Age-related driving mechanisms of retinal diseases and neuroprotection by transcription factor EB-targeted therapy.

Retinal aging has been recognized as a significant risk factor for various retinal disorders, including diabetic retinopathy, age-related macular degeneration, and glaucoma, following a growing understanding of the molecular underpinnings of their development. This comprehensive review explores the mechanisms of retinal aging and investigates potential neuroprotective approaches, focusing on the activation of transcription factor EB. Recent meta-analyses have demonstrated promising outcomes of transcription factor EB-targeted strategies, such as exercise, calorie restriction, rapamycin, and metformin, in patients and animal models of these common retinal diseases. The review critically assesses the role of transcription factor EB in retinal biology during aging, its neuroprotective effects, and its therapeutic potential for retinal disorders. The impact of transcription factor EB on retinal aging is cell-specific, influencing metabolic reprogramming and energy homeostasis in retinal neurons through the regulation of mitochondrial quality control and nutrient-sensing pathways. In vascular endothelial cells, transcription factor EB controls important processes, including endothelial cell proliferation, endothelial tube formation, and nitric oxide levels, thereby influencing the inner blood-retinal barrier, angiogenesis, and retinal microvasculature. Additionally, transcription factor EB affects vascular smooth muscle cells, inhibiting vascular calcification and atherogenesis. In retinal pigment epithelial cells, transcription factor EB modulates functions such as autophagy, lysosomal dynamics, and clearance of the aging pigment lipofuscin, thereby promoting photoreceptor survival and regulating vascular endothelial growth factor A expression involved in neovascularization. These cell-specific functions of transcription factor EB significantly impact retinal aging mechanisms encompassing proteostasis, neuronal synapse plasticity, energy metabolism, microvasculature, and inflammation, ultimately offering protection against retinal aging and diseases. The review emphasizes transcription factor EB as a potential therapeutic target for retinal diseases. Therefore, it is imperative to obtain well-controlled direct experimental evidence to confirm the efficacy of transcription factor EB modulation in retinal diseases while minimizing its risk of adverse effects.

18F-FDG PET/CT semi-quantitative parameters combined with SCC-Ag in predicting lymph node metastasis in stage I-II cervical cancer.

Objective: To explore the value of 18F-fluordeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) semi-quantitative parameters of primary tumor combined with squamous cell carcinoma antigen (SCC-Ag) in predicting lymph node metastasis (LNM) of cervical cancer (FIGO 2018 stage I-II). Materials and Methods: A total of 65 patients with stage I-II cervical cancer underwent 18F-FDG PET/CT were included in our study. Comparing the primary tumor 18F-FDG PET/CT semi-quantitative parameters and SCC-Ag between the LNM group and the non-LNM group. Logistic regression and receiver operating characteristic (ROC) were used to analyze the value of 18F-FDG PET/CT metabolic parameters and SCC-Ag in predicting LNM. Results: There were 14 and 51 patients were classified as having LNM and NLNM. The semi-quantitative parameters, including the maximum standardized uptake value (SUVmax), the mean standardized uptake value (SUVmean), the peak standardized uptake value (SUVpeak), the total lesion glycolysis (TLG), the metabolic tumor volume (MTV) of the tumor and SCC-Ag were all significantly higher in LNM than in NLNM (SUVmax, 16.07 ± 7.81 vs 11.19 ± 4.73, SUVmean, 9.16 ± 3.48 vs 6.29 ± 2.52, SUVpeak, 12.70 ± 5.26 vs 7.65 ± 3.26, MTV, 22.77 ± 12.36 vs 7.09 ± 5.21, TLG, 211.01 ± 154.25 vs 43.38 ± 36.17, SCC-Ag, 5.39 ± 4.56 vs 2.13 ± 2.50, all p<0.01). Logistic regression analysis showed that TLG was an independent predictor of LNM in stage I-II cervical cancer (OR 1.032, 95% CI 1.013-1.052, p<0.01). Moreover, the predictive value of TLG combined with SUVpeak and SCC-Ag increased and the area under the curve increased compared SUVpeak and SCC-Ag. Conclusion: 18F-FDG PET/CT semi-quantitative parameters and SCC-Ag have promise for assessing LNM in stage I-II cervical cancer. TLG of primary tumor provides independent and increasing values in predicting LNM in stage I-II cervical cancer.

Coenzyme Q10 eyedrops conjugated with vitamin E TPGS alleviate neurodegeneration and mitochondrial dysfunction in the diabetic mouse retina.

Diabetic retinopathy (DR) is a leading cause of blindness and vision impairment worldwide and represents one of the most common complications among diabetic patients. Current treatment modalities for DR, including laser photocoagulation, intravitreal injection of corticosteroid, and anti-vascular endothelial growth factor (VEGF) agents, target primarily vascular lesions. However, these approaches are invasive and have several limitations, such as potential loss of visual function, retinal scars and cataract formation, and increased risk of ocular hypertension, vitreous hemorrhage, retinal detachment, and intraocular inflammation. Recent studies have suggested mitochondrial dysfunction as a pivotal factor leading to both the vascular and neural damage in DR. Given that Coenzyme Q10 (CoQ10) is a proven mitochondrial stabilizer with antioxidative properties, this study investigated the effect of CoQ10 eyedrops [in conjunction with vitamin E d-α-tocopheryl poly(ethylene glycol) 1000 succinate (TPGS)] on DR-induced neurodegeneration using a type 2 diabetes mouse model (C57BLKsJ-db/db mice). Utilizing a comprehensive electroretinography protocol, supported by immunohistochemistry, our results revealed that topical application of CoQ10 eyedrops conjugated with vitamin E TPGS produced a neuroprotective effect against diabetic-induced neurodegeneration by preserving the function and histology of various retinal neural cell types. Compared to the control group, mice treated with CoQ10 exhibited thicker outer and inner nuclear layers, higher densities of photoreceptor, cone cell, and rod-bipolar cell dendritic boutons, and reduced glial reactivity and microglial cell density. Additionally, the CoQ10 treatment significantly alleviated retinal levels of MMP-9 and enhanced mitochondrial function. These findings provide further insight into the role of mitochondrial dysfunction in the development of DR and suggest CoQ10 eyedrops, conjugated with vitamin E TPGS, as a potential complementary therapy for DR-related neuropathy.

Combination effect of optical defocus and low dose atropine in myopia control: Study protocol for a randomized clinical trial.

BACKGROUND: Myopia, characterized by excessive axial elongation of the eyeball, increases risks of having sight-threatening diseases and impose a financial burden to healthcare system. Although myopic control interventions showed their effectiveness in slowing progression, the efficacy varies between individuals and does not completely halt progression. The study aims to investigate the efficacy of combining 0.01% atropine administered twice daily with optical defocus for myopia control in schoolchildren. METHODS AND DESIGN: This is a prospective, parallel-group, single-blinded, randomized, active-control trial (ClinicalTrials.gov identifier: NCT06358755). Myopic schoolchildren with no previous myopic control interventions aged between 7 to 12 years will be recruited. They will be randomly allocated into two groups (n = 56 per group) after baseline measurement. Both groups will receive 0.01% atropine twice per day for 18 months (one drop in the morning and the other drop at night before bedtime). Defocus incorporated multiple segments (DIMS) spectacle lenses will be prescribed in atropine plus optical defocus (ATD) treatment group while single vision spectacle lenses will be given in atropine only (AT) group. Cycloplegic refraction and axial lengths will be monitored every 6 months over 18-month study period. The primary outcomes are changes in cycloplegic refraction and axial lengths relative to the baseline over the study period. DISCUSSION: The result will examine the combination effect of low dose atropine and myopic defocus on myopia control in a randomized controlled study. The findings will also explore the potential benefits of applying 0.01% atropine twice per day on myopic control and its potential side effects.

Strategies to address inequity of uncorrected refractive error in the Western Pacific: A modified Delphi process.

PURPOSE: Uncorrected refractive error is the leading cause of vision impairment globally; however, little attention has been given to equity and access to services. This study aimed to identify and prioritise: (1) strategies to address inequity of access to refractive error services and (2) population groups to target with these strategies in five sub-regions within the Western Pacific. METHODS: We invited eye care professionals to complete a two-round online prioritisation process. In round 1, panellists nominated population groups least able to access refractive error services, and strategies to improve access. Responses were summarised and presented in round 2, where panellists ranked the groups (by extent of difficulty and size) and strategies (in terms of reach, acceptability, sustainability, feasibility and equity). Groups and strategies were scored according to their rank within each sub-region. RESULTS: Seventy five people from 17 countries completed both rounds (55% women). Regional differences were evident. Indigenous peoples were a priority group for improving access in Australasia and Southeast Asia, while East Asia identified refugees and Oceania identified rural/remote people. Across the five sub-regions, reducing out-of-pocket costs was a commonly prioritised strategy for refraction and spectacles. Australasia prioritised improving cultural safety, East Asia prioritised strengthening school eye health programmes and Oceania and Southeast Asia prioritised outreach to rural areas. CONCLUSION: These results provide policy-makers, researchers and funders with a starting point for context-specific actions to improve access to refractive error services, particularly among underserved population groups who may be left behind in existing private sector-dominated models of care.

Continuously Adjustable Thickness of Bi2MoO6 Nanosheets Enhances Photocatalytic Oxidation.

In this study, two-dimensional (2D) nanosheet photocatalysts of Bi2MoO6 with varying thicknesses were synthesized by adjusting the temperature during the hydrothermal reaction. The thinnest Bi2MoO6 nanosheet reached an approximate thickness of ∼4 nm, while the thickest nanosheet measured only ∼16 nm. The photocatalytic performance for Rhodamine B (RhB) degradation was found to be the most effective for the thinnest Bi2MoO6 nanosheet, displaying a degradation rate constant of 0.11 min-1. This rate was 2.5 times higher than that observed for the ∼16 nm thick Bi2MoO6 photocatalyst. The enhanced performance of the thinner two-dimensional nanostructure can be attributed to improved separation and migration of photogenerated charges. Additionally, the study identified hydroxyl radicals (•OH) and superoxide radicals (•O2-) as crucial oxidative species, contributing to the efficient mineralization of RhB dye. This work highlights the controllable synthesis of 2D materials with varying thicknesses and their specific applications in photocatalytic oxidation.

Research on the spatiotemporal evolution and influencing factors of urbanization and carbon emission efficiency coupling coordination: From the perspective of global countries.

Strategic coordination between urbanization and carbon emission efficiency (CEE) is vital for promoting low-carbon urbanization and sustainable urban planning. In order to assess the coupled coordination degree (CCD) of urbanization and CEE and investigate the factors influencing the CCD, this research employs the Super slacks-based measure (SBM) model, the coupled coordination degree model (CCDM), and the Tobit model. Four key findings emerge from the analysis of the temporal and spatial evolution traits of the CCD based on data from 106 nations worldwide between 2005 and 2020. (1) The global CEE shows a significant downward trend, and the spatial disparity is unambiguous. high CEE countries hang in the north and west of Europe, while those in Asia, Africa and the east of Europe have lower CEE. (2) The combined urbanization level and demographic, economic and social urbanization are all on an upward trend. Singapore has the greatest degree of urbanization overall globally. (3) The CCD of urbanization and CEE shows a fluctuating upward trend, with particularly strong changes in 2018-2020. 2017 and 2018 are the years with better global coupling coordination status. During the study period, the CCD results of countries are mostly uncoordinated and low coordination, and the CCD of the United States, China, India and Japan is in the front. (4) The effect of urban electrification rate on the CCD is positive; the effect of foreign trade and net inflow of foreign direct investment is negative; while energy structure and industrial structure have no significant effect. A number of policy proposals are put forth in light of the outcomes of the research to enhance the coordination.

Construct validity and test-retest reliability of a chrononutrition questionnaire for shift work and non-shift work populations.

The irregular eating patterns of both shift workers and evening chronotypes adversely affect cardiometabolic health. A tool that conveniently captures temporal patterns of eating alongside an indicator of circadian rhythm such as chronotype will enable researchers to explore relationships with diverse health outcome measures. We aimed to investigate the test-retest reliability and convergent validity of a Chrononutrition Questionnaire (CNQ) that captures temporal patterns of eating and chronotype in the general population (non-shift workers, university students, retirees, unemployed individuals) and shift work population. Participants attended two face-to-face/virtual sessions and completed the CNQ and food/sleep/work diaries. Outcomes included subjective chronotype, wake/sleep/mid-sleep time, sleep duration, meal/snack regularity, meal/snack/total frequency, times of first/last/largest eating occasions (EO), main meal (MM) 1/2/3, and duration of eating window (DEW). 116 participants enrolled (44.5 ± 16.5 years, BMI: 27.3 ± 5.8 kg/m2, 73% female, 52% general population); 105 completed the study. Reliability was acceptable for chronotype, sleep, and all temporal eating patterns except on night shifts. Convergent validity was good for chronotype and sleep except for certain shift/shift-free days. Generally, meal/snack regularity and frequency, and times of first/last EO showed good validity for the general population but not shift workers. Validity was good for DEW (except work-free days and afternoon shifts) and times of MM 1/2/3 (except afternoon and night shifts), while time of largest EO had poor validity. The CNQ has good test-retest reliability and acceptable convergent validity for the general and shift work population, although it will benefit from further validation, especially regarding regularity, frequency, and times of first and last eating occasions across more days amongst a larger sample size of shift workers. Use of the CNQ by researchers will expand our current understanding of chrononutrition as relationships between timing of food intake and the multitude of health outcomes are examined.

Potential actions of capsaicin for preventing vascular calcification of vascular smooth muscle cells in vitro and in vivo.

Vascular calcification (VC) is an accurate risk factor and predictor of adverse cardiovascular events; however, there is currently no effective therapy to specifically prevent VC progression. Capsaicin (Cap) is a bioactive alkaloid isolated from Capsicum annuum L., a traditional medicinal and edible plant that is beneficial for preventing cardiovascular diseases. However, the effect of Cap on VC remains unclear. This study aimed to explore the effects and related mechanisms of Cap on aortic calcification in a mouse and on Pi-induced calcification in vascular smooth muscle cells (VSMCs). First, we established a calcification mouse model with vitamin D3 and evaluated the effects of Cap on calcification mice using von Kossa staining, calcium content, and alkaline phosphatase activity tests. The results showed that Cap significantly improved calcification in mice. VSMCs were then cultured in 2.6 mM Na2HPO4 and 50 µg/mL ascorbic acid for 7 days to obtain a calcification model, and we investigated the effects and mechanisms of Cap on VSMCs calcification by assessing the changes of calcium deposition, calcium content, and subsequent VC biomarkers. These results showed that Cap alleviated VSMCs calcification by upregulating the expressions of TRPV1. Moreover, Cap reduced the expression of Wnt3a and ß-catenin, whereas DKK1 antagonised the inhibitory effect of Cap on VSMC calcification. This study is the first to offer direct evidence that Cap inhibits the Wnt/ß-catenin signaling pathway by upregulating the expression of the TRPV1 receptor, resulting in the decreased expression of Runx2 and BMP-2, thereby reducing VSMC calcification. Our study may provide novel strategies for preventing the progression of VC. This could serve as a theoretical basis for clinically treating VC with spicy foods.

Pharmaceutical Residues in Edible Oysters along the Coasts of the East and South China Seas and Associated Health Risks to Humans and Wildlife.

The investigation of pharmaceuticals as emerging contaminants in marine biota has been insufficient. In this study, we examined the presence of 51 pharmaceuticals in edible oysters along the coasts of the East and South China Seas. Only nine pharmaceuticals were detected. The mean concentrations of all measured pharmaceuticals in oysters per site ranged from 0.804 to 15.1 ng g-1 of dry weight, with antihistamines being the most common. Brompheniramine and promethazine were identified in biota samples for the first time. Although no significant health risks to humans were identified through consumption of oysters, 100-1000 times higher health risks were observed for wildlife like water birds, seasnails, and starfishes. Specifically, sea snails that primarily feed on oysters were found to be at risk of exposure to ciprofloxacin, brompheniramine, and promethazine. These high risks could be attributed to the monotonous diet habits and relatively limited food sources of these organisms. Furthermore, taking chirality into consideration, chlorpheniramine in the oysters was enriched by the S-enantiomer, with a relative potency 1.1-1.3 times higher when chlorpheniramine was considered as a racemate. Overall, this study highlights the prevalence of antihistamines in seafood and underscores the importance of studying enantioselectivities of pharmaceuticals in health risk assessments.

Category representation in primary visual cortex after visual perceptual learning.

The visual perceptual learning (VPL) leads to long-term enhancement of visual task performance. The subjects are often trained to link different visual stimuli to several options, such as the widely used two-alternative forced choice (2AFC) task, which involves an implicit categorical decision. The enhancement of performance has been related to the specific changes of neural activities, but few studies investigate the effects of categorical responding on the changes of neural activities. Here we investigated whether the neural activities would exhibit the categorical characteristics if the subjects are requested to respond visual stimuli in a categorical manner during VPL. We analyzed the neural activities of two monkeys in a contour detection VPL. We found that the neural activities in primary visual cortex (V1) converge to one pattern if the contour can be detected by monkey and another pattern if the contour cannot be detected, exhibiting a kind of category learning that the neural representations of detectable contour become less selective for number of bars forming contour and diverge from the representations of undetectable contour. Supplementary Information: The online version contains supplementary material available at 10.1007/s11571-022-09926-8.

Drivers of arthropod biodiversity in an urban ecosystem.

Our world is becoming increasingly urbanized with a growing human population concentrated around cities. The expansion of urban areas has important consequences for biodiversity, yet the abiotic drivers of biodiversity in urban ecosystems have not been well characterized for the most diverse group of animals on the planet, arthropods. Given their great diversity, comparatively small home ranges, and ability to disperse, arthropods make an excellent model for studying which factors can most accurately predict urban biodiversity. We assessed the effects of (i) topography (distance to natural areas and to ocean) (ii) abiotic factors (mean annual temperature and diurnal range), and (iii) anthropogenic drivers (land value and amount of impervious surface) on the occurrence of six arthropod groups represented in Malaise trap collections run by the BioSCAN project across the Greater Los Angeles Area. We found striking heterogeneity in responses to all factors both within and between taxonomic groups. Diurnal temperature range had a consistently negative effect on occupancy but this effect was only significant in Phoridae. Anthropogenic drivers had mixed though mostly insignificant effects, as some groups and species were most diverse in highly urbanized areas, while other groups showed suppressed diversity. Only Phoridae was significantly affected by land value, where most species were more likely to occur in areas with lower land value. Los Angeles can support high regional arthropod diversity, but spatial community composition is highly dependent on the taxonomic group.

Medicating the coast in a metropolitan city: Enantiomeric profiles and joint probabilistic risk assessment of antidepressants and antihistamines.

Pharmaceuticals are receiving increasing attention as emerging contaminants in the aquatic environment. Herein, we investigated the occurrence of 11 antidepressants, 6 antihistamines and 4 metabolites in treated wastewater effluents, rivers, stormwater, and seawater in Hong Kong, with special focus on chirality. The average levels of ∑pharmaceuticals ranged from 0.525 to 1070 ng/L in all samples and the total annual mass load of target pharmaceuticals in the marine environment of Hong Kong was 756 kg/y. Antihistamines accounted for >80 % of ∑pharmaceuticals, with diphenhydramine and fexofenadine being predominant. The occurrence and enantiomeric profiles of brompheniramine and promethazine sulfoxide were reported in global natural waters for the first time. Among chiral pharmaceuticals, mirtazapine and fexofenadine exhibited R-preference, while others mostly exhibited S-preference, implying that the ecological risks derived from achiral data for chiral pharmaceuticals may be biased. The joint probabilistic risk assessment of fluoxetine revealed that R-fluoxetine and rac-fluoxetine presented different ecological risks from that of S-fluoxetine; Such assessment also revealed that target pharmaceuticals posed only minimal to low risks, except that diphenhydramine posed an intermediate risk. As estimated, 10 % aquatic species will be affected when the environmental level of diphenhydramine exceeds 7.40 ng/L, which was seen in 46.9 % samples. Collectively, this study highlights further investigations on the enantioselectivity of chiral pharmaceuticals, particularly on environmental behavior and ecotoxicity using local aquatic species as target organisms.

Study of GCN repeats of PHOX2B gene among individuals from southwest China and diagnosis of two patients with Congenital central hypoventilation syndrome / 中华医学遗传学杂志

OBJECTIVE@#To study the trinucleotide repeats of GCN (GCA, GCT, GCC, GCG) encoding Alanine in exon 3 of the PHOX2B gene among healthy individuals from southwest China and two patients with Congenital central hypoventilation syndrome (CCHS).@*METHODS@#The number and sequence of the GCN repeats of the PHOX2B gene were analyzed by capillary electrophoresis, Sanger sequencing and cloning sequencing of 518 healthy individuals and two newborns with CCHS, respectively.@*RESULTS@#Among the 1036 alleles of the 518 healthy individuals, five alleles were identified, including (GCN)7, (GCN)13, (GCN)14, (GCN)15 and (GCN)20. The frequency of the (GCN)20 allele was the highest (94.79%). And five genotypes were identified, which included (GCN)7/(GCN)20, (GCN)13/(GCN)20, (GCN)14/(GCN)20, (GCN)15/(GCN)20, (GCN)20/(GCN)20. The homozygous genotypes were all (GCN)20/(GCN)20, and the carrier rate was 89.58%. Four GCN sequences of the (GCN)20 homozygous genotypes were identified among the 464 healthy individuals. The GCN repeat numbers in the exon 3 of the PHOX2B gene showed no significant difference between the expected and observed values, and had fulfilled the,Hardy-Weinberg equilibrium. The genotypes of the two CCHS patients were (GCN)20/(GCN)25 and (GCN)20/(GCN)30, respectively.@*CONCLUSION@#It is important to determine the GCN repeats and genotypic data of the exon 3 of the PHOX2B gene among the healthy individuals. The number of GCN repeats in 518 healthy individuals was all below 20. The selection of appropriate methods can accurately detect the polyalanine repeat mutations (PARMs) of the PHOX2B gene, which is conducive to the early diagnosis, intervention and treatment of CCHS.

Defocus incorporated multiple segments (DIMS) spectacle lenses increase the choroidal thickness: a two-year randomized clinical trial.

BACKGROUND: Myopia control interventions, such as defocus incorporated multiple segments (DIMS) spectacle lenses, have been adopted in school-aged children to reduce the prevalence of myopia and its complications. This study aimed to investigate the effect of DIMS spectacle lenses on subfoveal choroidal thickness (SfChT) over a period of two years, as the choroidal response to myopic control is a crucial factor in exploring its potential effect on predicting myopia progression. METHODS: This study involved a secondary analysis of our previous randomized clinical trial. Myopic school-aged children aged 8-13 years were recruited in a two-year study investigating the effect of DIMS spectacle lenses on myopia progression. The treated group received DIMS spectacle lenses (n = 78), while the control group was treated with a pair of single vision (SV) spectacle lenses (n = 80). SfChT was monitored at 1 week, 1, 3, 6, 12, 18 and 24 months post lens wear using spectral-domain optical coherence tomography and a custom made auto-segmentation algorithm utilizing convolutional neural networks. RESULTS: SfChT increased significantly after one week of DIMS spectacle lens wear compared to those wearing SV spectacle lenses (adjusted mean change relative to baseline ± SEM at one week; DIMS vs. SV, 6.75 ± 1.52 µm vs. - 3.17 ± 1.48 µm; P < 0.0001, general linear model). The thickness of choroid increased to 13.64 ± 2.62 µm after 12 months of DIMS lens wear while the choroid thinned in SV group (- 9.46 ± 2.55 µm). Choroidal changes demonstrated a significant negative association with axial elongation over two years in both the DIMS and SV groups. Choroidal change at three months significantly predicted the changes in AL at 12 months after controlling the effect of age and gender. CONCLUSIONS: Our study demonstrated a significant choroidal thickening in response to myopic defocus incorporated in a spectacle lens after one week of lens wear, sustained over the two-year study period. The results suggested that choroidal changes at three months may help predict changes in axial length after one year. Trial registration ClinicalTrials.gov. Myopia control with the multi-segment lens. NCT02206217. Registered 29 July 2014, https://clinicaltrials.gov/ct2/show/study/NCT02206217.

Functional and structural changes in the neuroretina are accompanied by mitochondrial dysfunction in a type 2 diabetic mouse model.

BACKGROUND: Diabetic retinopathy (DR), one of the leading causes of blindness and vision impairment, is suggested to exhibit functional and structural changes in retinal neurons as the earliest manifestation, which could be used to predict the progression of related angiopathy. While neural function and survival rely on proper mitochondrial function, and a growing body of literature has supported the role of mitochondrial dysfunction in the development of DR, how diabetes affects mitochondrial function in retinal tissue remains elusive. This study primarily aimed to investigate mitochondrial functional changes in a diabetic rodent model. We also characterized the early DR phenotype, in particular, neurodegeneration. METHODS: C57BLKsJ-db/db (db/db) mice (a type 2 diabetic mouse model) were used with their normoglycemic heterozygous littermates (db/+) serving as controls. Longitudinal changes in retinal function and morphology were assessed with electroretinography (ERG) and optical coherence tomography (OCT), respectively, at 9, 13, 17, and 25 weeks of age. At 25 weeks, the retinas were harvested for immunohistochemistry and ex vivo mitochondrial bioenergetics. RESULTS: Decreased ERG responses were observed in db/db mice as early as 13 weeks of age. OCT revealed that db/db mice had significantly thinner retinas than the controls. Immunohistochemistry showed that the retinas of the db/db mice at 25 weeks were thinner at the outer and inner nuclear layers, with lower photoreceptor and cone cell densities compared with the db/+ mice. The number of rod-bipolar cell dendritic boutons and axon terminals was significantly reduced in db/db mice relative to the db/+ mice, suggesting that diabetes may lead to compromised synaptic connectivity. More importantly, the retinas of db/db mice had weaker mitochondrial functions than the controls. CONCLUSIONS: Our longitudinal data suggest that diabetes-induced functional deterioration and morphological changes were accompanied by reduced mitochondrial function in the retina of db/db mice. These findings suggest that mitochondrial dysfunction may be a contributing factor triggering the development of DR. While the underlying mechanistic cause remains elusive, the db/db mice could be a useful animal model for testing potential treatment regimens targeting neurodegeneration in DR.

Retinal ganglion cells encode differently in the myopic mouse retina?

The etiology of myopia remains unclear. This study investigated whether retinal ganglion cells (RGCs) in the myopic retina encode visual information differently from the normal retina and to determine the role of Connexin (Cx) 36 in this process. Generalized linear models (GLMs), which can capture stimulus-dependent changes in real neurons with spike timing precision and reliability, were used to predict RGCs responses to focused and defocused images in the retinas of wild-type (normal) and Lens-Induced Myopia (LIM) mice. As the predominant subunit of gap junctions in the mouse retina and a plausible modulator in myopia development, Cx36 knockout (KO) mice were used as a control for an intact retinal circuit. The kinetics of excitatory postsynaptic currents (EPSCs) of a single αRGC could reflect projection of both focused and defocused images in the retinas of normal and LIM, but not in the Cx36 knockout mice. Poisson GLMs revealed that RGC encoding of visual stimuli in the LIM retina was similar to that of the normal retina. In the LIM retinas, the linear-Gaussian GLM model with offset was a better fit for predicting the spike count under a focused image than the defocused image. Akaike information criterion (AIC) indicated that nonparametric GLM (np-GLM) model predicted focused/defocused images better in both LIM and normal retinas. However, the spike counts in 33% of αRGCs in LIM retinas were better fitted by exponential GLM (exp-GLM) under defocus, compared to only 13% αRGCs in normal retinas. The differences in encoding performance between LIM and normal retinas indicated the possible amendment and plasticity of the retinal circuit in myopic retinas. The absence of a similar response between Cx36 KO mice and normal/LIM mice might suggest that Cx36, which is associated with myopia development, plays a role in encoding focused and defocused images.

CXCR5 Regulates Neuronal Polarity Development and Migration in the Embryonic Stage via F-Actin Homeostasis and Results in Epilepsy-Related Behavior.

Epilepsy is a common, chronic neurological disorder that has been associated with impaired neurodevelopment and immunity. The chemokine receptor CXCR5 is involved in seizures via an unknown mechanism. Here, we first determined the expression pattern and distribution of the CXCR5 gene in the mouse brain during different stages of development and the brain tissue of patients with epilepsy. Subsequently, we found that the knockdown of CXCR5 increased the susceptibility of mice to pentylenetetrazol- and kainic acid-induced seizures, whereas CXCR5 overexpression had the opposite effect. CXCR5 knockdown in mouse embryos via viral vector electrotransfer negatively influenced the motility and multipolar-to-bipolar transition of migratory neurons. Using a human-derived induced an in vitro multipotential stem cell neurodevelopmental model, we determined that CXCR5 regulates neuronal migration and polarization by stabilizing the actin cytoskeleton during various stages of neurodevelopment. Electrophysiological experiments demonstrated that the knockdown of CXCR5 induced neuronal hyperexcitability, resulting in an increased number of seizures. Finally, our results suggested that CXCR5 deficiency triggers seizure-related electrical activity through a previously unknown mechanism, namely, the disruption of neuronal polarity.

Prevalence of hypertension and its associations with body composition across Chinese and American children and adolescents.

BACKGROUND: The age of onset of hypertension (HTN) is decreasing, and obesity is a significant risk factor. The prevalence and racial disparities in pediatric HTN and the association between body composition and blood pressure are insufficiently studied. This study aimed to evaluate the prevalence of HTN in Chinese and American children and adolescents and to assess the relationship between various body composition indices and HTN. METHODS: Seven thousand, five hundred and seventy-three Chinese and 6239 American children and adolescents aged 8-18 years from the 2013-2015 China Child and Adolescent Cardiovascular Health study and the 2011-2018 National Health and Nutrition Examination Surveys were analyzed. Blood pressure and body composition (fat and muscle) were measured by trained staff. The crude prevalence and age-standardized prevalence rate (ASPR) of primary HTN and its subtypes [isolated systolic hypertension (ISH) and isolated diastolic hypertension (IDH)] were calculated based on 2017 American Academy of Pediatrics guidelines. Multivariable-adjusted linear regression coefficients and odds ratios (ORs) were calculated to assess the associations of body composition indicators with HTN, ISH and IDH. RESULTS: The ASPR of HTN was 18.5% in China (CN) and 4.6% in the United States (US), whereas the obesity prevalence was 7.4% and 18.6%, and the population attributable risk of HTN caused by overweight and obesity was higher in the US than in CN. Increased fat mass, muscle mass and body fat percentage mass were associated with a higher risk of HTN in both countries. The percent of muscle body mass had a protective effect on HTN and ISH in both countries [HTN (CN: OR = 0.83, 95% CI = 0.78-0.88; US: OR = 0.72, 95% CI = 0.64-0.81); ISH (CN: OR = 0.87, 95% CI = 0.80-0.94; US: OR = 0.71, 95% CI = 0.62-0.81)], and the protective effect was more common among children and adolescents with high levels of physical activity. CONCLUSIONS: The burden of HTN in Chinese children and adolescents was substantial and much greater than that in the US, and the contribution of obesity to HTN was higher in the US than in CN. Augmenting the proportion of muscle mass in body composition has a protective effect against HTN in both populations. Optimizing body composition positively influences blood pressure in children and adolescents, particularly those with high-level physical activity. Video abstract (MP4 149982 KB).