High precision polishing of aluminum alloy mirrors through a combination of magnetorheological finishing and chemical mechanical polishing.

After the aluminum alloy mirror machined by single point diamond turning (SPDT), the residual tool marks and surface accuracy of the aluminum alloy mirror cannot meet the requirements of visible or ultraviolet light system. In this study, a processing method combining magnetorheological finishing (MRF) and chemical mechanical polishing (CMP) is proposed to realize the polishing of aluminum alloy mirrors with high efficiency, high precision and high-quality. Firstly, the properties and composition of passivation layer after MRF were analyzed and the polishing performance of acidic, neutral and alkaline alumina polishing fluid on passivation layer were investigated based on the computer numerical control (CNC) polishing equipment. Based on the experimental results, a new acidic nano-silica polishing fluid which is suitable for the efficient and high-quality removal of passivation layers on aluminum alloy surfaces was developed. Finally, a combined approach of MRF-CMP was used to the directly polishing of a rapidly solidified aluminum mirror (RSA-6061) with a diameter of 100 mm after SPDT. With two iterative of MRF-CMP polishing in 220 minutes, the surface accuracy of the aluminum alloy mirror was improved from 0.1λ (λ=632.8 nm) to 0.024λ, and the surface roughness (Ra) decreased from 3.6 nm to 1.38 nm. The experiment results manifest that high precision, and high-quality aluminum alloy mirror can be achieved by MRF-CMP method with the new developed acid nano-silica polishing fluid and suitable MR polishing fluid. The research results will provide a new strategy for ultra-precision direct polishing of aluminum alloy mirrors and will also give the important technical support for the extensive use of aluminum alloy mirror in visible light and ultraviolet optical systems.

Preliminary study on AI-assisted diagnosis of bone remodeling in chronic maxillary sinusitis.

OBJECTIVE: To construct the deep learning convolution neural network (CNN) model and machine learning support vector machine (SVM) model of bone remodeling of chronic maxillary sinusitis (CMS) based on CT image data to improve the accuracy of image diagnosis. METHODS: Maxillary sinus CT data of 1000 samples in 500 patients from January 2018 to December 2021 in our hospital was collected. The first part is the establishment and testing of chronic maxillary sinusitis detection model by 461 images. The second part is the establishment and testing of the detection model of chronic maxillary sinusitis with bone remodeling by 802 images. The sensitivity, specificity and accuracy and area under the curve (AUC) value of the test set were recorded, respectively. RESULTS: Preliminary application results of CT based AI in the diagnosis of chronic maxillary sinusitis and bone remodeling. The sensitivity, specificity and accuracy of the test set of 93 samples of CMS, were 0.9796, 0.8636 and 0.9247, respectively. Simultaneously, the value of AUC was 0.94. And the sensitivity, specificity and accuracy of the test set of 161 samples of CMS with bone remodeling were 0.7353, 0.9685 and 0.9193, respectively. Simultaneously, the value of AUC was 0.89. CONCLUSION: It is feasible to use artificial intelligence research methods such as deep learning and machine learning to automatically identify CMS and bone remodeling in MSCT images of paranasal sinuses, which is helpful to standardize imaging diagnosis and meet the needs of clinical application.

miR-181c-5p/DERL1 pathway controls breast cancer progression mediated by TRAF6-linked K63 ubiquitination of AKT.

BACKGROUND: Aberrant Derlin-1 (DERL1) expression is associated with an overactivation of p-AKT, whose involvement in breast cancer (BRCA) development has been widely speculated. However, the precise mechanism that links DERL1 expression and AKT activation is less well-studied. METHODS: Bioinformatic analyses hold a promising approach by which to detect genes' expression levels and their association with disease prognoses in patients. In the present work, a dual-luciferase assay was employed to investigate the relationship between DERL1 expression and the candidate miRNA by both in vitro and in vivo methods. Further in-depth studies involving immunoprecipitation-mass spectrum (IP-MS), co-immunoprecipitation (Co-IP), as well as Zdock prediction were performed. RESULTS: Overexpression of DERL1 was detected in all phenotypes of BRCA, and its knockdown showed an inhibitory effect on BRCA cells both in vitro and in vivo. The Cancer Genome Atlas (TCGA) database reported that DERL1 overexpression was correlated with poor overall survival in BRCA cases, and so the quantification of DERL1 expression could be a potential marker for the clinical diagnosis of BRCA. On the other hand, miR-181c-5p was downregulated in BRCA, suggesting that its overexpression could be a potent therapeutic route to improve the overall survival of BRCA cases. Prior bioinformatic analyses indicated a somewhat positive correlation between DERL1 and TRAF6 as well as between TRAF6 and AKT, but not between miR-181c-5p and DERL1. In retrospect, DERL1 overexpression promoted p-AKT activation through K63 ubiquitination. DERL1 was believed to directly interact with the E3 ligase TRAF6. As Tyr77Ala or Tyr77Ala/Gln81Ala/Arg85Ala/Val158Ala attempts to prevent the interaction between DERL1 and TRAF domain of TRAF6, resulted in a significant reduction in K63-ubiquitinated p-AKT production. However, mutations in Gln81Ala, Arg85Ala, or Val158Ala could possibly interrupt with these processes. CONCLUSIONS: Our data confirm that mediation of the miR-181c-5p/DERL1 pathway by TRAF6-linked AKT K63 ubiquitination holds one of the clues to set our focus on toward meeting the therapeutic goals of BRCA.

Rational Design of a Highly Sensitive Carboxylesterase Probe and Its Application in High-Throughput Screening for Uncovering Carboxylesterase Inhibitors.

Tracking carboxylesterases (CESs) through noninvasive and dynamic imaging is of great significance for diagnosing and treating CES-related metabolic diseases. Herein, three BODIPY-based fluorescent probes with a pyridine unit quaternarized via an acetoxybenzyl group were designed and synthesized to detect CESs based on the photoinduced electron transfer process. Notably, among these probes, BDPN2-CES exhibited a remarkable 182-fold fluorescence enhancement for CESs within 10 min. Moreover, BDPN2-CES successfully enabled real-time imaging of endogenous CES variations in living cells. Using BDPN2-CES, a visual high-throughput screening method for CES inhibitors was established, culminating in the discovery of an efficient inhibitor, WZU-13, sourced from a chemical library. These findings suggest that BDPN2-CES could provide a new avenue for diagnosing CES-related diseases, and WZU-13 emerges as a promising therapeutic candidate for CES-overexpression pathological processes.

MOTS-c is an effective target for treating cancer-induced bone pain through the induction of AMPK-mediated mitochondrial biogenesis.

Bone cancer pain (BCP), due to cancer bone metastasis and bone destruction, is a common symptom of tumors, including breast, prostate, and lung tumors. Patients often experience severe pain without effective treatment. Here, using a mouse model of bone cancer, we report that MOTS-c, a novel mitochondrial-derived peptide, confers remarkable protection against cancer pain and bone destruction. Briefly, we find that the plasma level of endogenous MOTS-c is significantly lower in the BCP group than in the sham group. Accordingly, intraperitoneal administration of MOTS-c robustly attenuates bone cancer-induced pain. These effects are blocked by compound C, an AMPK inhibitor. Furthermore, MOTS-c treatment significantly enhances AMPKα 1/2 phosphorylation. Interestingly, mechanical studies indicate that at the spinal cord level, MOTS-c relieves pain by restoring mitochondrial biogenesis, suppressing microglial activation, and decreasing the production of inflammatory factors, which directly contribute to neuronal modulation. However, in the periphery, MOTS-c protects against local bone destruction by modulating osteoclast and immune cell function in the tumor microenvironment, providing long-term relief from cancer pain. Additionally, we find that chronic administration of MOTS-c has little effect on liver, renal, lipid or cardiac function in mice. In conclusion, MOTS-c improves BCP through peripheral and central synergistic effects on nociceptors, immune cells, and osteoclasts, providing a pharmacological and biological rationale for the development of mitochondrial peptide-based therapeutic agents for cancer-induced pain.

Obesity-Related Traits Mediate the Effects of Educational Attainment on the Risk of Varicose Veins, Venous Thromboembolism, and Phlebitis.

BACKGROUND: The extent to which educational attainment (EA) influences the risk of varicose veins (VVs), venous thromboembolism (VTE), and phlebitis occurrence, whether this pathway is mediated by obesity-related traits, and the proportion of their mediation is unknown. METHODS: A Mendelian randomization (MR) design was used to genetically investigate the causal effects of EA on the risk of VV, VTE, and phlebitis and to assess the mediating effect of obesity-related traits. Causal effects were estimated using primarily the multiplicative random-effects inverse variance-weighted method. This was supplemented by Cochran's Q-statistic, MR-Egger regression, MR funnel plots, and leave-one-out test to evaluate the reliability of the results. For the individual mediation effect, the coefficient product method was mainly utilized to estimate. RESULTS: An increase in genetically predicted EA was associated with a lower risk of VV, VTE, and phlebitis, as well as lower body mass index, basal metabolic rate, hip circumference, and waist circumference. As genetically predicted body mass index, basal metabolic rate, hip circumference, and waist circumference increased, the risk of developing VV, VTE, and phlebitis increased, respectively. Body mass index, basal metabolic rate, hip circumference, and waist circumference were identified as mediators of the protective effects of EA on VV, VTE, and phlebitis. CONCLUSION: The findings support a causal relationship between higher EA and lower risk of VV, VTE, and phlebitis. Obesity-related traits play a significant mediating role in these pathways, and there are interactions between them, with hip circumference mediating these pathways relatively independently from the other three.

Haplotype-resolved genome of Prunus zhengheensis provides insight into its evolution and low temperature adaptation in apricot.

Prunus zhengheensis, an extremely rare population of apricots, originated in warm South-East China and is an excellent material for genetic breeding. However, most apricots and two related species (P. sibirica, P. mandshurica) are found in the cold northern regions in China and the mechanism of their distribution is still unclear. In addition, the classification status of P. zhengheensis is controversial. Thus, we generated a high-quality haplotype-resolved genome for P. zhengheensis, exploring key genetic variations in its adaptation and the causes of phylogenetic incongruence. We found extensive phylogenetic discordances between the nuclear and organelle phylogenies of P. zhengheensis, which could be explained by incomplete lineage sorting. A 242.22-Mb pan-genome of the Armeniaca section was developed with 13 chromosomal genomes. Importantly, we identified a 566-bp insertion in the promoter of the HSFA1d gene in apricot and showed that the activity of the HSFA1d promoter increased under low temperatures. In addition, HSFA1d overexpression in Arabidopsis thaliana indicated that HSFA1d positively regulated plant growth under chilling. Therefore, we hypothesized that the insertion in the promoter of HSFA1d in apricot improved its low-temperature adaptation, allowing it to thrive in relatively cold locations. The findings help explain the weather adaptability of Armeniaca plants.

Knowledge, attitudes, and practice toward glioma of patients with neurological symptoms or diseases in henan, China.

Objective: To explore the knowledge, attitude, and practice (KAP) toward glioma of patients with neurological symptoms or diseases. Methods: This web-based cross-sectional study was conducted at two medical centers in Henan Province between January 2023 and April 2023 and enrolled patients with neurological symptoms or diseases. The demographic characteristics of the participants and their KAP toward glioma were collected using a self-administered questionnaire. A structural equation modeling (SEM) was used to examine the relationship among KAP dimensions. Results: The study included 442 valid questionnaires. The mean knowledge, attitude, and practice scores were 7.65 ± 1.62 (possible range: 0-9), 37.98 ± 3.17 (possible range: 9-45), and 40.16 ± 4.17 (possible range: 10-50), indicating good knowledge, favorable attitude, and active practice. The SEM analysis showed that knowledge directly affected attitudes (ß = 0.89, 95%CI: 0.73-1.06, P < 0.001) but not practice (ß = -0.08, 95%CI: -0.32-0.14, P = 0.487), while attitudes directly affected practice (ß = 0.35, 95%CI: 0.21-0.48, P < 0.001). Conclusion: Patients with neurological symptoms/diseases who had heard of gliomas had good knowledge, favorable attitudes, and active practice toward glioma. Specific knowledge items that would warrant improvements were identified in the specific population of patients with neurological symptoms/diseases who had heard of glioma. Future studies should also examine the general population.

Preventive effect of Lactobacillus johnsonii YH1136 against uric acid accumulation and renal damages.

Background: Hyperuricemia (HUA) is a prevalent metabolic disorder whose development is associated with intestinal microbiota. Therefore, probiotics have emerged as a potential and safe approach for lowering uric acid (UA) levels. However, the underlying mechanisms of many effective probiotic strains remain unknown. Methods and results: C57BL/6 mice were randomly divided into two groups: control and model groups. The model group received 12 weeks of potassium oxonate. Through 16s sequencing we found that HUA resulted in a significant decrease in the total diversity of all intestinal segments. When each intestinal segment was analyzed individually, the reduction in diversity was only significant in the cecum and colon sections. RDA analysis showed that lactobacilli in the rat colon exhibited a strong correlation with model group, suggesting that Lactobacillus may play an important role in HUA. Consequently, the preventive effects of Lactobacillus johnsonii YH1136 against HUA were investigated. C57BL/6 mice were randomly divided into three groups: control, model and YH1136 groups. The results showed that administering Lactobacillus johnsonii YH1136 effectively reduced serum UA levels in vivo by inhibiting hepatic xanthine oxidase (XOD) activity and promoting renal ABCG2 transporter expression. Moreover, supplementation with Lactobacillus johnsonii YH1136 significantly ameliorated pathological damage in the kidney and liver, thereby reducing UA accumulation. Conclusion: Hyperuricemia is accompanied by an altered composition of multiple gut bacteria, of which Lactobacillus is a key genus. Lactobacillus johnsonii YH1136 may ameliorate renal involvement in HUA via the gut-kidney axis.

Acoustofluidic manipulation for submicron to nanoparticles.

Particles, ranging from submicron to nanometer scale, can be broadly categorized into biological and non-biological types. Submicron-to-nanoscale bioparticles include various bacteria, viruses, liposomes, and exosomes. Non-biological particles cover various inorganic, metallic, and carbon-based particles. The effective manipulation of these submicron to nanoparticles, including their separation, sorting, enrichment, assembly, trapping, and transport, is a fundamental requirement for different applications. Acoustofluidics, owing to their distinct advantages, have emerged as a potent tool for nanoparticle manipulation over the past decade. Although recent literature reviews have encapsulated the evolution of acoustofluidic technology, there is a paucity of reports specifically addressing the acoustical manipulation of submicron to nanoparticles. This article endeavors to provide a comprehensive study of this topic, delving into the principles, apparatus, and merits of acoustofluidic manipulation of submicron to nanoparticles, and discussing the state-of-the-art developments in this technology. The discourse commences with an introduction to the fundamental theory of acoustofluidic control and the forces involved in nanoparticle manipulation. Subsequently, the working mechanism of acoustofluidic manipulation of submicron to nanoparticles is dissected into two parts, dominated by the acoustic wave field and the acoustic streaming field. A critical analysis of the advantages and limitations of different acoustofluidic platforms in nanoparticles control is presented. The article concludes with a summary of the challenges acoustofluidics face in the realm of nanoparticle manipulation and analysis, and a forecast of future development prospects.

PRG4 represses the genesis and metastasis of osteosarcoma by inhibiting PDL1 expression.

BACKGROUND: Osteosarcoma is originated from skeletal system. Recombinant human proteoglycan 4 (rhPRG4) can inhibit cell proliferation and migration in multiple cancers. This research is designed to dig out the role and mechanism of PRG4 in osteosarcoma. METHODS: Human osteosarcoma cell lines, MG63 and 143B, were transfected with programmed death 1 (PD-L1) overexpression vectors and/or treated with 20, 50, and 100 µg/mL rhPRG4, followed by the determination of cell viability, colony formation, sphere formation, invasion, migration, apoptosis, and the expressions of matrix metalloproteinases (MMPs), PD-L1 and apoptosis-related proteins. Tumor-bearing mouse models were constructed by injection of 143B cells and treatment of anti-PD-L1 antibody and/or adenovirus PRG4 (AdPRG4). Tumor volume was monitored, and immunohistochemical location of Ki67 was performed. Expressions of MMPs, transforming growth factor-ß (TGF-ß), PD-L1, and epithelial mesenchymal transition (EMT)-related proteins were measured in tumors. RESULTS: RhPRG4 (20, 50, and 100 µg/mL) inhibited the viability, colony formation, sphere formation, invasion, migration, and the expressions of MMP2, MMP9 and Bcl2 in osteosarcoma cells, while promoting cell apoptosis as well as Bax and c-caspase3 expressions, at a dose-dependent manner; by contrast, PD-L1 overexpression reversed the above effects of 100 µg/mL rhPRG4. AdPRG4 or anti-PD-L1 antibody decreased tumor volume, number of pulmonary metastasis nodule, Ki67 location, and expressions of TGF-ß, PD-L1, MMP2, MMP9, Vimentin, and Snail, but increased E-cadherin expression in tumor cells. Moreover, anti-PD-L1 antibody and AdPRG4 together functioned more effectively than them alone in reducing tumor burden. CONCLUSION: PRG4 represses the genesis and metastasis of osteosarcoma via inhibiting PD-L1 expression, and AdPRG4 enhances the effectiveness of anti-PD-L1 therapy.

Association analysis of FXYD5 with prognosis and immunological characteristics across pan-cancer.

Background: The FXYD domain-containing ion transport regulator 5 (FXYD5) gene is a cancer promoter. However, evidence for an association between FXYD5 and various types of cancer is still lacking. Using multi-omics bioinformatics, our study aimed to reveal the expression distribution, prognostic value, immune infiltration correlation, and molecular functions of FXYD5. Methods: Using pan-cancer multi-omics data (including The Cancer Genome Atlas, PrognoScan, Gene Expression Profiling Interactive Analysis, cBioPortal, Gene Expression Omnibus, TIMER and scTIME Portal), we assessed the differences in the expression and prognostic value of FXYD5 in malignant tumors. Furthermore, at the single-cell level, we analyze the expression distribution of FXYD5 across different cell types within the tumor microenvironment, and its relationship with the immune microenvironment. Finally, focusing on ovarian cancer, we conducted preliminary validation of the above findings using cell and molecular biology techniques. Results: Our results indicated that FXYD5 was up-regulated in various tumor types and was positively associated with tumor progression. We also revealed that FXYD5 was ubiquitously expressed in microenvironmental cells at the single-cell level, and its upregulation was associated with enhanced immune infiltration, cancer-associated fibroblast infiltration, and dysfunction of tumor-infiltrating cytotoxic T lymphocyte. Additionally, its expression was positively correlated with immune checkpoint genes, DNA mismatch repair genes, MSI (microsatellite instability) and TMB (tumor mutational burden) across various cancers. Its higher expression in cytotoxic T lymphocytes attenuated its ability to predict patient survival with PD-L1 (programmed death-ligand 1) blockade therapy, and FXYD5 was found to be a potential regulator of tumor immune escape and resistance to cancer immunotherapies. Based on GSEA (gene set enrichment analysis) and experimental verification, FXYD5 activated TGF-ß/SMAD signaling and drove EMT (epithelial-mesenchymal transition) to promote ovarian cancer progression. Conclusion: In summary, our study revealed that FXYD5-TGFß axis may coregulate the interaction between tumors, CAFs (carcinoma-associated fibroblasts) and immune cells to reshape the tumor immune microenvironment and promote tumorigenesis and tumor progression. Thus, FXYD5 could be used as an immune-related biomarker for diagnosing and predicting the prognosis of multiple cancer types. Therefore, our findings suggest that targeting FXYD5 in TME (tumor microenvironment) may be a promising therapeutic strategy.

Effect of addition of γ-poly glutamic acid on bacterial nanocellulose production under agitated culture conditions.

BACKGROUND: Bacterial nanocellulose (BNC), a natural polymer material, gained significant popularity among researchers and industry. It has great potential in areas, such as textile manufacturing, fiber-based paper, and packaging products, food industry, biomedical materials, and advanced functional bionanocomposites. The main current fermentation methods for BNC involved static culture, as the agitated culture methods had lower raw material conversion rates and resulted in non-uniform product formation. Currently, studies have shown that the production of BNC can be enhanced by incorporating specific additives into the culture medium. These additives included organic acids or polysaccharides. γ-Polyglutamic acid (γ-PGA), known for its high polymerization, excellent biodegradability, and environmental friendliness, has found extensive application in various industries including daily chemicals, medicine, food, and agriculture. RESULTS: In this particular study, 0.15 g/L of γ-PGA was incorporated as a medium additive to cultivate BNC under agitated culture conditions of 120 rpm and 30 â„ƒ. The BNC production increased remarkably by 209% in the medium with 0.15 g/L γ-PGA and initial pH of 5.0 compared to that in the standard medium, and BNC production increased by 7.3% in the medium with 0.06 g/L γ-PGA. The addition of γ-PGA as a medium additive resulted in significant improvements in BNC production. Similarly, at initial pH levels of 4.0 and 6.0, the BNC production also increased by 39.3% and 102.3%, respectively. To assess the characteristics of the BNC products, scanning electron microscopy, Fourier transform infrared spectroscopy, and thermogravimetric analysis were used. The average diameter of BNC fibers, which was prepared from the medium adding 0.15 g/L γ-PGA, was twice thicker than that of BNC fibers prepared from the control culture medium. That might be because that polyglutamic acid relieved the BNC synthesis from the shear stress from the agitation. CONCLUSIONS: This experiment held great significance as it explored the use of a novel medium additive, γ-PGA, to improve the production and the glucose conversion rate in BNC fermentation. And the BNC fibers became thicker, with better thermal stability, higher crystallinity, and higher degree of polymerization (DPv). These findings lay a solid foundation for future large-scale fermentation production of BNC using bioreactors.

Case report: Endobronchial closure of postoperative bronchopleural fistula with embolization coil: a sandwich-like approach.

Background: Embolization Coil has been reported to effectively treat postoperative bronchopleural fistula (BPF). Little detailed information was available on computer tomography (CT) imaging features of postoperative BPF and treating procedures with pushable Embolization Coil. Objective: We aimed to specify the imaging characteristics of postoperative BPFs and present our experience treating them with the pushable Embolization Coil. Methods: Six consecutive patients (four males and two females aged 29-56 years) diagnosed with postoperative BPF receiving bronchoscopic treatment with the pushable Nester® Embolization Coil (Cook Medical, Bloomington, Indiana) were included in this single-center, retrospective study. Multiplanar reconstruction of multidetector CT scans was reviewed for the presence, location, size, and radiological complications of each BPF, including air collection, pneumothorax, bronchiectasis, and chest tube. Using standardized data abstraction forms, demographic traits and clinical outcomes were extracted from the medical files of these patients. Results: The underlying diseases for lung resection surgery were pulmonary tuberculosis (n = 3), lung adenocarcinoma (n = 2), and pulmonary aspergillosis (n = 1). All patients had air or air-fluid collection with chest tubes on radiological findings. Multiplanar reconstruction identified the presence of postoperative BPF in all patients. Five fistulas were central, located proximal to the main or lobar bronchus, while one was peripheral, distant from the lobar bronchus. Fistula sizes ranged from 0.8 to 5.8 mm. Subsequent bronchoscopy and occlusion testing confirmed fistula openings in the bronchial stump: right main bronchus (n = 1), right upper lobe (n = 2), and left upper lobe (n = 3). The angioplasty catheter-based procedure allows precise fistula occlusion "like a sandwich" with the pushable Embolization Coil. Five patients with BPF sizes ranging from 0.8 to 1.5 mm were successfully treated with a pushable Embolization Coil, except for one with a BPF size of 5.8 mm. No adverse events or complications were observed throughout follow-up, ranging from 29 to 1,307 days. Conclusion: The pushable Nester® Embolization Coil seems a minimally invasive, cost-effective, and relatively easy-to-perform bronchoscopic treatment for postoperative BPF with a size less than 2 mm. Further studies are required to ensure the use of pushable Embolization Coil in treating postoperative BPF.

Deploying a Dipole Electric Field at the CsPbI3 Perovskite/Carbon Interface for Enhancing Hole Extraction and Photovoltaic Performance.

Carbon-based CsPbI3 perovskite solar cells without hole transporter (C-PSCs) have achieved intense attention due to its simple device structure and high chemical stability. However, the severe interface energy loss at the CsPbI3/carbon interface, attributed to the lower hole selectivity for inefficient charge separation, greatly limits device performance. Hence, dipole electric field (DEF) is deployed at the above interface to address the above issue by using a pole molecule, 4-trifluoromethyl-Phenylammonium iodide (CF3-PAI), in which the ─NH3 group anchors on the perovskite surface and the ─CF3 group extends away from it and connects with carbon electrode. The DEF is proven to align with the built-in electric field, that is pointing toward carbon electrode, which well enhances hole selectivity and charge separation at the interface. Besides, CF3-PAI molecules also serve as defect passivator for reducing trap state density, which further suppresses defect-induced non-radiative recombination. Consequently, the CsPbI3 C-PSCs achieve an excellent efficiency of 18.33% with a high VOC of 1.144 V for inorganic C-PSCs without hole transporter.

Pro-CRISPR PcrIIC1-associated Cas9 system for enhanced bacterial immunity.

The CRISPR system is an adaptive immune system found in prokaryotes that defends host cells against the invasion of foreign DNA1. As part of the ongoing struggle between phages and the bacterial immune system, the CRISPR system has evolved into various types, each with distinct functionalities2. Type II Cas9 is the most extensively studied of these systems and has diverse subtypes. It remains uncertain whether members of this family can evolve additional mechanisms to counter viral invasions3,4. Here we identify 2,062 complete Cas9 loci, predict the structures of their associated proteins and reveal three structural growth trajectories for type II-C Cas9. We found that novel associated genes (NAGs) tended to be present within the loci of larger II-C Cas9s. Further investigation revealed that CbCas9 from Chryseobacterium species contains a novel ß-REC2 domain, and forms a heterotetrameric complex with an NAG-encoded CRISPR-Cas-system-promoting (pro-CRISPR) protein of II-C Cas9 (PcrIIC1). The CbCas9-PcrIIC1 complex exhibits enhanced DNA binding and cleavage activity, broader compatibility for protospacer adjacent motif sequences, increased tolerance for mismatches and improved anti-phage immunity, compared with stand-alone CbCas9. Overall, our work sheds light on the diversity and 'growth evolutionary' trajectories of II-C Cas9 proteins at the structural level, and identifies many NAGs-such as PcrIIC1, which serves as a pro-CRISPR factor to enhance CRISPR-mediated immunity.

Nitrate Chemodenitrification by Iron Sulfides to Ammonium under Mild Conditions and Transformation Mechanism.

Autotrophic denitrification utilizing iron sulfides as electron donors has been well studied, but the occurrence and mechanism of abiotic nitrate (NO3-) chemodenitrification by iron sulfides have not yet been thoroughly investigated. In this study, NO3- chemodenitrification by three types of iron sulfides (FeS, FeS2, and pyrrhotite) at pH 6.37 and ambient temperature of 30 °C was investigated. FeS chemically reduced NO3- to ammonium (NH4+), with a high reduction efficiency of 97.5% and NH4+ formation selectivity of 82.6%, but FeS2 and pyrrhotite did not reduce NO3- abiotically. Electrochemical Tafel characterization confirmed that the electron release rate from FeS was higher than that from FeS2 and pyrrhotite. Quenching experiments and density functional theory calculations further elucidated the heterogeneous chemodenitrification mechanism of NO3- by FeS. Fe(II) on the FeS surface was the primary site for NO3- reduction. FeS possessing sulfur vacancies can selectively adsorb oxygen atoms from NO3- and water molecules and promote water dissociation to form adsorbed hydrogen, thereby forming NH4+. Collectively, these findings suggest that the NO3- chemodenitrification by iron sulfides cannot be ignored, which has great implications for the nitrogen, sulfur, and iron cycles in soil and water ecosystems.

Skeletal Muscle SIRT3 Deficiency Contributes to Pulmonary Vascular Remodeling in Pulmonary Hypertension Due to Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Pulmonary hypertension (PH) is a major complication linked to adverse outcomes in heart failure with preserved ejection fraction (HFpEF), yet no specific therapies exist for PH associated with HFpEF (PH-HFpEF). We have recently reported on the role of skeletal muscle SIRT3 (sirtuin-3) in modulation of PH-HFpEF, suggesting a novel endocrine signaling pathway for skeletal muscle modulation of pulmonary vascular remodeling. In this study, we attempted to define the processes by which skeletal muscle SIRT3 defects affect pulmonary vascular health in PH-HFpEF. METHODS AND RESULTS: Skeletal muscle-specific Sirt3 knockout mice (Sirt3skm-/-) exhibited reduced pulmonary vascular density accompanied by pulmonary vascular proliferative remodeling and elevated pulmonary pressures. Using mass spectrometry-based comparative secretome analysis, we demonstrated elevated secretion of LOXL2 (lysyl oxidase homolog 2) in SIRT3-deficient skeletal muscle cells. Elevated circulation and protein expression levels of LOXL2 were also observed in plasma and skeletal muscle of Sirt3skm-/- mice, a rat model of PH-HFpEF, and humans with PH-HFpEF. In addition, expression levels of CNPY2 (canopy fibroblast growth factor signaling regulator 2), a known proliferative and angiogenic factor, were increased in pulmonary artery endothelial cells and pulmonary artery smooth muscle cells of Sirt3skm-/- mice and animal models of PH-HFpEF. CNPY2 levels were also higher in pulmonary artery smooth muscle cells of subjects with obesity compared with nonobese subjects. Moreover, treatment with recombinant LOXL2 protein promoted pulmonary artery endothelial cell migration/proliferation and pulmonary artery smooth muscle cell proliferation through regulation of CNPY2-p53 signaling. Last, skeletal muscle-specific Loxl2 deletion decreased pulmonary artery endothelial cell and pulmonary artery smooth muscle cell expression of CNPY2 and improved pulmonary pressures in mice with high-fat diet-induced PH-HFpEF. CONCLUSIONS: This study demonstrates a systemic pathogenic impact of skeletal muscle SIRT3 deficiency in remote pulmonary vascular remodeling and PH-HFpEF. This study suggests a new endocrine signaling axis that links skeletal muscle health and SIRT3 deficiency to remote CNPY2 regulation in the pulmonary vasculature through myokine LOXL2. Our data also identify skeletal muscle SIRT3, myokine LOXL2, and CNPY2 as potential targets for the treatment of PH-HFpEF.

Plasma Proteomics Identifies B2M as a Regulator of Pulmonary Hypertension in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Pulmonary hypertension (PH) represents an important phenotype in heart failure with preserved ejection fraction (HFpEF). However, management of PH-HFpEF is challenging because mechanisms involved in the regulation of PH-HFpEF remain unclear. METHODS: We used a mass spectrometry-based comparative plasma proteomics approach as a sensitive and comprehensive hypothesis-generating discovery technique to profile proteins in patients with PH-HFpEF and control subjects. We then validated and investigated the role of one of the identified proteins using in vitro cell cultures, in vivo animal models, and independent cohort of human samples. RESULTS: Plasma proteomics identified high protein abundance levels of B2M (ß2-microglobulin) in patients with PH-HFpEF. Interestingly, both circulating and skeletal muscle levels of B2M were increased in mice with skeletal muscle SIRT3 (sirtuin-3) deficiency or high-fat diet-induced PH-HFpEF. Plasma and muscle biopsies from a validation cohort of PH-HFpEF patients were found to have increased B2M levels, which positively correlated with disease severity, especially pulmonary capillary wedge pressure and right atrial pressure at rest. Not only did the administration of exogenous B2M promote migration/proliferation in pulmonary arterial vascular endothelial cells but it also increased PCNA (proliferating cell nuclear antigen) expression and cell proliferation in pulmonary arterial vascular smooth muscle cells. Finally, B2m deletion improved glucose intolerance, reduced pulmonary vascular remodeling, lowered PH, and attenuated RV hypertrophy in mice with high-fat diet-induced PH-HFpEF. CONCLUSIONS: Patients with PH-HFpEF display higher circulating and skeletal muscle expression levels of B2M, the magnitude of which correlates with disease severity. Our findings also reveal a previously unknown pathogenic role of B2M in the regulation of pulmonary vascular proliferative remodeling and PH-HFpEF. These data suggest that circulating and skeletal muscle B2M can be promising targets for the management of PH-HFpEF.

Febuxostat attenuates secondary brain injury caused by cerebral hemorrhage through inhibiting inflammatory pathways.

Objectives: Neuroinflammation is considered an important step in the progression of secondary brain injury (SBI) induced by cerebral hemorrhage (ICH). The nucleotide-binding and oligomerization structural domain-like receptor family of pyridine structural domain-containing 3 (NLRP3) inflammasomes play an important role in the immune pathophysiology of SBI. Febuxostat (Feb) is a xanthine oxidase inhibitor that is approved for the treatment of gout and has been found to have potent anti-inflammatory effects. However, it has been less studied after ICH and we aimed to explore its protective role in ICH. Materials and Methods: We established an autologous blood-brain hemorrhage model in C57BL/6 mice. Functions of co-expressed genes were analyzed by trend analysis and bioinformatics analysis. Enzyme-linked immunosorbent assay were used to assess the inflammatory factor levels. Fluoro-Jade B histochemistry and TUNEL staining were used to detect neuronal apoptosis. Immunofluorescence staining and western blotting were used to detect the expression of NLRP3 inflammasomes. Results: Pretreatment with Feb reduced neuronal cell death and degeneration and alleviated neurobehavioral disorders in vivo. Feb was found to modulate inflammation-related pathways by trend analysis and bioinformatics analysis. In addition, Feb inhibited microglia activation and elevated cytokine levels after ICH. Furthermore, double immunofluorescence staining showed that co-localization of NLRP3 with Iba1 positive cells was reduced after treatment with Feb. Finally, we found that Feb inhibited the activation of the NLRP3/ASC/caspase-1 pathway after ICH. Conclusion: By inhibiting the NLRP3 inflammasome, preconditioning Feb attenuates inflammatory injury after ICH. Our findings may provide new insights into the role of Feb in neuroprotection.