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Banyan trees are distinguished by their extraordinary aerial roots. The Ficus genus includes species that have evolved a species-specific mutualism system with wasp pollinators. We sequenced genomes of the Chinese banyan tree, F. microcarpa, and a species lacking aerial roots, F. hispida, and one wasp genome coevolving with F. microcarpa, Eupristina verticillata. Comparative analysis of the two Ficus genomes revealed dynamic karyotype variation associated with adaptive evolution. Copy number expansion of auxin-related genes from duplications and elevated auxin production are associated with aerial root development in F. microcarpa. A male-specific AGAMOUS paralog, FhAG2, was identified as a candidate gene for sex determination in F. hispida. Population genomic analyses of Ficus species revealed genomic signatures of morphological and physiological coadaptation with their pollinators involving terpenoid- and benzenoid-derived compounds. These three genomes offer insights into and genomic resources for investigating the geneses of aerial roots, monoecy and dioecy, and codiversification in a symbiotic system.
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Evolución Biológica , Ficus/genética , Genoma de Planta , Polinización/fisiología , Árboles/genética , Avispas/fisiología , Animales , Cromosomas de las Plantas/genética , Elementos Transponibles de ADN/genética , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica de las Plantas , Genes de Plantas , Ácidos Indolacéticos/metabolismo , Anotación de Secuencia Molecular , Filogenia , Raíces de Plantas/crecimiento & desarrollo , Duplicaciones Segmentarias en el Genoma/genética , Cromosomas Sexuales/genética , Compuestos Orgánicos Volátiles/análisisRESUMEN
Class B G-protein-coupled receptors (GPCRs), including glucagon-like peptide 1 receptor (GLP1R) and parathyroid hormone 1 receptor (PTH1R), are important drug targets1-5. Injectable peptide drugs targeting these receptors have been developed, but orally available small-molecule drugs remain under development6,7. Here we report the high-resolution structure of human PTH1R in complex with the stimulatory G protein (Gs) and a small-molecule agonist, PCO371, which reveals an unexpected binding mode of PCO371 at the cytoplasmic interface of PTH1R with Gs. The PCO371-binding site is totally different from all binding sites previously reported for small molecules or peptide ligands in GPCRs. The residues that make up the PCO371-binding pocket are conserved in class B GPCRs, and a single alteration in PTH2R and two residue alterations in GLP1R convert these receptors to respond to PCO371. Functional assays reveal that PCO371 is a G-protein-biased agonist that is defective in promoting PTH1R-mediated arrestin signalling. Together, these results uncover a distinct binding site for designing small-molecule agonists for PTH1R and possibly other members of the class B GPCRs and define a receptor conformation that is specific only for G-protein activation but not arrestin signalling. These insights should facilitate the design of distinct types of class B GPCR small-molecule agonist for various therapeutic indications.
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Imidazolidinas , Receptores Acoplados a Proteínas G , Compuestos de Espiro , Humanos , Arrestina/metabolismo , Sitios de Unión , Subunidades alfa de la Proteína de Unión al GTP Gs/metabolismo , Imidazolidinas/farmacología , Ligandos , Péptidos/farmacología , Conformación Proteica , Receptor de Hormona Paratiroídea Tipo 1/agonistas , Receptor de Hormona Paratiroídea Tipo 1/clasificación , Receptor de Hormona Paratiroídea Tipo 1/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/clasificación , Receptores Acoplados a Proteínas G/metabolismo , Transducción de Señal/efectos de los fármacos , Compuestos de Espiro/farmacología , Diseño de FármacosRESUMEN
Corticotropin-releasing factor (CRF) and the three related peptides urocortins 1-3 (UCN1-UCN3) are endocrine hormones that control the stress responses by activating CRF1R and CRF2R, two members of class B G-protein-coupled receptors (GPCRs). Here, we present two cryoelectron microscopy (cryo-EM) structures of UCN1-bound CRF1R and CRF2R with the stimulatory G protein. In both structures, UCN1 adopts a single straight helix with its N terminus dipped into the receptor transmembrane bundle. Although the peptide-binding residues in CRF1R and CRF2R are different from other members of class B GPCRs, the residues involved in receptor activation and G protein coupling are conserved. In addition, both structures reveal bound cholesterol molecules to the receptor transmembrane helices. Our structures define the basis of ligand-binding specificity in the CRF receptor-hormone system, establish a common mechanism of class B GPCR activation and G protein coupling, and provide a paradigm for studying membrane protein-lipid interactions for class B GPCRs.
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Receptores de Hormona Liberadora de Corticotropina/ultraestructura , Secuencia de Aminoácidos , Sitios de Unión , Hormona Liberadora de Corticotropina , Microscopía por Crioelectrón/métodos , Subunidades alfa de la Proteína de Unión al GTP Gs/metabolismo , Proteínas de Unión al GTP/metabolismo , Humanos , Péptidos/metabolismo , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Urocortinas/metabolismoRESUMEN
Somatostatin receptor 5 (SSTR5) is an important G protein-coupled receptor and drug target for neuroendocrine tumors and pituitary disorders. This study presents two high-resolution cryogenicelectron microscope structures of the SSTR5-Gi complexes bound to the cyclic neuropeptide agonists, cortistatin-17 (CST17) and octreotide, with resolutions of 2.7 Å and 2.9 Å, respectively. The structures reveal that binding of these peptides causes rearrangement of a "hydrophobic lock", consisting of residues from transmembrane helices TM3 and TM6. This rearrangement triggers outward movement of TM6, enabling Gαi protein engagement and receptor activation. In addition to hydrophobic interactions, CST17 forms conserved polar contacts similar to somatostatin-14 binding to SSTR2, while further structural and functional analysis shows that extracellular loops differently recognize CST17 and octreotide. These insights elucidate agonist selectivity and activation mechanisms of SSTR5, providing valuable guidance for structure-based drug development targeting this therapeutically relevant receptor.
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Octreótido , Receptores de Somatostatina , Receptores de Somatostatina/metabolismo , Receptores de Somatostatina/agonistas , Receptores de Somatostatina/química , Humanos , Octreótido/química , Octreótido/farmacología , Octreótido/metabolismo , Neuropéptidos/metabolismo , Neuropéptidos/química , Microscopía por Crioelectrón , Unión Proteica , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacología , Péptidos Cíclicos/metabolismo , Somatostatina/metabolismo , Somatostatina/química , Somatostatina/análogos & derivados , Modelos Moleculares , Células HEK293RESUMEN
Homologous recombination (HR) is a conservative DNA repair pathway in which intact homologous sequences are used as a template for repair. How the homology search happens in the crowded space of the cell nucleus is, however, still poorly understood. Here, we measure chromosome and double-strand break (DSB) site mobility in Arabidopsis thaliana, using lacO/LacI lines and two GFP-tagged HR reporters. We observe an increase in chromatin mobility upon the induction of DNA damage, specifically at the S/G2 phases of the cell cycle. This increase in mobility is lost in the sog1-1 mutant, a central transcription factor of the DNA damage response in plants. Also, DSB sites show particularly high mobility levels and their enhanced mobility requires the HR factor RAD54. Our data suggest that repair mechanisms promote chromatin mobility upon DNA damage, implying a role of this process in the early steps of the DNA damage response.
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Cromatina , Daño del ADN , Cromatina/genéticaRESUMEN
Objectives: This study aims to assess the prognostic implications of gene signature of the tertiary lymphoid structures (TLSs) in head and neck squamous cell carcinoma (HNSCC) and scrutinize the influence of TLS on immune infiltration. Methods: Patients with HNSCC from the Cancer Genome Atlas were categorized into high/low TLS signature groups based on the predetermined TLS signature threshold. The association of the TLS signature with the immune microenvironment, driver gene mutation status, and tumor mutational load was systematically analyzed. Validation was conducted using independent datasets (GSE41613 and GSE102349). Results: Patients with a high TLS signature score exhibited better prognosis compared to those with a low TLS signature score. The group with a high TLS signature score had significantly higher immune cell subpopulations compared to the group with a low TLS signature score. Moreover, the major immune cell subpopulations and immune circulation characteristics in the tumor immune microenvironment were positively correlated with the TLS signature. Mutational differences in driver genes were observed between the TLS signature high/low groups, primarily in the cell cycle and NRF2 signaling pathways. Patients with TP53 mutations and high TLS signature scores demonstrated a better prognosis compared to those with TP53 wild-type. In the independent cohort, the relationship between TLS signatures and patient prognosis and immune infiltration was also confirmed. Additionally, immune-related biological processes and signaling pathways were activated with elevated TLS signature. Conclusion: High TLS signature is a promising independent prognostic factor for HNSCC patients. Immunological analysis indicated a correlation between TLS and immune cell infiltration in HNSCC. These findings provide a theoretical basis for future applications of TLS signature in HNSCC prognosis and immunotherapy.
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BACKGROUND: Modifying diet is crucial for diabetes and complication management. Numerous studies have shown that adjusting eating habits to align with the circadian rhythm may positively affect metabolic health. However, eating midpoint, eating duration, and their associations with diabetic kidney disease (DKD) are poorly understood. METHODS: The National Health and Nutrition Examination Survey (2013-2020) was examined for information on diabetes and dietary habits. From the beginning and ending times of each meal, we calculated the eating midpoint and eating duration. Urinary albumin-to-creatinine ratio (UACR) ≥ 30 mg/g and/or estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 were the specific diagnostic criteria for DKD. RESULTS: In total, details of 2194 subjects with diabetes were collected for analysis. The overall population were divided into four subgroups based on the eating midpoint quartiles. The prevalence of DKD varied noticeably (P = 0.037) across the four categories. When comparing subjects in the second and fourth quartiles of eating midpoint to those in the first one, the odds ratios (ORs) of DKD were 1.31 (95% CI, 1.03 to 1.67) and 1.33 (95% CI, 1.05 to 1.70), respectively. And after controlling for potential confounders, the corresponding ORs of DKD in the second and fourth quartiles were 1.42 (95% CI, 1.07 to 1.90) and 1.39 (95% CI, 1.04 to 1.85), respectively. CONCLUSIONS: A strong correlation was found between an earlier eating midpoint and a reduced incidence of DKD. Eating early in the day may potentially improve renal outcomes in patients with diabetes.
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Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Humanos , Nefropatías Diabéticas/epidemiología , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/metabolismo , Encuestas Nutricionales , Estudios Transversales , Riñón , Tasa de Filtración Glomerular , Diabetes Mellitus Tipo 2/complicacionesRESUMEN
The parathyroid hormone receptor 2 (PTH2R) is a class B1 G protein-coupled receptor (GPCR) involved in the regulation of calcium transport, nociception mediation, and wound healing. Naturally occurring mutations in PTH2R were reported to cause hereditary diseases, including syndromic short stature. Here, we report the cryogenic electron microscopy structure of PTH2R bound to its endogenous ligand, tuberoinfundibular peptide (TIP39), and a heterotrimeric Gs protein at a global resolution of 2.8 Å. The structure reveals that TIP39 adopts a unique loop conformation at the N terminus and deeply inserts into the orthosteric ligand-binding pocket in the transmembrane domain. Molecular dynamics simulation and site-directed mutagenesis studies uncover the basis of ligand specificity relative to three PTH2R agonists, TIP39, PTH, and PTH-related peptide. We also compare the action of TIP39 with an antagonist lacking six residues from the peptide N terminus, TIP(7-39), which underscores the indispensable role of the N terminus of TIP39 in PTH2R activation. Additionally, we unveil that a disease-associated mutation G258D significantly diminished cAMP accumulation induced by TIP39. Together, these results not only provide structural insights into ligand specificity and receptor activation of class B1 GPCRs but also offer a foundation to systematically rationalize the available pharmacological data to develop therapies for various disorders associated with PTH2R.
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Receptor de Hormona Paratiroídea Tipo 2/química , Receptor de Hormona Paratiroídea Tipo 2/metabolismo , Sitios de Unión , Microscopía por Crioelectrón , AMP Cíclico/metabolismo , Subunidades alfa de la Proteína de Unión al GTP Gs/química , Subunidades alfa de la Proteína de Unión al GTP Gs/metabolismo , Humanos , Ligandos , Simulación de Dinámica Molecular , Complejos Multiproteicos/química , Complejos Multiproteicos/metabolismo , Mutación , Neuropéptidos/química , Neuropéptidos/metabolismo , Conformación Proteica , Receptor de Hormona Paratiroídea Tipo 2/genéticaRESUMEN
Alternative splicing of G protein-coupled receptors has been observed, but their functions are largely unknown. Here, we report that a splice variant (SV1) of the human growth hormone-releasing hormone receptor (GHRHR) is capable of transducing biased signal. Differing only at the receptor N terminus, GHRHR predominantly activates Gs while SV1 selectively couples to ß-arrestins. Based on the cryogenic electron microscopy structures of SV1 in the apo state or GHRH-bound state in complex with the Gs protein, molecular dynamics simulations reveal that the N termini of GHRHR and SV1 differentiate the downstream signaling pathways, Gs versus ß-arrestins. As suggested by mutagenesis and functional studies, it appears that GHRH-elicited signal bias toward ß-arrestin recruitment is constitutively mediated by SV1. The level of SV1 expression in prostate cancer cells is also positively correlated with ERK1/2 phosphorylation but negatively correlated with cAMP response. Our findings imply that constitutive signal bias may be a mechanism that ensures cancer cell proliferation.
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Empalme Alternativo/genética , Variación Genética/genética , Receptores de Neuropéptido/genética , Receptores de Hormona Reguladora de Hormona Hipofisaria/genética , Animales , Línea Celular Tumoral , Proliferación Celular/genética , Células Cultivadas , Células HEK293 , Humanos , Sistema de Señalización de MAP Quinasas/genética , Células PC-3 , Células Sf9 , Transducción de Señal/genética , beta-Arrestinas/genéticaRESUMEN
The scarcity of donor kidneys greatly impacts the survival of patients with end-stage renal failure. Pigs are increasingly becoming potential organ donors but are limited by immunological rejection. Based on the human kidney organoid already established with the CHIR99021 and FGF9 induction strategy, we generated porcine kidney organoids from porcine naïve-like ESCs (nESCs). The derived porcine organoids had a tubule-like constructure and matrix components. The porcine organoids expressed renal markers including AQP1 (proximal tubule), WT1 and PODO (podocyte), and CD31 (vascular endothelial cells). These results imply that the organoids had developed the majority of the renal cell types and structures, including glomeruli and proximal tubules. The porcine organoids were also identified to have a dextran absorptive function. Importantly, porcine organoids have a certain abundance of vascular endothelial cells, which are the basis for investigating immune rejection. The derived porcine organoids might serve as materials for immunosuppressor screening for xenotransplantation.
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Células Endoteliales , Fallo Renal Crónico , Humanos , Porcinos , Animales , Riñón , Organoides , Células Madre EmbrionariasRESUMEN
Peroxiredoxin1(Prx1), also known as natural killer enhancing factor A (NKEF-A), is a crucial antioxidant involving in various cellular activities and immune response against bacterial and viral infection in fish. In the present study, a full-length Prx1 cDNA sequence (TfPrx1) was firstly cloned from roughskin sculpin (Trachidermus fasciatus), which was composed of 1044 bp nucleotides encoding a peptide of 199 amino acids with a molecular weight of 22.35 kDa and a theoretical pI of 6.42, respectively. The predicted peptide was a typical 2-cys Prx containing two conserved characteristic motifs 43FYPLDFTFVCPTEI56 and 170GEVCPA175 with the two conserved peroxidatic and resolving cysteine residuals forming disulfide bond. Quantitative real-time PCR analysis showed that TfPrx1 was ubiquitously expressed in all tested tissues with the highest expression in the intestine. It could be significantly induced following LPS injection and heavy metal exposure. Recombinant TfPrx1 (rTfPrx1) displayed insulin disulfide reduction and ROS-scavenging activity in a concentration-dependent manner, and further exhibited DNA and cytoprotective effects under oxidative stress. These results suggested that TfPrx1 protein may play an important role in fish immune protection from oxidative damage.
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Perciformes , Peroxirredoxinas , Animales , Secuencia de Aminoácidos , Secuencia de Bases , Alineación de Secuencia , Peroxirredoxinas/genética , Peroxirredoxinas/química , Perciformes/genética , Peces/genética , Péptidos/genética , Disulfuros , FilogeniaRESUMEN
Mastitis refers to the inflammation in the mammary gland caused by various reasons. Protocatechuic acid (PCA) exerts anti-inflammatory effect. However, no studies have shown the protective role of PCA on mastitis. We investigated the protective effect of PCA on LPS-induced mastitis in mice and elucidated its possible mechanism. LPS-induced mastitis model was established by injection of LPS into the mammary gland. The pathology of mammary gland, MPO activity and inflammatory cytokine production were detected to evaluate the effects of PCA on mastitis. In vivo, PCA significantly attenuated LPS-induced mammary pathological changes, MPO activity, TNF-α and IL-1ß production. In vitro, the production of inflammatory cytokines TNF-α and IL-1ß was significantly reduced by PCA. Furthermore, LPS-induced NF-κB activation was also inhibited by PCA. In addition, PCA was found to activate pregnane X receptor (PXR) transactivation and PCA dose-dependently increased the expression of PXR downstream molecule CYP3A4. In addition, the inhibitory effect of PCA on inflammatory cytokine production was also reversed when PXR was knocked down. In conclusion, the protective effects of PCA on LPS-induced mastitis in mice through regulating PXR.
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Lipopolisacáridos , Mastitis , Femenino , Humanos , Animales , Ratones , Receptor X de Pregnano , Lipopolisacáridos/toxicidad , Factor de Necrosis Tumoral alfa/genética , Mastitis/inducido químicamente , Mastitis/tratamiento farmacológico , CitocinasRESUMEN
Mastitis is a common and serious bacterial infection of the mammary gland. Saikosaponin A (SSA) is a triterpenoid saponin isolated from Bupleurum falcatum that has the ability to treat various diseases. However, little is known about the role of SSA in achieving mastitis remission. Here, we found that SSA alleviated Staphylococcus aureus (S. aureus)-induced mastitis by attenuating inflammation and maintaining blood-milk barrier integrity. Furthermore, S. aureus activated nuclear factor kappa B (NF-κB) pathway by upregulated p-p65 and p-IκB. S. aureus also induced ferroptosis in mammary gland in mice, mainly characterized by excessive iron accumulation, mitochondrial morphological changes and impaired antioxidant production. However, S. aureus-induced NF-κB activation and ferroptosis were prevented by SSA. Moreover, SAA could upregulate the expression of SIRT1, Nrf2, HO-1 and GPX4. And the inhibitory effects of SAA on inflammation and ferroptosis were reversed by SIRT1 inhibitor EX-527. In conclusion, SAA protected S. aureus-induced mastitis through suppressing inflammation and ferroptosis by activating SIRT1/Nrf2 pathway.
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Ferroptosis , Mastitis , Humanos , Femenino , Animales , Ratones , FN-kappa B/metabolismo , Staphylococcus aureus , Factor 2 Relacionado con NF-E2/metabolismo , Sirtuina 1 , Mastitis/tratamiento farmacológico , Mastitis/metabolismo , Mastitis/microbiología , Inflamación/metabolismoRESUMEN
Background: To assess the effectiveness of the nurse-led individualised self-care model on myocardial infarction (MI) patients with diabetes. Methods: A total of 120 MI patients were enrolled from May 2020 to December 2021. The intervention group received the nurse-led individualised self-care model (n = 60), whereas the control group only received routine health education (n = 60). The Myocardial Infarction Dimensional Assessment Scale (MIDAS), Coronary Heart Disease Self-Management Behavior Scale (CSMS), Self-Rated Abilities for Health Practices (SRAHP) scale, General Self-Efficacy Scale (GSES), Hospital Anxiety and Depression Scale (HADS), blood glucose and nursing satisfaction in both groups were observed and recorded. Results: The six MIDAS subscales except for insecurity, and all dimensions of the CSMS, SRAHP, GSES and HADS scores, of the intervention group were significantly improved compared to those of the control group (p < 0.05). Compared with the control group (5.69 ± 1.43 mmol/L), the intervention group showed a decrease in the serum levels of fasting blood glucose (4.83 ± 1.57 mmol/L; p < 0.01). Conclusions: Our pilot study provides preliminary evidence supporting the feasibility of implementing nurse-led individualised self-care, suggesting its preliminary effects in improving health-related quality of life, self-care ability, health behaviours, self-efficacy, social support and nursing satisfaction among MI patients with diabetes. However, considering the unblinded and pilot nature of this study, these positive results should be interpreted with caution. Clinical Trial Registration: OSF Registration number: DOI 10.17605/OSF.IO/DVW95 (https://archive.org/details/osf-registrations-dvw95-v1).
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Age-related gastrointestinal decline contributes to whole-organism frailty and mortality. Genistein is known to have beneficial effects on age-related diseases, but its precise role in homeostasis of the aging gut remains to be elucidated. Here, wild-type aging mice and Zmpste24-/- progeroid mice were used to investigate the role of genistein in lifespan and homeostasis of the aging gut in mammals. A series of longitudinal, clinically relevant measurements were performed to evaluate the effect of genistein on healthspan. It was found that dietary genistein promoted a healthier and longer life and was associated with a decrease in the levels of systemic inflammatory cytokines in aging mice. Furthermore, dietary genistein ameliorated gut dysfunctions, such as intestinal inflammation, leaky gut, and impaired epithelial regeneration. A distinct genistein-mediated alteration in gut microbiota was observed by increasing Lachnospira abundance and short-chain fatty acid (SCFA) production. Further fecal microbiota transplantation and dirty cage sharing experiments indicated that the gut microbiota from genistein-fed mice rejuvenated the aging gut and extended the lifespan of progeroid mice. It was demonstrated that genistein-associated SCFAs alleviated tumor necrosis factor alpha-induced intestinal organoid damage. Moreover, genistein-associated propionate promoted regulatory T cell-derived interleukin 10 production, which alleviated macrophage-derived inflammation. This study provided the first data, to the authors' knowledge, indicating that dietary genistein modulates homeostasis in the aging gut and extends the healthspan and lifespan of aging mammals. Moreover, the existence of a link between genistein and the gut microbiota provides a rationale for dietary interventions against age-associated frailty.
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Fragilidad , Microbioma Gastrointestinal , Ratones , Animales , Longevidad , Genisteína/farmacología , Ácidos Grasos Volátiles/farmacología , Envejecimiento , Inflamación , Homeostasis , Ratones Endogámicos C57BL , MamíferosRESUMEN
With the tremendous success of the artificial breeding of Hexagrammos otakii, the yield has been substantially improved. However, intensive farming often results in bacterial diseases; hence it is imperative to find new antimicrobial molecules. In the present study, we identified a homologous cDNA fragment of collectin-10 from H. otakii, designated as HoCL-10. The cDNA length is 899 bp, which contains an open reading frame (ORF) of 816 bp encoding a secreted protein with 272 amino acid residues. The peptide of HoCL-10 contains an N-terminal collagen domain, a neck region, and a C-terminal carbohydrate recognition domain. The qRT-PCR results revealed that HoCL-10 mRNA was highest expressed in the liver and skin and was significantly induced post-LPS stimulation. The sugar and bacteria binding assay suggested that the recombinant HoCL-10 (rHoCL-10) could recognize various pathogen-associated molecular patterns (PAMPs) and bacteria. For effect on cells, rHoCL-10 enhanced the phagocytosis and migration ability of the macrophage indicated using pro-phagocytosis assay and trans-well assay. To determine the role of HoCL-10 in the complement system, the interaction between HoCL-10 and mannose-binding lectin associated serine protease 1, 2 (MASP-1, 2) were analyzed and demonstrated using ELISA and Far-western. And in vivo, the concentration of membrane-attack complex (MAC) in fish plasma was significantly down-regulated post-injection with HoCL-10 antibody. Finally, the bacteria challenge experiment was performed, implying that HoCL-10 may assist the host in defending against microbial invasion. The findings suggest that HoCL-10 may play crucial roles in host defense against microorganisms, possibly through opsonizing pathogens and activating the complement system.
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Infecciones Bacterianas , Perciformes , Animales , ADN Complementario , Bacterias/genética , Activación de Complemento , Perciformes/genética , Proteínas del Sistema Complemento , Carbohidratos , Colectinas/genéticaRESUMEN
BACKGROUND: Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis and is related to the severity of the disease. This study aimed to develop and validate a nomogram for predicting severe bronchiolitis in infants and young children with RSV infection. METHODS: A total of 325 children with RSV-associated bronchiolitis were enrolled, including 125 severe cases and 200 mild cases. A prediction model was built on 227 cases and validated on 98 cases, which were divided by random sampling in R software. Relevant clinical, laboratory and imaging data were collected. Multivariate logistic regression models were used to determine optimal predictors and to construct nomograms. The performance of the nomogram was evaluated by the area under the characteristic curve (AUC), calibration ability and decision curve analysis (DCA). RESULTS: There were 137 (60.4%) mild and 90 (39.6%) severe RSV-associated bronchiolitis cases in the training group (n = 227) and 63 (64.3%) mild and 35 (35.7%) severe cases in the validation group (n = 98). Multivariate logistic regression analysis identified 5 variables as significant predictive factors to construct the nomogram for predicting severe RSV-associated bronchiolitis, including preterm birth (OR = 3.80; 95% CI, 1.39-10.39; P = 0.009), weight at admission (OR = 0.76; 95% CI, 0.63-0.91; P = 0.003), breathing rate (OR = 1.11; 95% CI, 1.05-1.18; P = 0.001), lymphocyte percentage (OR = 0.97; 95% CI, 0.95-0.99; P = 0.001) and outpatient use of glucocorticoids (OR = 2.27; 95% CI, 1.05-4.9; P = 0.038). The AUC value of the nomogram was 0.784 (95% CI, 0.722-0.846) in the training set and 0.832 (95% CI, 0.741-0.923) in the validation set, which showed a good fit. The calibration plot and HosmerâLemeshow test indicated that the predicted probability had good consistency with the actual probability both in the training group (P = 0.817) and validation group (P = 0.290). The DCA curve shows that the nomogram has good clinical value. CONCLUSION: A nomogram for predicting severe RSV-associated bronchiolitis in the early clinical stage was established and validated, which can help physicians identify severe RSV-associated bronchiolitis and then choose reasonable treatment.
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Bronquiolitis , Nacimiento Prematuro , Infecciones por Virus Sincitial Respiratorio , Virus Sincitial Respiratorio Humano , Lactante , Niño , Femenino , Humanos , Recién Nacido , Preescolar , Nomogramas , Infecciones por Virus Sincitial Respiratorio/complicaciones , Infecciones por Virus Sincitial Respiratorio/diagnóstico , Bronquiolitis/diagnóstico , Estudios RetrospectivosRESUMEN
Parathyroid hormone (PTH) and PTH-related peptide (PTHrP) are two endogenous hormones recognized by PTH receptor-1 (PTH1R), a member of class B G protein- coupled receptors (GPCRs). Both PTH and PTHrP analogs including teriparatide and abaloparatide are approved drugs for osteoporosis, but they exhibit distinct pharmacology. Here we report two cryo-EM structures of human PTH1R bound to PTH and PTHrP in the G protein-bound state at resolutions of 2.62 Å and 3.25 Å, respectively. Detailed analysis of these structures uncovers both common and unique features for the agonism of PTH and PTHrP. Molecular dynamics (MD) simulation together with site-directed mutagenesis studies reveal the molecular basis of endogenous hormones recognition specificity and selectivity to PTH1R. These results provide a rational template for the clinical use of PTH and PTHrP analogs as an anabolic therapy for osteoporosis and other disorders.
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Osteoporosis , Proteína Relacionada con la Hormona Paratiroidea , Humanos , Proteína Relacionada con la Hormona Paratiroidea/metabolismo , Proteína Relacionada con la Hormona Paratiroidea/farmacología , Secuencia de Aminoácidos , Hormona Paratiroidea/química , Hormona Paratiroidea/metabolismo , Receptores Acoplados a Proteínas G , Osteoporosis/tratamiento farmacológicoRESUMEN
PURPOSES: To explore the relationship between frailty and community-acquired pneumonia (CAP) in older patients. METHODS: A prospective observational study included 109 older patients(≥ 65 years) hospitalized with CAP in respiratory department of Fuxing hospital, Capital Medical University from June 2018 to December 2020. Frailty scores(Frail Scale, range 0-5) and pneumonia severity CURB-65 scale(mild = 1, modest = 2, and severe ≥ 3) were measured. We extracted clinical variables including white blood cell(WBC), neutrophil-to-lymphocyte ratio (NLR), C-reactive protein(CRP), hemoglobin, and albumin. Charlson Comorbidity Index(CCI) was calculated as well. The correlations between the variables and frailty scores were investigated, respectively. After adjusting for covariates, binomial logistic regression analysis was used to assess independent effect of frailty scores on the outcome(discharge or death/progression) in older CAP patients. RESULTS: The subjects had a median age 87(interquartile range,8.5) years, 60.6% male, 45.9% pre-frail, and 32.1% frail. There were positive correlations between frailty scores and CURB-65 scale (p = 0.000, r = 0.542), CCI(p = 0.000, r = 0.359) and NLR(p = 0.005, r = 0.268). Negative correlations were observed between frailty scores and hemoglobin (p = 0.002, r = - 0.298), albumin (p = 0.000, r = - 0.465). In multivariable logistic regression analysis, the factors associated with discharge or death/progression of CAP were frailty scores (OR = 1.623, p = 0.037), NLR (OR = 1.086, p = 0.008) and albumin (OR = 0.869, p = 0.034). CONCLUSIONS: Frailty is correlated with CURB-65 scale, CCI and hemoglobin, and albumin in older patients with CAP. Frailty is also a correlate of increased risk for death or progression in these older people.
Asunto(s)
Infecciones Comunitarias Adquiridas , Fragilidad , Neumonía , Humanos , Masculino , Anciano , Femenino , Fragilidad/diagnóstico , Linfocitos , Neutrófilos , AlbúminasRESUMEN
Objective: To assess the effectiveness and benefits of retrospective outcome special attention nursing in providing continuous care for patients with heart failure during a vulnerable period. Methods: 96 patients with heart failure discharged from the hospital between January 2021 and January 2022 were included in the study. Patients discharged from January 2021 to June 2021 (48 cases) formed the single group, while those from July 2021 to January 2022 (48 cases) constituted the combined group. The single group received standard continuous nursing, while the combined group underwent retrospective outcome special attention nursing intervention in addition to standard care. Following the interventions, cardiac function-related indicators, negative emotions, self-management ability, health behavior, quality of life, and readmission rates were compared between the two groups. Results: Following the intervention, the combined group exhibited significant improvements, including enhanced 6-minute walk test (6MWT) results (P < .05) and lower scores on the Hamilton Anxiety Rating Scale (HAMA) and Hamilton Depression Rating Scale (HAMD) (P < .05), indicating reduced anxiety and depression levels. The combined group also demonstrated superior self-management abilities, with higher scores in health behavior dimensions (nutrition, exercise, health responsibility, stress coping) and a higher overall self-management score (P < .05). However, the combined group had lower quality of life scores (P < .05). Notably, the combined group's readmission rate was significantly lower at 14.58% (7/48), compared to 33.33% (16/48) in the single group (P < .05). Conclusion: Retrospective outcome special attention nursing improves cardiac function, emotional regulation, self-management, health behaviors, quality of life, and reduces readmission rates in heart failure patients during vulnerable periods.