Structural Identification of Impurities in Pioglitazone Hydrochloride Preparations by 2D-UHPLC-Q-Exactive Orbitrap HRMS and Their Toxicity Prediction.

Pharmaceutical companies and regulatory agencies have more and more concerns for impurities in pharmaceuticals and their toxicity. In this work, heart-cutting two-dimensional ultrahigh-performance liquid chromatography (2D-UHPLC) in combination with high-resolution mass spectrometry (HRMS) was used, setting HRMS as positive mode of electrospray ionization to identify five impurities in pioglitazone hydrochloride preparations. With the heart-cutting 2D-UHPLC and online desalting technique, the structures of five impurities were deduced in an analysis of MSn data. And three of them, Impurity-2, Impurity-3, and Impurity-5, have never been reported before. The fragmentation patterns of five impurities were proposed on a basis of accurate mass and fragment ions in this study. Since the toxicity of impurities is relevant to their structures, toxicology of all five impurities was predicted by three software tools, and the result showed that these compounds have good safety profile.

Real-Time Online Goal Recognition in Continuous Domains via Deep Reinforcement Learning.

The problem of goal recognition involves inferring the high-level task goals of an agent based on observations of its behavior in an environment. Current methods for achieving this task rely on offline comparison inference of observed behavior in discrete environments, which presents several challenges. First, accurately modeling the behavior of the observed agent requires significant computational resources. Second, continuous simulation environments cannot be accurately recognized using existing methods. Finally, real-time computing power is required to infer the likelihood of each potential goal. In this paper, we propose an advanced and efficient real-time online goal recognition algorithm based on deep reinforcement learning in continuous domains. By leveraging the offline modeling of the observed agent's behavior with deep reinforcement learning, our algorithm achieves real-time goal recognition. We evaluate the algorithm's online goal recognition accuracy and stability in continuous simulation environments under communication constraints.

Assessing children's potential exposures to harmful metals in tire crumb rubber by accelerated photodegradation weathering.

Whether a tire crumb rubber (TCR) playground would expose children to potentially harmful chemicals such as heavy metals is an open question. The released metals available for pickup on the surface of TCR tiles was studied by accelerated 2-year aging of the TCRs in the NIST-SPHERE (National Institute of Standards and Technology Simulated Photodegradation via High Energy Radiant Exposure). The dermal contact was mimicked by a method of composite surface wiping from US Environmental Protection Agency throughout the weathering process. The surface release of ten most concerned harmful metals (Be, Cr, Cu, As, Se, Cd, Sb, Ba, Tl, Pb) was monitored through the course of aging. The cumulative release of Cu, As, Tl, and Sb reached potentially harmful levels at various times within 3 years, although only Cr was found at a harmful level on the surface of the tiles. Taking the cleansing effect of precipitation or periodic cleansing with rain into account, TCR playgrounds may still be safe for use.

Immunization with Tp0954, an adhesin of Treponema pallidum, provides protective efficacy in the rabbit model of experimental syphilis.

Syphilis, a chronic multisystemic disease caused by spirochete Treponema pallidum subspecies pallidum infection, continues to be a serious global health problem and congenital syphilis remains a major cause of adverse outcomes in pregnancy in developing countries. The development of an effective vaccine is the most cost-effective way to eliminate syphilis, but so far has been elusive. Here, we evaluated the immunogenicity and protective efficacy of Tp0954, a T. pallidum placental adhesin, as a potential vaccine candidate in a New Zealand White rabbit model of experimental syphilis. Animals immunized with recombinant Tp0954 (rTp0954) produced high titers of Tp0954-specific serum IgG, high levels of IFN-γ from splenocytes and specific splenocyte proliferation response when compared to control animals immunized with PBS and Freund's adjuvant (FA). Furthermore, rTp0954 immunization significantly delayed the development of cutaneous lesions, promoted inflammatory cellular infiltration at the primary lesion sites, as well as inhibited T. pallidum dissemination to distal tissues or organs when compared with that of the control animals. In addition, the naïve rabbits receiving popliteal lymph nodes from Tp0954-immunized, T. pallidum-challenged animals were not infected by T. pallidum, confirming sterile immunity. These findings suggest that Tp0954 is a potential vaccine candidate against syphilis.

The hydrogen bond between tryptophan and the host molecule induced fluorescence enhancement.

Tryptophan is one of important amino acids in the human body, therefore its detection is particularly important. The 3,5-bis(4-pyridyl)-4-amino-1,2,4-triazole (BPAT) organic molecule was designed to be used as fluorescence detectors to detect tryptophan molecules for the interaction between the host and the guest. BPAT shows good sensitivity and selectivity towards tryptophan compared with other amino acid molecules. The limit of detection obtained from formula 3δ/KSV is considered to be 5.43 × 10-7  mol/L. We speculated that this change is mainly caused by the hydrogen bond between tryptophan and the host molecule BPAT. This conjecture was verified by the controlled experiments with other host molecules.

Establishment and validation of a risk prediction model for high-grade cervical lesions.

OBJECTIVE: To establish and validate a risk prediction model for cervical high-grade squamous intraepithelial lesions (HSIL). METHODS: This retrospective study included patients who underwent cervical biopsies at the Cervical Disease Centre of Maternal and Child Hospital of Hubei Province between January 2021 and December 2021. RESULTS: A total of 1630 patients were divided into the HSIL + cervical lesion group (n = 186) and the ≤ LSIL cervical lesions group (n = 1444). LSIL, ASC-H, HSIL and SCC, high-risk HPV, HPV16, HPV18/45, multiple HPV strains, acetowhite epithelium, atypical vessels, and mosaicity were independently associated with HSIL + lesions. These factors were used to establish a risk prediction model with a demonstrated area under the curve (AUC) of 0.851 and a C-index of 0.829. Calibration curve analysis showed that the model performed well, with a mean absolute error (MAE) of 0.005. The decision curve showed that the model created by combining the risk factors was more specific and sensitive than each predictive variable. CONCLUSION: The model for predicting HSIL demonstrated promising predictive capability and might help identify patients requiring biopsy and treatment.

Quality evaluation of endometriosis guidelines using AGREE II.

BACKGROUND: To systematically evaluate the guidelines for endometriosis published in the past decade, and to provide reference for the selection of guidelines for endometriosis through quality evaluation and comparison. METHODS: PubMed database, Embase database, evidence-based medicine clinical practice guidelines (CPG) database and the National Institute for Health and Clinical Excellence in the United Kingdom were searched by computer from December 2012 to December 2020 to retrieve published endometriosis CPG published by professional institutions or organizations. The search languages are English and Portuguese. Two researchers evaluated the quality of included CPG according to appraisal of guidelines for research and evaluation (AGREE II). The evaluation includes 6 areas: scope and purpose, participants, rigor of formulation, clarity of expression, applicability and independence. The recommendation level of CPG is determined by the distribution of standardized scores in the above 6 areas. RESULTS: A total of 8 articles on endometriosis CPG were included, including 5 guidelines and 3 consensuses, covering 5 countries in 2 continents; the publication year was 2013 to 2020. The average standardized scores of the scope and purpose, participants, rigor, clarity, applicability and independence of CPG were 77.1%, 52.8%, 50.5%, 86.8%, 31.3%, and 36.5%, respectively. Among the 8 CPGs, 1 was grade A (recommended), 5 were grade B (recommended after improvement), and 2 were grade C (not recommended). Seven CPG recommendations were based on expert consensus, and one was developed through detailed literature retrieval, analysis and evidence rating evaluation. There was little difference between the guidelines in terms of treatment-related recommendations. CONCLUSIONS: The quality of endometriosis CPG released in 2013 to 2020 is quite different, and some CPGs are not ideal in terms of rigor, applicability and independence. The guidelines issued by NICE in 2017 are A-grade recommendations. The standardized scores in various fields are high, and the formation process of CPG is the most standardized, which is worth learning and reference.

Super-Hydrophobic Magnetic Fly Ash Coated Polydimethylsiloxane (MFA@PDMS) Sponge as an Absorbent for Rapid and Efficient Oil/Water Separation.

In this study, magnetic fly ash was prepared with fly ash and nano-magnetic Fe3O4, obtained by co-precipitation. Then, a magnetic fly ash/polydimethylsiloxane (MFA@PDMS) sponge was prepared via simple dip-coating PDMS containing ethanol in magnetic fly ash aqueous suspension and solidifying, whereby Fe3O4 played a vital role in achieving the uniformity of the FA particle coating on the skeletons of the sponge. The presence of the PDMS matrix made the sponge super-hydrophobic with significant lubricating oil absorption capacity; notably, it took only 10 min for the material to adsorb six times its own weight of n-hexane (oil phase). Moreover, the MFA@PDMS sponge demonstrated outstanding recyclability and stability, since no decline in absorption efficiency was observed after more than eight cycles. Furthermore, the stress-strain curves of 20 compression cycles presented good overlap, i.e., the maximum stress was basically unchanged, and the sponge was restored to its original shape, indicating that it had good mechanical properties, elasticity, and fatigue resistance.

Assessment of recombinant antigens Tp0100 and Tp1016 of Treponema pallidum for serological diagnosis of syphilis.

OBJECTIVE: To discover novel serodiagnostic candidates for the serological diagnosis of syphilis. METHODS: Two recombinant Treponema pallidum proteins Tp0100 and Tp1016 were expressed, purified, and identified by Western Blotting. A total of 600 clinical serum samples were tested with the Tp0100-based ELISA, the Tp1016-based ELISA, and the commercial LICA Syphilis TP kit (ChIVD, Beijing, China). The sensitivities were determined by testing 340 samples from individuals with clinically diagnosed primary, secondary, latent, and tertiary syphilis. The specificities were determined by screening 260 samples from healthy controls and individuals with potentially cross-reactive infections, including leptospirosis, Lyme disease, hepatitis B, tuberculosis, rheumatoid arthritis, systemic lupus erythematosus. Kappa (κ) values were applied to compare the agreement between clinical syphilis diagnosis and the Tp0100-based ELISA, the Tp1016-based ELISA, or the LICA Syphilis TP test. RESULTS: Using clinical syphilis diagnosis as the gold standard, Tp0100 exhibited an overall sensitivity of 95.6% and specificity of 98.1% for testing IgG antibody while Tp1016 demonstrated only an overall sensitivity of 75.0% and specificity of 79.6%. In contrast, the LICA Syphilis TP test revealed an overall sensitivity of 97.6% and specificity of 96.2%. In addition, the overall percent agreement and corresponding κ values were 96.7% (95% CI 95.6%-97.8%) and 0.93 for the Tp0100-based ELISA, 77.0% (95% CI 74.3%-79.7%) and 0.54 for the Tp1016-based ELISA, and 97.0% (95% CI 96.0%-98.0%) and 0.94 for the LICA Syphilis TP test, respectively. CONCLUSION: The recombinant T. pallidum protein Tp0100 shows promise as a novel diagnostic antigen in the serological tests for syphilis.

Treponema pallidum delays the apoptosis of human polymorphonuclear neutrophils through the intrinsic and extrinsic pathways.

Treponema pallidum is a "stealth pathogen" responsible for infectious sexually transmitted diseases. Although neutrophils are usually present in skin lesions of early syphilis, the role of these cells in T. pallidum infection has barely been investigated. Neutrophils are short-lived cells that undergo constitutive apoptosis, and phagocytosis usually accelerates this process. Here, we demonstrated that human polymorphonuclear neutrophils (hPMNs) could phagocytose T. pallidum in vitro. An unexpected discovery was that T. pallidum inhibited hPMNs apoptosis markedly in an opsonin-independent manner. Furthermore, this phenomenon was not affected by bacterial viability, as detected by annexin V, morphology studies, and TUNEL staining. Exploration of the underlying mechanism showed that expression of the cleaved forms of caspase-3, -8, and -9 and effector caspase activity were diminished significantly in T. pallidum-infected hPMNs. T. pallidum also impaired staurosporine- and anti-Fas-induced signaling for neutrophil apoptosis. Of note, these effects were accompanied by inducing the autocrine production of the anti-apoptotic cytokine IL-8. Taken together, our data revealed that T. pallidum could inhibit the apoptosis of hPMNs through intrinsic and extrinsic pathways and provide new insights for understanding the pathogenicity mechanisms of T. pallidum.

Preparation of a novel composite geopolymer based on calcium carbide slag-fly ash and its characterization, mechanism and adsorption properties.

In this study, a mixed precursor system of fly ash (50 wt%) and calcium carbide slag (50 wt%) was used to prepare a geopolymer, and the hydration and hardening mechanism of the whole system and the microscopic characterization of the calcium carbide-fly ash based polymer were investigated after the addition of calcium carbide slag. Ca(OH)2 in calcium carbide slag can effectively excite the volcanic ash activity of fly ash, which leads to a more adequate geopolymerization reaction and produces more hydrated calcium silicate (C-S-H) gels. These gels have very high specific surface area and surface adsorption energy. The results showed that the specific surface area of geopolymer was as high as 79.76 m2/g, and through the study of its adsorption capacity of Cu(II) in aqueous solution, the results showed that its removal efficiency of Cu(II) was 97.63% and its adsorption capacity was 58.58 mg/g. By using fly ash and calcium carbide slag as the auxiliary raw materials for the preparation of geopolymer, it not only can promote the reaction of proceeding, but can also act as an excellent adsorption material, and also as an effective way to utilize industrial waste resources.

Preparation of Honeycomb-Structured Activated Carbon-Zeolite Composites from Modified Fly Ash and the Adsorptive Removal of Pb(II).

In this paper, fly ash (FA) was successfully prepared into a honeycomb carbon-zeolite composite (CZC) with good adsorption and used for the removal of Pb(II) by a two-step method. Compared with general FA, the honeycomb structure of the CZC resulted in a ∼6× increase in the specific surface area, and the average pore size increased from 3.4 to 12.7 µm. The maximum adsorption capacity of CZCs for Pb(II) reached 185.68 mg/g in 40 min. The experimental data for the adsorption of Pb(II) by CZC showed that the results were in good agreement with the Langmuir adsorption model. The adsorbent prepared in this study has good application prospects in wastewater treatment and provides a new method for the resource recovery of FA.

Long non-coding RNA PRNCR1 promotes ovarian cancer cell proliferation, migration and invasion by targeting the miR-653-5p/ELF2 axis.

Recent studies have shown that prostate cancer-associated long non-coding RNA, PRNCR1, plays crucial roles in the development of multiple human cancers. However, its role in ovarian cancer is barely known. This study was carried out to investigate the role of PRNCR1 and the underlying mechanisms in OC. The expression of PRNCR1 and miR-653-5p in OC cell lines and tissues were detected by qRT-PCR. The expression of ELF2 protein was evaluated by Western blot analysis. Cell proliferation was measured by colony formation and MTT assay. Cell invasion and migration were evaluated by Transwell and wound healing assay. Luciferase reporter assay and RNA-binding protein immunoprecipitation assay were performed to determine the interaction between miR-653-5p and PRNCR1, as well as between miR-653-5p and ELF2. In vivo tumor xenograft model was established to evaluate the role of PRNCR1 in tumor growth. Our results demonstrated that PRNCR1 was significantly upregulated in both OC cell lines and tissues, and high expression of PRNCR1 was correlated with poor survival of OC patients. Overexpression of PRNCR1 accelerated OC cell invasion, migration and proliferation. Besides, the expression of PRNCR1 was negatively correlated with the expression of miR-653-5p, while positively correlated with the expression of E74-like factor 2 in OC tissues. Importantly, ELF2 could target miR-653-5p, and PRNCR1 increased the expression levels of ELF2 by sponging miR-653-5p in OC cells. Furthermore, the miR-145-5p/ELF2 axis was involved in the regulation of PRNCR1 in OC progression in vivo. PRNCR1 promotes OC tumor progress via the miR-653-5p/ELF2 axis and might be a potential therapeutic target for OC.

Diagnostic value of transvaginal three-dimensional ultrasound combined with color Doppler ultrasound for early cesarean scar pregnancy.

BACKGROUND: Our study sought to obtain data which assess the diagnostic value of transvaginal three-dimensional ultrasound (3D-US) combined with color Doppler ultrasound (US) for early cesarean scar pregnancy (CSP). METHODS: All participants were randomly divided into a Control group diagnosed using 3D-US and a Combination group diagnosed using 3D-US combined with color Doppler US. The preoperative US results were compared with postoperative pathological results. The diagnostic coincidence rate, sensitivity, and specificity of these two examination methods were compared, and their diagnostic results for different types of CSP were analyzed. Finally, the diagnostic effects of both methods were compared and analyzed, and the imaging of CSP was summarized. RESULTS: The diagnostic accuracy of transvaginal 3D-US combined with color Doppler US (92.96%) was significantly higher than that of transvaginal 3D-US (71.83%). For different types of CSP, the diagnostic rate of CSP with mixed echogenic mass and partial implantation of gestational sac in the Combination group was markedly higher than that in the Control group. CONCLUSIONS: Additionally, the sensitivity, specificity, and area under the receiver operating characteristic (ROC) curve (AUC) in the Combination group were higher than those in the Control group. Transvaginal 3D-US combined with color Doppler US can improve the sensitivity, specificity, and accuracy of diagnosis of early CSP, and has important reference value for clinical condition evaluation and treatment options.

Formation chitosan-based hydrogel film containing silicon for hops ß-acids release as potential food packaging material.

Hydrogel film composed of chitosan (CS) as raw material was prepared by free radical polymerization. Silicon was introduced into the hydrogel film in different ways (covalent/non-covalent) to improve the physical properties of the film, and ß-acids were loaded to enhance the antibacterial activity of the film. Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and X-ray diffraction (XRD) analysis were used to characterize the structure of films. The mechanical results indicated that when nano-silica (0.3%) was introduced into film (containing 0.2% ß-acids) by non-covalently bond, the tensile strength increased to 8.59 MPa. Meanwhile silicon (0.3%) entered the film by covalent bonding, the tensile strength increased to 7.99 MPa. The films loaded with ß-acids had well ability to blocks ultraviolet rays and exhibited inhibitory effect on E. coli and S. aureus. In the PBS (37 °C, pH = 7.4) simulant solution, the release mechanism of most films to release the ß-acids followed non-Fick diffusion (n > 0.5). It could be concluded that the prepared hydrogel films loading with ß-acids had broad application prospects in food packaging material with antibacterial property and controlled release.

Origin of the Drastic Current Decay during Potentiostatic Alkaline Methanol Oxidation.

The current production from the alkaline methanol electro-oxidation reaction does not reach a steady state on a smooth platinum catalyst under potentiostatic conditions. We investigated two possible explanations for this phenomenon: changes on the catalyst surface and changes in the solution near the electrode. In situ Fourier transform infrared spectroscopy experiments were conducted to evaluate the adsorbed species on the catalyst surface and a simulation model was set up to describe the changes of concentrations inside the solution. Linear- and bridge-bonded carbon monoxide are the only organic compounds which can be detected by in situ spectroscopy at fixed potentials, but their amount does not increase over time. The simulation shows that the consumption of hydroxide ions and production of carbonaceous species during alkaline oxidation causes a local pH shift near the catalyst surface. Assuming a one-electron transfer as the limiting step, this pH shift was found to contribute to the observed current loss at a potential of 0.77 V.

DFT-Calculated IR Spectrum Amide I, II, and III Band Contributions of N-Methylacetamide Fine Components.

The infrared spectrum (IR) characteristic peaks of amide I, amide II, and amide III bands are marked as amide or peptide characteristic peaks. Through the nuclear magnetic resonance study, N-methylacetamide has been determined to have six fine components, which include protonation, hydration, and hydroxy structures. Then the independent IR spectrum of every component in N-methylacetamide is calculated by using the density functional theory quantum chemistry method, and the contribution of each component to amide I, II, and III bands is analyzed. The results of this research can help to explain the formation of the amide infrared spectrum, which has positive significance in organic chemistry, analytical chemistry, and chemical biology.

Management of venous perforation during central venous catheterization in hemodialysis patients: Three case reports.

RATIONALE: In recent years, central venous catheterization (CVC) has become widely used for hemodialysis patients. Based on 3 cases, we discussed the detection and management of venous perforation at an early stage. PATIENTS CONCERNS: Patients 1 (male, 77 years), 2 (male, 82 years), and 3 (male, 30 years) were diagnosed with uremia and underwent hemodialysis. DIAGNOSES: Computed tomography suggested pneumomediastinum in patient 1 and pneumothorax in patient 2 after a replacement of the temporary hemodialysis catheter. In patient 3, X-ray suggested that the tip of the catheter was approximately at the plane of the fifth thoracic vertebrate after the temporary catheter was placed. INTERVENTIONS: In patients 1 and 2, the catheters were maintained where they were for about 2 weeks until a false lumen formed outside the catheter. In patient 3, the catheter was withdrawn at once when vein perforation was observed. OUTCOME: In patients 1 and 2, the catheters were adjusted successfully under digital subtraction angiography (DSA) guidance 2 weeks later. In patient 3, hemothorax developed, and a total of approximately 1000 mL of bloody fluid was drained. LESSONS: When venous perforation occurs during CVC, it is safer and more reliable to adjust or withdraw the catheter under DSA guidance after a false lumen forms outside the catheter.

Effect of surface-bound sulfide on oxygen reduction reaction on Pt: Breaking the scaling relationship and mechanistic insights.

A combined in situ electrochemical attenuated total reflection-surface enhanced IR absorption spectroscopy, microkinetic simulation, and density functional theory calculation study shows that not only can the adsorbed sulfide disproportionally affect the surface binding of OOH* (EOOH* ) vs OH* (EOH* ), i.e., breaking the original scaling relationship of pure metals (Ir, Pd, Pt, Au), to enhance oxygen reduction reaction (ORR) activity but can also be used as a reaction pathway alternating species to help deepen our mechanistic understanding of ORR.

Pathological significance of urinary complement activation in diabetic nephropathy: A full view from the development of the disease.

AIMS/INTRODUCTION: The aim of the present study was to obtain a full view of the changes of urinary complement activation products in the development of diabetic nephropathy and explore their possible significance in the disease process. MATERIALS AND METHODS: A total of 62 patients at different stages of diabetic nephropathy, 20 diabetes patients without nephropathy and 20 healthy persons were enrolled. Urinary complement activation products, including C3a, C5a and C5b-9, were measured, and their associations with the progression of the disease were analyzed. RESULTS: The urinary complement activation products increased markedly since the proteinuria stage, and were parallel with the progression of diabetic nephropathy. More severe renal tubular damage was observed in patients with higher levels of urinary complement activation products. The urinary complement activation products levels correlated closely with renal tubulointerstitial injury score and relative tubular interstitial volume. Multivariate regression analysis showed that elevated urinary complement activation products were independent risk factors for tubular injury in diabetic nephropathy patients. CONCLUSIONS: Urinary complement activation might have a role in renal tubular interstitial injury in patients with diabetic nephropathy, especially in patients at a later stage of the disease.