Discovery of novel aromatase inhibitors using a homogeneous time-resolved fluorescence assay.

AIM: Aromatase is an important target for drugs to treat hormone-dependent diseases, including breast cancer. The aim of this study was to develop a homogeneous time-resolved fluorescence (HTRF) aromatase assay suitable for high-throughput screening (HTS). METHODS: A 384-well aromatase HTRF assay was established, and used to screen about 7000 compounds from a compound library. Anti-proliferation activity of the hit was evaluated using alamarBlue(R) assay in a hormone-dependent breast cancer cell line T47D. Molecular docking was conducted to elucidate the binding mode of the hit using the Discovery Studio program. RESULTS: The Z' value and signal to background (S/B) ratio were 0.74 and 5.4, respectively. Among the 7000 compounds, 4 hits (XHN22, XHN26, XHN27 and triptoquinone A) were found to inhibit aromatase with IC50 values of 1.60±0.07, 2.76±0.24, 0.81±0.08 and 45.8±11.3 µmol /L, respectively. The hits XHN22, XHN26 and XHN27 shared the same chemical scaffold of 4-imidazolyl quinoline. Moreover, the most potent hit XHN27 at 10 and 50 µmol/L inhibited the proliferation of T47D cells by 45.3% and 35.2%, respectively. The docking study revealed that XHN27 docked within the active site of aromatase and might form a hydrogen bond and had a π-cation interaction with amino acid residues of the protein. CONCLUSION: XHN27, an imidazolyl quinoline derivative of flavonoid, is a potent aromatase inhibitor with anti-proliferation activity against breast cancer in vitro. The established assay can be used in HTS for discovering novel aromatase inhibitor.

Calcium Peroxide-Based Hydrogel Patch with Sustainable Oxygenation for Diabetic Wound Healing.

Nonhealing diabetic wounds are predominantly attributed to the inhibition of angiogenesis, re-epithelialization, and extracellular matrix (ECM) synthesis caused by hypoxia. Although oxygen therapy has demonstrated efficacy in promoting healing, its therapeutic impact remains suboptimal due to unsustainable oxygenation. Here, this work proposes an oxygen-releasing hydrogel patch embedded with polyethylene glycol-modified calcium peroxide microparticles, which sustainably releases oxygen for 7 days without requiring any supplementary conditions. The released oxygen effectively promotes cell migration and angiogenesis under hypoxic conditions as validated in vitro. The in vivo tests in diabetic mice models show that the sustainably released oxygen significantly facilitates the synthesis of ECM, induces angiogenesis, and decreases the expression of inflammatory cytokines, achieving a diabetic wound healing rate of 84.2% on day 7, outperforming the existing oxygen-releasing approaches. Moreover, the proposed hydrogel patch is designed with porous, soft, antibacterial, biodegradable, and storage stability for 15 days. The proposed hydrogel patch is expected to be promising in clinics treating diabetic wounds.

A comparison of the performances of an artificial neural network and a regression model for GFR estimation.

BACKGROUND: Accurate estimation of glomerular filtration rate (GFR) is important in clinical practice. Current models derived from regression are limited by the imprecision of GFR estimates. We hypothesized that an artificial neural network (ANN) might improve the precision of GFR estimates. STUDY DESIGN: A study of diagnostic test accuracy. SETTING & PARTICIPANTS: 1,230 patients with chronic kidney disease were enrolled, including the development cohort (n=581), internal validation cohort (n=278), and external validation cohort (n=371). INDEX TESTS: Estimated GFR (eGFR) using a new ANN model and a new regression model using age, sex, and standardized serum creatinine level derived in the development and internal validation cohort, and the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) 2009 creatinine equation. REFERENCE TEST: Measured GFR (mGFR). OTHER MEASUREMENTS: GFR was measured using a diethylenetriaminepentaacetic acid renal dynamic imaging method. Serum creatinine was measured with an enzymatic method traceable to isotope-dilution mass spectrometry. RESULTS: In the external validation cohort, mean mGFR was 49±27 (SD) mL/min/1.73 m2 and biases (median difference between mGFR and eGFR) for the CKD-EPI, new regression, and new ANN models were 0.4, 1.5, and -0.5 mL/min/1.73 m2, respectively (P<0.001 and P=0.02 compared to CKD-EPI and P<0.001 comparing the new regression and ANN models). Precisions (IQRs for the difference) were 22.6, 14.9, and 15.6 mL/min/1.73 m2, respectively (P<0.001 for both compared to CKD-EPI and P<0.001 comparing the new ANN and new regression models). Accuracies (proportions of eGFRs not deviating >30% from mGFR) were 50.9%, 77.4%, and 78.7%, respectively (P<0.001 for both compared to CKD-EPI and P=0.5 comparing the new ANN and new regression models). LIMITATIONS: Different methods for measuring GFR were a source of systematic bias in comparisons of new models to CKD-EPI, and both the derivation and validation cohorts consisted of a group of patients who were referred to the same institution. CONCLUSIONS: An ANN model using 3 variables did not perform better than a new regression model. Whether ANN can improve GFR estimation using more variables requires further investigation.

Estimation of glomerular filtration rate by a radial basis function neural network in patients with type-2 diabetes mellitus.

BACKGROUND: Accurate and precise estimates of glomerular filtration rate (GFR) are essential for clinical assessments, and many methods of estimation are available. We developed a radial basis function (RBF) network and assessed the performance of this method in the estimation of the GFRs of 207 patients with type-2 diabetes and CKD. METHODS: Standard GFR (sGFR) was determined by (99m)Tc-DTPA renal dynamic imaging and GFR was also estimated by the 6-variable MDRD equation and the 4-variable MDRD equation. RESULTS: Bland-Altman analysis indicated that estimates from the RBF network were more precise than those from the other two methods for some groups of patients. However, the median difference of RBF network estimates from sGFR was greater than those from the other two estimates, indicating greater bias. For patients with stage I/II CKD, the median absolute difference of the RBF network estimate from sGFR was significantly lower, and the P50 of the RBF network estimate (n = 56, 87.5%) was significantly higher than that of the MDRD-4 estimate (n = 49, 76.6%) (p < 0.0167), indicating that the RBF network estimate provided greater accuracy for these patients. CONCLUSIONS: In patients with type-2 diabetes mellitus, estimation of GFR by our RBF network provided better precision and accuracy for some groups of patients than the estimation by the traditional MDRD equations. However, the RBF network estimates of GFR tended to have greater bias and higher than those indicated by sGFR determined by (99m)Tc-DTPA renal dynamic imaging.

A Carbon Nanocomposite Material Used in the Physical Modelling of the Overburden Subsidence Process.

Carbon nanomaterial is widely used in structural health monitoring due to the advantage of sensitivity and good mechanical properties. This study presents a novel approach employing carbon nanocomposite materials (CNMs) to characterize deformation and damage evolution in physical modelling. As the primary measurement method, the CNM is used to investigate the deformation characteristics of a 200-400 m thick sandstone bed at a 1 km deep longwall mine. The sandstone unit is identified as an ultra-thick key stratum (UTKS), with its thicknesses varying across different mining panels of the UTKS. The results of CNM monitoring show that the UTKS remains stable even after a consecutive excavation of 900 m in width. This stability impedes the upward propagation of overlying strata failure, leading to minimal surface subsidence. The study demonstrates the huge potential of CNM in the mining area, which can be useful for investigating material damage in physical modelling studies. The findings suggest that the cumulative extraction width in individual mining areas of the mine should be controlled to avoid a sudden collapse of the UTKS, and that special attention should be paid to where the UTKS's thickness changes substantially. The substantial variation in UTKS thickness significantly impacts the pattern of overburden subsidence.

Variation in flavonoid and antioxidant activities of Pyrrosia petiolosa (Christ) Ching from different geographic origins.

Pyrrosia petiolosa (Christ) Ching has both medicinal and health benefits in China. The potential antioxidant activities of P. petiolosa, which are mainly attributed to its flavonoids, have attracted much attention in recent years. The present study aimed to determine the concentration of flavonoid components and evaluate the relative antioxidant activities of P. petiolosa from different geographic origins using a UPLC-MRM-MS-based metabolomics approach. In total, 97 flavonoid components were identified, and their concentrations in the samples from different geographic locations showed significant variation. Thirteen flavonoid components were identified as potential biomarkers for distinguishing between the two major regions, Guizhou (GZ) and Guangxi (GX). The GZ group showed higher total flavonoid content, free radical scavenging activities, and ferric reducing antioxidant power. The well positive correlations were found between the antioxidant capacities and some flavonoid markers. The ecogeographic factors, namely altitude and longitude, play a crucial role in the difference of antioxidant activities and flavonoids concentration. These results indicate that P. petiolosa is rich in flavonoid compounds and is a promising source of natural antioxidants, providing a basis for the quality control of P. petiolosa.

Robust Neural Interfaces with Photopatternable, Bioadhesive, and Highly Conductive Hydrogels for Stable Chronic Neuromodulation.

A robust neural interface with intimate electrical coupling between neural electrodes and neural tissues is critical for stable chronic neuromodulation. The development of bioadhesive hydrogel neural electrodes is a potential approach for tightly fixing the neural electrodes on the epineurium surface to construct a robust neural interface. Herein, we construct a photopatternable, antifouling, conductive (∼6 S cm-1), bioadhesive (interfacial toughness ∼100 J m-2), soft, and elastic (∼290% strain, Young's modulus of 7.25 kPa) hydrogel to establish a robust neural interface for bioelectronics. The UV-sensitive zwitterionic monomer can facilitate the formation of an electrostatic-assembled conductive polymer PEDOT:PSS network, and it can be further photo-cross-linked into elastic polymer network. Such a semi-interpenetrating network endows the hydrogel electrodes with good conductivity. Especially, the photopatternable feature enables the facile microfabrication processes of multifunctional hydrogel (MH) interface with a characteristic size of 50 µm. The MH neural electrodes, which show improved performance of impedance, charge storage capacity, and charge injection capability, can produce effective electrical stimulation with high current density (1 mA cm-2) at ultralow voltages (±25 mV). The MH interface could realize high-efficient electrical communication at the chronic neural interface for stable recording and stimulation of a sciatic nerve in the rat model.

Influence of stress distribution in coal seams of non-uniform extremely thick key stratum and disaster-causing mechanisms.

This paper analyzes the influence of the overlying extremely thick primary key stratum on the strong mine pressure hazard at the large mining face in Gaojiapu coal mine. The analysis of the distribution characteristics of the primary key stratum in the Gaojiapu coal mine reveals the bow-shaped structural characteristics of the overlying thick primary key stratum. An elastodynamic model was developed using the variational method to calculate and analyze the influence of the movement of the primary key stratum on the stress and energy of the underlying weak rock. The results show that the arch structure of the overlying extremely thick primary key stratum can significantly affect the distribution pattern of stress and strain energy in the coal body, and the stress and strain energy in the coal body are transferred to the middle of the coal column, and the middle region of the coal column enters a high stress state. These results suggest that the change in thickness of the overlying primary key stratum at Gaojiapu in the coal column area is a major factor in the frequent occurrence of impact ground pressure events at the mine. This study explains the causes of frequent impact ground pressure in the lower coal rock mass of the extremely thick primary key stratum, and provides a reference for the prevention and control of impact hazards in the extremely thick primary key stratum.

Magnetic soft robotic bladder for assisted urination.

The poor contractility of the detrusor muscle in underactive bladders (UABs) fails to increase the pressure inside the UAB, leading to strenuous and incomplete urination. However, existing therapeutic strategies by modulating/repairing detrusor muscles, e.g., neurostimulation and regenerative medicine, still have low efficacy and/or adverse effects. Here, we present an implantable magnetic soft robotic bladder (MRB) that can directly apply mechanical compression to the UAB to assist urination. Composed of a biocompatible elastomer composite with optimized magnetic domains, the MRB enables on-demand contraction of the UAB when actuated by magnetic fields. A representative MRB for a UAB in a porcine model is demonstrated, and MRB-assisted urination is validated by in situ computed tomography imaging after 14-day implantation. The urodynamic tests show a series of successful urination with a high pressure increase and fast urine flow. Our work paves the way for developing MRB to assist urination for humans with UABs.

Colonization of a medical center in Southern Taiwan by epidemic strains of carbapenem- and multidrug-resistant Acinetobacter baumannii and the genetic organization of their integrons.

A total of 46 carbapenem- and multidrug-resistant (CR- and MDR-)Acinetobacter baumannii bacteremic isolates from a Taiwanese medical center were investigated over the period 2000 to 2006 using randomly amplified polymorphic DNA (RAPD) profiling and by analysing the genetic organization of their integrons. The results of RAPD patterns revealed that before 2003 each CR- and MDR-A. baumannii bacteremic isolate was independent, but after 2003 the isolates appeared to belong in four epidemic strains and persisted in the hospital. All the CR- and MDR-A. baumannii strains harbored class I integron (intI1) genes. PCR amplification and nucleotide sequencing showed that the cassette genes of intI1 were found to form four different antibiotic-resistant gene alignments in those strains. The bla(IMP-1) gene in the cassette genes of intI1 was identified in a clone, which raised great concern that clonal spread of this strain or of an integron-mediated horizontal gene may have occurred.