane interface is unexpected, given
that HtrA1 protein is thought to contribute to diseases such as
osteoarthritis.
The discovery, however, was made possible by a unique
repository of more than 8,000 pairs of donated human
eyes to sample chromosome 10-directed AMD, narrowing down a smaller
region of chromosome 10 that is likely responsible for reduced
expression of HTRA1, and specifically studying HTRA1 expression in the
RPE-Bruch’s membrane interface (the primary site of AMD pathogenesis)
compared to the neural retina or white blood cells as was done in prior
studies. The senior researcher adds, “Unfortunately, data
generated by prior studies have led to the
development and testing of therapies—some of which are currently in
human clinical trials—designed to reduce overall levels of HtrA1, an
approach that may exacerbate AMD progression.” While such contradictions
might seem alarming, novel discoveries that expand and refresh the
literature, and discussion about findings of different research studies,
are commonplace in the scientific enterprise, including biomedical
research. The research team is currently working on therapies for
individuals with AMD due to mutations in chromosome 1 or chromosome 10,
which, according to the researchers, together account for more than 50%
of the genetic risk for developing AMD.
KCN1 Suppresses Metastatic Uveal Melanoma, in Mice
Uveal melanoma (UM) is a type of cancer of the vascular, pigmented
middle layer of the eye, the uvea. Though rare among cancers, uveal
melanoma is the most prevalent primary intraocular malignancy in adults
and can be both vision- and life-threatening as the cancer metastasizes
to other tissues of the body. Researchers have identified an inhibitory
molecule, arylsulfonamide KCN1, that dampens drivers of tumorgenesis in
animal models, limiting both the primary disease in the eye and
metastatic tumor dissemination to
the liver. The animals treated with KCN1 also survived longer, without
overt side effects. Tumor progression and metastasis in uveal melanoma
is associated with hypoxia-inducible transcription factor (HIF), which
turns on many gene products that promote cancer growth, including
proliferation, migration, invasion and adhesion of tumor cells as well
as angiogenesis to feed the tumor. Two of these gene products, P4HA1 and
P4HA2, promote collagen deposition in the extracellular matrix, which
in turn reorganizes the extracellular matrix in a way that aids cancer
progression and tumor cell invasion. Comparison of 46 patients with
non-metastatic UM and 46 with metastatic
UM showed that P4HA1 and P4HA2 were significantly overexpressed in
patients with
metastatic disease, and furthermore correlated with poor survival
outcomes in UM patients, suggesting that P4HA1 and P4HA2 could serve as
prognostic markers in UM. When tested in human UM cell lines, the
researchers found that P4HA1 and P4HA2 were induced by hypoxia, and this
induction was reduced by KCN1. In animal models injected
(intraperitoneally) with KCN1, the molecule was abundantly taken up in
the liver and in the eyes. KCN1 dampened tumor growth in the eye and
reduced metastases in the liver, especially when administered early.
Although the study suggests that “KCN1 has desirable properties as a
suppressor of
metastasis: It is well tolerated, has excellent distribution to the eye
and the liver, and is thus ideally suited for treating metastatic UM,"
the researchers also caution that the drug needs further optimization
before clinical use.
Gene Splicing Dysfunction in Usher Syndrome
Usher syndrome (USH) is the most common cause of combined hereditary
deafness and blindness. Alternatively known as retinitis
pigmentosa–dysacusis syndrome, vision loss results from progressive
degeneration of the photoreceptors in the retina (RP in this case)
within the first or second decade of life. More than a dozen genes and loci
have been identified as contributing to the disease; however, its
pathophysiology is not completely understood. Researchers in Germany
investigating the pathological mechanism underlying Usher syndrome
discovered that defects in a protein called SANS, synthesized from a
gene named Usher syndrome type 1G (USH1G), leads to errors in pre-mRNA
splicing related to cell division, ultimately leading to ciliopathy of
the photoreceptors (and hair cells in the inner ear, accounting for the
deafness aspect of the syndrome). Specifically, the authors explained,
"We show that SANS is found in Cajal bodies and nuclear speckles, where
it interacts with components of spliceosomal sub-complexes such as SF3B1
and the large splicing cofactor SON but also with PRPFs and snRNAs
related to the tri-snRNP complex. SANS is required for the transfer of
tri-snRNPs between Cajal bodies and nuclear speckles for spliceosome
assembly and may also participate in snRNP recycling back to Cajal
bodies." This new finding contrasts with earlier thinking that SANS was
simply a scaffold molecule that participates in transport processes in
the cytosol and cilia at the cell surface. Lack or dysfunction of SANS
prevents the spliceosome in the nucleus from being
correctly assembled and activated, without which genes are not correctly
spliced, ultimately leading to the clinical
manifestation of Usher syndrome.
In Other News
(1) Consumer Health: Are contact lenses right for you?
(2) Link between dual sensory loss and depression
(3) Wet AMD treatment breakthroughs/updates
How the Brain Relies on Sight in the Absence of Touch
Somatosensation, the combined sense of touch and proprioception, is
integral to how we navigate our body in space. We are aware of our
embodiment even when we close our eyes. But what happens when we lack
this sensory experience from our body, and how does our brain adapt? How
do other senses, notably sight, compensate to generate a sense of the
body? Researchers recently had that opportunity to study two unique
individuals without somatosensation, one case acquired, the other congenital. Ian from the U.K. developed a complete loss of his sense of
touch and proprioception (the awareness of our body's position and
movement) below the neck at age 19 after what is believed to be an
autoimmune response after illness; Ian required months of rehabilitation
to learn to move his body and limbs again. Kim from the U.S., on the
other hand, was born without sensory nerve fibers to feel her body,
consequently possessing neither touch sensation nor proprioception.
For
the study, Ian and Kim, along with age-matched controls, participated
in experiments designed to assess their mental image of
their bodies and their unconscious sense of their bodies in space. The
researchers found that Kim's representation of her hand was closer to
that of the controls in that both were distorted; for the controls, this
is due to a distorted sensory map. Ian, by contrast, had a more accurate
representation of his hand compared to Kim and the controls. The
investigators hypothesize that the greater accuracy is because Ian's
hands are always under his conscious control. In an experiment related
to body schema, the researchers looked at how the participants reacted
when a visual target appeared near their hand, i.e., within their
peri-personal space. Those with intact proprioception would react
rapidly. They found that Kim's results closely matched the controls
compared to Ian's, suggesting that Kim has an unconscious representation
of her body despite never having been able to feel it. This is similar
to the way a person will instinctively duck when a ball
flies toward them, even before consciously processing what the object
is. Ian, however, relies on much slower processes involving conscious
visual perception. The differences between Ian's and Kim's conditions
highlight how conscious compensatory mechanisms developed in adulthood
after sensory loss differ from the neuronal reorganization that might
occur in a person born without that sense. However, whether
unconsciously or consciously, we all arrive at a sense of self. As one
of the researchers concludes, "What we can learn from this is that you
might not do it in the way that
others do it, but you will find a way to make a body schema. You will
find a way to make a sense of yourself."
Interhemispheric Transfer of Visual Working Memory
When we shift our gaze around to look at a scene, or even temporarily
turn away, we rely on visual working memory to retain what we see in
mind. The ability to hold that memory enables volitional control of our
actions, allowing us to decide to react to something now or later. This
visual working memory is a cognitively interesting feat, given that our
left visual hemifields correspond to our right cerebral hemisphere, and
our right visual hemifields correspond to our left cerebral hemisphere.
New research by neuroscientists at MIT, using animal primate models,
found that when an object shifts across our field of
view, either because it moved or because our eyes did, the brain immediately
transfers a memory of it to the opposite (contralateral) brain hemisphere, in particular, to a group of neurons in the prefrontal cortex.
Remarkably, even though the new group of neurons encodes the object in
the new position, the brain continues to recognize it as the same object
that had been in the other hemisphere's field of view. That being said,
results in monkeys indicate decreased performance in cases where the
monkeys had to shift their gaze, suggesting that shifting gaze requires
extra cerebral processing. This switch from one side of one's field of
view to the other is accompanied by a signature change in the rhythm of
brain wave frequencies to transfer the memory information from one side
of the brain to the other. The news article explains, "As
the transfer occurred, the synchrony across
hemispheres of very low frequency 'theta' waves (~4-10 Hz) and high
frequency 'beta' waves (~17-40 Hz) rose and the synchrony of
'alpha/beta' waves (~11-17 Hz) declined." The lead author of the study
adds, “This
is another form of gating. This time alpha/beta is gating the memory
transfer between hemispheres.” Perhaps the most surprising discovery
from the experiments was that the
prefrontal cortex uses different neurons to encode the memory of an
object depending on whether the object (in the same spot of the visual
field) was initially seen at that location or transferred there from the
other hemisphere. The scientific implication of that finding is the
idea that even the same information could still be encoded by different, arbitrarily assembled ensembles of neurons.
Radiology Insights into COVID-19 Ocular Abnormalities
The COVID-19 pandemic has affected the entire globe since its onset in
early 2020, including impact in all specialties of healthcare. Within
ophthalmology, SARS-CoV-2 has been linked with ocular complications from
conjunctivitis to retinopathy. Insight from radiology provides
additional clues of ocular abnormalities in individuals with severe
COVID-19. A study by researchers at the French Society of Neuroradiology
(SFNR), from a sample of 129 patients with severe COVID-19 who
underwent brain MRI, found that nine of those patients, eight of whom
had spent time in the intensive care unit (ICU) for COVID-19, had
abnormal MRI findings of the globe. Specifically, the MRI scans showed
one or more nodules in the posterior pole, the first time these findings
have been described using MRI. The nodules occurred in the macular
region in all nine patients, eight of whom showed a bilateral
presentation and two of whom additionally had nodules beyond the macula.
The mechanism of nodule formation is unknown, although the researchers
speculate a relation to inflammation triggered by the virus as well as
inadequate ocular venous drainage while prone or intubated during
hospitalization. This study aligns with other research showing that
COVID-19 has greater impact on those with preexisting health conditions;
among the nine patients with eye nodules, two had diabetes, six were
obese, and two had hypertension. Eight of the nine patients were men.
The researchers will monitor the COVID-19 survivors to see if there is
any visual impairment from the nodules. The first author of the study
comments that because patients with severe COVID-19 are often being
treated for much more severe, life-threatening conditions, eye problems
could go unnoticed in the clinic. He states, “Our study advocates for
screening of all patients hospitalized in
the ICU for severe COVID-19. We believe those
patients should receive specific eye-protective treatments.”
Additionally, the researchers will conduct a prospective study with
dedicated high-resolution MRI to explore the eye and orbit in patients
with mild to moderate COVID-19.
Archeologists Examine a Color-Matching Device
Color perception, something most of us take for granted, is ultimately a
subjective and individual experience. The ability to perceive and
identify colors, however, becomes functionally relevant in some
professions, such as interior design and cosmetology, or even archeology
as in this case. Because color perception is subjective, scientists
were excited when a handheld color-matching gadget called the X-Rite
Capsure came on the market. Made by the same company that owns Pantone,
they had hoped that it would offer a consistent way of determining
color, free of human bias as well as variations in lighting, sample
quality, and observer perspective. However, a study by archeologists, to
whom the device was marketed to identify the color of artifacts and
soil samples, found that the X-Rite Capsure often misreads colors
readily distinguished by the human eye when tested against the Munsell
color
system, the current archeological standard for identifying colors using a
binder of 436 unique color chips. The study specifically tested the
Capsure's readings for all 436 color chips as well as 140 pottery
briquettes for the three elements of Munsell’s system: a color’s general
family (hue), intensity (chroma), and lightness (value). The details of
how the X-Rite Capsure differed from human observers in determining
color can be found in the articles. These differences are not
functionally trivial, however, since identifying subtle differences in
color gives information about a sample's composition, origins, and
history of use. Highlighting a device that is functionally relevant
within the field of archeology, the researchers argue, “We need to pay
really close attention and record how we’re describing color in order to
make good data. Ultimately, if we’re putting bad color data in, we’re
going to get bad data out.” Because the device is nonetheless internally
consistent in its color identifications, work remains to optimize the
advantages of such devices and artificial intelligence to match human
perception, arguably difficult for a quality as complex as color.
Literacy Screening Tool Developed for Young Children
“By screening early during pediatric
clinic visits, especially in practices serving disadvantaged families,
we can hopefully target effective interventions that help children
better prepare for kindergarten and improve reading outcomes,” the author of a book called The Reading House
offers. The researchers at Cincinnati Children's Hospital developed the
book (series) as a literacy screening tool for children ages 3 to 5 to
facilitate the early identification of reading difficulties in primary
care and preschool settings. The present study, involving 70 healthy
children (34 boys and 36 girls) between 3
and 5 years of age from various socioeconomic backgrounds, sought to
validate the book as a literacy screening tool. The
children completed standardized assessments of literacy
skills related to vocabulary, rhyming and rapid automatized naming.
Fifty-two of these children also completed
magnetic resonance imaging (MRI), including measurement of cortical
thickness, with thicker cortices (especially in the left hemisphere
involved with language processing) being predictive of better reading
outcomes. They found thicker gray matter cortex in the cerebral left
hemisphere in children with higher TRH scores. Higher TRH scores were
also strongly correlated with higher vocabulary,
rhyming and rapid naming scores, according to the researchers. Finally,
the researchers found that children from lower-SES households had a less
mature ("strained") cortical pattern and thinner cortices overall
compared to children from higher-SES households.
In Other News
(1) Color vision in butterflies
(2) Comprehensive eye exams before going back to school
(3) Can an experimental eye disease drug treat COVID-19 associated lung problems?
Article: HtrA1 Augmentation is Potential Therapy for Age-Related Macular Degeneration
Source: University of Utah Health, via NEI
Published: July 19, 2021
 |
| Analyses of HtrA1 protein in human donor ocular tissues (A–D), comparing homozygous nonrisk or risk genotype groups. Note that there is only a difference between nonrisk and risk in the RPE-choroid. |
Article: ...The human brain may tap into visual cues when lacking a sense of touch
Source: University of Chicago Medicine
Published: February 26, 2021
Article: Human brain taps into visual cues when lacking a sense of touch
Source: University of Birmingham (U.K.)
Published: February 18, 2021
Article: ...The brain compensates through visual cues when lacking sense of touch
Source: Bournemouth University (U.K.)
Published: February 16, 2021
Somatosensation, the combined sense of touch and proprioception, is integral to how we navigate our body in space. We are aware of our embodiment even when we close our eyes. But what happens when we lack this sensory experience from our body, and how does our brain adapt? How do other senses, notably sight, compensate to generate a sense of the body? Researchers recently had that opportunity to study two unique individuals without somatosensation, one case acquired, the other congenital. Ian from the U.K. developed a complete loss of his sense of touch and proprioception (the awareness of our body's position and movement) below the neck at age 19 after what is believed to be an autoimmune response after illness; Ian required months of rehabilitation to learn to move his body and limbs again. Kim from the U.S., on the other hand, was born without sensory nerve fibers to feel her body, consequently possessing neither touch sensation nor proprioception.
 |
| Kim's hand maps (top) and Ian's hand maps (bottom) |
Article: Glaucoma test ‘best yet’
Source: Flinders University (Australia), via ScienceDaily
Article: Glaucoma Prediction Improved by New Genetic Test
Source: Genetic Engineering & Biotechnology News
Published: July 16, 2021
Often called the silent thief of sight, glaucoma is a complex eye disease that results from irreversible damage to the optic nerve. Early screening and detection well before vision loss can inform clinical decisions and thereby potentially improve quality of life for patients. This early diagnosis of glaucoma often comes from clinical assessments; however, researchers in Australia are exploring genetic variation as a promising indicator of disease risk stratification. As tested in a sample of 2,507 individuals with open-angle glaucoma from the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG), along with clinical and genetic data from 411,337 individuals in cross-sectional cohort studies from the UK Biobank (between 2006 and 2010), the researchers report that their new genetic test can identify high polygenic risk of glaucoma (top 5% of the population) comparable to heterozygous monogenic risk (specifically for the MYOC p.Gln368Ter variant, the most common single-gene variant known to cause primary open-angle glaucoma), but is more than 15 times more prevalent in the general population (and more than 6 times more common in ANZRAG). The study concludes, "Monogenic and high polygenic risk were each associated with a more
than 2.5-fold increased odds of developing glaucoma and an equivalent
mean age at glaucoma diagnosis, with high polygenic risk more than 15
times more common in the general population." In other words, while both monogenic risk and high polygenic risk for open-angle glaucoma are equal, polygenic risk is much more prevalent, and their new genetic test can detect that risk from the contribution of multiple genes. The senior author of the study comments, “Genetic testing is not currently a routine part of glaucoma diagnosis
and care, but this test has the potential to change that. We’re now in a
strong position to start testing this in clinical trials” to begin in 2022.
My rating of this study: .
"Association of Monogenic and Polygenic Risk With the Prevalence of Open-Angle Glaucoma." JAMA Ophthalmology. 15 July 2021. https://doi.org/
Article: COVID-19 Linked to Potentially Dangerous Eye Abnormalities
Source: Radiological Society of North America
Published: February 16, 2021
Article: Melanoma of the eye: preclinical tests show path toward treatment
Source: University of Alabama at Birmingham, via ScienceDaily and NEI
Published: July 14, 2021
Uveal melanoma (UM) is a type of cancer of the vascular, pigmented middle layer of the eye, the uvea. Though rare among cancers, uveal melanoma is the most prevalent primary intraocular malignancy in adults and can be both vision- and life-threatening as the cancer metastasizes to other tissues of the body. Researchers have identified an inhibitory molecule, arylsulfonamide KCN1, that dampens drivers of tumorgenesis in animal models, limiting both the primary disease in the eye and metastatic tumor dissemination to
the liver. The animals treated with KCN1 also survived longer, without overt side effects. Tumor progression and metastasis in uveal melanoma is associated with hypoxia-inducible transcription factor (HIF), which turns on many gene products that promote cancer growth, including proliferation, migration, invasion and adhesion of tumor cells as well as angiogenesis to feed the tumor. Two of these gene products, P4HA1 and P4HA2, promote collagen deposition in the extracellular matrix, which in turn reorganizes the extracellular matrix in a way that aids cancer progression and tumor cell invasion. Comparison of 46 patients with non-metastatic UM and 46 with metastatic
UM showed that P4HA1 and P4HA2 were significantly overexpressed in patients with
metastatic disease, and furthermore correlated with poor survival outcomes in UM patients, suggesting that P4HA1 and P4HA2 could serve as prognostic markers in UM. When tested in human UM cell lines, the researchers found that P4HA1 and P4HA2 were induced by hypoxia, and this induction was reduced by KCN1. In animal models injected (intraperitoneally) with KCN1, the molecule was abundantly taken up in the liver and in the eyes. KCN1 dampened tumor growth in the eye and reduced metastases in the liver, especially when administered early. Although the study suggests that “KCN1 has desirable properties as a suppressor of
metastasis: It is well tolerated, has excellent distribution to the eye
and the liver, and is thus ideally suited for treating metastatic UM," the researchers also caution that the drug needs further optimization before clinical use.
Personal commentary: A direct quote from my notes regarding hypoxia-inducible transcription factor HIF-1, from August 20, 2018: "Toward
the end of the lecture, we learned about some of the nonstandard amino
acids. Of note in particular was hydroxylproline, which is an important
component of collagen, which in turn is an important component of both
skin and corneas. Hydroxylproline also acts as an oxygen sensor. In the
presence of oxygen, prolyl hydroxylase adds hydroxyl to proline residues
on transcription factor Hif-1, tagging it for ubiquitination. (HIF =
hypoxia-induced factor.) In hypoxia, proline is not hydroxylated, and
angiogenesis follows. Relevant to hypoxia-induced hyperemia and
vascular-related retinal diseases!!!"
My rating of this study:
. "Targeting HIF-activated collagen prolyl 4-hydroxylase expression disrupts collagen deposition and blocks primary and metastatic uveal melanoma growth." Oncogene. 3 July 2021. https://doi.org/10.1038/s41388-021-01919-x
Article: Human eye beats machine in archaeological color identification test
Source: University of Florida Museum of Natural History
Published: February 9, 2021
 |
| X-Rite Capsure device (right), along with color chips (left) and clay samples (top) |
. "Is It Better to Be Objectively Wrong or Subjectively Right? Testing the Accuracy and Consistency of the Munsell Capsure Spectrocolorimeter for Archaeological Applications." Advances in Archaeological Practice. 9(2):132-144. 8 February 2021. https://doi.org/10.1017/aap.2020.53
Article: Breakthrough into leading cause of blindness
Source: Queen Mary University of London (U.K.)
Published: July 13, 2021
Article: Breakthrough into leading cause of blindness
Source: University of Manchester (U.K.)
Published: July 14, 2021
Researchers in the U.K. and Germany conducted a genome-wide association study to investigate genetic variants that determine increased risk of AMD. From 604 blood plasma samples, they identified five proteins, Complement Factor H-Related 1 to 5 (CFHR-1 to CFHR-5), as being higher in individuals with age-related macular degeneration (AMD) than those without the disease. These FHR proteins are part of the complement pathway of the innate immune system. In AMD, the complement pathway is over-activated in the back of the eye, specifically in the intercapillary septa of the retinal pigment epithelium/Bruch's membrane/choriocapillaris (RPE/BrM/CC) complex, leading to a damaging inflammatory response. The findings are novel in the sense that they expand upon earlier information pointing to only Complement Factor H and its protein FH as being implicated in AMD pathogenesis. The study also employed technological advances in mass spectrometry to measure the levels of these proteins, which are usually present at low levels in the blood and are very similar to each other. The researchers emphasize that the study demonstrates association and that research of studies over time would be needed to predict risk. However, the results are the first step toward developing tests to predict risk of AMD and potential treatments. While elevated levels of each of the five FHR proteins is associated with AMD risk, the inflammation pathway is not the only driver of AMD. Therefore, being able to measure levels of these proteins would help to identify patients who would best benefit from FHR-targeting therapies.
My rating of this study:
. "Beyond factor H: The impact of genetic-risk variants for age-related macular degeneration on circulating factor-H-like 1 and factor-H-related protein concentrations." American Journal of Human Genetics. 13 July 2021. https://doi.org/10.1016/j.ajhg.2021.05.015
