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1.
Mol Cell ; 83(14): 2493-2508.e5, 2023 07 20.
Artículo en Inglés | MEDLINE | ID: mdl-37343553

RESUMEN

Type IV CRISPR-Cas systems, which are primarily found on plasmids and exhibit a strong plasmid-targeting preference, are the only one of the six known CRISPR-Cas types for which the mechanistic details of their function remain unknown. Here, we provide high-resolution functional snapshots of type IV-A Csf complexes before and after target dsDNA binding, either in the absence or presence of CasDinG, revealing the mechanisms underlying CsfcrRNA complex assembly, "DWN" PAM-dependent dsDNA targeting, R-loop formation, and CasDinG recruitment. Furthermore, we establish that CasDinG, a signature DinG family helicase, harbors ssDNA-stimulated ATPase activity and ATP-dependent 5'-3' DNA helicase activity. In addition, we show that CasDinG unwinds the non-target strand (NTS) and target strand (TS) of target dsDNA from the CsfcrRNA complex. These molecular details advance our mechanistic understanding of type IV-A CRISPR-Csf function and should enable Csf complexes to be harnessed as genome-engineering tools for biotechnological applications.


Asunto(s)
Proteínas Asociadas a CRISPR , ADN , ADN/genética , ADN de Cadena Simple/genética , Sistemas CRISPR-Cas , Proteínas Asociadas a CRISPR/metabolismo
2.
Nature ; 627(8002): 189-195, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38355798

RESUMEN

Phagocyte NADPH oxidase, a protein complex with a core made up of NOX2 and p22 subunits, is responsible for transferring electrons from intracellular NADPH to extracellular oxygen1. This process generates superoxide anions that are vital for killing pathogens1. The activation of phagocyte NADPH oxidase requires membrane translocation and the binding of several cytosolic factors2. However, the exact mechanism by which cytosolic factors bind to and activate NOX2 is not well understood. Here we present the structure of the human NOX2-p22 complex activated by fragments of three cytosolic factors: p47, p67 and Rac1. The structure reveals that the p67-Rac1 complex clamps onto the dehydrogenase domain of NOX2 and induces its contraction, which stabilizes the binding of NADPH and results in a reduction of the distance between the NADPH-binding domain and the flavin adenine dinucleotide (FAD)-binding domain. Furthermore, the dehydrogenase domain docks onto the bottom of the transmembrane domain of NOX2, which reduces the distance between FAD and the inner haem. These structural rearrangements might facilitate the efficient transfer of electrons between the redox centres in NOX2 and lead to the activation of phagocyte NADPH oxidase.


Asunto(s)
NADPH Oxidasa 2 , Fagocitos , Humanos , Electrones , Activación Enzimática , Flavina-Adenina Dinucleótido/metabolismo , Hemo/química , Hemo/metabolismo , NADP/metabolismo , NADPH Oxidasa 2/química , NADPH Oxidasa 2/metabolismo , Fagocitos/enzimología , Dominios Proteicos , Subunidades de Proteína/química , Subunidades de Proteína/metabolismo , Superóxidos/metabolismo , Unión Proteica
3.
Nature ; 622(7981): 74-79, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37591304

RESUMEN

The integer quantum anomalous Hall (QAH) effect is a lattice analogue of the quantum Hall effect at zero magnetic field1-3. This phenomenon occurs in systems with topologically non-trivial bands and spontaneous time-reversal symmetry breaking. Discovery of its fractional counterpart in the presence of strong electron correlations, that is, the fractional QAH effect4-7, would open a new chapter in condensed matter physics. Here we report the direct observation of both integer and fractional QAH effects in electrical measurements on twisted bilayer MoTe2. At zero magnetic field, near filling factor ν = -1 (one hole per moiré unit cell), we see an integer QAH plateau in the Hall resistance Rxy quantized to h/e2 ± 0.1%, whereas the longitudinal resistance Rxx vanishes. Remarkably, at ν = -2/3 and -3/5, we see plateau features in Rxy at [Formula: see text] and [Formula: see text], respectively, whereas Rxx remains small. All features shift linearly versus applied magnetic field with slopes matching the corresponding Chern numbers -1, -2/3 and -3/5, precisely as expected for integer and fractional QAH states. Additionally, at zero magnetic field, Rxy is approximately 2h/e2 near half-filling (ν = -1/2) and varies linearly as ν is tuned. This behaviour resembles that of the composite Fermi liquid in the half-filled lowest Landau level of a two-dimensional electron gas at high magnetic field8-14. Direct observation of the fractional QAH and associated effects enables research in charge fractionalization and anyonic statistics at zero magnetic field.

4.
Nature ; 622(7981): 63-68, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37315640

RESUMEN

The interplay between spontaneous symmetry breaking and topology can result in exotic quantum states of matter. A celebrated example is the quantum anomalous Hall (QAH) state, which exhibits an integer quantum Hall effect at zero magnetic field owing to intrinsic ferromagnetism1-3. In the presence of strong electron-electron interactions, fractional QAH (FQAH) states at zero magnetic field can emerge4-8. These states could host fractional excitations, including non-Abelian anyons-crucial building blocks for topological quantum computation9. Here we report experimental signatures of FQAH states in a twisted molybdenum ditelluride (MoTe2) bilayer. Magnetic circular dichroism measurements reveal robust ferromagnetic states at fractionally hole-filled moiré minibands. Using trion photoluminescence as a sensor10, we obtain a Landau fan diagram showing linear shifts in carrier densities corresponding to filling factor v = -2/3 and v = -3/5 ferromagnetic states with applied magnetic field. These shifts match the Streda formula dispersion of FQAH states with fractionally quantized Hall conductance of [Formula: see text] and [Formula: see text], respectively. Moreover, the v = -1 state exhibits a dispersion corresponding to Chern number -1, consistent with the predicted QAH state11-14. In comparison, several non-ferromagnetic states on the electron-doping side do not disperse, that is, they are trivial correlated insulators. The observed topological states can be electrically driven into topologically trivial states. Our findings provide evidence of the long-sought FQAH states, demonstrating MoTe2 moiré superlattices as a platform for exploring fractional excitations.

5.
EMBO J ; 43(8): 1499-1518, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38528181

RESUMEN

The intestinal pathogen Salmonella enterica rapidly enters the bloodstream after the invasion of intestinal epithelial cells, but how Salmonella breaks through the gut-vascular barrier is largely unknown. Here, we report that Salmonella enters the bloodstream through intestinal CX3CR1+ macrophages during early infection. Mechanistically, Salmonella induces the migration/invasion properties of macrophages in a manner dependent on host cell actin and on the pathogen effector SteC. SteC recruits host myosin light chain protein Myl12a and phosphorylates its Ser19 and Thr20 residues. Myl12a phosphorylation results in actin rearrangement, and enhanced migration and invasion of macrophages. SteC is able to utilize a wide range of NTPs other than ATP to phosphorylate Myl12a. We further solved the crystal structure of SteC, which suggests an atypical dimerization-mediated catalytic mechanism. Finally, in vivo data show that SteC-mediated cytoskeleton manipulation is crucial for Salmonella breaching the gut vascular barrier and spreading to target organs.


Asunto(s)
Cadenas Ligeras de Miosina , Salmonella enterica , Cadenas Ligeras de Miosina/genética , Cadenas Ligeras de Miosina/metabolismo , Actinas/metabolismo , Células Epiteliales/metabolismo , Macrófagos/metabolismo
6.
Immunity ; 50(2): 317-333.e6, 2019 02 19.
Artículo en Inglés | MEDLINE | ID: mdl-30683620

RESUMEN

Interleukin-1 (IL-1) signaling is important for multiple potentially pathogenic processes in the central nervous system (CNS), but the cell-type-specific roles of IL-1 signaling are unclear. We used a genetic knockin reporter system in mice to track and reciprocally delete or express IL-1 receptor 1 (IL-1R1) in specific cell types, including endothelial cells, ventricular cells, peripheral myeloid cells, microglia, astrocytes, and neurons. We found that endothelial IL-1R1 was necessary and sufficient for mediating sickness behavior and drove leukocyte recruitment to the CNS and impaired neurogenesis, whereas ventricular IL-1R1 was critical for monocyte recruitment to the CNS. Although microglia did not express IL-1R1, IL-1 stimulation of endothelial cells led to the induction of IL-1 in microglia. Together, these findings describe the structure and functions of the brain's IL-1R1-expressing system and lay a foundation for the dissection and identification of IL-1R1 signaling pathways in the pathogenesis of CNS diseases.


Asunto(s)
Encéfalo/inmunología , Neuroinmunomodulación/inmunología , Receptores Tipo I de Interleucina-1/inmunología , Transducción de Señal/inmunología , Animales , Astrocitos/citología , Astrocitos/inmunología , Astrocitos/metabolismo , Encéfalo/citología , Encéfalo/metabolismo , Línea Celular , Células Cultivadas , Células Endoteliales/efectos de los fármacos , Células Endoteliales/inmunología , Células Endoteliales/metabolismo , Interleucina-1/farmacología , Ratones Endogámicos C57BL , Ratones Transgénicos , Microglía/citología , Microglía/inmunología , Microglía/metabolismo , Neuroinmunomodulación/genética , Neuronas/citología , Neuronas/inmunología , Neuronas/metabolismo , Receptores Tipo I de Interleucina-1/genética , Receptores Tipo I de Interleucina-1/metabolismo , Transducción de Señal/genética
7.
Plant Cell ; 2024 Mar 27.
Artículo en Inglés | MEDLINE | ID: mdl-38537937

RESUMEN

Cold injury is a major environmental stress affecting the growth and yield of crops. Brassinosteroids (BRs) and salicylic acid (SA) play important roles in plant cold tolerance. However, whether or how BR signaling interacts with the SA signaling pathway in response to cold stress is still unknown. Here, we identified an SA methyltransferase, TaSAMT1, that converts SA to methyl SA (MeSA) and confers freezing tolerance in wheat (Triticum aestivum). TaSAMT1 overexpression greatly enhanced wheat freezing tolerance, with plants accumulating more MeSA and less SA, whereas Tasamt1 knockout lines were sensitive to freezing stress and accumulated less MeSA and more SA. Spraying plants with MeSA conferred freezing tolerance to Tasamt1 mutants, but SA did not. We revealed that BRASSINAZOLE-RESISTANT 1 (TaBZR1) directly binds to the TaSAMT1 promoter and induces its transcription. Moreover, TaBZR1 interacts with the histone acetyltransferase TaHAG1, which potentiates TaSAMT1 expression via increased histone acetylation and modulates the SA pathway during freezing stress. Additionally, overexpression of TaBZR1 or TaHAG1 altered TaSAMT1 expression and improved freezing tolerance. Our results demonstrate a key regulatory node that connects the BR and SA pathways in the plant cold stress response. The regulatory factors or genes identified could be effective targets for the genetic improvement of freezing tolerance in crops.

8.
Proc Natl Acad Sci U S A ; 121(4): e2317058121, 2024 Jan 23.
Artículo en Inglés | MEDLINE | ID: mdl-38232281

RESUMEN

Integration of methanogenic archaea with photocatalysts presents a sustainable solution for solar-driven methanogenesis. However, maximizing CH4 conversion efficiency remains challenging due to the intrinsic energy conservation and strictly restricted substrates of methanogenic archaea. Here, we report a solar-driven biotic-abiotic hybrid (biohybrid) system by incorporating cadmium sulfide (CdS) nanoparticles with a rationally designed methanogenic archaeon Methanosarcina acetivorans C2A, in which the glucose synergist protein and glucose kinase, an energy-efficient route for glucose transport and phosphorylation from Zymomonas mobilis, were implemented to facilitate nonnative substrate glucose for methanogenesis. We demonstrate that the photo-excited electrons facilitate membrane-bound electron transport chain, thereby augmenting the Na+ and H+ ion gradients across membrane to enhance adenosine triphosphate (ATP) synthesis. Additionally, this biohybrid system promotes the metabolism of pyruvate to acetyl coenzyme A (AcCoA) and inhibits the flow of AcCoA to the tricarboxylic acid (TCA) cycle, resulting in a 1.26-fold augmentation in CH4 production from glucose-derived carbon. Our results provide a unique strategy for enhancing methanogenesis through rational biohybrid design and reprogramming, which gives a promising avenue for sustainably manufacturing value-added chemicals.


Asunto(s)
Adenosina Trifosfato , Metano , Metano/metabolismo , Transporte de Electrón , Adenosina Trifosfato/metabolismo , Metabolismo Energético , Transporte Biológico , Methanosarcina/metabolismo
9.
Proc Natl Acad Sci U S A ; 120(18): e2219034120, 2023 May 02.
Artículo en Inglés | MEDLINE | ID: mdl-37094158

RESUMEN

Escape from metastable states in self-assembly of colloids is an intractable problem. Unlike the commonly adopted approach of thermal annealing, the recently developed enthalpy-mediated strategy provided a different option to address this dilemma in a dynamically controllable manner at room temperature. However, it required a complex catalytic-assembly DNA strand-displacement circuitry to mediate interaction between multiple components. In this work, we present a simple but effective way to achieve catalytic-assembly of DNA-functionalized colloidal nanoparticles, i.e., programmable atom equivalents, in a far-from-equilibrium system. A removable molecule named "catassembler" that acts as a catalyst was employed to rectify imperfect linkages and help the system escape from metastability without affecting the assembled framework. Notably, catalytic efficiency of the catassembler can be effectively improved by changing the seesaw catassembler in toehold length design or numbers of the repeat units. Leveraging this tractable catalytic-assembly approach, different ordered architectures were easily produced by directly mixing all reactants, as in chemical reactions. By switching bonding identities, solid-solid phase transformations between different colloidal crystals were achieved. This work opens up an avenue for programming colloid assembly in a far-from-equilibrium system.

10.
FASEB J ; 38(5): e23524, 2024 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-38466191

RESUMEN

The pathophysiology of osteoporosis is significantly influenced by the impaired functioning of osteoblasts, which is particularly caused by oxidative stress. Nevertheless, the underlying mechanisms responsible for this phenomenon are still not well understood. The objective of this study was to elucidate the impact of fibroblast growth factor 7 (FGF7) on the behavior of osteoblasts under conditions of oxidative stress. The osteoblast-like MC3T3 cells were pretreated with recombinant FGF7 in the presence of oxidative stress induced by hydrogen peroxide (H2 O2 ). We first provided the evidence that the endogenous FGF7 was significantly increased in osteoblasts in response to the increased H2 O2 levels. Recombined FGF7 demonstrated a remarkable capacity to resist the detrimental effects of H2 O2 -induced oxidative stress, including the increase in cell apoptosis, decrease in osteoblast viability, and impairment in osteogenic differentiation capacity, on osteoblasts. Furthermore, we extensively explored the mechanism underlying these protective effects and discovered a remarkable modulation of reactive oxygen species (ROS) homeostasis in H2 O2 -treated cells following the pronounced expression of FGF7, which significantly differed from the control group. Additionally, we observed that FGF7 exerted partial preservation on both the morphology and function of mitochondria when exposed to oxidative stress conditions. Furthermore, FGF7 exhibited the ability to enhance the activation of the p38/MAPK signaling pathway while concurrently suppressing the JNK/MAPK signaling pathway in response to oxidative stress. These results underscore the promising role and underlying mechanisms of FGF7 in preserving osteoblast homeostasis in the face of oxidative stress.


Asunto(s)
Factor 7 de Crecimiento de Fibroblastos , Osteogénesis , Mitocondrias , Osteoblastos , Estrés Oxidativo , Línea Celular , Animales , Ratones
11.
FASEB J ; 38(7): e23592, 2024 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-38581243

RESUMEN

Vascular calcification is an actively regulated biological process resembling bone formation, and osteogenic differentiation of vascular smooth muscle cells (VSMCs) plays a crucial role in this process. 1-Palmitoyl-2-(5'-oxo-valeroyl)-sn-glycero-3-phosphocholine (POVPC), an oxidized phospholipid, is found in atherosclerotic plaques and has been shown to induce oxidative stress. However, the effects of POVPC on osteogenic differentiation and calcification of VSMCs have yet to be studied. In the present study, we investigated the role of POVPC in vascular calcification using in vitro and ex vivo models. POVPC increased mineralization of VSMCs and arterial rings, as shown by alizarin red staining. In addition, POVPC treatment increased expression of osteogenic markers Runx2 and BMP2, indicating that POVPC promotes osteogenic transition of VSMCs. Moreover, POVPC increased oxidative stress and impaired mitochondria function of VSMCs, as shown by increased ROS levels, impairment of mitochondrial membrane potential, and decreased ATP levels. Notably, ferroptosis triggered by POVPC was confirmed by increased levels of intracellular ROS, lipid ROS, and MDA, which were decreased by ferrostatin-1, a ferroptosis inhibitor. Furthermore, ferrostatin-1 attenuated POVPC-induced calcification of VSMCs. Taken together, our study for the first time demonstrates that POVPC promotes vascular calcification via activation of VSMC ferroptosis. Reducing the levels of POVPC or inhibiting ferroptosis might provide a novel strategy to treat vascular calcification.


Asunto(s)
Ciclohexilaminas , Ferroptosis , Fenilendiaminas , Calcificación Vascular , Humanos , Músculo Liso Vascular/metabolismo , Fosfolípidos/metabolismo , Fosforilcolina/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Osteogénesis , Calcificación Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Células Cultivadas
12.
Nature ; 567(7748): 409-413, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30867599

RESUMEN

Chromatin remodellers include diverse enzymes with distinct biological functions, but nucleosome-sliding activity appears to be a common theme1,2. Among the remodelling enzymes, Snf2 serves as the prototype to study the action of this protein family. Snf2 and related enzymes share two conserved RecA-like lobes3, which by themselves are able to couple ATP hydrolysis to chromatin remodelling. The mechanism by which these enzymes couple ATP hydrolysis to translocate the nucleosome along the DNA remains unclear2,4-8. Here we report the structures of Saccharomyces cerevisiae Snf2 bound to the nucleosome in the presence of ADP and ADP-BeFx. Snf2 in the ADP-bound state adopts an open conformation similar to that in the apo state, and induces a one-base-pair DNA bulge at superhelix location 2 (SHL2), with the tracking strand showing greater distortion than the guide strand. The DNA distortion propagates to the proximal end, leading to staggered translocation of the two strands. The binding of ADP-BeFx triggers a closed conformation of the enzyme, resetting the nucleosome to a relaxed state. Snf2 shows altered interactions with the DNA in different nucleotide states, providing the structural basis for DNA translocation. Together, our findings suggest a fundamental mechanism for the DNA translocation that underlies chromatin remodelling.


Asunto(s)
Adenosina Trifosfatasas/metabolismo , Ensamble y Desensamble de Cromatina , Cromatina/genética , Cromatina/metabolismo , ADN/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae , Factores de Transcripción/metabolismo , Adenosina Difosfato/química , Adenosina Difosfato/metabolismo , Adenosina Trifosfatasas/química , Apoproteínas/química , Apoproteínas/metabolismo , Transporte Biológico , Cromatina/química , ADN/química , ADN/genética , Transferencia Resonante de Energía de Fluorescencia , Modelos Moleculares , Nucleosomas/química , Nucleosomas/metabolismo , Nucleótidos/química , Nucleótidos/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/química , Factores de Transcripción/química
13.
PLoS Genet ; 18(9): e1010338, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-36095000

RESUMEN

Actin cytoskeleton is essential for root hair formation. However, the underlying molecular mechanisms of actin dynamics in root hair formation in response to abiotic stress are largely undiscovered. Here, genetic analysis showed that actin-depolymerizing protein ADF7 and actin-bundling protein VILLIN1 (VLN1) were positively and negatively involved in root hair formation of Arabidopsis respectively. Moreover, RT-qPCR, GUS staining, western blotting, and genetic analysis revealed that ADF7 played an important role in inhibiting the expression and function of VLN1 during root hair formation. Filament actin (F-actin) dynamics observation and actin pharmacological experiments indicated that ADF7-inhibited-VLN1 pathway led to the decline of F-actin bundling and thick bundle formation, as well as the increase of F-actin depolymerization and turnover to promote root hair formation. Furthermore, the F-actin dynamics mediated by ADF7-inhibited-VLN1 pathway was associated with the reactive oxygen species (ROS) accumulation in root hair formation. Finally, ADF7-inhibited-VLN1 pathway was critical for osmotic stress-induced root hair formation. Our work demonstrates that ADF7 inhibits VLN1 to regulate F-actin dynamics in root hair formation in response to osmotic stress, providing the novel evidence on the F-actin dynamics and their molecular mechanisms in root hair formation and in abiotic stress.


Asunto(s)
Proteínas de Arabidopsis , Arabidopsis , Citoesqueleto de Actina/genética , Citoesqueleto de Actina/metabolismo , Actinas/genética , Actinas/metabolismo , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Destrina/metabolismo , Proteínas de Microfilamentos/genética , Proteínas de Microfilamentos/metabolismo , Presión Osmótica , Raíces de Plantas/genética , Raíces de Plantas/metabolismo , Especies Reactivas de Oxígeno/metabolismo
14.
Nano Lett ; 2024 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-38619329

RESUMEN

Excessive accumulation of reduced nicotinamide adenine dinucleotide (NADH) within biological organisms is closely associated with many diseases. It remains a challenge to efficiently convert superfluous and detrimental NADH to NAD+. NADH oxidase (NOX) is a crucial oxidoreductase that catalyzes the oxidation of NADH to NAD+. Herein, M1M2 (Mi=V/Mn/Fe/Co/Cu/Mo/Rh/Ru/Pd, i = 1 or 2) mated-atom nanozymes (MANs) are designed by mimicking natural enzymes with polymetallic active centers. Excitingly, RhCo MAN possesses excellent and sustainable NOX-like activity, with Km-NADH (16.11 µM) being lower than that of NOX-mimics reported so far. Thus, RhCo MAN can significantly promote the regeneration of NAD+ and regulate macrophage polarization toward the M2 phenotype through down-regulation of TLR4 expression, which may help to recover skin regeneration. However, RhRu MAN with peroxidase-like activity and RhMn MAN with superoxide dismutase-like activity exhibit little modulating effects on eczema. This work provides a new strategy to inhibit skin inflammation and promote skin regeneration.

15.
J Cell Mol Med ; 28(8): e18327, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38661437

RESUMEN

Cartilage defects in the knee are often associated with the progression of degenerative osteoarthritis (OA), and cartilage repair is a useful strategy for managing this disease. However, cartilage repair is challenging because of the unique environment within the tissue. Recently, stem cell-based therapies have shed new light on this issue. In this study, we prepared exosomes (EXOs) from cartilage stem/progenitor cells (CSPCs) and found that treatment with EXOs increased the viability, migration, and proliferation of cultured primary chondrocytes. In a subacute OA rat model, the application of EXOs facilitated cartilage regeneration as evidenced by histological staining. Exosomal protein analysis together with bioinformatics suggested that cyclin-dependent kinase 9 (CDK9) is a key factor for chondrocyte growth and migration. Functional studies confirmed this prediction, that is, inhibiting CDK9 reduced the beneficial effects induced by EXOs in primary chondrocytes; while overexpression of CDK9 recapitulated the EXOs-induced phenotypes. RNA-Seq data showed that a set of genes involved in cell growth and migration were up-regulated by EXOs in chondrocytes. These changes could be partially reproduced by CDK9 overexpression. Overall, our data suggest that EXOs derived from primary CSPCs hold great therapeutic potential for treating cartilage defect-associated disorders such as degenerative OA, and that CDK9 is a key factor in this process.


Asunto(s)
Cartílago Articular , Proliferación Celular , Condrocitos , Modelos Animales de Enfermedad , Exosomas , Animales , Exosomas/metabolismo , Ratas , Condrocitos/metabolismo , Cartílago Articular/metabolismo , Cartílago Articular/patología , Células Madre/metabolismo , Células Madre/citología , Movimiento Celular , Ratas Sprague-Dawley , Quinasa 9 Dependiente de la Ciclina/metabolismo , Quinasa 9 Dependiente de la Ciclina/genética , Osteoartritis de la Rodilla/metabolismo , Osteoartritis de la Rodilla/patología , Osteoartritis de la Rodilla/terapia , Masculino , Células Cultivadas , Regeneración , Osteoartritis/patología , Osteoartritis/metabolismo , Osteoartritis/terapia
16.
Mol Plant Microbe Interact ; 37(4): 416-423, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38171485

RESUMEN

Soybean cyst nematode (Heterodera glycines, soybean cyst nematode [SCN]) disease adversely affects the yield of soybean and leads to billions of dollars in losses every year. To control the disease, it is necessary to study the resistance genes of the plant and their mechanisms. Isoflavonoids are secondary metabolites of the phenylalanine pathway, and they are synthesized in soybean. They are essential in plant response to biotic and abiotic stresses. In this study, we reported that phenylalanine ammonia-lyase (PAL) genes GmPALs involved in isoflavonoid biosynthesis, can positively regulate soybean resistance to SCN. Our previous study demonstrated that the expression of GmPAL genes in the resistant cultivar Huipizhi (HPZ) heidou are strongly induced by SCN. PAL is the rate-limiting enzyme that catalyzes the first step of phenylpropanoid metabolism, and it responds to biotic or abiotic stresses. Here, we demonstrate that the resistance of soybeans against SCN is suppressed by PAL inhibitor l-α-(aminooxy)-ß-phenylpropionic acid (L-AOPP) treatment. Overexpression of eight GmPAL genes caused diapause of nematodes in transgenic roots. In a petiole-feeding bioassay, we identified that two isoflavones, daidzein and genistein, could enhance resistance against SCN and suppress nematode development. This study thus reveals GmPAL-mediated resistance against SCN, information that has good application potential. The role of isoflavones in soybean resistance provides new information for the control of SCN. [Formula: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.


Asunto(s)
Resistencia a la Enfermedad , Regulación de la Expresión Génica de las Plantas , Glycine max , Isoflavonas , Fenilanina Amoníaco-Liasa , Enfermedades de las Plantas , Tylenchoidea , Glycine max/genética , Glycine max/parasitología , Tylenchoidea/fisiología , Enfermedades de las Plantas/parasitología , Enfermedades de las Plantas/inmunología , Enfermedades de las Plantas/genética , Animales , Fenilanina Amoníaco-Liasa/genética , Fenilanina Amoníaco-Liasa/metabolismo , Resistencia a la Enfermedad/genética , Isoflavonas/farmacología , Isoflavonas/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Plantas Modificadas Genéticamente
17.
Immunology ; 172(2): 210-225, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38366844

RESUMEN

Numerous diseases of the immune system can be traced back to the malfunctioning of the regulatory T cells. The aetiology is unclear. Psychological stress can cause disruption to the immune regulation. The synergistic effects of psychological stress and immune response on immune regulation have yet to be fully understood. The intention of this study is to analyse the interaction between psychological stress and immune responses and how it affects the functional status of type 1 regulatory T (Tr1) cells. In this study, ovalbumin peptide T-cell receptor transgenic mice were utilised. Mice were subjected to restraint stress to induce psychological stress. An airway allergy murine model was established, in which a mouse strain with RING finger protein 20 (Rnf20)-deficient CD4+ T cells were used. The results showed that concomitant exposure to restraint stress and immune response could exacerbate endoplasmic reticulum stress in Tr1 cells. Corticosterone was responsible for the elevated expression of X-box protein-1 (XBP1) in mouse Tr1 cells after exposure to both restraint stress and immune response. XBP1 mediated the effects of corticosterone on inducing Rnf20 in Tr1 cells. The reduction of the interleukin-10 expression in Tr1 cells was facilitated by Rnf20. Inhibition of Rnf20 alleviated experimental airway allergy by restoring the immune regulatory ability of Tr1 cells. In conclusion, the functions of Tr1 cells are negatively impacted by simultaneous exposure to psychological stress and immune response. Tr1 cells' immune suppressive functions can be restored by inhibiting Rnf20, which has the translational potential for the treatment of diseases of the immune system.


Asunto(s)
Interleucina-10 , Ratones Transgénicos , Ovalbúmina , Estrés Psicológico , Linfocitos T Reguladores , Animales , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Ovalbúmina/inmunología , Estrés Psicológico/inmunología , Ratones , Interleucina-10/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores de Antígenos de Linfocitos T/inmunología , Proteína 1 de Unión a la X-Box/metabolismo , Proteína 1 de Unión a la X-Box/genética , Corticosterona/sangre , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Estrés del Retículo Endoplásmico/inmunología , Modelos Animales de Enfermedad , Restricción Física , Ratones Noqueados , Ratones Endogámicos C57BL , Hipersensibilidad Respiratoria/inmunología
18.
Immunology ; 2024 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-38859694

RESUMEN

SET domain-containing 2 (SETD2) is a histone methyltransferase. It regulates the activity of H3K36me3 to enhance gene transcription. Macrophages (Mϕs) are one of the cell types involved in immune response. The purpose of this study is to clarify the role of SETD2 in regulating the immune property of Mϕ. The Mφs were isolated from the bronchoalveolar lavage fluid (BALF) and analysed through flow cytometry and RNA sequencing. A mouse strain carrying Mφs deficient in SETD2 was used. A mouse model of airway allergy was established with the ovalbumin/alum protocol. Less expression of SETD2 was observed in airway Mϕs in patients with allergic asthma. SETD2 of M2 cells was associated with the asthmatic clinical response. Sensitization reduced the expression of SETD2 in mouse respiratory tract M2 cells, which is associated with the allergic reaction. Depletion of SETD2 in Mφs resulted in Th2 pattern inflammation in the lungs. SETD2 maintained the immune regulatory ability in airway M2 cells. SETD2 plays an important role in the maintenance of immune regulatory property of airway Mφs.

19.
J Am Chem Soc ; 146(23): 15977-15985, 2024 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-38713009

RESUMEN

Unveiling innovative mechanisms to design new highly efficient fluorescent materials and, thereby, fabricate high-performance organic light-emitting diodes (OLEDs) is a concerted endeavor in both academic and industrial circles. Polycyclic aromatic hydrocarbons (PAHs) have been widely used as fluorescent emitters in blue OLEDs, but device performances are far from satisfactory. In response, we propose the concept of "nitrogen effects" endowed by doping electron-withdrawing nitrogen atoms into PAH fluorescence emitters. The presence of the n orbital on the imine nitrogen is conducive to promoting electron coupling, which leads to increased molar absorptivity and an accelerated radiative decay rate of emitters, thereby facilitating the Förster energy transfer (FET) process in the OLEDs. Additionally, electronically withdrawing nitrogen atoms enhances host-guest interactions, thereby positively affecting the FET process and the horizontal orientation factor of the emitting layer. To validate the "nitrogen effects" concept, cobalt-catalyzed multiple C-H annulation has been utilized to incorporate alkynes into the imine-based frameworks, which enables various imine-embedded PAH (IE-PAH) fluorescence emitters. The cyclization demonstrates notable regioselectivity, thereby offering a practical tool to precisely introduce peripheral groups at desired positions with bulky alkyl units positioned adjacent to the nitrogen atoms, which were previously beyond reach through the Friedel-Crafts reaction. Blue OLEDs fabricated with IE-PAHs exhibit outstanding performance with a maximum external quantum efficiency (EQEmax) of 32.7%. This achievement sets a groundbreaking record for conventional blue PAH-based fluorescent emitters, which have an EQEmax of 24.0%.

20.
J Am Chem Soc ; 146(1): 1081-1088, 2024 Jan 10.
Artículo en Inglés | MEDLINE | ID: mdl-38113465

RESUMEN

The first asymmetric total synthesis of the hexacyclic veatchine-type C20-diterpenoid alkaloid (-)-garryine is presented. Key steps include a Pd-catalyzed enantioselective Heck reaction, a radical cyclization, and a photoinduced C-H activation/oxazolidine formation sequence. Of note, a highly enantioselective Heck reaction developed in this work provides efficient access to 6/6/6 tricyclic compounds, in particular, containing a C19-functionalitiy, which is useful for diverse transformations.

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