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Abstract Background Despite a growing body of observational studies indicating a potential link between metabolic syndrome and colorectal cancer, a definitive causal relationship has yet to be established. This study aimed to elucidate the causal relationship between metabolic syndrome and colorectal cancer through Mendelian randomization. Methods We screened for instrumental variables associated with metabolic syndrome and its diagnostic components and with colorectal cancer through the use of a genome-wide association study database, and conducted a preliminary Mendelian randomization analysis. To corroborate the dependability of our conclusions, an additional dataset was used for replication analysis in a Mendelian randomization method, which was further integrated with a meta-analysis. Results Preliminary analysis using the inverse variance weighted method revealed positive correlations between metabolic syndrome (OR [95% CI] = 1.37[1.15–1.63], P = 5.02 × 10–4) and waist circumference (OR [95% CI] = 1.39[1.21–1.61], P = 7.38 × 10–6) and the risk of colorectal cancer. Replication analysis also revealed the same results: metabolic syndrome (OR [95% CI] = 1.24[1.02–1.51], P = 0.030) and waist circumference (OR [95% CI] = 1.23[1.05–1.45], P = 0.013). The meta-analysis results further confirmed the associations between metabolic syndrome (OR [95% CI] = 1.31[1.15–1.49], P

Abstract The precision of workpiece machining is critically influenced by the geometric errors in the kinematics of grind robots, which directly affect their absolute positioning accuracy. To tackle this challenge, this paper introduces a logistic-tent chaotic mapping Levenberg Marquardt algorithm designed to accurately identify and compensate for this geometric error. the approach begins with the construction of a forward kinematic model and an error model specific to the robot. Then the algorithm is adopted to identify and compensate for the geometric error. The method establishes a mapping interval around the initial candidate solutions derived from iterative applications of the Levenberg Marquardt algorithm. Within this interval, the logistic-tent chaotic mapping method generates a diverse set of candidate solutions. These candidates are evaluated based on their fitness values, with the optimal solution selected for subsequent iterations. Empirical compensation experiments have validated the proposed method's precision and effectiveness, demonstrating a 6% increase in compensation accuracy and a 47.68% improvement in efficiency compared to existing state-of-the-art approaches. This process not only minimizes the truncation error inherent in the Levenberg Marquardt algorithm but also significantly enhances solution efficiency. Moreover, simulation experiments on grind processes further validate the method's ability to significantly improve the quality of workpiece machining.

Unmanned aerial vehicles (UAVs) are extensively employed in pursuit, rescue missions, and agricultural applications. These operations require substantial data and video transmission, demanding significant spectral resources. The ultra-broad bandwidth of 0.1–10 THz in the Terahertz (THz) frequency range is essential for future UAV-based wireless communications. However, the available bandwidth in the THz frequency spectrum varies with transmission distance. To enhance spectral efficiency over this variable bandwidth, we propose using hierarchical modulation (HM) in the overlapped spectrum and traditional quadrature amplitude modulation (QAM) in the non-overlapped spectrum for closer users. Furthermore, we analyze the single-user case and utilize the block-coordinated descent (BCD) method to jointly optimize the modulation order, subcarrier bandwidth, and sub-band power to improve the system sum rate. Finally, considering the mobility and randomness of UAV users, we design a modulation switching rule to dynamically adjust to changes in distance as users move, thereby enhancing data rates. Simulation results demonstrate superior performance in data rate and design complexity compared to existing methods such as hierarchical bandwidth modulation (HBM) and HM schemes.

Abstract Accumulation of inorganic nanoparticles in living organisms can cause an increase in cellular reactive oxygen species (ROS) in a dose-dependent manner. Low doses of nanoparticles have shown possibilities to induce moderate ROS increases and lead to adaptive responses of biological systems, but beneficial effects of such responses on metabolic health remain elusive. Here, we report that repeated oral administrations of various inorganic nanoparticles, including TiO2, Au, and NaYF4 nanoparticles at low doses, can promote lipid degradation and alleviate steatosis in the liver of male mice. We show that low-level uptake of nanoparticles evokes an unusual antioxidant response in hepatocytes by promoting Ces2h expression and consequently enhancing ester hydrolysis. This process can be implemented to treat specific hepatic metabolic disorders, such as fatty liver in both genetic and high-fat-diet obese mice without causing observed adverse effects. Our results demonstrate that low-dose nanoparticle administration may serve as a promising treatment for metabolic regulation.

The role of hypoxia in terms of affecting mammary epithelial cells (MECs) proliferation is closely associated with the milk synthesis of lactating mammals. Primary bovine MECs were cultured at 1, 6, 11, 16, and 21% O2 for 24 h. The results showed that cell proliferation decreased linearly, and hypoxic inducible factor (HIF)-1α expression increased linearly along with the declining O2. The linear increase in oxidative stress resulted in the accumulation of malondialdehyde and reactive oxygen species and decreased antioxidant enzyme activities following the reduced O2. Concerning mitochondria, the dynamin-related protein 1 showed improved expression, and optin atrophy protein 1 decreased along with the decreasing O2 gradient, which led to decreased mitochondrial mass and mitophagy emerging under 1% O2. Oxygen concentration-trend RNA-seq analysis was conducted. Specifically, HIF-1-MAPK (1% O2), PI3K-Akt-MAPK (6% O2), and p53-Hippo (11 and 16% O2) were found to primarily regulate cell proliferation in response to hypoxia compared with normoxia (21%), respectively. In conclusion, our study suggests that bMEC proliferation is suppressed in low-oxygen conditions, and is exacerbated following the reduced oxygen supply. The cross-oxygen gradient comparisons suggest that MAPK and Hippo, which are core pathways of mammary cell proliferation, are repressed by hypoxia via oxidative-stress-dependent signals.

Background and purposeRevascularization surgery for patients with moyamoya disease (MMD) is very complicated and has a high rate of postoperative complications. This pilot study aimed to prove the safety and efficacy of remote ischemic conditioning (RIC) in adult MMD patients undergoing revascularization surgery.MethodsA total of 44 patients with MMD were enrolled in this single-center, open-label, prospective, parallel randomized study, including 22 patients assigned to the sham group and 22 patients assigned to the RIC group. The primary outcome was the incidence of major neurologic complications during the perioperative period. Secondary outcomes were the modified Rankin Scale (mRS) score at discharge, at 90 days post-operation, and at 1 year after the operation. The outcome of safety was the incidence of adverse events associated with RIC. Blood samples were obtained to monitor the serum concentrations of cytokines (VEGF, IL-6).ResultsNo subjects experienced adverse events during RIC intervention, and all patients could tolerate the RIC intervention in the perioperative period. The incidence of major neurologic complications was significantly lower in the RIC group compared with the control group (18.2% vs. 54.5%, P = 0.027). The mRS score at discharge in the RIC group was also lower than the control group (0.86 ± 0.99 vs. 1.18 ± 1.22, P = 0.035). In addition, the serum IL-6 level increased significantly at 7 days after bypass surgery in the control group and the serum level of VEGF at 7 days post-operation in the RIC group.ConclusionIn conclusion, our study demonstrated the neuroprotective effect of RIC by reducing perioperative complications and improving cerebral blood flow in adult MMD patients undergoing revascularization surgery. Thus, RIC seems to be a potential treatment method for MMD.Clinical trial registrationClinicalTrials.gov, identifier: NCT05860946.

In order to promote the accomplishment of the national carbon neutrality goal and enhance the international discourse power in the field of marine carbon sinks, this paper focused on high-resolution methods on the exploration of ocean carbon sink mechanism, covering biological and chemical detection methods and extensive applications. The results showed that marine refractory dissolved organic carbon pool played a significant role in carbon sink expansion, which put forward new challenges for high-resolution detection methods of dissolved organic carbon sink resources. Currently, high-resolution detection methods capable of tracking "fingerprint characteristics" mainly included flow cytometry and GeoChip functional detection, chemical detection methods, such as spectral and mass spectrometry as well as stable carbon isotope labeling technique that could realize the coupling between biological and chemical detection, were having crucial application prospects. With the stable carbon isotope labeling method as the link between biological traceability and chemical detection, all the technologies would have important application prospects.

In photovoltaic (PV) model, it is an urgent problem to control and optimize the accurate parameters. Hence, many algorithms have been proposed for parameter extraction of different PV models. However, the ability of many optimization algorithms is greatly affected by parameters, and the same parameter is not suitable for different model problems. In recent years, reinforcement learning has achieved competitive results in solving the problem of maximizing returns through learning strategies in the process of interaction with the environment. Therefore, in this paper we propose a new algorithm which combines differential evolution algorithm with reinforcement learning. Specifically, in the iterative process, the fitness function value is evaluated to determine the action reward for adjustment of parameter value, and the parameter value is adjusted through reinforcement learning to obtain the most suitable algorithm parameters for the environment model. The performance of the proposed approach has been verified by extracting single diode model, double diode model and PV module parameters, The simulation results (root mean square error) of single diode model (9.8602E−04), double diode model (9.8248E−04) and 2.4251E−03 for the Photowatt-PWP201, 1.7298E−03 for STM6-40/36 and 1.6601E−02 for the STP6-120/36 comprehensively show that the algorithm has better accuracy and robustness when compared with other advanced algorithms.

Background: Disorders of mitochondrial carnitine–acylcarnitine cycle is a heterogeneous group of hereditary diseases of mitochondrial β-oxidation of fatty acids tested in NBS program in Zhejiang province, China. Large-scale studies reporting disorders of mitochondrial carnitine–acylcarnitine cycle among Chinese population in NBS are limited. The aim of this study was to explain the incidence and biochemical, clinical, and genetic characteristics of disorders of mitochondrial carnitine–acylcarnitine cycle in NBS.Methods: From January 2009 to June 2021, 4,070,375 newborns were screened by tandem mass spectrometry. Newborns with elevated C0 levels and/or C0/(C16 + C18) ratios were identified as having CPT1D, whereas those with decreased C0 levels and/or C0/(C16 + C18) ratios and/or elevated C12-C18:1 level were identified as having CPT2D or CACTD. Suspected positive patients were further subjected to genetic analysis. All confirmed patients received biochemical and nutritional treatment, as well as follow-up sessions.Results: Overall, 20 patients (12 with CPT1D, 4 with CPT2D, and 4 with CACTD) with disorders of mitochondrial carnitine–acylcarnitine cycle were diagnosed by NBS. The overall incidence of these disorders was one in 203,518 newborns. In toal, 11 patients with CPT1D exhibited increased C0 levels and C0/(C16 + C18) ratios. In all patients of CPT2D, all long chain acyl-carnitines levels were elevated except for case 14 having normal C12 levels. In all patients with CACTD, all long chain acyl-carnitines levels were elevated except for case 17 having normal C12, C18, and C18:1 levels. Most patients with CPT1D were asymptomatic. Overall, two of 4 patients with CPT2D did not present any clinical symptom, but other two patients died. In 4 cases with CACTD, the disease was onset after birth, and 75% patients died. In total, 14 distinct mutations were identified in CPT1A gene, of which 11 were novel and c.1910C > A (p.S637T), c.740C > T (p.P247L), and c.1328T > C (p.L443P) were the most common mutations. Overall, 3 novel mutations were identified in CPT2 gene, and the most frequent mutation was c.1711C > A (p.P571T). The most common variant in SLC25A20 gene was c.199-10T > G.Conclusion: Disorders of mitochondrial carnitine–acylcarnitine cycle can be detected by NBS, and the combined incidence of these disorders in newborns was rare in Zhejiang province, China. Most patients presented typical acylcarnitine profiles. Most patients with CPT1D presented normal growth and development, whereas those with CPT2D/CACTD exhibited a high mortality rate. Several novel CPT1A and CPT2 variants were identified, which expanded the variant spectrum.

In view of the problem of the GB/T 10414-2017 Synchronous belt drive car synchronous belt pulley standard does not provide the RU type and YU type pulley standard tool tooth profile parameter, the conjugate harmonic relationship between the pulley and tool tooth profile are studied. Firstly, the conjugate tool tooth surface of the pulley tooth profile is enveloped based on the meshing principle, and the discrete data of the envelope curve is mathematically fitted to determine the mathematical model of the cutter tooth profile. Secondly, through the second enveloping process of the cutter on the pulley, it is found that there is an undercut at the top of the tooth profile of the processed pulley tooth profile. Through the study of the mechanism of undercutting, the reason of singularity of cutter surface is revealed, and tooth profile model to eliminate the singular point of cutter tooth profile curve is proposed. The tooth profile error based on pulley is within the standard tolerance range, the cutter parameter is redesigned.

Curriculum Learning (CL) selects the training samples from the easy to difficult to boost the classification results. Most existing variates of CL measure the difficulty level of an example in an intuitive way, i.e., the loss value between the prediction and the ground truth. This way ignores the different distances to every class boundary, which is implied in the prediction vectors. In this paper, we propose a novel CL framework, named Balance Loss Curriculum Learning(BLCL), to reveal the comprehensive difficulty level of an example and improve the curriculum process based on the deep architectures. We follow the teacher-student learning module and train the teacher & student networks simultaneously. The predictions learned by the teacher network indicates the boundary information and is set as the difficulty measurement to guide the student network. The student network focuses on the easy samples according to the boundary information by decreasing the loss from difficult examples as well as increasing the loss from easy examples. Through extensive and rigor experiments, we demonstrate the effectiveness and generality of our framework.

In this paper, we consider a reconfigurable intelligent surface (RIS) aided millimeter wave (mmWave) multiple-input multiple-output (MIMO) system. The system can obtain the huge gain via joint active beamforming at the base station (BS) and passive beamforming at the RIS. However, due to weather and atmospheric effects, outdoor RIS antenna elements are subject to full or partial blockages from a plethora of particles like dirt, salt, ice, and water droplets. These blockages can cause an approximate squared power/SNR loss for the system. Different from the conventional array diagnosis, the RIS has no signal processing capability. Thus, we propose the joint array diagnosis and channel estimation techniques containing two stages to solve the problem. At the first stage the channel parameters at user equipment (UE) and BS are estimated using an iterative reweighted (IR) method. At the second stage, the array blockage coefficient vector and the effective sparse channel parameters at RIS are jointly estimated via solving a two-timescale non-convex optimization problem. We propose two algorithms, i.e., a batch algorithm (BA) and a two-timescale online joint array diagnosis and channel estimation (TOJADCE) algorithm to solve the problem and compare the performance of these two algorithms. Finally, to speed up the convergence of long-term variable and improve estimation performance, we propose a noise reduction (NR) algorithm. The simulations verify the effectiveness of our proposed algorithms.

Parameter extraction of photovoltaic (PV) models plays a vital role in simulation, evaluation and control of PV systems. It requires to identify the parameters of different PV models quickly and accurately. In this paper, an improved differential evolution by reusing the past individual vectors and adaptive mutation strategy is proposed to extract PV parameters. In the proposed method, the successful difference vectors from previous generations are introduced to produce the offspring in the next generations to improve the performance of differential evolution. In addition, to obtain a nice result, an adaptive mutation strategy is considered to establish a good balance of exploration and exploitation. The proposed method is applied to identify the parameters of different PV models, such as single diode, double diode, and PV models. Comparison results demonstrate that the proposed method obtains the competitive performance on accuracy, reliability and convergence when compared with other state-of-the-art methods.

ABSTRACT Marine phytoplankton and heterotrophic bacteria share a very close but usually changeable relationship. However, the ultimate fate of their unstable relationship on a long-term scale is unclear. Here, the relationship between Synechococcus and heterotrophic bacterial communities underwent a dramatic shift from antagonism to commensalism and eventually to mutualism during long-term cocultivation. The relationship change is attributed to the different (even opposite) effects of diverse bacterial members on Synechococcus and the ratio of beneficial to harmful bacteria. Different bacterial members also interact with each other (e.g., quorum-sensing communication, hostility, or mutual promotion) and drive a dynamic succession in the entire community structure that corresponds exactly to the shift in its relationship with Synechococcus. In the final mutualism stage, a self-sufficient nitrogen cycle, including nitrogen fixation, denitrification, and organic nitrogen degradation, contributed to the healthy survival of Synechococcus for 2 years without an exogenous nutrient supply. This natural selective trait of Synechococcus and heterotrophic bacteria toward mutualism under long-term coexistence provides a novel clue for understanding the ubiquity and competitive advantage of Synechococcus in global oceans. IMPORTANCE Phytoplankton and heterotrophic bacteria have a close but usually changeable relationship. Uncovering the dynamic changes and driving factors of their interrelationships is of great significance for an in-depth understanding of the ecological processes and functions of marine microorganisms. Here, we observed that Synechococcus and heterotrophic bacterial communities underwent a dramatic change in their relationship from antagonism to mutualism during a long-term cocultivation process. We revealed that the interactions between different members of the bacterial community and the combined effects of different bacterial individuals on Synechococcus promoted the dynamic changes of the Synechococcus-bacterium relationship. In the end, a self-sufficient nutrient cycle (especially nitrogen) established by Synechococcus and bacterial communities supported their long-term survival without any external nutrition supply. This study provides novel insight into the interaction between Synechococcus and heterotrophic bacteria in the ocean and provides a novel clue for understanding the ubiquity and competitive advantage of Synechococcus in global oceans.

BackgroundThe inverted classroom model differs from the traditional teaching model as it reverses the pattern of knowledge transfer and internalization. In recent years, this new teaching model has received much attention in undergraduate medical education. Pathophysiology is a course in the undergraduate Chinese medical curriculum that is critical in bridging basic medical science and clinical medicine. ObjectiveThe purpose of this study was to investigate the application of inverted classroom in delivering the course on pathophysiology to Chinese undergraduate medical students. MethodsIn the spring semester of 2018, inverted classroom teaching was implemented for second-year clinical medicine students at the College of Medicine at Nanchang University. The topics of hypoxia and respiratory failure were selected for the inverted classroom study. The effect of the inverted classroom on teaching pathophysiology was evaluated using classroom performance metrics, a final examination, and questionnaires. ResultsThis study found that students in the inverted classroom group achieved higher scores in their in-course assessments (82.35 [SD 11.45] vs 81.33 [SD 9.51], respectively) and in their final exams (73.41 [SD 10.37] vs 71.13 [SD 11.22], respectively) than those in the traditional lecture-based group, but the scores were not significantly different (P=.13, unpaired two-tailed t test). There was also no significant difference in the distribution of the score segments in the class quiz (P=.09, chi-square test) and in the final exams (P=.25, chi-square test) between the 2 groups. Further, most of the students reported that the inverted classroom increased their learning motivation, made them more confident, and helped them understand the content on pathophysiology better. The students in the inverted classroom also improved in their problem-solving skills and teamwork abilities. However, some students from the inverted classroom group also reported that the self-learning and preparatory work before class increased their learning burden. ConclusionsThis study shows the feasibility and promise of inverted classroom for teaching pathophysiology to undergraduate Chinese medical students. The inverted classroom improves students’ learning interests and attitudes toward learning. However, further studies are required to assess the benefits of broader acceptance and implementation of the inverted classroom among Chinese undergraduate medical students.

Background Chronic alcohol intake is associated with an increased risk of alcoholic cardiomyopathy, which may present with pathological changes such as myocardial insulin resistance, leading to ventricular dilation and cardiac dysfunction. Although a correlation between microRNA-155 (miR-155) and insulin signaling has been identified, the underlying mechanism has not been elucidated to date. The purpose of the study was to determine whether overexpression of miR-155-5p in vivo could ameliorate chronic alcohol-induced myocardial insulin resistance and cardiac dysfunction. Material and Methods Wistar rats were fed with either alcohol or water for 20 weeks to establish chronic alcohol intakes model. Then the alcohol group were divided into three groups: model group, miRNA-155 group and AAV-NC group. Rats undergoing alcohol treatment were injected with AAV-miRNA-155 (adeno-associated virus 9) or its negative control AAV-NC, respectively. Gene expression was determined by real-time PCR, and protein expression was determined by western blot. Echocardiography was performed to assess terminal cardiac function. Insulin responsiveness was determined through the quantification of phosphorylated insulin receptor substrate 1 (ser 307) and phosphorylated insulin receptor (Tyr 1185) levels. Results We found that cardiac function was attenuated in chronic alcohol intake rats, with an activated mammalian target of rapamycin (mTOR) signaling pathway, accompanied by an increase in p-IRS1(ser 307) and a decrease in p-IR (Tyr 1185) level in myocardial tissue. Also, alcohol drinking significantly up-regulated miR-155-5p level and its overexpression decreased p-IRS1 (ser 307) and increased p-IR (Tyr 1185) levels, and meanwhile inhibited the mTOR signaling pathway. Conclusion miR-155-5p upregulation ameliorates myocardial insulin resistance via the mTOR signaling in chronic alcohol drinking rats. We propose that miR-155 may serve as a novel potential therapeutic target for alcoholic heart disease.

Aiming at the problem of camshaft torsional oscillation caused by the torque of the engine camshaft spring, this paper carries out the research on the compensation of the elliptical pulley timing system for the torsional oscillation of the camshaft. In the quasi-static state, a dual overhead gasoline engine drive system model is established, and the increments of the tight and slack side belt lengths, the arc length of the pulley wrap angle and the direction angle of the pulley tangent point are studied. The relationship of the harmonic increments is determined. Based on the structure of fixed and automatic tensioners, a mathematical model of the elliptical eccentricity and the initial phase angle for compensating the harmonic oscillational torque of camshaft spring is proposed. The simulation results verify the correctness of the model. It is concluded that the elliptical eccentricity and the belt tension amplitude of the fixed tensioner are 50% smaller than the automatic tensioner, which reduces the dynamic excitation of the system. The tension distribution of the tight side and the slack side of the belt meshed with the elliptical pulley is different. The amplitude of the tension difference between the tight and side sides belts corresponding to the automatic tensioner is twice as large as that of the fixed tensioner. At the same time, the difference in tension will cause different elongation of the belt pitch between the tight and the slack sides, causing the meshing interference between the belt teeth and the elliptical pulley groove. Therefore, the tension distribution of the belt meshed with an ellipse is completely different from that of a circular pulley.

The blood gas profile is a routine method in the rapid disease diagnosis of farm animals, yet its potential in evaluating mammary health status of dairy cows remains to be investigated. This study was conducted to learn the potential of the blood gas parameter regarding the mammary gland health status in lactating dairy cows. Twenty animals were divided into two groups, the H-SCC group (milk SCC > 122 k/mL) and L-SCC group (milk SCC < 73.8 k/mL), to compare blood gas profiles from different blood vessels and to identify the key parameters associated with milk somatic cell count. H-SCC cows are higher in malondialdehyde content, but lower in SOD and T-AOC activities in the milk, compared to the L-SCC group. In terms of blood gas parameters, most differ across the three vessels, including K+, CO2 pressure, O2 pressure, HCO3−, base excess in the extracellular fluid compartment, and saturation of O2. The Pearson correlation analysis showed that oxygen-related variables in the mammary vein, including oxygen concentrations, O2 pressure, and saturation of O2, are negatively correlated with levels of malondialdehyde, lactate dehydrogenase, and plasmin in the milk. Our study revealed that oxygen-related variables in the mammary vein can be a marker in suggesting mammary-gland health status in high-yielding cows.

Background: As common pathogens in the human respiratory tract, fungal-spore-related health risks have been challenging to evaluate properly. This paper presents numerical simulations of particle deposition of Aspergillus niger spores in human nasal cavities. Methods: 30 healthy adults (including 60 nasal chambers) who lived in northwest China were recruited to conduct a nasal cavity numerical simulation using computational fluid dynamics–discrete phase model (CFD-DPM). The deposition rate in each anatomic area and its influencing variables, such as body position and respiratory flow rate, were analyzed. Results: (1) Under a resting condition, only about 5.57% ± 1.51% Aspergillus niger spores were deposited in the nasal cavity, while most of them escaped from the nasopharynx, and 0.31% ± 0.20% spores entered the maxillary sinus; (2) under an exercising condition, spores deposited in the nasal cavity were about 2.09 times as many as that in the resting state; (3) in a lying position, the A. niger spores deposited evenly on the lateral wall of the nasal cavity and the sinus when compared with a standing position. However, the deposition rate in each anatomic area did not change significantly.

Objective: Although microRNA-103a (miR-103a) dysfunction has been implicated in various cancers, its relevance to non-small cell lung cancer (NSCLC) has not been clarified. This study was conducted to examine the molecular mechanism underlying the regulatory role of miR-103a in NSCLC. Methods: Kaplan–Meier analysis was carried out to assess the relationship between overall survival of NSCLC patients and miR-103a expression. Reverse-transcription quantitative polymerase chain reaction and western blot analyses were applied to evaluate the expression of relevant genes in tissues and cells. Sphere formation, MTS, flow cytometry, and Transwell assays were performed to characterize stemness. Dual luciferase reporter gene assays were used to clarify the binding relationship between miR-103a and ovarian tumor domain-containing ubiquitin aldehyde binding protein 1 (OTUB1). Finally, western blot analysis was used to assess the involvement of the Hippo pathway in NSCLC. Results: In NSCLC tissues and cells, miR-103a was expressed at low levels, whereas OTUB1 was expressed at high levels. Higher miR-103 expression levels were associated with a better prognosis for patients with NSCLC. When miR-103a was overexpressed, cell viability and stemness decreased, whereas apoptosis and cell cycle arrest were facilitated. The expression of phosphorylated YAP also decreased significantly. Opposite trends were observed after miR-103a silencing. OTUB1 expression and YAP phosphorylation decreased in the presence of miR-103a, and OTUB1 overexpression blocked the inhibitory effects of miR-103a on NSCLC cells. Conclusion: The miR-103a/OTUB1/Hippo axis may play a role in modulating the malignant behavior and stemness of cancer stem cells and thus could be a potential therapeutic target for the management of NSCLC.

Some studies have shown that offset toothed double helical synchronous belts (OTDHSB) have lower transmission noise and higher fatigue life than straight toothed synchronous belts (STSB). However, the transmission errors of these belts have not been reported. The present study aims to elucidate the mechanisms of the transmission error due to the belt climbing at the beginning of the meshing and at the end of meshing. In theoretical analysis, a model was established under quasi-static conditions. The results of the model used to calculate the transmission error of the helical synchronous belt (HSB) agreed closely with the published paper results. And then, the influence of the belt width, the helical angle and the offset coefficient on the transmission error was studied using the model. Computational results revealed that the amplitude of the transmission error decreases as the increasing of the offset coefficient, belt width, and helical angle when the offset coefficient and helical ratio are less than 0.5 and 1 respectively. In addition, the amplitude of the transmission error is equal to zero when the offset coefficient and helical ratio are equal to 0.5 and an integer respectively.

Background: Spinal muscular atrophy (SMA) is the most common neurodegenerative disorder and the leading genetic cause of infant mortality. Early detection of SMA through newborn screening (NBS) is essential to selecting pre-symptomatic treatment and ensuring optimal outcome, as well as, prompting the urgent need for effective screening methods. This study aimed to determine the feasibility of applying an Agena iPLEX SMA assay in NBS for SMA in China.Methods: We developed an Agena iPLEX SMA assay based on the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, and evaluated the performance of this assay through assessment of 167 previously-genotyped samples. Then we conducted a pilot study to apply this assay for SMA NBS. The SMN1 and SMN2 copy number of screen-positive patients were determined by multiplex ligation-dependent probe amplification analysis.Results: The sensitivity and specificity of the Agena iPLEX SMA assay were both 100%. Three patients with homozygous SMN1 deletion were successfully identified and conformed by multiplex ligation-dependent probe amplification analysis. Two patients had two SMN2 copies, which was correlated with severe SMA type I phenotype; both of them exhibited neurogenic lesion and with decreased muscle power. Another patient with four SMN2 copies, whose genotype correlated with milder SMA type III or IV phenotype, had normal growth and development without clinical symptoms.Conclusions: The Agena iPLEX SMA assay is an effective and reliable approach for population-based SMA NBS. The first large-scale pilot study using this assay in the Mainland of China showed that large-scale implementation of population-based NBS for SMA is feasible.

Wideband sensing-based cognitive radio with simultaneous wireless information and power transfer can be designed for efficient spectrum and energy usage. We first aim to maximize the sum energy harvested by all the energy harvesters subject to constraints on rate, transmit power, interference, and subchannel assignment. Due to the non-convexity of the formulated problem, we relax the integer variable and introduce an auxiliary variable to transform the original problem into a convex problem. Then, the Lagrangian and subgradient methods are adopted to obtain the optimal solutions. However, this scheme may lead to a severe fairness issue among different links. In view of this fact, we further propose an energyharvesting scheme for max-min fairness. In particular, we aim to maximize the energy harvested by the worst case individual link. We show that this problem can be solved in a similar manner to the problem of sum harvested energy maximization. Simulation results are presented to verify the convergence and fairness performance of the proposed algorithm, and to reveal a novel tradeoff between the network harvested energy and sensing time.

The effects of six non-dissolved redox mediators (RM) immobilized in cellulose acetate beads on enhancing Cr(VI) reduction by Mangrovibacter plantisponsor CR1 were investigated. In addition, the voltammetric behaviours and electron transfer capacities of the redox mediators were examined using electrochemical methods. Compared to the control beads, the Cr(VI) bioreduction rate with 1-chloroanthraquinone cellulose acetate beads (1-CAQ/CA beads) was increased up to 4.5-fold, which was mainly attributed to enhanced electron transfer by 1-CAQ. The redox mediators also improved the oxidation–reduction potential values of the Cr(VI) bioreduction processes, which might assist in Cr(VI) bioreduction. The role of the redox mediators was discussed based on the cyclic voltammetric characteristics (E0') of the redox mediators and the electrochemical impedance spectroscopy characteristics (Rct) of the RM/CA beads. A linear correlation was found for the reaction constant k and the 1-CAQ concentration (C1-CAQ), which was k = 1.5674 C1-CAQ + 4.8506 (R2 = 0.9683). The Cr(VI) bioreduction was affected by temperature, and the optimum pH for the Cr(VI) bioreduction was 6.5. The results of repeated-batch operations showed that 1-CAQ/CA beads exhibited good stability and persistence. This study contributes to a better understanding of the effects of the redox mediator on Cr(VI) bioreduction process and demonstrates its promising potential for environmental bioremediation applications.

Cognitive radio networks (CRNs), which allow secondary users (SUs) to dynamically access a network without affecting the primary users (PUs), have been widely regarded as an effective approach to mitigate the shortage of spectrum resources and the inefficiency of spectrum utilization. However, the SUs suffer from frequent spectrum handoffs and transmission limitations. In this paper, considering the quality of service (QoS) requirements of PUs and SUs, we propose a novel dynamic flow-adaptive spectrum leasing with channel aggregation. Specifically, we design an adaptive leasing algorithm, which adaptively adjusts the portion of leased channels based on the number of ongoing and buffered PU flows. Furthermore, in the leased spectrum band, the SU flows with access priority employ dynamic spectrum access of channel aggregation, which enables one flow to occupy multiple channels for transmission in a dynamically changing environment. For performance evaluation, the continuous time Markov chain (CTMC) is developed to model our proposed strategy and conduct theoretical analyses. Numerical results demonstrate that the proposed strategy effectively improves the spectrum utilization and network capacity, while significantly reducing the forced termination probability and blocking probability of SU flows.

Cocaine- and amphetamine-regulated transcript (CART) peptides are neuropeptides that are expressed in brain regions associated with reward, such as the nucleus accumbens (NAc), and play a role in cocaine reward. Injection of CART into the NAc can inhibit the behavioral effects of cocaine, and injecting CART into the ventral tegmental area (VTA) reduces cocaine-seeking behavior. However, the exact mechanism of these effects is not clear. Recent research has demonstrated that Ca2+/calmodulin-dependent protein kinase II (CaMKII) and inhibitory G-protein coupled receptor (GPCR) signaling are involved in the mechanism of the effect of CART on cocaine reward. Hence, we review the role of CaMKII and inhibitory GPCR signaling in the effect of CART on cocaine reward and provide a new insight into the mechanism of that effect. In this article, we will first review the biological function of CART and discuss the role of CART in cocaine reward. Then, we will focus on the role of CaMKII and inhibitory GPCR signaling in cocaine reward. Furthermore, we will discuss how CaMKII and inhibitory GPCR signaling are involved in the mechanistic action of CART in cocaine reward. Finally, we will provide our opinions regarding the future directions of research on the role of CaMKII and inhibitory GPCR signaling in the effect of CART on cocaine reward.

Mxi1 plays an important role in the regulation of cell proliferation. Mxi1-0, a Mxi1 isoform, has a different N-terminal amino acid sequence, intracellular location and expression profile from Mxi1. However, the precise role of Mxi1-0 in cell proliferation and the molecular mechanism underlying its function remain poorly understood. Here, we showed that Mxi1-0 suppression decreased the proliferation of human umbilical vein endothelial cells (HUVECs) along with cell accumulation in the G2/M phase. Mxi1-0 suppression also significantly decreased the expression and secretion of interleukin (IL-8). Neutralizing IL-8 in conditioned medium (CM) from Mxi1-0-overexpressed HUVECs significantly eliminated CM-induced proliferation of HUVECs. In addition, Mxi1-0 suppression significantly decreased the activity of MAP kinase ERK1/2. Treatment of HUVECs with U0126, an ERK1/2 signaling inhibitor, attenuated autocrine production of IL-8 induced by Mxi1-0 overexpression. On the other hand, Mxi1-0 overexpression-induced IL-8 increased the level of phosphorylated ERK1/2 in HUVECs, and such increasing was diminished in cells incubated with CM, which neutralized with anti-IL-8 antibody. Taken together, our results suggest that Mxi1-0 regulates the growth of HUVECs via the IL-8 and ERK1/2 pathways, which apparently reciprocally activate each other.

The purpose of this study was to characterize the inhibitory modulation of cocaine- and amphetamine-regulated transcript (CART) peptides, particularly with respect to the function of the D3 dopamine receptor (D3R), which is activated by its interaction with phosphorylated CaMKIIα (pCaMKIIα) in the nucleus accumbens (NAc). After repeated oral administration of caffeine (30 mg/kg) for five days, microinjection of CART peptide (0.08 μM/0.5 μl/hemisphere) into the NAc affected locomotor behavior. The pCaMKIIα-D3R interaction, D3R phosphorylation and cAMP/PKA/phosphorylated CREB (pCREB) signaling pathway activity were measured in NAc tissues, and Ca2+ influx and pCaMKIIα levels were measured in cultured NAc neurons. We found that CART attenuated the caffeine-mediated enhancement of depolarization-induced Ca2+ influx and CaMKIIα phosphorylation in cultured NAc neurons. Repeated microinjection of CART peptides into the NAc decreased the caffeine-induced enhancement of Ca2+ channels activity, pCaMKIIα levels, the pCaMKIIα-D3R interaction, D3R phosphorylation, cAMP levels, PKA activity and pCREB levels in the NAc. Furthermore, behavioral sensitization was observed in rats that received five-day administration of caffeine following microinjection of saline but not in rats that were treated with caffeine following microinjection of CART peptide. These results suggest that caffeine-induced CREB phosphorylation in the NAc was ameliorated by CART peptide due to its inhibition of D3R phosphorylation. These effects of CART peptides may play a compensatory role by inhibiting locomotor behavior in rats.

The Dishevelled (Dvl) and Dishevelled-associated activator of morphogenesis 1 (Daam1) pathway triggered by Wnt5a regulates cellular polarity during development and tissue homoeostasis. However, Wnt5a signaling in breast cancer progression remains poorly defined.We showed here that Wnt5a activated Dvl2, Daam1 and RhoA, and promoted migration of breast cancer cells, which was, however, abolished by Secreted Frizzled-related protein 2 (sFRP2) pretreatment. Dominant negative Dvl2 mutants or Dvl2 siRNA significantly decreased Wnt5a-induced Daam1/RhoA activation and cell migration. Ectopic expression of N-Daam1, a dominant negative mutant, or Daam1 siRNA remarkably inhibited Wnt5a-induced RhoA activation, stress fiber formation and cell migration. Ectopic expression of dominant negative RhoA (N19) or C3 exoenzyme transferase, a Rho inhibitor, decreased Wnt5a-induced stress fiber formation and cell migration.Taken together, we demonstrated for the first time that Wnt5a promotes breast cancer cell migration via Dvl2/Daam1/RhoA.

BACKGROUND: Epidermal growth factor (EGF) signaling is implicated in the invasion and metastasis of hepatoma cells. However, the signaling pathways for EGF-induced motility of hepatoma cells remain undefined. METHODOLOGY/PRINCIPAL FINDINGS: We found that EGF dose-dependently stimulated the migration of human hepatoma cells HepG2, with the maximal effect at 10 ng/mL. Additionally, EGF increased Arf6 activity, and ectopic expression of Arf6 T27N, a dominant negative Arf6 mutant, largely abolish EGF-induced cell migration. Blocking GEP100 with GEP100 siRNA or GEP100-△PH, a pleckstrin homology (PH) domain deletion mutant of GEP100, blocked EGF-induced Arf6 activity and cell migration. EGF also increased ERK and Rac1 activity. Ectopic expression GEP100 siRNA, GEP100-△PH, or Arf6-T27N suppressed EGF-induced ERK and Rac1 activity. Furthermore, blocking ERK signaling with its inhibitor U0126 remarkably inhibited both EGF-induced Rac1 activation as well as cell migration, and ectopic expression of inactive mutant form of Rac1 (Rac1-T17N) also largely abolished EGF-induced cell migration. CONCLUSIONS/SIGNIFICANCE: Taken together, this study highlights the function of the PH domain of GEP100 and its regulated Arf6/ERK/Rac1 signaling cascade in EGF-induced hepatoma cell migration. These findings could provide a rationale for designing new therapy based on inhibition of hepatoma metastasis.

BackgroundHypoxia-inducible factor 1 (HIF-1α) expression induced by hypoxia plays a critical role in promoting tumor angiogenesis and metastasis. However, the molecular mechanisms underlying the induction of HIF-1α in tumor cells remain unknown.Methodology/principal findingsIn this study, we reported that hypoxia could induce HIF-1α and VEGF expression accompanied by Rac1 activation in MCF-7 breast cancer cells. Blockade of Rac1 activation with ectopic expression of an inactive mutant form of Rac1 (T17N) or Rac1 siRNA downregulated hypoxia-induced HIF-1α and VEGF expression. Furthermore, Hypoxia increased PI3K and ERK signaling activity. Both PI3K inhibitor LY294002 and ERK inhibitor U0126 suppressed hypoxia-induced Rac1 activation as well as HIF-1α expression. Moreover, hypoxia treatment resulted in a remarkable production of reactive oxygen species (ROS). N-acetyl-L-cysteine, a scavenger of ROS, inhibited hypoxia-induced ROS generation, PI3K, ERK and Rac1 activation as well as HIF-1α expression.Conclusions/significanceTaken together, our study demonstrated that hypoxia-induced HIF-1α expression involves a cascade of signaling events including ROS generation, activation of PI3K and ERK signaling, and subsequent activation of Rac1.

Enhanced motility of cancer cells is a critical step in promoting tumor metastasis. Lysophosphatidic acid (LPA), representing the major mitogenic activity in serum, stimulates migration in various types of cancer cells. However, the underlying signaling mechanisms for LPA-induced motility of cancer cells remain to be elucidated.In this study, we found that LPA dose-dependently stimulated migration of MDA-MB-231 breast cancer cells, with 10 µM being the most effective. LPA also increased ERK activity and the MEK inhibitor U0126 could block LPA-induced ERK activity and cell migration. In addition, LPA induced PAK1 activation while ERK activation and cell migration were inhibited by ectopic expression of an inactive mutant form of PAK1 in MDA-MB-231 cells. Furthermore, LPA increased PI3K activity, and the PI3K inhibitor LY294002 inhibited both LPA-induced PAK1/ERK activation and cell migration. Moreover, in the breast cancer cell, LPA treatment resulted in remarkable production of reactive oxygen species (ROS), while LPA-induced ROS generation, PI3K/PAK1/ERK activation and cell migration could be inhibited by N-acetyl-L-Cysteine, a scavenger of ROS.Taken together, this study identifies a PI3K/PAK1/ERK signaling pathway for LPA-stimulated breast cancer cell migration. These data also suggest that ROS generation plays an essential role in the activation of LPA-stimulated PI3K/PAK1/ERK signaling and breast cancer cell migration. These findings may provide a basis for designing future therapeutic strategy for blocking breast cancer metastasis.