Her6 and Prox1a are novel regulators of photoreceptor regeneration in the zebrafish retina.

Damage to light-sensing photoreceptors (PRs) occurs in highly prevalent retinal diseases. As humans cannot regenerate new PRs, these diseases often lead to irreversible blindness. Intriguingly, animals, such as the zebrafish, can regenerate PRs efficiently and restore functional vision. Upon injury, mature Müller glia (MG) undergo reprogramming to adopt a stem cell-like state. This process is similar to cellular dedifferentiation, and results in the generation of progenitor cells, which, in turn, proliferate and differentiate to replace lost retinal neurons. In this study, we tested whether factors involved in dedifferentiation of Drosophila CNS are implicated in the regenerative response in the zebrafish retina. We found that hairy-related 6 (her6) negatively regulates of PR production by regulating the rate of cell divisions in the MG-derived progenitors. prospero homeobox 1a (prox1a) is expressed in differentiated PRs and may promote PR differentiation through phase separation. Interestingly, upon Her6 downregulation, Prox1a is precociously upregulated in the PRs, to promote PR differentiation; conversely, loss of Prox1a also induces a downregulation of Her6. Together, we identified two novel candidates of PR regeneration that cross regulate each other; these may be exploited to promote human retinal regeneration and vision recovery.

Diet and physical activity behaviors: how are they related to illness perceptions, coping, and health-related quality of life in young people with hereditary cancer syndromes?

Individuals with inherited cancer syndromes, such as Li-Fraumeni syndrome (LFS), may be motivated to adopt health-protective behaviors, such as eating more fruits and vegetables and increasing physical activity. Examining these health behaviors among young people with high lifetime genetic cancer risk may provide important insights to guide future behavioral interventions that aim to improve health-related quality of life (HRQOL). We used a self-regulatory framework to investigate relationships among diet and physical activity behaviors and psychosocial constructs (e.g., illness perceptions, coping, HRQOL) in adolescents and young adults (AYAs; aged 15-39 years) with LFS. This longitudinal mixed-methods study included 57 AYAs aged 16-39 years at enrollment), 32 (56%) of whom had a history of one or more cancers. Participants completed one or two telephone interviews and/or an online survey. We thematically analyzed interview data and conducted regression analyses to evaluate relationships among variables. AYAs described adopting healthy diet and physical activity behaviors to assert some control over health and to protect HRQOL. More frequent use of active coping strategies was associated with greater reported daily fruit and vegetable intake. Greater reported physical activity was associated with better quality of psychological health. Healthy diet and physical activity behaviors may function as LFS coping strategies that confer mental health benefits. Clinicians might emphasize these potential benefits and support AYAs in adopting health behaviors that protect multiple domains of health. Future research could use these findings to develop behavioral interventions tailored to AYAs with high genetic cancer risk.

Notch Inhibition Promotes Regeneration and Immunosuppression Supports Cone Survival in a Zebrafish Model of Inherited Retinal Dystrophy.

Photoreceptor degeneration leads to irreversible vision loss in humans with retinal dystrophies such as retinitis pigmentosa. Whereas photoreceptor loss is permanent in mammals, zebrafish possesses the ability to regenerate retinal neurons and restore visual function. Following acute damage, Müller glia (MG) re-enter the cell cycle and produce multipotent progenitors whose progeny differentiate into mature neurons. Both MG reprogramming and proliferation of retinal progenitor cells require reactive microglia and associated inflammatory signaling. Paradoxically, in zebrafish models of retinal degeneration, photoreceptor death does not induce the MG to reprogram and regenerate lost cells. Here, we used male and female zebrafish cep290 mutants to demonstrate that progressive cone degeneration generates an immune response but does not stimulate MG proliferation. Acute light damage triggered photoreceptor regeneration in cep290 mutants but cones were only restored to prelesion densities. Using irf8 mutant zebrafish, we found that the chronic absence of microglia reduced inflammation and rescued cone degeneration in cep290 mutants. Finally, single-cell RNA-sequencing revealed sustained expression of notch3 in MG of cep290 mutants and inhibition of Notch signaling induced MG to re-enter the cell cycle. Our findings provide new insights on the requirements for MG to proliferate and the potential for immunosuppression to prolong photoreceptor survival.SIGNIFICANCE STATEMENT Inherited retinal degenerations (IRDs) are genetic diseases that lead to the progressive loss of photoreceptors and the permanent loss of vision. Zebrafish can regenerate photoreceptors after acute injury by reprogramming Müller glia (MG) into stem-like cells that produce retinal progenitors, but this regenerative process fails to occur in zebrafish models of IRDs. Here, we show that Notch pathway inhibition can promote photoreceptor regeneration in models of progressive degeneration and that immunosuppression can prevent photoreceptor loss. These results offer insight into the pathways that promote MG-dependent regeneration and the role of inflammation in photoreceptor degeneration.

How do young people with a hereditary cancer predisposition syndrome understand and experience cancer survivorship? "With Li-Fraumeni syndrome, it's just an intermission".

OBJECTIVES: Adolescents and young adult (AYA) cancer survivors face unique medical and psychosocial sequalae, including chronic health conditions, late effects of treatment and fear of recurrence. The meaning of cancer survivorship may be further complicated for AYAs with hereditary cancer predisposition syndromes. This study used a patient-centered framework to investigate how AYAs with Li-Fraumeni syndrome (LFS) consider cancer survivorship. METHODS: An interprofessional team conducted 30 semi-structured interviews with AYAs (aged 18-41, mean 31 years) enrolled in the National Cancer Institute's LFS Study (NCT01443468). Twenty had experienced at least one cancer diagnosis. Interview data were thematically analyzed by an inter-professional team using interpretive description and grounded theory methods. FINDINGS: Participants viewed "survivorship" as a period marked by no evidence of formerly diagnosed disease. By contrast, participants felt the label "survivor" was tenuous since LFS is characterized by multiple primary malignancies and uncertainty about intervals between one diagnosis and the next. Many AYAs viewed survivorship as requiring a high degree of suffering. Though many personally rejected "survivor" identities, almost all articulated its various functions including positive, negative, and more complicated connotations. Instead, they chose language to represent a range of beliefs about survival, longevity, prognosis, and activism. CONCLUSIONS: AYAs with LFS struggle with the term "survivor" due to their multi-organ cancer risk, short intervals between malignancies, and evolving identities. Loved ones' cancer-related suffering informed perspectives on survivorship. Survivorship care for AYAs with cancer risk syndromes requires interprofessional interventions that address their unique biomedical and psychosocial needs.

Perceptions and tolerance of uncertainty: relationship to trust in COVID-19 health information and vaccine hesitancy.

The COVID-19 crisis has exposed the public to considerable scientific uncertainty, which may promote vaccine hesitancy among individuals with lower tolerance of uncertainty. In a national sample of US adults in May-June 2020, we examined how both perceptions of uncertainty about COVID-19 and trait-level differences in tolerance of uncertainty arising from various sources (risk, ambiguity, and complexity) are related to vaccine hesitancy-related outcomes, including trust in COVID-19 information, COVID-19 vaccine intentions, and beliefs that COVID-19 vaccines should undergo a longer testing period before being released to the public. Overall, perceptions of COVID-19 uncertainty were not associated with trust in information, vaccine intentions, or beliefs about vaccine testing. However, higher tolerance of risk was associated with lower intentions to get vaccinated, and lower tolerance of ambiguity was associated with lower intentions to get vaccinated and preferring a longer period of vaccine testing. Critically, perceptions of COVID-19 uncertainty and trait-level tolerance for uncertainty also interacted as predicted, such that greater perceived COVID-19 uncertainty was more negatively associated with trust in COVID-19 information among individuals with lower tolerance for risk and ambiguity. Thus, although perceptions of uncertainty regarding COVID-19 may not reduce trust and vaccine hesitancy for all individuals, trait-level tolerance of uncertainty arising from various sources may have both direct and moderating effects on these outcomes. These findings can inform public health communication or other interventions to increase COVID-19 vaccination uptake.

Iron contributes to photoreceptor degeneration and Müller glia proliferation in the zebrafish light-treated retina.

Zebrafish possess the ability to completely regenerate the retina following injury, however little is understood about the damage signals that contribute to inducing Müller glia reprogramming and proliferation to regenerate lost neurons. Multiple studies demonstrated that iron contributes to various retinal injuries, however no link has been shown between iron and zebrafish retinal regeneration. Here we demonstrate that Müller glia exhibit transcriptional changes following injury to regulate iron levels within the retina, allowing for increased iron uptake and decreased export. The response of the zebrafish retina to intravitreal iron injection was then characterized, showing that ferrous, and not ferric, iron induces retinal cell death. Additionally, iron chelation resulted in decreased numbers of TUNEL-positive photoreceptors and fewer proliferating Müller glia. Despite the contribution of iron to retinal cell death, inhibition of ferroptosis did not significantly reduce cell death following light treatment. Finally, we demonstrate that both the anti-ferroptotic protein Glutathione peroxidase 4b and the Transferrin receptor 1b are required for Müller glia proliferation following light damage. Together these findings show that iron contributes to cell death in the light-damaged retina and is essential for inducing the Müller glia regeneration response.

Neuroticism, cancer mortality salience, and physician avoidance in cancer survivors: Proximity of treatment matters.

OBJECTIVE: To examine if the relationship between neuroticism and physician avoidance/physician visit concerns are mediated by perceptions that cancer is associated with death ("cancer mortality salience"; CMS) for cancer survivors to inform public health interventions and tailored health communications. METHODS: Cancer survivors comprised 42.3% of the total sample (n = 525). Participants completed a 4-item neuroticism scale, 4-item cancer perceptions scale, and 4-item physician avoidance and concerns scale. Multiple linear regression models were used to assess relationships among variables for cancer survivors and separately for those without a history of cancer. RESULTS: Neuroticism was positively associated with CMS for cancer survivors, b = 0.26, (p < 0.001), and those without cancer, b = 0.22, (p < 0.001). There was an association between neuroticism and physician avoidance among cancer survivors with temporally distant treatment courses after controlling for CMS, b = 0.56 (p = 0.006), but not for those currently or recently having had undergone treatment (p = 0.949). There was also an indirect relationship between neuroticism and physician visit concerns that was mediated by CMS for cancer survivors, b = 0.07, CI = [0.03, 0.13], but this relationship was again driven by cancer survivors with more distal treatment courses. CONCLUSIONS: High neuroticism in cancer survivors is associated with physician avoidance and physician visit concerns when treatment is temporally distant. Interventions aimed at decoupling the association between cancer and death can help increase the willingness of cancer survivors to attain cancer care follow-ups and healthcare more generally.

A qualitative exploration of facilitators and barriers of adherence to time-restricted eating.

Time-restricted eating (TRE), a dietary strategy that involves limiting daily energy intake to a window of ≤12 h is appealing for weight management and metabolic health due to its relative simplicity and the ability to consume ad libitum diet during eating windows. Despite the potential utility of TRE for improving health and reducing disease, the feasibility of adherence depends upon a variety of multilevel factors which are largely unexplored. The primary aim of our study was to explore facilitators and barriers of adherence to TRE among community-dwelling individuals. Semi-structured qualitative interviews were conducted among 24 individuals (50% male; M age: 34, range: 18-57; 58% overweight/obese) who currently or formerly practiced TRE. Thematic analysis identified facilitators of and barriers to TRE adherence at multiple levels of influence (i.e., biological, behavioral, psychosocial, environmental). Key facilitators of adherence included improvements in physical health and energy levels, alignment with other aspects of diet, exercise and sleep patterns, self-monitoring and positive psychological impacts, social support, and busy or regular schedules. Key barriers included negative physical health effects, feelings of hunger and sluggishness, difficulty in skipping valued baseline eating routines or inadequate diet quality during the eating window, misalignment of TRE with 24-h activity behaviors, difficulties with self-monitoring, the need to mitigate negative feelings, social situations that discourage TRE, and irregular or idle schedules. Results illustrate that key drivers of adherence differ across individuals and their unique settings and that multiple drivers of behavior should be considered in the successful implementation of TRE. Findings may inform interventions seeking to tailor TRE schedules to fit individuals' diverse behavioral patterns and preferences, thereby optimizing adherence.

Notch3 and DeltaB maintain Müller glia quiescence and act as negative regulators of regeneration in the light-damaged zebrafish retina.

Damage to the zebrafish retina stimulates resident Müller glia to reprogram, reenter the cell cycle, divide asymmetrically, and produce neuronal progenitor cells that amplify and differentiate into the lost neurons. The transition from quiescent to proliferative Müller glia involves both positive and negative regulators. We previously demonstrated that the Notch signaling pathway represses retinal regeneration by maintaining Müller glia quiescence in zebrafish. Here we examine which Notch receptor is necessary to maintain quiescence. Quantitative RT-PCR and RNA-Seq analyses reveal that notch3 is expressed in the undamaged retina and is downregulated in response to light damage. Additionally, Notch3 protein is expressed in quiescent Müller glia of the undamaged retina, is downregulated as Müller glia proliferate, and is reestablished in the Müller glia. Knockdown of Notch3 is sufficient to induce Müller glia proliferation in undamaged retinas and enhances proliferation during light damage. Alternatively, knockdown of Notch1a, Notch1b, or Notch2 decreases the number of proliferating cells during light damage, suggesting that Notch signaling is also required for proliferation during retinal regeneration. We also knockdown the zebrafish Delta and Delta-like proteins, ligands for the Notch receptors, and find that the deltaB morphant possesses an increased number of proliferating cells in the light-damaged retina. As with Notch3, knockdown of DeltaB is sufficient to induce Müller glia proliferation in the absence of light damage. Taken together, the negative regulation of Müller glia proliferation in zebrafish retinal regeneration is mediated by Notch3 and DeltaB.

Spiritual peace and life meaning may buffer the effect of anxiety on physical well-being in newly diagnosed cancer survivors.

OBJECTIVE: To assess the extent to which spiritual well-being moderates the relationship between anxiety and physical well-being in a diverse, community-based cohort of newly diagnosed cancer survivors. METHODS: Data originated from the Measuring Your Health (MY-Health) study cohort (n = 5506), comprising people assessed within 6-13 months of cancer diagnosis. Life meaning/peace was assessed using the 8-item subscale of the Spiritual Well-Being Scale (FACIT-Sp-12). Anxiety was measured with an 11-item PROMIS Anxiety short form, and physical well-being was assessed using the 7-item FACT-G subscale. Multiple linear regression models were used to assess relationships among variables. RESULTS: Life meaning and peace was negatively associated with anxiety, b = -0.56 (P < .001) and positively associated with physical well-being, b = 0.43 (P = <.001) after adjusting for race, education, income, and age. A significant interaction between life meaning/peace and anxiety emerged (P < .001) indicating that spiritual well-being moderates the relationship between anxiety and physical well-being. Specifically, for cancer survivors high in anxiety, physical well-being was dependent on levels of life meaning/peace, b = 0.19, P < .001. For those low in anxiety, physical well-being was not associated with levels of life meaning/peace, b = 0.01, P = .541. Differences in cancer clinical factors (cancer stage at diagnosis, cancer type) did not significantly impact results. CONCLUSIONS: Further research is needed to assess how spiritual well-being may buffer the negative effect of anxiety on physical well-being. A clinical focus on spiritual well-being topics such as peace and life meaning may help cancer survivors of all types as they transition into follow-up care.