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1.
EMBO J ; : e108065, 2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34487377

RESUMO

The pyruvate kinase M2 isoform (PKM2) is preferentially expressed in cancer cells to regulate anabolic metabolism. Although PKM2 was recently reported to regulate lipid homeostasis, the molecular mechanism remains unclear. Herein, we discovered an ER transmembrane protein 33 (TMEM33) as a downstream effector of PKM2 that regulates activation of SREBPs and lipid metabolism. Loss of PKM2 leads to up-regulation of TMEM33, which recruits RNF5, an E3 ligase, to promote SREBP-cleavage activating protein (SCAP) degradation. TMEM33 is transcriptionally regulated by nuclear factor erythroid 2-like 1 (NRF1), whose cleavage and activation are controlled by PKM2 levels. Total plasma cholesterol levels are elevated by either treatment with PKM2 tetramer-promoting agent TEPP-46 or by global PKM2 knockout in mice, highlighting the essential function of PKM2 in lipid metabolism. Although depletion of PKM2 decreases cancer cell growth, global PKM2 knockout accelerates allografted tumor growth. Together, our findings reveal the cell-autonomous and systemic effects of PKM2 in lipid homeostasis and carcinogenesis, as well as TMEM33 as a bona fide regulator of lipid metabolism.

2.
PLoS Pathog ; 17(9): e1009900, 2021 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-34516573

RESUMO

Infectious bursal disease virus (IBDV), a double-stranded RNA virus, causes immunosuppression and high mortality in 3-6-week-old chickens. Innate immune defense is a physical barrier to restrict viral replication. After viral infection, the host shows crucial defense responses, such as stimulation of antiviral effectors to restrict viral replication. Here, we conducted RNA-seq in avian cells infected by IBDV and identified TRIM25 as a host restriction factor. Specifically, TRIM25 deficiency dramatically increased viral yields, whereas overexpression of TRIM25 significantly inhibited IBDV replication. Immunoprecipitation assays indicated that TRIM25 only interacted with VP3 among all viral proteins, mediating its K27-linked polyubiquitination and subsequent proteasomal degradation. Moreover, the Lys854 residue of VP3 was identified as the key target site for the ubiquitination catalyzed by TRIM25. The ubiquitination site destroyed enhanced the replication ability of IBDV in vitro and in vivo. These findings demonstrated that TRIM25 inhibited IBDV replication by specifically ubiquitinating and degrading the structural protein VP3.

3.
Sci Rep ; 11(1): 17858, 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34504199

RESUMO

Protein lysine acetylation (Kac) is an important post-translational modification in both animal and plant cells. Global Kac identification has been performed at the proteomic level in various species. However, the study of Kac in oil and resource plant species is relatively limited. Soybean is a globally important oil crop and resouce plant. In the present study, lysine acetylome analysis was performed in soybean leaves with proteomics techniques. Various bioinformatics analyses were performed to illustrate the structure and function of these Kac sites and proteins. Totally, 3148 acetylation sites in 1538 proteins were detected. Motif analysis of these Kac modified peptides extracted 17 conserved motifs. These Kac modified protein showed a wide subcellular location and functional distribution. Chloroplast is the primary subcellular location and cellular component where Kac proteins were localized. Function and pathways analyses indicated a plenty of biological processes and metabolism pathways potentially be influenced by Kac modification. Ribosome activity and protein biosynthesis, carbohydrate and energy metabolism, photosynthesis and fatty acid metabolism may be regulated by Kac modification in soybean leaves. Our study suggests Kac plays an important role in soybean physiology and biology, which is an available resource and reference of Kac function and structure characterization in oil crop and resource plant, as well as in plant kingdom.

5.
Small ; : e2102454, 2021 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-34514698

RESUMO

Lithium (Li) metal has been generally noticed as the most prospective anode for next-generation batteries attributed to its outstanding theoretical capacity and low electrochemical potential. Nevertheless, the unstable solid-electrolyte interphase (SEI) and uncontrollable dendrite growth cause poor reversibility and fetter the practical application of Li metal anodes. Herein, a new organic-inorganic hybrid polymer artificial SEI (POSS-LiBMAB) layer with uniform lithium-ion paths at a molecular level is designed to stabilize Li metal anodes. The SEI layer is constructed by the thiol-ene "click chemistry" reaction between inorganic polyhedral oligomeric silsesquioxane containing eight-mercaptopropyl (POSS-SH) with lithium bis (allylmalonato) borate (LiBMAB) on Li foil. What is more, the POSS-LiBMAB film can be cross-linked and self-reinforced via intermolecular SC bonds. Benefiting from its flexible polymeric covalent structure and noble inorganic Si8 O16 -type cubes, the organic-inorganic hybrid polymer layer is flexible and effectively tolerates the volume change of Li metal anodes during plating/stripping cycles. In addition, this layer shows loose and uniformly distributed electrostatic interaction between Li+ and charge delocalized sp3 boron-oxygen anions, which aids to form a uniform intermolecular Li+ path regulating the homogeneous distribution of Li+ flux on Li anodes. Finally, the designed POSS-LiBMAB layer has high ionic conductivity and lithium-ion transference number, which can effectively promote Li+ diffusion and guide Li deposition beneath the SEI layer. Therefore, with the protection of the POSS-LiBMAB layer, the Li metal anode exhibits stable cycling at 5 mA cm-2 for more than 1000 h, and the LFP//Li full cells also present outstanding cycling stability.

6.
J Nucl Med ; 2021 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-34475235

RESUMO

This prospective non-randomized, multicenter clinical trial was performed to investigate efficacy and safety of 131I-labeled metuximab in adjuvant treatment of unresectable hepatocellular carcinoma. Methods: Patients were assigned to treatment with transcatheter arterial chemoembolization (TACE) combined with 131I-metuximab or TACE alone. The primary outcome was overall tumor recurrence. The secondary outcomes were safety and overall survival. Results: The median time to tumor recurrence was 6 months in the TACE+131I-metuximab group (n = 160) and 3 months in the TACE group (n = 160) (hazard ratio, 0.55; 95% confidence interval, 0.43 to 0.70; P < 0.001). The median overall survival was 28 months in the TACE+131I-metuximab group and 19 months in the TACE group (hazard ratio, 0.62; 95% confidence interval, 0.47 to 0.82; P = 0.001). Conclusion: TACE+131I-metuximab showed a greater anti-recurrence benefit, significantly improved the 5-year survival of patients with advanced hepatocellular carcinoma, and was well tolerated by patients.

7.
J Am Chem Soc ; 143(34): 13759-13768, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34465099

RESUMO

Herein we report the copper-catalyzed silylation of propargylic difluorides to generate axially chiral, tetrasubstituted monofluoroallenes in both good yields (27 examples >80%) and enantioselectivities (82-98% ee). Compared to previously reported synthetic routes to axially chiral allenes (ACAs) from prochiral substrates, a mechanistically distinct reaction has been developed: the enantiodiscrimination between enantiotopic fluorides to set an axial stereocenter. DFT calculations and vibrational circular dichroism (VCD) suggest that ß-fluoride elimination from an alkenyl copper intermediate likely proceeds through a syn-ß-fluoride elimination pathway rather than an anti-elimination pathway. The effects of the C1-symmetric Josiphos-derived ligand on reactivity and enantioselectivity were investigated. Not only does this report showcase that alkenyl copper species (like their alkyl counterparts) can undergo ß-fluoride elimination, but this elimination can be achieved in an enantioselective fashion.

8.
Mater Sci Eng C Mater Biol Appl ; 128: 112317, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34474868

RESUMO

Acid-triggered degradable polyprodrug P(DOX-AH) was designed for long-acting drug delivery with minimal leakage and enhanced antitumor efficacy. By facile polymerization of doxorubicin (DOX) and N-(tert-butoxycarbonyl)acryloylhydrazine (Boc-AH), P(DOX-AH) with drug as unique repeating unit was obtained, possessing an ultrahigh drug content. It was stable in the neutral media but could degrade completely into DOX-AH in the acidic media without any other by-product. The cleavage of the hydrazone linkage between the DOX-AH repeating units was revealed by the LC-MS/MS analysis. Furthermore, a slow solubility-controlled drug release performance was achieved in the acidic media because of the low solubility of the released DOX-AH. Even with the slow DOX-AH releasing, the enhanced antitumor efficacy was obtained than free DOX in the in vitro cellular experiments. These features demonstrated the promising potential of the proposed polyprodrug for long-acting drug delivery in future tumor chemotherapy.


Assuntos
Polímeros , Espectrometria de Massas em Tandem , Cromatografia Líquida , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Concentração de Íons de Hidrogênio , Micelas
9.
Biomed Res Int ; 2021: 9942152, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34485530

RESUMO

Lipid deposition is an etiology of renal damage caused by lipid metabolism disorder in diabetic nephropathy (DN). Thus, reducing lipid deposition is a feasible strategy for the treatment of DN. Morroniside (MOR), an iridoid glycoside isolated from the Chinese herb Cornus officinalis Sieb. et Zucc., is considered to be an effective drug in inhibiting oxidative stress, reducing inflammatory response, and countering apoptosis. To explore the protective mechanism of MOR in attenuating renal lipotoxicity in DN, we investigated the effect of MOR on an in vitro model of lipid metabolism disorder of DN established by stimulating mouse renal tubular epithelial cells (mRTECs) with sodium palmitate (PA) or high glucose (HG). Oil Red O and filipin cholesterol staining assays were used to determine intracellular lipid accumulation status. Results revealed that PA or HG stimulation inhibited the expressions of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), liver X receptors (LXR), ATP-binding cassette subfamily A member 1 (ABCA1), ABCG1, and apolipoprotein E (ApoE) in mRTECs as evidenced by western blot and quantitative real-time PCR, resulting in increased intracellular lipid deposition. Interestingly, MOR upregulated expressions of PGC-1α, LXR, ABCA1, ABCG1, and ApoE, thus reducing cholesterol accumulation in mRTECs, suggesting that MOR might promote cholesterol efflux from mRTECs via the PGC-1α/LXR pathway. Of note, silencing PGC-1α reversed the promotive effect of MOR on PA- or HG-induced cellular cholesterol accumulation. In conclusion, our results suggest that MOR has a protective effect on mRTECs under high lipid or high glucose conditions, which may be related to the promotion of intracellular cholesterol efflux mediated by PGC-1α.

10.
Accid Anal Prev ; 161: 106383, 2021 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-34469855

RESUMO

We are entering an era of automated vehicles (AVs), which has potential to improve road safety considerably. A compelling user experience is crucial to AV adoption in the future commercial market. The automated driving system (ADS) that replaces human drivers should be perceived as very useful before the latter are willing to give up their control and entrust their lives to the ADS. However, compared with the growing number of studies on public acceptance of AVs, there has been limited research focusing on user experience and usability. We examined AV and ADS user experience and usability, ADS failures' influence on them, and their influences on re-riding willingness. We conducted a field study using a real AV and a large-scale test track. We invited participants (N = 261) to travel in the AV as passengers in a low-speed environment. Participants were randomly assigned into the normal condition or the fault condition (its participants were exposed to an ADS failure). We measured participants' positive experience (feeling relaxed, safe, and comfortable) and negative experience (feeling tense and risky) while riding in the AV and perceived usability of the ADS based on the System Usability Scale. In both conditions, participants reported moderate positive experience and perceived usability but a relatively high level of willingness to ride in our AV again. The ADS failure reduced positive experience and perceived usability, and it increased negative experience. Positive experience and perceived usability, but not negative experience, influenced re-riding willingness. Compared with male participants, female participants reported less positive experience and lower perceived usability. We discuss implications of our results as well as limitations of this research.

11.
J Hazard Mater ; 423(Pt A): 127077, 2021 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-34482084

RESUMO

The great threat of pesticide residues to the environment and human health has drawn widespread interest to explore approaches for pesticide monitoring. Compared to commonly developed single-signal pesticide assays, multi-mode detection with inherent self-validation and self-correction is expected to offer more reliable and anti-interference results. However, how to realize multi-mode analysis of pesticides still remains challenging. Herein, we propose a dual-mode fluorescence and colorimetric method for pesticide determination by integrating stimulus-responsive luminescence with oxidase-mimetic activity into cerium-based coordination polymer nanoparticles (CPNs(Ⅳ)). The CPNs(Ⅳ) exhibit good oxidase-like activity of catalyzing the colorless 3,3',5,5'-tetramethylbenzidine (TMB) oxidation to its blue oxide, offering a visible color signal; by employing acid phosphatase (ACP) to hydrolyze ascorbic acid 2-phosphate (AAP), the generated ascorbic acid (AA) can chemically reduce the CPNs(Ⅳ) to CPNs(Ⅲ), which exhibit a remarkable fluorescence signal but lose the oxidase-mimicking ability to trigger the TMB chromogenic reaction; when pesticides exist, the enzymatic activity of ACP is restrained and the hydrolysis of AAP to AA is blocked, leading to the recovery of the catalytic TMB chromogenic reaction but the suppression of the fluorescence signal of CPNs(Ⅲ). According to this principle, by taking malathion as a pesticide model, dual-mode 'off-on-off' fluorescence and 'on-off-on' colorimetric detection of the pesticide with good sensitivity was realized. Excellent interference-tolerance and reliability were verified by applying it to analyze the target in real sample matrices. With good performance and practicability, the proposed dual-mode approach shows great potential in the facile and reliable monitoring of pesticide residues.

12.
IEEE Trans Cybern ; PP2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34495860

RESUMO

Multigoal reinforcement learning (RL) extends the typical RL with goal-conditional value functions and policies. One efficient multigoal RL algorithm is the hindsight experience replay (HER). By treating a hindsight goal from failed experiences as the original goal, HER enables the agent to receive rewards frequently. However, a key assumption of HER is that the hindsight goals do not change the likelihood of the sampled transitions and trajectories used in training, which is not the fact according to our analysis. More specifically, we show that using hindsight goals changes such a likelihood and results in a biased learning objective for multigoal RL. We analyze the hindsight bias due to this use of hindsight goals and propose the bias-corrected HER (BHER), an efficient algorithm that corrects the hindsight bias in training. We further show that BHER outperforms several state-of-the-art multigoal RL approaches in challenging robotics tasks.

13.
Anal Chem ; 93(33): 11540-11546, 2021 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-34369746

RESUMO

Pancreatic cancer is known to have a high mortality rate, and its early diagnosis remains challenging due to the occult location of the pancreas. Exosomes derived from pancreatic cancer cells specifically express glypican-1, which may provide a liquid biopsy opportunity for the early diagnosis of pancreatic cancer. Herein, an inductively coupled plasma mass spectrometry (ICP-MS) and photothermal dual-readout platform was proposed for the ultrasensitive and point-of-care analysis of pancreatic cancer exosomes. In our design, exosomes were specifically captured by the sandwich immunoassay, and simultaneously, alkaline phosphatase was introduced in a low-background manner. The alkaline phosphatase triggered the hydrolysis of l-ascorbic acid 2-phosphate to produce ascorbic acid, followed by the etching of Fe3O4@MnO2 nanoflowers. As a result, the Mn2+ generated by etching stripped off the Fe3O4 and was quantified using ICP-MS. Meanwhile, the reduced Fe3O4@MnO2 was applied for the photothermal assay by oxidizing dopamine with MnO2. The protocol exhibits a detection limit down to 19.1 particles mL-1, which is the most sensitive protocol reported so far. To our knowledge, this is the first endeavor for exosome quantification using ICP-MS and photothermal methods. The developed dual-readout platform not only is capable of distinguishing pancreatic cancer patients from healthy people, but also shows excellent discernibility of individual differences at low concentrations of exosomes. This dual-readout assay is a promising platform for the ultrasensitive and point-of-care detection of exosomes in liquid biopsy-based early cancer diagnosis.


Assuntos
Exossomos , Neoplasias Pancreáticas , Humanos , Compostos de Manganês , Óxidos , Sistemas Automatizados de Assistência Junto ao Leito
14.
J Am Chem Soc ; 143(35): 14196-14206, 2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34432468

RESUMO

The recent success of nickel catalysts in stereoconvergent cross-coupling and cross-electrophile coupling reactions partly stems from the ability of monovalent nickel species to activate C(sp3) electrophiles and generate radical intermediates. This electroanalytical study of the commonly applied (bpy)Ni catalyst elucidates the mechanism of this critical step. Data rule out outer-sphere electron transfer and two-electron oxidative addition pathways. The linear free energy relationship between rates and the bond-dissociation free energies, the electronic and steric effects of the nickel complexes and the electrophiles, and DFT calculations support a variant of the halogen-atom abstraction pathway, the inner-sphere electron transfer concerted with halogen-atom dissociation. This mechanism accounts for the observed reactivity of different electrophiles in cross-coupling reactions and provides a mechanistic rationale for the chemoselectivity obtained in cross-electrophile coupling over homocoupling.

15.
Bioresour Technol ; 340: 125674, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34364086

RESUMO

The Fe-modified biochar (FeBC) was used to remove aqueous As(III/V), and the role of oxygen (O2) in As removal was investigated by integrating aqueous and solid analyses. The removal efficiencies for As(III) and As(V) increased from 86.4% and 99.2% under anoxic conditions, respectively, to >99.9% when O2 was available. FeBC removed As(III) from As(III)-spiked systems by surface-oxidation following adsorption, where oxidation of As(III) was promoted by O2. As(V) was first reduced, re-oxidized in solutions, and then adsorbed to FeBC in As(V)-spiked systems, where reduction of As(V) was inhibited at the presence of O2. Both As(III) and As(V) were bidentate corner-sharing complexed to Fe oxides/hydroxides on FeBC, with As coordinated to Fe at ~3.4 Å according to As extended X-ray absorption fine structure (EXAFS) modeling. These findings identified the effect of ambient O2 in As(III/V) redox transformations and removal, guiding the further application of FeBC in environmental treatment.


Assuntos
Arsênio , Adsorção , Carvão Vegetal , Oxirredução , Oxigênio
16.
J Org Chem ; 86(17): 11926-11936, 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34379423

RESUMO

Kinase activity can be modulated reversibly or irreversibly by the reaction of targeted covalent inhibitors with nucleophilic residues in protein active sites. Herein, we present thiol reactivity studies that support α-methylene-γ-lactams as tunable surrogates for the highly reactive α-methylene-γ-lactones. The reactivity of the α-methylene is modulated via the N substituent, and the reaction rates toward glutathione were determined via mass spectrometry. Density functional theory calculations of transition states of thiol additions to α-methylene-γ-lactams revealed that the use of the M06-2X functional with the SMD solvation model and methyl thiolate as a model nucleophile reliably predicts the relative reactivities of the α-methylene-γ-lactams, and quasiharmonic approximations improve the agreement between experiment and computation.

18.
Brain Imaging Behav ; 2021 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-34417967

RESUMO

Premenstrual syndrome (PMS) is a menstrual cycle-related disorder. Previous studies have indicated alterations of brain functional connectivity in PMS patients. However, little is known about the overall organization of brain network in PMS patients. Functional magnetic resonance imaging data deriving from 20 PMS patients and 21 healthy controls (HCs). Pearson correlation between mean time-series was used to estimate connectivity matrix between each paired regions of interest, and the connectivity matrix for each participant was then binarized. Graph theory analysis was applied to assess each participant's global and local topological properties of brain functional network. Correlation analysis was performed to evaluate relationships between the daily rating of severity of problems (DRSP) and abnormal network properties. PMS patients had lower small-worldness values than HCs. PMS-related alterations of nodal properties were mainly found in the posterior cingulate cortex, precuneus and angular gyrus. The PMS-related abnormal connectivity components were mainly associated with the thalamus, putamen and middle cingulate cortex. In the PMS group, the DRSP score were negatively correlated with the area under the curves of nodal local efficiency in the posterior cingulate cortex. Our study suggests that the graph-theory method may be one potential tool to detect disruptions of brain connections and may provide important evidence for understanding the PMS from the disrupted network organization perspective.

19.
Sci Total Environ ; 791: 148333, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34412379

RESUMO

As a new pollutant, microplastics (MPs) exhibited more and more significant influence on the organisms in the environment. Especially, the effects on the growth and development of plants by MPs attracted wide attentions in recent period. In the review article, we summarized the important influences of MPs on terrestrial and aquatic plants. The properties, including type, size and oxygen-containing group of MPs on their physical injures toward plants were critically reviewed, which were significantly correlated to the toxicity to plants. The secondary risks of MPs including the additives and MP-derived organic products and the adsorbed environmental pollutants to plants were clearly revealed. The hydrophobic organic pollutants released from MPs showed significant chemical effects on the plants. We also outlined the effects of MPs to the various regions (e.g. the seed and rhizome) of plants and compared the toxic difference of MPs on terrestrial and aquatic plants. Generally, the seed and rhizome of plants were susceptible to MPs, and the effects of MPs on terrestrial and aquatic plants were different. The review paper improves the understanding of potential toxicity of MP themselves and the released and adsorbed chemicals to plants in the environment.


Assuntos
Poluentes Ambientais , Poluentes Químicos da Água , Monitoramento Ambiental , Poluentes Ambientais/análise , Microplásticos , Plásticos/toxicidade , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/toxicidade
20.
Cytotherapy ; 2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34426082

RESUMO

BACKGROUND AIMS: Hematopoietic stem and progenitor cells (HSPCs) are known to produce short-lived mature blood cells via proliferation and differentiation in a process that depends partially on regulatory cytokines from the bone marrow (BM) microenvironment. Delayed BM recovery after tremendous damage to the hematopoietic system can lead to neutropenia, anemia, thrombopenia and even death. However, efficiently promote BM recovery is still a big problem to be solved. Here, the authors aim to use heat-inactivated Escherichia coli (HIEC) to enhance BM recovery and further to find out the potential mechanism. METHODS: X-rad was used to establish HIEC/IL-1ß-induced radioprotection model. Single-cell RNA sequencing, RT-PCR, and western blotting were performed to detect the expression of IL-1R1 on HSPCs. Flow cytometry and automated hematology analyzer were used to analyze the percentage and absolute number of different populations of hematopoietic cells. The effects of IL-1ß on HSPCs were studied using in vivo and in vitro experiments. RESULTS: HIEC/IL-1ß pre-treatment can significantly increase the survival rate of lethally irradiated mice, and these mice showed better hematopoietic regeneration compared with control group. IL-1R was expressed on HSPCs, and IL-1ß could directly function on HSPCs to promote the proliferation and differentiation of HSPCs, and inhibit the apoptosis of HSPCs. CONCLUSIONS: HIEC pre-treatment can rescue lethally irradiated mice by promoting hematopoietic recovery via IL-1ß/IL-1R1 signaling, which can promote the proliferation of HSPCs by enhancing the cell cycle and attenuating the apoptosis of HSPCs.

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