Development of a Novel Water Jet Polisher Using Soft Abrasives for Small Complex-Structure Heat Pipes of Aluminum Alloy Produced Using Additive Manufacturing.

It is a challenge to polish the interior surface of a small bent pipe with complex structures and sizes less than 0.5 mm. This is because of the fact that traditional polishing methods could destroy, block, or break the small complex structures. For a small bent pipe made of aluminum alloy produced using additive manufacturing, the defects, such as adhered powders and spatters, are easy to jam the pipe without polishing, possibly resulting in catastrophic failure for aerospace applications. To overcome this challenge, a novel water jet polisher was developed using soft polymethyl methacrylate (PMMA) abrasives. After polishing a specific area, the adhered powders on the interior surface were reduced from over 140 to 2, 3, and 6 by the soft abrasives with mesh sizes of 200, 400, and 600, respectively. The surface roughness Sa was decreased from 3.41 to 0.92 µm after polishing using PMMA abrasives with a mesh size of 200. In comparison, silica abrasives were also employed to polish the small bent pipes, leading to the bent part of pipes breaking. However, this kind of failure was absent when using soft abrasives. Computational fluid dynamics calculations elucidate that a peak erosion rate of silica abrasives for a bent pipe with a turn angle of 30° is 2.18 kg/(m2·s), which is 17 times that of soft abrasives. This is why the small bent pipe was broken using silica abrasives, whereas it remained intact when polished with soft abrasives. In addition, water jet polishing has a lower erosion rate, a relatively smooth erosion curve, and less erosion energy, leaving the bent parts intact. The developed soft abrasive water jet polisher and the findings of this study suggest new possibilities for cleaning the adhered powders and spatters and polishing the interior surface of small bent pipes with complex structures.

Single­cell RNA sequencing reveals inflammatory retinal microglia in experimental autoimmune uveitis.

Autoimmune uveitis (AU) is a kind of immune-mediated disease resulting in irreversible ocular damage and even permanent vision loss. However, the precise mechanism underlying dynamic immune changes contributing to disease initiation and progression of AU remains unclear. Here, we induced an experimental AU (EAU) model with IRBP651-670 and found that day[D]14 was the inflammatory summit with remarking clinical and histopathological manifestations and the activation of retinal microglia exhibited a time-dependent pattern in the EAU course. We conducted single-cell RNA sequencing of retinal immune cells in EAU mice at four time points and found microglia constituting the largest proportion, especially on D14. A novel inflammatory subtype (Cd74high Ccl5high) of retinal microglia was identified at the disease peak that was closely associated with modulating immune responses. In vitro experiments indicated that inflammatory stimuli induced proinflammatory microglia with the upregulation of CD74 and CCL5, and CD74 overexpression in microglia elicited their proinflammatory phenotype via nuclear factor-kappa B signaling that could be attenuated by the treatment of neutralizing CCL5 antibody to a certain extent. In-vivo blockade of Cd74 and Ccl5 effectively alleviated retinal microglial activation and disease phenotype of EAU. Therefore, we propose targeting CD74 and CCL5 of retinal microglia as promising strategies for AU treatment.

Atomic surface of quartz glass induced by photocatalytic green chemical mechanical polishing using the developed SiO2@TiO2 core-shell slurry.

High-performance devices of quartz glass demand an atomic surface, which induces a challenge for chemical mechanical polishing (CMP) with a high material removal rate (MRR). Moreover, traditional CMP usually employs toxic and corrosive slurries, leading to the pollution of the environment. To overcome these challenges, a novel green photocatalytic CMP is proposed. In the CMP, SiO2@TiO2 core-shell abrasives were developed, and the CMP slurry included the developed abrasives, sodium carbonate, hydrogen peroxide and sorbitol. After photocatalytic CMP, the surface roughness Sa of quartz glass is 0.185 nm, with a scanning area of 50 × 50 µm2, and the MRR is 8.64 µm h-1. To the best of our knowledge, the MRR is the highest on such a big area of atomic surface for quartz glass. X-ray photoelectron spectroscopy reveals that SiO2@TiO2 core-shell abrasives were used as photocatalysts motivated by simulated solar light, generating electrons and holes and producing hydroxyl radicals through hydrogen peroxide. As a result, OH- could combine with Si atoms on the surface of quartz glass, forming Si-OH-Si bonds. Then the formed bonds were removed based on the balance between chemical and mechanical functions. The proposed CMP, developed SiO2@TiO2 abrasives and slurry provide new insights to achieve an atomic surface of quartz glass with a high MRR.

Atomic surface achieved through a novel cross-scale model from macroscale to nanoscale.

Chemical mechanical polishing (CMP) is widely used to achieve an atomic surface globally, yet its cross-scale polishing mechanisms are elusive. Moreover, traditional CMP normally employs toxic and corrosive slurries, resulting in potential pollution to the environment. To overcome these challenges, a novel cross-scale model from the millimeter to nanometer scale is proposed, which was confirmed by a newly developed green CMP process. The developed CMP slurry consisted of hydrogen peroxide, sodium carbonate, sodium hydroxycellulose, and silica. Prior to CMP, fused silica was polished by a ceria slurry. After CMP, the surface roughness (Sa) was 0.126 nm, the material-removal rate was 88.3 nm min-1, and the thickness of the damaged layer was 8.8 nm. The proposed model was built by fibers, through integrating Eulerian and Lagrangian models and reactive force field-molecular dynamics. The results predicted by the model were in good agreement with those of CMP experimentally. A model for large-sized fibers revealed that a direct contact area of 11.12% was obtained for a non-woven polishing pad during the CMP experiments. Another model constructed via combining Eulerian and Lagrangian functions showed that the stress at the intersections of the fibers varied mainly from 0.1 to 0.01 MPa and was higher than the stress at other parts. An increase in viscosity led to a decrease in the areas with low stress, demonstrating that viscosity enhanced the stress and facilitated the removal of material. At the microscale and nanoscale, the stress of the abrasive surface exposed to the workpiece changed from 2.21 to 6.43 GPa. Stress at the interface contributed to the formation of bridging bonds, further promoting the removal of material. With increasing the compressive stress, the material-removal form was transformed from a single atom to molecular chains. The proposed model and developed green CMP offer new insights to understand the cross-scale polishing mechanism, as well as for designing and manufacturing novel polishing slurries, pads, and setups.

Unprecedented atomic surface of silicon induced by environmentally friendly chemical mechanical polishing.

Silicon (Si) dominates the integrated circuit (IC), semiconductor, and microelectronic industries. However, it is a challenge to achieve a sub-angstrom surface of Si. Chemical mechanical polishing (CMP) is widely used in the manufacturing of Si, while toxic and polluted slurries are usually employed in CMP, resulting in pollution to the environment. In this study, a novel environmentally friendly CMP was developed, in which a slurry is composed of ceria, hydrogen peroxide, sodium pyrophosphate, sodium carboxymethyl cellulose, sodium carbonate, and deionized water. After CMP, the surface roughness Sa was 0.067 nm with a measurement area of 50 × 50 µm2, and a sub-angstrom surface is achieved. To the best of our knowledge, it is the lowest surface roughness in such a large area. Transmission electron microscopy shows that the thickness of the damaged layer after CMP is 2.8 nm. X-ray photoelectron spectroscopy and infrared Fourier transformation reveal that during CMP, a redox reaction firstly took place between Ce3+ and Ce4+. Si and ceria are hydroxylated, forming Si-OH and Ce-OH, then dehydration and condensation occur, generating Si-O-Ce. These findings propose new insights to fabricate a sub-angstrom surface of Si for use in IC, semiconductor, and microelectronic industries.

N6-methyladenosine demethylase FTO regulates inflammatory cytokine secretion and tight junctions in retinal pigment epithelium cells.

OBJECTIVE: Uveitis is an intraocular inflammatory disease. Epigenetics has been associated with its pathogenesis. However, the role of N6-methyladenosine (m6A) in uveitis has not been reported. We aimed to examine the role of m6A and its regulatory mechanism in experimental autoimmune uveitis (EAU). METHODS: The mRNA expression of m6A-related methylase and demethylase of retinal pigment epithelium (RPE) between mice with EAU and control mice was detected by RT-qPCR. The overall m6A level of ARPE-19 cells was detected by an m6A quantitative detection kit. Cell proliferation was observed by CCK-8 assays, and ELISA was used to test the secretion of inflammatory factors. The expression of tight junction proteins and the target genes of FTO were examined by western blotting and MeRIP-PCR. RESULTS: A decreased expression of FTO in RPE cells was found in mice with EAU. Increased overall m6A%, proliferation of cells and secretion of IL-6, IL-8 and MCP-1 were found after FTO knockdown in ARPE-19 cells. However, ZO-1 and occludin protein expression was decreased. ATF4 protein expression was decreased in the FTO knockdown (shFTO) group as compared with the control (shNC) group. In contrast, the m6A level of ATF4 was elevated, as shown by MeRIP-PCR. Functional analysis showed that p-STAT3 expression was increased in the shFTO group, and the change in occludin expression was reversed in ATF4 rescue experiment. CONCLUSION: FTO may affect the translation of ATF4 by regulating its m6A level, resulting in the increased expression of p-STAT3 and inflammatory factors, and leading to uveitis.

Low Expression of YTH Domain-Containing 1 Promotes Microglial M1 Polarization by Reducing the Stability of Sirtuin 1 mRNA.

The N6-methyladenosine (m6A) modification is the most abundant posttranscriptional mRNA modification in mammalian cells and is dynamically modulated by a series of "writers," "erasers," and "readers." Studies have shown that m6A affects RNA metabolism in terms of RNA processing, nuclear export, translation, and decay. However, the role of the m6A modification in retinal microglial activation remains unclear. Here, we analyzed the single-cell RNA sequencing data of retinal cells from mice with uveitis and found that the m6A-binding protein YTH domain-containing 1 (YTHDC1) was significantly downregulated in retinal microglia in the context of uveitis. Further studies showed that YTHDC1 deficiency resulted in M1 microglial polarization, an increased inflammatory response and the promotion of microglial migration. Mechanistically, YTHDC1 maintained sirtuin 1 (SIRT1) mRNA stability, which reduced signal transducer and activator of transcription 3 (STAT3) phosphorylation, thus inhibiting microglial M1 polarization. Collectively, our data show that YTHDC1 is critical for microglial inflammatory response regulation and can serve as a target for the development of therapeutics for autogenic immune diseases.

A Single-Cell Transcriptome Atlas of the Human Retinal Pigment Epithelium.

Human retinal pigment epithelium cells are arranged in a monolayer that plays an important supporting role in the retina. Although the heterogeneity of specific retinal cells has been well studied, the diversity of hRPE cells has not been reported. Here, we performed a single-cell RNA sequencing on 9,302 hRPE cells from three donors and profiled a transcriptome atlas. Our results identified two subpopulations that exhibit substantial differences in gene expression patterns and functions. One of the clusters specifically expressed ID3, a macular retinal pigment epithelium marker. The other cluster highly expressed CRYAB, a peripheral RPE marker. Our results also showed that the genes associated with oxidative stress and endoplasmic reticulum stress were more enriched in the macular RPE. The genes related to light perception, oxidative stress and lipid metabolism were more enriched in the peripheral RPE. Additionally, we provided a map of disease-related genes in the hRPE and highlighted the importance of the macular RPE and peripheral RPE clusters P4 and P6 as potential therapeutic targets for retinal diseases. Our study provides a transcriptional landscape for the human retinal pigment epithelium that is critical to understanding retinal biology and disease.

Small molecules targeting RORγt inhibit autoimmune disease by suppressing Th17 cell differentiation.

Th17 cells, a lymphocyte subpopulation that is characterized by the expression of the transcription factor "retinoic acid receptor-related orphan receptor gamma-t" (RORγt), plays an important role in the pathogenesis of autoimmune disease. The current study was set up to discover novel and non-steroidal small-molecule inverse agonists of RORγt and to determine their effects on autoimmune disease. Structure-based virtual screening (SBVS) was used to find compounds targeting RORγt. Flow cytometry was used to detect the Th17 cell differentiation. Inverse agonists were intraperitoneally administered to mice undergoing experimental autoimmune uveitis (EAU), experimental autoimmune encephalomyelitis (EAE) or type 1 diabetes. The effects of the inverse agonists were evaluated by clinical or histopathological scoring. Among 1.3 million compounds screened, CQMU151 and CQMU152 were found to inhibit Th17 cell differentiation without affecting the differentiation of Th1 and Treg lineages (both P = 0.001). These compounds also reduced the severity of EAU (P = 0.01 and 0.013) and functional studies showed that they reduced the number of Th17 cell and the expression of IL-17(Th17), but not IFN-γ(Th1) and TGF-ß(Treg) in mouse retinas. Further studies showed that these compounds may reduce the expression of p-STAT3 by reducing the positive feedback loop of IL-17/IL-6/STAT3. These compounds also reduced the impaired blood-retinal barrier function by upregulating the expression of tight junction proteins. These compounds were also found to reduce the severity of EAE and type 1 diabetes. Our results showed that RORγt inverse agonists may inhibit the development of autoimmune diseases and may provide new clues for the treatment of Th17-mediated immune diseases.