RESUMO
Adhesion G-protein-coupled receptors (aGPCRs) play key roles in a diversity of physiologies. A hallmark of aGPCR activation is the removal of the inhibitory GAIN domain and the dipping of the cleaved stalk peptide into the ligand-binding pocket of receptors; however, the detailed mechanism remains obscure. Here, we present cryoelectron microscopy (cryo-EM) structures of ADGRL3 in complex with Gq, Gs, Gi, and G12. The structures reveal unique ligand-engaging mode, distinctive activation conformation, and key mechanisms of aGPCR activation. The structures also reveal the uncharted structural information of GPCR/G12 coupling. A comparison of Gq, Gs, Gi, and G12 engagements with ADGRL3 reveals the key determinant of G-protein coupling on the far end of αH5 of Gα. A detailed analysis of the engagements allows us to design mutations that specifically enhance one pathway over others. Taken together, our study lays the groundwork for understanding aGPCR activation and G-protein-coupling selectivity.
Assuntos
Proteínas de Ligação ao GTP , Receptores Acoplados a Proteínas G , Ligantes , Microscopia Crioeletrônica , Receptores Acoplados a Proteínas G/metabolismo , Proteínas de Ligação ao GTP/metabolismoRESUMO
Iron-doped biochar has been widely used as an adsorbent to remove contaminants due to the high adsorption performance, but it still suffers from complicated preparation methods, unstable iron loading, unsatisfactory specific surface area, and uneven distribution of active sites. Here, a novel magnetic porous biochar (FeCS800) with nanostructure on surface was synthesized by one-pot pyrolysis method of corn straw with K2FeO4, and used in orange G (OG) and tetracycline (TC) adsorption. FeCS800 exhibited outstanding adsorption capacities for OG and TC after K2FeO4 activation and the adsorption data were fitted satisfactorily to Langmuir isotherm and Pseudo-second-order kinetic model. The maximum adsorption capacities of FeCS800 for OG and TC were around 303.03 mg/g and 322.58 mg/g, respectively, at 25 °C and pH 7.0, which were 16.27 and 24.61 times higher than that before modification. Thermodynamic studies showed that the adsorption of OG/TC by FeCS800 were thermodynamically favorable and highly spontaneous. And the adsorption capacity of OG and TC by FeCS800 remained 77% and 81% after 5 cycles, respectively, indicating that FeCS800 had good stability. The outstanding adsorption properties and remarkable reusability of FeCS800 show its great potential to be an economic and environmental adsorbent in contaminants removal.
Assuntos
Carvão Vegetal , Tetraciclina , Poluentes Químicos da Água , Adsorção , Tetraciclina/química , Carvão Vegetal/química , Poluentes Químicos da Água/química , Porosidade , Compostos Azo/química , Benzenossulfonatos/química , Cinética , TermodinâmicaRESUMO
Pyrroloquinoline quinone (PQQ) is a natural antioxidant with diverse applications in food and pharmaceutical industries. A lot of effort has been devoted toward the discovery of PQQ high-producing microbial species and characterization of biosynthesis, but it is still challenging to achieve a high PQQ yield. In this study, a combined strategy of random mutagenesis and adaptive laboratory evolution (ALE) with fermentation optimization was applied to improve PQQ production in Hyphomicrobium denitrificans H4-45. A mutant strain AE-9 was obtained after nearly 400 generations of UV-LiCl mutagenesis, followed by an ALE process, which was conducted with a consecutive increase of oxidative stress generated by kanamycin, sodium sulfide, and potassium tellurite. In the flask culture condition, the PQQ production in mutant strain AE-9 had an 80.4% increase, and the cell density increased by 14.9% when compared with that of the initial strain H4-45. Moreover, batch and fed-batch fermentation processes were optimized to further improve PQQ production by pH control strategy, methanol and H2O2 feed flow, and segmented fermentation process. Finally, the highest PQQ production and productivity of the mutant strain AE-9 reached 307 mg/L and 4.26 mg/L/h in a 3.7-L bioreactor, respectively. Whole genome sequencing analysis showed that genetic mutations in the ftfL gene and thiC gene might contribute to improving PQQ production by enhancing methanol consumption and cell growth in the AE-9 strain. Our study provided a systematic strategy to obtain a PQQ high-producing mutant strain and achieve high production of PQQ in fermentation. These practical methods could be applicable to improve the production of other antioxidant compounds with uncleared regulation mechanisms. KEY POINTS: ⢠Improvement of PQQ production by UV-LiCl mutagenesis combined with adaptive laboratory evolution (ALE) and fermentation optimization. ⢠A consecutive increase of oxidative stress could be used as the antagonistic factor for ALE to enhance PQQ production. ⢠Mutations in the ftfL gene and thiC gene indicated that PQQ production might be increased by enhancing methanol consumption and cell growth.
Assuntos
Antioxidantes , Hyphomicrobium , Cofator PQQ , Peróxido de Hidrogênio , Metanol , Estresse OxidativoRESUMO
BACKGROUND: High-intensity focused ultrasound (HIFU) is a promising and non-invasive therapy for symptomatic uterine fibroids. Currently, the main image-guided methods for HIFU include magnetic resonance-guided (MR-HIFU) and ultrasound-guided (US-HIFU). However, there are few comparative studies on the therapeutic efficacy and safety of MR-HIFU and US-HIFU in treating symptomatic uterine fibroids with a volume <300 cm3. OBJECTIVE: We performed this meta-analysis to evaluate the efficacy and safety of MR-HIFU and US-HIFU in treating symptomatic uterine fibroids with a volume <300 cm3. METHODS: We searched relevant literature in PubMed, EMBASE, Cochrane Library CNKI from inception until 2021. The mean value, the proportion, and their 95% confidence intervals (CIs) were measured by random-effects models. Publication bias was assessed using funnel plots. RESULTS: 48 studies met our inclusion criteria-28 describing MR-HIFU and 20 describing US-HIFU. The mean non-perfused volume rate (NPVR) was 81.07% in the US-HIFU group and 58.92% in the MR-HIFU group, respectively. The mean volume reduction rates at month-3, month-6, and month-12 were 42.42, 58.72, and 65.55% in the US-HIFU group, while 34.79, 37.39, and 36.44% in the MR-HIFU group. The incidence of post-operative abdominal pain and abnormal vaginal discharge in the US-HIFU group was lower than that of MRI-HIFU. However, post-operative skin burn and sciatic nerve pain were more common in the US-HIFU group compared with MRI-HIFU. The one-year reintervention rate after MR-HIFU was 13.4%, which was higher than 5.2% in the US-HIFU group. CONCLUSION: US-HIFU may show better efficiency and safety than MR-HIFU in treating symptomatic fibroids with a volume <300 cm3.
Assuntos
Ablação por Ultrassom Focalizado de Alta Intensidade , Leiomioma , Neoplasias Uterinas , Feminino , Humanos , Leiomioma/diagnóstico por imagem , Leiomioma/cirurgia , Imageamento por Ressonância Magnética , Resultado do Tratamento , Neoplasias Uterinas/diagnóstico por imagem , Neoplasias Uterinas/cirurgiaRESUMO
In this paper, we employed Ramen spectroscopy to monitor oxygen movement at the electrode/oxide interface by inserting single-layer graphene (SLG). Raman area mapping and single-point measurements show noticeable changes in the D-band, G-band, and 2D-band signals of the SLG during consecutive electrical programming repeated for nine cycles. In addition, the inserted SLG enables the reduction of RESET current by 22 times and programming power consumption by 47 times. Collectively, our results show that monitoring the oxygen movement by Raman spectroscopy for a resistive random access memory (RRAM) is made possible by inserting a single-layer graphene at electrode/oxide interface. This may open up an important analysis tool for investigation of switching mechanism of RRAM.
Assuntos
Grafite/química , Oxigênio/química , Impedância Elétrica , Eletrodos , Lasers , Nanotecnologia , Óxidos/química , Análise Espectral RamanRESUMO
Oral squamous cell carcinoma (OSCC), a type of malignant tumour that primarily occurs in the oral mucosa, has drawn considerable attention owing to its aggressive growth and potentially high metastatic rate. Surgical resection is the primary treatment method for OSCC and is typically combined with radiation therapy and chemotherapy. microRNA-149-3p (miR-149) is a negative regulator of the Pi3k/Akt pathway and can effectively inhibit the proliferation of tumour cells. However, the application of miR-149 is limited owing to its relatively low efficiency of cellular uptake and poor stability when used alone. To overcome these challenges, this study adopted a novel nucleic acid nanostructured material, tetrahedral framework nucleic acids (tFNAs). The use of tFNAs as carriers to assemble the T-miR-149 complex reduced the expression of Pi3k and Akt involved in tumorigenesis and alterations in proteins related to cell apoptosis. The results indicated that the bionic drug delivery system has an effective tumour suppressive effect on OSCC in mice, revealing its potential clinical value in the treatment of OSCC.
Assuntos
Carcinoma de Células Escamosas , MicroRNAs , Neoplasias Bucais , Proteínas Proto-Oncogênicas c-akt , MicroRNAs/genética , MicroRNAs/administração & dosagem , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/patologia , Neoplasias Bucais/metabolismo , Animais , Humanos , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/metabolismo , Camundongos , Linhagem Celular Tumoral , Proteínas Proto-Oncogênicas c-akt/metabolismo , Apoptose/efeitos dos fármacos , Camundongos Nus , Fosfatidilinositol 3-Quinases/metabolismo , Proliferação de Células/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Ácidos Nucleicos/uso terapêutico , Ácidos Nucleicos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodosRESUMO
Calendula officinalis L.is a versatile medicinal plant with numerous applications in various fields. However, its chloroplast genome structure, features, phylogeny, and patterns of evolution and mutation remain largely unexplored. This study examines the chloroplast genome, phylogeny, codon usage bias, and divergence time of C. officinalis, enhancing our understanding of its evolution and adaptation. The chloroplast genome of C. officinalis is a 150,465 bp circular molecule with a G + C content of 37.75% and comprises 131 genes. Phylogenetic analysis revealed a close relationship between C. officinalis, C. arvensis, and Osteospermum ecklonis. A key finding is the similarity in codon usage bias among these species, which, coupled with the divergence time analysis, supports their close phylogenetic proximity. This similarity in codon preference and divergence times underscores a parallel evolutionary adaptation journey for these species, highlighting the intricate interplay between genetic evolution and environmental adaptation in the Asteraceae family. Moreover unique evolutionary features in C. officinalis, possibly associated with certain genes were identified, laying a foundation for future research into the genetic diversity and medicinal value of C. officinalis.
Assuntos
Calendula , Evolução Molecular , Genoma de Cloroplastos , Filogenia , Plantas Medicinais , Plantas Medicinais/genética , Calendula/genética , Uso do Códon , Composição de Bases , Cloroplastos/genéticaRESUMO
Although GPR3 plays pivotal roles in both the nervous system and metabolic processes, such as cold-induced thermogenesis, its endogenous ligand remains elusive. Here, by combining structural approach (including cryo-electron microscopy), mass spectrometry analysis, and functional studies, we identify oleic acid (OA) as an endogenous ligand of GPR3. Our study reveals a hydrophobic tunnel within GPR3 that connects the extracellular side of the receptor to the middle of plasma membrane, enabling fatty acids to readily engage the receptor. Functional studies demonstrate that OA triggers downstream Gs signaling, whereas lysophospholipids fail to activate the receptor. Moreover, our research reveals that cold stimulation induces the secretion of OA in mice, subsequently activating Gs/cAMP/PKA signaling in brown adipose tissue. Notably, brown adipose tissues from Gpr3 knockout mice do not respond to OA during cold stimulation, reinforcing the significance of GPR3 in this process. Finally, we propose a "born to be activated and cold to enhance" model for GPR3 activation. Our study provides a starting framework for the understanding of GPR3 signaling in cold-stimulated thermogenesis.
Assuntos
Tecido Adiposo Marrom , Ácido Oleico , Receptores Acoplados a Proteínas G , Animais , Camundongos , Membrana Celular , Microscopia Crioeletrônica , Ligantes , Camundongos Knockout , Ácido Oleico/metabolismo , Ácido Oleico/farmacologia , Receptores Acoplados a Proteínas G/metabolismoRESUMO
The histamine H4 receptor (H4R) plays key role in immune cell function and is a highly valued target for treating allergic and inflammatory diseases. However, structural information of H4R remains elusive. Here, we report four cryo-EM structures of H4R/Gi complexes, with either histamine or synthetic agonists clobenpropit, VUF6884 and clozapine bound. Combined with mutagenesis, ligand binding and functional assays, the structural data reveal a distinct ligand binding mode where D943.32 and a π-π network determine the orientation of the positively charged group of ligands, while E1825.46, located at the opposite end of the ligand binding pocket, plays a key role in regulating receptor activity. The structural insight into H4R ligand binding allows us to identify mutants at E1825.46 for which the agonist clobenpropit acts as an inverse agonist and to correctly predict inverse agonism of a closely related analog with nanomolar potency. Together with the findings regarding receptor activation and Gi engagement, we establish a framework for understanding H4R signaling and provide a rational basis for designing novel antihistamines targeting H4R.
Assuntos
Agonismo Inverso de Drogas , Histamina , Imidazóis , Tioureia/análogos & derivados , Histamina/metabolismo , Receptores Histamínicos H4 , Receptores Acoplados a Proteínas G/metabolismo , Ligantes , Receptores Histamínicos/metabolismo , Antagonistas dos Receptores Histamínicos/farmacologiaRESUMO
Failing to balance developmental considerations of the urbanization level (UL) and ecosystem services (ESs) causes issues such as land degradation and social conflict, presenting significant challenges for regional sustainable development. Although numerous studies reported the relationship between UL and ESs, only a few have explored the coupling coordination relationship between urbanization subsystems and ESs from a multidimensional perspective. This study aimed to measure the spatiotemporal characteristics of UL and ESs in Hunan Province from 2000 to 2018 using statistical data and remote sensing monitoring data regarding land use. The multidimensional coupling coordination relationship between urbanization systems and ESs was analyzed using a coupling coordination degree (CCD) model. The results showed that the UL of Hunan Province increased from 2000 to 2018, was spatially high in the east and low in the west, and extended outward from city centers. The average ecosystem services value (ESV) in Hunan Province showed a decreasing trend with some fluctuation. The average ESV in mountainous areas and lake areas was higher than that in the areas surrounding major urban agglomerations. Although the overall CCD between UL and ESs in Hunan Province increased during the study period and entered the coordination stage, the degree of coupling coordination between urbanization subsystems and ESs varied greatly. Thus, the findings of the present study can support the formulation of policies for ecosystem protection and sustainable urbanization in Hunan Province.
Assuntos
Ecossistema , Urbanização , Conservação dos Recursos Naturais/métodos , Cidades , ChinaRESUMO
Cultivated land fragmentation (CLF) has severely affected China's agricultural production efficiency, large-scale operations, agricultural modernization, and food security. Exploring the spatiotemporal evolution patterns and driving forces of CLF is crucial for agricultural modernization. However, the driving forces of CLF in different agricultural regions in China still need to be clarified. In this study, CLF was measured in 2000, 2010, and 2020 based on remote sensing data with landscape pattern metrics, and the driving forces of spatial differentiation were detected based on a geographical detector model. The overall cultivated land area has slightly declined during the study period while the CLF has intensified. CLF showed significant spatial autocorrelation, with CLF increased-cultivated land decreased (2000 to 2010) and CLF decreased-cultivated land decreased (2010 to 2020). The contribution rate of land use intensity on CLF was the highest among all agricultural regions, excluding the Qinghai Tibet Plateau. In contrast, the contribution rates of other factors significantly varied across agricultural regions. These findings provide scientific support in formulating policies to conserve cultivated land for sustainable use of agricultural resources and CLF management in China.
Assuntos
Agricultura , Mudança Social , Geografia , China , Tibet , Conservação dos Recursos NaturaisRESUMO
The changes in landscape ecological risk (LER) of the Qinghai-Tibet Plateau (QTP) profoundly affect the ecological environment of China and the world. We measured the evolution of the LER level and its driving factors through the past 40 years using meteorological data, population density information, and land use data acquired through remote sensing monitoring techniques spanning the years 1980 to 2020. Several key findings were derived: (1) The overall LER of the QTP was at a medium level during 1980-2020, with a fluctuating but decreasing overall trend. (2) Between 1980 and 2020, the spatial distribution of LER in the QTP was high in the west and low in the east; the LER level of the six provinces (districts) showed an overall decrease. (3) During 2000-2020, the LER of the QTP was influenced by a complex mechanism of action. The interactions between different influencing factors were mainly non-linear reinforcement and two-factor reinforcement, and factor interaction significantly enhanced the effect on LER. The findings are of significance for the prevention, control, and management of LER in the QTP.
Assuntos
Ecossistema , Meio Ambiente , Tibet , ChinaRESUMO
Skin is the first barrier against external threats, and skin immune dysfunction leads to multiple diseases. Psoriasis is an inflammatory, chronic, common, immune-related skin disease that affects more than 125 million people worldwide. RNA interference (RNAi) therapy is superior to traditional therapies, but rapid degradation and poor cell uptake are the greatest obstacles to its clinical transformation. The transdermal delivery of siRNA and controllable assembly/disassembly of nanodrug delivery systems can maximize the therapeutic effect. Tetrahedral framework nucleic acid (tFNA) is undoubtedly the best carrier for the transdermal transport of genes due to its excellent noninvasive transdermal effect and editability. The authors combine acid-responsive tannic acid (TA), RNase H-responsive sequences, siRNA, and tFNA into a novel transdermal RNAi drug with controllable assembly and disassembly: STT. STT has heightened resistance to enzyme, serum, and lysosomal degradation, and its size is similar to that of tFNA, enabling easy transdermal transport. After transdermal administration, STT can specifically silence nuclear factor kappa-B (NF-κB) p65, thereby maintaining the stability of the skin's microenvironment and reshaping normal skin immune defense. This work demonstrates the advantages of STT in RNAi therapy and the potential for future treatment of skin-related diseases.
Assuntos
Ácidos Nucleicos , Psoríase , Dermatopatias , Humanos , Interferência de RNA , Polifenóis/uso terapêutico , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/uso terapêutico , Psoríase/terapia , Psoríase/tratamento farmacológico , Dermatopatias/tratamento farmacológico , ImunoterapiaRESUMO
Lysophosphatidylserine (LysoPS) is a lipid mediator that induces multiple cellular responses through binding to GPR174. Here, we present the cryo-electron microscopy (cryo-EM) structure of LysoPS-bound human GPR174 in complex with Gs protein. The structure reveals a ligand recognition mode, including the negatively charged head group of LysoPS forms extensive polar interactions with surrounding key residues of the ligand binding pocket, and the L-serine moiety buries deeply into a positive charged cavity in the pocket. In addition, the structure unveils a partially open pocket on transmembrane domain helix (TM) 4 and 5 for a lateral entry of ligand. Finally, the structure reveals a Gs engaging mode featured by a deep insertion of a helix 5 (αH5) and extensive polar interactions between receptor and αH5. Taken together, the information revealed by our structural study provides a framework for understanding LysoPS signaling and a rational basis for designing LysoPS receptor-targeting drugs.
Assuntos
Receptores Acoplados a Proteínas G , Transdução de Sinais , Humanos , Receptores Acoplados a Proteínas G/metabolismo , Ligantes , Microscopia CrioeletrônicaRESUMO
The main function zone (MFZ) is the major strategy of China's economic development and ecological environment protection. Clarifying the logical relationship between "MFZ strategy" and "territorial spatial layout" is vital to construct regional economic layout and territorial spatial supporting system of high-quality development. However, few studies have revealed the evolution process and formation mechanism of the production-living-ecological space (PLES) structure of China's MFZ over a long period of time. To bridge the gap, based on the land use dataset in China from 1980 to 2020, this study analyzed the evolution patterns of PLES in China's MFZs using multiple methods and measured the formation mechanism of PLES in different types of MFZs with the GeoDetector model. Results showed that the spatial structure of China's national territory has evolved drastically in the past 40 years, showing significant horizontal regional differentiation and vertical gradient differentiation. Ecological space has been continuously decreasing, while production space and living space have been continuously increasing, and the evolution of PLES varied significantly in different MFZs. During the study period, the gravity center of PLES in China all moved westward. The spatial distribution pattern of production space and living space was from northeast to southwest, and the ecological space was from east to west. The evolution of China's territorial spatial structure was subject to the combined effects of natural and socio-economic factors, exhibiting significant differences in different MFZs. Land use intensity had the most prominent influence on the formation of PLES, followed by elevation. The influences of different factors on PLES structure were strengthened mainly through two types of nonlinear enhancement and dual-factor enhancement. This study can provide scientific support for the optimal management and high-quality development of territorial space in China.
Assuntos
Desenvolvimento Econômico , Meio Ambiente , ChinaRESUMO
Acetobacter is the predominant microbe in vinegar production, particularly in those natural fermentations that are achieved by complex microbial communities. Co-evolution of prophages with Acetobacter, including integration, release, and dissemination, heavily affects the genome stability and production performance of industrial strains. However, little has been discussed yet about prophages in Acetobacter. Here, prophage prediction analysis using 148 available genomes from 34 Acetobacter species was carried out. In addition, the type II toxin-antitoxin systems (TAs) and CRISPR-Cas systems encoded by prophages or the chromosome were analyzed. Totally, 12,000 prophage fragments were found, of which 350 putatively active prophages were identified in 86.5% of the selected genomes. Most of the active prophages (83.4%) belonged to the order Caudovirales dominated by the families Siphoviridae and Myroviridae prophages (71.4%). Notably, Acetobacter strains survived in complex environments that frequently carried multiple prophages compared with that in restricted habits. Acetobacter prophages showed high genome diversity and horizontal gene transfer across different bacterial species by genomic feature characterization, average nucleotide identity (ANI), and gene structure visualization analyses. About 31.14% of prophages carry type II TAS, suggesting its important role in addiction, bacterial defense, and growth-associated bioprocesses to prophages and hosts. Intriguingly, the genes coding for Cse1, Cse2, Cse3, Cse4, and Cas5e involved in type I-E and Csy4 involved in type I-F CRISPR arrays were firstly found in two prophages. Type II-C CRISPR-Cas system existed only in Acetobacter aceti, while the other Acetobacter species harbored the intact or eroded type I CRISPR-Cas systems. Totally, the results of this study provide fundamental clues for future studies on the role of prophages in the cell physiology and environmental behavior of Acetobacter.
RESUMO
Territorial space is a multi-functional complex. The coordinated production-living-ecological space (PLES) effectively coordinates the man-land relationship, promotes regional sustainable development, and maximizes territorial space. How to build a high-quality national spatial layout and support system for development has become a hot topic of concern in all sectors of society. However, few studies have explored the coupling coordination considering the various production-living-ecological functions of land use type and its influencing factors of PLES at the county scale in China. To address the gap, based on the connotation of PLES theory, this study established a classification and evaluation system for PLES and analyzed the spatio-temporal characteristics, coupling coordination degree, spatial autocorrelation, and influencing factors of PLES in China from 2000 to 2020. The results are as follows: (1) The production space index and living space index in China showed a continuous increase tendency, while the ecological space index decreased continuously during the study period. The production space and living space were concentrated in the east of Hu Line, and the ecological space indexes in mountainous areas were significantly higher than those in plain areas during the study period. (2) The gravity centers of PLES all migrated to the west of China to different degrees during the study period. (3) From 2000 to 2020, the basically balanced category was the main coupling coordination type, and the number of seriously unbalanced categories accounted for the least. In the west of the Hu Line, the seriously unbalanced category was dominant, while in the east of the Hu Line were the moderately unbalanced categories and above. (4) During the study period, the low-low type was the main relationship type, widely distributed in western China, followed by the high-high type, mainly situated in the North China Plain, Yangtze River Delta, Pearl River Delta, Jianghan Plain, Chengdu Plain, Northeast China Plain, and some provincial capital cities. (5) Regression results showed that natural factors were the main reason restricting the coordinated development of PLES, and socioeconomic factors could effectively promote the coordinated development of PLES. Landscape pattern also significantly influenced the coordinated development of PLES, but varied greatly. The findings of this study can provide a scientific reference for the optimization of territorial space layout and the promotion of high-quality development of territorial space.
Assuntos
Conservação dos Recursos Naturais , Rios , China , Cidades , Desenvolvimento Econômico , Humanos , Análise Espacial , UrbanizaçãoRESUMO
Adhesion G protein-coupled receptors (aGPCRs) are keys of many physiological events and attractive targets for various diseases. aGPCRs are also known to be capable of self-activation via an autoproteolysis process that removes the inhibitory GAIN domain on the extracellular side of receptor and releases a stalk peptide to bind and activate the transmembrane side of receptor. However, the detailed mechanism of aGPCR activation remains elusive. Here, we report the cryo-electron microscopy structures of GPR110 (ADGRF1), a member of aGPCR, in complex with Gq, Gs, Gi, G12 and G13. The structures reveal distinctive ligand engaging model and activation conformations of GPR110. The structures also unveil the rarely explored GPCR/G12 and GPCR/G13 engagements. A comparison of Gq, Gs, Gi, G12 and G13 engagements with GPR110 reveals details of G-protein engagement, including a dividing point at the far end of the alpha helix 5 (αH5) of Gα subunit that separates Gq/Gs engagements from Gi/G12/G13 engagements. This is also where Gq/Gs bind the receptor through both hydrophobic and polar interaction, while Gi/G12/G13 engage receptor mainly through hydrophobic interaction. We further provide physiological evidence of GPR110 activation via stalk peptide. Taken together, our study fills the missing information of GPCR/G-protein engagement and provides a framework for understanding aGPCR activation and GPR110 signaling.
Assuntos
Proteínas de Ligação ao GTP , Receptores Acoplados a Proteínas G , Adesão Celular , Microscopia Crioeletrônica , Proteínas de Ligação ao GTP/metabolismo , Ligantes , Peptídeos/química , Ligação Proteica , Receptores Acoplados a Proteínas G/metabolismoRESUMO
The booming population and accelerating urbanization in the Huaihe River Basin have sped up the land use transformation and the cultivated land fragmentation (CLF), seriously impeded the advancement of agricultural modernization, and threatened regional stability and national food security as well. The analysis of CLF degree and its spatiotemporal distribution characteristics, along with the influencing factors in the Huaihe River Basin, is of great significance for promoting the intensive and efficient utilization of cultivated land resources and maintaining food security. Previous studies lack the measurement and cause analysis of CLF in Huaihe River Basin. To bridge the gap, this study introduces Fragstats4.2 and ArcGIS10.3 to analyze the spatiotemporal characteristics of CLF in county units in the Huaihe River Basin from 2000 to 2018 through the Lorentz curve, entropy method, and spatial auto-correlation method while the causes of the spatiotemporal differentiation of CLF in the basin were explored with the help of a geographic detector. The results show that the spatial distribution of cultivated land in the Huaihe River Basin is relatively balanced, and the Gini coefficients of cultivated land from 2000 to 2018 were 0.105, 0.108, and 0.113, respectively. More than 56% of the counties in the basin have a location entropy greater than 1. the percentage of landscape, area-weighted mean patch area, patch cohesion index, and aggregation index decrease year by year while the patch density and splitting index show an upward trend. The landscape pattern of cultivated land is highly complex, and the overall fragmentation degree is increasing. The county distribution pattern of the CLF degree with random and agglomeration is generally stable. The spatiotemporal differentiation of CLF in the Huaihe River Basin is affected by multiple factors, among which the influences of the normalized difference vegetation index, per capita cultivated land area, and intensity of human activity obviously stronger than other factors, and the contribution rate of the factors reached more than 0.4. The interaction effect among the factors is stronger than that of single factor, with dual-factor enhancement and nonlinear enhancement dominating. The results of this study have important implications for optimizing the agricultural structure in the Huaihe River Basin and alleviating the CLF in important grain production areas.
Assuntos
Rios , Urbanização , Agricultura , China , Conservação dos Recursos Naturais , Atividades Humanas , HumanosRESUMO
A sound ecosystem is the prerequisite for the sustainable development of human society, and the karst ecosystem is a key component of the global ecosystem, which is essential to human welfare and livelihood. However, there remains a gap in the literature on the changing trend and driving factors of ecosystem services value (ESV) in karst areas. In this study, Guizhou Province, a representative region of karst mountainous areas, was taken as a case to bridge the gap. ESV in the karst areas was predicted, based on the land use change data in 2009-2018, and the driving mechanisms were explored through the gray correlation analysis method. Results show that a total loss of CNY 21.47 billion ESV from 2009 to 2018 is due to the conversion of a total of 22.566% of the land in Guizhou, with forest land as the main cause of ESV change. By 2025 and 2030, the areas of garden land, water area, and construction land in Guizhou Province will continue to increase, whereas the areas of cultivated land, forest land, and garden land will decline. The total ESV shows a downward trend and will decrease to CNY 218.71 billion by 2030. Gray correlation analysis results illuminate that the total population and tertiary industry proportion are the uppermost, among all the driving factors that affect ESV change. The findings in this study have important implications for optimizing and adjusting the land use structure ecological protection and will enrich the literature on ESV in ecologically fragile areas.