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1.
Cell Death Dis ; 15(6): 436, 2024 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-38902268

RESUMO

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide, necessitating the identification of novel therapeutic targets. Lysosome Associated Protein Transmembrane 4B (LAPTM4B) is involved in biological processes critical to cancer progression, such as regulation of solute carrier transporter proteins and metabolic pathways, including mTORC1. However, the metabolic processes governed by LAPTM4B and its role in oncogenesis remain unknown. In this study, we conducted unbiased metabolomic screens to uncover the metabolic landscape regulated by LAPTM4B. We observed common metabolic changes in several knockout cell models suggesting of a role for LAPTM4B in suppressing ferroptosis. Through a series of cell-based assays and animal experiments, we demonstrate that LAPTM4B protects tumor cells from erastin-induced ferroptosis both in vitro and in vivo. Mechanistically, LAPTM4B suppresses ferroptosis by inhibiting NEDD4L/ZRANB1 mediated ubiquitination and subsequent proteasomal degradation of the cystine-glutamate antiporter SLC7A11. Furthermore, metabolomic profiling of cancer cells revealed that LAPTM4B knockout leads to a significant enrichment of ferroptosis and associated metabolic alterations. By integrating results from cellular assays, patient tissue samples, an animal model, and cancer databases, this study highlights the clinical relevance of the LAPTM4B-SLC7A11-ferroptosis signaling axis in NSCLC progression and identifies it as a potential target for the development of cancer therapeutics.


Assuntos
Sistema y+ de Transporte de Aminoácidos , Carcinoma Pulmonar de Células não Pequenas , Ferroptose , Neoplasias Pulmonares , Complexo de Endopeptidases do Proteassoma , Ubiquitina , Ferroptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/genética , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/genética , Animais , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitina/metabolismo , Camundongos , Sistema y+ de Transporte de Aminoácidos/metabolismo , Sistema y+ de Transporte de Aminoácidos/genética , Proteínas Oncogênicas/metabolismo , Proteínas Oncogênicas/genética , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Linhagem Celular Tumoral , Ubiquitinação , Camundongos Nus , Proteólise/efeitos dos fármacos
2.
J Hazard Mater ; 474: 134842, 2024 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-38852246

RESUMO

Heterogeneous catalytic ozonation (HCO) enables the destruction of organic pollutants in wastewater via oxidation by powerful hydroxyl radicals (·OH). However, the availability of short-lived ·OH in aqueous bulk is low in practical treatment scenarios due to mass transfer limitations and quenching of water constituents. Herein, we overcome these challenges by loading MgO catalysts inside the pores of a tubular ceramic membrane (denoted as CCM) to confine ·OH within the nanopores and achieve efficient pollutant removal. When the pore size of the membrane was reduced from 1000 to 50 nm, the removal of ibuprofen (IBU) by CCM was increased from 49.6 % to 90.2 % due to the enhancement of ·OH enrichment in the nanospace. In addition, the CCM exhibited high catalytic activity in the presence of co-existing ions and over a wide pH range, as well as good self-cleaning ability in treating secondary wastewater. The experimental results revealed that ·OH were the dominant reactive oxygen species (ROS) in pollutant degradation, while surface hydroxyl groups were active sites for the generation of ·OH via ozone decomposition. This work provides a promising strategy to enhance the utilization of ·OH in HCO for the efficient degradation of organic pollutants in wastewater under spatial confinement.

3.
IEEE Trans Image Process ; 33: 3456-3469, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38787666

RESUMO

Our work focuses on tackling the problem of fine-grained recognition with incomplete multi-modal data, which is overlooked by previous work in the literature. It is desirable to not only capture fine-grained patterns of objects but also alleviate the challenges of missing modalities for such a practical problem. In this paper, we propose to leverage a meta-learning strategy to learn model abilities of both fast modal adaptation and more importantly missing modality completion across a variety of incomplete multi-modality learning tasks. Based on that, we develop a meta-completion method, termed as MECOM, to perform multimodal fusion and explicit missing modality completion by our proposals of cross-modal attention and decoupling reconstruction. To further improve fine-grained recognition accuracy, an additional partial stream (as a counterpart of the main stream of MECOM, i.e., holistic) and the part-level features (corresponding to fine-grained objects' parts) selection are designed, which are tailored for fine-grained nature to capture discriminative but subtle part-level patterns. Comprehensive experiments from quantitative and qualitative aspects, as well as various ablation studies, on two fine-grained multimodal datasets and one generic multimodal dataset show our superiority over competing methods. Our code is open-source and available at https://github.com/SEU-VIPGroup/MECOM.

4.
Angew Chem Int Ed Engl ; : e202406452, 2024 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-38735843

RESUMO

Acidic H2O2 synthesis through electrocatalytic 2e- oxygen reduction presents a sustainable alternative to the energy-intensive anthraquinone oxidation technology. Nevertheless, acidic H2O2 electrosynthesis suffers from low H2O2 Faradaic efficiencies primarily due to the competing reactions of 4e- oxygen reduction to H2O and hydrogen evolution in environments with high H+ concentrations. Here, we demonstrate the significant effect of alkali metal cations, acting as competing ions with H+, in promoting acidic H2O2 electrosynthesis at industrial-level currents, resulting in an effective current densities of 50-421 mA cm-2 with 84-100 % Faradaic efficiency and a production rate of 856-7842 µmol cm-2 h-1 that far exceeds the performance observed in pure acidic electrolytes or low-current electrolysis. Finite-element simulations indicate that high interfacial pH near the electrode surface formed at high currents is crucial for activating the promotional effect of K+. In situ attenuated total reflection Fourier transform infrared spectroscopy and ab initio molecular dynamics simulations reveal the central role of alkali metal cations in stabilizing the key *OOH intermediate to suppress 4e- oxygen reduction through interacting with coordinated H2O.

5.
Cell Discov ; 10(1): 40, 2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38594245

RESUMO

Drug resistance poses a significant challenge in the development of effective therapies against SARS-CoV-2. Here, we identified two double mutations, M49K/M165V and M49K/S301P, in the 3C-like protease (3CLpro) that confer resistance to a novel non-covalent inhibitor, WU-04, which is currently in phase III clinical trials (NCT06197217). Crystallographic analysis indicates that the M49K mutation destabilizes the WU-04-binding pocket, impacting the binding of WU-04 more significantly than the binding of 3CLpro substrates. The M165V mutation directly interferes with WU-04 binding. The S301P mutation, which is far from the WU-04-binding pocket, indirectly affects WU-04 binding by restricting the rotation of 3CLpro's C-terminal tail and impeding 3CLpro dimerization. We further explored 3CLpro mutations that confer resistance to two clinically used inhibitors: ensitrelvir and nirmatrelvir, and revealed a trade-off between the catalytic activity, thermostability, and drug resistance of 3CLpro. We found that mutations at the same residue (M49) can have distinct effects on the 3CLpro inhibitors, highlighting the importance of developing multiple antiviral agents with different skeletons for fighting SARS-CoV-2. These findings enhance our understanding of SARS-CoV-2 resistance mechanisms and inform the development of effective therapeutics.

6.
Water Res ; 255: 121550, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38579590

RESUMO

Electrochemistry is a sustainable technology for oil-water separation. In the common flat electrode scheme, due to a few centimeters away from the anode, oil droplets have to undergo electromigration to and electrical neutralization at the anodic surface before they coalesce into large oil droplets and rise to water surface, resulting in slow demulsification and easy anode fouling. Herein, a novel strategy is proposed on basis of a TiO2-x/Ti anode with microchannels to overcome these problems. When oil droplets with several microns in diameter flow through channels with tens of microns in diameter, the electromigration distance is shortened by three orders of magnitude, electrical neutralization is replaced by polarization coupling ·OH oxidation. The new strategy was supported by experimental results and theoretical analysis. Taking the suspension containing emulsified oil as targets, COD value dropped from initial 500 mg/L to 117 mg/L after flowing through anodic microchannels in only 58 s of running time, and the COD removal was 21 times higher than that for a plate anode. At similar COD removal, the residence time was 48 times shorter than that of reported flat electrodes. Coalescences of oil droplets in microchannels were observed by a confocal laser scanning microscopy. This new strategy opens a door for using microchannel electrodes to accelerate electrochemical coalescence of oil-in-water droplets.

7.
Front Pharmacol ; 15: 1332394, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38645552

RESUMO

Endothelin-1 (ET-1) is a potent vasoconstrictor with strong anti-natriuretic and anti-diuretic effects. While many experimental studies have elucidated the mechanisms of ET-1 through its two receptors, ETA and ETB, the complexity of responses and sometimes conflicting data make it challenging to understand the effects of ET-1, as well as potential therapeutic antagonism of ET-1 receptors, on human physiology. In this study, we aimed to develop an integrated and quantitative description of ET-1 effects on cardiovascular and renal function in healthy humans by coupling existing experimental data with a mathematical model of ET-1 kinetics and an existing mathematical model of cardiorenal function. Using a novel agnostic and iterative approach to incorporating and testing potential mechanisms, we identified a minimal set of physiological actions of endothelin-1 through ETA and ETB receptors by fitting the physiological responses (changes in blood pressure, renal blood flow, glomerular filtration rate (GFR), and sodium/water excretion) to ET-1 infusion, with and without ETA/ETB antagonism. The identified mechanisms align with previous experimental studies on ET-1 and offer novel insights into the relative magnitude and significance of endothelin's effects. This model serves as a foundation for further investigating the mechanisms of ET-1 and its antagonists.

8.
Nano Lett ; 24(9): 2876-2884, 2024 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-38385324

RESUMO

Upconversion (UC)/downconversion (DC)-luminescent lanthanide-doped nanocrystals (LDNCs) with near-infrared (NIR, 650-1700 nm) excitation have been gaining increasing popularity in bioimaging. However, conventional NIR-excited LDNCs cannot be degraded and eliminated eventually in vivo owing to intrinsic "rigid" lattices, thus constraining clinical applications. A biodegradability-tunable heterogeneous core-shell-shell luminescent LDNC of Na3HfF7:Yb,Er@Na3ZrF7:Yb,Er@CaF2:Yb,Zr (abbreviated as HZC) was developed and modified with oxidized sodium alginate (OSA) for multimode bioimaging. The dynamic "soft" lattice-Na3Hf(Zr)F7 host and the varying Zr4+ doping content in the outmoster CaF2 shell endowed HZC with tunable degradability. Through elaborated core-shell-shell coating, Yb3+/Er3+-coupled UC red and green and DC second near-infrared (NIR-II) emissions were, respectively, enhanced by 31.23-, 150.60-, and 19.42-fold when compared with core nanocrystals. HZC generated computed tomography (CT) imaging contrast effects, thus enabling NIR-II/CT/UC trimodal imaging. OSA modification not only ensured the exemplary biocompatibility of HZC but also enabled tumor-specific diagnosis. The findings would benefit the clinical imaging translation of LDNCs.


Assuntos
Elementos da Série dos Lantanídeos , Nanopartículas , Háfnio , Zircônio , Nanopartículas/química , Tomografia Computadorizada por Raios X
9.
Clin Pharmacokinet ; 63(2): 255-267, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38236561

RESUMO

BACKGROUND: Cotadutide is a dual glucagon-like peptide-1 (GLP-1) and glucagon (GCG) receptor agonist peptide. The objective of this analysis was to develop a population pharmacokinetic (popPK) model of cotadutide, and to identify any potential effect on the PK from intrinsic and extrinsic covariates. METHODS: The popPK analysis utilized a non-linear mixed-effects modeling approach using the data from 10 clinical studies in different participant categories following once-daily subcutaneous dose administration ranging from 20 to 600 µg. Additionally, the covariates affecting cotadutide exposure were quantified, and the model performance was evaluated through the prediction-corrected visual predictive checks. RESULTS: A one-compartment model with first-order absorption and elimination adequately described the data as confirmed via visual predictive check plots and parameter plausibility. The mean values for cotadutide apparent clearance (CL/F), apparent volume of distribution (V/F), absorption rate constant (Ka), and half-life were 1.05 L/h, 20.0 L, 0.38 h-1, and 13.3 hours, respectively. Covariate modeling identified body weight, alanine transaminase, albumin, anti-drug antibody (ADA) titer values, formulation strength and injection device, and participant categories as significant covariates on PK parameters, where ADAs have been identified to decrease cotadutide clearance. The model demonstrated that a 150-kg participant was estimated to have 30% lower for both AUC and Cmax and a 66 kg participant was estimated to have 35% higher for both AUC and Cmax relative to a reference individual with a median weight of 96 kg. CONCLUSIONS: A popPK model was developed for cotadutide with cotadutide clinical data, and the impact of the statistically significant covariates identified was not considered clinically meaningful. The popPK model will be used to evaluate exposure-response relationships for cotadutide clinical data.


Assuntos
Diabetes Mellitus Tipo 2 , Fígado Gorduroso , Insuficiência Renal Crônica , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptores de Glucagon , Modelos Biológicos , Peptídeos , Obesidade , Peptídeo 1 Semelhante ao Glucagon
10.
Mater Horiz ; 11(7): 1732-1740, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38284790

RESUMO

The restricted energy density in dielectric ceramic capacitors is challenging for their integration with advanced electronic systems. Numerous strategies have been proposed to boost the energy density at different scales or combine those multiscale effects. Herein, guided by all-scale synergistic design, we fabricated Sr0.7Bi0.2TiO3 ceramics doped with (Bi0.5Na0.5)(Zr0.5Ti0.5)O3 by sintering the nanopowders by solution combustion synthesis, which demonstrate exceptional energy storage performance (ESP). Notably, an ultrahigh recoverable energy density of 11.33 J cm-3, accompanied by an impressive energy efficiency of 89.30%, was achieved at an extremely high critical electric field of 961 kV cm-1. These primary energy storage parameters outperform those of previously reported ceramic capacitors based on SrTiO3. Additionally, an excellent comprehensive performance is also realized, including a substantial power density of 156.21 MW cm-3 (at 300 kV cm-1), an extraordinarily short discharge time of 97 ns, a high Vickers hardness rating of approximately 8.23 GPa, and outstanding thermal and frequency stability. This enhancement can be attributed to the synergistic effect at all scales from atomic substitution, polar nano regions, submicrometer grain, and sample thickness. Consequently, this panoscopic approach has effectively demonstrated the potential to enhance the ESP of dielectric ceramics.

11.
Trends Cell Biol ; 2023 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-37993310

RESUMO

Nuclear bodies (NBs) are biomolecular condensates that participate in various cellular processes and respond to cellular stimuli in the nucleus. The assembly and function of these protein- and RNA-rich bodies, such as nucleoli, nuclear speckles, and promyelocytic leukemia (PML) NBs, contribute to the spatial organization of the nucleus, regulating chromatin activities locally and globally. Recent technological advancements, including spatial multiomics approaches, have revealed novel roles of nucleoli in modulating ribosomal DNA (rDNA) and adjacent non-rDNA chromatin activity, nuclear speckles in scaffolding active genome architecture, and PML NBs in maintaining genome stability during stress conditions. In this review, we summarize emerging functions of these important NBs in the spatial organization of the genome, aided by recently developed spatial multiomics approaches toward this direction.

12.
PLoS Comput Biol ; 19(11): e1011598, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37956217

RESUMO

In contrast to heart failure (HF) with reduced ejection fraction (HFrEF), effective interventions for HF with preserved ejection fraction (HFpEF) have proven elusive, in part because it is a heterogeneous syndrome with incompletely understood pathophysiology. This study utilized mathematical modeling to evaluate mechanisms distinguishing HFpEF and HFrEF. HF was defined as a state of chronically elevated left ventricle end diastolic pressure (LVEDP > 20mmHg). First, using a previously developed cardiorenal model, sensitivities of LVEDP to potential contributing mechanisms of HFpEF, including increased myocardial, arterial, or venous stiffness, slowed ventricular relaxation, reduced LV contractility, hypertension, or reduced venous capacitance, were evaluated. Elevated LV stiffness was identified as the most sensitive factor. Large LV stiffness increases alone, or milder increases combined with either decreased LV contractility, increased arterial stiffness, or hypertension, could increase LVEDP into the HF range without reducing EF. We then evaluated effects of these mechanisms on mechanical signals of cardiac outward remodeling, and tested the ability to maintain stable EF (as opposed to progressive EF decline) under two remodeling assumptions: LV passive stress-driven vs. strain-driven remodeling. While elevated LV stiffness increased LVEDP and LV wall stress, it mitigated wall strain rise for a given LVEDP. This suggests that if LV strain drives outward remodeling, a stiffer myocardium will experience less strain and less outward dilatation when additional factors such as impaired contractility, hypertension, or arterial stiffening exacerbate LVEDP, allowing EF to remain normal even at high filling pressures. Thus, HFpEF heterogeneity may result from a range of different pathologic mechanisms occurring in an already stiffened myocardium. Together, these simulations further support LV stiffening as a critical mechanism contributing to elevated cardiac filling pressures; support LV passive strain as the outward dilatation signal; offer an explanation for HFpEF heterogeneity; and provide a mechanistic explanation distinguishing between HFpEF and HFrEF.


Assuntos
Insuficiência Cardíaca , Hipertensão , Humanos , Volume Sistólico/fisiologia , Coração , Miocárdio/patologia , Hipertensão/complicações
13.
Nat Commun ; 14(1): 6952, 2023 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-37907462

RESUMO

O-GlcNAcylation is a conserved post-translational modification that attaches N-acetyl glucosamine (GlcNAc) to myriad cellular proteins. In response to nutritional and hormonal signals, O-GlcNAcylation regulates diverse cellular processes by modulating the stability, structure, and function of target proteins. Dysregulation of O-GlcNAcylation has been implicated in the pathogenesis of cancer, diabetes, and neurodegeneration. A single pair of enzymes, the O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), catalyzes the addition and removal of O-GlcNAc on over 3,000 proteins in the human proteome. However, how OGT selects its native substrates and maintains the homeostatic control of O-GlcNAcylation of so many substrates against OGA is not fully understood. Here, we present the cryo-electron microscopy (cryo-EM) structures of human OGT and the OGT-OGA complex. Our studies reveal that OGT forms a functionally important scissor-shaped dimer. Within the OGT-OGA complex structure, a long flexible OGA segment occupies the extended substrate-binding groove of OGT and positions a serine for O-GlcNAcylation, thus preventing OGT from modifying other substrates. Conversely, OGT disrupts the functional dimerization of OGA and occludes its active site, resulting in the blocking of access by other substrates. This mutual inhibition between OGT and OGA may limit the futile O-GlcNAcylation cycles and help to maintain O-GlcNAc homeostasis.


Assuntos
Processamento de Proteína Pós-Traducional , Proteínas , Humanos , Acetilglucosamina/metabolismo , Acetilglucosaminidase/metabolismo , Microscopia Crioeletrônica , N-Acetilglucosaminiltransferases/metabolismo , Proteínas/metabolismo
14.
Yeast ; 40(11): 540-549, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37818980

RESUMO

Five yeast strains isolated from tree bark and rotten wood collected in central and southwestern China, together with four Brazilian strains (three from soil and rotting wood collected in an Amazonian rainforest biome and one from Bromeliad collected in Alagoas state) and one Costa Rican strain isolated from a flower beetle, represent a new species closely related with Yueomyces sinensis in Saccharomycetaceae, as revealed by the 26S ribosomal RNA gene D1/D2 domain and the internal transcribed spacer region sequence analysis. The name Yueomyces silvicola sp. nov. is proposed for this new species with the holotype China General Microbiological Culture Collection Center 2.6469 (= Japan Collection of Microorganisms 34885). The new species exhibits a whole-genome average nucleotide identity value of 77.8% with Y. sinensis. The two Yueomyces species shared unique physiological characteristics of being unable to utilize ammonium and the majority of the amino acids, including glutamate and glutamine, as sole nitrogen sources. Among the 20 amino acids tested, only leucine and tyrosine can be utilized by the Yueomyces species. Genome sequence comparison showed that GAT1, which encodes a GATA family protein participating in transcriptional activation of nitrogen-catabolic genes in Saccharomyces cerevisiae, is absent in the Yueomyces species. However, the failure of the Yueomyces species to utilize ammonium, glutamate, and glutamine, which are generally preferred nitrogen sources for microorganisms, implies that more complicated alterations in the central nitrogen metabolism pathway might occur in the genus Yueomyces.


Assuntos
Compostos de Amônio , Saccharomycetales , Saccharomyces cerevisiae/genética , Glutamina/genética , Ácido Glutâmico/genética , Filogenia , DNA Espaçador Ribossômico/genética , Análise de Sequência de DNA , Saccharomycetales/genética , Aminoácidos/genética , DNA Fúngico/genética
15.
Diabetes ; 72(12): 1781-1794, 2023 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-37725942

RESUMO

Insulin activates insulin receptor (IR) signaling and subsequently triggers IR endocytosis to attenuate signaling. Cell division regulators MAD2, BUBR1, and p31comet promote IR endocytosis on insulin stimulation. Here, we show that genetic ablation of the IR-MAD2 interaction in mice delays IR endocytosis, increases IR levels, and prolongs insulin action at the cell surface. This in turn causes a defect in insulin clearance and increases circulating insulin levels, unexpectedly increasing glucagon levels, which alters glucose metabolism modestly. Disruption of the IR-MAD2 interaction increases serum fatty acid concentrations and hepatic fat accumulation in fasted male mice. Furthermore, disruption of the IR-MAD2 interaction distinctly changes metabolic and transcriptomic profiles in the liver and adipose tissues. Our findings establish the function of cell division regulators in insulin signaling and provide insights into the metabolic functions of IR endocytosis. ARTICLE HIGHLIGHTS: The physiological role of IR endocytosis in insulin sensitivity remains unclear. Disruption of the IR-MAD2 interaction delays IR endocytosis and prolongs insulin signaling. IR-MAD2 controls insulin clearance and glucose metabolism. IR-MAD2 maintains energy homeostasis.


Assuntos
Resistência à Insulina , Receptor de Insulina , Animais , Masculino , Camundongos , Endocitose , Glucose/metabolismo , Homeostase , Insulina/metabolismo , Fígado/metabolismo , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Proteínas Mad2/metabolismo
16.
J Biol Chem ; 299(11): 105296, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37774974

RESUMO

3D chromatin organization plays a critical role in regulating gene expression, DNA replication, recombination, and repair. While initially discovered for its role in sister chromatid cohesion, emerging evidence suggests that the cohesin complex (SMC1, SMC3, RAD21, and SA1/SA2), facilitated by NIPBL, mediates topologically associating domains and chromatin loops through DNA loop extrusion. However, information on how conformational changes of cohesin-NIPBL drive its loading onto DNA, initiation, and growth of DNA loops is still lacking. In this study, high-speed atomic force microscopy imaging reveals that cohesin-NIPBL captures DNA through arm extension, assisted by feet (shorter protrusions), and followed by transfer of DNA to its lower compartment (SMC heads, RAD21, SA1, and NIPBL). While binding at the lower compartment, arm extension leads to the capture of a second DNA segment and the initiation of a DNA loop that is independent of ATP hydrolysis. The feet are likely contributed by the C-terminal domains of SA1 and NIPBL and can transiently bind to DNA to facilitate the loading of the cohesin complex onto DNA. Furthermore, high-speed atomic force microscopy imaging reveals distinct forward and reverse DNA loop extrusion steps by cohesin-NIPBL. These results advance our understanding of cohesin by establishing direct experimental evidence for a multistep DNA-binding mechanism mediated by dynamic protein conformational changes.


Assuntos
Proteínas de Ciclo Celular , Proteínas Cromossômicas não Histona , Proteínas de Ciclo Celular/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , DNA/química , Cromatina , Coesinas
17.
Plants (Basel) ; 12(15)2023 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-37570944

RESUMO

Growth regulatory factors (GRF) are plant-specific transcription factors that play pivotal roles in growth and various abiotic stresses regulation. However, adaptive evolution of GRF gene family in land plants are still being elucidated. Here, we performed the evolutionary and expression analysis of GRF gene family from seven representative species. Extensive phylogenetic analyses and gene structure analysis revealed that the number of genes, QLQ domain and WRC domain identified in higher plants was significantly greater than those identified in lower plants. Besides, dispersed duplication and WGD/segmental duplication effectively promoted expansion of the GRF gene family. The expression patterns of GRF gene family and target genes were found in multiple floral organs and abundant in actively growing tissues. They were also found to be particularly expressed in response to various abiotic stresses, with stress-related elements in promoters, implying potential roles in floral development and abiotic stress. Our analysis in GRF gene family interaction network indicated the similar results that GRFs resist to abiotic stresses with the cooperation of other transcription factors like GIFs. This study provides insights into evolution in the GRF gene family, together with expression patterns valuable for future functional researches of plant abiotic stress biology.

18.
Mol Cell ; 83(16): 2856-2871.e8, 2023 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-37536339

RESUMO

Cohesin and CCCTC-binding factor (CTCF) are key regulatory proteins of three-dimensional (3D) genome organization. Cohesin extrudes DNA loops that are anchored by CTCF in a polar orientation. Here, we present direct evidence that CTCF binding polarity controls cohesin-mediated DNA looping. Using single-molecule imaging, we demonstrate that a critical N-terminal motif of CTCF blocks cohesin translocation and DNA looping. The cryo-EM structure of the cohesin-CTCF complex reveals that this CTCF motif ahead of zinc fingers can only reach its binding site on the STAG1 cohesin subunit when the N terminus of CTCF faces cohesin. Remarkably, a C-terminally oriented CTCF accelerates DNA compaction by cohesin. DNA-bound Cas9 and Cas12a ribonucleoproteins are also polar cohesin barriers, indicating that stalling may be intrinsic to cohesin itself. Finally, we show that RNA-DNA hybrids (R-loops) block cohesin-mediated DNA compaction in vitro and are enriched with cohesin subunits in vivo, likely forming TAD boundaries.


Assuntos
Cromatina , Estruturas R-Loop , Fator de Ligação a CCCTC/genética , Fator de Ligação a CCCTC/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , DNA/genética , DNA/metabolismo , Coesinas
19.
Water Res ; 242: 120195, 2023 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-37302179

RESUMO

Electrochemistry is a potential method for water softening. An essential disadvantage is OH¯ ions from water electrolysis accumulate on cathode surface, inducing the generation of the insulating CaCO3 layer and then interrupting the electrochemical reaction. In order to propel OH¯ diffusion into the bulk solution instead of aggregation at cathode, we designed an electrochemical reactor, whose electrodes were placed horizontally in the middle of the reactor, and the bubbles created by water electrolysis move upward, while the water flows downward. The visual evidence displayed that the unique reactor structure allowed OH¯ to spread to almost all the solution rapidly. Average pH value of bulk solution reached 10.6 in only 3 min. Therefore, homogeneous nucleation of CaCO3 in bulk solution would take primary responsibility for water softening, and the softening efficiency is up to 212.9 g CaCO3/h/m2, higher than reported results. The reactor is easy to scale up, providing a new idea for the softening of circulating cooling water.


Assuntos
Eletrólise , Eletroquímica , Íons , Difusão , Eletrodos
20.
J Hazard Mater ; 458: 131925, 2023 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-37385100

RESUMO

The heterogeneous Fenton oxidation is regarded as a promising technology for refractory organic pollutants removal relying on highly active •OH generated via the decomposition of H2O2 catalyzed by iron-based catalyst that overcomes the issues of pH limitation and iron sludge discharge encountered in conventional Fenton reaction. However, the efficiency of •OH production in heterogeneous Fenton remains low as the limited mass transfer between H2O2 and catalysts caused by the poor H2O2 adsorption. Here, a nitrogen-doped porous carbon (NPC) catalyst with tunable N configuration was prepared for electrochemical-activation of H2O2 to •OH by enhancing the H2O2 adsorption on catalysts. The resultant •OH production yield on NPC reached 0.83 mM in 120 min. Notably, the NPC catalyst could be more energy-efficient for actual coking wastewater treatment with an energy consumption of 10.3 kWh kgCOD-1 than other electro-Fenton catalysts reported (20-29.7 kWh kgCOD-1). Density function theory (DFT) revealed that highly efficient •OH production was ascribed to the graphitic N which enhances the adsorption energy of H2O2 on NPC catalyst. This study provides new insight into the fabrication of efficient carbonaceous catalysts by rationally modulating electronic structures for refractory organic pollutants degradation.

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