Escherichia coli O157:H7 senses microbiota-produced riboflavin to increase its virulence in the gut.

Riboflavin is produced by most commensal bacteria in the human colon, where enterohemorrhagic Escherichia coli (EHEC) colonizes and causes diseases. Sensing environmental signals to site-specifically express the type-III secretion system (T3SS), which injects effectors into host cells leading to intestinal colonization and disease, is key to the pathogenesis of EHEC. Here, we reveal that EHEC O157:H7, a dominant EHEC serotype frequently associated with severe diseases, acquired a previously uncharacterized two-component regulatory system rbfSR, which senses microbiota-produced riboflavin to directly activate the expression of LEE genes encoding the T3SS in the colon. rbfSR is present in O157:H7 and O145:H28 but absent from other EHEC serotypes. The binding site of RbfR through which it regulates LEE gene expression was identified and is conserved in all EHEC serotypes and Citrobacter rodentium, a surrogate for EHEC in mice. Introducing rbfSR into C. rodentium enabled bacteria to sense microbiota-produced riboflavin in the mouse colon to increase the expression of LEE genes, causing increased disease severity in mice. Phylogenic analysis showed that the O55:H7 ancestor of O157:H7 obtained rbfSR which has been kept in O157:H7 since then. Thus, acquiring rbfSR represents an essential step in the evolution of the highly pathogenic O157:H7. The expression of LEE genes and cell attachment ability of other EHEC serotypes in the presence of riboflavin significantly increased when rbfSR was introduced into them, indicating that those serotypes are ready to use RbfSR to increase their pathogenicity. This may present a potential public health issue as horizontal gene transfer is frequent in enteric bacteria.

Uropathogenic Escherichia coli Subverts Host Autophagic Defenses by Stalling Preautophagosomal Structures to Escape Lysosome Exocytosis.

Urinary tract infections are primarily caused by uropathogenic Escherichia coli (UPEC). UPEC infects bladder epithelial cells (BECs) via fusiform vesicles and escapes into the cytosol by disrupting fusiform vesicle membrane using outer membrane phospholipase PldA, and establishes biofilm-like intracellular bacterial communities (IBCs) for protection from host immune clearance. Cytosolic UPEC is captured by autophagy to form autophagosomes, then transported to lysosomes, triggering the spontaneous exocytosis of lysosomes. The mechanism by which UPEC evades autophagy to recognize and form IBCs remains unclear. Here, we demonstrate that by inhibiting autophagic flux, UPEC PldA reduces the lysosome exocytosis of BECs. By reducing intracellular phosphatidylinositol 3-phosphate levels, UPEC PldA increases the accumulation of NDP52 granules and decreases the targeting of NDP52 to autophagy, hence stalling preautophagosome structures. Thus, our results uncover a critical role for PldA to inhibit autophagic flux, favoring UPEC escapes from lysosome exocytosis, thereby contributing to acute urinary tract infection.

Current challenges and therapeutic advances of CAR-T cell therapy for solid tumors.

The application of chimeric antigen receptor (CAR) T cells in the management of hematological malignancies has emerged as a noteworthy therapeutic breakthrough. Nevertheless, the utilization and effectiveness of CAR-T cell therapy in solid tumors are still limited primarily because of the absence of tumor-specific target antigen, the existence of immunosuppressive tumor microenvironment, restricted T cell invasion and proliferation, and the occurrence of severe toxicity. This review explored the history of CAR-T and its latest advancements in the management of solid tumors. According to recent studies, optimizing the design of CAR-T cells, implementing logic-gated CAR-T cells and refining the delivery methods of therapeutic agents can all enhance the efficacy of CAR-T cell therapy. Furthermore, combination therapy shows promise as a way to improve the effectiveness of CAR-T cell therapy. At present, numerous clinical trials involving CAR-T cells for solid tumors are actively in progress. In conclusion, CAR-T cell therapy has both potential and challenges when it comes to treating solid tumors. As CAR-T cell therapy continues to evolve, further innovations will be devised to surmount the challenges associated with this treatment modality, ultimately leading to enhanced therapeutic response for patients suffered solid tumors.

The Key to MOF Membrane Fabrication and Application: the Trade-off between Crystallization and Film Formation.

Metal-organic frameworks (MOFs), owing the merits of ordered and tailored channel structures in the burgeoning crystalline porous materials, have demonstrated significant promise in construction of high-performance separation membranes. However, precisely because this crystal structure with strong molecular interaction in their lattice provides robust structural integrity and resistance to chemical and thermal degradation, crystalline MOFs typically exhibit insolubility, infusibility, stiffness and brittleness, and therefore their membrane-processing properties are far inferior to the flexible amorphous polymers and hinder their subsequent storage, transportation, and utilization. Hence, focusing on film-formation and crystallization is the foundation for exploring the fabrication and application of MOF membranes. In this review, the film-forming properties of crystalline MOFs are fundamentally analyzed from their inherent characteristics and compared with those of amorphous polymers, influencing factors of polycrystalline MOF membrane formation are summarized, the trade-off relationship between crystallization and membrane formation is discussed, and the strategy solving the film formation of crystalline MOFs in recent years are systematically reviewed, in anticipation of realizing the goal of preparing crystalline membranes with optimized processability and excellent performance.

Influence of dexamethasone-induced matrices on the TM transcriptome.

Pathologic bidirectional interactions between the extracellular matrix (ECM) and cells within the human trabecular meshwork (hTM) contribute to ocular hypertension. An in vitro model is needed to study these cell-matrix interactions and their effect on outflow homeostasis. This study aimed to determine whether pathogenic ECM derived from dexamethasone (DEX)-treated hTM cultures induces clinically relevant glaucoma-like changes in healthy hTM cells at the transcriptional level. Corneoscleral rims from non-glaucoma donors were used to isolate primary hTM cells after validation according to the consensus recommendations for TM culture. Normal hTM cells (n = 5) were plated on a coverslip and treated with 100 nM DEX or ethanol for four weeks. These cultures were then decellularized, plated with primary hTM cells, and allowed to grow for another 72 h. RNA was extracted from these hTM cells for stranded total RNA-Seq. Sequencing libraries prepared using the Zymo-Seq RiboFree Total RNA library kit were pooled and sequenced using Illumina NovaSeq 6000. After quality control, sequence reads were aligned to the human genome build hg19. Differential expression (DE) analyses were performed using paired multi-factorial ANOVA. The expression of several DE genes associated with glaucoma (ANGPTL2, PDE7B, C22orf23, COL4A1, ADAM12, IFT122, SEMA6C) was validated using EvaGreen-based Droplet Digital PCR (ddPCR) assays. Gene ontology analyses of the DE genes were performed using the PANTHER and NDEx IQA databases, and functional analyses were performed with the DAVID Bioinformatics software. Using a cutoff of p-value <0.05 and fold change ≥2.0, our differential analysis identified 267 up- and 135 down-regulated genes in DEX-induced ECM-treated cells compared to the control. These differentially expressed genes were found to play a significant role in pathways such as cytokine and oxidative stress-induced inflammation, integrin signaling, matrix remodeling, and angiogenesis. These findings were further supported by previously performed proteomics studies using the same model. Using ddPCR, we validated the expression of seven genes associated with the risk of primary open-angle glaucoma. These results not only provide support for the pathogenic ECM model of steroid-induced glaucoma, but also demonstrate that the pathologic changes induced by this model are indeed found at the transcriptional level. These findings further demonstrate that matrix changes significantly influence cell expression profiles, which enable further understanding of the molecular mechanisms underlying glaucomatous changes in the TM. However, future studies with a larger and more diverse set of samples and longer time points are needed to confirm the utility of this model for mechanistic studies.

Visible light-promoted difluoromethylthiolation of cycloalkanols by C-C bond cleavage.

A mild and general methodology for the difluoromethylthiolation of cycloalkanols has been developed by employing N-difluoromethylthiophthalimide as the SCF2H radical source, in combination with an acridinium-derived organo-photosensitizer, under redox-neutral conditions. This reaction protocol demonstrates high efficiency, scalability, and mild reaction conditions, thus presenting a green approach for the rapid synthesis of distal difluoromethylthiolated alkyl ketones that are challenging to be synthesized through alternative means.

PD-L2 mediates tobacco smoking-induced recruitment of regulatory T cells via the RGMB/NFκB/CCL20 cascade.

Programmed cell death ligand 2 (PD-L2), a ligand for the receptor programmed cell death 1 (PD-1), has an identity of 34% with its twin ligand PD-L1 and exhibits higher binding affinity with PD-1 than PD-L1. However, the role of PD-L2 in non-small cell lung cancer (NSCLC) progression, especially tobacco-induced cancer progression, has not been fully understood. Here, we found that PD-L2 promoted tumor growth in murine models with recruitment of regulatory T cells (Tregs). In patients with NSCLC, PD-L2 expression level in tumor samples was higher than in counterpart normal controls and was positively associated with patients' response to anti-PD-1 treatment. Mechanismly, PD-L2 bound its receptor Repulsive guidance molecule B (RGMB) on cancer cells and activated extracellular signal-regulated kinase (Erk) and nuclear factor κB (NFκB), leading to increased production of chemokine CCL20, which recruited Tregs and contributed to NSCLC progression. Consistently, knockdown of RGMB or NFκB p65 inhibited PD-L2-induced CCL20 production, and silencing of PD-L2 repressed Treg recruitment by NSCLC cells. Furthermore, cigarette smoke and carcinogen benzo(a)pyrene (BaP) upregulated PD-L2 in lung epithelial cells via aryl hydrocarbon receptor (AhR)-mediated transcription activation, whose deficiency markedly suppressed BaP-induced PD-L2 upregulation. These results suggest that PD-L2 mediates tobacco-induced recruitment of Tregs via the RGMB/NFκB/CCL20 cascade, and targeting this pathway might have therapeutic potentials in NSCLC.

Atmospheric Turbulence Phase Reconstruction via Deep Learning Wavefront Sensing.

The fast and accurate reconstruction of the turbulence phase is crucial for compensating atmospheric disturbances in free-space coherent optical communication. Traditional methods suffer from slow convergence and inadequate phase reconstruction accuracy. This paper introduces a deep learning-based approach for atmospheric turbulence phase reconstruction, utilizing light intensity images affected by turbulence as the basis for feature extraction. The method employs extensive light intensity-phase samples across varying turbulence intensities for training, enabling phase reconstruction from light intensity images. The trained U-Net model reconstructs phases for strong, medium, and weak turbulence with an average processing time of 0.14 s. Simulation outcomes indicate an average loss function value of 0.00027 post-convergence, with a mean squared error of 0.0003 for individual turbulence reconstructions. Experimental validation yields a mean square error of 0.0007 for single turbulence reconstruction. The proposed method demonstrates rapid convergence, robust performance, and strong generalization, offering a novel solution for atmospheric disturbance correction in free-space coherent optical communication.

Research on the Influence of Core Sensing Components on the Performance of Galvanic Dissolved Oxygen Sensors.

The galvanic dissolved oxygen sensor finds widespread applications in multiple critical fields due to its high precision and excellent stability. As its core sensing components, the oxygen-permeable membrane, electrode, and electrolyte significantly impact the sensor's performance. To systematically investigate the comprehensive effects of these core sensing components on the performance of galvanic dissolved oxygen sensors, this study selected six types of oxygen-permeable membranes made from two materials (Perfluoroalkoxy Polymer (PFA) and Fluorinated Ethylene Propylene Copolymer (FEP)) with three thicknesses (0.015 mm, 0.03 mm, and 0.05 mm). Additionally, five concentrations of KCl electrolyte were configured, and four different proportions of lead-tin alloy electrodes were chosen. Single-factor and crossover experiments were conducted using the OxyGuard dissolved oxygen sensor as the experimental platform. The experimental results indicate that under the same membrane thickness conditions, PFA membranes provide a higher output voltage compared to FEP membranes. Moreover, the oxygen permeability of FEP membranes is more significantly affected by temperature. Furthermore, the oxygen permeability of the membrane is inversely proportional to its thickness; the thinner the membrane, the better the oxygen permeability, resulting in a corresponding increase in sensor output voltage. When the membrane thickness is reduced from 0.05 mm to 0.015 mm, the sensor output voltage for PFA and FEP membranes increases by 86% and 74.91%, respectively. However, this study also observed that excessively thin membranes might compromise measurement accuracy. In a saturated, dissolved oxygen environment, the sensor output voltage corresponding to the six oxygen-permeable membranes used in the experiment exhibits a highly linear inverse relationship with temperature (correlation coefficient ≥ 98%). Meanwhile, the lead-tin ratio of the electrode and electrolyte concentration have a relatively minor impact on the sensor output voltage, demonstrating good stability at different temperatures (coefficient of variation ≤ 0.78%). In terms of response time, it is directly proportional to the thickness of the oxygen-permeable membrane, especially for PFA membranes. When the thickness increases from 0.015 mm to 0.05 mm, the response time extends by up to 2033.33%. In contrast, the electrode material and electrolyte concentration have a less significant effect on response time. To further validate the practical value of the experimental results, the best-performing combination of core sensing components from the experiments was selected to construct a new dissolved oxygen sensor. A performance comparison test was conducted between this new sensor and the OxyGuard dissolved oxygen sensor. The results showed that both sensors had the same response time (49 s). However, in an anaerobic environment, the OxyGuard sensor demonstrated slightly higher accuracy by 2.44%. This study not only provides a deep analysis of the combined effects of oxygen-permeable membranes, electrodes, and electrolytes on the performance of galvanic dissolved oxygen sensors but also offers scientific evidence and practical guidance for optimizing sensor design.

Oral Microbially-Induced Small Extracellular Vesicles Cross the Blood-Brain Barrier.

Porphyromonas gingivalis (Pg) and its gingipain proteases contribute to Alzheimer's disease (AD) pathogenesis through yet unclear mechanisms. Cellular secretion of small extracellular vesicles or exosomes (EXO) increases with aging as part of the senescence-associated secretory phenotype (SASP). We have shown that EXO isolated from Pg-infected dendritic cells contain gingipains and other Pg antigens and transmit senescence to bystander gingival cells, inducing alveolar bone loss in mice in vivo. Here, EXO were isolated from the gingiva of mice and humans with/without periodontitis (PD) to determine their ability to penetrate the blood-brain barrier (BBB) in vitro and in vivo. PD was induced by Pg oral gavage for 6 weeks in C57B6 mice. EXO isolated from the gingiva or brain of donor Pg-infected (PD EXO) or control animals (Con EXO) were characterized by NTA, Western blot, and TEM. Gingival PD EXO or Con EXO were labeled and injected into the gingiva of uninfected WT mouse model. EXO biodistribution in brains was tracked by an in vivo imaging system (IVIS) and confocal microscopy. The effect of human PD EXO on BBB integrity and permeability was examined using TEER and FITC dextran assays in a human in vitro 3D model of the BBB. Pg antigens (RGP and Mfa-1) were detected in EXO derived from gingival and brain tissues of donor Pg-infected mice. Orally injected PD EXO from donor mice penetrated the brains of recipient uninfected mice and colocalized with hippocampal microglial cells. IL-1ß and IL-6 were expressed in human PD EXO and not in Con EXO. Human PD EXO promoted BBB permeability and penetrated the BBB in vitro. This is the first demonstration that microbial-induced EXO in the oral cavity can disseminate, cross the BBB, and may contribute to AD pathogenesis.

Efficacy and safety of dacomitinib as first-line treatment for advanced non-small cell lung cancer patients with epidermal growth factor receptor 21L858R mutation: A multicenter, case-series study in China.

Objective: To provide real-world evidence for the application of first-line dacomitinib treatment for epidermal growth factor receptor (EGFR) 21L858R mutant non-small cell lung cancer (NSCLC) patients in China and to explore the factors influencing the efficacy and safety. Methods: A longitudinal, consecutive case-series, multicenter study with mixed prospective and retrospective data was conducted. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included duration of treatment (DOT), overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety. Results: A total of 155 EGFR 21L858R mutant patients treated with first-line dacomitinib were included. The median follow-up time for these patients was 20.4 months. Among 134 patients with evaluable lesions, the ORR was 70.9% and the DCR was 96.3%. The median PFS was 16.3 [95% confidence interval (95% CI), 13.7-18.9] months. Multivariate Cox regression analysis suggested that the baseline brain metastasis (BM) status [with vs. without BM: hazard ratio (HR), 1.331; 95% CI, 0.720-2.458; P=0.361] and initial doses (45 mg vs. 30 mg: HR, 0.837; 95% CI, 0.427-1.641; P=0.604) did not significantly affect the median PFS. The median DOT was 21.0 (95% CI, 17.5-24.6) months and the median OS was not reached. Genetic tests were performed in 64 patients after progression, among whom 29 (45.3%) patients developed the EGFR 20T790M mutation. In addition, among the 46 patients who discontinued dacomitinib treatment after progression, 31 (67.4%) patients received subsequent third-generation EGFR-tyrosine kinase inhibitors. The most common grade 3-4 adverse events were rash (10.4%), diarrhea (9.1%), stomatitis (7.1%) and paronychia (4.5%). The incidence of grade 3-4 rash was significantly higher in the 45 mg group than that in the 30 mg group (21.9% vs. 7.5%, P=0.042). Conclusions: First-line dacomitinib treatment demonstrated promising efficacy and tolerable adverse events among EGFR 21L858R mutant NSCLC patients in China.

Immune checkpoint inhibitors combined with angiogenic inhibitors in the treatment of locally advanced or metastatic lung adenocarcinoma patients.

BACKGROUND: To report the efficacy and safety data of immunotherapy plus angiogenic inhibitors treatment in lung adenocarcinoma patients. METHODS: Eligible patients with pathological or cytological confirmed locally advanced or metastatic lung adenocarcinoma and treated with immune checkpoint inhibitors (ICI) plus angiogenic inhibitors were enrolled. The primary endpoints were progressive free survival (PFS). The secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. RESULTS: A total of 46 consecutive enrolled patients received ICI plus angiogenic inhibitor, and the median follow-up was 9.6 months (range 1.5-32.5). The ORR and DCR were 8.7% (n = 4) and 50% (n = 23), respectively. Median PFS and OS were 2.9 months (95% CI 2.1-3.7) and 12.3 months (95% CI 7.6-17.0), respectively. Patients at stage IVB had an inferior PFS than stage IIIC or IVA (2.8 months vs 4.4 months, P = 0.003). The median PFS of patients who were treated with ICI plus bevacizumab was shorter than ICI plus anlotinib or apatinib (1.2 months vs 3.3 months, P = 0.005). The occurrence of hypertension during the combination treatment has been related to a tendency for prolonged PFS (5.5 months vs 2.6 months; P = 0.05). The overall incidence of treatment-related adverse events (TRAE) was 89.1% (n = 41), and grade 3-4 TRAE was occupied 21.4% (n = 10). CONCLUSION: This study objectively demonstrated that the treatment of ICI and antiangiogenic agents in lung adenocarcinoma could be a promising alternative therapeutic regimen, and the toxic effects were manageable. Subgroup analysis revealed that small molecular angiogenic inhibitors plus ICI and low tumor burden during treatment were better prognostic factors.

Estrogen dysregulation, intraocular pressure, and glaucoma risk.

Characterized by optic nerve atrophy due to retinal ganglion cell (RGC) death, glaucoma is the leading cause of irreversible blindness worldwide. Of the major risk factors for glaucoma (age, ocular hypertension, and genetics), only elevated intraocular pressure (IOP) is modifiable, which is largely regulated by aqueous humor outflow through the trabecular meshwork. Glucocorticoids such as dexamethasone have long been known to elevate IOP and lead to glaucoma. However, several recent studies have reported that steroid hormone estrogen levels inversely correlate with glaucoma risk, and that variants in estrogen signaling genes have been associated with glaucoma. As a result, estrogen dysregulation may contribute to glaucoma pathogenesis, and estrogen signaling may protect against glaucoma. The mechanism for estrogen-related protection against glaucoma is not completely understood but likely involves both regulation of IOP homeostasis and neuroprotection of RGCs. Based upon its known activities, estrogen signaling may promote IOP homeostasis by affecting extracellular matrix turnover, focal adhesion assembly, actin stress fiber formation, mechanosensation, and nitric oxide production. In addition, estrogen receptors in the RGCs may mediate neuroprotective functions. As a result, the estrogen signaling pathway may offer a therapeutic target for both IOP control and neuroprotection. This review examines the evidence for a relationship between estrogen and IOP and explores the possible mechanisms by which estrogen maintains IOP homeostasis.

Exosomes and their miRNA/protein profile in keratoconus-derived corneal stromal cells.

Keratoconus (KC) is a corneal thinning disorder and a leading cause of corneal transplantation worldwide. Exosomes are small, secreted extracellular vesicles (30-150 nm) that mediate cellular communication via their protein, lipid, and nucleic acid content. We aimed to characterize the exosomes secreted by primary corneal fibroblasts from subjects with or without KC. Using human keratoconus stromal fibroblast cells (HKC, n = 4) and healthy stromal fibroblasts (HCF, n = 4), we collected and isolated exosomes using serial ultracentrifugation. Using nanoparticle tracking analysis (NTA) with ZetaView®, we compared the size and concentration of isolated exosomes. Different exosomal markers were identified and quantified using a transmission electron microscope (TEM) (CD81) and Western blot (CD9 and CD63). Exosomal miRNA profiles were determined by qRT-PCR using Exiqon Human panel I miRNA assays of 368 pre-selected miRNAs. Proteomic profiles were determined using a label-free spectral counting method with mass spectrometry. Differential expression analysis for miRNAs and proteins was done using student's t-test with a significance cutoff of p-value ≤0.05. We successfully characterized exosomes isolated from HCFs using several complementary techniques. We found no significant differences in the size, quantity, or morphology between exosomes secreted by HCFs with or without KC. Expression of CD81 was confirmed by immuno-EM, and expression of CD63 and CD9 with western blots in all exosome samples. We detected the expression of 72-144 miRNAs (threshold cycle Ct < 36) in all exosome samples. In HKC-derived exosome samples, miR-328-3p, miR-532-5p, miR-345-5p, and miR-424-5p showed unique expression, while let-7c-5p and miR-665 have increased expression. Protein profiling identified 157 proteins in at least half of the exosome samples, with 38 known exosomal proteins. We identified 12 up- and 2 down-regulated proteins in HKC-derived exosomes. The proteins are involved in membrane-bounded vesicles, cytoskeletal, calcium binding, and nucleotide binding. These proteins are predicted to be regulated by NRF2, miR-205, and TGF-ß1, which are involved in KC pathogenesis. We successfully characterized the HKC-derived exosomes and profiled their miRNA and protein contents, suggesting their potential role in KC development. Further studies are necessary to determine if and how these exosomes with differential protein/miRNA profiles contribute to the pathogenesis of KC.

Glaucomatous aqueous humor vesicles are smaller and differ in composition compared to controls.

Cells communicate with each other using vesicles of varying sizes, including a specific repertoire known as exosomes. We isolated aqueous humor (AH)-derived vesicles using two different methods: ultracentrifugation and an exosome isolation kit. We confirmed a unique vesicle size distribution in the AH derived from control and primary open-angle glaucoma (POAG) patients using various techniques, including Nanotracker, dynamic light scattering, atomic force imaging, and electron microscopy. Bonafide vesicle and/or exosome markers were present by dot blot in both control and POAG AH-derived vesicles. Marker levels differed between POAG and control samples, while non-vesicle negative markers were absent in both. Quantitative labeled (iTRAQ) proteomics showed a reduced presence of a specific protein, STT3B, in POAG compared to controls, which was further confirmed using dot blot, Western blot, and ELISA assays. Along the lines of previous findings with AH profiles, we found vast differences in the total phospholipid composition of AH vesicles in POAG compared to controls. Electron microscopy further showed that the addition of mixed phospholipids alters the average size of vesicles in POAG. We found that the cumulative particle size of type I collagen decreased in the presence of Cathepsin D, which normal AH vesicles were able to protect against, but POAG AH vesicles did not. AH alone had no effect on collagen particles. We observed a protective effect on collagen particles with an increase in artificial vesicle sizes, consistent with the protective effects observed with larger control AH vesicles but not with the smaller-sized POAG AH vesicles. Our experiments suggest that AH vesicles in the control group provide greater protection for collagen beams compared to POAG, and their increased vesicle sizes are likely contributing factors to this protection.

Exercise improves angiogenic function of circulating exosomes in type 2 diabetes: Role of exosomal SOD3.

Exosomes, key mediators of cell-cell communication, derived from type 2 diabetes mellitus (T2DM) exhibit detrimental effects. Exercise improves endothelial function in part via the secretion of exosomes into circulation. Extracellular superoxide dismutase (SOD3) is a major secretory copper (Cu) antioxidant enzyme that catalyzes the dismutation of O2•- to H2 O2 whose activity requires the Cu transporter ATP7A. However, the role of SOD3 in exercise-induced angiogenic effects of circulating plasma exosomes on endothelial cells (ECs) in T2DM remains unknown. Here, we show that both SOD3 and ATP7A proteins were present in plasma exosomes in mice, which was significantly increased after two weeks of volunteer wheel exercise. A single bout of exercise in humans also showed a significant increase in SOD3 and ATP7A protein expression in plasma exosomes. Plasma exosomes from T2DM mice significantly reduced angiogenic responses in human ECs or mouse skin wound healing models, which was associated with a decrease in ATP7A, but not SOD3 expression in exosomes. Exercise training in T2DM mice restored the angiogenic effects of T2DM exosomes in ECs by increasing ATP7A in exosomes, which was not observed in exercised T2DM/SOD3-/- mice. Furthermore, exosomes overexpressing SOD3 significantly enhanced angiogenesis in ECs by increasing local H2 O2  levels in a heparin-binding domain-dependent manner as well as restored defective wound healing and angiogenesis in T2DM or SOD3-/- mice. In conclusion, exercise improves the angiogenic potential of circulating exosomes in T2DM in a SOD3-dependent manner. Exosomal SOD3 may provide an exercise mimetic therapy that supports neovascularization and wound repair in cardiometabolic disease.

First-principles study of controllable contact types in Janus MoSH/GaN van der Waals heterostructure.

The search for contact materials with low contact resistance and tunable Schottky barrier (SB) height of two-dimensional (2D) materials is important for improving the electronic performance. Inspired by the recently synthesized metallic Janus MoSH, this study employs first-principles calculations to investigate the electronic structure, mechanical properties, and interface characteristics of Janus MoSH/GaN and MoHS/GaN van der Waals (vdW) heterostructures. We find that both heterostructures exhibit isotropic mechanical properties and form p-type Schottky barrier contacts (p-ShC) and the SB height of MoHS/GaN is smaller than that of the MoSH/GaN heterostructure. The variation in SB height and contact type under biaxial strain and electric field is also studied for both vdW heterostructures, respectively. Compared to the MoSH/GaN heterostructure, the MoHS/GaN heterostructure can transition to Ohmic contact (OhC) under biaxial strain and electric field, making the S-face contact of MoSH with GaN a more effective contact approach. These findings could provide a new pathway for the design of controllable Schottky nanodevices and high-performance electronic devices on GaN-based vdW heterostructures.

Diagnostic value of multiple b-value diffusion-weighted imaging in discriminating the malignant from benign breast lesions.

OBJECTIVE: The conventional breast Diffusion-weighted imaging (DWI) was subtly influenced by microcirculation owing to the insufficient selection of the b values. However, the multiparameter derived from multiple b-value exhibits more reliable image quality and maximize the diagnostic accuracy. We aim to evaluate the diagnostic performance of stand-alone parameter or in combination with multiparameter derived from multiple b-value DWI in differentiating malignant from benign breast lesions. METHODS: A total of forty-one patients diagnosed with benign breast tumor and thirty-eight patients with malignant breast tumor underwent DWI using thirteen b values and other MRI functional sequence at 3.0 T magnetic resonance. Data were accepted mono-exponential, bi-exponential, stretched-exponential, aquaporins (AQP) model analysis. A receiver operating characteristic curve (ROC) was used to evaluate the diagnostic performance of quantitative parameter or multiparametric combination. The Youden index, sensitivity and specificity were used to assess the optimal diagnostic model. T-test, logistic regression analysis, and Z-test were used. P value < 0.05 was considered statistically significant. RESULT: The ADCavg, ADCmax, f, and α value of the malignant group were lower than the benign group, while the ADCfast value was higher instead. The ADCmin, ADCslow, DDC and ADCAQP showed no statistical significance. The combination (ADCavg-ADCfast) yielded the largest area under curve (AUC = 0.807) with sensitivity (68.42%), specificity (87.8%) and highest Youden index, indicating that multiparametric combination (ADCavg-ADCfast) was validated to be a useful model in differentiating the benign from breast malignant lesion. CONCLUSION: The current study based on the multiple b-value diffusion model demonstrated quantitatively multiparametric combination (ADCavg-ADCfast) exhibited the optimal diagnostic efficacy to differentiate malignant from benign breast lesions, suggesting that multiparameter would be a promising non-invasiveness to diagnose breast lesions.

Image Quality Assessment for Realistic Zoom Photos.

New CMOS imaging sensor (CIS) techniques in smartphones have helped user-generated content dominate our lives over traditional DSLRs. However, tiny sensor sizes and fixed focal lengths also lead to more grainy details, especially for zoom photos. Moreover, multi-frame stacking and post-sharpening algorithms would produce zigzag textures and over-sharpened appearances, for which traditional image-quality metrics may over-estimate. To solve this problem, a real-world zoom photo database is first constructed in this paper, which includes 900 tele-photos from 20 different mobile sensors and ISPs. Then we propose a novel no-reference zoom quality metric which incorporates the traditional estimation of sharpness and the concept of image naturalness. More specifically, for the measurement of image sharpness, we are the first to combine the total energy of the predicted gradient image with the entropy of the residual term under the framework of free-energy theory. To further compensate for the influence of over-sharpening effect and other artifacts, a set of model parameters of mean subtracted contrast normalized (MSCN) coefficients are utilized as the natural statistics representatives. Finally, these two measures are combined linearly. Experimental results on the zoom photo database demonstrate that our quality metric can achieve SROCC and PLCC over 0.91, while the performance of single sharpness or naturalness index is around 0.85. Moreover, compared with the best tested general-purpose and sharpness models, our zoom metric outperforms them by 0.072 and 0.064 in SROCC, respectively.

Homocysteine and Glaucoma.

Elevated levels of homocysteine (Hcy), a non-proteinogenic amino acid, may lead to a host of manifestations across the biological systems, particularly the nervous system. Defects in Hcy metabolism have been associated with many neurodegenerative diseases including glaucoma, i.e., the leading cause of blindness. However, the pathophysiology of elevated Hcy and its eligibility as a risk factor for glaucoma remain unclear. We aimed to provide a comprehensive review of the relationship between elevated Hcy levels and glaucoma. Through a systemic search of the PubMed and Google Scholar databases, we found that elevated Hcy might play an important role in the pathogenesis of glaucoma. Further research will be necessary to help clarify the specific contribution of elevated Hcy in the pathogenesis of glaucoma. A discovery and conceptual understanding of Hcy-associated glaucoma could be the keys to providing better therapeutic treatment, if not prophylactic treatment, for this disease.