Dysfunction of the homeostasis‐maintaining systems in specific cell types or tissues renders the organism susceptible to a range of diseases, including cancers. One of the emerging mechanisms for ...maintaining tissue homeostasis is cellular senescence. Here, we report that the Hippo pathway plays a critical role in controlling the fate of ovarian cells. Hyperactivation of Yes‐associated protein 1 (YAP1), the major effector of the Hippo pathway, induces senescence in cultured primary human ovarian surface epithelial cells (hOSEs). Large tumor suppressor 2 (LATS2), the primary upstream negative regulator of YAP1, is elevated in both YAP1‐induced and natural replicative‐triggered senescence. Deletion of LATS2 in hOSEs prevents these cells from natural replicative and YAP1‐induced senescence. Most importantly, loss of LATS2 switches ovarian cells from YAP‐induced senescence to malignant transformation. Our results demonstrate that LATS2 and YAP1, two major components of the Hippo/YAP signaling pathway, form a negative feedback loop to control YAP1 activity and prevent ovarian cells from malignant transformation. Human cancer genomic data extracted from TCGA datasets further confirm the clinical relevance of our finding.
Synopsis
The Hippo pathway plays a critical role in controlling ovarian cell fates. This study identifies a YAP1‐LATS2 feedback loop that dictates senescent or malignant fate. Its disruption switches YAP1‐induced senescence to malignant transformation.
YAP1 induces senescence in cultured primary cells in the presence of LATS2.
Lack of functional LATS2 in YAP1‐hyperactivated cells results in malignant transformation.
A YAP1‐LATS2 feedback loop forms a homeostatic rheostat for dictating senescent or malignant fate.
The Hippo pathway plays a critical role in controlling ovarian cell fates. This study identifies a YAP1‐LATS2 feedback loop that dictates senescent or malignant fate. Its disruption switches YAP1‐induced senescence to malignant transformation.
This paper proposed an n-type output capacitor-less low-dropout regulator (LDO) with high power supply rejection (PSR) and fast transient response. To enhance both performances, multiple-feedback ...loop structure is proposed. The LDO obtained PSR of -40 dB (-25 dB) at 1 MHz with load currents of 100 mA (600 mA). The LDO achieved undershoot of 116 mV when the load changes from 1 mA to 600 mA, while consuming a quiescent current of 27.5 μA. The chip was fabricated in 180 nm CMOS process with an area of 0.063 mm 2 .
This article presents an <inline-formula> <tex-math notation="LaTeX">X </tex-math></inline-formula>-band Cartesian error feedback loop transmitter (CEFLT) with a fully integrated power amplifier (PA) ...in a 65-nm CMOS. The extra reference path cancels the feedback signal to mitigate the inherent linearity-noise tradeoff in the conventional Cartesian feedback loop transmitter (CFLT). In this way, the nonlinearities from the feedback path are suppressed without using large attenuation, and thus the noise contribution from the feedback path is reduced as well. Compared with the conventional CFLT, the proposed CEFLT can improve the linearity without degrading the noise performance. The PA-included transmitter delivers a maximum power (<inline-formula> <tex-math notation="LaTeX">P_{\mathrm {SAT}} </tex-math></inline-formula>) of 21.4 dBm and output-referred 1-dB compression point ( OP 1 dB ) of 21 dBm, with 33.3% and 30.3% PA output stage efficiency, respectively, and 22.3% and 20.3% system efficiency, respectively. Compared with the open-loop condition, the closed-loop transmitter demonstrates up to 13.6-dB suppression of adjacent channel leakage ratio (ACLR) error vector magnitude (EVM) using 4 Msps 64 quadratic-amplitude modulation (QAM) signals. The out-of-band (OOB) noise at 100 MHz is −133/−131.8 dBm/Hz for the lower and upper sidebands, respectively.
This brief presents a low-voltage high <inline-formula> <tex-math notation="LaTeX">3\sigma </tex-math></inline-formula>-accuracy bandgap reference (BGR) circuit, which greatly reduces the area and ...power consumption. Its key highlight is the in-sensitivity to the input-referred offset of the error amplifier. This is advantageous compared to the prior work with high <inline-formula> <tex-math notation="LaTeX">3\sigma </tex-math></inline-formula>-accuracy. In the prior work, the offset of error amplifier affects not only the PTAT current but also the CTAT current. This makes it necessary to greatly reduce the offset of error amplifier, leading to a huge area and power consumption. By contrast, this work proposes a new automatic current-controlled feedback loop, which greatly reduces the influence of the error amplifier offset on the BGR accuracy. As a result, the error amplifier no longer needs to consume large area or power in order to reduce its offset. This effectively reduces the area and power of the entire BGR circuit. For a fair comparison, both the prior work and this work are designed under the same <inline-formula> <tex-math notation="LaTeX">0.13~\mu \text{m} </tex-math></inline-formula> CMOS process. Post-layout simulation results show that the power of the error amplifier is reduced by about 9 times when compared to the prior work. Furthermore, the total power of the proposed BGR circuit is also reduced by 2.5 times than the prior work.
This study aimed to elucidate the role of the Cdk1/p53/p21 feedback loop in the pathogenesis of interstitial cystitis (IC)/bladder pain syndrome (BPS).
An IC/BPS cell model was established. Cell ...viability was determined using the CCK-8 assay. Flow cytometry was adopted to assess cell apoptosis rates. ELISA was employed to measure secretion levels of inflammatory factors (IL-6, IL-8, and TNF-α). Gene expressions were assessed using PCR, while protein expressions were analyzed through Western blotting analysis. Epithelial permeability was demonstrated using the phenol red leakage experiment and FITC-dextran permeability assay. The interaction between proteins was determined using co-immunoprecipitation, and protein localization was investigated using immunofluorescence.
The CCK-8 assay revealed a significantly reduced viability of IC/BPS cells compared to normal epithelial cells (p < 0.05). Elevated levels of IL-6, IL-8, and TNF-α were detected in IC/BPS cells. Changes in the expressions of E-cadherin and ZO-1 were evident, leading to increased epithelial permeability in IC/BPS cells. Furthermore, within IC/BPS cells, Cdk1 phosphorylated p53 in the nucleus. The Cdk1/p53/p21 feedback loop was established to influence urothelial permeability. Both p21 and Cdk1 inhibitors notably reduced the epithelial permeability in IC/BPS cells.
The Cdk1/p53/p21 feedback loop was instrumental in IC/BPS, acting as a regulator of urothelial permeability. This discovery offered a novel therapeutic approach for IC/BPS management.
•In the context of IC/BPS, the presence of the Cdk1/p53/p21 feedback loop served as a crucial element that contributed to the balancing and stabilization of urothelial permeability.•This molecular insight shed light on the clinical refractoriness observed in IC/BPS cases and offered a fresh perspective and method for the potential effective treatment of this condition.•This discovery held promise for addressing IC/BPS at its molecular core, offering hope for more successful therapeutic interventions in the future.
The biological role of vacuolar protein sorting 33B (VPS33B) has not been examined in colorectal cancer (CRC). We report that VPS33B was downregulated in dextran sulfate sodium/azoxymethane (DSS/AOM) ...‐induced CRC mice models and nicotine‐treated CRC cells via the PI3K/AKT/c‐Jun pathway. Reduced VPS33B is an unfavorable factor promoting poor prognosis in human CRC patients. VPS33B overexpression suppressed CRC proliferation, intrahepatic metastasis and chemoresistance of cisplatin (DDP) in vivo and in vitro through modulating the epidermal growth factor receptor (EGFR)/RAS/ERK/c‐Myc/p53/miR‐133a‐3p feedback loop and the downstream cell cycle or EMT‐related factors. Furthermore, NESG1 as a newly identified tumor suppressor interacted with VPS33B via colocalization in the cytoplasm, and it was stimulated by VPS33B through the downregulation of RAS/ERK/c‐Jun‐mediated transcription. NESG1 also activated VPS33B expression via the RAS/ERK/c‐Jun pathway. Suppression of NESG1 increased cell growth, migration and invasion via the reversion of the VPS33B‐modulating signal in VPS33B‐overexpressed cells. Taken together, VPS33B as a tumor suppressor is easily dysregulated by chemical carcinogens and it interacts with NESG1 to modulate the EGFR/RAS/ERK/c‐Myc/p53/miR‐133a‐3p feedback loop and thus suppress the malignant phenotype of CRC.
What's new?
Vacuolar protein sorting 33B (VPS33B) has been suggested to serve as an important tumor suppressor in hepatocarcinogenesis. Here, the authors show that VPS33B is downregulated by chemical carcinogens and poorly expressed in colorectal cancer (CRC) tissues. CRC patients with higher expression of VPS33B have a longer survival time. Furthermore, they demonstrate that VPS33B can interact with NESG1 to suppress cell proliferation, invasion, migration, and intrahepatic metastasis and increase sensitivity to cisplatin via regulating the EGFR/RAS/ERK/c‐Myc/p53/miR‐133a‐3p feedback loop. The data provide novel insight into the significance of VPS33B in CRC and may pave the way for a new treatment strategy.
Autophagy is a cell's evolutionary conserved process for degrading and recycling cellular proteins and removing damaged organelles. There has been an increasing interest in identifying the basic ...cellular mechanism of autophagy and its implications in health and illness during the last decade. Many proteinopathies such as Alzheimer's and Huntington's disease are reported to be associated with impaired autophagy. The functional significance of autophagy in exfoliation syndrome/exfoliation glaucoma (XFS/XFG), remains unknown though it is presumed to be impaired autophagy to be responsible for the aggregopathy characteristic of this disease. In the current study we have shown that autophagy or ATG5 is enhanced in response to TGF-β1 in human trabecular meshwork (HTM) cells and TGF-β1 induced autophagy is necessary for increased expression of profibrotic proteins and epithelial to mesenchymal (EMT) through Smad3 that lead to aggregopathy. Inhibition of
by siRNA mediated knockdown reduced profibrotic and EMT markers and increased protein aggregates in the presence of TGF-β1 stimulation. The miR-122-5p, which was increased upon TGF exposure, was also reduced upon
inhibition. We thus conclude that TGF-β1 induces autophagy in primary HTM cells and a positive feedback loop exists between TGF-β1 and
that regulated TGF downstream effects mainly mediated by Smad3 signaling with miR-122-5p also playing a role.
This article investigates the metaphor of the Quantified Self (QS) as it is presented in the magazine Wired (2008–2012). Four interrelated themes—transparency, optimization, feedback loop, and ...biohacking—are identified as formative in defining a new numerical self and promoting a dataist paradigm. Wired captures certain interests and desires with the QS metaphor, while ignoring and downplaying others, suggesting that the QS positions self-tracking devices and applications as interfaces that energize technological engagements, thereby pushing us to rethink life in a data-driven manner. The thematic analysis of the QS is treated as a schematic aid for raising critical questions about self-quantification, for instance, detecting the merging of epistemological claims, technological devices, and market-making efforts. From this perspective, another definition of the QS emerges: a knowledge system that remains flexible in its aims and can be used as a resource for epistemological inquiry and in the formation of alternative paradigms.
Signal transduction and cytoskeleton networks in a wide variety of cells display excitability, but the mechanisms are poorly understood. Here, we show that during random migration and in response to ...chemoattractants, cells maintain complementary spatial and temporal distributions of Ras activity and phosphatidylinositol (3,4)-bisphosphate PI(3,4)P₂. In addition, depletion of PI(3,4)P₂ by disruption of the 5-phosphatase, Dd5P4, or by recruitment of 4-phosphatase INPP4B to the plasma membrane, leads to elevated Ras activity, cell spreading, and altered migratory behavior. Furthermore, RasGAP2 and RapGAP3 bind to PI(3,4)P₂, and the phenotypes of cells lacking these genes mimic those with low PI(3,4)P₂ levels, providing a molecular mechanism. These findings suggest that Ras activity drives PI(3,4)P₂ down, causing the PI(3,4)P₂-binding GAPs to dissociate from the membrane, further activating Ras, completing a positive-feedback loop essential for excitability. Consistently, a computational model incorporating such a feedback loop in an excitable network model accurately simulates the dynamic distributions of active Ras and PI(3,4)P₂ as well as cell migratory behavior. The mutually inhibitory Ras-PI(3,4)P₂ mechanisms we uncovered here provide a framework for Ras regulation that may play a key role in many physiological processes.
In this article, an approximation-based adaptive fractional sliding-mode control (SMC) scheme is proposed for a microgyroscope, where a double-loop recurrent fuzzy neural network (DLRFNN) is employed ...to approximate system uncertainties and disturbance. A fractional-order term is incorporated into the sliding surface that could add an extra degree of freedom and combine the advantages of fractional calculus and SMC. A new four-layer fuzzy neural network (FNN) is studied, which has two feedback loops (internal feedback loop and external feedback loop) to capture the weights and output signal calculated in the previous step and use it as a feedback signal for the next step. On the one hand, the proposed DLRFNN structure combines a fuzzy system to process uncertain information with a neural network to learn from the process. On the other hand, both the internal state information and the output signal are acquired and stored so that better approximation performance is obtained compared with a regular FNN system. Furthermore, the adaptive laws of DLRFNN parameters are derived, which can automatically update free parameters with a bound. Finally, the effectiveness of the proposed adaptive fractional SMC using the DLRFNN strategy is identified by the simulations' analysis with different fractional orders, whereby tracking errors are uniformly ultimately bounded. The proposed adaptive fractional SMC using the DLRFNN strategy can achieve remarkably superior tracking performance in terms of high precision and fast response by comprehensive comparisons.
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