Spatiotemporal PM2.5 estimations in China from 2015 to 2020 using an improved gradient boosting decision tree.

Fine particulate matter (PM2.5) with spatiotemporal continuity can provide important basis for the assessment of adverse effects on human health. In recent years, researchers have done a lot of work on the surface PM2.5 simulation. However, due to the limitations of data and models, it is difficult to accurately evaluate the spatial and temporal PM2.5 variations on a fine scale. In this study, we adopted the multi-angle implementation of atmospheric correction (MAIAC) aerosol products, and proposed a spatiotemporal model based on the gradient boosting decision tree (GBDT) algorithm to retrieve PM2.5 concentration across China from 2015 to 2020 at 1-km resolution. Our model achieved excellent performance, with overall CV-R2 of 0.92, and annual CV-R2 of 0.90-0.93. In addition, the model can also be used for evaluation on different time scales. Compared with previous studies, the model developed in our study performed better and more stable, which showed the highest accuracies in PM2.5 estimation works at 1-km resolution. During the study period, the overall national PM2.5 pollution showed a downward trend, with the annual mean concentration dropping from 42.42 µg/m3 to 27.91 µg/m3. The largest decrease occurred in Beijing-Tianjin-Hebei (BTH), with a trend of -5.17 µg/m3/yr, while it remains the most polluted region. The area meeting the secondary national air quality standard (<35 µg/m3) increased from ∼34% to ∼79%. These results indicate that the atmospheric environment has improved significantly. Moreover, different regions have different time nodes for the start of the continuous standard-met day during the year, and the duration is different as well. Overall, this study can provide reliable large-scale PM2.5 estimations.

ATP1A3 mutation as a candidate cause of autosomal dominant cone-rod dystrophy.

Cone-rod dystrophy (CORD) is an inherited retinal degenerative disease characterized by progressive loss of cone and rod photoreceptors. Although several genes have been reported to cause autosomal dominant CORD (adCORD), the genetic causes of adCORD have not been fully elucidated. Here, we identified the ATP1A3 gene, encoding the α3 subunit of Na+, K+-ATPase, as a novel gene associated with adCORD. Using whole-exome sequencing (WES), we found a candidate mutation of ATP1A3 that co-segregated with the disease in an analysis of two affected patients and one healthy relative in an adCORD family. According to our RNA-seq data, we demonstrated that the Atp1a3 mRNA level was extremely high in the murine retina. Overexpression of mutant ATP1A3 in vitro led to a reduced oxygen consumption rate (OCR), reflecting the limited mitochondrial reserve capacity. Furthermore, we generated transgenic mice expressing the ATP1A3 cDNA with patient variant and found decreased electroretinogram (ERG) responses. Moreover, the mutant ATP1A3 is highly expressed in photoreceptor inner segment, where mitochondria are enriched. These results suggest that the ATP1A3 mutation is a new genetic cause responsible for adCORD and indicate that ATP1A3 plays an important role in retinal function.

True S-cones are concentrated in the ventral mouse retina and wired for color detection in the upper visual field.

Color, an important visual cue for survival, is encoded by comparing signals from photoreceptors with different spectral sensitivities. The mouse retina expresses a short wavelength-sensitive and a middle/long wavelength-sensitive opsin (S- and M-opsin), forming opposing, overlapping gradients along the dorsal-ventral axis. Here, we analyzed the distribution of all cone types across the entire retina for two commonly used mouse strains. We found, unexpectedly, that 'true S-cones' (S-opsin only) are highly concentrated (up to 30% of cones) in ventral retina. Moreover, S-cone bipolar cells (SCBCs) are also skewed towards ventral retina, with wiring patterns matching the distribution of true S-cones. In addition, true S-cones in the ventral retina form clusters, which may augment synaptic input to SCBCs. Such a unique true S-cone and SCBC connecting pattern forms a basis for mouse color vision, likely reflecting evolutionary adaptation to enhance color coding for the upper visual field suitable for mice's habitat and behavior.

Many primates, including humans, can see color better than most other mammals. This difference is due to the variety of light-detecting proteins ­ called opsins ­ that are produced in the eye by cells known as cones. While humans have three, mice only have two different opsins, known as S and M, which detect blue/UV and green light, respectively. Mouse cones produce either S-opsins, M-opsins or both. Fewer than 10 percent of cone cells in mice produce just the S-opsin, and these cells are essential for color vision. Mice are commonly used in scientific research, and so their vision has been well studied. However, previous research has produced conflicting results. Some studies report that cone cells that contain only S-opsin are evenly spread out across the retina. Other evidence suggests that color vision in mice exists only for the upper field of their vision, in other words, that mice can only distinguish colors that appeared above them. Nadal-Nicolás et al. set out to understand how to reconcile these contrasting findings. Molecular tools were used to detect S- and M-opsin in the retina of mice and revealed large differences between the lower part, known as the ventral retina, and the upper part, known as the dorsal retina. The ventral retina detects light coming from above the animal, and about a third of cone cells in this region produced exclusively S-opsin, compared to only 1 percent of cones in the dorsal retina. These S-opsin cone cells in the ventral retina group into clusters, where they connect with a special type of nerve cells that transmit this signal. To better understand these findings, Nadal-Nicolás et al. also studied albino mice. Although albino mice have a different distribution of S-opsin protein in the retina, the cone cells producing only S-opsin are similarly clustered in the ventral retina. This suggests that the concentration of S-opsin cone cells in the ventral retina is an important feature in mouse sight. This new finding corrects the misconception that S-opsin-only cone cells are evenly spread throughout the retina and supports the previous evidence that mouse color vision is greatest in the upper part of their field of vision. Nadal-Nicolás et al. suggest this arrangement could help the mice to detect predators that may attack them from above during the daytime. Together, these new findings could help to improve the design of future studies involving vision in mice and potentially other similar species.

Deletion of miR-182 Leads to Retinal Dysfunction in Mice.

Purpose: MicroRNA-182 (miR-182) is abundantly expressed in mammalian retinas; however, the association between miR-182 and retinal function remains unclear. In this study, we explored whether miR-182 contributes to functional decline in retinas using a miR-182 depleted mouse. Methods: Electroretinogram (ERG) amplitudes at different ages were measured in miR-182 knockout (KO) mice. The thickness and lamination of retinas were assessed using a color fundus camera and high-resolution optical coherence tomography. Expression levels of key photoreceptor-specific genes and the miR-183/96/182 cluster (miR-183C) were quantified using quantitative real-time PCR. RNA sequencing and light-induced damage were carried out to observe the changes in the retinal transcriptome and sensitivity to light damage in the miR-182 KO mice. Results: The ERG recording reveals that the ERG response amplitude decreased both at early and later ages when compared with control littermates. The expression of some key photoreceptor-specific genes was down-regulated with deletion of miR-182 in retina. RNA sequencing indicated that some biological processes of visual system were affected, and the numbers of potential target genes of miR-182 were presented in the mouse retina using bioinformatics analysis. The miR-182 KO mice were characterized by progressively losing the outer segment after being treated with light-damage exposure. The thickness and lamination of retina as well as compensatory expression of miR-183C showed no apparent changes in retina of miR-182 KO mice under normal laboratory lighting condition. Conclusions: Our findings provided new insights into the relationship between the miR-182 and retinal development and revealed that miR-182 may play a critical role in maintaining retinal function.

miR-183/96 plays a pivotal regulatory role in mouse photoreceptor maturation and maintenance.

MicroRNAs (miRNAs) are known to be essential for retinal maturation and functionality; however, the role of the most abundant miRNAs, the miR-183/96/182 cluster (miR-183 cluster), in photoreceptor cells remains unclear. Here we demonstrate that ablation of two components of the miR-183 cluster, miR-183 and miR-96, significantly affects photoreceptor maturation and maintenance in mice. Morphologically, early-onset dislocated cone nuclei, shortened outer segments and thinned outer nuclear layers are observed in the miR-183/96 double-knockout (DKO) mice. Abnormal photoreceptor responses, including abolished photopic electroretinography (ERG) responses and compromised scotopic ERG responses, reflect the functional changes in the degenerated retina. We further identify Slc6a6 as the cotarget of miR-183 and miR-96. The expression level of Slc6a6 is significantly higher in the DKO mice than in the wild-type mice. In contrast, Slc6a6 is down-regulated by adeno-associated virus-mediated overexpression of either miR-183 or miR-96 in wild-type mice. Remarkably, both silencing and overexpression of Slc6a6 in the retina are detrimental to the electrophysiological activity of the photoreceptors in response to dim light stimuli. We demonstrate that miR-183/96-mediated fine-tuning of Slc6a6 expression is indispensable for photoreceptor maturation and maintenance, thereby providing insight into the epigenetic regulation of photoreceptors in mice.

Toll-Like Receptor 3 Activation Initiates Photoreceptor Cell Death In Vivo and In Vitro.

Purpose: Accumulating evidence has demonstrated that excessive immunoreaction plays a prominent role in the pathogenesis of dry AMD. Toll-like receptor 3 (TLR3) can be activated by double-stranded (ds)RNA in retinal pigment epithelia and trigger an innate immunity-mediated inflammatory response. However, its role in photoreceptor cells, the effectors of AMD geographic atrophy, remains unclear. Methods: The expression of TLR3 was examined in mouse retina and in a murine photoreceptor cell line (661W). Retinal structure, function, and cell death in the polyinosine-polycytidylic acid (poly I:C)-treated retina were investigated by optical coherence tomography, electroretinography (ERG), and immunostaining. Cytokine and chemokine expression as well as cell death were measured in poly I:C-exposed 661W cells and explant retinas. By comparing the RNA sequencing (seq) data of 661W cells and murine retina, we comprehensively investigated the contribution of photoreceptor in poly I:C-induced retinal immune response. Results: Toll-like receptor 3 was highly expressed in the inner segment of the photoreceptor and in 661W cells. We found poly I:C induced significant retinal structural damages and impairment of ERG responses. Focal ERG demonstrated that injected and parainjected zones were functionally damaged by poly I:C. In addition, poly I:C acted on cultured photoreceptor cells directly and evoked an inflammatory response that exhibited similarities with the immune response in mouse retina. Moreover, TLR3 activation initiated cell death in murine photoreceptor cells in vivo and in vitro. Additionally, poly I:C initiated immune response in explant retinas. Conclusions: We deciphered the TLR3-mediated inflammatory response in photoreceptor cells. Our findings suggested TLR3-mediated inflammatory response in photoreceptor cells may play an important role in dry AMD, offering new insights of potential treatments targeting photoreceptor immunity.

Targeted RP9 ablation and mutagenesis in mouse photoreceptor cells by CRISPR-Cas9.

Precursor messenger RNA (Pre-mRNA) splicing is an essential biological process in eukaryotic cells. Genetic mutations in many spliceosome genes confer human eye diseases. Mutations in the pre-mRNA splicing factor, RP9 (also known as PAP1), predispose autosomal dominant retinitis pigmentosa (adRP) with an early onset and severe vision loss. However, underlying molecular mechanisms of the RP9 mutation causing photoreceptor degeneration remains fully unknown. Here, we utilize the CRISPR/Cas9 system to generate both the Rp9 gene knockout (KO) and point mutation knock in (KI) (Rp9, c.A386T, P.H129L) which is analogous to the reported one in the retinitis pigmentosa patients (RP9, c.A410T, P.H137L) in 661 W retinal photoreceptor cells in vitro. We found that proliferation and migration were significantly decreased in the mutated cells. Gene expression profiling by RNA-Seq demonstrated that RP associated genes, Fscn2 and Bbs2, were down-regulated in the mutated cells. Furthermore, pre-mRNA splicing of the Fscn2 gene was markedly affected. Our findings reveal a functional relationship between the ubiquitously expressing RP9 and the disease-specific gene, thereafter provide a new insight of disease mechanism in RP9-related retinitis pigmentosa.