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Autophagic degradation of the endoplasmic reticulum (ER-phagy) is triggered by ER stress in diverse organisms. However, molecular mechanisms governing ER stress-induced ER-phagy remain insufficiently understood. Here we report that ER stress-induced ER-phagy in the fission yeast Schizosaccharomyces pombe requires Epr1, a soluble Atg8-interacting ER-phagy receptor. Epr1 localizes to the ER through interacting with integral ER membrane proteins VAPs. Bridging an Atg8-VAP association is the main ER-phagy role of Epr1, as it can be bypassed by an artificial Atg8-VAP tether. VAPs contribute to ER-phagy not only by tethering Atg8 to the ER membrane, but also by maintaining the ER-plasma membrane contact. Epr1 is upregulated during ER stress by the unfolded protein response (UPR) regulator Ire1. Loss of Epr1 reduces survival against ER stress. Conversely, increasing Epr1 expression suppresses the ER-phagy defect and ER stress sensitivity of cells lacking Ire1. Our findings expand and deepen the molecular understanding of ER-phagy.
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Estrés del Retículo Endoplásmico/genética , Endorribonucleasas/genética , Proteínas R-SNARE/genética , Autofagosomas/metabolismo , Autofagia/genética , Familia de las Proteínas 8 Relacionadas con la Autofagia/genética , Retículo Endoplásmico/genética , Regulación Fúngica de la Expresión Génica/genética , Proteolisis , Schizosaccharomyces/genética , Proteínas de Schizosaccharomyces pombe/genética , Respuesta de Proteína Desplegada/genéticaRESUMEN
In selective autophagy, cargo selectivity is determined by autophagy receptors. However, it remains scarcely understood how autophagy receptors recognize specific protein cargos. In the fission yeast Schizosaccharomyces pombe, a selective autophagy pathway termed Nbr1-mediated vacuolar targeting (NVT) employs Nbr1, an autophagy receptor conserved across eukaryotes including humans, to target cytosolic hydrolases into the vacuole. Here, we identify two new NVT cargos, the mannosidase Ams1 and the aminopeptidase Ape4, that bind competitively to the first ZZ domain of Nbr1 (Nbr1-ZZ1). High-resolution cryo-EM analyses reveal how a single ZZ domain recognizes two distinct protein cargos. Nbr1-ZZ1 not only recognizes the N-termini of cargos via a conserved acidic pocket, similar to other characterized ZZ domains, but also engages additional parts of cargos in a cargo-specific manner. Our findings unveil a single-domain bispecific mechanism of autophagy cargo recognition, elucidate its underlying structural basis, and expand the understanding of ZZ domain-mediated protein-protein interactions.
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Péptidos y Proteínas de Señalización Intracelular/química , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas de Schizosaccharomyces pombe/química , Proteínas de Schizosaccharomyces pombe/metabolismo , Sitios de Unión , Microscopía por Crioelectrón , Péptidos y Proteínas de Señalización Intracelular/genética , Mutación , Dominios Proteicos , Schizosaccharomyces/metabolismo , Proteínas de Schizosaccharomyces pombe/genéticaRESUMEN
Tripartite motif (TRIM) proteins are involved in different cellular functions, including regulating virus infection. In teleosts, two orthologous genes of mammalian TRIM2 are identified. However, the functions and molecular mechanisms of piscine TRIM2 remain unclear. Here, we show that trim2b-knockout zebrafish are more susceptible to spring viremia of carp virus (SVCV) infection than wild-type zebrafish. Transcriptomic analysis demonstrates that NOD-like receptor (NLR), but not RIG-I-like receptor (RLR), signaling pathway is significantly enriched in the trim2b-knockout zebrafish. In vitro, overexpression of Trim2b fails to degrade RLRs and those key proteins involved in the RLR signaling pathway but does for negative regulators NLRP12-like proteins. Zebrafish Trim2b degrades NLRP12-like proteins through its NHL_TRIM2_like and IG_FLMN domains in a ubiquitin-proteasome degradation pathway. SVCV-N and SVCV-G proteins are also degraded by NHL_TRIM2_like domains, and the degradation pathway is an autophagy lysosomal pathway. Moreover, zebrafish Trim2b can interfere with the binding between NLRP12-like protein and SVCV viral RNA and can completely block the negative regulation of NLRP12-like protein on SVCV infection. Taken together, our data demonstrate that the mechanism of action of zebrafish trim2b against SVCV infection is through targeting the degradation of host-negative regulators NLRP12-like receptors and viral SVCV-N/SVCV-G genes.IMPORTANCESpring viremia of carp virus (SVCV) is a lethal freshwater pathogen that causes high mortality in cyprinid fish. In the present study, we identified zebrafish trim2b, NLRP12-L1, and NLRP12-L2 as potential pattern recognition receptors (PRRs) for sensing and binding viral RNA. Zebrafish trim2b functions as a positive regulator; however, NLRP12-L1 and NLRP12-L2 function as negative regulators during SVCV infection. Furthermore, we find that zebrafish trim2b decreases host lethality in two manners. First, zebrafish Trim2b promotes protein degradations of negative regulators NLRP12-L1 and NLRP12-L2 by enhancing K48-linked ubiquitination and decreasing K63-linked ubiquitination. Second, zebrafish trim2b targets viral RNAs for degradation. Therefore, this study reveals a special antiviral mechanism in lower vertebrates.
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Carpas , Proteolisis , Receptores de Reconocimiento de Patrones , Rhabdoviridae , Proteínas de Motivos Tripartitos , Proteínas Virales , Proteínas de Pez Cebra , Pez Cebra , Animales , Carpas/virología , Proteína 58 DEAD Box/metabolismo , Enfermedades de los Peces/virología , Enfermedades de los Peces/metabolismo , Inmunidad Innata , Receptores de Reconocimiento de Patrones/metabolismo , Rhabdoviridae/metabolismo , Infecciones por Rhabdoviridae/metabolismo , Infecciones por Rhabdoviridae/veterinaria , Infecciones por Rhabdoviridae/virología , Transducción de Señal , Proteínas de Motivos Tripartitos/deficiencia , Proteínas de Motivos Tripartitos/genética , Proteínas de Motivos Tripartitos/metabolismo , Ubiquitinación , Proteínas Virales/metabolismo , Viremia/veterinaria , Viremia/virología , Pez Cebra/genética , Pez Cebra/metabolismo , Pez Cebra/virología , Proteínas de Pez Cebra/deficiencia , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismoRESUMEN
BACKGROUND AIMS: Biliary Atresia (BA) is a devastating fibro-inflammatory biliary disease that is the leading indication for pediatric liver transplants worldwide. Although cholangiocytes are the primary target cells, the pathogenic mechanisms involving cholangiocytes remain elusive. Here, we aimed to characterize the pathogenic role of cholangiocytes in BA. APPROACH RESULTS: Integration of single-cell RNA sequencing of 12 liver tissues (from 9 BA and 3 controls) and the spatial transcriptome of another four liver sections (from 2 BA and 2 controls) provided a comprehensive spatial liver cell atlas of BA. In particular, we identified a cholangiocyte-enriched spatial niche with infiltration of activated hepatic stellate cells, activated portal fibroblasts, macrovascular endothelial cells and TREM2+ macrophages that were elevated in the portal triad of BA. This niche was positively correlated with bile duct profiles, liver fibrosis and poor survival in two independent cohorts of patients with BA. Using integrative bioinformatics analyses to mine the cell-cell communication and regulatory network in BA cholangiocytes, we uncovered the fibro-inflammatory phenotype of cholangiocytes with TNFSF12-TNFRSF12A as a significant signal. Genetic ablation or blockade of TNFRSF12A suppresses liver injury, inflammation, and bile duct profiles in a mouse model of disease. Using human biliary organoids, we revealed that BA organoids expressed higher levels of CCL2 in response to TNFSF12 stimulation and promoted monocyte chemotaxis via the CCL2-CCR2 axis. CONCLUSIONS: Pathogenic cholangiocytes enriched niche identifies TNFRSF12A as a potential therapeutic target for BA.
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The homeostatic link between oxidative stress and autophagy plays an important role in cellular responses to a wide variety of physiological and pathological conditions. However, the regulatory pathway and outcomes remain incompletely understood. Here, we show that reactive oxygen species (ROS) function as signaling molecules that regulate autophagy through ataxia-telangiectasia mutated (ATM) and cell cycle checkpoint kinase 2 (CHK2), a DNA damage response (DDR) pathway activated during metabolic and hypoxic stress. We report that CHK2 binds to and phosphorylates Beclin 1 at Ser90/Ser93, thereby impairing Beclin 1-Bcl-2 autophagy-regulatory complex formation in a ROS-dependent fashion. We further demonstrate that CHK2-mediated autophagy has an unexpected role in reducing ROS levels via the removal of damaged mitochondria, which is required for cell survival under stress conditions. Finally, CHK2-/- mice display aggravated infarct phenotypes and reduced Beclin 1 p-Ser90/Ser93 in a cerebral stroke model, suggesting an in vivo role of CHK2-induced autophagy in cell survival. Taken together, these results indicate that the ROS-ATM-CHK2-Beclin 1-autophagy axis serves as a physiological adaptation pathway that protects cells exposed to pathological conditions from stress-induced tissue damage.
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Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Beclina-1/metabolismo , Quinasa de Punto de Control 2/metabolismo , Accidente Cerebrovascular Isquémico/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Animales , Autofagia , Línea Celular , Modelos Animales de Enfermedad , Células HCT116 , Células HEK293 , Células HeLa , Humanos , Ratones , Estrés Oxidativo , FosforilaciónRESUMEN
CAPZA2 encodes the α2 subunit of CAPZA, which is vital for actin polymerization and depolymerization in humans. However, understanding of diseases associated with CAPZA2 remains limited. To date, only three cases have been documented with neurodevelopmental abnormalities such as delayed motor development, speech delay, intellectual disability, hypotonia, and a history of seizures. In this study, we document a patient who exhibited seizures, mild intellectual disability, and impaired motor development yet did not demonstrate speech delay or hypotonia. The patient also suffered from recurrent instances of respiratory infections, gastrointestinal and allergic diseases. A novel de novo splicing variant c.219+1 G > A was detected in the CAPZA2 gene through whole-exome sequencing. This variant led to exon 4 skipping in mRNA splicing, confirmed by RT-PCR and Sanger sequencing. To our knowledge, this is the third study on human CAPZA2 defects, documenting the fourth unambiguously diagnosed case. Furthermore, this splicing mutation type is reported here for the first time. Our research offers additional support for the existence of a CAPZA2-related non-syndromic neurodevelopmental disorder. Our findings augment our understanding of the phenotypic range associated with CAPZA2 deficiency and enrich the knowledge of the mutational spectrum of the CAPZA2 gene.
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Proteína CapZ , Discapacidades del Desarrollo , Epilepsia , Heterocigoto , Hipotonía Muscular , Mutación , Preescolar , Femenino , Humanos , Masculino , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/patología , Epilepsia/genética , Secuenciación del Exoma , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Hipotonía Muscular/genética , Hipotonía Muscular/patología , Fenotipo , Empalme del ARN/genética , Proteína CapZ/genéticaRESUMEN
Hepatocellular carcinoma (HCC) is a malignant tumor that occurs in the liver, with a high degree of malignancy and relatively poor prognosis. Gypenoside L has inhibitory effects on liver cancer cells. However, its mechanism of action is still unclear. This study aims to investigate the inhibitory effects of gypenoside L on HCC in vitro and in vivo, and explore its potential mechanisms. The results showed that gypenoside L reduced the cholesterol and triglyceride content in HepG2 and Huh-7 cells, inhibited cell proliferation, invasion and metastasis, arrested cell cycle at G0/G1 phase, promoted cell apoptosis. Mechanistically, it targeted the transcription factor SREPB2 to inhibit the expression of HMGCS1 protein and inhibited the downstream proteins HMGCR and MVK, thereby regulating the mevalonate (MVA) pathway. Overexpression HMGCS1 led to significant alterations in the cholesterol metabolism pathway of HCC, which mediated HCC cell proliferation and conferred resistance to the therapeutic effect of gypenoside L. In vivo, gypenoside L effectively suppressed HCC growth in tumor-bearing mice by reducing cholesterol production, exhibiting favorable safety profiles and minimal toxic side effects. Gypenoside L modulated cholesterol homeostasis, enhanced expression of inflammatory factors by regulating MHC I pathway-related proteins to augment anticancer immune responses. Clinical samples from HCC patients also exhibited high expression levels of MVA pathway-related genes in tumor tissues. These findings highlight gypenoside L as a promising agent for targeting cholesterol metabolism in HCC while emphasizing the effectiveness of regulating the SREBP2-HMGCS1 axis as a therapeutic strategy.
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Carcinoma Hepatocelular , Proliferación Celular , Gynostemma , Neoplasias Hepáticas , Proteína 2 de Unión a Elementos Reguladores de Esteroles , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/metabolismo , Gynostemma/química , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Proteína 2 de Unión a Elementos Reguladores de Esteroles/metabolismo , Proteína 2 de Unión a Elementos Reguladores de Esteroles/antagonistas & inhibidores , Proliferación Celular/efectos de los fármacos , Animales , Ratones , Relación Dosis-Respuesta a Droga , Estructura Molecular , Ensayos de Selección de Medicamentos Antitumorales , Apoptosis/efectos de los fármacos , Relación Estructura-Actividad , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/química , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias Hepáticas Experimentales/tratamiento farmacológico , Neoplasias Hepáticas Experimentales/patología , Neoplasias Hepáticas Experimentales/metabolismo , Extractos VegetalesRESUMEN
Background: The single nucleotide polymorphism (SNP) of Gastrokine-1 (GKN1) is associated with lung cancer but its association with prognosis is not clear. Methods: Genomic DNA was extracted from the blood samples of 888 patients with lung cancer. The association between GKN1 polymorphism rs4254535 and prognostic was analyzed by the Kaplan-Meier (KM) method, Log-rank test, and Cox proportional hazards model. Results: In females and patients diagnosed with late-stage lung cancer, the CC genotype (CC vs TT, adjusted odds ratio [HR] = 0.57, 95% Confidence Interval [CI]: 0.33-0.99, P = 0.045; HR = 0.66, 95% CI: 0.48-0.92, P = 0.014) and recessive CC genotype (CC vs TT + TC, HR = 0.55, 95% CI: 0.32-0.94, P = 0.028; HR = 0.64, 95% CI: 0.47-0.89, P = 0.006) of rs4254535 conferred a better prognosis, compared with the TT and TT + TC genotype. Rs4254535 dominate TC + CC genotype, recessive CC genotype, and C allele who were adenocarcinoma patients had a significantly better prognosis. The recessive CC genotype of non-smoking patients has a better prognosis, compared to the TT + TC genotype. Additionally, in the dominant TT + TC genotype and C allele, no family history patients had a significantly better prognosis, compared to the TT genotype. Conclusion: For lung cancer patients, GKN1 polymorphism rs4254535 may be a protective genetic marker and predicts the prognosis of lung cancer patients.
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Neoplasias Pulmonares , Hormonas Peptídicas , Femenino , Humanos , Pronóstico , Neoplasias Pulmonares/genética , Genotipo , Polimorfismo de Nucleótido Simple/genética , ChinaRESUMEN
BACKGROUND: This cross-sectional study aims to explore whether there exists an interaction between selenium and menopause concerning type 2 diabetes (T2D) prevalence and its related indicators such as fasting blood glucose (FBG) and homeostasis model assessment of insulin resistance (HOMA-IR). METHODS: 150 women aged 35-60 years old were finally analyzed in this study. Multivariate linear or logistic regression modeling was conducted to explore the association of selenium and the prevalence of T2D besides its related indicators. Subgroup analyses were conducted based on menopause status to assess the potential impact on the relationship. RESULTS: In the fully adjusted model, serum selenium was positively associated with FBG (ß: 0.03, CI: 0.01-0.05) and the prevalence of T2D (OR: 1.04, CI: 1.00-1.08). After stratifying the data by menopause status, compared with the postmenopausal women group, as the serum selenium concentrations increased, the FBG concentrations were significantly higher in the premenopausal women group (p for interaction = 0.0020). CONCLUSIONS: The present study found serum selenium was positively associated with FBG and the prevalence of T2D. Furthermore, the relationship between serum selenium and FBG was different in the premenopausal and postmenopausal women. More studies are still needed in the future to verify the relationship as well as to explore the specific mechanisms.
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Glucemia , Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Menopausia , Selenio , Humanos , Femenino , Selenio/sangre , Estudios Transversales , Persona de Mediana Edad , Glucemia/análisis , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/epidemiología , Adulto , Menopausia/sangre , Resistencia a la Insulina/fisiología , Ayuno/sangre , Prevalencia , Posmenopausia/sangre , Premenopausia/sangreRESUMEN
BACKGROUND: The association between dietary selenium(Se) intake and type 2 diabetes mellitus (T2DM) remains controversial. The present study aimed to investigate this association using data from the National Health and Nutrition Examination Survey (NHANES) database for the years 2007-2012. METHODS: Three thousand seventy three individuals aged 20 years and above were eligible for inclusion in this cross-sectional study. The average age of the participants was 50.74 years and the proportions of males and females were nearly equal (49.12% vs. 50.88%). The odds ratios (OR) of the association between dietary Se intake (log2-transformed) and T2DM were examined through the multivariate logistic regression model. Subgroup analyses were conducted based on age, sex, and thyroid autoimmunity to assess the potential impact of these variables on the relationship. Fitted smoothing curves and threshold effect analysis were conducted to describe the nonlinear relationship. RESULTS: In the fully adjusted model, a significant positive association between Se intake and T2DM was observed (OR = 1.49, 95% CI: 1.16, 1.90, p = 0.0017). After stratifying the data by age, sex, and thyroid autoimmunity, a significant positive association between Se intake and T2DM was observed in individuals under 65 years of age, males, and those with negative thyroid autoimmunity. A two-segment linear regression model was analyzed for sex stratification, revealing a threshold effect in males with an inflection point of 90.51 µg, and an inverted U-shaped relationship in females with an inflection point of 109.90 µg, respectively. CONCLUSIONS: The present study found a positive relationship between Se intake and the prevalence of T2DM. This association is particularly significant in younger individuals, males, and those with negative thyroid autoimmunity. Our results should be validated in future large prospective studies in different populations.
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Diabetes Mellitus Tipo 2 , Selenio , Masculino , Femenino , Humanos , Persona de Mediana Edad , Preescolar , Diabetes Mellitus Tipo 2/epidemiología , Glándula Tiroides , Encuestas Nutricionales , Autoinmunidad , Estudios Prospectivos , Estudios TransversalesRESUMEN
Selfish, non-long terminal repeat (non-LTR) retroelements and mobile group II introns encode reverse transcriptases (RTs) that can initiate DNA synthesis without substantial base pairing of primer and template. Biochemical characterization of these enzymes has been limited by recombinant expression challenges, hampering understanding of their properties and the possible exploitation of their properties for research and biotechnology. We investigated the activities of representative RTs using a modified non-LTR RT from Bombyx mori and a group II intron RT from Eubacterium rectale Only the non-LTR RT supported robust and serial template jumping, producing one complementary DNA (cDNA) from several templates each copied end to end. We also discovered an unexpected terminal deoxynucleotidyl transferase activity of the RTs that adds nucleotide(s) of choice to 3' ends of single- and/or double-stranded RNA or DNA. Combining these two types of activity with additional insights about nontemplated nucleotide additions to duplexed cDNA product, we developed a streamlined protocol for fusion of next-generation sequencing adaptors to both cDNA ends in a single RT reaction. When benchmarked using a reference pool of microRNAs (miRNAs), library production by Ordered Two-Template Relay (OTTR) using recombinant non-LTR retroelement RT outperformed all commercially available kits and rivaled the low bias of technically demanding home-brew protocols. We applied OTTR to inventory RNAs purified from extracellular vesicles, identifying miRNAs as well as myriad other noncoding RNAs (ncRNAs) and ncRNA fragments. Our results establish the utility of OTTR for automation-friendly, low-bias, end-to-end RNA sequence inventories of complex ncRNA samples.
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ARN no Traducido/genética , ADN Polimerasa Dirigida por ARN/metabolismo , Retroelementos , Moldes GenéticosRESUMEN
In this study, infrared spectroscopy, high-performance liquid chromatography, and matrix-assisted laser desorption ionization-time-of-flight-mass spectrometry (MALDI-TOF-MS) technology were applied to systematically explain the Schisandra chinensis's polysaccharide transformation in configuration, molecular weight, monosaccharide composition, and anti-ulcerative colitis (UC) activity after vinegar processing. Scanning electron microscopic results showed that the appearance of S. chinensis polysaccharide changed significantly after steaming with vinegar. The MALDI-TOF-MS results showed that the mass spectra of raw S. chinensis polysaccharides (RSCP) were slightly lower than those of vinegar-processed S. chinensis polysaccharides (VSCP). The RSCP showed higher peaks at m/z 1350.790, 2016.796, and 2665.985, all with left-skewed distribution, and the molecular weights were concentrated in the range of 1300-3100, with no higher peak above m/z 5000. The VSCPs showed a whole band below m/z 3000, with m/z 1021.096 being the highest peak, and the intensity decreased with the increase of m/z. In addition, compared to RSCPs, VSCPs can significantly increase the content of intestinal short-chain fatty acids (SCFAs). This study showed that the apparent morphology and molecular weight of S. chinensis's polysaccharides significantly changed after steaming with vinegar. These changes directly affect its anti-UC effect significantly, and its mechanism is closely related to improving the structure and diversity of gut microbiota and SCFA metabolism.
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Colitis Ulcerosa , Medicamentos Herbarios Chinos , Schisandra , Ácido Acético , Schisandra/química , Medicamentos Herbarios Chinos/química , Polisacáridos/farmacologíaRESUMEN
Four isocoumarin derivatives (1-4) and five phenols (5-9) were obtained from the endophytic fungus Pezicula neosporulosa VDB39, which was isolated from the branches of Vaccinium dunalianum Wight (Ericaceae). Compound 1 is a new derivative of isocoumarin. The structures were elucidated by spectroscopic methods. Single X-ray crystallography confirmed the absolute configuration of compound 1. Additionally, the antiphytopathogenic fungi activity of isocoumarin derivatives (1-4) was evaluated.
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BACKGROUND: The clinical efficacy and safety of intravenous immunoglobulin (IVIg) treatment for COVID-19 remain controversial. This study aimed to map the current status and gaps of available evidence, and conduct a meta-analysis to further investigate the benefit of IVIg in COVID-19 patients. METHODS: Electronic databases were searched for systematic reviews/meta-analyses (SR/MAs), primary studies with control groups, reporting on the use of IVIg in patients with COVID-19. A random-effects meta-analysis with subgroup analyses regarding study design and patient disease severity was performed. Our outcomes of interest determined by the evidence mapping, were mortality, length of hospitalization (days), length of intensive care unit (ICU) stay (days), number of patients requiring mechanical ventilation, and adverse events. RESULTS: We included 34 studies (12 SR/MAs, 8 prospective and 14 retrospective studies). A total of 5571 hospitalized patients were involved in 22 primary studies. Random-effects meta-analyses of very low to moderate evidence showed that there was little or no difference between IVIg and standard care or placebo in reducing mortality (relative risk [RR] 0.91; 95% CI 0.78-1.06; risk difference [RD] 3.3% fewer), length of hospital (mean difference [MD] 0.37; 95% CI - 2.56, 3.31) and ICU (MD 0.36; 95% CI - 0.81, 1.53) stays, mechanical ventilation use (RR 0.92; 95% CI 0.68-1.24; RD 2.8% fewer), and adverse events (RR 0.98; 95% CI 0.84-1.14; RD 0.5% fewer) of patients with COVID-19. Sensitivity analysis using a fixed-effects model indicated that IVIg may reduce mortality (RR 0.76; 95% CI 0.60-0.97), and increase length of hospital stay (MD 0.68; 95% CI 0.09-1.28). CONCLUSION: Very low to moderate certainty of evidence indicated IVIg may not improve the clinical outcomes of hospitalized patients with COVID-19. Given the discrepancy between the random- and fixed-effects model results, further large-scale and well-designed RCTs are warranted.
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COVID-19 , Inmunoglobulinas Intravenosas , Humanos , Inmunoglobulinas Intravenosas/efectos adversos , Estudios Prospectivos , Estudios Retrospectivos , Revisiones Sistemáticas como AsuntoRESUMEN
OBJECTIVES: To explore the diagnostic efficacy of serum 14-3-3ß protein combined with fractional exhaled nitric oxide (FeNO) and conventional ventilatory lung function parameters in diagnosing bronchial asthma (referred to as "asthma") in children. METHODS: A prospective study included 136 children initially diagnosed with asthma during an acute episode as the asthma group, and 85 healthy children undergoing routine health checks as the control group. The study compared the differences in serum 14-3-3ß protein concentrations between the two groups, analyzed the correlation of serum 14-3-3ß protein with clinical indices, and evaluated the diagnostic efficacy of combining 14-3-3ß protein, FeNO, and conventional ventilatory lung function parameters for asthma in children. RESULTS: The concentration of serum 14-3-3ß protein was higher in the asthma group than in the control group (P<0.001). Serum 14-3-3ß protein showed a positive correlation with the percentage of neutrophils and total serum immunoglobulin E, and a negative correlation with conventional ventilatory lung function parameters (P<0.05). Cross-validation of combined indices showed that the combination of 14-3-3ß protein, FeNO, and the percentage of predicted value of forced expiratory flow at 75% of lung volume had an area under the curve of 0.948 for predicting asthma, with a sensitivity and specificity of 88.9% and 93.7%, respectively, demonstrating good diagnostic efficacy (P<0.001). The model had the best extrapolation. CONCLUSIONS: The combination of serum 14-3-3ß protein, FeNO, and the percentage of predicted value of forced expiratory flow at 75% of lung volume can significantly improve the diagnostic efficacy for asthma in children. Citation:Chinese Journal of Contemporary Pediatrics, 2024, 26(7): 723-729.
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Proteínas 14-3-3 , Asma , Óxido Nítrico , Humanos , Asma/diagnóstico , Asma/sangre , Asma/fisiopatología , Masculino , Femenino , Niño , Proteínas 14-3-3/sangre , Óxido Nítrico/análisis , Óxido Nítrico/sangre , Preescolar , Estudios Prospectivos , Pruebas de Función Respiratoria , Prueba de Óxido Nítrico Exhalado Fraccionado , Adolescente , Pruebas RespiratoriasRESUMEN
Post-stroke depression, a common complication after stroke, severely affects the recovery and quality of life of patients with stroke. Owing to its complex mechanisms, post-stroke depression treatment remains highly challenging. Hippocampal synaptic plasticity is one of the key factors leading to post-stroke depression; however, the precise molecular mechanisms remain unclear. Numerous studies have found that neurotrophic factors, protein kinases and neurotransmitters influence depressive behaviour by modulating hippocampal synaptic plasticity. This review further elaborates on the role of hippocampal synaptic plasticity in post-stroke depression by summarizing recent research and analysing possible molecular mechanisms. Evidence for the correlation between hippocampal mechanisms and post-stroke depression helps to better understand the pathological process of post-stroke depression and improve its treatment.
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Depresión , Calidad de Vida , Humanos , Depresión/etiología , Plasticidad Neuronal/fisiología , Hipocampo/metabolismo , Factores de Crecimiento Nervioso/metabolismoRESUMEN
Data on the distribution of voriconazole (VRC) in the human peritoneal cavity are sparse. This prospective study aimed to describe the pharmacokinetics of intravenous VRC in the peritoneal fluid of critically ill patients. A total of 19 patients were included. Individual pharmacokinetic curves, drawn after single (first dose on day 1) and multiple (steady-state) doses, displayed a slower rise and lower fluctuation of VRC concentrations in peritoneal fluid than in plasma. Good but variable penetration of VRC into the peritoneal cavity was observed, and the median (range) peritoneal fluid/plasma ratios of the area under the concentration-time curve (AUC) were 0.54 (0.34 to 0.73) and 0.67 (0.63 to 0.94) for single and multiple doses, respectively. Approximately 81% (13/16) of the VRC steady-state trough concentrations (Cmin,ss) in plasma were within the therapeutic range (1 to 5.5 µg/mL), and the corresponding Cmin,ss (median [range]) in peritoneal fluid was 2.12 (1.39 to 3.72) µg/mL. Based on the recent 3-year (2019 to 2021) surveillance of the antifungal susceptibilities for Candida species isolated from peritoneal fluid in our center, the aforementioned 13 Cmin,ss in peritoneal fluid exceeded the MIC90 of C. albicans, C. glabrata, and C. parapsilosis (0.06, 1.00, and 0.25 µg/mL, respectively), which supported VRC as a reasonable choice for initial empirical therapies against intraabdominal candidiasis caused by these three Candida species, prior to the receipt of susceptibility testing results.
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Líquido Ascítico , Enfermedad Crítica , Humanos , Voriconazol/farmacocinética , Estudios Prospectivos , Antifúngicos/farmacocinética , Candida glabrata , Pruebas de Sensibilidad MicrobianaRESUMEN
Protein-protein interactions are vital for executing nearly all cellular processes. To facilitate the detection of protein-protein interactions in living cells of the fission yeast Schizosaccharomyces pombe, here we present an efficient and convenient method termed the Pil1 co-tethering assay. In its basic form, we tether a bait protein to mCherry-tagged Pil1, which forms cortical filamentary structures, and examine whether a GFP-tagged prey protein colocalizes with the bait. We demonstrate that this assay is capable of detecting pairwise protein-protein interactions of cytosolic proteins and nuclear proteins. Furthermore, we show that this assay can be used for detecting not only binary protein-protein interactions, but also ternary and quaternary protein-protein interactions. Using this assay, we systematically characterized the protein-protein interactions in the Atg1 complex and in the phosphatidylinositol 3-kinase (PtdIns3K) complexes and found that Atg38 is incorporated into the PtdIns3K complex I via an Atg38-Vps34 interaction. Our data show that this assay is a useful and versatile tool and should be added to the routine toolbox of fission yeast researchers. This article has an associated First Person interview with the first author of the paper.
Asunto(s)
Proteínas de Schizosaccharomyces pombe , Schizosaccharomyces , Citoesqueleto , Humanos , Proteínas Nucleares , Schizosaccharomyces/genética , Proteínas de Schizosaccharomyces pombe/genéticaRESUMEN
The inter-relationships between cellular phosphorus (P) storage, dissolved inorganic P (DIP) uptake affinity, alkaline phosphatase activity (APA) and dissolved inorganic nitrogen (DIN) concentrations were studied in two ubiquitous diazotrophic freshwater cyanobacteria, Raphidiopsis raciborskii (six strains) and Chrysosporum ovalisporum (two strains). DIP uptake kinetics were measured using rates of incorporation of the radio-isotope, 33P and APA as a proxy for DOP-ester utilization. The study showed that DIP uptake of individual strains followed Michaelis-Menten kinetics (modified in our study to incorporate cellular P quotas), but differed with DIN and P availability, and between growth stages. High-affinity DIP uptake and APA were activated below a P quota threshold of approximately 0.01 µg P µg-1 C across the species and strains. C. ovalisporum had significantly higher APA and P quotas (per unit C and cell) but lower uptake affinity than R. raciborskii. Demand for DIP by C. ovalisporum increased when N fixation occurred, but typically not for R. raciborskii. Our results indicate that cyanobacterial species and strains differ in their strategies to P limiting conditions, and highlight the interplay between N and P. Physiological adaptations like APA and diazotrophy of cyanobacteria adapting to low DIP and/or DIN conditions may occur simultaneously and drive species dominance in oligotrophic environments.
Asunto(s)
Cianobacterias , Fósforo , Agua Dulce , Cinética , Fijación del NitrógenoRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.