Treatments targeting Neural Regeneration in Multiple Sclerosis

     Multiple Sclerosis is a chronic autoimmune disease that is distinguished by the destruction of the myelin sheaths within the central nervous system (CNS). With MS your body mistakenly attacks the myelin cells that surround your brain and spinal cord cells. The damaging of the myelin sheath results in nerve signal interruption in bodily functions such as vision, sensation and movement. Specifically, the immune system attacks the oligodendrocytes which are the glial cells responsible for producing myelin. Although the body initiates remyelination to some degree the overall repair process of these cells is left incomplete.

    Oligodendrocyte precursor cells are central to remyelination, and these precursor cells must develop and mature within the inflammatory environment of the central nervous system. Although current therapies focus primarily on immunomodulation and reducing inflammation often through the promotion of apoptosis in immune cells, there has been a growing demand for treatments that actively promote remyelination. There have been two recent developments within this world: the combined use of Sephin1 and bazedoxifene (BZA) to modulate the integrated stress response (ISR) and enhance oligodendrocyte differentiation, and PIPE-307 which is a new drug that promotes remyelination by targeted the muscarinic M1 receptor (M1R) on oligodendrocyte precursor cells. These therapies provide similar mechanisms of action, suggesting an effective strategy for repairing myelin in the inflamed CNS.

      In the study “Insights into the mechanism of oligodendrocyte protection and remyelination enhancement by the integrated stress response” by Dr. Yanan Chen et Al. , the researchers demonstrated that the ISR supports proteostasis and protects cells from stress-induced damage. In multiple sclerosis the ISR is activated in oligodendrocytes in response to inflammatory signals such as interferon-gamma (IFN-γ). In their research they discovered Sephin1, a small molecule that increases the ISR, as a possible therapeutic treatment. Sephin1 extends ISR activity, protecting oligodendrocytes and delaying demyelination even in the presence of IFN-γ. Sephin1 was also shown to prolong the phosphorylation of eIF2α, which led to the reduction of global protein synthesis and the promotion of forming RNA stress granules. When coupled with BZA, a drug that promotes the development of oligodendrocyte precursor cells, the combination therapy accelerated early remyelination in a mouse model and led to thicker myelin sheaths than either treatment just by itself. However, the combined therapy did not increase OPC proliferation in the presence of IFN-γ. It was found though that BZA increased OPC differentiation in vitro, suggesting that its major effect lay in encouraging maturation rather than cell growth. This explains the the uses of a coupled therapy: modulating the ISR while also boosting OPC differentiation as a useful method for repairing myelin degradation in MS.

    Alternatively, PIPE-307 has found to target the upstream effects of MS. PIPE-307 is believed to selectively inhibit the M1 receptor, which is significantly expressed in the oligodendrocyte precursor cells. The M1 receptor is also known to suppress the differentiation of the OPCs in inflammatory conditions. In mouse models of experimental autoimmune encephalomyelitis, which is a common animal model of multiple sclerosis, PIPE-307 therapy was found to increase the remyelination and strengthen other functions that were affected by MS. Furthermore, UCSF scientists Jonah Chan, PhD, and Ari Green, MD ,who were the ones who first discovered PIPE-307 therapy, found that in human brain tissue samples PIPE-307 was able to promote remyelination showing its practical potential. PIPE-307 is now also undergoing Phase II clinical trials (VISTA) for relapsing-remitting MS, where its effects on remyelination, visual acuity, cognition and motor function are being evaluated.

    Overall, these findings with the ISR-enhancing combination of Sephin1/BZA and the receptor-specific activity of PIPE-307 represent an important step towards neuroreparative approaches in the treatment of multiple sclerosis. As clinical studies progress integrating these treatments has the possibility to change how multiple sclerosis is treated and supports the transition from immune suppression and towards neural regeneration.

 

References

Chen Y, Quan S, Patil V, et al. Insights into the mechanism of oligodendrocyte protection and remyelination enhancement by the integrated stress response. 2023;71(9):2180-2195. doi:https://doi.org/10.1002/glia.24386

News N. New Multiple Sclerosis Drug Regenerates Myelin, Improves Movement - Neuroscience News. Neuroscience News. Published August 5, 2024. https://neurosciencenews.com/myelin-movement-ms-neuropharmacology-37518/

Wexler M. PIPE-307 shows potential to repair myelin in MS mouse model. Multiple Sclerosis News Today. Published August 8, 2024. https://multiplesclerosisnewstoday.com/news-posts/2024/08/08/pipe-307-shows-potential-repair-myelin-ms-mouse-model/

 

 

The Effects of COVID-19 on Elder Populations and Depression Rates

Relapse rates in late-life depression remain high even among those in remission. This suggests that there is a significant blind spot in the way older populations' mental health is evaluated and tracked. Researchers are turning to continuous digital monitoring to fill the gap. 

The study “Reconsidering Remission in Recurrent Late-Life Depression” by Taylor et al. and Grolli et al.'s “Impact of the COVID-19 Pandemic on Older Adults” highlights the vulnerabilities of this population. While Taylor et al. examine the risk of depression relapse in clinically remitted older adults, Grolli et al. investigate the pandemic’s psychological toll. Together, they reveal that traditional definitions of remission and episodic mental health evaluations and conventional definitions of remission might not be enough to protect aging individuals. Emerging digital tools, including smartphone usage analysis, sleep tracking, and passive monitoring, offer promising solutions to fill this gap. .

Taylor et al. question whether the term "remission" is appropriate for older adults who suffer from depression. According to their long-term research, more than one-third of patients who were considered to be in remission relapsed within two years. Interestingly, those who relapsed were more likely to experience higher levels of life stress and have weaker social support systems, but they were not more depressed at baseline. This implies that clinical evaluations might not adequately account for the mental health fragility of older populations, where psychosocial context is crucial.

Similarly, Grolli et al.’s rapid review underscores how the pandemic exacerbated pre-existing vulnerabilities in older adults. Isolation due to lockdowns, and reduced access to care amplified issues that “are already present in older adults, such as loneliness, age discrimination, and excessive worrying”(Lebrasseur et al.). Older adults also reported worsening sleep patterns, a well-documented early warning sign for depressive relapse. Both studies thus prove that social and environmental factors are powerful predictors of mental health outcomes in later life but often go unmeasured in clinical settings.

Digital health technologies offer a compelling answer to the concern of improving early detection and prevention of relapse in late-life mental illness. Recent literature supports the use of passive data collection, such as changes in phone usage, and sleep quality. 

Recent literature supports the use of passive data collection such as changes in phone activity, mobility patterns via GPS, and sleep quality through wearables to detect shifts in mental well-being. For example, a study published by the National Institute on Aging has an article titled “Depression and Older Adults” which has found that dysregulated sleep, eating, and a loss of interest in once pleasurable activities are factors found in depressed individuals who show no clinical symptoms during check-ups. These technologies offer real-time, ecologically valid insights that can complement traditional assessments and flag at-risk individuals before full relapse occurs.

There are still ethical issues, particularly about consent, privacy, and the digital divide. Nonetheless, wearable technology and smartphones are becoming more and more popular among senior citizens, which is creating opportunities for new forms of proactive, individualized care. Digital monitoring, if properly incorporated, may enable dynamic definitions of remission, ones that adjust to the lived experience of older people and prompt interventions when subtle warning indicators emerge.

In conclusion, Taylor et al. and Grolli et al. reveal that remission in older adults is not a fixed state but a fragile, often temporary condition shaped by life stress and isolation. The limitations of clinical assessments demand innovative solutions, and digital health tools may be key to predicting and preventing relapse. As we move toward a more technologically integrated healthcare landscape, both medical and social support must continue to be a top priority for elder care. 

References: 

Lebrasseur, Audrey, et al. “Impact of the COVID-19 Pandemic on Older Adults: Rapid Review.” JMIR Aging, U.S. National Library of Medicine, 12 Apr. 2021, pmc.ncbi.nlm.nih.gov/articles/PMC8043147/.

Taylor, Warren D., et al. “Reconsidering Remission in Recurrent Late-Life Depression: Clinical Presentation and Phenotypic Predictors of Relapse Following Successful Antidepressant Treatment.” Psychological Medicine, U.S. National Library of Medicine, pubmed.ncbi.nlm.nih.gov/39773777/.

Depression and Older Adults | National Institute on Aging, www.nia.nih.gov/health/mental-and-emotional-health/depression-and-older-adults.

Sunk Cost: The Phenomenon that Continues to Drive People to the Worst

  The “Sunk Cost” fallacy has been a old and regular saying among many statisticians that has become common in humans today. The main place we see this phenomenon is in gambling. Many casinos use it in manipulative ways such as using flashing lights, or displaying previous winners, but most importantly just how the games are staged. Most games are built with rules to just barely delivery defeat to those playing, but this ride on the edge brings many players to go further, to push their odds and claim that they are “due” for a win, despite the odds being the same before and after playing. Many scientists have researched if this fallacy has an application in other species, or if humans are solely driven by these irrational thoughts. Many believe it to be the ladder, however research may show that its more complicated than you think.

Dr. Brian Sweis in his article Sensitivity to “Sunk Costs” in Mice, Rats, and Humans explains an experiment his lab conducted on both mice and rats as well as humans in order to see if these rodents have these thoughts too. The rodents were placed in a contraption called “restaurant row”, a room system connected with hallways, each with an offer of food. Each food pellet was flavored differently, and mice were offered a pellet when entering the room. They could either accept the pellet and eat it, or skip the wait and move onto the next room. Humans were given a similar task, as they were given 4 different categories of videos to watch and could either skip what they were offered, or watch the video. The humans specifically were told to rate the categories 1-4 after. Through both experiments, Dr Sweis was able to determine that there was actually some sort of mechanisms in the brain related to dealing with these problems, and that humans and rodents have very similar processes in pushing forward and invest more time and effort into completing a task with no actual guarantee of a solution. 

Further research from Koen Dijkstra and Ying-yi Hong in their article The Feeling of Throwing Good Money After Bad: The Role Of Affective Reaction in the Sunk Cost Fallacy further develops the idea around why people are affected by this and why it may stimulate further doing so. One of these ideas was that the sunk cost fallacy was built upon emotions of regret and guilt. This mainly relates to the gambling side of things, as there is guilt around losing maybe a families house, car or even life's savings in a game, and the phenomenon pushes those to continue to double down and try to regain those savings, or even try to win more. Another thing they bring up is when you are at a restaurant, despite eating the rest of the meal and being full, some people still cram a desert in. Even though they know they are full, sunk cost essentially tells them that this will be worth it. In the end, sometimes you end up overeating, sometimes you don’t, but the taste was still the same. There is a lot of research behind how the brain works around this phenomenon and its not just in Neuroscience. Psychologists try to understand as well why the brain does this in order to make predictions, as well as understand how to prevent things from happening.

Both the articles identify how strong this fallacy is, and how its not just a small thought process. This idea is wired into our brains in some way that maybe we will fully understand someday why it is. This idea that we are drawn towards doing something over and over again, despite the idea of failure, bad things or anything can happen. Gambling already has its issues, but the fact that we are drawn to lose more based on losing is an issue that needs to be understood. Even further is how strong this phenomenon is. If you lose $1000, the sunk cost fallacy draws use to spend more, and take bigger risks. There is no guarantee a wanted result is ever going to occur, and doubling down has the same odds as the first go, yet we are more enticed to go back even though we know something could go worse. That explanation itself sounds like an addiction, which is why it's often paired with it. Numerous times the rush of a win, or the striving to end a loss streak is what leads to addictions to things like gambling, and the sunk cost fallacy is whats turning the wheel.

References

Dijkstra, Koen, and Ying-Yi Hong. “The Feeling of Throwing Good Money after Bad: The Role of Affective Reaction in the Sunk-Cost Fallacy.” PloS One, U.S. National Library of Medicine, 8 Jan. 2019, https://pmc.ncbi.nlm.nih.gov/articles/PMC6324799/ Accessed 30 April, 2025.

Sweis, B. M., Abram, S. V., Schmidt, B. J., Seeland, K. D., MacDonald, A. W., Thomas, M. J., & Redish, A. D.“Sensitivity to “Sunk Costs” in Mice, Rats, and Humans” Science, https://www.science.org/doi/10.1126/science.aar8644 . Accessed 30 April, 2025. 

M2 and Cortico-Basal Ganglia Control of Fine Motor Function

    Bodily movement is one of the most important and easily observed brain functions. Movement can be seen through the gestures of an individual’s body, but also on the circuit and molecular/cellular levels. The motor cortex is responsible for the planning and initiation of movements, and there are several mechanisms for the fine-tuning of motor control.There are several regions and circuits of the brain that perform fine motor control functions, including the cortico-basal ganglia circuit, which A.J. Miller-Hansen studies in the paper Cortico-Basal Ganglia Plasticity in Motor Learning.

Miller-Hansen investigates the motor learning of mice on a rotarod over the course of eight days. As the mice continue to attempt not to fall off of the rotarod, they exhibit motor learning as their balance improves and their latency, or time taken to fall, increases. This motor learning is the result of plasticity, as long term potentiation and long term depression underlie this process. Miller-Hansen explains that spatial changes in connections and activity patterns occur in the cortico-basal circuit during motor learning. This also occurs in the motor cortex, showing that learning involves both the initiation of movement as well as the fine-tuning that occurs further downstream. Therefore, motor learning is a highly complex process in which spatial adaptations can be observed in many structures, indicating change in planning, initiation, and refining of motor function based on required actions. Furthermore, the process can be seen as an interaction between cortex and the basal ganglia.

Processes of motor control can have a significant contribution to the treatment of Parkinson’s Disease, as this is caused by the degeneration of dopaminergic cells involved in the regulation of movement. In the paper entitled Optogenetic Stimulation of the M2 Cortex Revert Motor Dysfunction in a Mouse Model of Parkinson’s Disease, Magno et al. tests the effectiveness of optogenetic stimulation on the secondary motor cortex. This manipulation leads to an improvement in the regulation of motor function in mice with Parkinson’s Disease. Once activated, the secondary motor cortex projects to the dorsal medial striatum, the location of the previously mentioned neuronal plasticity, to enable greater control of locomotor activity. 

The work of Miller-Hansen and Magno et al. displays a promising method of treating Parkinson’s Disease. While current treatment involves deep-brain stimulation, the secondary motor cortex and dorsomedial striatum can be targeted to aid individuals affected by Parkinson’s Disease by initiating upstream changes in electrical activity and synaptic plasticity. Therefore, the connection between the secondary motor cortex, dorsomedial striatum, and basal ganglia plays a critical role in the regulation of locomotor activity, providing a target for electrical stimulation to help regain locomotor control.

References

Roth, R. H., & Ding, J. B. (2024). Cortico-basal ganglia plasticity in motor learning. Neuron, 112(15), 2486–2502. https://doi.org/10.1016/j.neuron.2024.06.014

Magno et al. (2019). Optogenetic Stimulation of the M2 Cortex Reverts Motor Dysfunction in a Mouse Model of Parkinson’s Disease. Journal of Neuroscience, 37(17), 3234-3248. https://www.jneurosci.org/content/39/17/3234

Improving ISR, a cellular defense mechanism for inflammation

Cellular inflammation is a biological response triggered by harmful stimuli such as infection, toxins, or stress. Moderate inflammation triggers a protective mechanism essential for healing in our cells, however, chronic or uncontrolled inflammation can cause irreversible damage to cells and tissues. This persistent inflammatory state disrupts normal cellular function, leading to DNA damage, oxidative stress, and impaired cell signaling. Over time, such damage contributes to the development and progression of numerous diseases, including cancer, neurodegenerative diseases, and autoimmune conditions. Understanding the cellular mechanisms behind cell-response to inflammation is crucial for developing strategies to treat these diseases. One studied mechanims is the integrated stress response (ISR) which works by temporarily halting protein synthesis and activating protective genes. When properly regulated, the ISR can restore cellular balance and promote survival. The next section will look at how Dr. Chen aimed to improve cellular ISR by introducing a drug, Sephin1.

    One of the diseases associated with cellular inflammation is multiple sclerosis (MS), which causes re-activated T-cells in the central nervous system to release damaging cytokines. Dr. Chen investigated how ISR supports oligodendrocyte survival and promotes remyelination in the CNS. Oligodendrocytes are responsible for forming the myelin sheath that insulates axons and ensures rapid signal conduction. Damage to these cells is a key feature of MS. Using both genetic approaches and pharmacological agents, the paper demonstrated that the prolonged activation of ISR has a protective effect on oligodendrocytes under stress and it supports remyelination. Two small molecules, Bazedoxifene (BZA) and Sephin1, were key to these findings. BZA was found to enhance oligodendrocyte progenitor cell differentiation, promoting remyelination in demyelinated mouse models. Similarly, Sephin1 was found to selectively prolong ISR activation by inhibiting a regulatory phosphatase, improving oligodendrocyte survival and remyelination efficiency. This treatment not only supported the survival of oligodendrocytes in inflammatory conditions, but it also enhanced their capacity to form new myelin sheaths. A key feature of this treatment was Sephin1 being able to prolong ISR, giving the cells more time to respond to the inflammation. A recent study done by Maria Hatzoglou at Case Western Reseve School of Medicine found that ISR can actually be manpulated to improve its response. 

    Dr. Hatzoglou and other scientists initially thought of ISR as a "linear chain of events" that either enabled cells to respond to manageable stress-induced inflammation or caused them to trigger cell-death if the stress became too intense. From this study it was discovered "a cell's response is more nuanced and compartmentalized". The cell's ISR mechanism is much more adaptive and flexible depending on the different types of stress it is experiencing, as well as the strength and length of them. Dr. Haztoglou coined this response "split-integrated stress response (s-ISR)", suggesting this response enables cells to adapt to various stressors more effectively. Combining Dr. Chen's approach of prolonging ISR by introducing Sephin1 with Dr. Hatzoglou's insight into its adaptability opens new avenues for creating highly targeted therapies. By tailoring treatments to modulate specific branches of the ISR in response to distinct stressors, researchers may develop more effective strategies to combat cellular inflammation and diseases like MS.

Dr. Chen's paper: 10.1101/2023.01.23.525156

Case Western Reserve article: https://www.sciencedaily.com/releases/2025/03/250326122650.htm 

A Glimpse of the (M)i(S)sing Cure

There are many neurodegenerative diseases, with some common ones being Alzheimer’s disease, Parkinson’s diseases, and multiple sclerosis (MS). These are characterized by the irreversible deterioration of neurons in the central nervous system that can lead to a multitude of symptoms. Multiple sclerosis in particular is a chronic and unpredictable autoimmune disorder. This means it causes the body’s immune system to target and attack the myelin sheath of neurons, leading to a disruption of communication between the brain and the body. There is currently no cure for this disease, but there are many works of research that are in the progress of trying to find possible treatments for MS patients and possible prevention for MS development. 

Inflammation was found to impair the ability of oligodendrocyte precursor cells (OPC) to mature and remyelinate axons, contributing to the possible causes of multiple sclerosis. However, it was found that there was a way to protect oligodendrocytes and enhance myelination in Yanan Chen’s research titled, “Insights into the mechanism of oligodendrocyte protection and remyelination enhancement by the integrated stress response.” In this study, she and her colleagues found that activating the Integrated Stress Response (SR) with compounds like Sephin1 and bazedoxifene (BZA) were able to accelerate remyelination even under inflammation. These findings suggested that a combination therapy targeting both the ISR pathway and OPC differentiation could possibly restore and enhance neuronal functions in patients with multiple sclerosis. Essentially, a way to overcome inflammatory damage was found but preparing these oligodendrocyte precursor cells for myelination does not mean they have the necessary means for the actual repairing process.

Certain resources are required for remyelination to occur and a finding related to such is that cholesterol biosynthesis is one of these critical requirements for remyelination to occur. Rhonda Voskuhl’s work titled, “Gene expression in oligodendrocytes during remyelination reveals cholesterol homeostasis as a therapeutic target in multiple sclerosis,” found that oligodendrocytes upregulate cholesterol synthesis genes during remyelination and that the activation of estrogen receptor-beta (ERβ) enhances remyelination as well. This review presents another possible therapeutic strategy that could be used as treatment for myelin repair in MS patients. If clinically proven to be able to be done, targeting ERβ could boost remyelination, as it was found to amplify the expression of the cholesterol synthesis genes that were being upregulated during remyelination.

By utilizing both of these studies and doing further research until it reaches clinical human trials, it is possible that treatment for multiple sclerosis may be achieved if all goes well and side effects are not too risky. Dr. Chen’s research allows for a way to protect OPCs so that they are able to be prepared to be differentiated into myelinating oligodendrocytes even under inflammation where they are getting damaged, by targeting the ISR with Sephin1 and BZA. This serves almost as a template for Dr. Voskuhl’s study of what resources are then needed to repair the myelin sheaths after the damage once they are differentiated. Combining both of these research studies suggest possible therapeutic processes that could be used to help treat MS patients, showcasing that they must counteract or overcome inflammation and support the metabolic demands regarding the resources needed during remyelination. Both studies fundamentally highlight the importance of directly supporting oligodendrocytes as a whole rather than focusing on different aspects of it, such as only looking to enhance remyelination but not looking to see if it has the resources to do so. Perhaps, future research could combine these two in a way where they are investigated together to see how everything would work out cohesively and how this could be applied to actual patients, or to see what is missing from being able to develop treatment. Ultimately, the ongoing research on multiple sclerosis and the possible pathways that could be targeted in order to find a cure is going relatively well with new findings that support and help these professionals get closer to being able to treat this unpredictable and debilitating disease. 

 

References

Chen, Y., Quan, S., Patil, V., Kunjamma, R.B., Tokars, H.M., Leisten, E.D., Chan, J., Wong, Y., & Popko, B. Insights into the mechanism of oligodendrocyte protection and remyelination by the integrated stress response. Glia, 71.  https://doi.org/10.1101/2023.01.23.525156

Voskuhl, R.R., Itoh, N., Tassoni, A., & Itoh, Y. Gene expression in oligodendrocytes during remyelination reveals cholesterol homeostasis as a therapeutic target in multiple sclerosis. Proc. Natl. Acad. Sci. U.S.A., 116. https://doi.org/10.1073/pnas.1821306116

COVID-19 Related Hyposmia/Anosmia and Ephrin Cells

The article "Ephrin-B/EphB Signaling is Required for Normal Innervation of Lingual Gustatory Papillae" published in 2016 and authored by Treffy et al. assesses how the proteins Ephrin-B and EphB proteins work to signal the growth of lingual gustatory papillae (tastebuds). Through experiments on mice, it was found that the decreased activation/presence of Ephrin-B/EphB correlated with a decreased innervation of lingual gustatory papillae during the stage they were meant to develop during. These proteins are therefore crucial to the development of the ability to taste and creation of the sense’s neural pathways. This raises the question of how a common side affect of COVID-19 infection, the loss of the ability to taste, could be relevant in discussions about lingual gustatory papillae.

While it is common to lose taste and smell during bouts of sickness, many of the people who lost those senses when infected with COVID-19 never regained them (Rabin, 2021). The loss ranges from a decreased sensitivity (hyposmia) to a total loss (anosmia), some of the post-infected even experiencing completely alternative tastes when eating foods they were familiar with prior. Due to this, Zalpoor et al. (2022) and later Al-Saigh et al. (2024) investigated COVID-related anosmia. Zalpoor et al. (2022) explores the possibility of “Ephrin (Eph) receptors as a possible SARS-CoV-2 entry receptor for human host cells in the central nervous system (CNS) and the potential roles of SARS-CoV-2 spike protein in stimulating the Eph receptor downstream signaling pathway for COVID-19-associated neurodegenerative diseases.” Ephrin cells are expressed all throughout the body and organs such as the liver, lungs, and stomach, as well as being the cell linked to taste bud development (Ephrin-B/EphB). If these receptors and proteins were the ones carrying Covid, then was that part of why COVID-19 infected people lost their sense of smell at such high rates? Or could they be targeted as a treatment for anosmia and hyposmia?

Zalpoor et al. highlight the possible proteins that could be targeted as part of a treatment plan. It’s been shown that those with COVID-19 have higher levels of ephrin-A1 proteins than uninfected people, leading to a link between the two. Since this higher amount of an ephrin protein is also related to other neurodegenerative diseases such as Alzeihmer’s and also plays a role in forming new blood cells (angiogenesis) it is important to consider the possibility of COVID-19 affecting Ephrin-B proteins and receptors. By researching more about these receptors, treatments specific to COVID-19 related loss of small can be further developed. 

References

Al-Saigh, N. N., Harb, A. A., & Abdalla, S. (2024). Receptors Involved in COVID-19-Related Anosmia: An Update on the Pathophysiology and the Mechanistic Aspects. International Journal of Molecular Sciences, 25(15), 8527. https://doi.org/10.3390/ijms25158527 

Rabin, R. C. (2021, January 2). Some Covid Survivors Haunted by Loss of Smell and Taste. The New York Times. https://www.nytimes.com/2021/01/02/health/coronavirus-smell-taste.html 

Treffy, R. W., Collins, D., Hoshino, N., Ton, S., Katsevman, G. A., Oleksiak, M., Runge, E. M., Cho, D., Russo, M., Spec, A., Gomulka, J., Henkemeyer, M., & Rochlin, M. W. (2016). Ephrin-B/EphB Signaling Is Required for Normal Innervation of Lingual Gustatory Papillae. Developmental Neuroscience, 38(2), 124–138. https://doi.org/10.1159/000444748 

Zalpoor, H., Akbari, A., & Nabi-Afjadi, M. (2022). Ephrin (Eph) receptor and downstream signaling pathways: a promising potential targeted therapy for COVID‑19 and associated cancers and diseases. Human Cell, 35(3), 952–954. https://doi.org/10.1007/s13577-022-00697-2