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The direction of left-right visceral asymmetry is conserved in vertebrates. Deviations of the standard asymmetric pattern are rare, and the underlying mechanisms are not understood. Here, we use the teleost Astyanax mexicanus, consisting of surface fish with normal left-oriented heart asymmetry and cavefish with high levels of reversed right-oriented heart asymmetry, to explore natural changes in asymmetry determination. We show that Sonic Hedgehog (Shh) signaling is increased at the posterior midline, Kupffer's vesicle (the teleost left-right organizer) is enlarged and contains longer cilia, and the number of dorsal forerunner cells is increased in cavefish. Furthermore, Shh increase in surface fish embryos induces asymmetric changes resembling the cavefish phenotype. Asymmetric expression of the Nodal antagonist Dand5 is equalized or reversed in cavefish, and Shh increase in surface fish mimics changes in cavefish dand5 asymmetry. Shh decrease reduces the level of right-oriented heart asymmetry in cavefish. Thus, naturally occurring modifications in cavefish heart asymmetry are controlled by the effects of Shh signaling on left-right organizer function.
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Padronização Corporal , Coração , Proteínas Hedgehog , Transdução de Sinais , Animais , Proteínas Hedgehog/metabolismo , Proteínas Hedgehog/genética , Padronização Corporal/genética , Coração/embriologia , Characidae/embriologia , Characidae/genética , Regulação da Expressão Gênica no Desenvolvimento , Cílios/metabolismo , Embrião não Mamífero/metabolismoRESUMO
PURPOSE: To evaluate (1) the long-term efficacy of low-concentration atropine over 5 years, (2) the proportion of children requiring re-treatment and associated factors, and (3) the efficacy of pro re nata (PRN) re-treatment using 0.05% atropine from years 3 to 5. DESIGN: Randomized, double-masked extended trial. PARTICIPANTS: Children 4 to 12 years of age originally from the Low-Concentration Atropine for Myopia Progression (LAMP) study. METHODS: Children 4 to 12 years of age originally from the LAMP study were followed up for 5 years. During the third year, children in each group originally receiving 0.05%, 0.025%, and 0.01% atropine were randomized to continued treatment and treatment cessation. During years 4 and 5, all continued treatment subgroups were switched to 0.05% atropine for continued treatment, whereas all treatment cessation subgroups followed a PRN re-treatment protocol to resume 0.05% atropine for children with myopic progressions of 0.5 diopter (D) or more over 1 year. Generalized estimating equations were used to compare the changes in spherical equivalent (SE) progression and axial length (AL) elongation among groups. MAIN OUTCOMES MEASURES: (1) Changes in SE and AL in different groups over 5 years, (2) the proportion of children who needed re-treatment, and (3) changes in SE and AL in the continued treatment and PRN re-treatment groups from years 3 to 5. RESULTS: Two hundred seventy (82.8%) of 326 children (82.5%) from the third year completed 5 years of follow-up. Over 5 years, the cumulative mean SE progressions were -1.34 ± 1.40 D, -1.97 ± 1.03 D, and -2.34 ± 1.71 D for the continued treatment groups with initial 0.05%, 0.025%, and 0.01% atropine, respectively (P = 0.02). Similar trends were observed in AL elongation (P = 0.01). Among the PRN re-treatment group, 87.9% of children (94/107) needed re-treatment. The proportion of re-treatment across all studied concentrations was similar (P = 0.76). The SE progressions for continued treatment and PRN re-treatment groups from years 3 to 5 were -0.97 ± 0.82 D and -1.00 ± 0.74 D (P = 0.55) and the AL elongations were 0.51 ± 0.34 mm and 0.49 ± 0.32 mm (P = 0.84), respectively. CONCLUSIONS: Over 5 years, the continued 0.05% atropine treatment demonstrated good efficacy for myopia control. Most children needed to restart treatment after atropine cessation at year 3. Restarted treatment with 0.05% atropine achieved similar efficacy as continued treatment. Children should be considered for re-treatment if myopia progresses after treatment cessation. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.
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Atropina , Progressão da Doença , Midriáticos , Soluções Oftálmicas , Refração Ocular , Humanos , Atropina/administração & dosagem , Criança , Pré-Escolar , Masculino , Feminino , Método Duplo-Cego , Midriáticos/administração & dosagem , Refração Ocular/fisiologia , Seguimentos , Resultado do Tratamento , Miopia Degenerativa/tratamento farmacológico , Miopia Degenerativa/fisiopatologia , Miopia/tratamento farmacológico , Miopia/fisiopatologiaRESUMO
BACKGROUND: A recent prospective demonstrated that cardiovascular risk factors in early childhood were associated with later cardiovascular events. However, the impact of secondhand smoke (SHS) on children is unclear. The aims of this study is to determine the effects of SHS exposure on the retinal vasculature of children. METHODS: This is a population-based cross-sectional study of children aged 6 to 8 years. All participants received comprehensive ophthalmic examinations and retinal photography. Data on SHS exposure was derived from a validated questionnaire. A validated deep-learning system was used to automatically estimate retinal arteriolar and venular calibers from retinal photographs. Associations of quantitative retinal vessel caliber values with SHS exposure, number of smokers in the household, and total number of cigarettes smoked were determined by analyses of covariance (ANCOVA) after adjusting for potential confounders. Test of trend was determined by treating categorical risk factors as continuous ordinal variables. RESULTS: Here we show children exposed to SHS have wider retinal arteriolar (CRAE 152.1 µm vs. 151.3 µm, p < 0.001) and venular (CRVE 216.7 µm vs. 215.5 µm, p < 0.001) calibers compared to those in smoke-free homes, after adjustment for different factors. Wider arteriolar and venular calibers are also associated with increasing number of smokers in the family (p trend < 0.001) and more cigarettes smoked among family smokers (p trend<0.001). CONCLUSIONS: Exposure to SHS at home is associated with changes in retinal vasculature among children. This reinforces the adverse effect of secondhand smoking around children though further research incorporating comprehensive assessment of potential confounders is necessary.
Exposure to secondhand smoke can be harmful, particularly for our heart and lung health as adults. However, the impact of secondhand smoke on children is less clear. Here, we looked at the effects of secondhand smoke exposure on vessels within children's eyes. The health of these vessels is a potential indicator of overall eye health and is also associated with cardiovascular disease. Pictures were taken of children's eyes and analyzed using a computer program. We looked at the association between vessel measurements in the eye and how much secondhand smoke the children are exposed to. We observed differences in the vessels in children exposed to secondhand smoke, compared to those from smoke-free homes. These findings indicate that secondhand smoke may affect the health of children's eyes and highlight the need to promote smoke-free home environments.
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BACKGROUND: Unidirectional regeneration in the basal chordate Ciona intestinalis involves the proliferation of adult stem cells residing in the branchial sac vasculature and the migration of progenitor cells to the site of distal injury. However, after the Ciona body is bisected, regeneration occurs in the proximal but not in the distal fragments, even if the latter include a part of the branchial sac with stem cells. A transcriptome was sequenced and assembled from the isolated branchial sacs of regenerating animals, and the information was used to provide insights into the absence of regeneration in distal body fragments. RESULTS: We identified 1149 differentially expressed genes, which were separated into two major modules by weighted gene correlation network analysis, one consisting of mostly upregulated genes correlated with regeneration and the other consisting of only downregulated genes associated with metabolism and homeostatic processes. The hsp70, dnaJb4, and bag3 genes were among the highest upregulated genes and were predicted to interact in an HSP70 chaperone system. The upregulation of HSP70 chaperone genes was verified and their expression confirmed in BS vasculature cells previously identified as stem and progenitor cells. siRNA-mediated gene knockdown showed that hsp70 and dnaJb4, but not bag3, are required for progenitor cell targeting and distal regeneration. However, neither hsp70 nor dnaJb4 were strongly expressed in the branchial sac vasculature of distal fragments, implying the absence of a stress response. Heat shock treatment of distal body fragments activated hsp70 and dnaJb4 expression indicative of a stress response, induced cell proliferation in branchial sac vasculature cells, and promoted distal regeneration. CONCLUSIONS: The chaperone system genes hsp70, dnaJb4, and bag3 are significantly upregulated in the branchial sac vasculature following distal injury, defining a stress response that is essential for regeneration. The stress response is absent from distal fragments, but can be induced by a heat shock, which activates cell division in the branchial sac vasculature and promotes distal regeneration. This study demonstrates the importance of a stress response for stem cell activation and regeneration in a basal chordate, which may have implications for understanding the limited regenerative activities in other animals, including vertebrates.
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Ciona intestinalis , Ciona , Animais , Ciona/genética , Ciona intestinalis/genética , Células-Tronco , Mapeamento Cromossômico , Chaperonas Moleculares/genética , Proteínas de Choque Térmico HSP70/genéticaRESUMO
Importance: Secondhand smoke (SHS) exposure potentially threatens ocular health; however, its association with myopia is unknown. Objective: To examine the association between SHS exposure and childhood myopia. Design, Setting, and Participants: Cross-sectional data from the population-based Hong Kong Children Eye Study were used. Data were collected from March 5, 2015, to September 12, 2021, at The Chinese University of Hong Kong Eye Center. Participants included children aged 6 to 8 years. Secondhand smoke exposure was evaluated using a validated questionnaire. All participants underwent comprehensive ophthalmic and physical examinations. Exposure: Secondhand smoke exposure. Main Outcomes and Measures: Generalized estimating equations were constructed to examine the association of SHS exposure with spherical equivalent and axial length; logistic regression models, with myopia rate; and linear regression models, with myopia onset. Results: A total of 12â¯630 children (mean [SD] age, 7.37 [0.88] years; 53.2% boys) were included in the analysis. Among the participants, 4092 (32.4%) had SHS exposure. After adjusting for age, sex, parental myopia, body mass index, near-work time, outdoor time, and family income, SHS exposure was associated with greater myopic refraction (ß = -0.09 [95% CI, -0.14 to -0.03]) and longer axial length (ß = 0.05 [95% CI, 0.02-0.08]). Children with SHS exposure were more likely to develop moderate (odds ratio [OR], 1.30 [95% CI, 1.06-1.59]) and high myopia (OR, 2.64 [95% CI, 1.48-4.69]). The association of SHS exposure with spherical equivalence and axial length was magnified in younger children. For each younger year of a child's exposure to SHS, SHS exposure was associated with a 0.07-D decrease in spherical equivalence (ß = 0.07 [95% CI, 0.01-0.13]) and a 0.05-mm increase in axial length (ß = -0.05 [95% CI, -0.08 to -0.01]). Exposure to SHS was associated with an earlier mean (SD) age at onset of myopia (72.8 [0.9] vs 74.6 [0.6] months; P = .01). Every increase in SHS exposure in units of 10 cigarettes per day was associated with greater myopic refraction (ß = -0.07 [95% CI, -0.11 to -0.02]), axial length (ß = 0.04 [95% CI, 0.01-0.06]), and likelihood of developing moderate (OR, 1.23 [95% CI, 1.05-1.44]) and high myopia (OR, 1.75 [95% CI, 1.20-2.56]), and earlier myopia onset (ß = -1.30 [95% CI, -2.32 to -0.27]). Conclusions and Relevance: The findings of this cross-sectional study suggest that SHS exposure was associated with greater myopic refraction, longer axial length, greater likelihood of developing moderate and high myopia, and earlier myopia onset. The larger the quantity of SHS exposure and the younger the child, the more advanced myopia development and progression with which SHS exposure is associated.
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Miopia , Poluição por Fumaça de Tabaco , Masculino , Humanos , Criança , Feminino , Estudos Transversais , Poluição por Fumaça de Tabaco/efeitos adversos , Hong Kong/epidemiologia , Miopia/epidemiologia , Miopia/etiologia , OlhoRESUMO
Importance: Childhood myopia increased during the COVID-19 pandemic. Limited evidence exists about whether myopia development was reversed or worsened after the lockdown. Objective: To determine the prevalence of myopia and its associated factors before, during, and after COVID-19 restrictions. Design, Setting, and Participants: This population-based, repeated cross-sectional study evaluated children aged 6 to 8 years from the Hong Kong Children Eye Study between 2015 and 2021 in 3 cohorts: before COVID-19 (2015-2019), during COVID-19 restrictions (2020), and after COVID-19 restrictions were lifted (2021). Exposures: All the children received ocular examinations, including cycloplegic autorefraction and axial length. Data about the children's lifestyle, including time spent outdoors, near-work time, and screen time, were collected from a standardized questionnaire. Main Outcomes and Measures: The main outcomes were the prevalence of myopia, mean spherical equivalent refraction, axial length, changes in lifestyle, and the associated factors over 7 years. Data were analyzed using descriptive statistics, logistic regression, and generalized estimating equations. Results: Of 20â¯527 children (mean [SD] age, 7.33 [0.89] years; 52.8% boys and 47.2% girls), myopia prevalence was stable from 2015 to 2019 (23.5%-24.9%; P = .90) but increased to 28.8% (P < .001) in 2020 and 36.2% (P < .001) in 2021. The mean (SD) time spent outdoors was much lower in 2020 (0.85 [0.53] h/d; P < .001) and 2021 (1.26 [0.48] h/d; P < .001) compared with pre-COVID-19 levels (1.40 [0.47]-1.46 [0.65] h/d). The trend was reversed for total near-work time and screen time. High myopia prevalence was associated with the COVID-19 pandemic (odds ratio [OR], 1.40; 95% CI, 1.28-1.54; P < .001), younger age (OR, 1.84; 95% CI, 1.76-1.93; P < .001), male sex (OR, 1.11; 95% CI, 1.03-1.21; P = .007), lower family income (OR, 1.05; 95% CI, 1.00-1.09; P = .04), and parental myopia (OR, 1.61; 95% CI, 1.52-1.70; P < .001). During the pandemic, mean (SD) near-work and screen times in children from lower-income families were 5.16 (2.05) h/d and 3.44 (1.97) h/d, more than from higher-income families (4.83 [1.85] and 2.90 [1.61] h/d, respectively). Conclusions and Relevance: The findings of this cross-sectional study revealed that after COVID-19 restrictions were lifted in Hong Kong, myopia prevalence among children was higher than before the pandemic, and lifestyle did not return to pre-COVID-19 levels. Younger children and those from low-income families were at a higher risk of myopia development during the pandemic, suggesting that collective efforts for myopia control should be advocated for these groups.
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COVID-19 , Miopia , Feminino , Humanos , Masculino , Criança , Prevalência , Hong Kong/epidemiologia , Estudos Transversais , Pandemias , COVID-19/epidemiologia , Controle de Doenças Transmissíveis , Miopia/epidemiologiaRESUMO
Importance: Early onset of myopia is associated with high myopia later in life, and myopia is irreversible once developed. Objective: To evaluate the efficacy of low-concentration atropine eyedrops at 0.05% and 0.01% concentration for delaying the onset of myopia. Design, Setting, and Participants: This randomized, placebo-controlled, double-masked trial conducted at the Chinese University of Hong Kong Eye Centre enrolled 474 nonmyopic children aged 4 through 9 years with cycloplegic spherical equivalent between +1.00 D to 0.00 D and astigmatism less than -1.00 D. The first recruited participant started treatment on July 11, 2017, and the last participant was enrolled on June 4, 2020; the date of the final follow-up session was June 4, 2022. Interventions: Participants were assigned at random to the 0.05% atropine (n = 160), 0.01% atropine (n = 159), and placebo (n = 155) groups and had eyedrops applied once nightly in both eyes over 2 years. Main Outcomes and Measures: The primary outcomes were the 2-year cumulative incidence rate of myopia (cycloplegic spherical equivalent of at least -0.50 D in either eye) and the percentage of participants with fast myopic shift (spherical equivalent myopic shift of at least 1.00 D). Results: Of the 474 randomized patients (mean age, 6.8 years; 50% female), 353 (74.5%) completed the trial. The 2-year cumulative incidence of myopia in the 0.05% atropine, 0.01% atropine, and placebo groups were 28.4% (33/116), 45.9% (56/122), and 53.0% (61/115), respectively, and the percentages of participants with fast myopic shift at 2 years were 25.0%, 45.1%, and 53.9%. Compared with the placebo group, the 0.05% atropine group had significantly lower 2-year cumulative myopia incidence (difference, 24.6% [95% CI, 12.0%-36.4%]) and percentage of patients with fast myopic shift (difference, 28.9% [95% CI, 16.5%-40.5%]). Compared with the 0.01% atropine group, the 0.05% atropine group had significantly lower 2-year cumulative myopia incidence (difference, 17.5% [95% CI, 5.2%-29.2%]) and percentage of patients with fast myopic shift (difference, 20.1% [95% CI, 8.0%-31.6%]). The 0.01% atropine and placebo groups were not significantly different in 2-year cumulative myopia incidence or percentage of patients with fast myopic shift. Photophobia was the most common adverse event and was reported by 12.9% of participants in the 0.05% atropine group, 18.9% in the 0.01% atropine group, and 12.2% in the placebo group in the second year. Conclusions and Relevance: Among children aged 4 to 9 years without myopia, nightly use of 0.05% atropine eyedrops compared with placebo resulted in a significantly lower incidence of myopia and lower percentage of participants with fast myopic shift at 2 years. There was no significant difference between 0.01% atropine and placebo. Further research is needed to replicate the findings, to understand whether this represents a delay or prevention of myopia, and to assess longer-term safety. Trial Registration: Chinese Clinical Trial Registry: ChiCTR-IPR-15006883.
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Atropina , Miopia , Criança , Feminino , Humanos , Masculino , Atropina/administração & dosagem , Atropina/efeitos adversos , Atropina/uso terapêutico , Progressão da Doença , Incidência , Midriáticos/efeitos adversos , Miopia/diagnóstico , Miopia/prevenção & controle , Soluções Oftálmicas/administração & dosagem , Soluções Oftálmicas/efeitos adversos , Soluções Oftálmicas/uso terapêutico , Refração Ocular , Idade de Início , Método Duplo-Cego , Pré-EscolarRESUMO
Combining left ventricular assist device (LVAD) implantation and longitudinal sleeve gastrectomy may enable patients with morbid obesity to lose enough weight for heart transplant eligibility. In a retrospective study, we evaluated long-term outcomes of patients with body mass indexes ≥35 who underwent LVAD implantation and longitudinal sleeve gastrectomy during the same hospitalization (from January 2013 through July 2018) and then adhered to a dietary protocol. We included 22 patients (mean age, 49.9 ± 12.5 yr; mean preoperative body mass index, 43.3 ± 6.2). Eighteen months after gastrectomy, all 22 patients were alive, and 16 (73%) achieved a body mass index of less than 35. Myocardial recovery in 2 patients enabled LVAD removal. As of October 2020, 10 patients (45.5%) had undergone heart transplantation, 5 (22.3%) were waitlisted, 5 (22.3%) still had a body mass index ≥35, and 2 (9%) had died. With LVAD support, longitudinal sleeve gastrectomy, and dietary protocols, most of our patients with morbid obesity and advanced heart failure lost enough weight for transplant eligibility. Support from physicians and dietitians can maximize positive results in these patients.
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Insuficiência Cardíaca , Transplante de Coração , Coração Auxiliar , Obesidade Mórbida , Adulto , Dieta , Gastrectomia/métodos , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/cirurgia , Humanos , Pessoa de Meia-Idade , Obesidade Mórbida/diagnóstico , Obesidade Mórbida/cirurgia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
The direction of visceral organ asymmetry is highly conserved during vertebrate evolution with heart development biased to the left and pancreas and liver development restricted to opposing sides of the midline. Here we show that reversals in visceral organ asymmetry have evolved in Astyanax mexicanus, a teleost species with interfertile surface-dwelling (surface fish) and cave-dwelling (cavefish) forms. Visceral organ asymmetry is conventional in surface fish but some cavefish have evolved reversals in heart, liver, and pancreas development. Corresponding changes in the normally left-sided expression of the Nodal-Pitx2/Lefty signaling system are also present in the cavefish lateral plate mesoderm (LPM). The Nodal antagonists lefty1 (lft1) and lefty2 (lft2), which confine Nodal signaling to the left LPM, are expressed in most surface fish, however, lft2, but not lft1, expression is absent during somitogenesis of most cavefish. Despite this difference, multiple lines of evidence suggested that evolutionary changes in L-R patterning are controlled upstream of Nodal-Pitx2/Lefty signaling. Accordingly, reciprocal hybridization of cavefish and surface fish showed that modifications of heart asymmetry are present in hybrids derived from cavefish mothers but not from surface fish mothers. The results indicate that changes in visceral asymmetry during cavefish evolution are influenced by maternal genetic effects.
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Padronização Corporal , Characidae/embriologia , Animais , Evolução Biológica , FemininoRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Vestigial structures are key indicators of evolutionary descent, but the mechanisms underlying their development are poorly understood. This study examines vestigial eye formation in the teleost Astyanax mexicanus, which consists of a sighted surface-dwelling morph and multiple populations of blind cave morphs. Cavefish embryos initially develop eyes, but they subsequently degenerate and become vestigial structures embedded in the head. The mutated genes involved in cavefish vestigial eye formation have not been characterized. Here we identify cystathionine ß-synthase a (cbsa), which encodes the key enzyme of the transsulfuration pathway, as one of the mutated genes responsible for eye degeneration in multiple cavefish populations. The inactivation of cbsa affects eye development by increasing the transsulfuration intermediate homocysteine and inducing defects in optic vasculature, which result in aneurysms and eye hemorrhages. Our findings suggest that localized modifications in the circulatory system may have contributed to the evolution of vestigial eyes in cavefish.
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Cistationina beta-Sintase/genética , Cistationina/metabolismo , Olho/embriologia , Olho/metabolismo , Peixes/fisiologia , Animais , Apoptose , Evolução Biológica , Encéfalo/embriologia , Sistema Cardiovascular , Cistationina beta-Sintase/metabolismo , Biologia do Desenvolvimento , Olho/citologia , Olho/crescimento & desenvolvimento , Feminino , Peixes/embriologia , Peixes/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Técnicas de Silenciamento de Genes , Cabeça , Cristalino/citologia , Cristalino/metabolismo , Masculino , Modelos AnimaisRESUMO
BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019, causing a respiratory disease (coronavirus disease 2019, COVID-19) of varying severity in Wuhan, China, and subsequently leading to a pandemic. The transmissibility and pathogenesis of SARS-CoV-2 remain poorly understood. We evaluate its tissue and cellular tropism in human respiratory tract, conjunctiva, and innate immune responses in comparison with other coronavirus and influenza virus to provide insights into COVID-19 pathogenesis. METHODS: We isolated SARS-CoV-2 from a patient with confirmed COVID-19, and compared virus tropism and replication competence with SARS-CoV, Middle East respiratory syndrome-associated coronavirus (MERS-CoV), and 2009 pandemic influenza H1N1 (H1N1pdm) in ex-vivo cultures of human bronchus (n=5) and lung (n=4). We assessed extrapulmonary infection using ex-vivo cultures of human conjunctiva (n=3) and in-vitro cultures of human colorectal adenocarcinoma cell lines. Innate immune responses and angiotensin-converting enzyme 2 expression were investigated in human alveolar epithelial cells and macrophages. In-vitro studies included the highly pathogenic avian influenza H5N1 virus (H5N1) and mock-infected cells as controls. FINDINGS: SARS-CoV-2 infected ciliated, mucus-secreting, and club cells of bronchial epithelium, type 1 pneumocytes in the lung, and the conjunctival mucosa. In the bronchus, SARS-CoV-2 replication competence was similar to MERS-CoV, and higher than SARS-CoV, but lower than H1N1pdm. In the lung, SARS-CoV-2 replication was similar to SARS-CoV and H1N1pdm, but was lower than MERS-CoV. In conjunctiva, SARS-CoV-2 replication was greater than SARS-CoV. SARS-CoV-2 was a less potent inducer of proinflammatory cytokines than H5N1, H1N1pdm, or MERS-CoV. INTERPRETATION: The conjunctival epithelium and conducting airways appear to be potential portals of infection for SARS-CoV-2. Both SARS-CoV and SARS-CoV-2 replicated similarly in the alveolar epithelium; SARS-CoV-2 replicated more extensively in the bronchus than SARS-CoV. These findings provide important insights into the transmissibility and pathogenesis of SARS-CoV-2 infection and differences with other respiratory pathogens. FUNDING: US National Institute of Allergy and Infectious Diseases, University Grants Committee of Hong Kong Special Administrative Region, China; Health and Medical Research Fund, Food and Health Bureau, Government of Hong Kong Special Administrative Region, China.
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Betacoronavirus/imunologia , Túnica Conjuntiva/virologia , Infecções por Coronavirus/imunologia , Imunidade Inata/imunologia , Pneumonia Viral/imunologia , Sistema Respiratório/virologia , Tropismo Viral/fisiologia , Replicação Viral/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus/fisiologia , COVID-19 , Túnica Conjuntiva/imunologia , Túnica Conjuntiva/fisiopatologia , Infecções por Coronavirus/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/fisiopatologia , Mucosa Respiratória/imunologia , Mucosa Respiratória/fisiopatologia , Mucosa Respiratória/virologia , Sistema Respiratório/imunologia , Sistema Respiratório/fisiopatologia , SARS-CoV-2RESUMO
A widely accepted model for the evolution of cave animals posits colonization by surface ancestors followed by the acquisition of adaptations over many generations. However, the speed of cave adaptation in some species suggests mechanisms operating over shorter timescales. To address these mechanisms, we used Astyanax mexicanus, a teleost with ancestral surface morphs (surface fish, SF) and derived cave morphs (cavefish, CF). We exposed SF to completely dark conditions and identified numerous altered traits at both the gene expression and phenotypic levels. Remarkably, most of these alterations mimicked CF phenotypes. Our results indicate that many cave-related traits can appear within a single generation by phenotypic plasticity. In the next generation, plasticity can be further refined. The initial plastic responses are random in adaptive outcome but may determine the subsequent course of evolution. Our study suggests that phenotypic plasticity contributes to the rapid evolution of cave-related traits in A. mexicanus.
The Mexican tetra is a fish that has two forms: a surface-dwelling form, which has eyes and silvery grey appearance, and a cave-dwelling form, which is blind and has lost its pigmentation. Recent studies have shown that the cave-dwelling form evolved rapidly within the last 200,000 years from an ancestor that lived at the surface. The recent evolution of the cave-dwelling form of the tetra poses an interesting evolutionary question: how did the surface-dwelling ancestor of the tetra quickly adapt to the new and challenging environment found in the caves? 'Phenotypic plasticity' is a phenomenon through which a single set of genes can produce different observable traits depending on the environment. An example of phenotypic plasticity occurs in response to diet: in animals, poor diets can lead to an increase in the size of the digestive organs and to the animals eating more. To see if surface-dwelling tetras can quickly adapt to cave environments through phenotypic plasticity, Bilandzija et al. have exposed these fish to complete darkness (the major feature of the cave environment) for two years. After spending up to two years in the dark, these fish were compared to normal surface-dwelling and cave-dwelling tetras. Results revealed that surface-dwelling tetras raised in the dark exhibited traits associated with cave-dwelling tetras. These traits included changes in the activity of many genes involved in diverse processes, resistance to starvation, metabolism, and levels of hormones and molecules involved in neural signaling, which could lead to changes in behavior. However, the fish also exhibited traits, including an increase in the cells responsible for pigmentation, that would have no obvious benefit in the darkness. Even though the changes observed require no genetic mutations, they can help or hinder the fish's survival once they occur, possibly determining subsequent evolution. Thus, a trait beneficial for surviving in the dark that appears simply through phenotypic plasticity may eventually be selected for and genetic mutations that encode it more reliably may appear too. These results shed light on how species may quickly adapt to new environments without accumulating genetic mutations, which can take hundreds of thousands of years. They also may help to explain how colonizer species succeed in challenging environments. The principles described by Bilandzija et al. can be applied to different organisms adapting to new environments, and may help understand the role of phenotypic plasticity in evolution.
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Adaptação Fisiológica/fisiologia , Cavernas , Characidae/fisiologia , Animais , Evolução Biológica , FenótipoRESUMO
Astyanax mexicanus consists of two forms, a sighted surface dwelling form (surface fish) and a blind cave-dwelling form (cavefish). Embryonic eyes are initially formed in cavefish but they are subsequently arrested in growth and degenerate during larval development. Previous lens transplantation studies have shown that the lens plays a central role in cavefish eye loss. However, several lines of evidence suggest that additional factors, such as the retinal pigment epithelium (RPE), which is morphologically altered in cavefish, could also be involved in the eye regression process. To explore the role of the RPE in cavefish eye degeneration, we generated an albino eyed (AE) strain by artificial selection for hybrid individuals with large eyes and a depigmented RPE. The AE strain exhibited an RPE lacking pigment granules and showed reduced expression of the RPE specific enzyme retinol isomerase, allowing eye development to be studied by lens ablation in an RPE background resembling cavefish. We found that lens ablation in the AE strain had stronger negative effects on eye growth than in surface fish, suggesting that an intact RPE is required for normal eye development. We also found that the AE strain develops a cartilaginous sclera lacking boney ossicles, a trait similar to cavefish. Extrapolation of the results to cavefish suggests that the RPE and lens have dual roles in eye degeneration, and that deficiencies in the RPE may be associated with evolutionary changes in scleral ossification.
Assuntos
Characidae/embriologia , Olho/embriologia , Cristalino/embriologia , Epitélio Pigmentado da Retina/embriologia , Animais , Cavernas , Characidae/anatomia & histologia , Characidae/crescimento & desenvolvimento , Olho/crescimento & desenvolvimento , Anormalidades do Olho/embriologia , Feminino , Cristalino/crescimento & desenvolvimento , Masculino , Epitélio Pigmentado da Retina/anatomia & histologia , Epitélio Pigmentado da Retina/crescimento & desenvolvimentoRESUMO
Importance: Secondhand smoking is a risk to adult ocular health, but its effect on children's ocular development is not known. Objective: To assess the association between choroidal thickness and secondhand smoking exposure in children. Design, Setting, and Participants: Children aged 6 to 8 years were consecutively recruited from January 2016 to July 2017 from the population-based Hong Kong Children Eye Study at the Chinese University of Hong Kong Eye Centre. All participants underwent detailed ophthalmic investigations. Choroidal thickness was measured by swept-source optical coherence tomography, with built-in software that automatically segmented the choroid layer to analyze its terrain imagery. History of secondhand smoking was obtained from a questionnaire. Multiple linear regression analyses were performed to assess the correlation between choroidal thickness and secondhand exposure when controlling for confounding factors. Analysis began July 2018 and ended in April 2019. Main Outcomes and Measurements: The association between children's choroidal thickness and their exposure to secondhand smoking. Results: Of 1400 children, 941 (67.2%) had no exposure to secondhand smoking, and 459 (32.8%) had exposure to secondhand smoking. The mean (SD) age was 7.65 (1.09) years for children in the nonexposure group and 7.54 (1.11) years for children in the exposure group. After adjustment for age, sex, body mass index, axial length, and birth weight, exposure to secondhand smoking was associated with a thinner choroid by 8.3 µm in the central subfield, 7.2 µm in the inner inferior, 6.4 µm in the outer inferior, 6.4 µm in the inner temporal, and 7.3 µm in the outer temporal. Choroidal thinning with also associated with increased number of family smokers and increased quantity of secondhand smoking. An increase of 1 family smoker was associated with choroidal thinning by 7.86 µm in the central subfield, 4.51 µm in the outer superior, 6.23 µm in the inner inferior, 5.59 µm in the outer inferior, 6.06 µm in the inner nasal, and 6.55 µm in the outer nasal. An increase of exposure to 1 secondhand cigarette smoke per day was associated with choroidal thinning by 0.54 µm in the central subfield, 0.42 µm in the inner temporal, and 0.47 µm in the outer temporal. Conclusions and Relevance: This investigation showed that exposure to secondhand smoking in children was associated with choroidal thinning along with a dose-dependent effect. These results support evidence regarding the potential hazards of secondhand smoking to children.
Assuntos
Doenças da Coroide/etiologia , Corioide/patologia , Poluição por Fumaça de Tabaco/efeitos adversos , Criança , Corioide/diagnóstico por imagem , Doenças da Coroide/diagnóstico por imagem , Estudos Transversais , Feminino , Hong Kong , Humanos , Masculino , Tamanho do Órgão , Inquéritos e Questionários , Tomografia de Coerência Óptica , Acuidade VisualRESUMO
Despite causing regular seasonal epidemics with substantial morbidity, mortality and socioeconomic burden, there is still a lack of research into influenza B viruses (IBVs). In this study, we provide for the first time a systematic investigation on the tropism, replication kinetics and pathogenesis of IBVs in the human respiratory tract.Physiologically relevant ex vivo explant cultures of human bronchus and lung, human airway organoids, and in vitro cultures of differentiated primary human bronchial epithelial cells and type-I-like alveolar epithelial cells were used to study the cellular and tissue tropism, replication competence and induced innate immune response of 16 IBV strains isolated from 1940 to 2012 in comparison with human seasonal influenza A viruses (IAVs), H1N1 and H3N2. IBVs from the diverged Yamagata- and Victoria-like lineages and the earlier undiverged period were included.The majority of IBVs replicated productively in human bronchus and lung with similar competence to seasonal IAVs. IBVs infected a variety of cell types, including ciliated cells, club cells, goblet cells and basal cells, in human airway organoids. Like seasonal IAVs, IBVs are low inducers of pro-inflammatory cytokines and chemokines. Most results suggested a higher preference for the conducting airway than the lower lung and strain-specific rather than lineage-specific pathogenicity of IBVs.Our results highlighted the non-negligible virulence of IBVs which require more attention and further investigation to alleviate the disease burden, especially when treatment options are limited.
Assuntos
Vírus da Influenza B/fisiologia , Organoides/patologia , Organoides/virologia , Sistema Respiratório/patologia , Sistema Respiratório/virologia , Tropismo Viral , Animais , Brônquios/patologia , Diferenciação Celular , Cães , Células Epiteliais/virologia , Eritrócitos/citologia , Humanos , Imunidade Inata , Imuno-Histoquímica , Vírus da Influenza A Subtipo H1N1/fisiologia , Vírus da Influenza A Subtipo H3N2/fisiologia , Concentração Inibidora 50 , Pulmão/patologia , Células Madin Darby de Rim Canino , Técnicas de Cultura de Órgãos , PerusRESUMO
Middle East Respiratory Syndrome Coronavirus (MERS-CoV) has emerged as a coronavirus infection of humans in the past 5 years. Though confined to certain geographical regions of the world, infection has been associated with a case fatality rate of 35%, and this mortality may be higher in ventilated patients. As there are few readily available animal models that accurately mimic human disease, it has been a challenge to ethically determine what optimum treatment strategies can be used for this disease. We used in-vitro and human ex-vivo explant cultures to investigate the effect of two immunomodulatory agents, interferon alpha and cyclosporine, singly and in combination, on MERS-CoV replication. In both culture systems the combined treatment was more effective than either agent used alone in reducing MERS-CoV replication. PCR SuperArray analysis showed that the reduction of virus replication was associated with a greater induction of interferon stimulated genes. As these therapeutic agents are already licensed for clinical use, it may be relevant to investigate their use for therapy of human MERS-CoV infection.