Cumulus cells (CCs) originating from undifferentiated granulosa cells (GCs) differentiate in mural granulosa cells (MGCs) and CCs during antrum formation in the follicle by the distribution of ...location. CCs are supporting cells of the oocyte that protect the oocyte from the microenvironment, which helps oocyte growth and maturation in the follicles. Bi-directional communications between an oocyte and CCs are necessary for the oocyte for the acquisition of maturation and early embryonic developmental competence following fertilization. Follicle-stimulation hormone (FSH) and luteinizing hormone (LH) surges lead to the synthesis of an extracellular matrix in CCs, and CCs undergo expansion to assist meiotic resumption of the oocyte. The function of CCs is involved in the completion of oocyte meiotic maturation and ovulation, fertilization, and subsequent early embryo development. Therefore, understanding the function of CCs during follicular development may be helpful for predicting oocyte quality and subsequent embryonic development competence, as well as pregnancy outcomes in the field of reproductive medicine and assisted reproductive technology (ART) for infertility treatment.
Intracellular redox homeostasis is crucial for many cellular functions but accurate measurements of cellular compartment-specific redox states remain technically challenging. Genetically encoded ...biosensors including the glutathione-specific redox-sensitive yellow fluorescent protein (rxYFP) may provide an alternative way to overcome the limitations of conventional glutathione/glutathione disulfide (GSH/GSSG) redox measurements. This study describes the use of rxYFP sensors for investigating compartment-specific steady redox state and their dynamics in response to stress in human cells. RxYFP expressed in the cytosol, nucleus, or mitochondrial matrix of HeLa cells was responsive to the intracellular redox state changes induced by reducing as well as oxidizing agents. Compartment-targeted rxYFP sensors were able to detect different steady-state redox conditions among the cytosol, nucleus, and mitochondrial matrix. These sensors expressed in human epidermal keratinocytes HEK001 responded to stress induced by ultraviolet A radiation in a dose-dependent manner. Furthermore, rxYFP sensors were able to sense dynamic and compartment-specific redox changes caused by 100μM hydrogen peroxide (H₂O₂). Mitochondrial matrix-targeted rxYFP displayed a greater dynamics of oxidation in response to a H₂O₂ challenge than the cytosol- and nucleus-targeted sensors, largely due to a more alkaline local pH environment. These observations support the view that mitochondrial glutathione redox state is maintained and regulated independently from that of the cytosol and nucleus. Taken together, our data show the robustness of the rxYFP sensors to measure compartmental redox changes in human cells. Complementary to existing redox sensors and conventional redox measurements, compartment-targeted rxYFP sensors provide a novel tool for examining mammalian cell redox homeostasis, permitting high-resolution readout of steady glutathione state and dynamics of redox changes.
In this paper, a novel self-constructing adaptive robust fuzzy neural control (SARFNC) scheme for tracking surface vehicles, whereby a self-constructing fuzzy neural network (SCFNN) is employed to ...approximate system uncertainties and unknown disturbances, is proposed. The salient features of the SARFNC scheme are as follows: 1) unlike the predefined-structure approaches, the SCFNN is able to online self-construct dynamic-structure fuzzy neural approximator by generating and pruning fuzzy rules, and achieve accurate approximation; 2) an adaptive approximation-based controller (AAC) is designed by combining sliding-mode control with SCFNN approximation using improved projection-based adaptive laws, which avoid parameter drift and singularity in membership functions simultaneously; 3) to compensate for approximation errors, a robust supervisory controller (RSC) is presented to enhance the robustness of the overall SARFNC control system; and 4) the SARFNC consisting of AAC and RSC can achieve an excellent tracking performance, whereby tracking errors and their first derivatives are globally uniformly ultimately bounded. Simulation studies and comprehensive comparisons with traditional adaptive control schemes demonstrate remarkable performance and superiority of the SARFNC scheme in terms of tracking errors and online approximation.
Compelling evidence supports a tight link between oxidative stress and protein aggregation processes, which are noticeably involved in the development of proteinopathies, such as Alzheimer's disease, ...Parkinson's disease, and prion disease. The literature is tremendously rich in studies that establish a functional link between both processes, revealing that oxidative stress can be either causative, or consecutive, to protein aggregation. Because oxidative stress monitoring is highly challenging and may often lead to artefactual results, cutting-edge technical tools have been developed recently in the redox field, improving the ability to measure oxidative perturbations in biological systems. This review aims at providing an update of the previously known functional links between oxidative stress and protein aggregation, thereby revisiting the long-established relationship between both processes.
Intracellular redox homeostasis is crucial for many cellular functions but accurate measurements of cellular compartment-specific redox states remain technically challenging. To better characterize ...redox control in the nucleus, we targeted a yellow fluorescent protein-based redox sensor (rxYFP) to the nucleus of the yeast Saccharomyces cerevisiae. Parallel analyses of the redox state of nucleus-rxYFP and cytosol-rxYFP allowed us to monitor distinctively dynamic glutathione (GSH) redox changes within these two compartments under a given condition. We observed that the nuclear GSH redox environment is highly reducing and similar to the cytosol under steady-state conditions. Furthermore, these sensors are able to detect redox variations specific for their respective compartments in glutathione reductase (Glr1) and thioredoxin pathway (Trr1, Trx1, Trx2) mutants that have altered subcellular redox environments. Our mutant redox data provide in vivo evidence that glutathione and the thioredoxin redox systems have distinct but overlapping functions in controlling subcellular redox environments. We also monitored the dynamic response of nucleus-rxYFP and cytosol-rxYFP to GSH depletion and to exogenous low and high doses of H2O2 bursts. These observations indicate a rapid and almost simultaneous oxidation of both nucleus-rxYFP and cytosol-rxYFP, highlighting the robustness of the rxYFP sensors in measuring real-time compartmental redox changes. Taken together, our data suggest that the highly reduced yeast nuclear and cytosolic redox states are maintained independently to some extent and under distinct but subtle redox regulation. Nucleus- and cytosol-rxYFP register compartment-specific localized redox fluctuations that may involve exchange of reduced and/or oxidized glutathione between these two compartments. Finally, we confirmed that GSH depletion has profound effects on mitochondrial genome stability but little effect on nuclear genome stability, thereby emphasizing that the critical requirement for GSH during growth is linked to a mitochondria-dependent process.
► A redox-sensitive yellow fluorescent protein (rxYFP) was targeted to the yeast nucleus. ► Nucleus- and cytosol-rxYFP can monitor compartment-specific dynamic redox changes. ► The glutathione (GSH) and thioredoxin systems play overlapping roles in subcellular redox control. ► Nuclear redox may be regulated independent of the cytosol. ► An oxidized nuclear redox environment upon GSH depletion does not affect nuclear genome stability.
Objectives
Developing a dynamic regulation strategy is an essential step in establishing an automatic control system for manipulating metabolic fluxes and cellular behaviors. To broaden the extent of ...the application, a system that can generally control any gene of interest is demanded.
Results
Through characterization and optimization, the strategy repressed the immediate expression incrementally from 0 to 90% during culturing. Moreover, by changing single base pair in the lux box of the P
lux
promoter, the degree of repression of the target genomic gene was tuned to a difference of 70%. This strategy is expected to control metabolic flux without disrupting cell growth.
Conclusions
We engineered bacterial small RNA to develop a pathway-independent strategy that can dynamically repress the expression of any gene at the posttranscription level.
In this paper, a multilayer path planner (MPP) with global path-planning (GPP), collision avoidance (CA) and routine correction (RC) for an unmanned surface vehicle (USV) under complex marine ...environments including both coastal and surface constraints is presented. The main contributions of this paper are as follow: 1) An MPP framework consisting of multiple layers, i.e., backbone, CA and RC, is established, and achieves self-tuning path-planning which adapts time-varying environments. 2) To minimize yaw-cost for the USV within local path, a novel CA algorithm is developed by the B-Spline method. 3) For capturing environmental influences arisen from reefs around the coastline, a stochastic dynamic coastal environments (SDCE) model is built by virtue of Poisson distribution. In combination with the fast marching method (FMM) and the SCDE model, the RC algorithm is proposed to handle environmental uncertainties. Simulation results show that the proposed MPP achieves remarkable path-planning performance in terms of both collision avoidance and adaptability to complex environments.
•A multilayer path planner (MPP) for a USV under complex environments is presented.•The MPP achieves self-tuning path planning adapting to time-varying environments.•A novel collision avoidance is developed by the B-spline method.•A stochastic dynamic coastal environments model is built.
Abstract
Background
Cancer cells from different origins exhibit various basal redox statuses and thus respond differently to intrinsic or extrinsic oxidative stress. These intricate characteristics ...condition the success of redox-based anticancer therapies that capitalize on the ability of reactive oxygen species to achieve selective and efficient cancer cell killing.
Methods
Redox biology methods, stable isotope labeling by amino acids in cell culture (SILAC)-based proteomics, and bioinformatics pattern comparisons were used to decipher the underlying mechanisms for differential response of lung and breast cancer cell models to redox-modulating molecule auranofin (AUF) and to combinations of AUF and vitamin C (VC). The in vivo effect of AUF, VC, and two AUF/VC combinations on mice bearing MDA-MB-231 xenografts (n = 5 mice per group) was also evaluated. All statistical tests were two-sided.
Results
AUF targeted simultaneously the thioredoxin and glutathione antioxidant systems. AUF/VC combinations exerted a synergistic and hydrogen peroxide (H2O2)-mediated cytotoxicity toward MDA-MB-231 cells and other breast cancer cell lines. The anticancer potential of AUF/VC combinations was validated in vivo on MDA-MB-231 xenografts in mice without notable side effects. On day 14 of treatments, mean (SD) tumor volumes for the vehicle-treated control group and the two AUF/VC combination–treated groups (A/V1 and A/V2) were 197.67 (24.28) mm3, 15.66 (10.90) mm3, and 10.23 (7.30)mm3, respectively; adjusted P values of the differences between mean tumor volumes of vehicle vs A/V1 groups and vehicle vs A/V2 groups were both less than .001. SILAC proteomics, bioinformatics analysis, and functional experiments linked prostaglandin reductase 1 (PTGR1) expression levels with breast cancer cell sensitivity to AUF/VC combinations.
Conclusion
The combination of AUF and VC, two commonly available drugs, could be efficient against triple-negative breast cancer and potentially other cancers with similar redox properties and PTGR1 expression levels. The redox-based anticancer activity of this combination and the discriminatory potential of PTGR1 expression are worth further assessment in preclinical and clinical studies.
Glutathione is the most abundant antioxidant molecule in living organisms and has multiple functions. Intracellular glutathione homeostasis, through its synthesis, consumption, and degradation, is an ...intricately balanced process. Glutathione levels are often high in tumor cells before treatment, and there is a strong correlation between elevated levels of intracellular glutathione/sustained glutathione-mediated redox activity and resistance to pro-oxidant anticancer therapy. Recent Advances: Ample evidence demonstrates that glutathione and glutathione-based systems are particularly relevant in cancer initiation, progression, and the development of anticancer drug resistance.
This review highlights the multifaceted roles of glutathione and glutathione-based systems in carcinogenesis, anticancer drug resistance, and clinical applications.
The evidence summarized here underscores the important role played by glutathione and the glutathione-based systems in carcinogenesis and anticancer drug resistance. Future studies should address mechanistic questions regarding the distinct roles of glutathione in different stages of cancer development and cancer cell death. It will be important to study how metabolic alterations in cancer cells can influence glutathione homeostasis. Sensitive approaches to monitor glutathione dynamics in subcellular compartments will be an indispensible step. Therapeutic perspectives should focus on mechanism-based rational drug combinations that are directed against multiple redox targets using effective, specific, and clinically safe inhibitors. This new strategy is expected to produce a synergistic effect, prevent drug resistance, and diminish doses of single drugs. Antioxid. Redox Signal. 27, 1217-1234.
The majority of the existing work on random vector functional link networks (RVFLNs) is not scalable for data stream analytics because they work under a batch learning scenario and lack a ...self-organizing property. A novel RVLFN, namely the parsimonious random vector functional link network (pRVFLN), is proposed in this paper. pRVFLN adopts a fully flexible and adaptive working principle where its network structure can be configured from scratch and can be automatically generated, pruned and recalled from data streams. pRVFLN is capable of selecting and deselecting input attributes on the fly as well as capable of extracting important training samples for model updates. In addition, pRVFLN introduces a non-parametric type of hidden node which completely reflects the real data distribution and is not constrained by a specific shape of the cluster. All learning procedures of pRVFLN follow a strictly single-pass learning mode, which is applicable for online time-critical applications. The advantage of pRVFLN is verified through numerous simulations with real-world data streams. It was benchmarked against recently published algorithms where it demonstrated comparable and even higher predictive accuracies while imposing the lowest complexities.
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