Renewable energy sources (RESs), e.g., wind and solar photovoltaics, have been increasingly used to meet worldwide growing energy demands and reduce greenhouse gas emissions. However, RESs are ...normally coupled to the power grid through fast-response power converters without any inertia, leading to decreased power system inertia. As a result, the grid frequency may easily go beyond the acceptable range under severe frequency events, resulting in undesirable load-shedding, cascading failures, or even large-scale blackouts. To address the ever-decreasing inertia issue, this paper proposes the concept of distributed power system virtual inertia, which can be implemented by grid-connected power converters. Without modifications of system hardware, power system inertia can be emulated by the energy stored in the dc-link capacitors of grid-connected power converters. By regulating the dc-link voltages in proportional to the grid frequency, the dc-link capacitors are aggregated into an extremely large equivalent capacitor serving as an energy buffer for frequency support. Furthermore, the limitation of virtual inertia, together with its design parameters, is identified. Finally, the feasibility of the proposed concept is validated through simulation and experimental results, which indicate that 12.5% and 50% improvements of the frequency nadir and rate of change of frequency can be achieved.
Tumor cells often exhibit augmented capacity to maintain endoplasmic reticulum (ER) homeostasis under adverse conditions, yet the underlying mechanisms are not well defined. Here, through the ...evaluation of all human TRIM proteins, we find that TRIM25 is significantly induced upon ER stress. Upregulation of TRIM25 ameliorates oxidative stress, promotes ER-associated degradation (ERAD), and reduces IRE1 signaling in the UPR pathway. In contrast, depletion of TRIM25 leads to ER stress and attenuates tumor cell growth in vitro and in vivo. Mechanistically, TRIM25 directly targets Keap1 by ubiquitination and degradation. This leads to Nrf2 activation, which bolsters anti-oxidant defense and cell survival. TRIM25 expression is positively associated with Nrf2 expression and negatively with Keap1 expression in hepatocellular carcinoma (HCC) xenografts and specimens. Moreover, high TRIM25 expression correlates with poor patient survival in HCC. These findings reveal TRIM25 as a regulator of ER homeostasis and a potential target for tumor therapy.
Krüppel-like factor 4 (KLF4), a key transcription factor, acts as a multifunctional player involved in the progression of numerous aggressive cancers. The proteasome-dependent pathway is one of the ...main modalities in controlling KLF4 abundance at a posttranslational level. Although some of the ubiquitin ligases have been identified, the deubiquitinases of KLF4 and the regulatory function remain unexplored. Here, by screening ubiquitin-specific proteases that may interact with KLF4, we found ubiquitin-specific peptidase 10 (USP10) as a deubiquitinating enzyme for KLF4. Forced expression of USP10 remarkably increases KLF4 protein level by blocking the latter degradation, whereas the depletion of USP10 promotes KLF4 degradation and thus enhances tumorigenesis. Loss of USP10 in mice downregulates KLF4 expression and accelerates Kras
-driven lung adenocarcinoma initiation and progression. In addition, our data revealed that KLF4 can facilitate the transcription of tumor suppressor TIMP3 by directly binding to the TIMP3 promoter. Clinically, reduction of USP10 expression, concomitant with decreased KLF4 and TIMP3 abundance in carcinoma tissue, predicts poor prognosis of lung cancer patient. Taken together, our results demonstrate that USP10 is a critical regulator of KLF4, pinpointing USP10-KLF4-TIMP3 axis as a promising therapeutic target in lung cancer.
Abstract MHC class I (MHC I) antigen presentation of exogenous antigens (so called “cross presentation”) is a central mechanism of CD8+ cytotoxic T lymphocyte (CTL) responses essential for successful ...vaccine-based cancer immunotherapy. The present study constructed amphiphilic pH-sensitive galactosyl dextran-retinal (GDR) nanogels for cancer vaccine delivery, in which dextran was conjugated with all-trans retinal (a metabolite of vitamin A) through a pH-sensitive hydrazone bond, followed by galactosylation to acquire dendritic cell (DC)-targeting ability. Our results showed that pH-sensitive GDR nanogel was a self-adjuvanted vaccine carrier that not only promoted DC maturation through activating retinoic acid receptor (RAR) signaling, but also facilitated antigen uptake and cytosolic antigen release in DCs. Furthermore, pH-sensitive GDR nanogel effectively augmented MHC I antigen presentation and evoked potent anti-cancer immune responses in vivo. More importantly, we first reported that nanoparticle-triggered lysosome rupture could directly induce ROS production in DCs, which was found to be essential for augmenting proteasome activity and downstream MHC I antigen presentation. Hence, DC-targeted pH-sensitive GDR nanogels could be a potent delivery system for cancer vaccine development. Triggering lyososomal rupture in DCs with pH-sensitive nanoparticles might be a plausible strategy to elevate intracellular ROS production for promoting antigen cross presentation, thereby improving cancer vaccine efficacy.
Gallium nitride high electron mobility transistors (GaN HEMTs) are promising switching devices in high-efficiency and high-density dc-dc converters due to their fast switching speed and small ...conduction resistance. However, GaN HEMTs are very sensitive to parasitic inductance because of their high switching speed, low-threshold voltage, and small driving safety margin. Parasitic inductance can cause severe voltage overshoot and ringing, which may result in electromagnetic interference issues, false turn-on, or even device breakdown. This paper aims at reducing the parasitic inductance (including power loop inductance and driver loop inductance) by optimizing the layout. First, a multiloop method is proposed to reduce the parasitic inductance. Optimization of both the conventional single-loop structure and the proposed multiloop structure are presented. Second, three kinds of power loop layouts based on the proposed multiloop structure are realized on PCB substrate and one of them is realized on aluminum nitride (AlN) substrate, which has higher thermal conductivity but less copper layers. The power loop inductance on PCB substrate is reduced to 0.1 nH, which is only 25% of the state-of-art layout. The power loop inductance on AlN substrate is reduced to 0.22 nH. Third, the driver loop layout is optimized and achieves 50% reduction of driver loop inductance compared with the conventional single-layer layout. Finally, integrated modules using the proposed layouts are built to validate the analyses and designs.
High-order passive filters, such as the well-known LCL filters, are normally employed in the grid-connected power conversion systems to effectively attenuate the switching frequency harmonic ...introduced by the modulation of power converters. Although much more compact than the conventional single-inductor L filters, such passive filters are still bulky and expensive when compared with their active counterparts, e.g., the semiconductor switches. In order to improve the system power density and reduce its cost, the magnetic integration technique has been widely adopted so that the discrete inductors of passive filters are replaced by the integrated inductor, resulting in smaller magnetic cores and, therefore, the decreased volumes of passive filters. For conventional magnetic integrated LCL filters, the converter-side inductor and the grid-side inductor are integrated together and their coupling coefficient is intentionally minimized. In this letter, this coupling coefficient is fully utilized and properly designed, and the resulting coupling effect is equivalent to inserting an additional inductor into the filter capacitor branch loop. The integrated inductor and the filter capacitor can form an integrated LLCL filter, which exhibits the advantages of both the LLCL filter and magnetic integration, e.g., enhanced harmonic attenuation, reduced filter inductances, and system volume without adding the extra trap inductor. Finally, experimental results obtained from a single-phase grid-connected voltage-source converter interfaced by the proposed integrated filter are presented to validate its effectiveness.
The deubiquitylase OTUD3 plays a suppressive role in breast tumorigenesis through stabilizing PTEN protein, but its role in lung cancer remains unclear. Here, we demonstrate that in vivo deletion of ...OTUD3 indeed promotes breast cancer development in mice, but by contrast, it slows down Kras
-driven lung adenocarcinoma (ADC) initiation and progression and markedly increases survival in mice. Moreover, OTUD3 is highly expressed in human lung cancer tissues and its higher expression correlates with poorer survival of patients. Further mechanistic studies reveal that OTUD3 interacts with, deubiquitylates and stabilizes the glucose-regulated protein GRP78. Knockdown of OTUD3 results in a decrease in the level of GRP78 protein, suppression of cell growth and migration, and tumorigenesis in lung cancer. Collectively, our results reveal a previously unappreciated pro-oncogenic role of OTUD3 in lung cancer and indicate that deubiquitylases could elicit tumor-suppressing or tumor-promoting activities in a cell- and tissue-dependent context.
Ovarian tumour domain-containing protein 3 (OTUD3), a key OTU (ovarian tumour protease) family deubiquitylase, plays context-dependent roles in cancers. It suppresses tumorigenesis in breast, colon, ...liver and cervical cancer through stabilizing PTEN (phosphatase and tension homologue deleted on chromosome 10) while promotes lung tumorigenesis through stabilizing GRP78 (The glucose-regulated protein 78 kDa). The regulation especially post-translational modification of OTUD3 remains unclear. Here, we report that the carboxyl terminus of Hsc70-interacting protein (CHIP) is a ubiquitin ligase for OTUD3. CHIP interacts with, polyubiquitylates OTUD3 and promotes OTUD3 degradation. Knockdown of CHIP stabilizes OTUD3 which leads to elevated GRP78 levels in lung cancer cells. CHIP-knockdown lung cancer cells exhibit increased invasion in OTUD3 and GRP78 dependent manner. Further study demonstrates that CHIP-knockdown lung cancer cells are more prone to metastasize to mice lung when injected intravenously or subcutaneously. Moreover, the expression of CHIP is low in human lung cancer tissues and inversely correlates with OTUD3 expression and GRP78 expression. Furthermore, we identified CHIP mutations in human lung cancers, which reduce CHIP catalytic activity. These findings demonstrate that CHIP is a negative regulator of OTUD3 and CHIP suppresses lung cancer metastasis through inhibiting OTUD3-GRP78 signaling axis.
Although nanomaterials have shown promising biomedical application potential, incomplete understanding of their molecular interactions with biological systems prevents their inclusion into mainstream ...clinical applications. Here we show that black phosphorus (BP) nanomaterials directly affect the cell cycle's centrosome machinery. BP destabilizes mitotic centrosomes by attenuating the cohesion of pericentriolar material and consequently leads to centrosome fragmentation within mitosis. As a result, BP-treated cells exhibit multipolar spindles and mitotic delay, and ultimately undergo apoptosis. Mechanistically, BP compromises centrosome integrity by deactivating the centrosome kinase polo-like kinase 1 (PLK1). BP directly binds to PLK1, inducing its aggregation, decreasing its cytosolic mobility and eventually restricting its recruitment to centrosomes for activation. With this mechanism, BP nanomaterials show great anticancer potential in tumour xenografted mice. Together, our study reveals a molecular mechanism for the tumoricidal properties of BP and proposes a direction for biomedical application of nanomaterials by exploring their intrinsic bioactivities.
When colloidal particles are deposited in a heat transfer channel, they increase the flow resistance in the channel, resulting in a substantial decrease in heat transfer efficiency. It is critical to ...have a comprehensive understanding of particle properties in heat transfer channels for practical engineering applications. This study employed the Reynolds stress model (RSM) and the discrete particle model (DPM) to simulate particle deposition in a 3D corrugated rough-walled channel. The turbulent diffusion of particles was modeled with the discrete random walk model (DRW). A user-defined function (UDF) was created for particle–wall contact, and an improved particle bounce deposition model was implemented. The research focused on investigating secondary flow near the corrugated wall, Q-value standards, turbulent kinetic energy distribution, and particle deposition through validation of velocity in the tube and particle deposition modeling. The study analyzed the impact of airflow velocity, particle size, corrugation height, and corrugation period on particle deposition efficiency. The findings suggest that the use of corrugated walls can significantly improve the efficiency of deposition for particles less than 20 μm in size. Specifically, particles with a diameter of 3 μm showed five times higher efficacy of deposition with a corrugation height of 24 mm compared to a smooth surface.
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