Oxidative stress has a critical role in the pathogenesis of vitiligo. However, the specific molecular mechanism involved in oxidative stress-induced melanocyte death is not well characterized. Given ...the powerful role of microRNAs (miRNAs) in the regulation of cell survival as well as the fact that the generation of miRNAs can be affected by oxidative stress, we hypothesized that miRNAs may participate in vitiligo pathogenesis by modulating the expression of vital genes in melanocytes. In the present study, we initially found that miR-25 was increased in both serum and lesion samples from vitiligo patients, and its serum level was correlated with the activity of vitiligo. Moreover, restoration of miR-25 promoted the H2O2-induced melanocyte destruction and led to the dysfunction of melanocytes. Further experiments proved that MITF, a master regulator in melanocyte survival and function, accounted for the miR-25-caused damaging impact on melanocytes. Notably, other than the direct role on melanocytes, we observed that miR-25 inhibited the production and secretion of SCF and bFGF from keratinocytes, thus impairing their paracrine protective effect on the survival of melanocytes under oxidative stress. At last, we verified that oxidative stress could induce the overexpression of miR-25 in both melanocytes and keratinocytes possibly by demethylating the promoter region of miR-25. Taken together, our study demonstrates that oxidative stress-induced overexpression of miR-25 in vitiligo has a crucial role in promoting the degeneration of melanocytes by not only suppressing MITF in melanocytes but also impairing the paracrine protective effect of keratinocytes. Therefore, it is worthy to investigate the possibility of miR-25 as a potential drug target for anti-oxidative therapy in vitiligo.
Objective
To evaluate the causal effects of sleep traits (i.e., chronotype, insomnia, and sleep duration) on bioavailable testosterone (BT), sex hormone-binding globulin (SHBG), and total ...testosterone (TT) levels in women and men.
Methods
We performed Mendelian randomization (MR) using random-effect inverse-variance weighted (IVW) and 7 other MR analyses. Exposure data for sleep traits were obtained from the largest-to-date genome-wide association study (GWAS) from 339,926 to 1,331,010 individuals. Summary data for testosterone levels were obtained from GWAS based on the UK Biobank.
Results
For women, our study supported that chronotype was associated with decreased BT (IVW:
β
= − 0.042, 95% CI − 0.060, − 0.023,
p
= 1.17E–05) and TT (IVW: − 0.053, 95% CI − 0.075, − 0.031,
p
= 2.30E–06). Besides, insomnia can significantly increase BT (IVW:
β
= 0.025, 95% CI 0.009, 0.041,
p
= 0.002). These findings were significant in most sensitivity analyses. For men, statistical significance was found between chronotype and BT (
β
= − 0.027, 95% CI − 0.048, − 0.005,
p
= 0.016), and insomnia and TT (
β
= − 0.028, 95% CI − 0.049, 0.007,
p
= 0.009) in IVW. However, the effect estimates were not broadly consistent with other sensitivity analyses. Our study did not find support for causal effects of sleep duration on testosterone levels in both women and men.
Conclusion
Our study reveals the sex differences in the effects of sleep traits on testosterone levels. A healthy sleep habit is vital for the maintenance of testosterone homeostasis in women. Further studies are warranted to investigate the associations between sleep traits and testosterone levels in men.
Wireless sensor networks with mobile sinks enable a mobile device to move into the sensing area for the purpose of collecting the sensing data. Mobile sinks increase the flexibility and convenience ...of data gathering in such systems. Taking the energy consumption of the mobile sink into account, the moving distance of the mobile sink must be reduced efficiently. Hence, it is important and necessary to develop an efficient path planning scheme for mobile sinks in large-scale wireless sensor network systems. According to several greedy-based algorithms, we adopt an angle bisector concept to create the moving path for the mobile sink. In this paper, a novel and efficient data collection path planning scheme is proposed to reduce the moving distances and to prolong the lifetimes of mobile sinks in wireless sensor networks. Considering the communication range limitations of sensor nodes and the obstacles within sensing areas, we design an inner center path planning algorithm to reduce the moving distance for the mobile sink. A back-routing avoidance method is included to address the moving path backpropagation problem. We account for the obstacles in sensing area. The reference point of obstacle avoidance is employed to address the obstacle problem. The proposed scheme makes an adaptive decision for creating the moving path of the mobile sink. A suitable moving path planning scheme can be achieved, and the moving distance of the mobile sink can be reduced. The proposed scheme is promising in large-scale wireless sensor networks. When the number of sensor nodes in the sensing area is increased by 50, the proposed scheme yields an average moving distance that is 1.1 km shorter than that of the heuristic tour-planning algorithm, where the sensing area is 5 km × 5 km. Simulation results demonstrate that the proposed data collection path planning scheme outperforms the previously developed greedy-based scheme in terms of the moving paths and moving distances of mobile sinks in wireless sensor networks.
To systematically review the evidence for the radiotherapeutic and surgical management of patients newly diagnosed with intraparenchymal brain metastases.
Key clinical questions to be addressed in ...this evidence-based Guideline were identified. Fully published randomized controlled trials dealing with the management of newly diagnosed intraparenchymal brain metastases were searched systematically and reviewed. The U.S. Preventative Services Task Force levels of evidence were used to classify various options of management.
The choice of management in patients with newly diagnosed single or multiple brain metastases depends on estimated prognosis and the aims of treatment (survival, local treated lesion control, distant brain control, neurocognitive preservation).
Single brain metastasis and good prognosis (expected survival 3 months or more): For a single brain metastasis larger than 3 to 4 cm and amenable to safe complete resection, whole brain radiotherapy (WBRT) and surgery (level 1) should be considered. Another alternative is surgery and radiosurgery/radiation boost to the resection cavity (level 3). For single metastasis less than 3 to 4 cm, radiosurgery alone or WBRT and radiosurgery or WBRT and surgery (all based on level 1 evidence) should be considered. Another alternative is surgery and radiosurgery or radiation boost to the resection cavity (level 3). For single brain metastasis (less than 3 to 4 cm) that is not resectable or incompletely resected, WBRT and radiosurgery, or radiosurgery alone should be considered (level 1). For nonresectable single brain metastasis (larger than 3 to 4 cm), WBRT should be considered (level 3).
Multiple brain metastases and good prognosis (expected survival 3 months or more): For selected patients with multiple brain metastases (all less than 3 to 4 cm), radiosurgery alone, WBRT and radiosurgery, or WBRT alone should be considered, based on level 1 evidence. Safe resection of a brain metastasis or metastases causing significant mass effect and postoperative WBRT may also be considered (level 3).
Patients with poor prognosis (expected survival less than 3 months): Patients with either single or multiple brain metastases with poor prognosis should be considered for palliative care with or without WBRT (level 3).
It should be recognized, however, that there are limitations in the ability of physicians to accurately predict patient survival. Prognostic systems such as recursive partitioning analysis, and diagnosis-specific graded prognostic assessment may be helpful.
Radiotherapeutic intervention (WBRT or radiosurgery) is associated with improved brain control. In selected patients with single brain metastasis, radiosurgery or surgery has been found to improve survival and locally treated metastasis control (compared with WBRT alone).
Idiopathic pulmonary fibrosis (IPF) is a complex disease for which the pathogenesis is poorly understood. In this study, we identified lactic acid as a metabolite that is elevated in the lung tissue ...of patients with IPF.
This study examines the effect of lactic acid on myofibroblast differentiation and pulmonary fibrosis.
We used metabolomic analysis to examine cellular metabolism in lung tissue from patients with IPF and determined the effects of lactic acid and lactate dehydrogenase-5 (LDH5) overexpression on myofibroblast differentiation and transforming growth factor (TGF)-β activation in vitro.
Lactic acid concentrations from healthy and IPF lung tissue were determined by nuclear magnetic resonance spectroscopy; α-smooth muscle actin, calponin, and LDH5 expression were assessed by Western blot of cell culture lysates. Lactic acid and LDH5 were significantly elevated in IPF lung tissue compared with controls. Physiologic concentrations of lactic acid induced myofibroblast differentiation via activation of TGF-β. TGF-β induced expression of LDH5 via hypoxia-inducible factor 1α (HIF1α). Importantly, overexpression of both HIF1α and LDH5 in human lung fibroblasts induced myofibroblast differentiation and synergized with low-dose TGF-β to induce differentiation. Furthermore, inhibition of both HIF1α and LDH5 inhibited TGF-β-induced myofibroblast differentiation.
We have identified the metabolite lactic acid as an important mediator of myofibroblast differentiation via a pH-dependent activation of TGF-β. We propose that the metabolic milieu of the lung, and potentially other tissues, is an important driving force behind myofibroblast differentiation and potentially the initiation and progression of fibrotic disorders.
Stereotactic body radiation therapy (SBRT) involves the delivery of a small number of ultra-high doses of radiation to a target volume using very advanced technology and has emerged as a novel ...treatment modality for cancer. The role of SBRT is most important at two cancer stages-in early primary cancer and in oligometastatic disease. This modality has been used in the treatment of early-stage non-small-cell lung cancer, prostate cancer, renal-cell carcinoma, and liver cancer, and in the treatment of oligometastases in the lung, liver, and spine. A large body of evidence on the use of SBRT for the treatment of primary and metastatic tumors in various sites has accumulated over the past 10-15 years, and efficacy and safety have been demonstrated. Several prospective clinical trials of SBRT for various sites have been conducted, and several other trials are currently being planned. The results of these clinical trials will better define the role of SBRT in cancer management. This article will review the radiobiologic, technical, and clinical aspects of SBRT.
A microautoclave magic angle spinning NMR rotor is developed enabling in situ monitoring of solid–liquid–gas reactions at high temperatures and pressures. It is used in a kinetic and mechanistic ...study of the reactions of cyclohexanol on zeolite HBEA in 130 °C water. The 13C spectra show that dehydration of 1‐13C‐cyclohexanol occurs with significant migration of the hydroxy group in cyclohexanol and the double bond in cyclohexene with respect to the 13C label. A simplified kinetic model shows the E1‐type elimination fully accounts for the initial rates of 1‐13C‐cyclohexanol disappearance and the appearance of the differently labeled products, thus suggesting that the cyclohexyl cation undergoes a 1,2‐hydride shift competitive with rehydration and deprotonation. Concurrent with the dehydration, trace amounts of dicyclohexyl ether are observed, and in approaching equilibrium, a secondary product, cyclohexyl‐1‐cyclohexene is formed. Compared to phosphoric acid, HBEA is shown to be a more active catalyst exhibiting a dehydration rate that is 100‐fold faster per proton.
Hot analysis: The catalytic conversion of cyclohexanol on zeolite HBEA in hot liquid water leads to dehydration as well as alkylation products. A novel microautoclave suitable for application in magic angle spinning (MAS) NMR at high temperatures has been successfully applied to obtain new insight into the mechanistic pathway leading to an understanding of the reactions under selected experimental conditions.
Conventional radiation therapy for cancer usually consists of multiple treatments (called fractions) with low doses of radiation. These dose schemes are planned with the guidance of the ...linear-quadratic (LQ) model, which has been the most prevalent model for designing dose schemes in radiation therapy. The high-dose fractions used in newer advanced radiosurgery, stereotactic radiation therapy, and high-dose rate brachytherapy techniques, however, cannot be accurately calculated with the traditional LQ model. To address this problem, we developed a generalized LQ (gLQ) model that encompasses the entire range of possible dose delivery patterns and derived formulas for special radiotherapy schemes. We show that the gLQ model can naturally derive the traditional LQ model for low-dose and low-dose rate irradiation and the target model for high-dose irradiation as two special cases of gLQ. LQ and gLQ models were compared with published data obtained in vitro from Chinese hamster ovary cells across a wide dose range 0 to approximately 11.5 gray (Gy) and from animals with dose fractions up to 13.5 Gy. The gLQ model provided consistent interpretation across the full dose range, whereas the LQ model generated parameters that depended on dose range, fitted only data with doses of 3.25 Gy or less, and failed to predict high-dose responses. Therefore, the gLQ model is useful for analyzing experimental radiation response data across wide dose ranges and translating common low-dose clinical experience into high-dose radiotherapy schemes for advanced radiation treatments.
Shock tube is used to study the ignition delay of RP-3 under ultra-low pressure (0.01–0.1 MPa). The ignition delay of RP-3/O2/N2 mixture is obtained with the characteristic emission signal of OH* ...radical at 306.5 nm and the pressure signal near the end of the driven section. The pressure range is from 0.01 MPa to 0.1 MPa, the temperature range is from 1113 K to 1600 K, and the equivalence ratio range is from 0.5 to 1.5. The influence of temperature, pressure, and equivalence ratio on the ignition delay characteristics of RP-3 is investigated. Results show that the increase in temperature and pressure and the decrease in equivalence ratio shorten the ignition delay time. The fitting formula of the relationship between the ignition delay time of RP-3 and temperature, pressure, and equivalence ratio under low pressure is obtained, and the results are verified by experimental data.
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