The malate–aspartate shuttle is indispensable for the net transfer of cytosolic NADH into mitochondria to maintain a high rate of glycolysis and to support rapid tumor cell growth. The ...malate–aspartate shuttle is operated by two pairs of enzymes that localize to the mitochondria and cytoplasm, glutamate oxaloacetate transaminases (GOT), and malate dehydrogenases (MDH). Here, we show that mitochondrial GOT2 is acetylated and that deacetylation depends on mitochondrial SIRT3. We have identified that acetylation occurs at three lysine residues, K159, K185, and K404 (3K), and enhances the association between GOT2 and MDH2. The GOT2 acetylation at these three residues promotes the net transfer of cytosolic NADH into mitochondria and changes the mitochondrial NADH/NAD+ redox state to support ATP production. Additionally, GOT2 3K acetylation stimulates NADPH production to suppress ROS and to protect cells from oxidative damage. Moreover, GOT2 3K acetylation promotes pancreatic cell proliferation and tumor growth in vivo. Finally, we show that GOT2 K159 acetylation is increased in human pancreatic tumors, which correlates with reduced SIRT3 expression. Our study uncovers a previously unknown mechanism by which GOT2 acetylation stimulates the malate–aspartate NADH shuttle activity and oxidative protection.
Synopsis
Acetylation of oxaloacetate transaminase (GOT2) promotes its binding with malate dehydrogenase (MDH2), thereby regulating the malate–aspartate shuttle activity, cytosol‐to‐mitochondrion transfer of NADH, oxidative protection and tumor growth.
GOT2 acetylation at three lysine residues enhances its association with MDH2.
SIRT3 is the major deacetylase of GOT2.
Acetylation of GOT2 modulates mitochondrial NADH/NAD+ redox status, energy production, and cell survival during oxidative stress.
GOT2 K159 acetylation is increased in human pancreatic tumors, correlating with reduced SIRT3 expression.
Acetylation of oxaloacetate transaminase (GOT2) promotes its binding with malate dehydrogenase (MDH2), thereby regulating the malate–aspartate shuttle activity, cytosol‐to‐mitochondrion transfer of NADH, oxidative protection and tumor growth.
It has been generally believed and assumed that organometal halide perovskites would form type II P–N junctions with fullerene derivatives (C60 or PCBM), and the P–N junctions would provide driving ...force for exciton dissociation in perovskite‐based solar cell. To the best of our knowledge, there is so far no experiment proof on this assumption. On the other hand, whether photogenerated excitons can intrinsically dissociate into free carrier in the perovskite without any assistance from a P–N junction is still controversial. To address these, the interfacial electronic structures of a vacuum‐deposited perovskite/C60 and a solution‐processed perovskite/PCBM junctions is directly measured by ultraviolet photoelectron spectroscopy. Contrary to the common believes, both junctions are found to be type I N–N junctions with band gap of the perovskites embedded by that of the fullerenes. Meanwhile, device with such a charge inert junction can still effectively functions as a solar cell. These results give direct experimental evidence that excitons are dissociated to free carriers in the perovskite film even without any assistance from a P–N junction.
While perovskites/fullerene is commonly assumed to form a type II P–N junction with its internal E‐field facilitating exciton dissociation, it is found that perovskite/C60 (PCBM) is a charge inert type I N–N junction. Devices with such a junction show photovoltaic effects effectively, thus photogenerated excitons can indeed dissociate to free carriers in the perovskite film.
Enhanced glycolysis in cancer cells has been linked to cell protection from DNA damaging signals, although the mechanism is largely unknown. The 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 ...(PFKFB3) catalyzes the generation of fructose-2,6-bisphosphate, a potent allosteric stimulator of glycolysis. Intriguingly, among the four members of PFKFB family, PFKFB3 is uniquely localized in the nucleus, although the reason remains unclear. Here we show that chemotherapeutic agent cisplatin promotes glycolysis, which is suppressed by PFKFB3 deletion. Mechanistically, cisplatin induces PFKFB3 acetylation at lysine 472 (K472), which impairs activity of the nuclear localization signal (NLS) and accumulates PFKFB3 in the cytoplasm. Cytoplasmic accumulation of PFKFB3 facilitates its phosphorylation by AMPK, leading to PFKFB3 activation and enhanced glycolysis. Inhibition of PFKFB3 sensitizes tumor to cisplatin treatment in a xenograft model. Our findings reveal a mechanism for cells to stimulate glycolysis to protect from DNA damage and potentially suggest a therapeutic strategy to sensitize tumor cells to genotoxic agents by targeting PFKFB3.
•The effects of BFRP and HSS bars reinforced ECC as the strengthening layer were compared and evaluated to improve the flexural behavior of RC beams.•The difference between the two strengthening ...systems confirmed the excellent strain compatibility of BFRP bars and ECC matrix.•The advantages of ECC due to its high ultra-high ductility and crack control capability over polymer mortar as the matrix of the strengthening layer are obvious.•The proposed analytical model predicted the flexural load response and failure modes accurately.
This paper has investigated the flexural behavior of reinforced concrete (RC) beams strengthened with BFRP (basalt fiber reinforced polymer) or HSS (high strength steel) bar reinforced ECC matrix. A total of six strengthened RC beams and one control RC beam were tested under four-point bending up to their failure. The test variables included the cement matrix (ECC and polymer mortar), the reinforcements type (BFRP and HSS bars) as well as the reinforcement ratio (0.94% and 1.41%) of the strengthening layer. Two failure modes including the rupture of BFRP bars and the rupture of ECC matrix followed by the slippage of the steel bars were obtained in the strengthened beams. The rupture of BFRP bars dominated the failure of beams strengthened with BFRP bar reinforced cement matrix owing to the limited tensile strength of BFRP bars, and the percentage of enhancement in flexural capacity ranged from 18.6% to 47.8% compared with the control beam. The beams strengthened with HSS bar reinforced ECC matrix all failed due to the rupture of ECC matrix followed by the slippage of HSS bars, mainly owing to the high stiffness and strength of the HSS bars, leading to larger enhancements in flexural capacity at a range of 60.0–75.6%. In addition, a beam strengthened with BFRP bar reinforced polymer mortar was also tested with the purpose of conforming the advantage of ECC over polymer mortar as the matrix of the strengthening layer. The test results showed that the application of ECC matrix with BFRP bars resulted in larger enhancement in the yield and ultimate loads compared to the use of polymer mortar matrix. The difference between the two strengthening systems confirmed the excellent strain compatibility of BFRP bars and ECC matrix. Finally, a flexural theoretical analysis based on three possible failure cases was proposed, and its reliability was verified through comparing the test results and the theoretical predictions.
Glucose‐6‐phosphate dehydrogenase (G6PD) is a key enzyme in the pentose phosphate pathway (PPP) and plays an essential role in the oxidative stress response by producing NADPH, the main intracellular ...reductant. G6PD deficiency is the most common human enzyme defect, affecting more than 400 million people worldwide. Here, we show that G6PD is negatively regulated by acetylation on lysine 403 (K403), an evolutionarily conserved residue. The K403 acetylated G6PD is incapable of forming active dimers and displays a complete loss of activity. Knockdown of G6PD sensitizes cells to oxidative stress, and re‐expression of wild‐type G6PD, but not the K403 acetylation mimetic mutant, rescues cells from oxidative injury. Moreover, we show that cells sense extracellular oxidative stimuli to decrease G6PD acetylation in a SIRT2‐dependent manner. The SIRT2‐mediated deacetylation and activation of G6PD stimulates PPP to supply cytosolic NADPH to counteract oxidative damage and protect mouse erythrocytes. We also identified KAT9/ELP3 as a potential acetyltransferase of G6PD. Our study uncovers a previously unknown mechanism by which acetylation negatively regulates G6PD activity to maintain cellular NADPH homeostasis during oxidative stress.
Synopsis
The pentose phosphate pathway plays an important role in the oxidative stress response by supplying the reductant NADPH. SIRT2‐mediated deacetylation and activation of the glucose‐6‐phosphate dehydrogenase, the rate‐limiting enzyme in this pathway, stimulates the production of cytosolic NADPH to counteract oxidative damage.
K403 acetylation decreases G6PD activity by inhibiting dimer formation.
SIRT2 and KAT9/ELP3 regulate G6PD K403 acetylation.
Regulation of G6PD K403 acetylation modulates NADPH homeostasis and cell survival during oxidative stress.
Following oxidative stress, production of the reductant NADPH via the pentose phosphate pathway is stimulated by SIRT2‐mediated deacetylation and activation of G6PD.
Heavy metal(loid)s and organic pollutants have garnered global concern due to their potential for bioaccumulation and carcinogenic effects. The aquatic environment is one of the most important ...receiving compartments for these pollutants. Therefore, researchers are committed to developing inexpensive and highly efficient technologies for the removal of these recalcitrant contaminants from water. Zero-valent iron (ZVI), which has a strong reduction ability, low cost and can be recycled, has been considered as an environmentally benign element for removal of heavy metal(loid)s and organic chlorinated pollutants. However, some factors limit the ZVI application, with passivation of ZVI considered as the main limitation. Recent research has focused on methods to eliminate or alleviate these interferences and maximize ZVI performance. This review summarizes recent findings for the removal of typical heavy metal(loid)s and organic pollutants in the aquatic environment by ZVI-based technologies. Different combinations of chemical, physical, biological, or other methods with ZVI and their operating conditions and influencing factors are presented and discussed. Finally, we also present the removal mechanisms of ZVI-based technologies and recommendations for future research. This review provides an up-to-date perspective on the removal of pollutants using ZVI-based technologies and collates references for future large-scale application to wastewater treatment.
Display omitted
•ZVI-based technologies can effectively remove heavy metal(loid)s and organic pollutants.•ZVI-based removal mechanisms for heavy metal(loid)s and organic pollutants are summarized.•Combinations of chemical, physical, biological methods with ZVI are presented.•The ZVI-based technologies are compared and their limitations are discussed.•Future recommendations for the development of ZVI-based technologies are suggested.
Twisted light carrying orbital angular momentum (OAM) provides an additional degree of freedom for modern optics and an emerging resource for both classical and quantum information technologies. Its ...inherently infinite dimensions can potentially be exploited by using mode multiplexing to enhance data capacity for sustaining the unprecedented growth in big data and internet traffic and can be encoded to build large-scale quantum computing machines in high-dimensional Hilbert space. While the emission of twisted light from the surface of integrated devices to free space has been widely investigated, the transmission and processing inside a photonic chip remain to be addressed. Here, we present the first laser-direct-written waveguide being capable of supporting OAM modes and experimentally demonstrate a faithful mapping of twisted light into and out of a photonic chip. The states OAM_{0}, OAM_{-1}, OAM_{+1}, and their superpositions can transmit through the photonic chip with a total efficiency up to 60% with minimal crosstalk. In addition, we present the transmission of quantum twisted light states of single photons and measure the output states with single-photon imaging. Our results may add OAM as a new degree of freedom to be transmitted and manipulated in a photonic chip for high-capacity communication and high-dimensional quantum information processing.
Vector vortex beams simultaneously carrying spin and orbital angular momentum of light promise additional degrees of freedom for modern optics and emerging resources for both classical and quantum ...information technologies. The inherently infinite dimensions can be exploited to enhance data capacity for sustaining the unprecedented growth in big data and internet traffic and can be encoded to build quantum computing machines in high-dimensional Hilbert space. So far, much progress has been made in the emission of vector vortex beams from a chip surface into free space; however, the generation of vector vortex beams inside a photonic chip has not been realized yet. Here, we demonstrate the first vector vortex beam emitter embedded in a photonic chip by using femtosecond laser direct writing. We achieve a conversion of vector vortex beams with an efficiency up to 30% and scalar vortex beams with an efficiency up to 74% from Gaussian beams. We also present an expanded coupled-mode model for understanding the mode conversion and the influence of the imperfection in fabrication. The fashion of embedded generation makes vector vortex beams directly ready for further transmission, manipulation, and emission without any additional interconnection. Together with the ability to be integrated as an array, our results may enable vector vortex beams to become accessible inside a photonic chip for high-capacity communication and high-dimensional quantum information processing.
Innovative coronavirus disease 2019 (COVID-19) vaccines, with elevated global manufacturing capacity, enhanced safety and efficacy, simplified dosing regimens, and distribution that is less cold ...chain-dependent, are still global imperatives for tackling the ongoing pandemic. A previous phase I trial indicated that the recombinant COVID-19 vaccine (V-01), which contains a fusion protein (IFN-PADRE-RBD-Fc dimer) as its antigen, is safe and well tolerated, capable of inducing rapid and robust immune responses, and warranted further testing in additional clinical trials. Herein, we aimed to assess the immunogenicity and safety of V-01, providing rationales of appropriate dose regimen for further efficacy study.
A randomized, double-blind, placebo-controlled phase II clinical trial was initiated at the Gaozhou Municipal Centre for Disease Control and Prevention (Guangdong, China) in March 2021. Both younger (n = 440; 18-59 years of age) and older (n = 440; ≥60 years of age) adult participants in this trial were sequentially recruited into two distinct groups: two-dose regimen group in which participants were randomized either to follow a 10 or 25 μg of V-01 or placebo given intramuscularly 21 days apart (allocation ratio, 3:3:1, n = 120, 120, 40 for each regimen, respectively), or one-dose regimen groups in which participants were randomized either to receive a single injection of 50 μg of V-01 or placebo (allocation ratio, 3:1, n = 120, 40, respectively). The primary immunogenicity endpoints were the geometric mean titers of neutralizing antibodies against live severe acute respiratory syndrome coronavirus 2, and specific binding antibodies to the receptor binding domain (RBD). The primary safety endpoint evaluation was the frequencies and percentages of overall adverse events (AEs) within 30 days after full immunization.
V-01 provoked substantial immune responses in the two-dose group, achieving encouragingly high titers of neutralizing antibody and anti-RBD immunoglobulin, which peaked at day 35 (161.9 95% confidence interval CI: 133.3-196.7 and 149.3 95%CI: 123.9-179.9 in 10 and 25 μg V-01 group of younger adults, respectively; 111.6 95%CI: 89.6-139.1 and 111.1 95%CI: 89.2-138.4 in 10 and 25 μg V-01 group of older adults, respectively), and remained high at day 49 after a day-21 second dose; these levels significantly exceed those in convalescent serum from symptomatic COVID-19 patients (53.6, 95%CI: 31.3-91.7). Our preliminary data show that V-01 is safe and well tolerated, with reactogenicity predominantly being absent or mild in severity and only one vaccine-related grade 3 or worse AE being observed within 30 days. The older adult participants demonstrated a more favorable safety profile compared with those in the younger adult group: with AEs percentages of 19.2%, 25.8%, 17.5% in older adults vs. 34.2%, 23.3%, 26.7% in younger adults at the 10, 25 μg V-01 two-dose group, and 50 μg V-01 one-dose group, respectively.
The vaccine candidate V-01 appears to be safe and immunogenic. The preliminary findings support the advancement of the two-dose, 10 μg V-01 regimen to a phase III trial for a large-scale population-based evaluation of safety and efficacy.
http://www.chictr.org.cn/index.aspx (No. ChiCTR2100045107, http://www.chictr.org.cn/showproj.aspx?proj=124702).
•A more understandable description for the DRLP is presented.•An innovative decomposition-based algorithm is proposed for the DRLP.•A property of the objective function of the DRLP is proved and ...used.•The experimental results demonstrate the high competitiveness of our proposed algorithm.
The double row layout problem (DRLP) is a common pattern of facility layout problem, which has practical applications in flexible manufacturing systems. The double row layout problem is vital to save transportation cost and enhance productivity. Nevertheless, it is very hard to handle the DRLP because of its characteristic of combination of combinatorial and continuous aspects. In this paper, a decomposition-based algorithm is proposed to solve the DRLP. We decompose the DRLP into two subproblems. In the first subproblem, the adjustable clearances between adjacent facilities are temporarily ignored. A first improvement based local search is applied to optimize the sequences of facilities on double rows. During this process, the facilities of double rows are placed starting at different abscissas rather than starting at the same abscissa for each arrangement. A property of the objective function of the DRLP is used to obtain the optimal difference between two starting abscissas. In the second subproblem, a particle swarm optimization is applied to optimize the adjustable clearances between adjacent facilities under the condition that the sequences of facilities are fixed. Our proposed algorithm is evaluated on 59 test instances and compared with the state-of-the-art methods. The experimental results demonstrate the high competitiveness of our proposed algorithm.
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