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Gene co-expression networks may encode hitherto inadequately recognized vulnerabilities for adult gliomas. By identifying evolutionally conserved gene co-expression modules around EGFR (EM) or PDGFRA (PM), we recently proposed an EM/PM classification scheme, which assigns IDH-wildtype glioblastomas (GBM) into the EM subtype committed in neural stem cell compartment, IDH-mutant astrocytomas and oligodendrogliomas into the PM subtype committed in early oligodendrocyte lineage. Here, we report the identification of EM/PM subtype-specific gene co-expression networks and the characterization of hub gene polypyrimidine tract-binding protein 1 (PTBP1) as a genomic alteration-independent vulnerability in IDH-wildtype GBM. Supervised by the EM/PM classification scheme, we applied weighted gene co-expression network analysis to identify subtype-specific global gene co-expression modules. These gene co-expression modules were characterized for their clinical relevance, cellular origin and conserved expression pattern during brain development. Using lentiviral vector-mediated constitutive or inducible knockdown, we characterized the effects of PTBP1 on the survival of IDH-wildtype GBM cells, which was complemented with the analysis of PTBP1-depedent splicing pattern and overexpression of splicing target neuron-specific CDC42 (CDC42-N) isoform. Transcriptomes of adult gliomas can be robustly assigned into 4 large gene co-expression modules that are prognostically relevant and are derived from either malignant cells of the EM/PM subtypes or tumor microenvironment. The EM subtype is associated with a malignant cell-intrinsic gene module involved in pre-mRNA splicing, DNA replication and damage response, and chromosome segregation, and a microenvironment-derived gene module predominantly involved in extracellular matrix organization and infiltrating immune cells. The PM subtype is associated with two malignant cell-intrinsic gene modules predominantly involved in transcriptional regulation and mRNA translation, respectively. Expression levels of these gene modules are independent prognostic factors and malignant cell-intrinsic gene modules are conserved during brain development. Focusing on the EM subtype, we identified PTBP1 as the most significant hub for the malignant cell-intrinsic gene module. PTBP1 is not altered in most glioma genomes. PTBP1 represses the conserved splicing of CDC42-N. PTBP1 knockdown or CDC42-N overexpression disrupts actin cytoskeleton dynamics, causing accumulation of reactive oxygen species and cell apoptosis. PTBP1-mediated repression of CDC42-N splicing represents a potential genomic alteration-independent, developmentally conserved vulnerability in IDH-wildtype GBM.
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Glioblastoma , Ribonucleoproteínas Nucleares Heterogéneas , Proteína de Unión al Tracto de Polipirimidina , Proteína de Unión al GTP cdc42 , Proteína de Unión al Tracto de Polipirimidina/genética , Proteína de Unión al Tracto de Polipirimidina/metabolismo , Humanos , Ribonucleoproteínas Nucleares Heterogéneas/genética , Ribonucleoproteínas Nucleares Heterogéneas/metabolismo , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patología , Proteína de Unión al GTP cdc42/genética , Proteína de Unión al GTP cdc42/metabolismo , Línea Celular Tumoral , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Redes Reguladoras de Genes , Regulación Neoplásica de la Expresión Génica , Empalme del ARN , Neuronas/metabolismo , Neuronas/patologíaRESUMEN
Specific mechanisms of precipitation change due to global climate variability on plant communities in coastal salt marsh ecosystems remain unknown. Hence, a field manipulative precipitation experiment was established in 2014 and 5 years of field surveys of vegetation from 2017 to 2021 to explore the effects of precipitation changes on plant community composition. The results showed that changes in plant community composition were driven by dominant species, and that the dominance of key species changed significantly with precipitation gradient and time, and that these changes ultimately altered plant community traits (i.e., community density, height, and species richness). Community height increased but community density decreased with more precipitation averaged five years. Furthermore, changes in precipitation altered dominant species composition and functional groups mainly by influencing soil salinity. Salinity stress caused by decreased precipitation shifted species composition from a dominance of taller perennials and grasses to dwarf annuals and forbs, while the species richness decreased. Conversely, soil desalination caused by increased precipitation increased species richness, especially increasing in the dominance of grasses and perennials. Specifically, Apocynaceae became dominance from rare while Amaranthaceae decreased in response to increased precipitation, but Poaceae was always in a position of dominance. Meanwhile, the dominance of grasses and perennials has the cumulative effect of years and their proportion increased under the increased 60% of ambient precipitation throughout the years. However, the annual forb Suaeda glauca was gradually losing its dominance or even becoming extinct over years. Our study highlights that the differences in plant salinity tolerance are key to the effects of precipitation changes on plant communities in coastal salt marsh. These findings aim to provide a theoretical basis for predicting vegetation dynamics and developing ecological management strategies to adapt to future precipitation changes.
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The tumor microenvironment (TME) considerably influences colorectal cancer (CRC) progression, therapeutic response and clinical outcome, but studies of interindividual heterogeneities of the TME in CRC are lacking. Here, by integrating human colorectal single-cell transcriptomic data from approximately 200 donors, we comprehensively characterized transcriptional remodeling in the TME compared to noncancer tissues and identified a rare tumor-specific subset of endothelial cells with T cell recruitment potential. The large sample size enabled us to stratify patients based on their TME heterogeneity, revealing divergent TME subtypes in which cancer cells exploit different immune evasion mechanisms. Additionally, by associating single-cell transcriptional profiling with risk genes identified by genome-wide association studies, we determined that stromal cells are major effector cell types in CRC genetic susceptibility. In summary, our results provide valuable insights into CRC pathogenesis and might help with the development of personalized immune therapies.
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Coastal wetlands play an important role in regulating atmospheric carbon dioxide (CO2) concentrations and contribute significantly to climate change mitigation. However, climate change, reclamation, and restoration have been causing substantial changes in coastal wetland areas and carbon exchange in China during recent decades. Here we compiled a carbon flux database consisting of 15 coastal wetland sites to assess the magnitude, patterns, and drivers of carbon fluxes and to compare fluxes among contrasting natural, disturbed, and restored wetlands. The natural coastal wetlands have the average net ecosystem exchange of CO2 (NEE) of -577 g C m-2 year-1, with -821 g C m-2 year-1 for mangrove forests and -430 g C m-2 year-1 for salt marshes. There are pronounced latitudinal patterns for carbon dioxide exchange of natural coastal wetlands: NEE increased whereas gross primary production (GPP) and respiration of ecosystem decreased with increasing latitude. Distinct environmental factors drive annual variations of GPP between mangroves and salt marshes; temperature was the dominant controlling factor in salt marshes, while temperature, precipitation, and solar radiation were co-dominant in mangroves. Meanwhile, both anthropogenic reclamation and restoration had substantial effects on coastal wetland carbon fluxes, and the effect of the anthropogenic perturbation in mangroves was more extensive than that in salt marshes. Furthermore, from 1980 to 2020, anthropogenic reclamation of China's coastal wetlands caused a carbon loss of ~3720 Gg C, while the mangrove restoration project during the period of 2021-2025 may switch restored coastal wetlands from a carbon source to carbon sink with a net carbon gain of 73 Gg C. The comparison of carbon fluxes among these coastal wetlands can improve our understanding of how anthropogenic perturbation can affect the potentials of coastal blue carbon in China, which has implications for informing conservation and restoration strategies and efforts of coastal wetlands.
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Ecosistema , Humedales , Dióxido de Carbono , Ciclo del Carbono , ChinaRESUMEN
BACKGROUND: Genetic variation underly inter-individual variation in host immune responses to infectious diseases, and may affect susceptibility or the course of signs and symptoms. METHODS: We performed genome-wide association studies in a prospective cohort of 1138 patients with physician-confirmed Lyme borreliosis (LB), the most common tick-borne disease in the Northern hemisphere caused by the bacterium Borrelia burgdorferi sensu lato. Genome-wide variants in LB patients-divided into a discovery and validation cohort-were compared to two healthy cohorts. Additionally, ex vivo monocyte-derived cytokine responses of peripheral blood mononuclear cells to several stimuli including Borrelia burgdorferi were performed in both LB patient and healthy control samples, as were stimulation experiments using mechanistic/mammalian target of rapamycin (mTOR) inhibitors. In addition, for LB patients, anti-Borrelia antibody responses were measured. Finally, in a subset of LB patients, gene expression was analysed using RNA-sequencing data from the ex vivo stimulation experiments. RESULTS: We identified a previously unknown genetic variant, rs1061632, that was associated with enhanced LB susceptibility. This polymorphism was an eQTL for KCTD20 and ETV7 genes, and its major risk allele was associated with upregulation of the mTOR pathway and cytokine responses, and lower anti-Borrelia antibody production. In addition, we replicated the recently reported SCGB1D2 locus that was suggested to have a protective effect on B. burgdorferi infection, and associated this locus with higher Borrelia burgdorferi antibody indexes and lower IL-10 responses. CONCLUSIONS: Susceptibility for LB was associated with higher anti-inflammatory responses and reduced anti-Borrelia antibody production, which in turn may negatively impact bacterial clearance. These findings provide important insights into the immunogenetic susceptibility for LB and may guide future studies on development of preventive or therapeutic measures. TRIAL REGISTRATION: The LymeProspect study was registered with the International Clinical Trials Registry Platform (NTR4998, registration date 2015-02-13).
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Grupo Borrelia Burgdorferi , Borrelia burgdorferi , Borrelia , Enfermedad de Lyme , Humanos , Estudio de Asociación del Genoma Completo , Estudios Prospectivos , Leucocitos Mononucleares , Susceptibilidad a Enfermedades , Enfermedad de Lyme/genética , Enfermedad de Lyme/diagnóstico , Borrelia burgdorferi/genética , Citocinas/genética , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/uso terapéutico , Grupo Borrelia Burgdorferi/genética , Secretoglobinas/genéticaRESUMEN
Human cytomegalovirus (HCMV) is a widespread pathogen that in immunocompromised hosts can cause life-threatening disease. Studying HCMV-exposed monocyte-derived dendritic cells by single-cell RNA sequencing, we observe that most cells are entered by the virus, whereas less than 30% of them initiate viral gene expression. Increased viral gene expression is associated with activation of the stimulator of interferon genes (STING) that usually induces anti-viral interferon responses, and with the induction of several pro- (RHOB, HSP1A1, DNAJB1) and anti-viral (RNF213, TNFSF10, IFI16) genes. Upon progression of infection, interferon-beta but not interferon-lambda transcription is inhibited. Similarly, interferon-stimulated gene expression is initially induced and then shut off, thus further promoting productive infection. Monocyte-derived dendritic cells are composed of 3 subsets, with one being especially susceptible to HCMV. In conclusion, HCMV permissiveness of monocyte-derived dendritic cells depends on complex interactions between virus sensing, regulation of the interferon response, and viral gene expression.
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Citomegalovirus , Interferones , Humanos , Citomegalovirus/fisiología , Transducción de Señal/genética , Antivirales/metabolismo , Células Dendríticas/metabolismo , Proteínas del Choque Térmico HSP40/metabolismo , Adenosina Trifosfatasas/metabolismo , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
The identification of novel age-related biomarkers represents an area of intense research interest. Despite multiple studies associating DNA damage with aging, there is a glaring paucity of DNA damage-based biomarkers of age, mainly due to the lack of precise methods for genome-wide surveys of different types of DNA damage. Recently, we developed two techniques for genome-wide mapping of the most prevalent types of DNA damage, single-strand breaks and abasic sites, with nucleotide-level resolution. Herein, we explored the potential of genomic patterns of DNA damage identified by these methods as a source of novel age-related biomarkers using mice as a model system. Strikingly, we found that models based on genomic patterns of either DNA lesion could accurately predict age with higher precision than the commonly used transcriptome analysis. Interestingly, the informative patterns were limited to relatively few genes and the DNA damage levels were positively or negatively correlated with age. These findings show that previously unexplored high-resolution genomic patterns of DNA damage contain useful information that can contribute significantly to both practical applications and basic science.
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Envejecimiento , Daño del ADN , Daño del ADN/genética , Animales , Envejecimiento/genética , Ratones , Ratones Endogámicos C57BL , Genoma/genética , MasculinoRESUMEN
Arrestins have pivotal roles in regulating G protein-coupled receptor (GPCR) signalling by desensitizing G protein activation and mediating receptor internalization1,2. It has been proposed that the arrestin binds to the receptor in two different conformations, 'tail' and 'core', which were suggested to govern distinct processes of receptor signalling and trafficking3,4. However, little structural information is available for the tail engagement of the arrestins. Here we report two structures of the glucagon receptor (GCGR) bound to ß-arrestin 1 (ßarr1) in glucagon-bound and ligand-free states. These structures reveal a receptor tail-engaged binding mode of ßarr1 with many unique features, to our knowledge, not previously observed. Helix VIII, instead of the receptor core, has a major role in accommodating ßarr1 by forming extensive interactions with the central crest of ßarr1. The tail-binding pose is further defined by a close proximity between the ßarr1 C-edge and the receptor helical bundle, and stabilized by a phosphoinositide derivative that bridges ßarr1 with helices I and VIII of GCGR. Lacking any contact with the arrestin, the receptor core is in an inactive state and loosely binds to glucagon. Further functional studies suggest that the tail conformation of GCGR-ßarr governs ßarr recruitment at the plasma membrane and endocytosis of GCGR, and provides a molecular basis for the receptor forming a super-complex simultaneously with G protein and ßarr to promote sustained signalling within endosomes. These findings extend our knowledge about the arrestin-mediated modulation of GPCR functionalities.
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Receptores de Glucagón , beta-Arrestina 1 , beta-Arrestina 1/química , beta-Arrestina 1/metabolismo , Membrana Celular/metabolismo , Endocitosis , Endosomas/metabolismo , Glucagón/metabolismo , Proteínas de Unión al GTP Heterotriméricas/metabolismo , Ligandos , Fosfatidilinositoles/metabolismo , Receptores de Glucagón/química , Receptores de Glucagón/metabolismo , Unión ProteicaRESUMEN
Climate warming has substantial influences on plant water-use efficiency (PWUE), which is defined as the ratio of plant CO2 uptake to water loss and is central to the cycles of carbon and water in ecosystems. However, it remains uncertain how does climate warming affect PWUE in wetland ecosystems, especially those with seasonally alternating water availability during the growing season. In this study, we used a continuous 10-year (2011-2020) eddy covariance (EC) dataset from a seasonal hydroperiod wetland coupled with a 15-year (2003-2017) satellite-based dataset (called PML-V2) and an in situ warming experiment to examine the climate warming impacts on wetland PWUE. The 10-year EC observational results revealed that rising temperatures had significant negative impacts on the interannual variations in wetland PWUE, and increased transpiration (Et) rather than changes in gross primary productivity (GPP) dominated these negative impacts. Furthermore, the 15-year satellite-based evidence confirmed that, in the study region, climate warming had significant negative consequences for the interannual variations in wetland PWUE by enhancing wetland Et. Lastly, at the leaf-scale, the light response curves of leaf photosynthesis, leaf Et, and leaf-scale PWUE indicated that wetland plants need to consume more water during the photosynthesis process under warmer conditions. These findings provide a fresh perspective on how climate warming influences carbon and water cycles in wetland ecosystems.
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Ecosistema , Humedales , Estaciones del Año , Agua , Dióxido de Carbono , Plantas , Carbono , Cambio ClimáticoRESUMEN
Heterodimerization of the metabotropic glutamate receptors (mGlus) has shown importance in the functional modulation of the receptors and offers potential drug targets for treating central nervous system diseases. However, due to a lack of molecular details of the mGlu heterodimers, understanding of the mechanisms underlying mGlu heterodimerization and activation is limited. Here we report twelve cryo-electron microscopy (cryo-EM) structures of the mGlu2-mGlu3 and mGlu2-mGlu4 heterodimers in different conformational states, including inactive, intermediate inactive, intermediate active and fully active conformations. These structures provide a full picture of conformational rearrangement of mGlu2-mGlu3 upon activation. The Venus flytrap domains undergo a sequential conformational change, while the transmembrane domains exhibit a substantial rearrangement from an inactive, symmetric dimer with diverse dimerization patterns to an active, asymmetric dimer in a conserved dimerization mode. Combined with functional data, these structures reveal that stability of the inactive conformations of the subunits and the subunit-G protein interaction pattern are determinants of asymmetric signal transduction of the heterodimers. Furthermore, a novel binding site for two mGlu4 positive allosteric modulators was observed in the asymmetric dimer interfaces of the mGlu2-mGlu4 heterodimer and mGlu4 homodimer, and may serve as a drug recognition site. These findings greatly extend our knowledge about signal transduction of the mGlus.
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Dimerización , Microscopía por CrioelectrónRESUMEN
The effects in field manipulation experiments are strongly influenced by amplified interannual variation in ambient climate as the experimental duration increases. Soil respiration (SR), as an important part of the carbon cycle in terrestrial ecosystems, is sensitive to climate changes such as temperature and precipitation changes. A growing body of evidence has indicated that ambient climate affects the temperature sensitivity of SR, which benchmarks the strength of terrestrial soil carbon-climate feedbacks. However, whether SR sensitivity to precipitation changes is influenced by ambient climate is still not clear. In addition, the mechanism driving the above phenomenon is still poorly understood. Here, a long-term field manipulation experiment with five precipitation treatments (-60%, -40%, +0%, +40%, and +60% of annual precipitation) was conducted in a marsh in the Yellow River Delta, China, which is sensitive to soil drying-wetting cycle caused by precipitation changes. Results showed that SR increased exponentially along the experimental precipitation gradient each year and the sensitivity of SR (standardized by per 100 mm change in precipitation under precipitation treatments) exhibited significant interannual variation from 2016 to 2021. In addition, temperature, net radiation, and ambient precipitation all exhibited dramatic interannual variability; however, only ambient precipitation had a significant negative correlation with SR sensitivity. Moreover, the sensitivity of SR was significantly positively related to the sensitivity of belowground biomass (BGB) across 6 years. Structural equation modeling and regression analysis also showed that precipitation treatments significantly affected SR and its autotrophic and heterotrophic components by altering BGB. Our study demonstrated that ambient precipitation determines the sensitivity of SR to precipitation treatments in marshes. The findings underscore the importance of ambient climate in regulating ecosystem responses in long-term field manipulation experiments.
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Ecosistema , Humedales , Suelo/química , Biomasa , Respiración , Cambio ClimáticoRESUMEN
Behavioral interventions that address other-regarding motivations (i.e., other-regarding interventions) are gaining momentum as promising tools to stimulate household recycling. However, previous studies have shown considerable variability in the impact of such strategies, and the factors that moderate treatment effects remain poorly studied. Using a field experiment with 7195 households in Quzhou, China, this study investigated treatment effect heterogeneity systematically based on intervention types, treatment durations, personal motivations, and social networks. Three strategies were examined, including biospheric and altruistic appeals and personalized normative feedback. We found that normative feedback outperformed other strategies in inducing household participation in recycling, that the influences of all strategies attenuated over time, and that the feedback effect was greater among recipients with weaker biospheric or altruistic concerns and those embedded within stronger neighbor networks. However, no significant treatment effects were found on the amount of waste recycled. These findings improve the understanding of the heterogeneous impact of other-regarding interventions, with important implications for the design of recycling policies. Future studies need to explore additional moderators and the effects of treatment combinations.
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Reciclaje , Administración de Residuos , China , Composición Familiar , Motivación , Proyectos de InvestigaciónRESUMEN
Neuromedin U receptor 2 (NMU2), an emerging attractive target for treating obesity, has shown the capability in reducing food intake and regulating energy metabolism when activated. However, drug development of NMU2 was deferred partially due to the lack of structural information. Here, we present the cryo-electron microscopy (cryo-EM) structure of NMU2 bound to the endogenous agonist NmU-25 and Gi1 at 3.3 Å resolution. Combined with functional and computational data, the structure reveals the key factors that govern the recognition and selectivity of peptide agonist as well as non-peptide antagonist, providing the structural basis for design of novel and highly selective drugs targeting NMU2. In addition, a 25-degree rotation of Gi protein in reference to NMU2 is also observed compared in other structures of class A GPCR-Gi complexes, suggesting heterogeneity in the processes of G protein-coupled receptors (GPCRs) activation and G protein coupling.
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Receptores Acoplados a Proteínas G , Receptores de Neurotransmisores , Ligandos , Microscopía por Crioelectrón , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neurotransmisores/metabolismo , Proteínas de Unión al GTP/metabolismoRESUMEN
The first wave of Foxp3+ regulatory T cells (Tregs) generated in neonates is critical for the life-long prevention of autoimmunity. Although it is widely accepted that neonates are highly susceptible to infections, the impact of neonatal infections on this first wave of Tregs is completely unknown. Here, we challenged newborn Treg fate-mapping mice (Foxp3eGFPCreERT2xROSA26STOP-eYFP) with the Toll-like receptor (TLR) agonists LPS and poly I:C to mimic inflammatory perturbations upon neonatal bacterial or viral infections, respectively, and subsequently administrated tamoxifen during the first 8 days of life to selectively label the first wave of Tregs. Neonatally-tagged Tregs preferentially accumulated in non-lymphoid tissues (NLTs) when compared to secondary lymphoid organs (SLOs) irrespective of the treatment. One week post challenge, no differences in the frequency and phenotypes of neonatally-tagged Tregs were observed between challenged mice and untreated controls. However, upon aging, a decreased frequency of neonatally-tagged Tregs in both NLTs and SLOs was detected in challenged mice when compared to untreated controls. This decrease became significant 12 weeks post challenge, with no signs of altered Foxp3 stability. Remarkably, this late decrease in the frequency of neonatally-tagged Tregs only occurred when newborns were challenged, as treating 8-days-old mice with TLR agonists did not result in long-lasting alterations of the first wave of Tregs. Combined single-cell T cell receptor (TCR)-seq and RNA-seq revealed that neonatal inflammatory perturbations drastically diminished TCR diversity and long-lastingly altered the transcriptome of neonatally-tagged Tregs, exemplified by lower expression of Tigit, Foxp3, and Il2ra. Together, our data demonstrate that a single, transient encounter with a pathogen in early life can have long-lasting consequences for the first wave of Tregs, which might affect immunological tolerance, prevention of autoimmunity, and other non-canonical functions of tissue-resident Tregs in adulthood.
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Linfocitos T Reguladores , Transcriptoma , Animales , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Lipopolisacáridos/metabolismo , Ratones , Poli I/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Tamoxifeno/metabolismo , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismoRESUMEN
As the only member of the CX3C chemokine receptor subfamily, CX3CR1 binds to its sole endogenous ligand CX3CL1, which shows notable potential as a therapeutic target in atherosclerosis, cancer, and neuropathy. However, the drug development of CX3CR1 is hampered partially by the lack of structural information. Here, we present two cryo-electron microscopy structures of CX3CR1-Gi1 complexes in ligand-free and CX3CL1-bound states at 2.8- and 3.4-Å resolution, respectively. Together with functional data, the structures reveal the key factors that govern the recognition of CX3CL1 by both CX3CR1 and US28. A much smaller conformational change of helix VI upon activation than previously solved class A GPCR-Gi complex structures is observed in CX3CR1, which may correlate with three cholesterol molecules that play essential roles in conformation stabilization and signaling transduction. Thus, our data deepen the understanding of cholesterol modulation in GPCR (G protein-coupled receptor) signaling and provide insights into the diversity of G protein coupling.
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Quimiocina CX3CL1 , Receptores de Quimiocina , Receptor 1 de Quimiocinas CX3C/metabolismo , Quimiocina CX3CL1/metabolismo , Colesterol , Microscopía por Crioelectrón , Humanos , Receptores de Quimiocina/metabolismo , Transducción de SeñalAsunto(s)
Perfilación de la Expresión Génica , Humanos , RNA-Seq , Análisis de Secuencia de ARN , EpitelioRESUMEN
Somatostatin receptors (SSTRs) play versatile roles in inhibiting the secretion of multiple hormones such as growth hormone and thyroid-stimulating hormone, and thus are considered as targets for treating multiple tumors. Despite great progress made in therapeutic development against this diverse receptor family, drugs that target SSTRs still show limited efficacy with preferential binding affinity and conspicuous side-effects. Here, we report five structures of SSTR2 and SSTR4 in different states, including two crystal structures of SSTR2 in complex with a selective peptide antagonist and a non-peptide agonist, respectively, a cryo-electron microscopy (cryo-EM) structure of Gi1-bound SSTR2 in the presence of the endogenous ligand SST-14, as well as two cryo-EM structures of Gi1-bound SSTR4 in complex with SST-14 and a small-molecule agonist J-2156, respectively. By comparison of the SSTR structures in different states, molecular mechanisms of agonism and antagonism were illustrated. Together with computational and functional analyses, the key determinants responsible for ligand recognition and selectivity of different SSTR subtypes and multiform binding modes of peptide and non-peptide ligands were identified. Insights gained in this study will help uncover ligand selectivity of various SSTRs and accelerate the development of new molecules with better efficacy by targeting SSTRs.
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Neoplasias , Receptores de Somatostatina , Microscopía por Crioelectrón , Humanos , Ligandos , Neoplasias/metabolismo , Receptores de Somatostatina/agonistas , Receptores de Somatostatina/metabolismo , Somatostatina/metabolismo , Somatostatina/farmacología , Somatostatina/uso terapéuticoRESUMEN
Background: The large inter-individual variability in immune-cell composition and function determines immune responses in general and susceptibility o immune-mediated diseases in particular. While much has been learned about the genetic variants relevant for type 1 diabetes (T1D), the pathophysiological mechanisms through which these variations exert their effects remain unknown. Methods: Blood samples were collected from 243 patients with T1D of Dutch descent. We applied genetic association analysis on >200 immune-cell traits and >100 cytokine production profiles in response to stimuli measured to identify genetic determinants of immune function, and compared the results obtained in T1D to healthy controls. Results: Genetic variants that determine susceptibility to T1D significantly affect T cell composition. Specifically, the CCR5+ regulatory T cells associate with T1D through the CCR region, suggesting a shared genetic regulation. Genome-wide quantitative trait loci (QTLs) mapping analysis of immune traits revealed 15 genetic loci that influence immune responses in T1D, including 12 that have never been reported in healthy population studies, implying a disease-specific genetic regulation. Conclusions: This study provides new insights into the genetic factors that affect immunological responses in T1D. Funding: This work was supported by an ERC starting grant (no. 948207) and a Radboud University Medical Centre Hypatia grant (2018) to YL and an ERC advanced grant (no. 833247) and a Spinoza grant of the Netherlands Association for Scientific Research to MGN CT received funding from the Perspectief Biomarker Development Center Research Programme, which is (partly) financed by the Netherlands Organisation for Scientific Research (NWO). AJ was funded by a grant from the European Foundation for the Study of Diabetes (EFSD/AZ Macrovascular Programme 2015). XC was supported by the China Scholarship Council (201706040081).
Every year around the world, over 100,000 people are diagnosed with type 1 diabetes. This disease develops when the immune system mistakenly destroys the cells that produce a hormone called insulin, leaving affected individuals unable to regulate their blood sugar levels. Type 1 diabetes patients must rely on regular injections of manufactured insulin to survive. The composition and activity of the human immune system is under genetic control, and people with certain changes in their genes are more susceptible than others to develop type 1 diabetes. Previous studies have identified around 60 locations in the human DNA (known as loci) associated with the condition, but it remains unclear how these loci influence the immune system and whether diabetes will emerge. Chu, Janssen, Koenen et al. explored how variations in genetic information can influence the composition of the immune system, and the type of molecules it releases to perform its role. To do so, blood samples from 243 individuals of Dutch descent with type 1 diabetes were collected, and genetic associations were investigated. The results revealed that a major type of immune actors known as T cells are under the control of genetic factors associated with type 1 diabetes susceptibility. For instance, a specific type of T cells showed shared genetic control with type 1 diabetes. In addition, 15 loci were identified that influenced immune responses in the patients. Among those, 12 have never been reported to be involved in immune responses in healthy people, implying that these regions might only regulate the immune system of individuals with type 1 diabetes and other similar disorders. Finally, Chu, Janssen, Koenen et al. propose 11 genes within the identified loci as potential targets for new diabetes medication. These results represent an important resource for researchers exploring the genetic and immune basis of type 1 diabetes, and they could open new avenues for drug development.
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Diabetes Mellitus Tipo 1 , China , Diabetes Mellitus Tipo 1/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genómica , Humanos , Fenotipo , Sitios de Carácter CuantitativoRESUMEN
The senescence of cardiovascular endothelial cells (ECs) is a major risk factor in the development of aging-related cardiovascular diseases. However, the molecular dynamics in cardiovascular EC aging are poorly understood. Here, we characterized the transcriptomic landscape of cardiovascular ECs during aging and observed that ribosome biogenesis, inflammation, apoptosis and angiogenesis-related genes and pathways changed with age. We also highlighted the importance of collagen genes in the crosstalk between ECs and other cell types in cardiovascular aging. Moreover, transcriptional regulatory network analysis revealed Jun as a candidate transcription factor involved in murine cardiovascular senescence and we validated the upregulation of Jun in aged cardiovascular ECs both in vitro and in vivo. Altogether, our study reveals the transcriptomic reprogramming in the aging murine cardiovascular ECs, which deepens the understanding of the molecular mechanisms of cardiovascular aging and provides new insights into potential therapeutic targets against age-related cardiovascular diseases.