M2-polarized macrophages, also known as alternatively activated macrophages, have long been associated with pulmonary fibrosis; however, the mechanism has not been fully defined. Gab1 and Gab2 proteins belong to the Gab family of adaptors and are integral components of the signal specificity in response to various extracellular stimuli. In this report, we found that levels of both Gab1 and Gab2 were elevated in M2-polarized macrophages isolated from bleomycin-induced fibrotic lungs. Gab1/2 deficiency in bone marrow-derived macrophages abrogated IL-4-mediated M2 polarization. Furthermore, conditional removal of (Gab1) and germ line knock-out of (Gab2) in macrophages prevented a bias toward the M2 phenotype and attenuated bleomycin-induced fibrotic lung remodeling. In support of these observations, Gab1/2 were involved in responses predominated by IL-4 signaling, an essential determinant for macrophage M2 polarization. Further investigation revealed that both Gab1 and -2 are recruited to the IL-4 receptor, synergistically enhancing downstream signal amplification but conferring IL-4 signal preference. Mechanistically, the loss of Gab1 attenuated AKT activation, whereas the absence of Gab2 suppressed STAT6 activation in response to IL-4 stimulation, both of which are commonly attributed to M2-driven pulmonary fibrosis in mice. Taken together, these observations define a non-redundant role of Gab docking proteins in M2 polarization, adding critical insights into the pathogenesis of idiopathic pulmonary fibrosis.

Background: Age-related Macular Degeneration (AMD) is the leading cause of blindness. This study aims to analyze regional differences on the global burden of AMD and help direct related policy making. Methods: Disability-adjusted life years (DALY) data were collected from the Global Burden of Disease Study (GBD) 2017 to estimate the AMD burden. Mean education years, human development index (HDI) and Public Health Expenditure were extracted from the Human Development Report 2018, and latitude data were obtained from the Google Earth. These four factors were analyzed to see their importance in regional differences of AMD burden, using Kruskal-Wallis test, Dunn's multiple comparisons test as well as regression analysis. Results: Global age-standardized DALY rates have decreased since 2011. Based on the WHO region system, agestandardized DALY rates in African and Eastern Mediterranean region were significantly lower than those of other four regions. Linear regression analysis indicated that age-standardized DALY rates were inversely related to HDI and mean education years. Conclusions: The age-standardized AMD burden had a decreasing tendency recently. Lower socioeconomic status and fewer education years were associated with higher AMD burden. The finding of this study may highlight the importance of national development and education on relieving AMD burden.

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As the primary indication for corneal transplantation, the pathogenesis of keratoconus remains elusive. Aiming to identify whether any mutation from extracellular-matrix (ecM)-related genes contributes to the patients with sporadic cases of keratoconus (Kc) from chinese Han population, one hundred and fifty-three participants in total were enrolled in our study, including fifty-three KC patients and one hundred healthy controls. Mutational analysis of three ecM-related genes (LOX, COL5A1 and TIMP3) with next-generation sequencing and Sanger sequencing was performed. To further confirm the function of three ecM-related genes in the pathogenesis of keratoconus, we performed Realtime Quantitative pcR in vitro. Results showed that three new sequence variants (c.95 G > A in LOX, c.1372 C > t in COL5A1 and c.476 C > t in TIMP3) were identified in aforementioned ECM-related genes in Kc patients without being detected among the healthy controls. According to the results of QpcR, we found that the expression levels of LOX and TIMP3 were decreased in the Kc patients, while COL5A1 showed no significant difference of expression. This is the first time to screen so many ECMrelated genes in Chinese keratoconus patients using next-generation sequencing. We find numerous underlying causal variants, enlarging lots of mutation spectrums and thus providing new sites for other investigators to replicate and for further research. Keratoconus (KC) is a progressive disorder characterized by central cornea thinning and ectasia in a cone-shape fashion, leading to myopia, irregular astigmatism and even vision loss 1,2. KC usually occurs from the second decade to the fourth decade of life, and affects both genders. The prevalence of KC ranges from 900 to 3300 per 100,000 in recent population-based studies 2. Clinically, corneal tomography is most frequently used for diagnosis of KC, while mild or subclinical KC can be diagnosed by posterior corneal elevation abnormalities 3. The treatments of KC often begin with verbal guidance such as not rubbing eyes and wearing contact lenses, with 10-20% of patients finally turning to corneal transplantation 3,4. Collagen cross-linking (CXL) is a novel intervention effective in the therapy of KC. However, the exact etiology and pathogenesis of KC remains unclear, in which genetic, environmental, biomechanical and biochemical factors may involve 3. Eye rubbing 5 , atopy 6,7 and sun exposure 2 are important environmental factors indicating a high risk of KC. In addition, there are increasing evidences suggesting a genetic predisposition in the pathogenesis of keratoconus, with lots of genomic loci and genes identified, including visual system homeobox 1 (VSX1) 8-10 , superoxide dismutase 1 (SOD1) 10,11 , transforming growth factor beta-induced (TGFβI) 12 and microRNA 184 (MIR184) 13,14. Nevertheless, it is to be further explored whether and how these genomic loci and genes participate in the progression of KC. As a major component of the cornea, the corneal stroma rich in extracellular matrix (ECM) plays...

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