Nanoceria-Mediated Cyclosporin A Delivery for Dry Eye Disease Management through Modulating Immune-Epithelial Crosstalk.

Dry eye disease (DED) affects a substantial worldwide population with increasing frequency. Current single-targeting DED management is severely hindered by the existence of an oxidative stress-inflammation vicious cycle and complicated intercellular crosstalk within the ocular microenvironment. Here, a nanozyme-based eye drop, namely nanoceria loading cyclosporin A (Cs@P/CeO2), is developed, which possesses long-term antioxidative and anti-inflammatory capacities due to its regenerative antioxidative activity and sustained release of cyclosporin A (CsA). In vitro studies showed that the dual-functional Cs@P/CeO2 not only inhibits cellular reactive oxygen species production, sequentially maintaining mitochondrial integrity, but also downregulates inflammatory processes and repolarizes macrophages. Moreover, using flow cytometric and single-cell sequencing data, the in vivo therapeutic effect of Cs@P/CeO2 was systemically demonstrated, which rebalances the immune-epithelial communication in the corneal microenvironment with less inflammatory macrophage polarization, restrained oxidative stress, and enhanced epithelium regeneration. Collectively, our data proved that the antioxidative and anti-inflammatory Cs@P/CeO2 may provide therapeutic insights into DED management.

Atomic-Limit Mott Insulator in [4]Triangulene Frameworks.

Triangulene, one unique class of zigzag-edged triangular graphene molecules, has attracted tremendous research interest. In this work, as an ultimate phase of the Mott insulator, we present the realization of the atomic-limit Mott insulator in experimentally synthesized [4]triangulene frameworks ([4]-TGFs) from first-principles calculations. The frontier molecular orbitals of the nonmagnetic [4]triangulene consist of three coupled corner modes. After the isolated [4]triangulene is assembled into [4]-TGF, one special enantiomorphic flat band is created through the coupling of these corner modes, which is identified to be a second-order topological insulator with half-filled topological corner states at the Fermi level. Moreover, [4]-TGF prefers an antiferromagnetic ground state under Hubbard interactions, which further splits these metallic zero-energy states into an atomic-limit Mott insulator with spin-polarized corners. Since the fractional filling of topological corner states is a smoking-gun signature of higher-order topology, our results demonstrate a universal approach to explore the atomic-limit Mott insulators in higher-order topological materials.

[Effects of Straw Returning and Biochar Addition on Greenhouse Gas Emissions from High Nitrate Nitrogen Soil After Flooding in Rice-vegetable Rotation System in Tropical China].

In rice-vegetable rotation systems in tropical areas, a large amount of nitrate nitrogen accumulates after fertilization in the melon and vegetable season, which leads to the leaching of nitrate nitrogen and a large amount of N2O emission after the seasonal flooding of rice, which leads to nitrogen loss and intensification of the greenhouse effect. How to improve the utilization rate of nitrate nitrogen and reduce N2O emissions has become an urgent problem to be solved. Six treatments were set up [200 mg·kg-1 KNO3 (CK); 200 mg·kg-1 KNO3 + 2% biochar addition (B); 200 mg·kg-1 KNO3+1% peanut straw addition (P); 200 mg·kg-1 KNO3 + 2% biochar + 1% peanut straw addition (P+B); 200 mg·kg-1 KNO3 + 1% rice straw addition (R); 200 mg·kg-1 KNO3 + 2% biochar+1% rice straw addition (R+B)] and cultured at 25℃ for 114 d to explore the effects of organic material addition on greenhouse gas emissions and nitrogen use after flooding in high nitrate nitrogen soil. The results showed that compared with that in CK, adding straw or combining straw with biochar significantly increased soil pH (P<0.05). The B and P treatments significantly increased the cumulative N2O emissions by 41.6% and 28.5% (P<0.05), and the P+B, R, and R+B treatments significantly decreased the cumulative N2O emissions by 14.1%, 24.7%, and 36.7% (P<0.05), respectively. The addition of straw increased the net warming potential of greenhouse gases (NGWP). The addition of coir biochar significantly reduced the effect of straw on NGWP (P<0.05). The combined application of straw and biochar decreased NGWP, and P+B significantly decreased NGWP, but that with R+B was not significant (P>0.05). Adding straw or biochar significantly increased soil microbial biomass carbon (MBC) (P<0.05), and that of P+B was the highest (502.26 mg·kg-1). The combined application of straw and biochar increased soil microbial biomass nitrogen (MBN), and that of P+B was the highest. The N2O emission flux was negatively correlated with pH (P<0.01) and positively correlated with NH4+-N and NO3--N (P<0.01). The cumulative emission of N2O was negatively correlated with MBN (P<0.05). There was a significant negative correlation between NO3--N and MBN (P<0.01), indicating that the reduction in NO3--N was likely to be held by microorganisms, and the increase in the microbial hold of NO3--N also reduced N2O emission. In conclusion, the combined application of peanut straw and coconut shell biochar could significantly inhibit N2O emission and increase soil MBC and MBN, which is a reasonable measure to make full use of nitrogen fertilizer, reduce nitrogen loss, and slow down N2O emission after the season of Hainan vegetables.

Accuracy of routine external ventricular drain placement following a mixed reality-guided twist-drill craniostomy.

OBJECTIVE: The traditional freehand placement of an external ventricular drain (EVD) relies on empirical craniometric landmarks to guide the craniostomy and subsequent passage of the EVD catheter. The diameter and trajectory of the craniostomy physically limit the possible trajectories that can be achieved during the passage of the catheter. In this study, the authors implemented a mixed reality-guided craniostomy procedure to evaluate the benefit of an optimally drilled craniostomy to the accurate placement of the catheter. METHODS: Optical marker-based tracking using an OptiTrack system was used to register the brain ventricular hologram and drilling guidance for craniostomy using a HoloLens 2 mixed reality headset. A patient-specific 3D-printed skull phantom embedded with intracranial camera sensors was developed to automatically calculate the EVD accuracy for evaluation. User trials consisted of one blind and one mixed reality-assisted craniostomy followed by a routine, unguided EVD catheter placement for each of two different drill bit sizes. RESULTS: A total of 49 participants were included in the study (mean age 23.4 years, 59.2% female). The mean distance from the catheter target improved from 18.6 ± 12.5 mm to 12.7 ± 11.3 mm (p = 0.0008) using mixed reality guidance for trials with a large drill bit and from 19.3 ± 12.7 mm to 10.1 ± 8.4 mm with a small drill bit (p < 0.0001). Accuracy using mixed reality was improved using a smaller diameter drill bit compared with a larger bit (p = 0.039). Overall, the majority of the participants were positive about the helpfulness of mixed reality guidance and the overall mixed reality experience. CONCLUSIONS: Appropriate indications and use cases for the application of mixed reality guidance to neurosurgical procedures remain an area of active inquiry. While prior studies have demonstrated the benefit of mixed reality-guided catheter placement using predrilled craniostomies, the authors demonstrate that real-time quantitative and visual feedback of a mixed reality-guided craniostomy procedure can independently improve procedural accuracy and represents an important tool for trainee education and eventual clinical implementation.

A review of application of combined biochar and iron-based materials in anaerobic digestion for enhancing biogas productivity: Mechanisms, approaches and performance.

Strengthening direct interspecies electron transfer (DIET), via adding conductive materials, is regarded as an effective way for improving methane productivity of anaerobic digestion (AD). Therein, the supplementation of combined materials (composition of biochar and iron-based materials) has attracted increasing attention in recent years, because of their advantages of promoting organics reduction and accelerating biomass activity. However, as far as we known, there is no study comprehensively summarizing the application of this kind combined materials. Here, the combined methods of biochar and iron-based materials in AD system were introduced, and then the overall performance, potential mechanisms, and microbial contribution were summarized. Furthermore, a comparation of the combinated materials and single material (biochar, zero valent iron, or magnetite) in methane production was also evaluated to highlight the functions of combined materials. Based on these, the challenges and perspectives were proposed to point the development direction of combined materials utilization in AD field, which was hoped to provide a deep insight in engineering application.

PPM1G promotes the progression of lung adenocarcinoma by inhibiting p38 activation via dephosphorylation of MEK6.

The p38 MAP kinase (MAPK) signaling pathway is a key signal transduction cascade that cancer cells employ to sense and adapt to a plethora of environmental stimuli and has attracted much attention as a promising target for cancer therapy. Although the kinases that phosphorylate p38 have been extensively studied, the negative regulation of p38 phosphorylation remains to be elucidated. Here, we found that PPM1G was highly expressed in lung adenocarcinoma (LUAD) compared to normal tissues, and higher levels of PPM1G were observed in adverse staged LUAD. Furthermore, the higher levels of PPM1G were highly correlated with poor prognosis, according to the Cancer Genome Atlas cohort. Most importantly, we identified phospho-MEK6 as a direct substrate of PPM1G. PPM1G, a metal-dependent protein phosphatase family phosphatase, could reduce p38 phosphorylation via MEK6 dephosphorylation and contribute to the proliferation, invasion and metastasis of LUAD. Our study highlighted the essential role of PPM1G in LUAD and shed new light on unveiling the regulation of p38 activity via direct dephosphorylation of MEK6 in malignant transformation. Together, this study provides new insight into the complexity of regulating the versatile p38 signaling and suggests new directions in intervening in p38 MAPK signaling.

KFWC: A Knowledge-Driven Deep Learning Model for Fine-grained Classification of Wet-AMD.

BACKGROUND AND OBJECTIVES: Automated diagnosis using deep neural networks can help ophthalmologists detect the blinding eye disease wet Age-related Macular Degeneration (AMD). Wet-AMD has two similar subtypes, Neovascular AMD and Polypoidal Choroidal Vasculopathy (PCV). However, due to the difficulty in data collection and the similarity between images, most studies have only achieved the coarse-grained classification of wet-AMD rather than a fine-grained one of wet-AMD subtypes. Therefore, designing and building a deep learning model to diagnose neovascular AMD and PCV is a great challenge. METHODS: To solve this issue, in this paper, we propose a Knowledge-driven Fine-grained Wet-AMD Classification Model (KFWC) to enhance the model's accuracy in the fine-grained disease classification with insufficient data. We innovatively introduced a two-stage method. In the first stage, we present prior knowledge of 10 lesion signs through pre-training; in the second stage, the model implements the classification task with the help of human knowledge. With the pre-training of priori knowledge of 10 lesion signs from input images, KFWC locates the powerful image features in the fine-grained disease classification task and therefore achieves better classification. RESULTS: To demonstrate the effectiveness of KFWC, we conduct a series of experiments on a clinical dataset collected in cooperation with a Grade III Level A ophthalmology hospital in China. The AUC score of KFWC reaches 99.71%, with 6.69% over the best baseline and 4.14% over ophthalmologists. KFWC can also provide good interpretability and effectively alleviate the pressure of data collection and annotation in the field of fine-grained disease classification for wet-AMD. CONCLUSIONS: The model proposed in this paper effectively solves the difficulties of small data volume and high image similarity in the wet-AMD fine-grained classification task through a knowledge-driven approach. Besides, this method effectively relieves the pressure of data collection and annotation in the field of fine-grained classification. In the diagnosis of wet-AMD, KFWC is superior to previous work and human ophthalmologists.

Tumor-associated macrophages are shaped by intratumoral high potassium via Kir2.1.

The tumor microenvironment (TME) is a unique niche governed by constant crosstalk within and across all intratumoral cellular compartments. In particular, intratumoral high potassium (K+) has shown immune-suppressive potency on T cells. However, as a pan-cancer characteristic associated with local necrosis, the impact of this ionic disturbance on innate immunity is unknown. Here, we reveal that intratumoral high K+ suppresses the anti-tumor capacity of tumor-associated macrophages (TAMs). We identify the inwardly rectifying K+ channel Kir2.1 as a central modulator of TAM functional polarization in high K+ TME, and its conditional depletion repolarizes TAMs toward an anti-tumor state, sequentially boosting local anti-tumor immunity. Kir2.1 deficiency disturbs the electrochemically dependent glutamine uptake, engendering TAM metabolic reprogramming from oxidative phosphorylation toward glycolysis. Kir2.1 blockade attenuates both murine tumor- and patient-derived xenograft growth. Collectively, our findings reveal Kir2.1 as a determinant and potential therapeutic target for regaining the anti-tumor capacity of TAMs within ionic-imbalanced TME.

Biodiversity and degradation potential of oil-degrading bacteria isolated from sediments of hydrothermal and non-hydrothermal areas of the Southwest Mid-Indian Ocean Ridge.

In this study, sediments from eight sites were collected from hydrothermal areas (e.g., the Tiancheng, Tianzuo, and Longqi hydrothermal areas) and non-hydrothermal area on the Southwest Mid-Indian Ocean Ridge. Using crude oil as the only carbon and energy source, 162 strains of culturable oil-degrading bacteria were isolated and obtained. The rate of oil degradation of the consortia was 39.48-46.00% in hydrothermal and non-hydrothermal areas. High-throughput sequencing found that the alpha diversity indices (e.g., Shannon and Simpson) of the communities in hydrothermal areas were higher than those in non-hydrothermal area. The species diversities of the oil-degrading bacteria were different among different hydrothermal areas. The composition of the oil-degrading bacterial species in the Tianzuo hydrothermal area tended to be more similar to that in the non-hydrothermal area. This similarity is attributed to the changes in the bacterial community that followed the cessation of hydrothermal vent eruptions at this site. The Alphaproteobacteria abundance of the oil-degrading bacteria was significantly different in oil-degrading bacteria between the hydrothermal and non-hydrothermal areas.

Determination and Characterization of Phenolic Compounds from Australia-Grown Sweet Cherries (Prunus avium L.) and Their Potential Antioxidant Properties.

Sweet cherries (Prunus avium L.) are popular fruits around the world with a high nutritional value and abundant phenolic compounds. Phenolic compounds of cherries contribute to positive health benefits. This study aimed at determining the phenolic content and antioxidant activities in four Australian-grown sweet cherry cultivars, including Bing, Ron's, Merchant, and Lapins, as well as the identification of individual phenolic compounds with liquid chromatography-electrospray ionization-quantum time-of-flight-mass spectrometry (LC-ESI-QTOF-MS2). Lapins exhibits the highest total phenolic content (TPC) value (1.73 ± 0.90 mg gallic acid equivalents (GAE)/g) while Ron's exhibits the highest total flavonoid content (TFC) value (0.51 ± 0.02 mg QE/g). In 2,2'-azinobis-(3-ethylbenzo-thiazoline-6-sulfonic acid) (ABTS), reducing power assay (RPA), and total antioxidant content (TAC) assays, Merchant exhibited the highest values (0.51 ± 0.07, 1.74 ± 0.04, and 2.79 ± 0.09 mg AAE/g, respectively) and almost showed the highest antioxidant activity. Ron's presented the highest value (1.21 ± 0.09 mg EDTA/g) in ferrous ion-chelating activity (FICA) assay and exhibits the strongest metal chelating ability. The correlation between phenolic contents and antioxidant assays was observed. In the LC-ESI-QTOF-MS2 analysis, a total of 43 phenolic compounds has been detected in four sweet cherry cultivars, including 11 phenolic acids, 25 flavonoids, 5 other phenolic compounds, 1 lignan, and 1 stilbene. Venn graph showed that Lapins has the greatest number of unique compounds. Our study shows the presence of phenolic acids and provides information to be utilized as an ingredient in food, pharmaceutical, and nutraceutical industries.

Combined effects of 17ß-estradiol and copper on growth, biochemical characteristics and pollutant removals of freshwater microalgae Scenedesmus dimorphus.

Contamination by estrogens and heavy metals can cause great environment concern and necessitate efficient approaches for their removals. In this study, the combined effects of 17ß-estradiol (E2) and Cu(II) on microalgae growth and biochemical characteristics were investigated. Results showed that 1 mg/L Cu(II) promoted the growth of Scenedesmus dimorphus, while 2 mg/L Cu(II) exhibited growth inhibition, compared with the same concentration of E2. Biochemical characteristics including enzyme activities as well as the contents of chlorophyll, protein and carbohydrate were significantly affected by the coexistence of E2 and Cu(II) after 12 d of cultivation. S. dimorphus exhibited high E2 and Cu(II) removal efficiencies (89.9% of E2 and 76.6% Cu(II) under the coexistence of 0.5 mg/L E2 and 1 mg/L Cu(II), respectively). Lower concentration of Cu(II) might serve as a bridge during E2 removal by S. dimorphus while competitive adsorption of Cu(II) and E2 occurred under the condition of excessive Cu(II). Results could confirm that S. dimorphus was a potential bioresource for the effective removal of E2 and Cu(II).

Suppression of Exosomal PD-L1 Induces Systemic Anti-tumor Immunity and Memory.

PD-L1 on the surface of tumor cells binds its receptor PD-1 on effector T cells, thereby suppressing their activity. Antibody blockade of PD-L1 can activate an anti-tumor immune response leading to durable remissions in a subset of cancer patients. Here, we describe an alternative mechanism of PD-L1 activity involving its secretion in tumor-derived exosomes. Removal of exosomal PD-L1 inhibits tumor growth, even in models resistant to anti-PD-L1 antibodies. Exosomal PD-L1 from the tumor suppresses T cell activation in the draining lymph node. Systemically introduced exosomal PD-L1 rescues growth of tumors unable to secrete their own. Exposure to exosomal PD-L1-deficient tumor cells suppresses growth of wild-type tumor cells injected at a distant site, simultaneously or months later. Anti-PD-L1 antibodies work additively, not redundantly, with exosomal PD-L1 blockade to suppress tumor growth. Together, these findings show that exosomal PD-L1 represents an unexplored therapeutic target, which could overcome resistance to current antibody approaches.

iTAP, a novel iRhom interactor, controls TNF secretion by policing the stability of iRhom/TACE.

The apical inflammatory cytokine TNF regulates numerous important biological processes including inflammation and cell death, and drives inflammatory diseases. TNF secretion requires TACE (also called ADAM17), which cleaves TNF from its transmembrane tether. The trafficking of TACE to the cell surface, and stimulation of its proteolytic activity, depends on membrane proteins, called iRhoms. To delineate how the TNF/TACE/iRhom axis is regulated, we performed an immunoprecipitation/mass spectrometry screen to identify iRhom-binding proteins. This identified a novel protein, that we name iTAP (iRhom Tail-Associated Protein) that binds to iRhoms, enhancing the cell surface stability of iRhoms and TACE, preventing their degradation in lysosomes. Depleting iTAP in primary human macrophages profoundly impaired TNF production and tissues from iTAP KO mice exhibit a pronounced depletion in active TACE levels. Our work identifies iTAP as a physiological regulator of TNF signalling and a novel target for the control of inflammation.

Phosphorylation of iRhom2 Controls Stimulated Proteolytic Shedding by the Metalloprotease ADAM17/TACE.

Cell surface metalloproteases coordinate signaling during development, tissue homeostasis, and disease. TACE (TNF-α-converting enzyme), is responsible for cleavage ("shedding") of membrane-tethered signaling molecules, including the cytokine TNF, and activating ligands of the EGFR. The trafficking of TACE within the secretory pathway requires its binding to iRhom2, which mediates the exit of TACE from the endoplasmic reticulum. An important, but mechanistically unclear, feature of TACE biology is its ability to be stimulated rapidly on the cell surface by numerous inflammatory and growth-promoting agents. Here, we report a role for iRhom2 in TACE stimulation on the cell surface. TACE shedding stimuli trigger MAP kinase-dependent phosphorylation of iRhom2 N-terminal cytoplasmic tail. This recruits 14-3-3 proteins, enforcing the dissociation of TACE from complexes with iRhom2, promoting the cleavage of TACE substrates. Our data reveal that iRhom2 controls multiple aspects of TACE biology, including stimulated shedding on the cell surface.

From the Cover: Neutralization of terminal differentiation in gliomagenesis.

An immature state of cellular differentiation--characterized by stem cell-like tendencies and impaired differentiation--is a hallmark of cancer. Using glioblastoma multiforme (GBM) as a model system, we sought to determine whether molecular determinants that drive cells toward terminal differentiation are also genetically targeted in carcinogenesis and whether neutralizing such genes also plays an active role to reinforce the impaired differentiation state and promote malignancy. To that end, we screened 71 genes with known roles in promoting nervous system development that also sustain copy number loss in GBM through antineoplastic assay and identified A2BP1 (ataxin 2 binding protein 1, Rbfox1), an RNA-binding and splicing regulator that is deleted in 10% of GBM cases. Integrated in silico analysis of GBM profiles to elucidate the A2BP1 pathway and its role in glioma identified myelin transcription factor 1-like (Myt1L) as a direct transcriptional regulator of A2BP1. Reintroduction of A2BP1 or Myt1L in GBM cell lines and glioma stem cells profoundly inhibited tumorigenesis in multiple assays, and conversely, shRNA-mediated knockdown of A2BP1 or Myt1L in premalignant neural stem cells compromised neuronal lineage differentiation and promoted orthotopic tumor formation. On the mechanistic level, with the top-represented downstream target TPM1 as an illustrative example, we demonstrated that, among its multiple functions, A2BP1 serves to regulate TPM1's alternative splicing to promote cytoskeletal organization and terminal differentiation and suppress malignancy. Thus, in addition to the activation of self-renewal pathways, the neutralization of genetic programs that drive cells toward terminal differentiation may also promote immature and highly plastic developmental states that contribute to the aggressive malignant properties of GBM.