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In this study, a novel strategy based on acetone stable-isotope derivatization coupled with HPLC-MS for profiling and accurate quantification of aminophospholipids (phosphatidylethanolamine and phosphatidylserine) in biological samples was developed. Acetone derivatization leads to alkylation of the primary amino groups of aminophospholipids with an isopropyl moiety; the use of deuterium-labeled acetone (d6-acetone) introduced a 6 Da mass shift that was ideally suited for profiling and quantification analysis with high selectivity and accuracy. After derivatization, significantly increased column efficiency for chromatographic separation and detection sensitivity for MS analysis of aminophospholipids was observed. Furthermore, an accuracy quantification method was developed. Aminophospholipids in biological samples were derivatized with d0-acetone; while more than two aminophospholipid standards were selected for each class of aminophospholipid and derivatized with d6-acetone, which were then used as the internal standards to typically construct a calibration curve for each class to normalize the nonuniformity response caused by the differential fragmentation kinetics resulting from the distinct chemical constitution of individual aminophospholipid species in the biological samples. The excellent applicability of the developed method was validated by profiling and quantification of aminophospholipids presented in liver samples from rats fed with different diets.

Abstract Background Drugs that inhibit the MEK/ERK pathway have therapeutic benefit in bladder cancer treatment but responses vary with patients, for reasons that are still not very clear. Interferon-α (IFN-α) is also used as a therapeutic agent for bladder cancer treatment but the response rate is low. It was found that IFN-α could enhance the cytotoxic effect of MEK inhibition. However, the potential mechanisms of that are still unclear. Understanding of the cross-talk between the IFN-α and MEK/ERK pathway will help enhance the efficacy of IFN-α or MEK inhibitors on bladder cancer. Methods Immunoprecipitation and pull-down assay were used to reveal the formation of signaling complex. The protein expressions were detected by western blot and immunohistochemistry. The cAMP level, Phosphodiesterase 4D (PDE4D) activity and Prostaglandin E2 (PGE2) concentration in cells, serum and tissues were detected by enzyme-linked immunosorbent assay. The role of PDE4D in bladder tumorigenesis in vivo was examined by the xenograft model. Tissue microarray chips were used to investigate the prognostic roles of PDE4D and tumor progression locus 2 (TPL2) in bladder cancer patients. Results IFN-α down-regulated the cyclooxygenase-2 (COX-2) expression in bladder cancer cells through the inhibition of TPL2/NF-κB pathway; IFN-α also inhibited COX-2 expression by suppressing cAMP signaling through TPL2-ERK mediated PDE4D activity. Reduction of the intracellular cAMP level by PDE4D potentiated the antitumor effect of IFN-α against bladder cancer in vitro and in vivo. Further analysis of clinical samples indicated that low PDE4D expression and high level of TPL2 phosphorylation were correlated to the development and poor prognosis in bladder cancer patients. Conclusions Our data reveal that IFN-α can exert its antitumor effect through a non-canonical JAK-STAT pathway in the bladder cancer cells with low activity of IFN pathway, and the TPL2 inhibition is another function of IFN-α in the context of bladder cancer therapy. The antitumor effects of IFN-α and MEK inhibition also depend on the PDE4D-mediated cAMP level in bladder cancer cells. Suppression of the TPL2 phosphorylation and intracellular cAMP level may be possible therapeutic strategies for enhancing the effectiveness of IFN-α and MEK inhibitors in bladder cancer treatment.

This study aimed to develop an automated computer-based algorithm to estimate axial length and subfoveal choroidal thickness (SFCT) based on color fundus photographs. In the population-based Beijing Eye Study 2011, we took fundus photographs and measured SFCT by optical coherence tomography (OCT) and axial length by optical low-coherence reflectometry. Using 6394 color fundus images taken from 3468 participants, we trained and evaluated a deep-learning-based algorithm for estimation of axial length and SFCT. The algorithm had a mean absolute error (MAE) for estimating axial length and SFCT of 0.56 mm [95% confidence interval (CI): 0.53,0.61] and 49.20 μm (95% CI: 45.83,52.54), respectively. Estimated values and measured data showed coefficients of determination of r2 = 0.59 (95% CI: 0.50,0.65) for axial length and r2 = 0.62 (95% CI: 0.57,0.67) for SFCT. Bland–Altman plots revealed a mean difference in axial length and SFCT of −0.16 mm (95% CI: −1.60,1.27 mm) and of −4.40 μm (95% CI, −131.8,122.9 μm), respectively. For the estimation of axial length, heat map analysis showed that signals predominantly from overall of the macular region, the foveal region, and the extrafoveal region were used in the eyes with an axial length of < 22 mm, 22–26 mm, and > 26 mm, respectively. For the estimation of SFCT, the convolutional neural network (CNN) used mostly the central part of the macular region, the fovea or perifovea, independently of the SFCT. Our study shows that deep-learning-based algorithms may be helpful in estimating axial length and SFCT based on conventional color fundus images. They may be a further step in the semiautomatic assessment of the eye.

Mechanical stimulation induces bone growth and remodeling by the secondary messenger, cyclic guanosine 3’, 5’-monophosphate (cGMP), in osteoblasts. However, the role of cGMP in the regulation of estrogen biosynthesis, whose deficiency is a major cause of osteoporosis, remains unclear. Here, we found that the prenylated flavonoids, 3-O-methoxymethyl-7-O-benzylicaritin (13), 7-O-benzylicaritin (14), and 4'-O-methyl-8-isopentylkaempferol (15), which were synthesized using icariin analogs, promoted estrogen biosynthesis in osteoblastic UMR106 cells, with calculated EC50 values of 1.53, 3.45, and 10.57 µM, respectively. 14 and 15 increased the expression level of the bone specific promoter I.4-driven aromatase, the only enzyme that catalyzes estrogen formation by using androgens as substrates, in osteoblastic cells. 14 inhibited phosphodiesterase 5 (PDE5), stimulated intracellular cGMP level and promoted osteoblast cell differentiation. Inhibition of cGMP dependent-protein kinase G (PKG) abolished the stimulatory effect of 14 on estrogen biosynthesis and osteoblast cell differentiation. Further, PKG activation by 14 stimulated the activity of SHP2 (Src homology 2 domain-containing tyrosine phosphatase 2), thereby activating Src and ERK (extracellular signal-regulated kinase) signaling and increasing ERK-dependent aromatase expression in osteoblasts. Our findings reveal a previously unknown role of cGMP in the regulation of estrogen biosynthesis in the bone. These results support the further development of 14 as a PKG-activating drug to mimic the anabolic effects of mechanical stimulation of bone in the treatment of osteoporosis.

The key to fault diagnosis of rotating machinery is to extract fault features effectively and select the appropriate classification algorithm. As a common signal decomposition method, the effect of wavelet packet decomposition (WPD) largely depends on the applicability of the wavelet basis function (WBF). In this paper, a novel fault diagnosis approach for rotating machinery based on feature importance ranking and selection is proposed. Firstly, a two-step principle is proposed to select the most suitable WBF for the vibration signal, based on which an optimized WPD (OWPD) method is proposed to decompose the vibration signal and extract the fault information in the frequency domain. Secondly, FE is utilized to extract fault features of the decomposed subsignals of OWPD. Thirdly, the categorical boosting (CatBoost) algorithm is introduced to rank the fault features by a certain strategy, and the optimal feature set is further utilized to identify and diagnose the fault types. A hybrid dataset of bearing and rotor faults and an actual dataset of the one-stage reduction gearbox are utilized for experimental verification. Experimental results indicate that the proposed approach can achieve higher fault diagnosis accuracy using fewer features under complex working conditions.

Objective Perioperative shivering (POS) is a common complication in patients undergoing spinal anaesthesia. The present study investigated the efficacy of 5-HT3 receptor antagonists in preventing POS following spinal anaesthesia.Design Systematic review and meta-analysis.Data sources Pubmed, Embase, the Web of Science and Cochrane Library were searched from database establishment on 31 July 2019.Eligibility criteria Randomised controlled trials that reported the effects of 5-HT3 receptor antagonists in the prevention of POS in patients after spinal anaesthesia.Data extraction and synthesis Two reviewers independently extracted data. The primary outcome of the present study was the incidence of POS. The risk of bias for the included studies was assessed according to the Cochrane Handbook. The quality of primary outcome was evaluated by Grading of Recommendations Assessment, Development and Evaluation. Trial sequential analysis for the primary outcome was performed to reduce the type 1 error caused by repeated meta-analysis and the required information size was calculated.Results A total of 13 randomised controlled trials consisting of 1139 patients were included. The overall incidence of POS was significantly lower in the 5-HT3 receptor antagonists group (risk ratio 0.31; 95% CI 0.26 to 0.38; p

Objective Previous studies reported the effect of dexmedetomidine on intrathecal anesthesia. In this review, we explored the impact of dexmedetomidine as an adjunct for lumbar anesthesia in patients undergoing cesarean section. Methods Two authors searched eligible random controlled trials in electronic databases, including PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, the Chinese BioMedical database, Chinese Scientific Journal Database, and the Wanfang database. Results Ten trials comprising 970 patients were included in this review. Intrathecal dexmedetomidine significantly reduced the onset time of sensory block (standardized mean difference (SMD), −1.50, 95% confidence interval (CI) −2.15, −0.85, I 2 = 92%) and motor block (SMD −0.77, 95% CI −1.50, −0.49, I 2 = 60%) and prolonged the block duration time (sensory block: SMD 2.02, 95% CI 1.29, 2.74, I 2 = 93%; motor block: SMD 1.90, 95% CI 1.07, 2.74, I 2 = 94%). Patients who received dexmedetomidine showed a lower incidence of shivering. No significant difference was reported for the neonatal Apgar score and other complications. Conclusion The use of intrathecal dexmedetomidine during cesarean section can shorten the onset time of spinal anesthesia and enhance the effect of local anesthetic. It has no significant impact on neonates and there were no other adverse events.

Objective Postoperative delirium (POD) is a perennial and distressing complication in older patients, and it may be caused by various factors. This study aimed to determine whether serum melatonin levels are associated with POD in older patients who undergo major abdominal surgery. Methods We collected serum samples from patients undergoing major abdominal surgery. Melatonin was measured by enzyme-linked immunosorbent assay and delirium was assessed by the Confusion Assessment Method after surgery. We classified the patients into the POD group and non-POD group. Results A total of 120 patients met the inclusion criteria and 104 patients were included in the analysis. Postoperative serum melatonin levels were significantly lower than preoperative levels. Multivariate analyses showed that a longer duration of anesthesia (odds ratio [OR] = 1.29, 95% confidence interval [CI] = 1.02–1.64), advanced age (OR = 3.36, 95% CI = 1.37–8.22), and lower postoperative levels of melatonin (OR = 0.50, 95% CI = 0.25–1.00) were associated with POD. Conclusions Serum melatonin levels significantly decline after surgery and anesthesia. Significantly decreased serum melatonin concentrations postoperatively may be a biomarker for predicting POD in older patients undergoing major abdominal surgery with general anesthesia.

Abstract Background To investigate the unique features of inflammatory bowel disease (IBD) in children, we wanted to identify whether there might be a strong correlation between the disease phenotype and its prognosis at various ages in paediatric patients. Methods We collected data from patients diagnosed with IBD (ulcerative colitis (UC) or Crohn’s disease (CD)) from 2002 to 2016. The diagnosis was made according to the Porto criteria and Paris Classification. Patient characteristics, clinical manifestations and treatments were collected. Risk factors for surgery, mortality and relapse were analysed by Cox proportional hazard models. Results Of the 143 patients, 113 had CD, and 30 had UC; there were 89 males and 54 females with a median age of 9 years (y). Thirteen patients in the 0–2 y group were identified as having mutations in IL-10 receptor A, and this mutation was significantly more common in this age group than in 3–9 and 10–16 y patients. The risk factor for surgery was the B3 phenotype; risk factors for death were age 0–2 y and B3 phenotype; 0–2 y, B3 phenotype and steroid dependency were risk factors for early relapse. Conclusions Clinical manifestations of the onset of IBD in infants and toddlers were extensive and aggressive and were closely associated with early relapse and death. It is of particular interest that some of these patients developed IBD due to monogenic disorders; thus, introduction of genetic testing is essential for these patients.

In ovarian cancer, the mechanism of chemoresistance is a key question. Here, the authors demonstrate that C/EBPβ and DOT1L together increase methylation of H3K79, which upregulates expression of oncogenic genes and drives poor platinum response and poor survival in ovarian cancer.

This study reports the outcomes of a secondary IOL implantation technique in patients that suffered from rhegmatogenous retinal detachment combined with a cataract, which included reopening the capsular bag, enabling secondary intracapsular intraocular lens (IOL) implantation. We included consecutive cases with rhegmatogenous retinal detachment (RRD) treated with vitrectomy and silicone oil tamponade, and subsequent secondary IOL implantation during silicone oil removal between September 2019 and June 2022. Demographics, pre- and postoperative clinical data, and complications were collected. Visual and refractive outcomes and IOL position were evaluated. Thirty eyes were included and followed up for a mean of 24.2 ± 5.06 months. Compared with the preoperative values, no significant changes were observed in the intraocular pressure (p = 0.170) and endothelial cell density (p = 0.336); however, the best-corrected visual acuity (Snellen: 20/83 vs. 20/38; logMAR: 0.66 ± 0.23 vs. 0.37 ± 0.32; p < 0.001) and spherical equivalent (p < 0.001) improved significantly. The mean prediction error (ME) was −0.45 ± 0.68 D (−1.9–0.54 D), and the mean absolute prediction error (MAE) was 0.62 ± 0.52 D (0.01–1.9 D). The macula-on subgroup demonstrated significantly better refractive outcomes than the macula-off subgroup (ME, p = 0.046; MAE, p = 0.008). The IOL was well positioned, with a mean horizontal and vertical tilt and decentration of 0.53 ± 0.49° and 0.21 ± 0.16 mm, and 0.54 ± 0.45° and 0.22 ± 0.16 mm, respectively. Secondary intracapsular IOL implantation provided a good and stable IOL position and satisfactory refractive outcomes, and is a feasible treatment option for patients with RRD. [ABSTRACT FROM AUTHOR]

Poly(p-phenylene terephthalamide) (PPTA) is a typical high-performance fiber and usually synthesized by low temperature solution polycondensation in twin screw extruder. During the reactive extrusion, flow behavior, rheokinetics, and temperature are highly coupled, which makes it difficult to ensure the quality of product. In the present work, the rheokinetics of the PPTA solution is established by experiments and its reactive extrusion is investigated via 3-D numerical simulation. The flow pattern, molecular weight distribution and temperature have been investigated for the extruders with three different elements, i.e., full flight screw (FF), kneading block (KB), and screw mixing element (SME). The results indicate that the unique flow characteristic of different screw elements affects mixing experience of the reactants and further the PPTA qualities. By numerical simulation, it shows the temperature increase within the tested extrusion stage is 7 K and reaction heat is found the main energy source for extrusion stage. Furthermore, heat removal method is verified with consideration of industrial production process. The numerical simulation work also discusses the reaction and mixing process in the extruders with three combined screws. The results show the introduction of more reverse FF and KB elements can lead to higher quality of PPTA., INTRODUCTION Poly(p-phenylene terephthalamide) (PPTA) is a high-performance fiber for its excellent mechanical and thermal properties. Since the decomposition temperature is higher than its melting point, PPTA is usually synthesized by [...]

Overnutrition has been linked to increased risk of cancer. Here, the authors show that exceeding nutrients suppress Enoyl-CoA hydratase-1 (ECHS1) activity by inducing its acetylation resulting in accumulation of fatty acids and branched-chain amino acids and oncogenic mTOR activation.

Background/AimsPatients with active ulcerative colitis (UC) have elevated levels of activated myeloid-derived leukocytes as a source of inflammatory cytokines. The selective depletion of these leukocytes by adsorptive granulocyte/monocyte apheresis (GMA) with an Adacolumn should alleviate inflammation, promote remission and enhance drug efficacy. However, studies have reported contrasting efficacy outcomes based on patients’ baseline demographic variables. This study was undertaken to understand the demographic features of GMA responders and nonresponders.Methods : This was a multicenter study in China involving four institutions and 34 patients with active UC. Baseline conventional medications were continued without changing the dosage. The treatment efficacy was evaluated based on the endoscopic activity index and the Mayo score.Results : Thirty of the 34 patients completed all 10 GMA treatment sessions. The overall efficacy rate was 70.59%. The receiver operating characteristic analysis showed that the area under the curve was approximately 0.766 for a Mayo score of ≤5.5 with 0.273 specificity and 0.857 sensitivity (Youden index, 0.584) for GMA responders. No GMA-related serious adverse events were observed.Conclusion : sThe overall efficacy of GMA in patients with active UC who were taking first-line medications or were corticosteroid refractory was encouraging. Additionally, GMA was well tolerated and had a good safety profile.