Tobacco toxins trigger bone marrow mesenchymal stem cells aging by inhibiting mitophagy.

Smoking disrupts bone homeostasis and serves as an independent risk factor for the development and progression of osteoporosis. Tobacco toxins inhibit the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), promote BMSCs aging and exhaustion, but the specific mechanisms are not yet fully understood. Herein, we successfully established a smoking-related osteoporosis (SROP) model in rats and mice through intraperitoneal injection of cigarette smoke extract (CSE), which significantly reduced bone density and induced aging and inhibited osteogenic differentiation of BMSCs both in vivo and in vitro. Bioinformatics analysis and in vitro experiments confirmed that CSE disrupts mitochondrial homeostasis through oxidative stress and inhibition of mitophagy. Furthermore, we discovered that CSE induced BMSCs aging by upregulating phosphorylated AKT, which in turn inhibited the expression of FOXO3a and the Pink1/Parkin pathway, leading to the suppression of mitophagy and the accumulation of damaged mitochondria. MitoQ, a mitochondrial-targeted antioxidant and mitophagy agonist, was effective in reducing CSE-induced mitochondrial oxidative stress, promoting mitophagy, significantly downregulating the expression of aging markers in BMSCs, restoring osteogenic differentiation, and alleviating bone loss and autophagy levels in CSE-exposed mice. In summary, our results suggest that BMSCs aging caused by the inhibition of mitophagy through the AKT/FOXO3a/Pink1/Parkin axis is a key mechanism in smoking-related osteoporosis.

First-Principles Calculations of the Phonon, Elastic, and Thermoelectric Properties of a Ti2CO2 Monolayer.

The phonon, elastic, and thermoelectric properties of Ti2CO2 are investigated by first-principles calculations. The dynamic and mechanical stabilities of Ti2CO2 are confirmed. The Ti2CO2 monolayer exhibits strong acoustic-optical coupling with the lowest optical frequency of 122.83 cm-1. The TA mode originates from the contribution of Ti(XY) vibrations and has the largest gruneisen parameter at the Γ point; the LA mode has the main contribution of O(XY) and Ti(XY) vibrations and has the lowest gruneisen parameter at the M point. The analysis of the phonon spectrum indicates that the vibration contributions from C, O, and Ti atoms are mainly located in the low-, middle-, and high-energy regions, respectively. The Seebeck coefficient and electronic conductivity increase with increasing carrier concentration under room temperature. The analysis of mechanical properties shows that Ti2CO2 possesses a larger Young's modulus and bending modulus, which has a better ability to resist deformation. Thermal properties are further investigated.

External Electric Field-Induced the Modulation of the Band Gap and Quantum Capacitance of F-Functionalized Two-Dimensional Sc2C.

The modulation of electronic properties and quantum capacitance of Sc2CF2 under a perpendicular external E-field was investigated using density functional calculations for the potential application of nanoelectronics and nanophotonics. Sc2CF2 has an indirect band gap of 0.959 eV without an E-field. Furthermore, it undergoes a semiconducting-metallic transition under a positive E-field and a semiconductor-insulator transition under a negative E-field. The application of the negative E-field makes Sc2CF2 have an indirect band gap. Sc-d, F-p, and C-p states are mainly responsible for the significant variation of the band gap. Sc2CF2 under an external E-field always keeps the character of a cathode material under the whole potential. Especially, Sc2CF2 under a negative external E-field is more suitable for the cathode material due to its much smaller |Qp|/|Qn| with much higher Qn. The charge analysis is further performed.

Risk factors and prognostic factors for pulmonary large cell neuroendocrine carcinoma with brain metastasis.

BACKGROUND: As the studies regarding the brain metastasis (BM) of pulmonary large cell neuroendocrine carcinoma (LCNEC) are insufficient, the present research aims to describe the risk factors and prognostic factors that are related to cancer-specific survival (CSS) for LCNEC patients with BM. METHODS: The data of LCNEC patients between January 2010 and October 2018 were obtained from the SEER database. Binary logistic regression analyses were utilized to screen the possible risk factors related to BM. Prognostic factors for LCNEC patients with BM were indentified by Cox regression analyses. Moreover, a nomogram was established to predict the 6-, 12-, and 18-month CSS rates. The concordance index (C-index), receiver operating characteristic (ROC) curves and calibration curves were utilized to assess the discrimination and reliability of the model. Clinical decision curves (DCAs) were used to evaluate the clinical benefits and utility of our model. RESULTS: Totally, 1875 patients were enrolled, with 294 (15.7%) of them having BM at diagnosis. Multivariate logistic regression analyses revealed that patients with age < 65 (odds ratio, OR = 1.564) and N2 staging (OR = 1.775) had a greater chance of developing BM. Age (≥ 65 vs. < 65: hazard ratio, HR = 1.409), T staging (T1 vs. T0: HR = 4.580; T2 vs. T0: HR = 6.008; T3 vs. T0: HR = 7.065; T4 vs. T0: HR = 6.821), N staging (N2 vs. N0: HR = 1.592; N3 vs. N0: HR = 1.654), liver metastasis (HR = 1.410), primary site surgery (HR = 0.581) and chemotherapy (HR = 0.452) were independent prognostic factors for LCNEC patients with BM. A nomogram prediction model was constructed by incorporating these factors. Using the C-index, calibration curves, ROC curves, and DCAs, we found that the clinical prediction model performed well. CONCLUSION: We described the risk factors and prognostic factors that were associated with CSS for LCNEC patients with BM. The related nomogram was established and validated to help clinicians formulate more rational and effective treatment strategies.

A Three-Point Hyperbolic Combination Model for the Settlement Prediction of Subgrade Filled with Construction and Demolition Waste.

Using construction and demolition waste (CDW) as road subgrade filling materials is an excellent way to solve the disparity between increased demand and road construction aggregate shortages. However, a key quality control problem is predicting the subgrade settlement, primarily because the CDW subgrade settlement prediction methods are not yet mature. To go some way in overcoming this problem, in this paper we developed a three-point hyperbolic combination model to predict CDW subgrade settlement, in which three appropriate points for the measured settlement curve were selected in the prediction samples to improve the hyperbolic model. Then, common prediction models-namely, the hyperbolic model, the three-point model, and the Hushino model-were compared with the proposed combination model to assess its viability. Finally, the three-point hyperbolic combination prediction accuracy was analyzed for different start points t0 and time intervals Δt. The analyses found that the proposed model was in good agreement with the measured data, had a high correlation coefficient, and had only small errors. However, the time interval Δ t needed to be greater than 80 days and the start point t0 needed to be selected at the beginning of the stable post-filling period, that is, t0 = 90-100 days. The application parameters were also determined to provide a reference for the large-scale application and settlement predictions of CDW subgrade.

[Combination of dispersive liquid-liquid microextraction using multifunctional ionic liquids with high performance chromatography for determination of phthalate ester metabolites in human urine sample].

A novel sensitive method for the determination of the five primary metabolites of phthalate esters (PAEs) in urine was developed by combining dispersive liquid-liquid microextraction (DLLME) using ionic liquids with high performance liquid chromatography (HPLC). The factors affecting the efficiency of DLLME were optimized. The types and proportions of extraction solvent and dispersants, as well the ultrasonic extraction time, cooling time, and centrifugal time, were determined. The optimal conditions were as follows:extraction solvent[C8MIM]PF6] 35 µL; dispersants[BSO3HMIm]OTf] 30 µL,[C4MIM]BF6] 120 µL; NH4PF6 0.1 g, extraction at 35℃, ultrasonic dispersion for 5 min, cooling in ice water for 5 min, centrifugation at 4000 r/min for 5 min. After optimization, the five primary metabolites of PAEs were determined. The method showed a good linear relationship within the concentration range of 0.5-1000 µg/L. The determination coefficients (R2) were greater than 0.9955. The detection limit was in the range of 0.16-0.19 µg/L. Under the optimized conditions, the extraction recoveries for the PAEs were 92.9%-105.0%, and the relative standard deviations (RSDs) of the intra- and inter-day precisions were < 5.96%. Urine samples collected from 10 diabetic patients were tested, and the exposure level of the population to the PAE metabolites was evaluated. All the PAE metabolites were detected in these samples, and the detection rate of 2-ethylhexyl hydrogen phthalate (MEHP) was 100%. In conclusion, no toxic organic reagents were added during the extraction process in this method, and multifunctional ionic liquids were used as the extraction agent, dispersant, and salting-out agent. In other words, the extraction process was demonstrated to be green, simple, and efficient. The developed method has high sensitivity and stability, and it is suitable for the determination of trace PAE metabolites in human urine.

A new hybrid anchoring balloon for direct peroral cholangioscopy using an ultraslim upper endoscope.

BACKGROUND AND AIM: Large impacted or residual invisible common bile duct (CBD) stones after mechanical lithotripsy are challenging. We aimed to evaluate the feasibility and success rate of a new hybrid anchoring balloon-guided direct peroral cholangioscopy (POC) for these conditions using an ultraslim endoscope. METHODS: Sixty-five patients with large or residual invisible CBD stones for direct POC from July 2012 to July 2016 were identified, including six cases in whom an additional interventional procedure was required. There were altogether 55 cases undergoing a procedure with our new device, with a 0.021-inch guidewire tied to a balloon catheter at its distal end in this single-center retrospective study. Technical success, procedure time, diagnostic and therapeutic efficacy of direct POC, and procedure-related complications were studied. RESULTS: The hybrid anchoring balloon-guided direct POC was successful in 51/55 (92.7%) procedures, including 18 cases in whom the conventional wire-guided method failed within 25 min. Mean time for technical success by our method was 12.4 ± 3.4 min. In total, of the 43 cases with previous removal of CBD stones, seven (16.3%) were found to have residual stones ≥4 mm, excluding three cases in whom direct POC failed. In another 25 cases for difficult stones, 24 lithotripsies were carried out, resulting in 23 complete fragmentations. No significant procedure-related complications were observed. CONCLUSION: The new hybrid anchoring balloon device performs well in facilitating direct POC using an ultraslim endoscope for evaluation and extraction of residual or large impacted CBD stones.

Long-term Clinical and Cost Outcomes of a Pharmacist-managed Risk Factor Management Clinic in Singapore: An Observational Study.

PURPOSE: Few studies have determined the benefits of pharmacist-run clinics within a tertiary institution, and specifically on their capability to improve clinical outcomes as well as reduce the cost of illness. This study was designed to investigate the effectiveness of a pharmacist-managed risk factor management clinic (RFMP) in an acute care setting through the comparison of clinical (improvement in glycosylated hemoglobin level) and cost outcomes with patients receiving usual care. METHODS: This single-center, observational study included patients aged ≥21 years old and diagnosed with type 2 diabetes mellitus (DM) who received care within the cardiology department of a tertiary institution between January 1, 2014, and December 31, 2015. The intervention group comprised patients who attended the RFMP for 3 to 6 months, and the usual-care group comprised patients who received standard cardiologist care. Univariate analysis and multiple linear regression were conducted to analyze the clinical and cost outcomes. FINDINGS: A total of 142 patients with DM (71 patients in the intervention group and 71 patients in the usual-care group) with similar baseline characteristics were included. After adjusting for differences in baseline systolic blood pressure and triglyceride levels, the mean reduction in glycosylated hemoglobin level at 6 months from baseline in the intervention group was significantly lower by 0.78% compared with the usual-care group. Patients in the usual-care group had a significantly higher risk of hospital admissions within the 12 months from baseline compared with the intervention group (odds ratio, 3.84 [95% CI, 1.17-12.57]; P = 0.026). Significantly lower mean annual direct medical costs were also observed in the intervention group (US $8667.03 [$17,416.20] vs US $56,665.02 [$127,250.10]; P = 0.001). IMPLICATIONS: The pharmacist-managed RFMP exhibited improved clinical outcomes and reduced health care costs compared with usual care within a tertiary institute.