Design, synthesis, and biological evaluation of (thio)urea derivatives as potent Escherichia coli ß-glucuronidase inhibitors.

EcGUS has drawn considerable attention for its role as a target in alleviating serious GIAEs. In this study, a series of 72 (thio)urea derivatives were designed, synthesised, and biologically assayed. The bioassay results revealed that E-9 (IC50 = 2.68 µM) exhibited a promising inhibitory effect on EcGUS, surpassing EcGUS inhibitor D-saccharic acid-1,4-lactone (DSL, IC50 = 45.8 µM). Additionally, the inhibitory kinetic study indicated that E-9 (Ki = 1.64 µM) acted as an uncompetitive inhibitor against EcGUS. The structure-activity relationship revealed that introducing an electron-withdrawing group into the benzene ring at the para-position is beneficial for enhancing inhibitory activity against EcGUS. Furthermore, molecular docking analysis indicated that E-9 has a strong affinity to EcGUS by forming interactions with residues Asp 163, Tyr 472, and Glu 504. Overall, these results suggested that E-9 could be a potent EcGUS inhibitor, providing valuable insights and guidelines for the development of future inhibitors targeting EcGUS.

Enantioselective Synthesis of 2,3,3a,8a-Tetrahydrofuro[2,3-b]benzofuran Scaffolds Enabled by Cu(II)/SPDO-Catalyzed [3+2] Cycloaddition of 2,3-Dihydrofuran and Quinone Esters.

An asymmetric [3+2] cycloaddition of quinone esters with 2,3-dihydrofuran has been realized via a newly developed Cu(II)/SPDO complex. It provides straightforward access to 2,3,3a,8a-tetrahydrofuro[2,3-b]benzofurans (TFB) with high enantioselectivity (up to 97.5:2.5 er) and diastereoselectivity (all >20:1 dr). The resulting adducts contain two adjacent stereocenters and a continuously functionalized benzene ring. Additionally, this transformation could be easily performed on a gram scale, allowing for expedient synthesis of natural dihydroaflatoxin D2 and aflatoxin B2.

Design, synthesis, and biological evaluation of benzoheterocyclic sulfoxide derivatives as quorum sensing inhibitors in Pseudomonas aeruginosa.

Six series of benzoheterocyclic sulfoxide derivatives were designed and synthesised as Pseudomonas aeruginosa (P. aeruginosa) quorum sensing inhibitors in this paper. We experimentally demonstrated that 6b significantly inhibited the formation of P. aeruginosa PAO1 biofilm without affecting the growth. Further mechanistic studies showed that 6b affected the luminescence of quorum sensing reported strain PAO1-lasB-gfp and the production of P. aeruginosa PAO1 elastase virulence factor which was regulated by las system. These experimental results indicate that 6b acts as a quorum sensing inhibitor mainly through the las system. Furthermore, silico molecular docking studies demonstrated that 6b and the P. aeruginosa quorum sensing receptor LasR were molecularly bound via hydrogen bonding interactions. Preliminary structure-activity relationship and docking studies illustrated that 6b shows great promise as anti-biofilm compounds for further studies in order to solve the problem of microbial resistance in future.

Design, Synthesis, and Biological Evaluation of Phenyloxadiazole Sulfoxide Derivatives as Potent Pseudomonas aeruginosa Biofilm Inhibitors.

With the development of antimicrobial agents, researchers have developed new strategies through key regulatory systems to block the expression of virulence genes without affecting bacterial growth. This strategy can minimize the selective pressure that leads to the emergence of resistance. Quorum sensing (QS) is an intercellular communication system that plays a key role in the regulation of bacterial virulence and biofilm formation. Studies have revealed that the QS system controls 4-6% of the total number of P. aeruginosa genes, and quorum sensing inhibitors (QSIs) could be a promising target for developing new prevention and treatment strategies against P. aeruginosa infection. In this study, four series of phenyloxadiazole and phenyltetrazole sulfoxide derivatives were synthesized and evaluated for their inhibitory effects on P. aeruginosa PAO1 biofilm formation. Our results showed that 5b had biofilm inhibitory activity and reduced the production of QS-regulated virulence factors in P. aeruginosa. In addition, silico molecular docking studies have shown that 5b binds to the P. aeruginosa QS receptor protein LasR through hydrogen bond interaction. Preliminary structure-activity relationship and docking studies show that 5b has broad application prospects as an anti-biofilm compound, and further research will be carried out in the future to solve the problem of microbial resistance.

Mendelian randomization analysis identified genes pleiotropically associated with central corneal thickness.

OBJECTIVE: To prioritize genes that were pleiotropically or potentially causally associated with central corneal thickness (CCT). METHODS: We applied the summary data-based Mendelian randomization (SMR) method integrating summarized data of genome-wide association study (GWAS) on CCT and expression quantitative trait loci (eQTL) data to identify genes that were pleiotropically associated with CCT. We performed separate SMR analysis using CAGE eQTL data and GTEx eQTL data. SMR analyses were done for participants of European and East Asian ancestries, separately. RESULTS: We identified multiple genes showing pleiotropic association with CCT in the participants of European ancestry. CLIC3 (ILMN_1796423; PSMR = 4.15 × 10- 12), PTGDS (ILMN_1664464; PSMR = 6.88 × 10- 9) and C9orf142 (ILMN_1761138; PSMR = 8.09 × 10- 9) were the top three genes using the CAGE eQTL data, and RP11-458F8.4 (ENSG00000273142.1; PSMR = 5.89 × 10- 9), LCNL1 (ENSG00000214402.6; PSMR = 5.67 × 10- 8), and PTGDS (ENSG00000107317.7; PSMR = 1.92 × 10- 7) were the top three genes using the GTEx eQTL data. No genes showed significantly pleiotropic association with CCT in the participants of East Asian ancestry after correction for multiple testing. CONCLUSION: We identified several genes pleiotropically associated with CCT, some of which represented novel genes influencing CCT. Our findings provided important leads to a better understanding of the genetic factors influencing CCT, and revealed potential therapeutic targets for the treatment of primary open-angle glaucoma and keratoconus.

Discovery of a series of 5-phenyl-2-furan derivatives containing 1,3-thiazole moiety as potent Escherichia coli ß-glucuronidase inhibitors.

Gut microbial ß-glucuronidases have drawn much attention due to their role as a potential therapeutic target to alleviate some drugs or their metabolites-induced gastrointestinal toxicity. In this study, fifteen 5-phenyl-2-furan derivatives containing 1,3-thiazole moiety (1-15) were synthesized and evaluated for their inhibitory effects against Escherichia coli ß-glucuronidase (EcGUS). Twelve of them showed satisfactory inhibition against EcGUS with IC50 values ranging from 0.25 µM to 2.13 µM with compound 12 exhibited the best inhibition. Inhibition kinetics studies indicated that compound 12 (Ki = 0.14 ± 0.01 µM) was an uncompetitive inhibitor for EcGUS and molecular docking simulation further predicted the binding model and capability of compound 12 with EcGUS. A preliminary structure-inhibitory activity relationship study revealed that the heterocyclic backbone and bromine substitution of benzene may be essential for inhibition against EcGUS. The compounds have the potential to be applied in drug-induced gastrointestinal toxicity and the findings would help researchers to design and develop more effective 5-phenyl-2-furan type EcGUS inhibitors.

Clinical features and optical coherence tomography findings of retinal astrocytic hamartomas in Chinese patients with tuberous sclerosis complex.

PURPOSE: To investigate the clinical features and spectral-domain optical coherence tomography (SD-OCT) findings of retinal astrocytic hamartoma (RAH) in Chinese patients with tuberous sclerosis complex (TSC). METHODS: The medical records of 91 consecutive patients with established TSC diagnosis were retrospectively reviewed. Fundus findings regarding RAH documented by fundus photography and SD-OCT at presentation were collected and analyzed. RESULTS: RAHs were seen in 69 of the 91 patients (75.8%); 50.7% of these patients showed bilateral retinal involvement. Type 1 RAH was found the most common type with a prevalence of 94.2%, while type 2 and type 3 RAH with 7.2% and 18.8% respectively. A significant correlation between age and RAH types was shown by Fisher's exact test (p < 0.001). By SD-OCT, non-calcified RAHs featured in hyperreflective thickening of the retinal nerve fiber layer with some degree of retinal disorganization, while multinodular calcified RAHs characterized with moth-eaten appearances representing intraretinal calcification with posterior dense optical shadowing. CONCLUSION: A higher prevalence of TSC-associated RAH but an unexpected lower prevalence of calcified RAHs was shown in Chinese compared with that of Caucasians. SD-OCT can be used to facilitate the detection and follow-up of RAHs.

Research on the reconfigurable bottle beam based on adjusting the spot shape of the incident beam.

An optical system was designed that can generate a bottle beam with a reconfigurable function. The incident beam is produced by transmitting a circular Gaussian beam through the oblique circular aperture, effectively forming the elliptic beam spot. Due to the asymmetry of the elliptically limited Gaussian beam, the bottle beam with locally vanishing light intensity is generated after the optical system. The results show that the bottle beam can be opened and closed freely by the oblique circular aperture, which is of great significance to particle capture.

Design, synthesis, biological activities, and dynamic simulation study of novel thiourea derivatives with gibberellin activity towards Arabidopsis thaliana.

Computer-aided drug design has advanced by leaps and bounds, and has been widely used in various fields, and especially in the field of drug discovery. Although the crystal structure of the gibberellin (GA) receptor GID1A had been reported in previous studies, there is still a lack of designs of gibberellin functional analogue based GID1A. In the present study, a series of 30 thiourea derivatives were designed, synthesized and biologically assayed. The results suggested that the synthetic compounds had good GA-like activities. Furthermore, the structure-activity relationship of the synthetic compounds was discussed, and the dynamic simulation and docking study revealed the binding properties of the GID1A receptor and compounds Y1, Y11, and Y21.

Design of bottle beam based on dual-beam for trapping particles in air.

An optical system structure, consisting of a tunable bottle beam, was designed to capture micron absorbing particles in air. Using a 670 nm semiconductor laser as the light source, a bottle beam was formed with beam shaping elements, a double-axicon lens, and parabolic annular mirrors. Taking a particle of carbon nanoclusters as an example, the capturing effect of the bottle beam on a particle was analyzed. By adjusting the size of the bottle beam, the capture performance for particles of different radii could be optimized. When the optical power of the conical doughnut hollow beam was P=0.05 W, the composite bottle beam could capture a particle of carbon nanoclusters smaller than 237 µm.

Internal limiting membrane transplantation for unclosed and large macular holes.

BACKGROUND: To present the surgical technique and clinical outcomes of transplantation of autologous internal limiting membrane (ILM) for large macular holes (MHs) after failed surgeries with ILM removal. METHODS: Thirteen eyes of 13 consecutive patients with MHs larger than 500 µm after failed surgeries with ILM removal underwent vitrectomy with transplantation of autologous ILM. In the ILM transplantation technique, a small piece of the ILM was peeled off and transplanted inside the macular hole. Fluid-air exchange was then performed. The air was then replaced with 10 % perfluoropropane (C3F8) gas. Comprehensive ophthalmologic examinations and spectral-domain optical coherence tomography were performed preoperatively and postoperatively. The main outcome measures were best-corrected Snellen visual acuity (BCVA) and MH closure rate. RESULTS: The preoperative mean base diameter of the MHs was 1637.6 + 412.7 µm (range, 814-2092 µm). The preoperative mean minimum diameter was 814.4 + 255.0 µm (range, 546 µm-1485 µm). Complete MH sealing was achieved in 12 eyes after transplantation of the ILM flap. The mean BCVA was 1.15 + 0.21 (range, 1.0-1.6) before surgery and 0.99 + 0.17 (range, 0.7-1.3) at 12 months postoperatively. There was a significant difference in BCVA before versus after the surgery (t = 3.825, P = 0.0002, paired t- test). CONCLUSIONS: Transplantation of autologous ILM is an effective addition to the surgical options for large macular holes after failed surgeries with ILM removal.

[Association between optical coherence tomography findings and visual acuity of Behcet's disease-associated uveitis patients during remission stage].

OBJECTIVE: To study the relationship between the structure of macular central fovea and the best-corrected visual acuity (BCVA) during remission stage of Behcet's disease associated uveitis. METHODS: Retrospective case series studies. The study covered 51 patients (79 eyes) during remission stage of Behcet's disease-associated uveitis from Peking Union Medical College Hospital in a three-year period from January 2012 to January 2015. There were 40 males, 11 females with the average age of 31.5 ± 6.9 years old (ranging from 18 to 46). All the patients received a complete set of ophthalmic examination, including BCVA, intraocular pressure, slit-lamp microscope, ophthalmoscope and frequency domain optical coherence tomography (OCT). All the eyes were divided into 4 groups according to central macular thickness (CMT) (the thick CMT group: CMT ≥ 130 µm; the thin CMT group: CMT < 130 µm) and the existence of ellipsoid zone. Group 1: thick CMT and ellipsoid (+); Group 2: thick CMT and ellipsoid (-); Group 3: thin CMT and ellipsoid (+); Group 4: thin CMT and ellipsoid (-). Sight disparity among multiple groups was tested with Kruskal Wallis, while the difference between two groups was tested with Mann-Whitney U test. Bonferroni correction was conducted when necessary. RESULTS: The mean CMT was (151.4 ± 62.3) µm in all eyes (43 eyes in thick CMT group, 36 eyes in thin CMT group). According to grouping rule, there were 32 eyes in group 1, 11 eyes in group 2, 2 eyes in group 3 and 34 eyes in group 4. The BCVA of thick CMT group was better than that of thin CMT group (logMAR0.1 and logMAR1.0) (z = -6.88, P < 0.01). In addition, the BCVA of ellipsoid (+) group was better than the ellipsoid (-) group. (log MAR0.1 and log MAR1.0) (z = -6.60, P < 0.01). CONCLUSION: Thick CMT and intact ellipsoid zone usually associated with relatively better BCVA in Behcet's disease-associated uveitis patients.

Ultra-Wide-Field Optical Coherence Tomography and Gaussian Curvature to Assess Macular and Paravascular Retinoschisis in High Myopia.

PURPOSE: To evaluate the severity and related factors of macular retinoschisis (MRS) and paravascular retinoschisis (PVRS) in high myopia (HM) using ultra-wide-field optical coherence tomography (UWF-OCT) and a novel Gaussian curvature (K). DESIGN: A cross-sectional study. METHODS: Patients diagnosed with HM in Peking Union Medical College Hospital were recruited between January 2022 and November 2022. The presence and severity of retinoschisis, along with the three highest K values, were assessed using UWF-OCT and en face images. Logistic regressions were employed to identify factors associated with MRS, PVRS, and the severity of retinoschisis in the 24 × 20 mm scan region. RESULTS: A total of 108 HM eyes from 55 patients were recruited. The highest Gaussian curvature (K1) was predominantly found in the vascular arcade (43, 40%). Multivariable logistic regression found that age and PVRS were significant risk factors for MRS occurrence (P < .05), while MRS and higher K1 were significantly associated with the presence of PVRS in HM patients (P < .05). The axial length (AL) and spherical equivalent were associated with the severity of MRS, while AL and K1 values were associated with the severity of retinoschisis in the 24 × 20 mm scan region (P < .05). CONCLUSIONS: An association existed between large Gaussian curvature and the presence of MRS and PVRS, as well as the severity of retinoschisis in a wide field of view. UWF-OCT, which enables visualization of the central and peripheral retinal areas, holds promise as an imaging technique for the early detection of extrafoveal retinoschisis.

The current application of 3D printing simulator in surgical training.

In the rapidly evolving field of medical education, the integration of innovative technologies has become paramount to enhance the training and proficiency of future surgeons. Among these advancements, the application of 3D printing technology stands out as a useful tool in surgical training. The advantages of the 3D printing model include customization, re-usability and low-cost. The average cost of the 3D printing simulators was between $100-1000. However, there were extremely high potential labor cost during the 3D printing that hadn't been calculated into. Additionally, in the current stage, the 3D printing simulator still have specific limitations. The most mentioned limitation was poor haptic feedback of the simulators, which was very important during the surgical training, since it is the key element for junior doctors to master practical procedures. Also, some simulators didn't possess the integrated and elaborate structure as the human tissue, hence not the whole surgical procedures can be practiced by the trainees, and further improvement should be made. Although there are shortages, many studies have proved that 3D printing simulator can effectively reduce learning curves and is useful to enhance the trainees' surgical skills.

Ocular fundus changes and association with systemic conditions in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease that affects multiple organs and systems. Ocular involvement is estimated to manifest in one-third of individuals with SLE, of which lupus retinopathy and choroidopathy represent the severe subtype accompanied by vision impairment. Advancements in multimodal ophthalmic imaging have allowed ophthalmologists to reveal subclinical microvascular and structural changes in fundus of patients with SLE without ocular manifestations. Both ocular manifestations and subclinical fundus damage have been shown to correlate with SLE disease activity and, in some patients, even precede other systemic injuries as the first presentation of SLE. Moreover, ocular fundus might serve as a window into the state of systemic vasculitis in patients with SLE. Given the similarities of the anatomy, physiological and pathological processes shared among ocular fundus, and other vital organ damage in SLE, such as kidney and brain, it is assumed that ocular fundus involvement has implications in the diagnosis and evaluation of other systemic impairments. Therefore, evaluating the fundus characteristics of patients with SLE not only contributes to the early diagnosis and intervention of potential vision damage, but also holds considerate significance for the evaluation of SLE vasculitis state and prediction of other systemic injuries.

Incorporation of Lactococcus lactis and Chia Mucilage for Improving the Physical and Biological Properties of Gelatin-Based Coating: Application for Strawberry Preservation.

In this work, a gelatin/chia mucilage (GN/CM) composite coating material doped with Lactococcus lactis (LS) was developed for strawberry preservation applications. The results of the scanning electron microscope and Fourier transform infrared spectroscopy stated that the enhanced molecular interaction between the CM and GN matrix strengthened the density and compactness of the GN film. Antifungal results indicated that the addition of LS significantly (p < 0.05) improved the ability of the GN coating to inhibit the growth of Botrytis cinerea (inhibition percentage = 62.0 ± 4.6%). Adding CM significantly (p < 0.05) decreased the water vapour permeability and oxygen permeability of the GN coating by 32.7 ± 4.0% and 15.76 ± 1.89%, respectively. In addition, the incorporated CM also significantly (p < 0.05) improved the LS viability and elongation at break of the film by 13.11 ± 2.05% and 42.58 ± 1.21%, respectively. The GN/CM/LS composite coating material also exhibited an excellent washability. The results of this study indicated that the developed GN/CM/LS coating could be used as a novel active material for strawberry preservation.

Design, synthesis, and bioactivity evaluation of novel indole-selenide derivatives as P-glycoprotein inhibitors against multi-drug resistance in MCF-7/ADR cell.

The inhibition of P-glycoprotein (P-gp) has emerged as an intriguing strategy for circumventing multidrug resistance (MDR) in anticancer chemotherapy. In this study, we have designed and synthesized 30 indole-selenides as a new class of P-gp inhibitors based on the scaffold hopping strategy. Among them, the preferred compound H27 showed slightly stronger reversal activity (reversal fold: 271.7 vs 261.6) but weaker cytotoxicity (inhibition ratio: 33.7% vs 45.1%) than the third-generation P-gp inhibitor tariquidar on the tested MCF-7/ADR cells. Rh123 accumulation experiments and Western blot analysis demonstrated that H27 displayed excellent MDR reversal activity by dose-dependently inhibiting the efflux function of P-gp rather than its expression. Besides, UIC-2 reactivity shift assay revealed that H27 could bind to P-gp directly and induced a conformation change of P-gp. Moreover, docking study revealed that H27 matched well in the active pockets of P-gp by forming some key H-bonding interactions, arene-H interactions and hydrophobic contacts. These results suggested that H27 is worth to be a starting point for the development of novel Se-containing P-gp inhibitors for clinic use.

The feasibility and safety of biomaterials for posterior scleral reinforcement in rabbits.

To explore the feasibility and safety of biomaterials for posterior scleral reinforcement (PSR) in rabbits. Decellularization and genipin crosslink were applied to the fresh bovine pericardium and porcine endocranium, and then mechanical properties, suture retention strength, and stability were tested. PSR operation was performed on 24 rabbit eyes using treated biological materials. Ophthalmic examination was performed regularly before and after PSR operation (1 week, 1 month, 3 months, 6 months). To evaluate the effectiveness, A ultrasound, diopter, and optical coherence tomography were conducted. General condition, fundus photograph, and pathological examination were recorded to evaluate the safety. Compared with genipin crosslinked bovine pericardium (Gen-BP) (21.29 ± 13.29 Mpa), genipin crosslinked porcine endocranium (Gen-PE) (34.85 ± 3.67 Mpa,P< 0.01) showed a closer elastic modulus to that of genipin crosslinked human sclera. There were no complications or toxic reactions directly related to the materials. Capillary hyperplasia, inflammatory cell infiltration, and collagen fiber deposition were observed, and the content of type I collagen fibers increased after PSR. Overall, the choroidal thickness of treated eyes was significantly thickened at different time points after PSR, which were 96.84 ± 21.08 µm, 96.72 ± 22.00 µm, 90.90 ± 16.57 µm, 97.28 ± 14.74 µm, respectively. The Gen-PE group showed changes that were almost consistent with the overall data. Gen-BP and Gen-PE are safe biological materials for PSR. The Gen-PE group demonstrated more significant advantages over the Gen-BP group in terms of material properties.

Lactobacillus bulgaricus-loaded and chia mucilage-rich gum arabic/pullulan nanofiber film: An effective antibacterial film for the preservation of fresh beef.

In recent years, the development of probiotic film by incorporating probiotics into edible polymers has attracted significant research attention in the field of active packaging. However, the influence of the external environment substantially reduces the vitality of probiotics, limiting their application. Therefore, to improve the probiotic activity, this study devised a novel nanofiber film incorporating chia mucilage protection solution (CPS), gum arabic (GA), pullulan (PUL), and Lactobacillus bulgaricus (LB). SEM images indicated the successful preparation of the nanofiber film incorporating LB. CPS incorporation significantly improved the survival ability of LB, with a live cell count reaching 7.62 log CFU/g after 28 days of storage at 4 °C - an increase of 1 log CFU/g compared to the fiber film without CPS. The results showed that the fiber film containing LB inhibited Escherichia coli and Staphylococcus aureus. Finally, the novel probiotic nanofiber film was applied to beef. The results showed that the shelf life of the beef during the experiments was extended for 2 days at 4 °C. Therefore, the novel probiotic film containing LB was suitable for meat preservation.

Comparison of the adjuvant effect of conbercept intravitreal injection at different times before vitrectomy for proliferative diabetic retinopathy.

Purpose: To assess the optimal time of intravitreal conbercept (IVC) treatment prior to pars plana vitrectomy (PPV) in patients with severe proliferative diabetic retinopathy (PDR). Method: This study was exploratory in nature. Forty-eight consecutive patients (48 eyes) with PDR were divided into four groups according to different IVC times (0.5 mg/0.05 mL) before PPV: group A (3 days), group B (7 days), group C (14 days), and group D (non-IVC). Intraoperative and postoperative effectiveness were assessed, and vitreous VEGF concentrations were detected. Result: For intraoperative effectiveness, groups A and D had a higher incidence of intraoperative bleeding than groups B and C (P = 0.041). Furthermore, groups A-C required less surgical time than group D (P < 0.05). For postoperative effectiveness, group B had a significantly higher proportion of visual acuity that improved or remained unchanged than group D (P = 0.014), and groups A-C had lower proportions of postoperative bleeding than group D. The vitreous VEGF concentration of group B (67.04 ± 47.24 pg/mL) was significantly lower than that of group D (178.29 ± 110.50 pg/mL) (P = 0.005). Conclusion: IVC treatment that was administered 7 days preoperatively was associated with better effectiveness and a lower vitreous VEGF concentration than its administration at other time points.