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Fuchs endothelial corneal dystrophy (FECD) is a leading cause of corneal endothelial (CE) degeneration resulting in impaired visual acuity. It is a genetically complex and age-related disorder, with higher incidence in females. In this study, we established a nongenetic FECD animal model based on the physiologic outcome of CE susceptibility to oxidative stress by demonstrating that corneal exposure to ultraviolet A (UVA) recapitulates the morphological and molecular changes of FECD. Targeted irradiation of mouse corneas with UVA induced reactive oxygen species (ROS) production in the aqueous humor, and caused greater CE cell loss, including loss of ZO-1 junctional contacts and corneal edema, in female than male mice, characteristic of late-onset FECD. UVA irradiation caused greater mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) damage in female mice, indicative of the sex-driven differential response of the CE to UVA, thus accounting for more severe phenotype in females. The sex-dependent effect of UVA was driven by the activation of estrogen-metabolizing enzyme CYP1B1 and formation of reactive estrogen metabolites and estrogen-DNA adducts in female but not male mice. Supplementation of N-acetylcysteine (NAC), a scavenger of reactive oxygen species (ROS), diminished the morphological and molecular changes induced by UVA in vivo. This study investigates the molecular mechanisms of environmental factors in FECD pathogenesis and demonstrates a strong link between UVA-induced estrogen metabolism and increased susceptibility of females for FECD development.

Increased intraocular pressure (IOP) represents a major risk factor for glaucoma, a prevalent eye disease characterized by death of retinal ganglion cells; lowering IOP is the only proven treatment strategy to delay disease progression. The main determinant of IOP is the equilibrium between production and drainage of aqueous humor, with compromised drainage generally viewed as the primary contributor to dangerous IOP elevations. Drainage occurs through two pathways in the anterior segment of the eye called conventional and uveoscleral. To gain insights into the cell types that comprise these pathways, we used high-throughput single-cell RNA sequencing (scRNAseq). From ∼24,000 single-cell transcriptomes, we identified 19 cell types with molecular markers for each and used histological methods to localize each type. We then performed similar analyses on four organisms used for experimental studies of IOP dynamics and glaucoma: cynomolgus macaque (Macaca fascicularis), rhesus macaque (Macaca mulatta), pig (Sus scrofa), and mouse (Mus musculus). Many human cell types had counterparts in these models, but differences in cell types and gene expression were evident. Finally, we identified the cell types that express genes implicated in glaucoma in all five species. Together, our results provide foundations for investigating the pathogenesis of glaucoma and for using model systems to assess mechanisms and potential interventions.

Alzheimer's disease (AD) is an ageing-related neurodegenerative disease characterized and diagnosed by deposition of insoluble amyloid-β (Aβ) plaques in the brain. The plaque accumulation in the brain directly affects reduced levels of Aβ in cerebrospinal fluid (CSF) and blood, as Aβ can freely transport the blood-brain barrier, and clinical investigations have suggested these two biofluids as promising samples for in vitro diagnosis. Given that the human eye structurally resembles the brain and Aβ accumulation often observed in the ocular region of AD patients, in this study, we examined aqueous humor Aβ as another possible surrogate biomarker. First, using the acute Aβ-infused AD mouse model by injecting Aβ to the CSF in intracerebroventricular region of normal ICR mice, we investigated whether Aβ concentration in the aqueous humor in AD models is positively correlated with the concentration in the CSF. Then, we examined the correlation of aqueous humor Aβ levels with increased plaque deposition in the brain and reduced Aβ levels in both CSF and blood in adult and aged 5XFAD Alzheimer transgenic mice. Collectively, the synthetic Aβ injected into CSF immediately migrate to the aqueous humor, however, the age-dependently reducing pattern of Aβ levels in CSF and blood was not observed in the aqueous humor.

Ultraviolet absorption (UV) spectroscopy is an invaluable method for analyzing compounds in ocular fluids, identifying chemical structures, and understanding molecular interactions. The widespread use of additives in food production is well documented; these additives color, flavor, preserve, and enhance the texture or nutrition of food, ensuring a broader range of products and reducing costs. This study employed UV spectroscopy to examine changes in aqueous humor composition after daily intake of permitted amounts of food additives over 45–90 days. The rats were administered colorant dyes (carmoisine or tartrazine), a sodium benzoate preservative, or a combination of all three through oral gavage. Aqueous humor samples were collected post sedation from the anterior chamber via a 30-gauge needle without additional processing. The spectra of these samples were analyzed via secondary derivative calculations and chemometric analysis (principal component and hierarchical analyses) with OriginPro 2015 software. The common outcome observed was ocular toxicity, resulting from decreased antioxidant defense mechanisms, leading to ocular side effects on the cornea and lens. These changes in aqueous humor composition are indirectly linked to food additives rather than the mechanisms of aqueous humor formation.

Primary congenital glaucoma (PCG) is a severe disease characterized by developmental defects in the trabecular meshwork (TM) and Schlemm’s canal (SC), comprising the conventional aqueous humor outflow pathway of the eye. Recently, heterozygous loss of function variants in TEK and ANGPT1 or compound variants in TEK / SVEP1 were identified in children with PCG. Moreover, common variants in ANGPT1 and SVEP1 have been identified as risk alleles for primary open angle glaucoma (POAG) in GWAS studies. Here, we show tissue-specific deletion of Angpt1 or Svep1 from the TM causes PCG in mice with severe defects in the adjacent SC. Single-cell transcriptomic analysis of normal and glaucomatous Angpt1 deficient eyes allowed us to identify distinct TM and SC cell populations and discover additional TM-SC signaling pathways. Furthermore, confirming the importance of angiopoietin signaling in SC, delivery of a recombinant ANGPT1-mimetic promotes developmental SC expansion in healthy and Angpt1 deficient eyes, blunts intraocular pressure (IOP) elevation and RGC loss in a mouse model of PCG and lowers IOP in healthy adult mice. Our data highlight the central role of ANGPT1-TEK signaling and TM-SC crosstalk in IOP homeostasis and provide new candidates for SC-targeted glaucoma therapy. Primary congenital glaucoma (PCG) is characterised by increased intraocular pressure, and variants in ANGPT1 , or SVEP1 have been identified as risk alleles. Here, the authors show that deletion of these genes induces glaucoma in mice, and that activation of ANGPT1-TEK signaling ameliorates disease progression in mouse models.

In this Perspective article, Reiss and colleagues summarize the most recent neuroimaging studies attempting to determine the neural correlates of humour and discuss the influence of sex, personality traits and certain psychiatric disorders on humour appreciation. Humour is a vital component of human socio-affective and cognitive functioning. Recent advances in neuroscience have enabled researchers to explore this human attribute in children and adults. Humour seems to engage a core network of cortical and subcortical structures, including temporo-occipito-parietal areas involved in detecting and resolving incongruity (mismatch between expected and presented stimuli); and the mesocorticolimbic dopaminergic system and the amygdala, key structures for reward and salience processing. Examining personality effects and sex differences in the neural correlates of humour may aid in understanding typical human behaviour and the neural mechanisms underlying neuropsychiatric disorders, which can have dramatic effects on the capacity to experience social reward.

Myopia is the most common eye disease in the world which is caused by a mismatch between the optical power of the eye and its excessive axial length. Scleral remodeling, oxidative stress, inflammation, pathological states of angiogenesis and fibrosis and metabolism are closely associated with the onset and progression of myopia and the pathological changes that may ultimately result. Intraocular fluid is a collective term for the fluid within the eye, and changes in its composition can reflect the physiological and pathological status within the eye, with aqueous humor and vitreous being the commonly tested specimens. Recent studies have revealed potential changes in a variety of molecules in intraocular fluid during myopia progression. Abnormal expression of these molecules may reflect different stages of myopia and provide new perspectives for disease monitoring and treatment. Therefore, in this review, we systematically review the molecular changes in intraocular fluid associated with myopia, as well as the possible mechanisms, with a view to informing basic myopia research and clinical work.

Primary Open Angle Glaucoma (POAG) is the most common form of glaucoma that leads to irreversible vision loss. Dysfunction of trabecular meshwork (TM) tissue, a major regulator of aqueous humor (AH) outflow resistance, is associated with intraocular pressure (IOP) elevation in POAG. However, the underlying pathological mechanisms of TM dysfunction in POAG remain elusive. In this regard, transient receptor potential vanilloid 4 (TRPV4) cation channels are known to be important Ca2+ entry pathways in multiple cell types. Here, we provide direct evidence supporting Ca2+ entry through TRPV4 channels in human TM cells and show that TRPV4 channels in TM cells can be activated by increased fluid flow/shear stress. TM-specific TRPV4 channel knockout in mice elevated IOP, supporting a crucial role for TRPV4 channels in IOP regulation. Pharmacological activation of TRPV4 channels in mouse eyes also improved AH outflow facility and lowered IOP. Importantly, TRPV4 channels activated endothelial nitric oxide synthase (eNOS) in TM cells, and loss of eNOS abrogated TRPV4-induced lowering of IOP. Remarkably, TRPV4-eNOS signaling was significantly more pronounced in TM cells compared to Schlemm’s canal cells. Furthermore, glaucomatous human TM cells show impaired activity of TRPV4 channels and disrupted TRPV4-eNOS signaling. Flow/shear stress activation of TRPV4 channels and subsequent NO release were also impaired in glaucomatous primary human TM cells. Together, our studies demonstrate a central role for TRPV4-eNOS signaling in IOP regulation. Our results also provide evidence that impaired TRPV4 channel activity in TM cells contributes to TM dysfunction and elevated IOP in glaucoma.

On the surface, fear and humor seem like polar opposite states of mind, yet throughout our lives they continually interact. In this paper, we synthesize neurobiological, psychological, and evolutionary research on fear and humor, arguing that the two are deeply connected. The evolutionary origins of humor reside in play, a medium through which animals benignly explore situations and practice strategies, such as fight or flight, which would normally be accompanied by fear. Cognitively, humor retains the structure of play. Adopting a view of humor as requiring two appraisals, a violation appraisal and a benign appraisal, we describe how fear-inducing stimuli can be rendered benignly humorous through contextual cues, psychological distance, reframing, and cognitive reappraisal. The antagonistic relationship between humor and fear in terms of their neurochemistry and physiological effects in turn makes humor ideal for managing fear in many circumstances. We review five real-world examples of humor and fear intersecting, presenting new data in support of our account along the way. Finally, we discuss the possible therapeutic relevance of the deep connection between humor and fear.

Elevated intraocular pressure is the only treatable risk factor for glaucoma, an eye disease that is the leading cause of irreversible blindness worldwide. We have identified cromakalim prodrug 1 (CKLP1), a novel water-soluble ATP-sensitive potassium channel opener, as a new ocular hypotensive agent. To evaluate the pharmacokinetic and safety profile of CKLP1 and its parent compound levcromakalim, Dutch-belted pigmented rabbits were treated intravenously (0.25 mg/kg) or topically (10 mM; 4.1 mg/ml) with CKLP1. Body fluids (blood, aqueous and vitreous humor) were collected at multiple time points and evaluated for the presence of CKLP1 and levcromakalim using a liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) based assay. Histology of tissues isolated from Dutch-belted pigmented rabbits treated once daily for 90 days was evaluated in a masked manner by a certified veterinary pathologist. The estimated plasma parameters following intravenous administration of 0.25 mg/kg of CKLP1 showed CKLP1 had a terminal half-life of 61.8 ± 55.2 min, Tmax of 19.8 ± 23.0 min and Cmax of 1968.5 ± 831.0 ng/ml. Levcromakalim had a plasma terminal half-life of 85.0 ± 37.0 min, Tmax of 61.0 ± 32.0 min and Cmax of 10.6 ± 1.2 ng/ml. Topical CKLP1 treatment in the eye showed low levels (<0.3 ng/mL) of levcromakalim in aqueous and vitreous humor, and trace amounts of CKLP1 and levcromakalim in the plasma. No observable histological changes were noted in selected tissues that were examined following topical application of CKLP1 for 90 consecutive days. These results suggest that CKPL1 is converted to levcromakalim in the eye and likely to some extent in the systemic circulation.