Search

In the era of precision medicine, the highly aggressive and heterogenous triple-negative breast cancer (TNBC) is still characterized by limited options to support personalized prognosis and guide therapeutic interventions. Thereafter, the aim of the present study has been the thorough evaluation of miR-146a as a novel molecular indicator of TNBC prognosis and treatment outcome, utilizing four independent TNBC cohorts.miR-146a levels were clinically evaluated in our screening (n=122) and three external validation TNBC cohorts (de Rinaldis et al. 2013, n=114; Jézéquel et al. 2015, n=107; TCGA, n=180). Analysis of miR-146a and validated gene targets was performed in Jézéquel et al. and TCGA validation cohorts. Patients' survival, recurrence and metastasis were determined as clinical endpoints for the survival analysis. Internal validation was performed by bootstrap analysis and clinical net benefit was evaluated by decision curve analysis.Reduction of miR-146a is strongly associated with patients' poor survival and can predict post-treatment disease early-recurrence, independently of tumor size, lymph node status, histological grade and patients' age. The analysis of the external validation cohorts corroborated the unfavorable nature of miR-146a repression regarding patients' survival and, strikingly, unveiled the ability of miR-146a to predict TNBC metastasis. Combined assessment of miR-146a levels and lymph node status resulted in superior risk-stratification of TNBC patients and higher clinical benefit regarding disease prognosis and post-treatment outcome. Ultimately, miR-146a was negatively associated with EGFR and SOX2 expression in TNBC.miR-146a evaluation could ameliorate personalized prognosis and support precision medicine decisions in TNBC.

Objective Our study aimed to investigate the correlations between microstructural changes of cingulum and patients with mild cognitive impairment (MCI) by diffusion kurtosis imaging (DKI) technique. Method A total of 104 patients with cerebral small vessel diseases (cSVD) were retrospectively enrolled in this study. According to Montreal Cognitive Assessment Scale (MoCA) scores, these patients were divided into MCI group (n = 59) and non-MCI group (n = 45). The general clinical data was collected and analyzed. The regions of interests (ROIs) were selected for investigation in cingulum. The values of DKI parameters were measured in each ROI and compared between the two groups, the correlations between DKI parameters and MoCA scores were examined. Results Compared to non-MCI group, MCI patients had more severe white matter hyperintensities (WMHs) (P = 0.038) and lower MoCA scores (P P r = 0.348, 0.409, 0.310, 0.441, 0.422, all P r = 0.338, 0.352, 0.289, 0.380, 0.370, all P Conclusion DKI technique could be used to explore the microstructural changes of cingulum in MCI patients and DKI-derived parameters might be feasible to evaluate MCI patients.

In this work, we demonstrate a novel structure that can generate extraordinary optical transmission with a silicon hemisphere placed on a conventional bull’s eye structure. There is a single subwavelength aperture surrounded by concentric periodic grooves on a substrate. The extraordinary optical transmission in this work is realized by the coupling of the surface plasmon polaritons in the periodic grooves and the localized electromagnetic field generated by the Mie resonance in the silicon hemisphere. The maximum normalized-to-area transmission peak can reach up to 662 with a decreasing device area and size. The electromagnetic field distribution at different geometry parameters is analyzed to clarify the mechanisms of the work in this paper. Additionally, the use of dielectric material in the aperture can avoid ohmic losses of metal material compared with the conventional one, which may suggest that a wider range of bull’s-eye-structure applications is possible.

Objective Kalman filtering has previously been applied to track neural model states and parameters, particularly at the scale relevant to electroencephalography (EEG). However, this approach lacks a reliable method to determine the initial filter conditions and assumes that the distribution of states remains Gaussian. This study presents an alternative, data-driven method to track the states and parameters of neural mass models (NMMs) from EEG recordings using deep learning techniques, specifically a Long Short-Term Memory (LSTM) neural network. Approach An LSTM filter was trained on simulated EEG data generated by a neural mass model using a wide range of parameters. With an appopriately customised loss function, the LSTM filter can learn the behaviour of NMMs. As a result, it can output the state vector and parameters of NMMs given observation data as the input. Main Results Test results using simulated data yielded correlations with R squared of around 0.99 and verified that the method is robust to noise and can be more accurate than a nonlinear Kalman filter when the initial conditions of the Kalman filter are not accurate. As an example of real-world application, the LSTM filter was also applied to real EEG data that included epileptic seizures, and revealed changes in connectivity strength parameters at the beginnings of seizures. Significance Tracking the state vector and parameters of mathematical brain models is of great importance in the area of brain modelling, monitoring, imaging and control. This approach has no need to specify the initial state vector and parameters, which is very difficult to do in practice because many of the variables being estimated cannot be measured directly in physiological experiments. This method may be applied using any neural mass model and, therefore, provides a general, novel, efficient approach to estimate brain model variables that are often difficult to measure.

Ovarian cancer (OC) is identified as one of the most aggressive malignant diseases that imperil women health. Anoikis has been proved to be significantly correlated with the aggressiveness of dislodged cancer cells and poor prognosis of cancer patients. Currently, few researches focus on the prognostic role of anoikis-related genes (AIRGs) on the OC cases. Here, we firstly and systematically analyzed the predictive ability of AIRGS on the prognosis of patients with OC. The genomics data and clinicopathologic information of OC patients were retrieved from TCGA project. Univariate Cox regression and least absolute shrinkage and selection operator (LASSO) method were executed to construct an anoikis–related risk score (AIRS) indicator based on 11 AIRGs. ICGC-OV and GSE26712 were used as independent validation datasets. A nomogram integrated AIRS and pathologic parameters, survival analysis and time-dependent receiver operating characteristic (ROC) curves were utilized to assess the predictive performance of this signature. Successfully, OC patients were divided into two sets based on the optimum cut-off value of risk scores. High risk category evidently suffers from more unfavorable survival outcomes. What is more, AIRS was closely connected with tumor microenvironment (TME) characteristics, mutant landscape, m6A modification and clinical implications. Interestingly, we validated EML2 as a crucial risk gene in OC based on GSEA, single-cell analysis and immunohistochemical staining results. Collectively, AIRS was validated as an independent prognostic indicator with good predictive validity in OC. It can function as a robust clinical parameter which effectively stratifies OC patients and promotes the development of precise medicine.

Background: Thyroid cancer is a common malignant tumor of the endocrine system that has shown increased incidence in recent decades. We explored the relationship between tumor-infiltrating immune cell classification and the prognosis of thyroid carcinoma.Methods: RNA-seq, SNV, copy number variance (CNV), and methylation data for thyroid cancer were downloaded from the TCGA dataset. ssGSEA was used to calculate pathway scores. Clustering was conducted using ConsensusClusterPlus. Immune infiltration was assessed using ESTIMATE and CIBERSORT. CNV and methylation were determined using GISTIC2 and the KNN algorithm. Immunotherapy was predicted based on TIDE analysis. Results: Three molecular subtypes (Immune-enrich(E), Stromal-enrich(E), and Immune-deprived(D)) were identified based on 15 pathways and the corresponding genes. Samples in Immune-E showed higher immune infiltration, while those in Immune-D showed increased tumor mutation burden (TMB) and mutations in tumor driver genes. Finally, Immune-E showed higher CDH1 methylation, higher progression-free survival (PFS), higher suitability for immunotherapy, and higher sensitivity to small-molecule chemotherapeutic drugs. Additionally, an immune score (IMScore) based on four genes was constructed, in which the low group showed better survival outcome, which was validated in 30 cancers. Compared to the TIDE score, the IMScore showed better predictive ability.Conclusion: This study constructed a prognostic evaluation model and molecular subtype system of immune-related genes to predict the thyroid cancer prognosis of patients. Moreover, the interaction network between immune genes may play a role by affecting the biological function of immune cells in the tumor microenvironment.

This article details the development and evaluation of a practical solution for path-constrained proximity maneuvers of spacecraft. Whereas no velocity measurement is utilized within the feedback structure, the controller rigorously enforces actuator magnitude constraints. Specifically, the control algorithm is constructed from a potential function method repelling the spacecraft from possible collisions. The proposed controller can guarantee potential functions to be navigated to the origin and thus overcome the stubborn local minima problem. Moreover, the control capability under any given control limit can be estimated and adjusted by changing the feedback gains. The specific performance with guaranteed safety can be also explicitly calculated by designers. The results are obtained through a Lyapunov-based stability analysis to prove uniformly ultimate boundedness. Numerical simulation results illustrate the performance and features of the developed control method.

This study mainly aims to detect the county-level spatio-temporal variability of LULCC (Land Use and Land Cover Change) spatial patterns in Southwest China. Multi-temporal Remote Sensing (RS) images (Landsat TM/OLI in 2000, 2005, 2010, and 2015) were applied to extract land use/cover types at each of the four-time nodes using the Support Vector Machine (SVM) method. Then, the trajectory map methodology was adopted to identify the spatio-temporal distribution characteristics of LULCC patterns throughout the given time series. According to the results, the area of unused land decreased continuously, 0.094% total. An evident decline of grassland by 2.17% was documented, and a notable increase was observed in forestland by 63.94 km2 during the period from 2000 to 2015. Water bodies, built-up land, and unused land showed no significant change throughout the study period. The conversion from grassland to forestland and vice-versa (code 13 or 31) was prominent due to an adjustment made to local forestry policy during the first two periods (2000-2005 and 2005-2010), accounting for 17.55% and 17.56% of the study region, respectively. The anaphase trajectory transition type occupied the smallest area of all the trajectory maps. By contrast, the repetitive trajectory was the leading land-use transition type and covered the largest area. Trajectory analysis provides an effective approach for detecting the spatio-temporal changes in LULCC patterns.

The Hippo/YAP (yes-associated protein) pathway is an important signaling pathway to control organ development and tissue homeostasis. YAP is a downstream effector of the Hippo pathway and a critical mediator of mechanic stress. Hypertensive nephropathy is characterized with glomerular sclerosis stiffness and renal fibrosis. The present study investigated the role of YAP pathway in angiotensin (Ang) II hypertensive renal injury by using YAP activation inhibitor verteporfin. Ang II increased the protein expression of YAP in renal nucleus fraction, decreased phospho-YAP, and phospho-LATS1/2 (large tumor suppressors 1 and 2) expressions in renal cytoplasmic fraction, suggesting Ang II activation of renal YAP. Ang II significantly increased systolic blood pressure (SBP), proteinuria, glomerular sclerosis, and fibrosis; treatment with verteporfin attenuated Ang II–induced proteinuria and renal injury with a mild reduction in SBP. Moreover, Ang II increased the protein expressions of inflammatory factors including tumor necrosis factor α, interleukin 1β, and monocyte chemoattractant protein-1, and profibrotic factors including transforming growth factor β, phospho-Smad3 and fibronectin. Verteporfin reversed abovementioned Ang II–induced molecule expressions. Our results for the first time demonstrate that the activation of the YAP pathway promotes hypertensive renal inflammation and fibrosis, which may promote hypertensive renal injury. YAP may be a new target for prevention and treatment of hypertensive renal diseases.

With the fast pace of globalization, cultivating Intercultural Communicative Competence (ICC) has gradually become a vital goal in English language teaching. However, whether the English Viewing-Listening-Speaking (VLS) course can be used to improve learners’ ICC is less researched. This paper tends to adopt skills of discovery, comparison and analysis in Byram’s ICC model as methods to explore how students interpret in VLS class and how the interpretation processes improve students’ intercultural communicative competence. The design and implementation of teaching activities, combined with the research data including quizzes, students’ statement recording and reports, are introduced to illustrate how to improve learners’ ICC in VLS course.

Zero-index metamaterials (ZIMs) feature a uniform electromagnetic mode over a large area in arbitrary shapes, enabling many applications including high-transmission supercouplers with arbitrary shapes, direction-independent phase matching for nonlinear optics, and collective emission of many quantum emitters. However, most ZIMs reported till date are passive, with no method for the dynamic modulation of their electromagnetic properties. Here, we design and fabricate a magnetically tunable ZIM consisting of yttrium iron garnet (YIG) pillars sandwiched between two copper clad laminates in the microwave regime. By harnessing the Cotton-Mouton effect of YIG, the metamaterial was successfully toggled between gapless and bandgap states, leading to a "phase transition" between a zero-index phase and a single negative phase of the metamaterial. Using an S-shaped ZIM supercoupler, we experimentally demonstrated a tunable supercoupling state with a low intrinsic loss of 0.95 dB and a high extinction ratio of up to 30.63 dB at 9 GHz. Our work enables dynamic modulation of the electromagnetic characteristics of ZIMs, enabling various applications in tunable linear, nonlinear, quantum and nonreciprocal electromagnetic devices.

In this work, a hemispheric gold particle is introduced to the conventional bull’s eye structure that enhances extraordinary optical transmission in the terahertz region. Transmission enhancement is a result of the coupling of surface plasmon polaritons generated by periodic grooves and localized surface plasmon resonances generated by the hemisphere particle. The maximum normalized-to-area transmission peak reaches 556 for the hemisphere-in-hole bull’s eye structure, which is significantly higher than conventional bull’s eye structure. Such a transmission property is insensitive to polarization direction. The physical mechanisms are thoroughly analyzed by geometric parameter optimization and electromagnetic simulations. The modified structure can reduce the number of grooves in need, thereby reducing the device area. This novel design can be instructive for future improvement of bull’s eye applications.

Biliary tract cancer (BTC) is a highly aggressive malignant tumor. Serum microRNAs (ser-miRNAs) serve as noninvasive biomarkers to identify high risk individuals, thereby facilitating the design of precision therapies. The study is to prioritize key synergistic ser-miRNAs for the diagnosis of early BTC. Sampling technology, significant analysis of microarrays, Pearson Correlation Coefficients, t-test, decision tree, and entropy weight were integrated to develop a global optimization algorithm of decision forest. The source code is available at https://github.com/SuFei-lab/GOADF.git. Four key synergistic ser-miRNAs were prioritized and the synergistic classification performance was better than the single miRNA’ s. In the internal feature evaluation dataset, the area under the receiver operating characteristic curve (AUC) for each single miRNA was 0.8413 (hsa-let-7c-5p), 0.7143 (hsa-miR-16-5p), 0.8571 (hsa-miR-17-5p), and 0.9365 (hsa-miR-26a-5p), respectively, whereas the synergistic AUC value increased to 1.0000. In the internal test dataset, the single AUC was 0.6500, 0.5125, 0.6750, and 0.7500, whereas the synergistic AUC increased to 0.8375. In the independent test dataset, the single AUC was 0.7280, 0.8313, 0.8957, and 0.8303, and the synergistic AUC was 0.9110 for discriminating between BTC patients and healthy controls. The AUC for discriminating BTC from pancreatic cancer was 0.9000. Hsa-miR-26a-5p was a predictor of prognosis, patients with high expression had shorter survival than those with low expression. In conclusion, hsa-let-7c-5p, hsa-miR-16-5p, hsa-miR-17-5p, and hsa-miR-26a-5p may act as key synergistic biomarkers and provide important molecular mechanisms that contribute to pathogenesis of BTC.

Neural mechanisms are complex and difficult to image. This paper presents a new space-time resolved whole-brain imaging framework, called Neurophysiological Mechanism Imaging (NMI), that identifies neurophysiological mechanisms within cerebral cortex at the macroscopic scale. By fitting neural mass models to electromagnetic source imaging data using a novel nonlinear inference method, population averaged membrane potentials and synaptic connection strengths are efficiently and accurately imaged across the whole brain at a resolution afforded by source imaging. The efficiency of the framework enables return of the augmented source imaging results overnight using high performance computing. This suggests it can be used as a practical and novel imaging tool. To demonstrate the framework, it has been applied to resting-state magnetoencephalographic source estimates. The results suggest that endogenous inputs to cingulate, occipital, and inferior frontal cortex are essential modulators of resting-state alpha power. Moreover, endogenous input and inhibitory and excitatory neural populations play varied roles in mediating alpha power in different resting-state sub-networks. The framework can be applied to arbitrary neural mass models and has broad applicability to image neural mechanisms in different brain states.HighlightsThe whole-brain imaging framework can disclose the neurophysiological substrates of complicated brain functions in a spatiotemporal manner.Developed a semi-analytical Kalman filter to estimate neurophysiological variables in the nonlinear neural mass model efficiently and accurately from large-scale electromagnetic time-series.The semi-analytical Kalman filter is 7.5 times faster and 5% more accurate in estimating model parameters than the unscented Kalman filter.Provided several group-level statistical observations based on neurophysiological variables and visualised them in a whole-brain manner to show different perspectives of neurophysiological mechanisms.Applied the framework to study resting-state alpha oscillation and found novel relationships between local neurophysiological variables in specific brain regions and alpha power.

Purpose: Ovarian cancer is the most lethal malignancy with depressive 5-year survival rate, mainly due to patients with advanced stages experience tumor recurrence and resistance to the current chemotherapeutic agents. Thus, discovering the underlying molecular mechanisms involved in chemo-resistance is crucial for management of treatment to improve therapeutic outcomes. Methods: The protein and mRNA expression of FAM46A in ovarian cancer cell lines and patient tissues were determined using Real-time PCR and Western blot and IHC respectively. Functional assays, such as MTT, FACS assay used to determine the oncogenic role of FAM46A in human ovarian cancer progression. Furthermore, western blotting and luciferase assay were used to determine the mechanism of FAM46A promotes chemoresistance in ovarian cancer cells. Results: In the current study, we found overexpression of FAM46A expression in ovarian cancer patients demonstrated an aggressive phenotype and poor prognosis. Furthermore, FAM46A overexpression in ovarian cancer cells demonstrated higher CDDP resistance ability; however, inhibition of FAM46A sensitized ovarian cancer cell lines to CDDP cytotoxicity both in vitro and in vivo. Mechanically, upregulation of FAM46A activated transforming growth factor-β (TGF-β)/Smad signaling and upregulated the levels of nuclear Smad2. Conclusions: Taken together, our results highlight the important oncogenic role of FAM46A in ovarian cancer progression and might provide a potential clinical target for patients with chemoresistant ovarian cancer.

In this study, a Mg–Zn–Y–Zr alloy was laser cladded with Al–SiC powder using different weight percentages and different grain sizes of SiC to improve its surface properties. We observed that the laser-cladded layer primarily comprised α-Mg, Mg2Si, Mg17Al12, Al2Y and Al3Y phases. Moreover, the cladded layer exhibited a progressive microstructure and composition, and the volume fraction and size of the Mg17Al12, Al2Y and Al3Y phases decreased with the increase in depth. Because of the formation of these hardened phases, the average hardness of the sample with 10% of nSiCp was 4.06 times that of the substrate. In comparison with four laser-cladded samples, the sample cladded with 5% of nSiCp had the lowest friction coefficient and the highest wear resistance. The potentio-dynamic polarisation curves, measured in an aqueous NaCl (3.5 wt%) solution, demonstrated that for samples with a cladding of 10% nm, the corrosion potential increased from − 1.63 V for the untreated Mg–Zn–Y–Zr alloy to − 1.32 V for the laser-cladded alloy. The corrosion current density significantly decreased from 3.60 × 10−5 to 4.03 × 10−6 A cm−2. These results demonstrate that laser cladding with nano-SiC is an effective method to significantly improve the surface properties of Mg-rare earth alloys.

This paper addresses the attitude-maneuver control problem for a rigid-body spacecraft in the presence of attitude-constrained zones as well as input saturation. More specifically, attitude-constra...

It has been shown that the inflammatory cytokine tumor necrosis factor α (TNFα) plays a role in the development of hypertension and end-stage renal diseases. We hypothesize that TNFα contributes to endothelial dysfunction and cardiac and vascular injury in deoxycorticosterone acetate (DOCA)/salt-hypertensive mice. The wild-type or TNFα-deficient mice were uninephrectomized and implanted with DOCA pellet treatment for 5 weeks; the mice were given either tap water or 1% NaCl drinking water. DOCA mice developed hypertension (systolic blood pressure (SBP): 167±5 vs. 110±4 mmHg in control group, p<0.05), cardiac and vascular hypertrophy, and the impairment of endothelium-dependent relaxation to acetylcholine (EDR). TNFα deficiency improved EDR and lowered cardiac and vascular hypertrophy with a mild reduction in SBP (152±4 vs. 167±5 mmHg in DOCA group, p<0.05) in DOCA mice. The mRNA expressions of the inflammatory cytokines, including TNFα, interleukin 1β (IL1β), monocyte chemotactic protein 1 (MCP1), and monocyte/macrophage marker F4/80 were significantly increased in the aorta of DOCA-hypertensive mice; TNFα deficiency reduced these inflammatory gene expressions. DOCA-hypertensive mice also exhibited an increase in the vascular oxidative fluorescence intensities, the protein expressions of gp91phox and p22phox, and the fibrotic factors transforming growth factor β and fibronectin. TNFα deficiency reduced oxidative stress and fibrotic protein expressions. The DOCA mice also showed a decrease in the protein expression of eNOS associated with increased miR155 expression; TNFα deficiency prevented a decrease in eNOS expression and an increase in miR155 expression in DOCA mice. These results support the idea that TNFα significantly contributes to vascular inflammation, vascular dysfunction, and injury in hypertension.

Background The serine protease KLK12 belongs to the human fifteen-member family of kallikrein-related peptidases. Differential expression accompanied by either increased or decreased enzymatic activity has been linked to several diseases including cancer. Triple-negative breast cancer (TNBC) represents a very aggressive subgroup of breast cancer with high tumor recurrence rates and poor patient prognosis. Here, we quantified the KLK12 mRNA expression levels in tumor tissue of TNBC patients and analyzed their prognostic value. Methods In the present study, KLK12 mRNA expression in tumor tissue of TNBC patients (n = 116) was determined by quantitative real-time PCR assay. The association of KLK12 mRNA levels with clinical parameters, and patients’ outcome was analyzed using Chi-square tests, Cox regression models and Kaplan-Meier survival analysis. Results Positive, but low KLK12 mRNA levels were detected in about half of the cases (54 out of 116; 47%), the other samples were negative for KLK12 mRNA expression. No significant association was observed between KLK12 mRNA levels and clinicopathological variables (age, lymph node status, tumor size, and histological grade). In univariate Cox analyses, positive KLK12 mRNA expression was significantly associated with shortened disease-free survival (DFS; hazard ratio [HR] = 2.12, 95% CI = 1.19–3.78, p = 0.010) as well as overall survival (OS; HR = 1.91, 95% CI = 1.04–3.50, p = 0.037). In multivariable Cox analysis, including all clinical parameters plus KLK12 mRNA, the latter - together with age - remained an independent unfavorable predictive marker for DFS (HR = 2.33, 95% CI = 1.28–4.24, p = 0.006) and showed a trend towards significance in case of OS (HR = 1.80, 95% CI = 0.96–3.38, p = 0.066). Conclusions Positive KLK12 expression is remarkably associated with shortened DFS and OS, suggesting that KLK12 plays a tumor-supporting role in TNBC.

A low Schottky barrier height (SBH) of metal–semiconductor contact is essential for achieving high performance electronic devices. Based on first principles calculations, we have comprehensively investigated the interfacial properties of β-Ga2O3 (100) with different metals including Mg, Ni, Cu, Pd and Pt. SBHs have been calculated via layered partial density of states (PDOS) and validated by visual wavefunctions. The results surprisingly show that Mg contact possesses the lowest SBH of 0.23 eV, while other SBHs range from 1.06 eV for Ni, 1.17 eV for Pd and 1.27 eV for Cu to 1.39 eV for Pt. This shows that SBHs of β-Ga2O3 are not fully dependent on metal work functions due to a Fermi level pinning effect. The tunneling barrier was also calculated via electrostatic potential with a 72.85% tunneling probability of the Mg/Ga2O3 interface. The present study will provide an insight into characteristics of Ga2O3/metal interfaces and give guidance for metal choice for Ga2O3 electronic devices.

We report a magnetic tunable structure consists of YIG nanorods. Applied magnetic field leading to a tunable band gap from 0 to 0.67 GHz, effective refractive index from 0 to 0+0.09i at 9 GHz frequency.

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with poor patient prognosis and limited therapeutic options. A lack of prognostic biomarkers and therapeutic targets fuels the need for new approaches to tackle this severe disease. Extracellular matrix degradation, release, and modulation of the activity of growth factors/cytokines/chemokines, and the initiation of signaling pathways by extracellular proteolytic networks, have been identified as major processes in the carcinogenesis of breast cancer. Members of the kallikrein-related peptidase (KLK) family contribute to these tumor-relevant processes, and are associated with breast cancer progression and metastasis. In this study, the clinical relevance of mRNA expression of two members of this family, KLK10 and KLK11, has been evaluated in TNBC. For this, their expression levels were quantified in tumor tissue of a large, well-characterized patient cohort (n = 123) via qPCR. Although, in general, the overall expression of both factors are lower in tumor tissue of breast cancer patients (encompassing all subtypes) compared to normal tissue of healthy donors, in the TNBC subtype, expression is even increased. In our cohort, a significant, positive correlation between the expression levels of both KLKs was detected, indicating a coordinate expression mode of these proteases. Elevated KLK10 and KLK11 mRNA levels were associated with poor patient prognosis. Moreover, both factors were found to be independent of other established clinical factors such as age, lymph node status, or residual tumor mass, as determined by multivariable Cox regression analysis. Thus, both proteases, KLK10 and KLK11, may represent unfavorable prognostic factors for TNBC patients and, furthermore, appear as promising potential targets for therapy in TNBC.

Ischemic stroke can induce neurogenesis. However, most stroke-generated newborn neurons cannot survive. It has been shown that MR-409, a potent synthetic agonistic analog of growth hormone–releasing hormone (GHRH), can protect against some life-threatening pathological conditions by promoting cell proliferation and survival. The present study shows that long-term treatment with MR-409 (5 or 10 μg/mouse/d) by subcutaneous (s.c.) injection significantly reduces the mortality, ischemic insult, and hippocampal atrophy, and improves neurological functional recovery in mice operated on for transient middle cerebral artery occlusion (tMCAO). Besides, MR-409 can stimulate endogenous neurogenesis and improve the tMCAO-induced loss of neuroplasticity. MR-409 also enhances the proliferation and inhibits apoptosis of neural stem cells treated with oxygen and glucose deprivation–reperfusion. The neuroprotective effects of MR-409 are closely related to the activation of AKT/CREB and BDNF/TrkB pathways. In conclusion, the present study demonstrates that GHRH agonist MR-409 has remarkable neuroprotective effects through enhancing endogenous neurogenesis in cerebral ischemic mice.

Calcineurin is a Ca

Autophagy functions as a critical process that can suppress the proliferation of Mycobacterium tuberculosis (Mtb) within infected host cells. Wnt5a is a secreted protein that plays a range of physiological functions, activating several signaling pathways and thereby controlling cellular responses to particular stimuli. The importance of Wnt5a as a regulator of protection against Mtb infection, however, has yet to be fully characterized. Here, changes in murine pulmonary epithelial-like TC-1 cell morphology, autophagy, the Wnt/Ca

In this paper, the effects of doping structure of multi-proton injection (MPI) buffer layer on static and short circuit characteristics of IGBT were studied, and the relationship between donor concentration of the buffer layer and injection dose and annealing temperature was studied. The MPI buffer layer suitable for 4500V IGBT was optimized by comparative experiments. This MPI buffer layer can solve the problem of high-temperature activation of the traditional IGBT buffer layer and lower thermal budget and can be fabricated on large wafers for better parameter consistency.

Neural processes are complex and difficult to image. This paper presents a new space-time resolved brain imaging framework, called Neurophysiological Process Imaging (NPI), that identifies neurophysiological processes within cerebral cortex at the macroscopic scale. By fitting uncoupled neural mass models to each electromagnetic source time-series using a novel nonlinear inference method, population averaged membrane potentials and synaptic connection strengths are efficiently and accurately inferred and imaged across the whole cerebral cortex at a resolution afforded by source imaging. The efficiency of the framework enables return of the augmented source imaging results overnight using high performance computing. This suggests it can be used as a practical and novel imaging tool. To demonstrate the framework, it has been applied to resting-state magnetoencephalographic source estimates. The results suggest that endogenous inputs to cingulate, occipital, and inferior frontal cortex are essential modulators of resting-state alpha power. Moreover, endogenous input and inhibitory and excitatory neural populations play varied roles in mediating alpha power in different resting-state sub-networks. The framework can be applied to arbitrary neural mass models and has broad applicability to image neural processes of different brain states.

Epilepsy is characterized by recurrent seizures that have a variety of manifestations. The severity of, and risks for patients associated with, seizures are largely linked to the duration of seizures. Methods that determine seizure duration based on seizure onsets could be used to help mitigate the risks associated with what might be extended seizures by guiding timely interventions.Using long-term intracranial electroencephalography (iEEG) recordings, this article presents a method for predicting whether a seizure is going to be long or short by analyzing the seizure onset. The definition of long and short depends on each patient's seizure distribution. By analyzing 2954 seizures from 10 patients, patient-specific classifiers were built to predict seizure duration given the first few seconds from the onset.The proposed methodology achieved an average area under the receiver operating characteristic curve (AUC) performance of 0.7 for the 5 of 10 patients with above chance prediction performance (p value from 0.04 to 10Our results imply that the duration of seizures can be predicted from the onset in some patients. This could form the basis of methods for predicting status epilepticus or optimizing the amount of electrical stimulation delivered by seizure control devices.

Yes-associated protein (YAP) and its associated coactivator of PDZ-binding motif (TAZ) are co-transcriptional regulators and down effectors of the Hippo signaling pathway. Recent studies have shown that the Hippo/YAP signaling pathway may play a role in mediating vascular homeostasis. This study investigated the role of YAP/TAZ in endothelial dysfunction and vascular inflammation in angiotensin (Ang)II hypertensive mice. The infusion of AngII (1.1 mg/kg/day by mini-pump) for 3 weeks induced the activation of YAP/TAZ, manifested by decreased cytosolic phosphor-YAP and phosphor-TAZ, and increased YAP/TAZ nuclear translocation, which were prevented by YAP/TAZ inhibitor verteporfin. AngII significantly increased systolic blood pressure (SBP), macrophage infiltration, and expressions of proinflammatory cytokines, and impaired endothelial function in the aorta of the mice. Treatment with verteporfin improved endothelial function and reduced vascular inflammation with a mild reduction in SBP. AngII also induced YAP/TAZ activation in human umbilical vein endothelial cells in vitro, which were prevented by LB-100, an inhibitor of protein phosphatase 2A (PP2A, a major dephosphorylase). Treatment with LB-100 reversed AngII-induced proinflammatory cytokine expression and impairment of phosphor-eNOS expression in vitro. Our results suggest that AngII induces YAP/TAZ activation via PP2A-dependent dephosphorylation, which may contribute to the impairment of endothelial function and the induction of vascular inflammation in hypertension. YAP/TAZ may be a new target for hypertensive vascular injury.

We aimed to identify miRNAs that were closely related to breast cancer (BRCA). By integrating several methods including significance analysis of microarrays, fold change, Pearson’s correlation analysis, t test, and receiver operating characteristic analysis, we developed a decision-tree-based scoring algorithm, called Optimized Scoring Mechanism for Primary Synergy MicroRNAs (O-PSM). Five synergy miRNAs (hsa-miR-139-5p, hsa-miR-331-3p, hsa-miR-342-5p, hsa-miR-486-5p, and hsa-miR-654-3p) were identified using O-PSM, which were used to distinguish normal samples from pathological ones, and showed good results in blood data and in multiple sets of tissue data. These five miRNAs showed accurate categorization efficiency in BRCA typing and staging and had better categorization efficiency than experimentally verified miRNAs. In the Protein-Protein Interaction (PPI) network, the target genes of hsa-miR-342-5p have the most regulatory relationships, which regulate carcinogenesis proliferation and metastasis by regulating Glycosaminoglycan biosynthesis and the Rap1 signaling pathway. Moreover, hsa-miR-342-5p showed potential clinical application in survival analysis. We also used O-PSM to generate an R package uploaded on github (SuFei-lab/OPSM accessed on 22 October 2021). We believe that miRNAs included in O-PSM could have clinical implications for diagnosis, prognostic stratification and treatment of BRCA, proposing potential significant biomarkers that could be utilized to design personalized treatment plans in BRCA patients in the future.

A continuous saturated attitude control scheme is proposed that meets the control object of reorientation and attitude forbidden zone avoidance. Constructed from the classical potential-function-based control methodology, the derived controller can achieve uniformly ultimate boundedness without the obstruction of local minima or saddle points of the potential function. Specifically, the properties of derived potential are analyzed meticulously. Moreover, an explicit controllable domain is integrated into certain inequalities featuring initial states and control parameters to describe the capability of avoidance. The control performance can be also estimated and adjusted by tuning control parameters. A Lyapunov-based analysis is provided to show the convergence of the potential function, the gradient of the potential function and the closed-loop system. Furthermore, simulations are performed to demonstrate the effectiveness and features of the control law.

This paper proposes an overall design scheme of Line-of-sight (LOS) tracking control for the integrated satellite system with vibration isolation platform (VIP) and control moment gyroscopes (CMGs). First, the three-axis attitude and motion trajectory are established for tracking the on-orbit dynamic target. To improve the accuracy and stability of target tracking, the VIP is applied to isolate CMGs micro vibration, and then controller parameters of integrated satellite system are synthetically designed based on the classical control theory. Subsequently, the effectiveness of the control scheme is verified by frequency and time domain simulation. The numerical examples show that the tracking accuracy can be increased by 80% and the stability can be improved by two orders of magnitude after adding VIP in the presence of the sample time of controller and the rotor static and dynamic imbalance.

Background N-methyl-d-aspartate receptors (NMDARs) have been demonstrated to play central roles in stroke pathology and recovery, including dual roles in promoting either neuronal survival or death with their different subtypes and locations. Purpose We have previously demonstrated that pseudoginsenoside-F11 (PF11) can provide long-term neuroprotective effects on transient and permanent ischemic stroke-induced neuronal damage. However, it is still needed to clarify whether NMDAR-2A (NR2A)-mediated pro-survival signaling pathway is involved in the beneficial effect of PF11 on permanent ischemic stroke. Material and Methods PF11 was administrated in permanent middle cerebral artery occlusion (pMCAO)-operated rats. The effect of PF11 on oxygen-glucose deprivation (OGD)-exposed primary cultured neurons were further evaluated. The regulatory effect of PF11 on NR2A expression and the activation of its downstream AKT-CREB pathway were detected by Western blotting and immunofluorescence in the presence or absence of a specific NR2A antagonist NVP-AAM077 (NVP) both in vivo and in vitro. Results PF11 dose- and time-dependently decreased calpain1 (CAPN1) activity and its specific breakdown product α-Fodrin expression, while the expression of Ca2+/calmodulin-dependent protein kinase II alpha (CaMKII-α) was significantly upregulated in the cortex and striatum of rats at 24 h after the onset of pMCAO operation. Moreover, PF11 prevented the downregulation of NR2A, p-AKT/AKT, and p-CREB/CREB in both in vivo and in vitro stroke models. Finally, the results indicated treatment with NVP can abolish the effects of PF11 on alleviating the ischemic injury and activating NR2A-mediated AKT-CREB signaling pathway. Conclusions Our results demonstrate that PF11 can exert neuroprotective effects on ischemic stroke by inhibiting the activation of CAPN1 and subsequently enhancing the NR2A-medicated activation of AKT-CREB pathway, which provides a mechanistic link between the neuroprotective effect of PF11 against cerebral ischemia and NR2A-associated pro-survival signaling pathway.

Objective: Hypertension is associated with a low-grade systemic inflammation in cardiovascular system. Macrophage infiltration may initiate an inflammatory process that contributes to vascular and ventricular remodeling in hypertensive human and mice. The present study investigated the effect of chemical depletion of macrophage using liposome encapsulated clodronate (LEC) on cardiac hypertrophy and remodeling in angiotensin (Ang) II hypertensive mice.Methods: C57BL/6 mice received an Ang II (1.1 mg/kg/day with a minipump) infusion for 2 weeks to induce hypertension. Endothelium-dependent relaxation (ED) was examined by organ bath, hematoxylin and staining and Masson-Trichrome staining were used to evaluate aorta and cardiac hypertrophy and fibrosis.Results: Ang II infusion significantly increased systolic blood pressure (SBP), cardiac hypertrophy and fibrosis, and impaired EDR accompanied by increased macrophage infiltration in the heart. Treatment with LEC significantly lowered Ang II-induced cardiac hypertrophy and fibrosis and cardiac macrophage infiltration, and improved EDR with a mild reduction in SBP. Ang II increased the expression of inflammatory cytokines tumor necross factor alpha and interleukin 1 beta and profibrotic factors transforming growth factor beta 1 and fibronectin in the heart, with was reduced by LEC treatment. Treatment with LEC prevented Ang II-induced the phosphorphorylation of ERK1/2 and c-Jun-N-terminal kinase.Conclusions: Our study suggests that cardiac macrophage may be critical for hypertensive cardiac hypertrophy and remodeling, the underlying mechanisms may involve initial heart inflammation and the activation of hypertrophic MAPKs pathway.

A novel adaptive control solution for pose tracking problems of spacecraft proximity operations subject to not only motion constraints but also parameter uncertainties is proposed in this paper. Sp...

Effect of gasifying agents, such as air, oxygen-enriched air, air-steam, and oxygen-steam, on sawdust gasification was investigated in a novel pilot scale bubbling fluidized bed gasification system. The results showed that gasifying agents had a significant effect on gasification performance and producer gas properties. H2 content in the producer gas increased as equivalence ratio (ER) increased from 0.20 to 0.30 for all gasifying agents used. CO, CH4, and CnHm decreased and CO2 presented two different trends as ER increased from 0.20 to 0.30, resulting in lower heating value decreasing, gas yield increasing, carbon conversion efficiency and cold gas efficiency change. Compared to sawdust gasification using air only, oxygen-enriched air increased lower heating value due to reducing N2 dilution, air-steam favored H2 production because of enhancing water gas shift reaction, and oxygen-steam took both advantages of N2 free and steam addition. The maximum value of the H2/CO ratio was 1.44 by using air-steam and oxygen-steam as the gasifying agents at the ER of 0.30.

Calcium overload has been reported to trigger neuronal death following stroke. Pseudoginsenoside-F11 (PF11), an ocotillol-type ginsenoside with various neuroprotective activities, has displayed therapeutic efficacy against permanent ischemic stroke. The present study examined the protective potential of PF11 in rats subjected to 2-h transient middle cerebral artery occlusion (tMCAO) and in cultured primary cortical neuron (PCN) exposed to oxygen–glucose deprivation/reoxygenation (OGD/R). Single intravenous administration of PF11 (12 mg/kg) significantly reduced infarct volume, brain edema, neurological deficit and cortex neuron loss at 24 h after reperfusion. Immunoblotting and immunofluorescence demonstrated that PF11 inhibited the over activation of μ-Calpain and the reduction of calcium calmodulin kinase II-α, reduced the degradation of sarcoplasmic/endoplasmic reticulum ATPase-2 and alleviated endoplasmic reticulum stress (ERS) in tMCAO rats. What's more, rats treated with PF11 (12 mg/kg) intravenously immediately after reperfusion, and then intraperitoneally every 24 h for 14 days exhibited lessened cortex neuron loss, reduced mortality and improved performances of rotarod, grip strength and gait patterns at 1, 4, 7, and 14 days after tMCAO. Furthermore, in vitro investigations showed PF11 increased cell viability, reduced neurites decline, restored ATP level and decreased calcium content in cultured PCN under OGD/R. Moreover, PF11 alleviated ERS, reversed the diminished levels of NMDA-2B subunit, postsynaptic density protein 95 and neuronal nitric oxide synthase both in vivo and in vitro. Our study indicates that PF11 produced neuroprotection and improved long-term outcomes while repressing calcium overload in model of transient focal ischemia, suggesting that PF11 might be a considerable candidate for stroke treatment.

Background In ovarian cancer, dysregulation of mRNA expression of several components of the family of the kallikrein-related peptidases (KLKs) is observed. In this study, we have analyzed the KLK5 mRNA expression pattern in tumor tissue of patients suffering from high-grade serous ovarian cancer stage FIGO III/IV. Moreover, we have correlated the KLK5 mRNA levels with clinical outcome. Methods We assessed the mRNA expression levels of KLK5 in tumor tissue of 138 patients using quantitative PCR (qPCR). The mRNA levels were correlated with KLK5 antigen tumor tissue levels measured by ELISA (available for 41 of the 138 patients), established clinical features as well as patients’ outcome, using Chi-square-tests, Mann-Whitney U-tests and Spearman rank calculations as well as Cox regression models, Kaplan-Meier survival analysis and the log-rank test. Results A highly significant correlation between the mRNA expression levels and protein levels of KLK5 in tumor tissues was observed (rs = 0.683, p 0 mm), but not ascites fluid volume (≤500 ml vs. > 500 ml), remained an independent indicator for both OS and PFS (p

This paper addresses the approaching trajectory control problem for the final phase of non-cooperative spacecraft proximity operations in the presence of disturbances and even input saturation. As a stepping stone, a novel line-of-sight tracking model is developed to describe attitude maneuver towards the target in the proximity. Then, a two-stage artificial potential function is employed to enable the pursuer spacecraft to comply the safety trajectory during approaching the target. In each stage, gradients of potential function are analyzed and the local minimum problem associated with potential function can be addressed. Furthermore, a saturated control law is proposed to ensure a reliable real-time tracking measurement of the target, and the controller rigorously enforces safe path and actuator magnitude constraints. The associated stability proof is accomplished through Lyapunov method. Simulations are carried out to evaluate the effectiveness of the proposed method.