Lhx2 promotes axon regeneration of adult retinal ganglion cells and rescues neurodegeneration in mouse models of glaucoma.

The axons of retinal ganglion cells (RGCs) form the optic nerve, transmitting visual information from the eye to the brain. Damage or loss of RGCs and their axons is the leading cause of visual functional defects in traumatic injury and degenerative diseases such as glaucoma. However, there are no effective clinical treatments for nerve damage in these neurodegenerative diseases. Here, we report that LIM homeodomain transcription factor Lhx2 promotes RGC survival and axon regeneration in multiple animal models mimicking glaucoma disease. Furthermore, following N-methyl-D-aspartate (NMDA)-induced excitotoxicity damage of RGCs, Lhx2 mitigates the loss of visual signal transduction. Mechanistic analysis revealed that overexpression of Lhx2 supports axon regeneration by systematically regulating the transcription of regeneration-related genes and inhibiting transcription of Semaphorin 3C (Sema3C). Collectively, our studies identify a critical role of Lhx2 in promoting RGC survival and axon regeneration, providing a promising neural repair strategy for glaucomatous neurodegeneration.

Single-cell transcriptomic Atlas of aging macaque ocular outflow tissues.

The progressive degradation in the trabecular meshwork (TM) is related to age-related ocular diseases like primary open-angle glaucoma. However, the molecular basis and biological significance of the aging process in TM have not been fully elucidated. Here, we established a dynamic single-cell transcriptomic landscape of aged macaque TM, wherein we classified the outflow tissue into 12 cell subtypes and identified mitochondrial dysfunction as a prominent feature of TM aging. Furthermore, we divided TM cells into 13 clusters and performed an in- depth analysis on cluster 0, which had the highest aging score and the most significant changes in cell proportions between the two groups. Ultimately, we found that the APOE gene was an important differentially expressed gene in cluster 0 during the aging process, highlighting the close relationship between cell migration and extracellular matrix regulation, and TM function. Our work further demonstrated that silencing the APOE gene could increase migration and reduce apoptosis by releasing the inhibition on the PI3K-AKT pathway and downregulating the expression of extracellular matrix components, thereby increasing the aqueous outflow rate and maintaining intraocular pressure within the normal range. Our work provides valuable insights for future clinical diagnosis and treatment of glaucoma.

iPSC-derived cells stimulate ABCG2+ /NES+ endogenous trabecular meshwork cell proliferation and tissue regeneration.

A major risk factor for glaucoma, the first leading cause of irreversible blindness worldwide, is the decellularisation of the trabecular meshwork (TM) in the conventional outflow pathway. Stem cell-based therapy, particularly the utilisation of induced pluripotent stem cells (iPSCs), presents an enticing potential for tissue regeneration and intraocular pressure (IOP) maintenance in glaucoma. We have previously observed that differentiated iPSCs can stimulate endogenous cell proliferation in the TM, a pivotal factor in TM regeneration and aqueous humour outflow restoration. In this study, we investigated the response of TM cells in vivo after interacting with iPSC-derived cells and identified two subpopulations responsible for this relatively long-term tissue regeneration: ATP Binding Cassette Subfamily G Member 2 (ABCG2)-positive cells and Nestin (NES)-positive cells. We further uncovered that alterations of these responsive cells are linked to ageing and different glaucoma etiologies, suggesting that ABCG2+ subpopulation decellularization could serve as a potential risk factor for TM decellularization in glaucoma. Taken together, our findings illustrated the proliferative subpopulations in the conventional outflow pathway when stimulated with iPSC-derived cells and defined them as TM precursors, which may be applied to develop novel therapeutic approaches for glaucoma.

Serine to proline mutation at position 341 of MYOC impairs trabecular meshwork function by causing autophagy deregulation.

Glaucoma is a highly heritable disease, and myocilin was the first identified causal and most common pathogenic gene in glaucoma. Serine-to-proline mutation at position 341 of myocilin (MYOCS341P) is associated with severe glaucoma phenotypes in a five-generation primary open-angle glaucoma family. However, the underlying mechanisms are underexplored. Herein, we established the MYOCS341P transgenic mouse model and characterized the glaucoma phenotypes. Further, we systematically explored the functional differences between wild-type and MYOCS341P through immunoprecipitation, mass spectrometry, and RNA-seq analyses. We found that MYOCS341P transgenic mice exhibit glaucoma phenotypes, characterized by reduced aqueous humor outflow, elevated intraocular pressure, decreased trabecular meshwork (TM) cell number, narrowed Schlemm's canal, retinal ganglion cell loss, and visual impairment. Mechanistically, the secretion of dysfunctional MYOCS341P accumulated in the endoplasmic reticulum (ER), inducing ER stress and dysregulation of autophagy, thereby promoting TM cell death. We describe an effective transgenic model for mechanistic studies and the screening of therapeutic targets. Our data generated from high-throughput analyses help elucidate the mechanism underlying mutant MYOC-related glaucoma.

Early Proteomic Characteristics and Changes in the Optic Nerve Head, Optic Nerve, and Retina in a Rat Model of Ocular Hypertension.

The pathogenesis of glaucoma is still unknown. There are few studies on the dynamic change of tissue-specific and time-specific molecular pathophysiology caused by ocular hypertension (OHT). This study aimed to identify the early proteomic alterations in the retina, optic nerve head (ONH), and optic nerve (ON). After establishing a rat model of OHT, we harvested the tissues from control and glaucomatous eyes and analyzed the changes in protein expression using a multiplexed quantitative proteomics approach (TMT-MS3). Our study identified 6403 proteins after 1-day OHT and 4399 proteins after 7-days OHT in the retina, 5493 proteins after 1-day OHT and 4544 proteins after 7-days OHT in ONH, and 5455 proteins after 1-day OHT and 3835 proteins after 7-days OHT in the ON. Of these, 560 and 489 differential proteins were identified on day 1 and 7 after OHT in the retina, 428 and 761 differential proteins were identified on day 1 and 7 after OHT in the ONH, and 257 and 205 differential proteins on days 1 and 7 after OHT in the ON. Computational analysis on day 1 and 7 of OHT revealed that alpha-2 macroglobulin was upregulated across two time points and three tissues stably. The differentially expressed proteins between day 1 and 7 after OHT in the retina, ONH, and ON were associated with glutathione metabolism, mitochondrial dysfunction/oxidative phosphorylation, oxidative stress, microtubule, and crystallin. And the most significant change in retina are crystallins. We validated this proteomic result with the Western blot of crystallin proteins and found that upregulated on day 1 but recovered on day 7 after OHT, which are promising as therapeutic targets. These findings provide insights into the time- and region-order mechanisms that are specifically affected in the retina, ONH, and ON in response to elevated IOP during the early stages.

Different serum levels of IgG and complements and recurrence rates in IgG4-positive and negative lacrimal gland benign lymphoepithelial lesion.

AIM: To analyze the differences in immune indicators and prognosis between IgG4-positive and negative lacrimal gland benign lymphoepithelial lesion (LGBLEL). METHODS: This was a single-center retrospective clinical study including 105 cases of IgG4-positive LGBLEL and 41 cases of IgG4-negative LGBLEL. Basic information, related indicators of peripheral venous blood samples using immunoscattering turbidimetry, treatment (partial surgical excision and glucocorticoid therapy) and prognosis (recurrence and death) were collected. Survival curves for recurrence were created using the Kaplan-Meier analysis. Univariate analysis and multivariate regression analysis were used to analyze prognostic factors. RESULTS: The mean age was 50.10±14.23y and 44.76±11.43y (P=0.033) in IgG4-positive and negative group respectively. The serum C3 and C4 was lower in IgG4-positive group (P=0.005, P=0.002), while the serum IgG and IgG2 was higher in IgG4-positive group (P=0.000 and P=0.008). Twenty-one cases had recurrence in IgG4-positive group and 3 cases recurrence in IgG4-negative group. The 5-year recurrence-free cumulative percentages of IgG4-positive group was 81.85%, and 83.46% in the IgG-negative group (P=0.216). The history of preoperative glucocorticoid therapy, serum C4, IgG1 and IgG2 were the factors affecting recurrence in IgG4-positive group, while serum C4, and IgG1 were the factors affecting recurrence of LGBLEL. CONCLUSION: Serum C4 and IgG1 are the factors affecting recurrence of LGBLEL, while the IgG4 does not affect recurrence of LGBLEL.

The heterogeneous drivers of CO2 emissions in China's two major economic belts: new evidence from spatio-temporal analysis.

CO2 emissions have become increasingly prominent in China, and the primary emitters are economic belts that are spread throughout China. Two major economic belts, i.e., the Yangtze River Economic Belt (YTREB) and the Yellow River Economic Belt (YREB). Combined with stochastic impacts by regression on population, affluence and technology model, the spatial Durbin model under the space-and-time fixed effect and the Geographical and Time-Weighted Regression are employed to explore the spatio-temporal distribution characteristics and heterogeneous drivers of CO2 emissions in the two economic belts. The results are as follows. First, CO2 emissions exhibit obvious spatial correlation features in the YREB, but no such obvious spatial correlation is found in the YRETB. Second, in the YREB, the magnitude of the total influencing factors on CO2 emissions follows an order where affluence (A) is the biggest driver, followed by energy intensity (EI), technology (TEC) and openness (OP), while the biggest driver in the YRETB is industrial structure supererogation (ISS), followed by population (P), energy intensity (EI), and affluence (A). Both direct and spatial spillover effects of the drivers are observed in the two economic belts. Third, the CO2 emissions show a notable temporal lag effect in the YREB, but not in the YRETB. Fourth, the effects of the CO2 emission drivers illustrate significant spatio-temporal heterogeneity in the two economic belts.

Cerebrospinal Fluid Pressure Reduction Induces Glia-Mediated Retinal Inflammation and Leads to Retinal Ganglion Cell Injury in Rats.

Low intracranial pressure (LICP)-induced translaminar cribrosa pressure difference (TLCPD) elevation has been proven as a risk factor in glaucomatous neurodegeneration, whereas the underlying retinal immune features of LICP-induced retinal ganglion cells (RGC) injury remain elusive. Here, we identified the retinal immune characteristics of LICP rats, and minocycline (Mino) treatment was utilized to analyze its inhibitory role in glia-mediated retinal inflammation of LICP rats. The results showed that retrograde axonal transport was decreased in LICP rats without significant RGC loss, indicating the RGC injury was at an early stage before the morphological loss. The activation of retinal microglia and astrocytes with morphologic and M1 or A1-marker alternations was detected in TLCPD elevation rats, the activation level is more dramatic in HIOP rats than in the LICP rats (P<0.05). Besides, we detected reduced retinal tight junction protein expressions, accompanied by specific imbalance patterns of T lymphocytes in the retina of both LICP and HIOP rats (P<0.05). Further Mino treatment showed an effective inhibitory role in glia-driven inflammatory responses in LICP rats, including improving retrograde axonal transport, inhibiting retinal glial activation and proinflammatory subtype polarization, and alleviating the blood-retina barrier compromise. This study identified the glia-mediated retinal inflammation features triggered by LICP stimulus, and Mino application exhibited an effective role in the inhibition of retinal glia-mediated inflammation in LICP-induced TLCPD elevation rats.

Pathogenicity and Transcriptomic Analyses of Two "Candidatus Liberibacter asiaticus" Strains Harboring Different Types of Phages.

"Candidatus Liberibacter asiaticus" is one of the putative causal agents of citrus Huanglongbing (HLB), a highly destructive disease threatening the global citrus industry. Several types of phages had been identified in "Ca. Liberibacter asiaticus" strains and found to affect the biology of "Ca. Liberibacter asiaticus." However, little is known about the influence of phages in "Ca. Liberibacter asiaticus" pathogenicity. In this study, two "Ca. Liberibacter asiaticus" strains, PYN and PGD, harboring different types of phages were collected and used for pathogenicity analysis in periwinkle (Catharanthus roseus). Strain PYN carries a type 1 phage (P-YN-1), and PGD harbors a type 2 phage (P-GD-2). Compared to strain PYN, strain PGD exhibited a faster reproduction rate and higher virulence in periwinkle: leaf symptoms appeared earlier, and there was a stronger inhibition in the growth of new flush. Estimation of phage copy numbers by type-specific PCR indicated that there are multiple copies of phage P-YN-1 in strain PYN, while strain PGD carries only a single copy of phage P-GD-2. Genome-wide gene expression profiling revealed the lytic activity of P-YN-1 phage, as evidenced by the unique expression of genes involved in lytic cycle, which may limit the propagation of strain PYN and lead to a delayed infection in periwinkle. However, the activation of genes involved in lysogenic conversion of phage P-GD-1 indicated it could reside within the "Ca. Liberibacter asiaticus" genome as a prophage form in strain PGD. Comparative transcriptome analysis showed that the significant differences in expression of virulence factor genes, including genes associated with pathogenic effectors, transcriptional factors, the Znu transport system, and the heme biosynthesis pathway, could be another major determinant of virulence variation between two "Ca. Liberibacter asiaticus" strains. This study expanded our knowledge of "Ca. Liberibacter asiaticus" pathogenicity and provided new insights into the differences in pathogenicity between "Ca. Liberibacter asiaticus" strains. IMPORTANCE Citrus Huanglongbing (HLB), also called citrus greening disease, is a highly destructive disease threatening citrus production worldwide. "Candidatus Liberibacter asiaticus" is one of the most common putative causal agents of HLB. Phages of "Ca. Liberibacter asiaticus" have recently been identified and found to affect "Ca. Liberibacter asiaticus" biology. Here, we found that "Ca. Liberibacter asiaticus" strains harboring different types of phages (type 1 or type 2) showed different levels of pathogenicity and multiplication patterns in the periwinkle plant (Catharanthus roseus). Transcriptome analysis revealed the possible lytic activity of type 1 phage in a "Ca. Liberibacter asiaticus" strain, which could limit the propagation of "Ca. Liberibacter asiaticus" and lead to the delayed infection in periwinkle. The heterogeneity in the transcriptome profiles, particularly the significant differences in expression of virulence factors genes, could be another major determinant of difference in virulence observed between the two "Ca. Liberibacter asiaticus" strains. These findings improved our understanding of "Ca. Liberibacter asiaticus"-phage interaction and provided insight into "Ca. Liberibacter asiaticus" pathogenicity.

How does technological innovation affect carbon emission efficiency in the Yellow River Economic Belt: the moderating role of government support and marketization.

The Yellow River Economic Belt (YREB) is a fundamental ecological protection barrier for China. Its carbon pollution issues are currently severe owing to the extensive energy consumption and unsatisfactory industrial constructions. In this context, this paper estimates carbon emission efficiency (CEE) based on the panel data from 56 cities in the YREB during the period 2006-2019 and analyzes its spatial distribution characteristics. Additionally, the spatial Durbin model (SDM) is utilized to examine the effect of technological innovation (TI) on CEE as a result of the moderating effects of government support (GS) and marketization (MA), respectively. The results indicated that (i) in the YREB, CEE exhibited significant spatial autocorrelation characteristics; (ii) TI negatively affected local CEE; (iii) the moderating effect of local GS on the relationship between TI and CEE in the local area was negative, but its spatial spillover effect was still not significant; (iv) the moderating effect of local MA on the relationship between TI and CEE in the local area was also negative, but positive in the surrounding areas. Based on the empirical analysis, a series of policy suggestions are proposed to improve the YREB's CEE.

Leaf Cuticular Waxes of Bermudagrass Response to Environment-Driven Adaptations of Climate Effect Inferred from Latitude and Longitude Gradient in China.

Bermudagrass (Cynodon dactylon) is a widely used warm season lawn grass. Cuticular wax covering the surface of plant leaves plays an important role in helping plants resist biotic and abiotic stresses. We analyzed the changes of cuticle wax in 25 bermudagrass populations from different longitude and latitude gradients, in order to verify how environmental conditions affect the structure and chemical composition of cuticle wax. Five wax components were identified, including alkanes, esters, alkenes, aldehydes and primary alcohols. The wax characteristics were divided into two principal components, explaining 58.2 % and 66.7 % of the total variability in latitude and longitude, even some populations had a certain correlation with each other. Pearson correlation analysis further showed that the total wax coverage, wax component content and antioxidant enzyme activity of bermudagrass populations on the latitudinal gradient had different responses to environmental factors. Finally, nineteen key genes involved in wax biosynthesis, redox and photosynthesis were identified and verified by RT-qPCR. The results showed that the responses of bermudagrass in different populations to climate change were quite different, which was of great significance for the evolution of bermudagrass populations.

Mechanosensitive channel Piezo1 is an essential regulator in cell cycle progression of optic nerve head astrocytes.

Optic nerve head (ONH) astrocytes provide structural and metabolic support to neuronal axons in developmental, physiological, and pathological progression. Mechanosensitive properties of astrocytes allow them to sense and respond to mechanical cues from the local environment. We confirmed that ONH astrocytes express the mechanosensitive ion channel Piezo1 in vivo. By manipulating Piezo1 knockdown or overexpression in vitro, we found that Piezo1 is necessary but insufficient for ONH astrocyte proliferation. Loss of Piezo1 can lead to cell cycle arrest at G0/G1 phase, a possible mechanism involving decreased yes-associated protein (YAP) nuclear localization and downregulation of YAP-target cell cycle-associated factors, including cyclin D1 and c-Myc. Gene ontology enrichment analysis of differential expression genes from RNA-seq data indicates that the absence of Piezo1 affects biological processes involving cell division. Our results demonstrate that Piezo1 is an essential regulator in cell cycle progression in ONH astrocytes.

Human Pro370Leu Mutant Myocilin Induces the Phenotype of Open-Angle Glaucoma in Transgenic Mice.

To investigate the characteristics of mutation myocilin proteins and glaucoma pathological phenotype in transgenic mice with full-length human Pro370Leu mutant myocilin gene (Tg-MYOCP370L). Tg-MYOCP370L mice were established using the CRISPR/Cas9 system. Long-term intraocular pressure (IOP) was measured, myocilin protein expressions in anterior chamber angle, retina, optic nerve tissues and aqueous humor were detected by western blot. RBPMS, myocilin, Iba-1 and GFAP expression were visualized by immunofluorescence. H&E staining was applied to assess the ocular angle and retinal morphology. Aqueous humor dynamics were visualized by Gadolinium magnetic resonance imaging (Gd-MRI). TUNEL assay was used to evaluate the specific cell apoptosis in trabecular meshwork and retina. Optomotor and electroretinography tests were employed to evaluate the visual function in Tg-MYOCP370L and wild-type (WT) mice. Homozygous myocilin mutation at position 503 (C > T) was identified by PCR and sequencing in Tg-MYOCP370L mice. Myocilin protein expression was overexpressed in eye tissues of Tg-MYOCP370L mice with reduced myocilin secretion in aqueous humor. H&E staining showed normal histological morphology of anterior chamber angle whereas decreased thickness and nuclei in ganglion cell layer were found (P < 0.05). Gd signals were significantly increased in the anterior chamber of Tg-MYOCP370L compared with WT eyes (P < 0.05). IOP was elevated in Tg-MYOCP370L mice starting at 5 months of age, with significant RGC loss (P < 0.05). Upregulation of caspase-3 and caspase-9 expressions and increased TUNEL-positive cells were found in eyes of Tg-MYOCP370L mice. Excessive activation of retinal glial cells and impaired visual function were detected in Tg-MYOCP370L mice. Tg-MYOCP370L mice can induce the phenotype of open-angle glaucoma, featured as IOP elevation, activated retinal glial cells, loss of RGCs and impaired visual function. These pathologic changes may arise from the abnormal mutant myocilin protein accumulation in the trabecular meshwork and injured aqueous humor drainage. Therefore, Tg-MYOCP370L mice model can serve as an effective animal model for glaucoma research, especially for glaucoma-associated myocilin mutation studies.

Histological characteristics, cell wall hydrolytic enzyme activity, and transcriptome analysis with seed shattering of Stylosanthes accessions.

Stylosanthes spp. (stylo) are annual or perennial legume forages that are widely grown as forage and cover crops in tropical and subtropical regions. However, the seed yield of stylo is very low due to serious seed shattering. In the present study, we found that, although seed shattering was common among the stylo accessions, the shattering rates were genetically different. Therefore, we first synthesized the morphological, histological characteristic, physiochemical, and transcriptome analyses to determine the seed shattering mechanism in stylo. In general, the stylo germplasm with shorter lobules and thicker stems had a lower seed shattering rate and a higher seed weight. The seed and seed stalk joint is the abscission zone in stylo. Multiplex histology and hydrolytic enzyme activity analysis showed that the tearing of the abscission zone occurs due to the intense enzymatic degradation of polygalacturonase and cellulase in the seed shattering-susceptible accession TF0275. cDNA libraries from the abscission zone tissues of TF0041 and TF0275 at 14, 21, and 28 days after flowering were constructed and sequenced. A total of 47,606 unigenes were annotated and 18,606 differentially expressed genes (DEGs) were detected, including 9,140 upregulated and 9,446 downregulated unigenes. Furthermore, the 26 candidate DEGs involved in lignin biosynthesis, cellulase synthesis, and plant hormone signal transduction were found at all three developmental stages. This study provides valuable insights for future mechanistic studies of seed shattering in stylo.

A Novel Beta-Glucosidase Gene for Plant Type Was Identified by Genome-Wide Association Study and Gene Co-Expression Analysis in Widespread Bermudagrass.

Bermudagrass (Cynodon spp.) is one of the most widely distributed warm-season grasses globally. The growth habits and plant type of bermudagrass are strongly associated with the applied purpose of the landscape, livestock, and eco-remediation. Therefore, persistent efforts are made to investigate the genetic basis of plant type and growth habits of bermudagrass. Here, we dissect the genetic diversity of 91 wild bermudagrass resources by genome-wide association studies (GWAS) combined with weighted gene co-expression analysis (WGCNA). This work is based on the RNA-seq data and the genome of African bermudagrass (Cynodon transvaalensis Burtt Davy). Sixteen reliable single-nucleotide polymorphisms (SNPs) in transcribed regions were identified to be associated with the plant height and IAA content in diverse bermudagrass by GWAS. The integration of the results from WGCNA indicates that beta-glucosidase 31 (CdBGLU31) is a candidate gene underlying a G/A SNP signal. Furthermore, both qRT-PCR and correlation coefficient analyses indicate that CdBGLU31 might play a comprehensive role in plant height and IAA biosynthesis and signal. In addition, we observe lower plant height in Arabidopsis bglu11 mutants (homologs of CdBGLU31). It uncovers the breeding selection history of different plant types from diverse bermudagrass and provides new insights into the molecular function of CdBGLU31 both in plant types and in IAA biosynthetic pathways.

Phylogeographical Pattern and Population Evolution History of Indigenous Elymus sibiricus L. on Qinghai-Tibetan Plateau.

Elymus sibiricus L. is a perennial allotetraploid belonging to Triticeae of Poaceae, Elymus L., as the type species of genus Elymus L. The existing geographical distribution pattern and genetic spatial structure of E. sibiricus on Qinghai-Tibetan Plateau (QTP) are not yet clear. In this study, population genetic structure and demography history of 216 individuals from 44 E. sibiricus populations on QTP were studied used specific-locus amplified fragment sequencing (SLAF-seq). The result of genetic diversity showed that there was no single genetic diversity center was observed across all E. sibiricus populations. The results of genetic variation showed that 44 populations were clearly divided into the following three groups: Qinghai Plateau (Group I), South Tibet (Group II), and Hengduan Mountains (Group III). From the three analyses of AMOVA, Mantel test and Treemix, strong genetic differentiation across all populations and low genetic differentiation among populations within three groups. Molecular dating indicated that E. sibiricus diverged at 16.08 Ma (during the early Miocene) can be linked to the Himalayan Motion stage of QTP uplift. It is speculated that the reasons affecting the current phylogeographical pattern are as follows: (1) The environmental changes due to the uplift of the QTP; (2) The geographic distance between the populations (Groups I and III are close in geographic distance, and gene flow are frequent); (3) Geographical barriers (the Tanggula and Bayangela Mountains between Groups I and II). This study provides new evidence and historical perspective to the future exploration of the evolution and geographic distribution pattern of Elymus L.

[Retracted] MicroRNA­448 inhibits the progression of retinoblastoma by directly targeting ROCK1 and regulating PI3K/AKT signalling pathway.

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that three data panels featured in the flow cytometric plots shown in Figs. 5D and 6D, and several panels from the cell invasion assays shown in Figs. 5C and 6C, were strikingly similar to data appearing in different form in other articles by different authors. Owing to the fact that the contentious data in the above article were already under consideration for publication prior to its submission to Oncology Reports, the Editor has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they agreed with the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [Oncology Reports 39: 2402­2412, 2018; DOI: 10.3892/or.2018.6302].

Myocilin Gene Mutation Induced Autophagy Activation Causes Dysfunction of Trabecular Meshwork Cells.

Trabecular meshwork dysfunction is the main cause of primary open angle glaucoma (POAG) associated with elevated intraocular pressure (IOP). Mutant myocilin causes glaucoma mainly via elevating IOP. Previously we have found that accumulated Asn 450 Tyr (N450Y) mutant myocilin impairs human trabecular meshwork (TM) cells by inducing chronic endoplasmic reticulum (ER) stress response in vitro. However, it is unclear how ER stress leads to TM damage and whether N450Y myocilin mutation is associated with POAG in vivo. Here we found that N450Y mutant myocilin induces autophagy, which worsens cell viability, whereas inhibition of autophagy increases viability and decreases cell death in human TM cells. Furthermore, we construct a transgenic mouse model of N450Y myocilin mutation (Tg-MYOCN450Y) and Tg-MYOCN450Y mice exhibiting glaucoma phenotypes: IOP elevation, retinal ganglion cell loss and visual impairment. Consistent with our published in vitro studies, mutant myocilin fails to secrete into aqueous humor, causes ER stress and actives autophagy in Tg-MYOCN450Y mice, and aqueous humor dynamics are altered in Tg-MYOCN450Y mice. In summary, our studies demonstrate that activation of autophagy is correlated with pathogenesis of POAG.

Spatio-Temporal Heterogeneity of Carbon Emissions and Its Key Influencing Factors in the Yellow River Economic Belt of China from 2006 to 2019.

The Yellow River Economic Belt (YREB) performs an essential function in the low-carbon development of China as an important ecological protection barrier, and it is of great importance to identify its spatio-temporal heterogeneity and key influencing factors. In this study, we propose a comprehensively empirical framework to conduct this issue. The STIRPAT model was applied to determine the influencing factors of carbon emissions in the YREB from 2006 to 2019. The results show that the carbon emissions in the YREB had significant clustering characteristics in the spatial auto-correlation analysis. In addition, the estimation results of the spatial panel analysis demonstrate that the carbon emissions showed a distinct spatial lag effect and temporal lag effect. Moreover, the three traditional factors including population, affluence, technology are identified as the key influencing factors of carbon emissions in the YREB of China. Furthermore, the spatio-temporal heterogeneity is illustrated vividly by employing the GTWR-STIRPAT model. Finally, policy implications are provided to respond to the demand for low-carbon development.