Notes

Lianhua Qingwen prescribed regarding Coronavirus disease 2019 (COVID-19) therapy: Developments as well as prospective customers.
The endolysosome system plays central roles in both autophagic degradation and secretory pathways, including the release of extracellular vesicles and particles (EVPs). Although previous work reveals important interconnections between autophagy and EVP-mediated secretion, our understanding of these secretory events during endolysosome inhibition remains incomplete. Here, we delineate a secretory autophagy pathway upregulated in response to endolysosomal inhibition, which mediates EVP-associated release of autophagic cargo receptors, including p62/SQSTM1. This secretion is highly regulated and dependent on multiple ATGs required for autophagosome formation, as well as the small GTPase Rab27a. Furthermore, disrupting autophagosome maturation, either via genetic inhibition of autophagosome-to-autolysosome fusion or expression of SARS-CoV-2 ORF3a, is sufficient to induce EVP secretion of autophagy cargo receptors. Finally, ATG-dependent EVP secretion buffers against the intracellular accumulation of autophagy cargo receptors when classical autophagic degradation is impaired. Thus, we propose secretory autophagy via EVPs functions as an alternate route to clear sequestered material and maintain proteostasis during endolysosomal dysfunction or impaired autophagosome maturation.
The purpose of this study was to investigate the effects of Forkhead Domain Inhibitor-6 (FDI-6) on regulating inflammatory corneal angiogenesis and subsequent fibrosis induced by alkali burn.

A corneal alkali burn model was established in Sprague Dawley rats using NaOH and the rat eyes were topically treated with FDI-6 (40 µM) or a control vehicle four times daily for 7 days. Corneal neovascularization, inflammation and epithelial defects were observed on days 1, 4, and 7 under a slit lamp microscope after corneal alkali burn. Analysis of angiogenesis-, inflammation-, and fibrosis-related indicators was conducted on day 7. Murine macrophages (RAW264.7 cells) and mouse retinal microvascular endothelial cells (MRMECs) were used to examine the effects of FDI-6 on inflammatory angiogenesis in vitro.

Topical delivery of FDI-6 significantly attenuated alkali burn-induced corneal inflammation, neovascularization, and fibrosis. FDI-6 suppressed the expression of angiogenic factors (vascular epidermal growth factor, CD31, matrix metalloproteinase-9, and endothelial NO synthase), fibrotic factors (α-smooth muscle actin and fibronectin), and pro-inflammatory factor interleukin-6 in alkali-injured corneas. FDI-6 downregulated the expression of monocyte chemotactic protein-1, pro-inflammatory cytokines (interleukin-1β and tumor necrosis factor-alpha), nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3, and vascular endothelial growth factor in RAW264.7 cells and inhibited the proliferation, migration, and tube formation of MRMECs in vitro.

FDI-6 can attenuate corneal neovascularization, inflammation, and fibrosis in alkali-injured corneas.
FDI-6 can attenuate corneal neovascularization, inflammation, and fibrosis in alkali-injured corneas.
Positional judgments in amblyopia are impaired more at the center of the visual field than in the periphery. However, the effects of visual field position frequently are confounded with stimulus separation. The purpose of this experiment was to parse the effects of stimulus separation and eccentricity on the positional deficit in amblyopia.

Subjects adjusted the positions of stimuli of varying separations on isoeccentric arcs. The task was simultaneous bisection and alignment of broadband, high-contrast, uncrowded targets with reference to central fixation. Ten strabismic amblyopes and five normally sighted controls performed the task dichoptically; a subset of amblyopes performed the task monocularly with the amblyopic eye. Spread (inverse of precision) and bias were measured at multiple visual field locations comprising two to three separation (times) four eccentricity conditions in each visual field quadrant.

In normal controls, both spread and bias increased with eccentricity, and spread (but not bias) increased linearly with separation until 7° eccentricity. Strabismic amblyopes showed a different profile spread and bias were higher at small separations at all eccentricities, such that performance showed a quadratic trend against separation. Thus, at each eccentricity, the difference in performance between groups was largest at the smallest separation.

These results are consistent with disruptions in Weber mechanisms of positional encoding in strabismic amblyopia, and indicate that binocular stimulation by proximal targets produces a loss of spatial precision well beyond the fovea.
These results are consistent with disruptions in Weber mechanisms of positional encoding in strabismic amblyopia, and indicate that binocular stimulation by proximal targets produces a loss of spatial precision well beyond the fovea.
Foveal center marking is a key step in retinal image analysis. We investigated the discordance between the adaptive optics (AO) montage center (AMC) and the foveal pit center (FPC) and its implications for cone mosaic analysis using a commercial flood-illumination AO camera.

Thirty eyes of 30 individuals (including 15 healthy and 15 patients with rod-cone dystrophy) were included. Spectral-domain optical coherence tomography was used to determine the FPC, and flood-illumination AO imaging was performed with overlapping image frames to create an AO montage. The AMC was determined by averaging the (0,0) coordinates in the four paracentral overlapping AO image frames. Cone mosaic measurements at various retinal eccentricities were compared between corresponding retinal loci relative to the AMC or FPC.

AMCs were located temporally to the FPCs in 14 of 15 eyes in both groups. The average AMC-FPC discordance was 0.85° among healthy controls and 0.33° among patients with rod-cone dystrophy (P<0.05). The discalization of the eccentricities and regions of interest for cone mosaic analysis.
To identify structural abnormalities in the papillary and peripapillary area in eyes with pathologic myopia (PM) and normal IOP and to determine their relationship to visual field (VF) defects.

One hundred eight eyes of 70 patients with PM were retrospectively studied. The disc-centered swept source optical coherence tomographic images and the Goldmann VF recorded within 1 year of the optical coherence tomographic examination were analyzed. Four structural abnormalities were identified lamina cribrosa (LC) defects, ridge protrusions, intrachoroidal cavitations (ICC), and prelaminar schisis. The correspondence of the VF defects with the structural abnormalities was assessed.

The mean age, axial length, and optic disc area of the 108 eyes were 58.7 ± 10.0 years, 31.1 ± 2.4 mm, and 4.7 ± 2.2 mm2, respectively. Eighty-five of the 108 eyes (78.7%) had at least one abnormality and 49.4% (42/85) had two or more abnormalities. LC defects, ridge protrusions, ICC, and prelaminar schisis were detected in 47.2%, 33.3%, 21.3%, and 30.6% of the eyes, respectively. VF defects at the corresponding areas of these structural abnormalities were seen in 63% of the eyes with LC defects, 39% of the eyes with ridge protrusions, and 21% of the eyes with ICC.

Four kinds of structural abnormalities with corresponding VF defects are commonly observed in the papillary and peripapillary region of eyes with PM. The presence of these abnormalities suggests a possibility of functional damage.
Four kinds of structural abnormalities with corresponding VF defects are commonly observed in the papillary and peripapillary region of eyes with PM. The presence of these abnormalities suggests a possibility of functional damage.Type 2 ryanodine receptor (RYR2) is a cardiac Ca2+ release channel in the ER. Mutations in RYR2 are linked to catecholaminergic polymorphic ventricular tachycardia (CPVT). CPVT is associated with enhanced spontaneous Ca2+ release, which tends to occur when [Ca2+]ER reaches a threshold. Mutations lower the threshold [Ca2+]ER by increasing luminal Ca2+ sensitivity or enhancing cytosolic [Ca2+] ([Ca2+]cyt)-dependent activity. Here, to establish the mechanism relating the change in [Ca2+]cyt-dependent activity of RYR2 and the threshold [Ca2+]ER, we carried out cell-based experiments and in silico simulations. We expressed WT and CPVT-linked mutant RYR2s in HEK293 cells and measured [Ca2+]cyt and [Ca2+]ER using fluorescent Ca2+ indicators. CPVT RYR2 cells showed higher oscillation frequency and lower threshold [Ca2+]ER than WT cells. The [Ca2+]cyt-dependent activity at resting [Ca2+]cyt, Arest, was greater in CPVT mutants than in WT, and we found an inverse correlation between threshold [Ca2+]ER and Arest. In addition, lowering RYR2 expression increased the threshold [Ca2+]ER and a product of Arest, and the relative expression level for each mutant correlated with threshold [Ca2+]ER, suggesting that the threshold [Ca2+]ER depends on the net Ca2+ release rate via RYR2. Modeling reproduced Ca2+ oscillations with [Ca2+]cyt and [Ca2+]ER changes in WT and CPVT cells. Interestingly, the [Ca2+]cyt-dependent activity of specific mutations correlated with the age of disease onset in patients carrying them. find more Our data suggest that the reduction in threshold [Ca2+]ER for spontaneous Ca2+ release by CPVT mutation is explained by enhanced [Ca2+]cyt-dependent activity without requiring modulation of the [Ca2+]ER sensitivity of RYR2.
Understanding whether physicians accurately detect symptoms in patients with breast cancer is important because recognition of symptoms facilitates supportive care, and clinical trials often rely on physician assessments using Common Toxicity Criteria for Adverse Events (CTCAE).

To compare the patient-reported outcomes (PROs) of patients with breast cancer who received radiotherapy from January 1, 2012, to March 31, 2020, with physicians' CTCAE assessments to assess underrecognition of symptoms.

This cohort study included a total of 29 practices enrolled in the Michigan Radiation Oncology Quality Consortium quality initiative. Of 13 725 patients with breast cancer who received treatment with radiotherapy after undergoing lumpectomy, 9941 patients (72.4%) completed at least 1 PRO questionnaire during treatment with radiotherapy and were evaluated for the study. Of these, 9868 patients (99.3%) were matched to physician CTCAE assessments that were completed within 3 days of the PRO questionnaires.

Patiennts may miss important symptoms. Moreover, since physicians in this study systematically missed substantial symptoms in certain patients, including younger patients and Black individuals or those of Other race and ethnicity, improving symptom detection may be a targetable mechanism to reduce disparities.
The results of this cohort study suggest that PRO collection may be essential for trials because relying on the CTCAE to detect adverse events may miss important symptoms. Moreover, since physicians in this study systematically missed substantial symptoms in certain patients, including younger patients and Black individuals or those of Other race and ethnicity, improving symptom detection may be a targetable mechanism to reduce disparities.
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