Ocular Dominance Shift in Refractive Cataract Surgery: A prospective, observational study.

PURPOSE: To explore the features of the dominant and non-dominant eyes in patients with cataracts and predict ocular dominance shift (ODS) based on preoperative indicators. DESIGN: and setting: This prospective, observational study was conducted in Changsha Aier Eye Hospital in Changsha, Hunan province, China. METHODS: Patients with age-related cataracts who underwent unilateral cataract surgery were enrolled in this study. Before the procedure, uncorrected visual acuity (UCVA) was assessed, and non-cycloplegic subjective refraction evaluations were conducted to determine best-corrected visual acuity (BCVA). Total astigmatism, corneal astigmatism, and intraocular astigmatism were measured using OPD-Scan III. Cataract type was assessed using slit-lamp biomicroscopy based on the Lens Opacities Classification System III (LOCS III). Ocular dominance (OD) was determined under corrected conditions using the hole-in-card test. Follow-up visits occurred at 1 day, 1 week, and 1-month post-surgery. After 1 month, OD was re-evaluated, and participants completed the Catquest-9SF questionnaire. RESULTS: 94 patients (188 eyes) were enrolled in the study. The analysis showed that the ODS rate of unilateral cataract surgery was 40.4%. In addition, age, uncorrected visual acuity of non-dominant eye, posterior subcapsular cataract and total astigmatism are risk factors for ODS. Besides, no difference in vision-related quality of life was detected between patients who had ODS and those who did not. CONCLUSIONS: We identified several preoperative parameters as potential risk factors of ODS after cataract surgery. These findings provide guidance for predicting changes in the dominant eye, thus improve the precise selection of intraocular lenses and the implementation of monovision strategies.

Impact of peripapillary staphylomas on the vascular and structural characteristics in myopic eyes: a propensity score matching analysis.

PURPOSE: To apply propensity score matching to evaluate the impact of peripapillary staphylomas (PPS) on vascular and structural characteristics in the myopic eyes. METHODS: This was a prospective, cross-sectional study. Forty-one control eyes and 41 eyes with PPS were analyzed. The eyes were selected using propensity score matching analysis based on the age and axial length. All subjects underwent ophthalmologic examinations for assessing vessel and structure parameters using swept-source optical coherence tomography (SS-OCT), OCT angiography, color fundus photography, and ocular biometry. RESULTS: As compared with control eyes, the eyes with PPS had shallower anterior chamber depth (3.61 ± 0.24 mm vs 3.77 ± 0.24 mm, P = 0.004), higher intraocular pressure (IOP) (16.59 ± 2.88 mmHg vs 14.53 ± 2.45 mmHg, P = 0.002), and higher myopic spherical equivalent (- 11.52 ± 3.22D vs - 9.88 ± 2.20D, P = 0.009). while corneal curvature and lens thickness between the two groups were not statistically different. Compared with control eyes, increased macular deep vessel density, reduced macular choriocapillaris and radial peripapillary capillary, and thinning retinal layer, ganglion cell complex, choroidal layer as well as the superior and inferior peripapillary retinal nerve fiber layer were observed in eyes with PPS, apart from larger disc area, parapapillary atrophy area, and degree of disc rotation. Logistic regression analysis revealed that the IOP (P = 0.046), disc rotation (P = 0.003), and average peripapillary choroidal thickness (P = 0.009) were associated with the presence of PPS. CONCLUSION: Close association of PPS with exacerbation of myopia and anatomical alterations was observed which not only affected the eye posterior segment but also the anterior segments. We further identified significant reductions in the radial peripapillary capillary and macular choroidal perfusion with the increase in macular deep retinal flow blood of myopic eyes with PPS. Higher IOP, thinner peripapillary choroidal thickness, and rotated optic disc were risk factors for the presence of PPS.

Detection of a novel PAX6 variant in a Chinese family with multiple ocular abnormalities.

BACKGROUND: Aniridia is a congenital, panocular disease that can affect the cornea, anterior chamber angle, iris, lens, retina and optic nerve. PAX6 loss-of-function variants are the most common cause of aniridia, and variants throughout the gene have been linked to a range of ophthalmic abnormalities. Furthermore, particular variants at a given site in PAX6 lead to distinct phenotypes. This study aimed to characterize genetic variants associated with congenital aniridia in a Chinese family. METHODS: The proband and family underwent ophthalmologic examinations. DNA was sampled from the peripheral blood of all 6 individuals, and whole-exome sequencing was performed. Sanger sequencing was used to verify the variant in this family members. RESULTS: A novel variant (c.114_119delinsAATTTCC: p.Pro39llefsTer17) in the PAX6 gene was identified in subjects II-1, III-1 and III-2, who exhibited complete aniridia and cataracts. The proband and the proband's brother also had glaucoma, high myopia, and foveal hypoplasia. CONCLUSIONS: We identified that a novel PAX6 frameshift heterozygous deletion variant is the predominant cause of aniridia in this Chinese family. TRIAL REGISTRATION: We did not perform any health-related interventions for the participants.

Research advance in optic disc tilt and rotation in high myopia and its implications for glaucoma and visual field defects.

High myopia is of worldwide concern due to its high prevalence, and myopia is an independent risk factor for glaucoma. The purpose of this paper is to review the mechanism and clinical manifestations of optic disc tilt and rotation in high myopia and its relationship with glaucoma, to provide clues for monitoring fundus changes in high myopia and the early diagnosis of high myopia with glaucoma.

Structure-based design of a novel third-generation antipsychotic drug lead with potential antidepressant properties.

Partial agonist activity at the dopamine D2 receptor (DRD2) is a key feature of third-generation antipsychotics (TGAs). However, TGAs also act as antagonists or weak partial agonists to the serotonin (5-hydroxytryptamine; 5-HT) 2A receptor (5-HT2AR). Here we present the crystal structures of aripiprazole- and cariprazine-bound human 5-HT2AR. Both TGAs adopt an unexpected 'upside-down' pose in the 5-HT2AR binding pocket, with secondary pharmacophores inserted in a similar way to a 'bolt'. This insight into the binding modes of TGAs offered a structural mechanism underlying their varied partial efficacies at 5-HT2AR and DRD2. These structures enabled the design of a partial agonist at DRD2/3 and 5-HT1AR with negligible 5-HT2AR binding that displayed potent antipsychotic-like activity without motor side effects in mice. This TGA lead also had antidepressant-like effects and improved cognitive performance in mouse models via 5-HT1AR. This work indicates that 5-HT2AR affinity is a dispensable contributor to the therapeutic actions of TGAs.

Posterior staphyloma is associated with the microvasculature and microstructure of myopic eyes.

OBJECTIVE: To investigate the microvasculature and structural characteristics of the eyes of myopic patients and their association with posterior staphyloma (PS). METHODS: This was a retrospective, case-control study comprising of 106 eyes from 72 individuals. Using 1:1 matching of axial length (AL) of their eyes, patients were allocated into a PS group or no posterior staphyloma (NPS) group. All patients were examined using ultra-widefield fundus imaging, optical coherence tomography angiography, and ocular biometry to acquire microvasculature and microstructure parameters. RESULTS: The anterior chamber depth (ACD) of the PS group was significantly different from that of the NPS group (3.56 mm vs 3.76 mm, P < 0.001), as was 1ens thickness (3.72 mm vs 3.57 mm, P = 0.005) and spherical equivalent (SE)(-10.11D vs -8.80D, P = 0.014). The PS group had reduced choriocapillaris flow, subfoveal choroidal thickness (SFCT), and a thinner retinal layer compared with the NPS group. No difference in retinal blood flow between the two groups was observed. The PS group exhibited a smaller disc area (15082.89 vs 17,043.32, P = 0.003) and angle α between temporal retinal arterial vascular arcades (113.29°vs 128.39°, P = 0.003), a larger disc tilt ratio (1.41 vs 1.24, P < 0.001) and parapapillary atrophy (PPA) area (13840.98 vs 8753.86, P = 0.020), compared with the NPS group. Multivariate regression analysis indicated that disc tilt ratio (P = 0.031) and SFCT (P = 0.015) were significant predictors of PS. In addition, PS (P = 0.049), AL (P = 0.003), corneal refractive power (P < 0.001), ACD (P = 0.022), relative lens position (P = 0.045), and disc area (P = 0.011) were significant predictors of SE. CONCLUSIONS: PS was found to be closely linked to a reduction in choriocapillaris perfusion and anatomical abnormalities including posterior and anterior segments. Furthermore, PS exacerbated the progression of myopia.

Haloperidol bound D2 dopamine receptor structure inspired the discovery of subtype selective ligands.

The D2 dopamine receptor (DRD2) is one of the most well-established therapeutic targets for neuropsychiatric and endocrine disorders. Most clinically approved and investigational drugs that target this receptor are known to be subfamily-selective for all three D2-like receptors, rather than subtype-selective for only DRD2. Here, we report the crystal structure of DRD2 bound to the most commonly used antipsychotic drug, haloperidol. The structures suggest an extended binding pocket for DRD2 that distinguishes it from other D2-like subtypes. A detailed analysis of the structures illuminates key structural determinants essential for DRD2 activation and subtype selectivity. A structure-based and mechanism-driven screening combined with a lead optimization approach yield DRD2 highly selective agonists, which could be used as chemical probes for studying the physiological and pathological functions of DRD2 as well as promising therapeutic leads devoid of promiscuity.

The plant sesquiterpene lactone parthenolide inhibits Wnt/ß-catenin signaling by blocking synthesis of the transcriptional regulators TCF4/LEF1.

The Wnt/ß-catenin pathway is essential for embryonic development and homeostasis, but excessive activation of this pathway is frequently observed in various human diseases, including cancer. Current therapeutic drugs targeting the Wnt pathway often lack sufficient efficacy, and new compounds targeting this pathway are therefore greatly needed. Here we report that the plant-derived natural product parthenolide (PTL), a sesquiterpene lactone, inhibits Wnt signaling. We found that PTL dose-dependently inhibits Wnt3a- and CHIR99021-induced transcriptional activity assessed with the T-cell factor (TCF)/lymphoid enhancer factor (LEF) firefly luciferase (TOPFlash) assay in HEK293 cells. Further investigations revealed that PTL decreases the levels of the transcription factors TCF4/LEF1 without affecting ß-catenin stability or subcellular distribution. Moreover, this effect of PTL on TCF4/LEF1 was related to protein synthesis rather than to proteasome-mediated degradation. Of note, siRNA-mediated knockdown of RPL10, a ribosome protein PTL binds, substantially decreased TCF4/LEF1 protein levels and also Wnt3a-induced TOPFlash activities, suggesting a potential mechanism by which PTL may repress Wnt/ß-catenin signaling. In summary, PTL binds RPL10 and thereby potently inhibits the Wnt/ß-catenin pathway.

Chemical biology reveals CARF as a positive regulator of canonical Wnt signaling by promoting TCF/ß-catenin transcriptional activity.

Wnt/ß-catenin signaling regulates multiple biological processes and aberration of this pathway is frequently observed in human cancers. Previously, we uncovered NC043 as a small-molecule inhibitor of Wnt/ß-catenin signaling. Here, we identified CARF as the cellular target of NC043. We found that NC043 binds directly to CARF through forming a covalent bond with the Cys-516 residue of CARF. Further study revealed that CARF interacts with Dvl, which potentiates the Dvl-c-Jun-ß-catenin-TCF transcriptional complex and thus promotes Wnt signaling activation. NC043 could disrupt the interaction between CARF and Dvl, thereby impairing Wnt signal transduction. In line with this, knockdown of CARF in zebrafish leads to impairment of embryonic development, hematopoietic stem cell generation and caudal fin regeneration. Collectively, we identified CARF as the cellular target of NC043 and revealed CARF as a positive regulator of Wnt/ß-catenin signal transduction.

Thymine DNA glycosylase promotes transactivation of ß-catenin/TCFs by cooperating with CBP.

Thymine DNA glycosylase (TDG), an enzyme that initiates the repair of G/T and G/U mismatches, has been lately found crucial in embryonic development to maintain epigenetic stability and facilitate the active DNA demethylation. Here we report a novel role of TDG in Wnt signaling as a transcriptional coactivator of ß-catenin/TCFs complex. Our data show that TDG binds to the transcriptional factor family LEF1/TCFs and potentiates ß-catenin/TCFs transactivation, while TDG depletion suppresses Wnt3a-stimulated reporter activity or target gene transcription. Next, we show that CBP, a known coactivator, is also required for TDG function through forming a cooperative complex on target promoters. Moreover, there is an elevation of TDG levels in human colon cancer tissue, and knockdown of TDG inhibits proliferation of the colon cells. Overall, our results reveal that TDG, as a new coactivator, promotes ß-catenin/TCFs transactivation and functionally cooperates with CBP in canonical Wnt signaling.

Small-molecule modulation of Wnt signaling via modulating the Axin-LRP5/6 interaction.

The Wnt/ß-catenin signaling pathway has a crucial role in embryonic development, stem cell maintenance and human disease. By screening a synthetic chemical library of lycorine derivatives, we identified 4-ethyl-5-methyl-5,6-dihydro-[1,3]dioxolo[4,5-j]phenanthridine (HLY78) as an activator of the Wnt/ß-catenin signaling pathway, which acts in a Wnt ligand-dependent manner. HLY78 targets the DIX domain of Axin and potentiates the Axin-LRP6 association, thus promoting LRP6 phosphorylation and Wnt signaling transduction. Moreover, we identified the critical residues on Axin for HLY78 binding and showed that HLY78 may weaken the autoinhibition of Axin. In addition, HLY78 acts synergistically with Wnt in the embryonic development of zebrafish and increases the expression of the conserved hematopoietic stem cell (HSC) markers, runx1 and cmyb, in zebrafish embryos. Collectively, our study not only provides new insights into the regulation of the Wnt/ß-catenin signaling pathway by a Wnt-specific small molecule but also will facilitate therapeutic applications, such as HSC expansion.

The E3 ubiquitin ligase ITCH negatively regulates canonical Wnt signaling by targeting dishevelled protein.

Dishevelled (Dvl) is a key component in the canonical Wnt signaling pathway and becomes hyperphosphorylated upon Wnt stimulation. Dvl is required for LRP6 phosphorylation, which is essential for subsequent steps of signal transduction, such as Axin recruitment and cytosolic ß-catenin stabilization. Here, we identify the HECT-containing Nedd4-like ubiquitin E3 ligase ITCH as a new Dvl-binding protein. ITCH ubiquitinates the phosphorylated form of Dvl and promotes its degradation via the proteasome pathway, thereby inhibiting canonical Wnt signaling. Knockdown of ITCH by RNA interference increased the stability of phosphorylated Dvl and upregulated Wnt reporter gene activity as well as endogenous Wnt target gene expression induced by Wnt stimulation. In addition, we found that both the PPXY motif and the DEP domain of Dvl are critical for its interaction with ITCH, as mutation in the PPXY motif (Dvl2-Y568F) or deletion of the DEP domain led to reduced affinity for ITCH. Consistently, overexpression of ITCH inhibited wild-type Dvl2-induced, but not Dvl2-Y568F mutant-induced, Wnt reporter activity. Moreover, the Y568F mutant, but not wild-type Dvl2, can reverse the ITCH-mediated inhibition of Wnt-induced reporter activity. Collectively, these results indicate that ITCH plays a negative regulatory role in modulating canonical Wnt signaling by targeting the phosphorylated form of Dvl.

Enhanced hyperplasia in muscles of transgenic zebrafish expressing Follistatin1.

Myostatin is a member of the transforming growth factor-ß (TGF-ß) super-family and functions as a negative regulator of muscle growth. Binding of the specific receptor, Activin receptor IIB (Act RIIB), with myostatin or other related TGF-ß members, could be inhibited by the activin-binding protein follistatin (Fst) in mammals. Overexpressing Fst in mouse skeletal muscle leads to muscle hypertrophy and hyperplasia. To determine if Fst has similar roles in fish, we generated transgenic zebrafish expressing high levels of zebrafish Fst1 using the promoter of the zebrafish skeletal muscle-specific gene, myosin, light polypeptide 2, skeletal muscle (Mylz2). Independent transgenic zebrafish lines exhibited elevated expression levels of myogenic regulatory genes MyoD and Pax7 in muscle cells. Adult Fst1 overexpressing transgenic zebrafish exhibited a slight body weight increase. The high level of Fst1 expression dramatically increased myofiber numbers in skeletal muscle, without significantly changing the fiber size. Our findings suggest that Fst1 overexpression can promote zebrafish muscle growth by enhancing myofiber hyperplasia.

Histone H4 Lys 20 monomethylation by histone methylase SET8 mediates Wnt target gene activation.

Histone methylation has an important role in transcriptional regulation. However, unlike H3K4 and H3K9 methylation, the role of H4K20 monomethylation (H4K20me-1) in transcriptional regulation remains unclear. Here, we show that Wnt3a specifically stimulates H4K20 monomethylation at the T cell factor (TCF)-binding element through the histone methylase SET8. Additionally, SET8 is crucial for activation of the Wnt reporter gene and target genes in both mammalian cells and zebrafish. Furthermore, SET8 interacts with lymphoid enhancing factor-1 (LEF1)/TCF4 directly, and this interaction is regulated by Wnt3a. Therefore, we conclude that SET8 is a Wnt signaling mediator and is recruited by LEF1/TCF4 to regulate the transcription of Wnt-activated genes, possibly through H4K20 monomethylation at the target gene promoters. Our findings also indicate that H4K20me-1 is a marker for gene transcription activation, at least in canonical Wnt signaling.

[Effects of rearing density on juvenile Acipenser schrenckii digestibility, feeding rate and growth].

A 60-day rearing experiment was conducted in this study. The initial weight of juvenile Acipenser schrenckii was 43.90 +/- 1.75 g, and the initial rearing density was 0.525 (LSD), 1.171 (MSD), and 2.138 (HSD) kg x m(-2), respectively. The results showed that with increasing rearing density, the specific growth rate (SGR) and daily weight gain (DWG) of juvenile A. schrenckii were significantly decreased, while net yield (NY) was increased. The digestibility was significantly higher in LSD and MSD than in HSD, while that in LSD and MSD was nearly the same. The feeding rate in MSD was significantly-lower than that in HSD, but slimly higher than that in LSD. There was a significant negative linear correlation between food conversion ratio (FCR) and digestibility, and a significant positive linear correlation between SGR and digestibility.

Comparative blood biochemistry of Amur sturgeon, Acipenser schrenckii, and Chinese surgeon, Acipenser sinensis.

This study compared Amur sturgeon (Acipenser schrenckii) and Chinese sturgeon (Acipenser sinensis) on several biochemical parameters including glucose (GLU), urea, lactate dehydrogenase (LDH-L), activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), direct bilirubin (D.BILI), alkaline phosphatase (ALP), cholesterol (CHOL), triglyceride (TGL), creatinine (CREA), total protein (TP), and total bilirubin (T.BILI). The results showed that there were great differences in these parameters between the two species. The concentrations of GLU, UREA, LDH-L, ALT, AST, D.BILI, ALP, CHOL, TGL, CREA, and T.P for the Amur sturgeon were significantly higher than those for Chinese sturgeon.The T.BILI level of the Amur sturgeon was, however, significantly lower than that for the Chinese sturgeon.