Asymmetric synthesis of P-stereogenic phosphindane oxides via kinetic resolution and their biological activity.

The importance of P-stereogenic heterocycles has been widely recognized with their extensive use as privileged chiral ligands and bioactive compounds. The catalytic asymmetric synthesis of P-stereogenic phosphindane derivatives, however, remains a challenging task. Herein, we report a catalytic kinetic resolution of phosphindole oxides via rhodium-catalyzed diastereo- and enantioselective conjugate addition to access enantiopure P-stereogenic phosphindane and phosphindole derivatives. This kinetic resolution method features high efficiency (s factor up to >1057), excellent stereoselectivities (all >20:1 dr, up to >99% ee), and a broad substrate scope. The obtained chiral phosphindane oxides exhibit promising therapeutic efficacy in autosomal dominant polycystic kidney disease (ADPKD), and compound 3az is found to significantly inhibit renal cyst growth both in vitro and in vivo, thus ushering in a promising scaffold for ADPKD drug discovery. This study will not only advance efforts towards the asymmetric synthesis of challenging P-stereogenic heterocycles, but also surely inspire further development of P-stereogenic entities for bioactive small-molecule discovery.

Hierarchical medical image report adversarial generation with hybrid discriminator.

BACKGROUND AND OBJECTIVES: Generating coherent reports from medical images is an important task for reducing doctors' workload. Unlike traditional image captioning tasks, the task of medical image report generation faces more challenges. Current models for generating reports from medical images often fail to characterize some abnormal findings, and some models generate reports with low quality. In this study, we propose a model to generate high-quality reports from medical images. METHODS: In this paper, we propose a model called Hybrid Discriminator Generative Adversarial Network (HDGAN), which combines Generative Adversarial Network (GAN) with Reinforcement Learning (RL). The HDGAN model consists of a generator, a one-sentence discriminator, and a one-word discriminator. Specifically, the RL reward signals are judged on the one-sentence discriminator and one-word discriminator separately. The one-sentence discriminator can better learn sentence-level structural information, while the one-word discriminator can learn word diversity information effectively. RESULTS: Our approach performs better on the IU-X-ray and COV-CTR datasets than the baseline models. For the ROUGE metric, our method outperforms the state-of-the-art model by 0.36 on the IU-X-ray, 0.06 on the MIMIC-CXR and 0.156 on the COV-CTR. CONCLUSIONS: The compositional framework we proposed can generate more accurate medical image reports at different levels.

An Autotaxin-Induced Ocular Hypertension Mouse Model Reflecting Physiological Aqueous Biomarker.

Purpose: Animal models of ocular hypertension (OH) have been developed to understand the pathogenesis of glaucoma and facilitate drug discovery. However, many of these models are fraught with issues, including severe intraocular inflammation and technical challenges. Lysophosphatidic acid (LPA) is implicated in trabecular meshwork fibrosis and increased resistance of aqueous outflow, factors that contribute to high intraocular pressure (IOP) in human open-angle glaucoma. We aimed to elevate IOP by increasing expression of the LPA-producing enzyme autotaxin (ATX) in mouse eyes. Methods: Tamoxifen-inducible ATX transgenic mice were developed. Tamoxifen was administered to six- to eight-week-old mice via eye drops to achieve ATX overexpression in the eye. IOP and retinal thickness were measured over time, and retinal flat-mount were evaluated to count retinal ganglion cells (RGCs) loss after three months. Results: Persistent elevation of ATX expression in mouse eyes was confirmed through immunohistochemistry and LysoPLD activity measurement. ATX Tg mice exhibited significantly increased IOP for nearly two months following tamoxifen treatment, with no anterior segment changes or inflammation. Immunohistochemical analysis revealed enhanced expression of extracellular matrix near the angle after two weeks and three months of ATX induction. This correlated with reduced outflow facility, indicating that sustained ATX overexpression induces angle fibrosis, elevating IOP. Although inner retinal layer thickness remained stable, peripheral retina showed a notable reduction in RGC cell count. Conclusions: These findings confirm the successful creation of an open-angle OH mouse model, in which ATX expression in the eye prompts fibrosis near the angle and maintains elevated IOP over extended periods.

Catechol oxidase nanozyme based colorimetric sensors array for highly selective distinction among multiple catecholamines.

In order to effectively monitor multiple catecholamine (CA) neurotransmitters with extreme similar structures, a rapid, sensitive and selective detection strategy has become an urgent problem to be solved. In this paper, a novel colorimetric sensors array based on CuNCs protected by various ligands such as tannic acid, ascorbic acid and polymethylacrylic acid (CuNCs@TA, CuNCs@AA and CuNCs@PMAA) was constructed. All of these CuNCs could mimic catechol oxidase to selective catalyze catechol-type analogues (such as CAs) to corresponding quinones along with color changes. Furthermore, experiments and theory calculations demonstrated that Cr6+-modification on the surface of CuNCs facilitated the steady-state kinetics of enzymatic activity. Based on these CuNCs as sensing probes, this sensors array can quickly detect different CAs (such as epinephrine (EP), including dopamine (DA), norepinephrine (NE) and l-dopa) with similar structures. When those analogues were added to the CuNC-based colorimetric array sensors, different absorbance changes were produced at 485 nm. Linear discriminant analysis (LDA) showed that the tri-probe colorimetric array sensors could recognize and distinguish these analogues, and corresponding binary and ternary mixtures could be well categorized. The value of Factor 1 of an array with varied CA concentrations had a good linear correlation, and the detection limit (LOD) was as low as 10-8∼10-9 mol/L. Four CA analogues in real samples were identified by CuNCs-based colorimetric array sensors. This work provides a fast and convenient experimental basis for monitoring the complex structure CAs neurotransmitters.

Effects of Brimonidine, Omidenepag Isopropyl, and Ripasudil Ophthalmic Solutions to Protect against H2O2-Induced Oxidative Stress in Human Trabecular Meshwork Cells.

PURPOSE: We investigated whether hydrogen peroxide (H2O2)-induced oxidative stress causes human trabecular meshwork (HTM) cell dysfunction observed in open angle glaucoma (OAG) in vitro, and the effects of topical glaucoma medications on oxidative stress in HTM cells. METHODS: We used commercially available ophthalmic solutions of brimonidine, omidenepag isopropyl, and ripasudil in the study. HTM cells were exposed to H2O2 for 1 h, with or without glaucoma medications. We assessed cell viability and senescence via WST-1 and senescence-associated-ß-galactosidase (SA-ß-Gal) activity assays. After exposure to H2O2 and glaucoma medications, we evaluated changes in markers of fibrosis and stress by using real-time quantitative polymerase chain reaction (qPCR) to measure the mRNA levels of collagen type I alpha 1 chain (COL1A1), fibronectin, alpha-smooth muscle actin (α-SMA), matrix metalloproteinase-2 (MMP-2), endoplasmic reticulum stress markers of C/EBP homologous protein (CHOP), 78-kDa glucose-regulated protein (GRP78), and splicing X-box binding protein-1 (sXBP-1). RESULTS: HTM cell viability decreased and SA-ß-Gal activity increased significantly after exposure to H2O2. Treatment with three ophthalmic solutions attenuated these changes. Real-time qPCR revealed that H2O2 upregulated the mRNA levels of COL1A1, fibronectin, α-SMA, CHOP, GRP78, and sXBP-1, whereas it downregulated MMP-2 mRNA expression significantly. Brimonidine suppressed the upregulation of stress markers CHOP and GRP78. Additionally, omidenepag isopropyl and ripasudil decreased the upregulation of COL1A1 and sXBP-1. Furthermore, ripasudil significantly suppressed fibrotic markers fibronectin and α-SMA, compared with the other two medications. CONCLUSION: In vitro, H2O2 treatment of HTM cells induced characteristic changes of OAG, such as fibrosis changes and the upregulation of stress markers. These glaucomatous changes were attenuated by additional treatments with brimonidine, omidenepag isopropyl, and ripasudil ophthalmic solutions.

Fibrotic Response of Human Trabecular Meshwork Cells to Transforming Growth Factor-Beta 3 and Autotaxin in Aqueous Humor.

This study examines the potential role of transforming growth factor-beta 3 (TGF-ß3) on the fibrotic response of cultured human trabecular meshwork (HTM) cells. The relationships and trans-signaling interactions between TGF-ß3 and autotaxin (ATX) in HTM cells were also examined. The levels of TGF-ß and ATX in the aqueous humor (AH) of patients were measured by an immunoenzymetric assay. The TGF-ß3-induced expression of the fibrogenic markers, fibronectin, collagen type I alpha 1 chain, and alpha-smooth muscle actin, and ATX were examined by quantitative real-time PCR, Western blotting, and immunocytochemistry, and the trans-signaling regulatory effect of TGF-ß3 on ATX expression was also evaluated. In HTM cells, the significant upregulation of ATX was induced by TGF-ß3 at a concentration of 0.1 ng/mL, corresponding to the physiological concentration in the AH of patients with exfoliative glaucoma (XFG). However, higher concentrations of TGF-ß3 significantly suppressed ATX expression. TGF-ß3 regulated ATX transcription and signaling in HTM cells, inducing the upregulation of fibrogenic proteins in a dose-dependent manner. Trans-signaling of TGF-ß3 regulated ATX transcription, protein expression, and signaling, and was thereby suggested to induce fibrosis of the trabecular meshwork. Modulation of trans-signaling between TGF-ß3 and ATX may be key to elucidate the pathology of XFG, and for the development of novel treatment modalities.

NH2-MIL-101(Fe) nanozyme-based dual-modality sensor for determination of alendronate sodium and study of two-dimensional correlation spectroscopy.

We developed a dual-modality sensing platform for ratiometric fluorescence and colorimetric determination of alendronate sodium (ALDS). This platform was performed by using a NH2- MIL-101(Fe) as a peroxidase mimic. Since preferential complexing between Fe3+ (active site for peroxidase) and ALDS, the production of 2,3-diaminophenazine (DAP, oxidized product of OPD) has been inhibited in the presence of H2O2. As a result, the ratiometric fluorescence value of F556/F456 and absorbance at 450 nm exhibited significant changes, which could be used as the dual-modality sensing platform. In addition, Two-dimensional correlation spectroscopy (2D-COS) analysis on Fourier-transform infrared (FTIR), ultraviolet visible and ratiometric fluorescence spectra were applied to investigate the binding features. Synchronous and asynchronous maps of these spectra confirmed our above hypothesis, in which Fe3+-ALDS complex was the critical factor that regulated dual-modality signals. To our knowledge, the 2D-COS method was applied to study the catalytic and sensing mechanism of nanozyme as NH2- MIL-101(Fe) for the first time. This technique was helpful to understand interaction of substrates on nanozyme and develop more sensitive sensors for assaying.

Highly dispersive Ru confined in porous ultrathin g-C3N4 nanosheets as an efficient peroxymonosulfate activator for removal of organic pollutants.

Ru species were loaded on a two-dimensional (2D) material of graphitic carbon nitride (2D g-C3N4) to serve as the efficient AOP catalysts. The catalytic activity was closely related to the dispersion degree of Ru, as determined by the inherent nanoarchitecture of the supporting material. Ultrathin g-C3N4 nanosheets with a unique porous structure were fabricated by further thermally oxidizing and etching bulk g-C3N4 (bCN) in air. Homogeneous dispersion of Ru species was successfully achieved on the porous few-layered g-C3N4 nanosheets (pCN) by stirring, washing, freeze drying and annealing processes to obtain Ru-pCN catalysts, whereas bCN or multilayered g-C3N4 (mCN) led to the aggregation of Ru nanoparticles in Ru-bCN and Ru-mCN materials. The conventional impregnation method also caused the resulting Ru-pCN-imp catalyst with undesirable Ru aggregation in spite of employing pCN. The optimal 4.4Ru-pCN removed 100% of 2,4,6-trichlorophenol (TCP) within only 3 min, superior to its counterpart samples, and exhibited remarkable degradation efficiencies for methyl orange, neutral red, 4-chlorophenol, tetracycline and oxytetracycline. Mechanistic studies suggested that four radicals, e.g., •OH, SO4• -, O2• - and 1O2 were generated during the peroxymonosulfate (PMS) activation, in which SO4• - and 1O2 played a major role.

Supramolecule self-assembly synthesis of amyloid phenylalanine-Cu fibrils with laccase-like activity and their application for dopamine determination.

Laccases are multicopper proteins for dioxygen-involved oxidation of a broad spectrum of organic compounds. I Novel amyloid-like phenylalanine-Cu (F-Cu(II)) fibrils were developed, which were obtained via supramolecular self-assembly of Cu2+ and phenylalanine (F) under basic condition. The obtained amyloid-like fibrils represented highly periodic structure, of which the lattice unit was constructed via alternating hydrophobic (aromatic environment) and hydrophilic (both hydrogen bonding and Cu(II) coordination) interactions. Relative to natural laccases, the amyloid-like F-Cu(II) architecture exhibited comparable substrate affinity (Michaelis constant, Km = 0.75 mM) and higher catalytic efficiency (kcat/Km = 773.33 × 10-3 g-1 min-1L). Moreover, it exhibited remarkable tolerances in pH (4 ~ 10), temperature (room temperature ~ 200 ℃), organic solvent, and long-term storage (> 15 days). These stabilities were superior among the reported nature and artificial laccases, presenting a more promising candidate in various chemo- or bio-applications. In addition, F-Cu(II) fibrils could catalyze the oxidation of dopamine (DA) to a brown product, in which a new absorption band at 470 nm was observed. Based on this, a simple colorimetric assay for the detection of DA could be performed. We reported a novel amyloid-like phenylalanine-Cu fibrils, in which F-Cu+ complex can mimick the T1 site of natural laccase to oxidize the substrates. Then electrons transferred to F-Cu2+ complex via N-H···O=C hydrogen binding pathway. Finally, the dioxygen was transformed to water though radical reaction.

Synthesis of water-soluble, ultrabright Cu nanoclusters with core-shell structure via facile reduction approach for determination of 4-nitrophenol.

In this work, we reported a facile reduction approach for fabrication of water-soluble and ultrabright Cu nanoclusters with core-shell structure. A certain amount of reducing agent as NaBH4was introduced into the polyethyleneimine-stabilized Cu nanoclusters (CuNCs@PEI) system, which exhibited 4-fold fluorescence enhancement along with a blue shift of the emission peak. The variations of morphology, valence states and functional groups demonstrated that a Cu shell was formed surround CuNCs (defined as CuNCs-Cu@PEI), attributable to metal complex (PEI-Cu+and PEI-Cu2+) reduction. The effect of core-shell morphology on luminous and electron relaxation mechanism of CuNCs-Cu@PEI was investigated via temperature-dependent steady and time-resolved fluorescence measurements. The CuNCs-Cu@PEI with a high fluorescence quantum yields of 22.59% were able to homogeneously disperse in aqueous phase, indicating their potential applications in biological labeling, sensing and invivoimaging. Finally, the CuNCs-Cu@PEI was employed as a fluorescence probe to determine 4-nitrophenol, of which the detection limit was much lower than initial CuNCs@PEI.

Encapsulation of cuprous/cobalt sites in metal organic framework for enhanced C2H4/C2H6 separation.

Adsorbents based on CuI for π-complexative separation of C2H4/C2H6 have attracted widespread interests. However, they are still confronting some challenges, for example, (i) a low separation efficiency, resulted from the ineffective reduction of CuII to CuI along with aggregation, and (ii) poor stability due to the oxidation of CuI to inactive CuII. In this study, active Cu and auxiliary Co species are simultaneously encapsulated within the nanopores of MIL-101 using a double-solvent (DS) method to obtain CuCoM-DS. The Cu species at the interior of MIL-101 are homogeneously dispersed and can be completely reduced to CuI without any structural damage to MIL-101. The resulting CuCoM-DS exhibits a superior performance in C2H4/C2H6 separation not only to the pristine MIL-101, but to the counterpart samples of single Cu and/or Cu/Co at the exterior of MIL-101. The best sample of 1.5CuCoM-DS adsorbent is capable to adsorb 50.5 mL·g-1 of C2H4, and the C2H4/C2H6 selectivity is 2.6 at 100 kPa. Both C2H4 uptake and C2H4/C2H6 selectivity are higher than those reference samples. Moreover, 1.5CuCoM-DS preserves over 90% of fresh C2H4 uptake after the exposure to atmospheric air for 12 days. This study provides new design ideas for confining bimetallic sites in MOFs for broad applications.

Interocular symmetry of the foveal avascular zone area in healthy eyes: a swept-source optical coherence tomography angiography study.

PURPOSE: To determine the presence or absence of interocular differences in the foveal avascular zone (FAZ) area in healthy eyes. STUDY DESIGN: Cross-sectional study. METHODS: We examined 236 healthy eyes of 118 consecutive subjects (mean age, 39.1 ± 18.9 years). We used swept-source optical coherence tomography angiography (OCTA) images of the FAZ to measure its area from both the superficial capillary plexus (SCP-FAZ) and the whole retinal capillary plexus (WCP-FAZ). We also investigated the relationship between interocular differences in SCP-FAZ and other factors such as: axial length, spherical equivalent, central retinal thickness, and retinal vascular density. RESULTS: There was no significant difference in the FAZ area between the right and left eyes in either the SCP-FAZ (P = 0.61) or WCP-FAZ (P = 0.80), and the FAZ areas of both eyes showed significant positive correlations (SCP-FAZ; P < 0.001, R2 = 0.884, WCP-FAZ; P < 0.001, R2 = 0.856). Bland-Altman plots showed that the mean interocular difference in SCP-FAZ area was 0.002 ± 0.037 mm2 (95% confidence interval, -0.072-0.075 mm2), and in the WCP-FAZ area, 0.050 ± 0.044 mm2 (95% confidence interval, -0.036-0.137 mm2). Multivariate regression analysis showed that none of the investigated factors were significantly associated with interocular differences in SCP-FAZ (P = 0.61, R2 = 0.138). CONCLUSIONS: There was no significant interocular difference in SCP- and WCP-FAZ areas in healthy eyes. The normal range of values for interocular difference in SCP-FAZ area was 0.002 ± 0.037 mm2 and in the WCP-FAZ area, 0.050 ± 0.044 mm2.

Biomarkers for Pulmonary Inflammation and Fibrosis and Lung Ventilation Function in Chinese Occupational Refractory Ceramic Fibers-Exposed Workers.

Refractory ceramic fibers (RCFs) can cause adverse health effects on workers' respiratory system, yet no proper biomarkers have been used to detect early pulmonary injury of RCFs-exposed workers. This study assessed the levels of two biomarkers that are related to respiratory injury in RCFs-exposed workers, and explored their relations with lung function. The exposure levels of total dust and respirable fibers were measured simultaneously in RCFs factories. The levels of TGF-ß1 and ceruloplasmin (CP) increased with the RCFs exposure level (p < 0.05), and significantly increased in workers with high exposure level (1.21 ± 0.49 ng/mL, 115.25 ± 32.44 U/L) when compared with the control group (0.99 ± 0.29 ng/mL, 97.90 ± 35.01 U/L) (p < 0.05). The levels of FVC and FEV1 were significantly decreased in RCFs exposure group (p < 0.05). Negative relations were found between the concentrations of CP and FVC (B = -0.423, p = 0.025), or FEV1 (B = -0.494, p = 0.014). The concentration of TGF-ß1 (B = 0.103, p = 0.001) and CP (B = 8.027, p = 0.007) were associated with respirable fiber exposure level. Occupational exposure to RCFs can impair lung ventilation function and may have the potential to cause pulmonary inflammation and fibrosis. TGF-ß1 and CP might be used as sensitive and noninvasive biomarkers to detect lung injury in occupational RCFs-exposed workers. Respirable fiber concentration can better reflect occupational RCFs exposure and related respiratory injuries.

Positive Rates and Factors Associated with Abnormal Lung Function of Greenhouse Workers in China: A Cross-Sectional Study.

Since the number of greenhouse workers are increasing in China, this observational cross-sectional study was designed to evaluate lung function and discuss the potential risk factors, to provide evidence in the surveillance of greenhouse workers' health. 678 greenhouse workers in Gansu Province, China were enrolled. A questionnaire which included demographic and occupational information was used. Vital capacity (VC), forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and FEV1:FVC ratios (FEV1/FVC), maximal expiratory flow after 50% of the FVC has not been exhaled (MEF50), maximal expiratory flow after 25% of the FVC has not been exhaled (MEF25) and maximal mid-expiratory flow curve (MMEF) were measured as lung function indicators. The mean values and standard deviations (SDs) of VC% predicted, FVC% predicted, FEV1% predicted and FEV1/FVC ratio were 106.07 ± 13.36, 107.60 ± 13.95, 97.19 ± 14.80 and 89.76 ± 10.78 respectively. The positive rates of above four and abnormal lung ventilation function were 2.9%, 2.8%, 11.2%, 4.6% and 6.5% respectively. Gender, age, BMI and number of greenhouses owned were influence factors of lung ventilation function (p < 0.05). The mean values and SDs of MEF50% predicted, MEF25% predicted and MMEF% predicted were 69.63 ± 24.95, 54.04 ± 24.94 and 66.81 ± 24.53. The positive rates of above three and abnormal small airway function were 45.0%, 72.1%, 47.2% and 49.4% respectively. Age, education and number of greenhouses owned were influence factors for small airway function (p < 0.05). Working in a greenhouse might influence lung function of the workers. Small airway function indicators could be used as priority indicators for the surveillance of greenhouse workers' health.

[Evaluation and analysis of monitoring and early warning functions of the occupational disease reporting system in China].

OBJECTIVE: To evaluate the monitoring and early warning functions of the occupational disease reporting system right now in China, and to analyze their influencing factors. METHODS: An improved audit tool (ODIT) was used to score the monitoring and early warning functions with a total score of 10. The nine indices were completeness of information on the reporting form, coverage of the reporting system, accessibility of criteria or guidelines for diagnosis, education and training for physicians, completeness of the reporting system, statistical methods, investigation of special cases, release of monitoring information, and release of early warning information. RESULTS: According to the evaluation, the occupational disease reporting system in China had a score of 5.5 in monitoring existing occupational diseases with a low score for release of monitoring information; the reporting system had a score of 6.5 in early warning of newly occurring occupational diseases with low scores for education and training for physicians as well as completeness of the reporting system. CONCLUSION: The occupational disease reporting system in China still does not have full function in monitoring and early warning. It is the education and participation of physicians from general hospitals in the diagnosis and treatment of occupational diseases and suspected occupational diseases that need to be enhanced. In addition, the problem of monitoring the incidence of occupational diseases needs to be solved as soon as possible.