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1.
FASEB J ; 38(5): e23501, 2024 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-38411462

RESUMEN

In the adult mammalian brain, new neurons are continuously generated from neural stem cells (NSCs) in the subventricular zone (SVZ)-olfactory bulb (OB) pathway. YAP, a transcriptional co-activator of the Hippo pathway, promotes cell proliferation and inhibits differentiation in embryonic neural progenitors. However, the role of YAP in postnatal NSCs remains unclear. Here, we showed that YAP was present in NSCs of the postnatal mouse SVZ. Forced expression of Yap promoted NSC maintenance and inhibited differentiation, whereas depletion of Yap by RNA interference or conditional knockout led to the decline of NSC maintenance, premature neuronal differentiation, and collapse of neurogenesis. For the molecular mechanism, thyroid hormone receptor-interacting protein 6 (TRIP6) recruited protein phosphatase PP1A to dephosphorylate LATS1/2, therefore inducing YAP nuclear localization and activation. Moreover, TRIP6 promoted NSC maintenance, cell proliferation, and inhibited differentiation through YAP. In addition, YAP regulated the expression of the Sonic Hedgehog (SHH) pathway effector Gli2 and Gli1/2 mediated the effect of YAP on NSC maintenance. Together, our findings demonstrate a novel TRIP6-YAP-SHH axis, which is critical for regulating postnatal neurogenesis in the SVZ-OB pathway.


Asunto(s)
Proteínas Hedgehog , Células-Madre Neurales , Animales , Ratones , Neuronas , Neurogénesis , Encéfalo , Mamíferos
2.
NMR Biomed ; : e5260, 2024 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-39254055

RESUMEN

Isoflurane is one of the most widely used anesthetic agents in rodent imaging studies. However, the impact of isoflurane on brain metabolism has not been fully characterized to date, primarily due to a scarcity of noninvasive technologies to quantitatively measure the brain's metabolic rate in vivo. In this study, using noncontrast MRI techniques, we dynamically measured cerebral metabolic rate of oxygen (CMRO2) under varying doses of isoflurane anesthesia in mice. Concurrently, systemic parameters of heart and respiration rates were recorded alongside CMRO2. Additionally, electroencephalogram (EEG) recording was used to identify changes in neuronal activities under the same anesthetic regimen employed in the MRI experiments. We found suppression of the CMRO2 by isoflurane in a dose-dependent manner, concomitant with a diminished high-frequency EEG activity. The degree of metabolic suppression by isoflurane was strongly correlated with the respiration rate, which offers a potential approach to calibrate CMRO2 measurements. Furthermore, the metabolic level associated with neural responses of the somatosensory and motor cortices in mice was estimated as 308.2 µmol/100 g/min. These findings may facilitate the integration of metabolic parameters into future studies involving animal disease models and anesthesia usage.

3.
BMC Cancer ; 24(1): 654, 2024 May 29.
Artículo en Inglés | MEDLINE | ID: mdl-38811891

RESUMEN

BACKGROUND: Immune checkpoint inhibitors (ICIs) have demonstrated superior clinical efficacy in prolonging overall survival (OS) as the second-line treatment for advanced or metastatic esophageal squamous cell carcinoma (ESCC), and were recommended by the guidelines. However, it remains uncertain which ICI is the most cost-effective. This study assessed the cost-effectiveness of ICIs as the second-line treatment for ESCC based on the perspective of the Chinese healthcare system. METHODS: A network meta-analysis (NMA) was performed to obtain the Hazard ratios (HRs) for indirect comparisons. A three-state Markov model with a 10-year time horizon was conducted to assess the cost-effectiveness. The state transition probabilities were calculated with Kaplan-Meier (KM) curves data from clinical trial and HRs from the NMA. Utilities and costs were derived from local charges or previously published studies. Univariate and probabilistic sensitivity analyses (PSA) were performed to examine model robustness. The results were assessed based on the total costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). RESULTS: Five clinical trials (ATTRACTION-3, ESCORT, KEYNOTE-181, ORIENT-2, RATIONALE-302) with a total of 1797 patients were included in the NMA. The NMA showed that both camrelizumab and tislelizumab received relatively high rankings for progression-free survival (PFS) and OS. Compared with sintilimab, treatment with tislelizumab and camrelizumab gained 0.018 and 0.034 additional QALYs, resulting in incremental ICERs of $75,472.65/QALY and $175,681.9/QALY, respectively. Nivolumab and pembrolizumab produced lower QALYs and greater costs, suggesting that both were dominated in comparison to sintilimab. HRs and health state utilities were the most influential parameters in most univariate sensitivity analyses of paired comparisons. PSA results suggested that sintilimab had an 84.4% chance of being the most cost-effective treatment regimen at the WTP threshold of $38,223.34/QALY. In the scenario analysis, sintilimab would no longer be cost-effective, if the price of camrelizumab was assumed to decrease by 64.6% or the price of tislelizumab was assumed to decrease by 16.9%. CONCLUSIONS AND RELEVANCE: Among the five potential competing ICIs, sintilimab was likely to be the most cost-effective regimen as the second-line treatment for locally advanced or metastatic ESCC in China.


Asunto(s)
Análisis Costo-Beneficio , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Inhibidores de Puntos de Control Inmunológico , Metaanálisis en Red , Años de Vida Ajustados por Calidad de Vida , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/economía , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/mortalidad , Carcinoma de Células Escamosas de Esófago/economía , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/economía , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/economía , Cadenas de Markov , Nivolumab/uso terapéutico , Nivolumab/economía , Análisis de Costo-Efectividad
4.
Ann Hematol ; 103(9): 3605-3613, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38907072

RESUMEN

Myelofibrosis is a rare and often fatal hematological neoplasm, and the treatment of myelofibrosis-associated anemia remains suboptimal, with no improved therapies. Luspatercept was shown to display some efficacy in a phase 2 clinical trial for Myelofibrosis with anemia, yet relevant research are limited. Threrfore, data from patients diagnosed with refractory anemic primary or post-essential thrombocythemia/polycythemia vera myelofibrosis, who were treated with luspatercept for at least 9 weeks, were retrospectively collected. Eighteen patients with myelofibrosis treated with luspatercept were enrolled. Median age was 68 years (range, 44-80 years), and 27.8% were males. Ten (55.6%) were transfusion-dependent. Ten (55.6%) were Dynamic International Prognostic Scoring System intermediate-1, and eight (44.4%) were intermediate-2. The median follow-up was 7 (4-16) months. Erythroid response occurred in eight patients (44.4%) at week 12, four patients (30.8%) at week 24, and nine (50%) at the end of follow-up. Patients who were transfusion-dependent and not transfusion-dependent had similar HI-E responses, at different time points (P > 0.05). Patients had a significantly higher hemoglobin level at 12 weeks, 24 weeks, and at the end of follow-up, than at baseline (P = 0.001, P = 0.021, and P = 0.005, respectively). Treatment-related adverse events occurred in five (16.7%) patients, with no serious adverse events. Two (11.1%) patients relapsed at weeks 15 and 31. One patient progressed to acute myeloid leukemia. No patients had died by the end of follow-up. Luspatercept induced a good response in patients with anemic myelofibrosis, with a low relapse rate and good tolerance.


Asunto(s)
Mielofibrosis Primaria , Proteínas Recombinantes de Fusión , Humanos , Masculino , Mielofibrosis Primaria/tratamiento farmacológico , Mielofibrosis Primaria/complicaciones , Femenino , Persona de Mediana Edad , Anciano , Adulto , Anciano de 80 o más Años , Estudios Retrospectivos , Proteínas Recombinantes de Fusión/uso terapéutico , Proteínas Recombinantes de Fusión/efectos adversos , China , Anemia Refractaria/tratamiento farmacológico , Receptores de Activinas Tipo II/uso terapéutico , Fragmentos Fc de Inmunoglobulinas/uso terapéutico , Resultado del Tratamiento , Estudios de Seguimiento , Anemia/tratamiento farmacológico , Anemia/etiología
5.
Anesthesiology ; 141(1): 44-55, 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38625679

RESUMEN

BACKGROUND: During one-lung ventilation (OLV), positive end-expiratory pressure (PEEP) can improve lung aeration but might overdistend lung units and increase intrapulmonary shunt. The authors hypothesized that higher PEEP shifts pulmonary perfusion from the ventilated to the nonventilated lung, resulting in a U-shaped relationship with intrapulmonary shunt during OLV. METHODS: In nine anesthetized female pigs, a thoracotomy was performed and intravenous lipopolysaccharide infused to mimic the inflammatory response of thoracic surgery. Animals underwent OLV in supine position with PEEP of 0 cm H2O, 5 cm H2O, titrated to best respiratory system compliance, and 15 cm H2O (PEEP0, PEEP5, PEEPtitr, and PEEP15, respectively, 45 min each, Latin square sequence). Respiratory, hemodynamic, and gas exchange variables were measured. The distributions of perfusion and ventilation were determined by IV fluorescent microspheres and computed tomography, respectively. RESULTS: Compared to two-lung ventilation, the driving pressure increased with OLV, irrespective of the PEEP level. During OLV, cardiac output was lower at PEEP15 (5.5 ± 1.5 l/min) than PEEP0 (7.6 ± 3 l/min) and PEEP5 (7.4 ± 2.9 l/min; P = 0.004), while the intrapulmonary shunt was highest at PEEP0 (PEEP0: 48.1% ± 14.4%; PEEP5: 42.4% ± 14.8%; PEEPtitr: 37.8% ± 11.0%; PEEP15: 39.0% ± 10.7%; P = 0.027). The relative perfusion of the ventilated lung did not differ among PEEP levels (PEEP0: 65.0% ± 10.6%; PEEP5: 68.7% ± 8.7%; PEEPtitr: 68.2% ± 10.5%; PEEP15: 58.4% ± 12.8%; P = 0.096), but the centers of relative perfusion and ventilation in the ventilated lung shifted from ventral to dorsal and from cranial to caudal zones with increasing PEEP. CONCLUSIONS: In this experimental model of thoracic surgery, higher PEEP during OLV did not shift the perfusion from the ventilated to the nonventilated lung, thus not increasing intrapulmonary shunt.


Asunto(s)
Estudios Cruzados , Ventilación Unipulmonar , Respiración con Presión Positiva , Animales , Respiración con Presión Positiva/métodos , Porcinos , Femenino , Ventilación Unipulmonar/métodos , Intercambio Gaseoso Pulmonar/fisiología , Pulmón/fisiología , Circulación Pulmonar/fisiología , Distribución Aleatoria , Hemodinámica/fisiología
6.
Inorg Chem ; 63(22): 10397-10402, 2024 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-38767325

RESUMEN

A micron-sized long-afterglow material, Sr2MgSi2O7:Eu,Ce, was utilized to conduct the hydrogen evolution reaction and oxygen evolution reaction, two half-reactions of water splitting, in the presence of sacrificial agents under both light and dark conditions for the first time. The as-synthesized Sr2MgSi2O7:Eu,Ce exhibited higher photocatalytic activity compared to that of the referenced Sr2MgSi2O7:Eu and Sr2MgSi2O7:Ce samples. Herein, in addition to benefiting from the long photogenerated carrier lifetime of long-afterglow materials, the higher photocatalytic activity was attributed to the conjugated electronic structure between Eu and Ce ions. This structure facilitates charge and energy transfer between them, leading to an enhanced photocatalytic efficiency. This research provides a new strategy for designing efficient long-afterglow material photocatalysts through the construction of conjugated electronic structures.

7.
BMC Pregnancy Childbirth ; 24(1): 543, 2024 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-39148025

RESUMEN

BACKGROUND: Preeclampsia is a severe obstetric disorder that significantly affects the maternal and neonatal peri-partum safety and long-term quality of life. However, there is limited research exploring the common mechanisms and potential clinical significance between early-onset preeclampsia and full-term preeclampsia from an immunological perspective. METHODS: In this study, data analysis was conducted. Initially, immune-related co-expressed genes involving both subtypes of preeclampsia were identified through Weighted Gene Co-expression Network Analysis (WGCNA). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were further employed to investigate the shared pathways regulated by immune-related genes. Binary logistic regression identified co-expressed genes with diagnostic value for preeclampsia, and a diagnostic model was constructed. Gene Set Enrichment Analysis (GSEA) predicted the potential biological functions of the selected genes. Lasso and Cox regression analyses identified genes closely associated with gestational duration, and a risk score model was established. A 4-gene feature, immune-related gene model for predicting the risk of preterm birth in preeclamptic pregnant women, was developed and validated through qPCR experiments. Immune cell infiltration analysis determined differences in immune cell infiltration between the two subtypes of preeclampsia. RESULTS: This study identified 4 immune-related co-expressed genes (CXCR6, PIK3CB, IL1RAP, and OSMR). Additionally, diagnostic and preterm birth risk prediction models for preeclampsia were constructed based on these genes. GSEA analysis suggested the involvement of these genes in the regulation of galactose metabolism, notch signaling pathway, and RIG-I like receptor signaling pathway. Immune pathway analysis indicated that the activation of T cell co-inhibition could be a potential intervention target for immunotherapy in early-onset preeclampsia. CONCLUSION: Our study provides promising insights into immunotherapy and mechanistic research for preeclampsia, discovering novel diagnostic and intervention biomarkers, and offering personalized diagnostic tools for preeclampsia.


Asunto(s)
Preeclampsia , Nacimiento Prematuro , Adulto , Femenino , Humanos , Embarazo , Relevancia Clínica , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Preeclampsia/diagnóstico , Preeclampsia/genética , Preeclampsia/inmunología , Nacimiento Prematuro/genética , Nacimiento Prematuro/inmunología
8.
Molecules ; 29(16)2024 Aug 21.
Artículo en Inglés | MEDLINE | ID: mdl-39203020

RESUMEN

Licorice (Glycyrrhiza uralensis Fisch), a significant traditional Chinese herbal medicine, has been extensively utilized in China to treat various ailments. Natural bioactive coumarins, glycycoumarin, glycyrin, and 3-O-methylglycyrol, were isolated from licorice, and they exhibited various pharmacological properties. In this report, we have accomplished the total synthesis of glycycoumarin, glycyrin, and 3-O-methylglycyrol in 5-7 linear steps from commercially available 2,4,6-trihydroxybenzaldehyde with yields of 12.3-21.2%. Additionally, their anti-inflammatory activities were studied and compared. Glycycoumarin, glycyrin, and 3-O-methylglycyrol exhibited different levels of anti-inflammatory activities, with glycyrin being the most potent. Mechanistic studies indicated that glycyrin exerted its anti-inflammatory properties by inhibiting the activation of TNF-α, IL-6, and IL-1ß, making it a potential anti-inflammatory lead compound for further optimization and discovery of new agents.


Asunto(s)
Antiinflamatorios , Cumarinas , Cumarinas/farmacología , Cumarinas/química , Cumarinas/síntesis química , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/síntesis química , Animales , Ratones , Estructura Molecular , Humanos , Citocinas/metabolismo
9.
J Anesth ; 2024 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-39164406

RESUMEN

PURPOSE: Ultrasound view of the interlaminar structure is likely to be associated with difficult spinal anesthesia (DSA), and a poor ultrasound view which cannot show the anterior and posterior complex predicts a difficult spinal technique. As our target site is the posterior complex, this study aimed to assess whether the ratio of posterior complex length to depth measured by ultrasound can predict DSA in cesarean delivery. METHODS: Four anesthesiologists with 1-2 years of experience located and marked the puncture interspace using a traditional surface landmark. Subsequently, the ultrasound examiner located and measured the marked interspace via an oblique parasagittal ultrasound scan. The anesthesiologists, who were blinded to the ultrasound results, performed spinal anesthesia using a 25-gauge Whitacre spinal needle. The total number of attempts, including skin punctures and needle passes, was recorded and the DSA was defined as 10 unsuccessful attempts. A multivariable logistic regression analysis was used to determine the independent predictors, and receiver operating characteristic curves were constructed to evaluate the performance of the ratio of posterior complex length to depth for predicting DSA. RESULTS: A total of 397 cesarean delivery parturients with successfully measured posterior complex were included in the analysis. DSA occurred in 64 parturients (16.1%). Reduced length [odds ratio (OR) = 0.010, 95% confidence interval (CI), 0.002-0.062, P < 0.001] and increased depth [OR = 6.127, 95% CI, 2.671-14.056, P < 0.001] of the posterior complex were independently predictive of DSA compared with body mass index, abdominal circumference, and palpable surface landmarks. The ratio of posterior complex length to depth for predicting DSA had an area under the curve of 0.86 (95% CI, 0.82-0.90). The optimal cutoff was 0.23, with a sensitivity of 86% (95% CI, 74-93%) and specificity of 72% (95% CI, 67-77%). CONCLUSION: The ratio of posterior complex length to depth measured by ultrasound demonstrated a considerable accuracy in predicting DSA for inexperienced anesthesiologists. A higher ratio at ultrasound is an indication to evaluate the optimal puncture body position and interspace in the clinic practice. CLINICAL TRIAL REGISTRATION: ChiCTR2200065171 https://www.chictr.org.cn/showproj.html?proj=180855.

10.
Respir Res ; 24(1): 280, 2023 Nov 14.
Artículo en Inglés | MEDLINE | ID: mdl-37964270

RESUMEN

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic fatal disease with limited therapeutic options. The infiltration of monocytes and fibroblasts into the injured lungs is implicated in IPF. Enolase-1 (ENO1) is a cytosolic glycolytic enzyme which could translocate onto the cell surface and act as a plasminogen receptor to facilitate cell migration via plasmin activation. Our proprietary ENO1 antibody, HL217, was screened for its specific binding to ENO1 and significant inhibition of cell migration and plasmin activation (patent: US9382331B2). METHODS: In this study, effects of HL217 were evaluated in vivo and in vitro for treating lung fibrosis. RESULTS: Elevated ENO1 expression was found in fibrotic lungs in human and in bleomycin-treated mice. In the mouse model, HL217 reduced bleomycin-induced lung fibrosis, inflammation, body weight loss, lung weight gain, TGF-ß upregulation in bronchial alveolar lavage fluid (BALF), and collagen deposition in lung. Moreover, HL217 reduced the migration of peripheral blood mononuclear cells (PBMC) and the recruitment of myeloid cells into the lungs. In vitro, HL217 significantly reduced cell-associated plasmin activation and cytokines secretion from primary human PBMC and endothelial cells. In primary human lung fibroblasts, HL217 also reduced cell migration and collagen secretion. CONCLUSIONS: These findings suggest multi-faceted roles of cell surface ENO1 and a potential therapeutic approach for pulmonary fibrosis.


Asunto(s)
Fibrosis Pulmonar Idiopática , Neumonía , Ratones , Humanos , Animales , Leucocitos Mononucleares/metabolismo , Anticuerpos Monoclonales/uso terapéutico , Células Endoteliales/metabolismo , Fibrinolisina/metabolismo , Fibrinolisina/farmacología , Fibrinolisina/uso terapéutico , Pulmón/metabolismo , Fibrosis , Fibrosis Pulmonar Idiopática/inducido químicamente , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Fibrosis Pulmonar Idiopática/metabolismo , Neumonía/metabolismo , Colágeno/metabolismo , Bleomicina/toxicidad , Fibroblastos/metabolismo , Fosfopiruvato Hidratasa/metabolismo , Fosfopiruvato Hidratasa/farmacología , Fosfopiruvato Hidratasa/uso terapéutico , Ratones Endogámicos C57BL
11.
BMC Womens Health ; 23(1): 408, 2023 08 04.
Artículo en Inglés | MEDLINE | ID: mdl-37542252

RESUMEN

BACKGROUND: 17α-hydroxylase deficiency, which is caused by a CYP17A1 gene mutation, is a rare type of congenital adrenocortical hyperplasia that mainly manifests as hypertension, hypokalaemia and sexual dysplasia. To date, few pregnancies associated with this syndrome have been reported. CASE PRESENTATION: We describe a 35-year-old Chinese woman with nonclassical congenital adrenal hyperplasia (NCCAH) due to 17α-hydroxylase/17,20-lyase deficiency who achieved pregnancy after in vitro fertilization (IVF) and frozen-thawed embryo transfer. She had secondary amenorrhea since she was 27, and subsequently, high level of progesterone in the follicular phase was found during a blood test. A compound heterozygous mutation was found in the CYP17A1 gene, c.1263G > A and c.985_987delinsAA. The patient was given standardized treatment with dexamethasone. Due to ovulation disorder, IVF was performed. She underwent whole embryo vitrification freezing. Frozen-thawed embryo transplantation was performed following the artificial cycle protocol of endometrium preparation, resulting in a singleton pregnancy. At 39 weeks and 1 day of gestation, caesarean section was performed due to the breech position of the foetus. CONCLUSION: A high level of progesterone reduces endometrial receptivity. Standardized treatment with dexamethasone and frozen-thawed embryo transfer with an artificial cycle protocol of endometrium preparation should be the choice for infertile female patients with CYP17A1 deficiency.


Asunto(s)
Nacimiento Vivo , Esteroide 17-alfa-Hidroxilasa , Humanos , Femenino , Embarazo , Adulto , Esteroide 17-alfa-Hidroxilasa/genética , Progesterona , Oxigenasas de Función Mixta , Cesárea , Dexametasona
12.
Ann Hepatol ; 28(4): 101099, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37030571

RESUMEN

INTRODUCTION AND OBJECTIVES: Hepatocellular carcinoma (HCC) may be diagnosed using the GAAP and ASAP models; our goal was to verify and evaluate their diagnostic effectiveness compared to alpha-fetoprotein (AFP), des-gamma-carboxy prothrombin (DCP), and AFP & DCP for both HCC and HCC caused by the hepatitis B virus (HBV). PATIENTS AND METHODS: GAAP and ASAP models were validated and compared using a retrospective investigation of 938 patients from our hospital between July 2020 and July 2021. RESULTS: Both the GAAP and ASAP models had better diagnostic efficacy than AFP, DCP, AFP & DCP. The GAAP model achieved better performance in section A for the detection of HCC and in section C for the detection of HBV-HCC than the ASAP model. The Hosmer-Lemeshow test showed that the GAAP and ASAP models were well-calibrated for the diagnoses of these two groups. To be more specific, the area under curve (AUC) of the GAAP model for HCC detection in section A was 0.862 [95% confidence interval (CI): 0.838-0.883], and that of the ASAP model was 0.850 [95% CI: 0.826-0.872]. The AUC of the GAAP model for HBV-HCC detection in section C was 0.897 [95% CI: 0.872-0.918], and that of the ASAP model was 0.878 [95% CI: 0.852-0.902]. CONCLUSIONS: The GAAP model was more accurate and reliable than the AFP, DCP, AFP and DCP, as well as the ASAP model in section A for the detection of HCC and in section C for the detection of HBV-HCC.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patología , alfa-Fetoproteínas , Estudios Retrospectivos , Neoplasias Hepáticas/patología , Biomarcadores de Tumor , Biomarcadores , Precursores de Proteínas , Protrombina , Virus de la Hepatitis B
13.
Infect Immun ; 90(5): e0005922, 2022 05 19.
Artículo en Inglés | MEDLINE | ID: mdl-35416705

RESUMEN

The Borrelia burgdorferi BB0323 protein undergoes a complex yet poorly defined proteolytic maturation event that generates N-terminal and C-terminal proteins with essential functions in cell growth and infection. Here, we report that a borrelial protease, B. burgdorferi high temperature requirement A protease (BbHtrA), cleaves BB0323 between asparagine (N) and leucine (L) at positions 236 and 237, while the replacement of these residues with alanine in the mutant protein prevents its cleavage, despite preserving its normal secondary structure. The N-terminal BB0323 protein binds BbHtrA, but its cleavage site mutant displays deficiency in such interaction. An isogenic borrelial mutant with NL-to-AA substitution in BB0323 (referred to as Bbbb0323NL) maintains normal growth yet is impaired for infection of mice or transmission from infected ticks. Notably, the BB0323 protein is still processed in Bbbb0323NL, albeit with lower levels of mature N-terminal BB0323 protein and multiple aberrantly processed polypeptides, which could result from nonspecific cleavages at other asparagine and leucine residues in the protein. The lack of infectivity of Bbbb0323NL is likely due to the impaired abundance or stoichiometry of a protein complex involving BB0238, another spirochete protein. Together, these studies highlight that a precise proteolytic event and a particular protein-protein interaction, involving multiple borrelial virulence determinants, are mutually inclusive and interconnected, playing essential roles in the infectivity of Lyme disease pathogens.


Asunto(s)
Borrelia burgdorferi , Enfermedad de Lyme , Animales , Asparagina/metabolismo , Proteínas Bacterianas/metabolismo , Leucina/metabolismo , Enfermedad de Lyme/metabolismo , Ratones , Péptido Hidrolasas/metabolismo , Proteolisis , Virulencia , Factores de Virulencia/genética , Factores de Virulencia/metabolismo
14.
J Med Virol ; 94(4): 1402-1411, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-34766661

RESUMEN

Patients with COVID-19 may be recurrence positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA after being cured and discharged from the hospital. The aim of this study was to explore independent influencing factors as markers for predicting positive SARS-CoV-2 RNA recurrence. The study included 601 COVID-19 patients who were cured and discharged from the Public and Health Clinic Centre of Chengdu from January 2020 to March 2021, and the recurrence positive of patients within 6 weeks after SARS-CoV-2 RNA turned negative was followed up. We used propensity score matching to eliminate the influence of confounding factors, and multivariate Logistic regression analysis was used to determine the independent influencing factors for positive SARS-CoV-2 RNA recurrence. Multivariate Logistic regression showed that the elevated serum potassium (odds ratio [OR] = 6.537, 95% confidence interval [CI]: 1.864-22.931, p = 0.003), elevated blood chlorine (OR = 1.169, 95% CI: 1.032-1.324, p = 0.014) and elevated CD3+ CD4+ count (OR = 1.003, 95% CI: 1.001-1.004, p < 0.001) were identified as independent risk factors for positive SARS-CoV-2 RNA recurrence (p < 0.05). The difference in virus shedding duration (OR = 1.049, 95% CI: 1.000-1.100, p = 0.05) was borderline statistically significant. For sensitivity analysis, we included virus shedding duration as a categorical variable in the model again and found that the OR value related to recurrence positively increased with delayed virus shedding duration, and the trend test showed a statistical difference (P trend = 0.03). Meanwhile, shortening of activated partial prothrombinase time (OR = 0.908, 95% CI: 0.824-1.000, p = 0.049) was identified as an independent protection factor for SARS-CoV-2 RNA recurrence positive. We have identified independent factors that affect the recurrence of SARS-CoV-2 RNA positive. It is recommended that doctors pay attention to these indicators when first admitted to the hospital.


Asunto(s)
COVID-19/virología , ARN Viral/aislamiento & purificación , SARS-CoV-2/fisiología , Esparcimiento de Virus/fisiología , Adulto , Antivirales/administración & dosificación , COVID-19/epidemiología , China , Femenino , Hospitalización , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Puntaje de Propensión , Recurrencia , Estudios Retrospectivos , Factores de Riesgo , Esparcimiento de Virus/efectos de los fármacos
15.
Cell Microbiol ; 23(2): e13275, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33006213

RESUMEN

The peritrophic matrix (PM) is an acellular membrane that covers the gut epithelium in arthropods and physically separates it from the lumen. The structure is thought to play an important role in tick biology. The PM is also known to impact the persistence of tick-borne pathogens like Borrelia burgdorferi, although limited information is available about its molecular constituents or their biological significance. Herein, we characterise a novel PM-associated gut protein in Ixodes scapularis ticks, annotated as Peritrophic Membrane Chitin Binding Protein (PM_CBP), for its role in the integrity and function of the matrix. The PM_CBP displays homology to the chitin deacetylase metalloenzyme, shows upregulation during tick feeding, and is localized at the luminal surface of the gut epithelium. The structural integrity of the PM was impaired both by the knock down of PM_CBP expression via RNA interference and by treatment with anti-PM_CBP antibodies, as revealed by its electron microscopic appearance. Additionally, the duration of tick engorgement on mice and the passage of experimentally-inoculated fluorescent dextran molecules across the PM are affected by the knock down of PM_CBP expression. The transfer of anti-PM_CBP antibodies into the tick gut impacted the overall composition of the resident microbiome, and also influenced B. burgdorferi acquisition in ticks and its transmission to mice. Taken together, these data highlight the biological significance of the Ixodes PM and suggest that the targeting of its molecular constituents may contribute to the development of novel interventions against tick-borne infections.


Asunto(s)
Proteínas de Artrópodos/metabolismo , Borrelia burgdorferi/fisiología , Microbioma Gastrointestinal , Interacciones Huésped-Patógeno , Ixodes/metabolismo , Ixodes/microbiología , Enfermedad de Lyme/microbiología , Animales , Borrelia burgdorferi/patogenicidad , Proteínas Portadoras/metabolismo , Quitina/metabolismo , ADN Bacteriano , Femenino , Técnicas de Silenciamiento del Gen , Mucosa Intestinal/microbiología , Ratones , Ratones Endogámicos C3H , Unión Proteica , Interferencia de ARN , ARN Ribosómico 16S
16.
J Opt Soc Am A Opt Image Sci Vis ; 39(6): 1034-1044, 2022 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-36215533

RESUMEN

The grain number on the rice panicle, which directly determines the rice yield, is a very important agronomic trait in rice breeding and yield-related research. However, manual counting of grain number per rice panicle is time-consuming, error-prone, and laborious. In this study, a novel prototype, dubbed the "GN-System," was developed for the automatic calculation of grain number per rice panicle based on a deep convolutional neural network. First, a whole panicle grain detection (WPGD) model was established using the Cascade R-CNN method embedded with the feature pyramid network for grain recognition and location. Then, a GN-System integrated with the WPGD model was developed to automatically calculate grain number per rice panicle. The performance of the GN-System was evaluated through estimated stability and accuracy. One hundred twenty-four panicle samples were tested to evaluate the estimated stability of the GN-System. The results showed that the coefficient of determination (R2) was 0.810, the mean absolute percentage error was 8.44%, and the root mean square error was 16.73. Also, another 12 panicle samples were tested to further evaluate the estimated accuracy of the GN-System. The results revealed that the mean accuracy of the GN-System reached 90.6%. The GN-System, which can quickly and accurately predict the grain number per rice panicle, can provide an effective, convenient, and low-cost tool for yield evaluation, crop breeding, and genetic research. It also has great potential in assisting phenotypic research.


Asunto(s)
Oryza , Grano Comestible/genética , Redes Neurales de la Computación , Oryza/genética , Fenotipo
17.
Int J Mol Sci ; 23(18)2022 Sep 07.
Artículo en Inglés | MEDLINE | ID: mdl-36142250

RESUMEN

Mining the key genes involved in the balance of rice salt tolerance is extremely important for developing salt-tolerant rice varieties. A library of japonica mutants was screened under salinity conditions to identify putative salt stress-responsive genes. We identified a highly salt-sensitive mutant ss3 and used a map-based cloning approach to isolate the gene SS3, which encodes mannose-1-phosphate guanylyltransferase. Under salt treatment, ss3 mutants have decreased ascorbic acid (AsA) content and increased reactive oxygen species (ROS) levels compared with the wild type (WT). Exogenous AsA restored the salt tolerance of ss3 plants, indicating that inhibition of AsA synthesis was an important factor in the salt sensitivity of the mutant. Functional complementation using the WT allele rescued the mutation, and transcription of SS3 was induced by salt stress. Vector SS3p:SS3 was constructed containing the 1086 bp coding sequence of SS3. Under salinity conditions, transgenic seedlings expressing SS3p:SS3 had improved salt tolerance relative to WT, as demonstrated by better growth status, higher chlorophyll content, a lower level of Na+, and a reduced Na+/K+ ratio. Further investigation revealed that several senescence- and autophagy-related genes were expressed at lower levels in salt-stressed transgenic lines compared to WT. These results demonstrate the positive impact of SS3 on salt tolerance in rice through the regulation of AsA synthesis and ROS accumulation, and indicate that SS3 is a valuable target for genetic manipulation.


Asunto(s)
Oryza , Tolerancia a la Sal , Ácido Ascórbico/farmacología , Clorofila , Regulación de la Expresión Génica de las Plantas , Manosa , Fosfatos , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Plantas Modificadas Genéticamente/genética , Plantas Modificadas Genéticamente/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Tolerancia a la Sal/genética
18.
Small ; 17(34): e2101080, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-34263546

RESUMEN

Transition metal oxides (TMOs) are promising anode materials for next-generation lithium-ion batteries (LIBs). Nevertheless, their poor electronic and ionic conductivity as well as huge volume change leads to low capacity release and rapid capacity decay. Herein, a reduced graphene oxide (rGO)-encapsulated TMOs strategy is developed to address the above problems. The Co3 O4 -CoFe2 O4 @rGO composites with rGO sheets-encapsulated Co3 O4 -CoFe2 O4 microcubes are successfully constructed through a simple metal-organic frameworks precursor route, in which Co[Fe(CN)5 NO] microcubes are in situ coated by graphene oxide sheets, followed by a two-step calcination process. As anode material of LIBs, Co3 O4 -CoFe2 O4 @rGO exhibits remarkable reversible capacity (1393 mAh g-1 at 0.2 A g-1 after 300 cycles), outstanding long-term cycling stability (701 mAh g-1 at 2.0 A g-1 after 500 cycles), and excellent rate capability (420 mAh g-1 at 4.0 A g-1 ). The superior lithium storage performance can be attributed to the unique double-buffer structure, in which the outer flexible rGO shells can prevent the structure collapse of the electrode and improve its conductivity, while the hierarchical porous cores of Co3 O4 -CoFe2 O4 microcubes can buffer the volume expansion. This work provides a general and straightforward strategy for the construction of novel rGO-encapsulated bimetal oxides for energy storage and conversion application.

19.
Langmuir ; 37(2): 894-907, 2021 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-33400541

RESUMEN

An interfacial structure is crucial to the photoinduced electron transport for a heterostructure photocatalyst. Constructing an interfacial electron channel with an optimized interfacial structure can efficiently improve the electron-transfer efficiency. Herein, the rapid electron-transfer channels were built up in a Cu2O/SrFe0.5Ta0.5O3 heterojunction (Cu2O/SFTO) based on the selective bonding effect of heterologous surface oxygen vacancies in the SFTO component. The heterologous surface oxygen vacancies, namely, VO-Fe and VO-Ta, respectively, adjacent to Fe and Ta atoms, were introduced into fabricating the Z-scheme Cu2O/SFTO heterojunction. Compared with sample Cu2O/SFTO with VO-Fe, the photocatalytic NO removal efficiency of sample Cu2O/SFTO with VO-Fe and VO-Ta was increased by 22.5%. The enhanced photocatalytic performance originated from the selective bonding effect of heterologous VO-Fe and VO-Ta on the interfacial electron-separating and -transfer efficiency. VO-Fe is the main body to construct the interfacial electron-transfer channels by forming interfacial Fe-O-Cu(I) bonds, which causes lattice distortion at the interface, and VO-Ta can optimize the structure of interfacial channels by balancing the electron density of SFTO to control the average space of the interface transition zone. This research provides a new cognitive perspective for constructing double perovskite oxide-based heterostructure photocatalysts.

20.
BMC Musculoskelet Disord ; 22(1): 1046, 2021 Dec 20.
Artículo en Inglés | MEDLINE | ID: mdl-34930202

RESUMEN

BACKGROUND: Characterizing the impacts of postoperative opioid use on total knee arthroplasty (TKA) patients may help optimize the pain management after TKA. The aim of the study is to examine the prevalence and risk factors for opioid use with an enhanced-recovery programme after primary TKA. METHODS: We identified 361 patients undergoing TKA, and separated those on the basis of whether to receive opioid use after surgery. Themultivariate logistic regression model was used to identify independent risk factors for opioid use after primary TKA. Length of stay (LOS) and postoperative complications were also recorded and compared. RESULTS: The prevalence of opioid use after primary TKA was 23.0%. The significant risk factor was the longer operative time (OR [odds ratio] = 1.017, 95% CI [confidence interval] = 1.001 to 1.032, p = 0.034) and the protective factor was the utilization of tranexamic acid(OR= 0.355, 95% CI = 0.161 to 0.780, p = 0.010). In addition, the LOS was longer in opioid group (p < 0.05). CONCLUSION: Considering the adverse health effects of opioid use, strategies need to be developed to prevent persistent opioid use after TKA. Reducing operative time and the application of tranexamic acid could lower the risk of opioid use with an enhanced-recovery programme after primary TKA.


Asunto(s)
Artroplastia de Reemplazo de Rodilla , Analgésicos Opioides/efectos adversos , Artroplastia de Reemplazo de Rodilla/efectos adversos , Humanos , Factores de Riesgo
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