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The activation of T cells by the T cell antigen receptor (TCR) results in the formation of signaling protein complexes (signalosomes), the composition of which has not been analyzed at a systems level. Here, we isolated primary CD4+ T cells from 15 gene-targeted mice, each expressing one tagged form of a canonical protein of the TCR-signaling pathway. Using affinity purification coupled with mass spectrometry, we analyzed the composition and dynamics of the signalosomes assembling around each of the tagged proteins over 600 s of TCR engagement. We showed that the TCR signal-transduction network comprises at least 277 unique proteins involved in 366 high-confidence interactions, and that TCR signals diversify extensively at the level of the plasma membrane. Integrating the cellular abundance of the interacting proteins and their interaction stoichiometry provided a quantitative and contextual view of each documented interaction, permitting anticipation of whether ablation of a single interacting protein can impinge on the whole TCR signal-transduction network.
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Linfocitos T CD4-Positivos/inmunología , Mapas de Interacción de Proteínas/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción de Señal/inmunología , Animales , Linfocitos T CD4-Positivos/metabolismo , Cromatografía de Afinidad/métodos , Espectrometría de Masas/métodos , Ratones , Ratones Transgénicos , Cultivo Primario de Células , Mapeo de Interacción de Proteínas/métodos , Receptores de Antígenos de Linfocitos T/inmunología , Transducción de Señal/genéticaRESUMEN
It is challenging to sufficiently regulate endogenous neuronal reactive oxygen species (ROS) production, reduce neuronal apoptosis, and reconstruct neural networks under spinal cord injury conditions. Here, hydrogel surface grafting and microsol electrospinning are used to construct a composite biomimetic scaffold with "external-endogenous" dual regulation of ROS. The outer hydrogel enhances local autophagy through responsive degradation and rapid release of rapamycin (≈80% within a week), neutralizing extracellular ROS and inhibiting endogenous ROS production, further reducing neuronal apoptosis. The inner directional fibers continuously supply brain-derived neurotrophic factors to guide axonal growth. The results of in vitro co-culturing show that the dual regulation of oxidative metabolism by the composite scaffold approximately doubles the neuronal autophagy level, reduces 60% of the apoptosis induced by oxidative stress, and increases the differentiation of neural stem cells into neuron-like cells by ≈2.5 times. The in vivo results show that the composite fibers reduce the ROS levels by ≈80% and decrease the formation of scar tissue. RNA sequencing results show that composite scaffolds upregulate autophagy-associated proteins, antioxidase genes, and axonal growth proteins. The developed composite biomimetic scaffold represents a therapeutic strategy to achieve neurofunctional recovery through programmed and accurate bidirectional regulation of the ROS cascade response.
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BACKGROUND: Daptomycin is widely used in critically ill patients for Gram-positive bacterial infections. Extracorporeal membrane oxygenation (ECMO) is increasingly used in this population and can potentially alter the pharmacokinetic (PK) behaviour of antibiotics. However, the effect of ECMO has not been evaluated in daptomycin. Our study aims to explore the effect of ECMO on daptomycin in critically ill patients through population pharmacokinetic (PopPK) analysis and to determine optimal dosage regimens based on both efficacy and safety considerations. METHODS: A prospective, open-label PK study was carried out in critically ill patients with or without ECMO. The total concentration of daptomycin was determined by UPLC-MS/MS. NONMEM was used for PopPK analysis and Monte Carlo simulations. RESULTS: Two hundred and ninety-three plasma samples were collected from 36 critically ill patients, 24 of whom received ECMO support. A two-compartment model with first-order elimination can best describe the PK of daptomycin. Creatinine clearance (CLCR) significantly affects the clearance of daptomycin while ECMO has no significant effect on the PK parameters. Monte Carlo simulations showed that, when the MICs for bacteria are â≥1â mg/L, the currently recommended dosage regimen is insufficient for critically ill patients with CLCRâ>â30â mL/min. Our simulations suggest 10â mg/kg for patients with CLCR between 30 and 90â mL/min, and 12â mg/kg for patients with CLCR higher than 90â mL/min. CONCLUSIONS: This is the first PopPK model of daptomycin in ECMO patients. Optimal dosage regimens considering efficacy, safety, and pathogens were provided for critical patients based on pharmacokinetic-pharmacodynamic analysis.
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Antibacterianos , Enfermedad Crítica , Daptomicina , Oxigenación por Membrana Extracorpórea , Método de Montecarlo , Humanos , Daptomicina/farmacocinética , Daptomicina/administración & dosificación , Antibacterianos/farmacocinética , Antibacterianos/administración & dosificación , Masculino , Femenino , Persona de Mediana Edad , Estudios Prospectivos , Adulto , Anciano , Pruebas de Sensibilidad Microbiana , Espectrometría de Masas en Tándem , Infecciones por Bacterias Grampositivas/tratamiento farmacológicoRESUMEN
Schistosomiasis is caused by parasitic flatworms known as schistosomes and affects over 200 million people worldwide. Prevention of T cell exhaustion by blockade of PD-1 results in clinical benefits to cancer patients and clearance of viral infections, however it remains largely unknown whether loss of PD-1 could prevent or cure schistosomiasis in susceptible mice. In this study, we found that S. japonicum infection dramatically induced PD-1 expression in T cells of the liver where the parasites chronically inhabit and elicit deadly inflammation. Even in mice infected by non-egg-producing unisex parasites, we still observed potent induction of PD-1 in liver T cells of C57BL/6 mice following S. japonicum infection. To determine the function of PD-1 in schistosomiasis, we generated PD-1-deficient mice by CRISPR/Cas9 and found that loss of PD-1 markedly increased T cell count in the liver and spleen of infected mice. IL-4 secreting Th2 cells were significantly decreased in the infected PD-1-deficient mice whereas IFN-γ secreting CD4+ and CD8+ T cells were markedly increased. Surprisingly, such beneficial changes of T cell response did not result in eradication of parasites or in lowering the pathogen burden. In further experiments, we found that loss of PD-1 resulted in both beneficial T cell responses and amplification of regulatory T cells that prevented PD-1-deficient T cells from unleashing anti-parasite activity. Moreover, such PD-1-deficient Tregs exert excessive immunosuppression and express larger amounts of adenosine receptors CD39 and CD73 that are crucial for Treg-mediated immunosuppression. Our experimental results have elucidated the function of PD-1 in schistosomiasis and provide novel insights into prevention and treatment of schistosomiasis on the basis of modulating host adaptive immunity.
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Schistosoma japonicum , Esquistosomiasis Japónica , Animales , Humanos , Terapia de Inmunosupresión , Ratones , Ratones Endogámicos C57BL , Receptor de Muerte Celular Programada 1/genética , Linfocitos T ReguladoresRESUMEN
OBJECTIVE: The optimal timing for surgery following neoadjuvant immunochemotherapy for lung squamous cell carcinoma appears to be a topic of limited data. Many clinical studies lack stringent guidelines regarding this timing. The objective of this study is to explore the effect of the interval between neoadjuvant immunochemotherapy and surgery on survival outcomes in patients with lung squamous cell carcinoma. METHODS: This study conducted a retrospective analysis of patients with lung squamous cell carcinoma who underwent neoadjuvant immunochemotherapy between January 2019 and October 2022 at The First Affiliated Hospital, Zhejiang University School of Medicine. Patients were divided into two groups based on the treatment interval: ≤33 days and > 33 days. The primary observational endpoints of the study were Disease-Free Survival (DFS) and Overall Survival (OS). Secondary observational endpoints included Objective response rate (ORR), Major Pathological Response (MPR), and Pathological Complete Remission (pCR). RESULTS: Using the Kaplan-Meier methods, the ≤ 33d group demonstrated a superior DFS curve compared to the > 33d group (p = 0.0015). The median DFS for the two groups was 952 days and 590 days, respectively. There was no statistical difference in the OS curves between the groups (p = 0.66), and the median OS was not reached for either group. The treatment interval did not influence the pathologic response of the tumor or lymph nodes. CONCLUSIONS: The study observed that shorter treatment intervals were associated with improved DFS, without influencing OS, pathologic response, or surgical safety. Patients should avoid having a prolonged treatment interval between neoadjuvant immunochemotherapy and surgery.
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Carcinoma de Células Escamosas , Neoplasias Pulmonares , Terapia Neoadyuvante , Humanos , Masculino , Terapia Neoadyuvante/métodos , Femenino , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Persona de Mediana Edad , Estudios Retrospectivos , Anciano , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Supervivencia sin Enfermedad , Neumonectomía , Tiempo de Tratamiento , Adulto , Resultado del TratamientoRESUMEN
In China, the Grain for Green Program (GGP) is an ambitious project to convert croplands into natural vegetation, but exactly how changes in vegetation translate into changes in soil organic carbon remains less clear. Here we conducted a meta-analysis using 734 observations to explore the effects of land recovery on soil organic carbon and nutrients in four provinces in Southwest China. Following GGP, the soil organic carbon content (SOCc) and soil organic carbon stock (SOCs) increased by 33.73% and 22.39%, respectively, compared with the surrounding croplands. Similarly, soil nitrogen increased, while phosphorus decreased. Outcomes were heterogeneous, but depended on variations in soil and environmental characteristics. Both the regional land use and cover change indicated by the landscape type transfer matrix and net primary production from 2000 to 2020 further confirmed that the GGP promoted the forest area and regional mean net primary production. Our findings suggest that the GGP could enhance soil and vegetation carbon sequestration in Southwest China and help to develop a carbon-neutral strategy.
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Carbono , Suelo , Carbono/análisis , Bosques , Grano Comestible , ChinaRESUMEN
AIMS: Pulmonary bronchiolar adenoma is a benign lung tumour characterised by nodular proliferation of bilayered bronchiolar-type epithelium with a continuous layer of basal cells. The aim of this study was to describe a distinct and rare histological type of pulmonary bronchiolar adenoma: bronchiolar adenoma with squamous metaplasia. METHODS AND RESULTS: We examined the clinicopathological, immunohistochemical, and molecular characteristics of five cases (two cases from the same patient). The samples were histopathologically characterised by bilayered bronchiolar-type cells with sheets like spindle-oval and polygonal cells. Immunohistochemistry analysis revealed that columnar surface cells of the tumour were diffusely positive for TTF-1 and Napsin A, while basal cells were positive for P40 and P63. Moreover, the squamous metaplastic cells in the stroma were positive for P40, and P63, while being negative for TTF-1, Napsin A, S100, and SMA. Genomic analyses uncovered that all five samples had BRAF V600E mutations. Notably, both squamous metaplastic and basal cells were positive for BRAF V600E staining. CONCLUSION: We discovered a distinct subtype of pulmonary bronchiolar adenoma termed bronchiolar adenoma with squamous metaplasia. It is composed of columnar surface cells, basal cells, and sheet-like spindle-oval cells with squamous metaplasia in the stroma. All five samples harboured the BRAF V600E mutation. Importantly, BASM may be misdiagnosed as pulmonary sclerosing pneumocytoma upon frozen sections analysis. It may need further immunohistochemistry staining.
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Adenoma , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Humanos , Proteínas Proto-Oncogénicas B-raf , Adenoma/genética , Adenoma/patología , Epitelio/patología , Neoplasias Pulmonares/patología , MetaplasiaRESUMEN
OBJECTIVES: We aimed to compare the long-term outcomes and surgical benefits between moyamoya disease (MMD) and atherosclerosis-associated moyamoya vasculopathy (AS-MMV) using high-resolution MRI (HRMRI). METHODS: MMV patients were retrospectively included and divided into the MMD and AS-MMV groups according to vessel wall features on HRMRI. Kaplan-Meier survival and Cox regression were performed to compare the incidence of cerebrovascular events and prognosis of encephaloduroarteriosynangiosis (EDAS) treatment between MMD and AS-MMV. RESULTS: Of the 1173 patients (mean age: 42.4±11.0 years; male: 51.0%) included in the study, 881 were classified into the MMD group and 292 into the AS-MMV group. During the average follow-up of 46.0±24.7 months, the incidence of cerebrovascular events in the MMD group was higher compared with that in the AS-MMV group before (13.7% vs 7.2%; HR 1.86; 95% CI 1.17 to 2.96; p=0.008) and after propensity score matching (6.1% vs 7.3%; HR 2.24; 95% CI 1.34 to 3.76; p=0.002). Additionally, patients treated with EDAS had a lower incidence of events than those not treated with EDAS, regardless of whether they were in the MMD (HR 0.65; 95% CI 0.42 to 0.97; p=0.043) or AS-MMV group (HR 0.49; 95% CI 0.51 to 0.98; p=0.048). CONCLUSIONS: Patients with MMD had a higher risk of ischaemic stroke than those with AS-MMV, and patients with both MMD and AS-MMV could benefit from EDAS. Our findings suggest that HRMRI could be used to identify those who are at a higher risk of future cerebrovascular events.
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Aterosclerosis , Isquemia Encefálica , Enfermedad de Moyamoya , Accidente Cerebrovascular , Humanos , Masculino , Adulto , Persona de Mediana Edad , Enfermedad de Moyamoya/complicaciones , Enfermedad de Moyamoya/diagnóstico por imagen , Enfermedad de Moyamoya/epidemiología , Estudios Retrospectivos , Isquemia Encefálica/complicaciones , Accidente Cerebrovascular/complicaciones , Imagen por Resonancia Magnética , Aterosclerosis/complicaciones , Aterosclerosis/diagnóstico por imagenRESUMEN
T and B cells continually recirculate between blood and secondary lymphoid organs. To promote their trans-endothelial migration (TEM), chemokine receptors control the activity of RHO family small GTPases in part via GTPase-activating proteins (GAPs). T and B cells express several RHO-GAPs, the function of most of which remains unknown. The ARHGAP45 GAP is predominantly expressed in hematopoietic cells. To define its in vivo function, we describe two mouse models where ARHGAP45 is ablated systemically or selectively in T cells. We combine their analysis with affinity purification coupled to mass spectrometry to determine the ARHGAP45 interactome in T cells and with time-lapse and reflection interference contrast microscopy to assess the role of ARGHAP45 in T-cell polarization and motility. We demonstrate that ARHGAP45 regulates naïve T-cell deformability and motility. Under physiological conditions, ARHGAP45 controls the entry of naïve T and B cells into lymph nodes whereas under competitive repopulation it further regulates hematopoietic progenitor cell engraftment in the bone marrow, and T-cell progenitor thymus seeding. Therefore, the ARGHAP45 GAP controls multiple key steps in the life of T and B cells.
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Linfocitos T , Internalización del Virus , Animales , Linfocitos B , Movimiento Celular , Proteínas Activadoras de GTPasa/genética , Ganglios Linfáticos , Ratones , TimoRESUMEN
OBJECTIVES: This study aimed to determine the association between vessel wall enhancement and progression of arterial stenosis and clinical outcomes in patients with moyamoya (MMD) using high-resolution magnetic resonance (HRMR) vessel wall imaging. METHODS: Consecutive participants diagnosed with MMD were prospectively recruited and underwent HRMR at baseline and during follow-up, which had an interval period of ≥ 6 months and were clinically followed up for ≤ 24 months to record the occurrence of ischemic stroke. The relationship between vessel wall enhancement and arterial stenosis progression and stroke occurrence was evaluated. RESULTS: HRMR vessel wall imaging was used to identify 309 stenotic lesions at the internal carotid artery (ICA) in 170 participants (mean age: 37.7 ± 11.3 years old, male: 44.1%). The baseline presence (adjusted odds ratio [aOR] = 3.57, 95% CI = 1.97-6.44, p < 0.001) and progression (aOR = 2.96, 95% CI = 1.29-6.80, p = 0.010) of vessel wall enhancement and middle cerebral artery (MCA) involvement (aOR = 4.98, 95% CI = 1.50-16.52, p = 0.009) were significantly associated with rapid progression of arterial stenosis. Furthermore, vessel wall enhancement (adjusted HR = 3.59, 95% CI = 1.33-9.70, p = 0.011) and rapid progression of arterial stenosis (adjusted HR = 4.52, 95% CI = 1.48-13.81, p = 0.008) were correlated with future stroke occurrence. CONCLUSION: The baseline presence of vessel wall enhancement was associated with rapid progression of arterial stenosis and increased risk for stroke in MMD patients. Our findings suggest that vessel wall enhancement may serve as a predictor of disease progression and poor outcomes in MMD. KEY POINTS: ⢠The baseline presence of vessel wall enhancement was significantly associated with the rapid progression of arterial stenosis. ⢠The baseline presence of vessel wall enhancement and rapid progression of arterial stenosis were both correlated with increased risk for future occurrence of stroke. ⢠Our findings suggest that vessel wall enhancement may serve as a predictor of rapid progression of arterial stenosis and poor outcomes in MMD patients.
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Enfermedad de Moyamoya , Accidente Cerebrovascular , Humanos , Masculino , Adulto , Persona de Mediana Edad , Enfermedad de Moyamoya/diagnóstico por imagen , Constricción Patológica , Imagen por Resonancia Magnética/métodos , Accidente Cerebrovascular/etiologíaRESUMEN
OBJECTIVE: Data on preoperative immunotherapy combined with chemotherapy in potentially resectable lung squamous cell carcinoma (LUSC) remain scarce. This study was designed to investigate the safety and efficacy of preoperative immunotherapy and chemotherapy for stage IIIA-IIIB LUSC. METHODS: This study consecutively enrolled stage IIIA-IIIB LUSC who received preoperative immunotherapy combined with chemotherapy between January 2019 and July 2021. Patients received two to four cycles of immunotherapy combined with platinum-based doublet chemotherapy (platinum + paclitaxel) before surgery. Patients were assessed radiographically every one to two cycles until surgery. Postoperative pathological evaluation was also performed. Follow-up was performed until at least 3 months after surgery. RESULTS: Sixty-five patients with stage IIIA-IIIB LUSC were enrolled. The objective response rate was 78.46% (51/65), and no patients had progressive disease. Fifty-seven patients underwent surgery, and 55 patients achieved R0 resection. There were no perioperative deaths. The rate of pathological complete response (pCR) was 31.58% (18/57) and major pathological response was 68.42% (39/57). The incidence of grade 3 and 4 adverse reactions was 21.21 and 1.54%, respectively. CONCLUSION: Perioperative immunotherapy combined with chemotherapy followed by surgical resection for male patients with stage IIIA-IIIB LUSC was effective with a tolerable toxicity profile.
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Carcinoma de Pulmón de Células no Pequeñas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Masculino , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Resultado del Tratamiento , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Neoplasias Pulmonares/cirugía , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/etiología , Carcinoma de Células Escamosas/patología , Pulmón/patología , Estadificación de NeoplasiasRESUMEN
Clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) is an efficient tool for establishing genetic models including cellular models, and has facilitated unprecedented advancements in biomedical research. In both patients and cancer animal models, immune cells infiltrate the tumor microenvironment and some of them migrate to draining lymph nodes to exert antitumor effects. Among these immune cells, phagocytes such as macrophages and dendritic cells engulf tumor antigens prior to their crosstalk with T cells and elicit adaptive immune response against tumors. Melanoma cells are frequently used as a tumor model because of their relatively high level of somatic mutations and antigenicity. However, few genetic models have been developed using melanoma cell lines to track tumor cell phagocytosis, which is essential for understanding protective immune response in vivo. In this study, we used CRISPR/Cas9-mediated DNA cleavage and homologous recombination to develop a novel knock-in tool which expresses the ultra-bright fluorescent probe ZsGreen in YUMM1.7 melanoma cells. Using this novel tool, we measured the macrophagic engulfment of melanoma cells inside the tumor microenvironment. We also found that in tumor-grafted mice, a subset of dendritic cells efficiently engulfed YUMM1.7 cells and was preferentially trafficking tumor antigens to draining lymph nodes. In addition, we used this knock-in tool to assess the impact of a point mutation of CD11b on phagocytosis in the tumor microenvironment. Our results demonstrate that the ZsGreen-expressing YUMM1.7 melanoma model provides a valuable tool for the study of phagocytosis in vivo.
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Antígeno CD11b , Melanoma , Fagocitosis , Animales , Antígenos de Neoplasias , Antígeno CD11b/genética , Línea Celular , Línea Celular Tumoral , Colorantes Fluorescentes , Melanoma/genética , Ratones , Mutación Puntual , Microambiente TumoralRESUMEN
BACKGROUND: This study aimed to compare the characteristics of carotid plaques between patients with transient ischemic attack (TIA) and ischemic stroke using magnetic resonance (MR) imaging. METHODS: Patients with a recent ischemic stroke or TIA who exhibited atherosclerotic plaques of carotid arteries in the symptomatic sides determined by MR vessel wall imaging were recruited. The plaque morphology and compositions including intraplaque hemorrhage (IPH), lipid-rich necrotic-core (LRNC) and calcification were compared between TIA and stroke patients. Logistic regression was performed to relate the plaque characteristics to the types of ischemic events. RESULTS: A total of 270 patients with TIA or ischemic stroke were recruited. Stroke patients had a significantly higher prevalence of diabetes (42.2% vs. 28.2%, p = 0.021), greater mean wall area (35.1 ± 10.1 mm2 vs. 32.0 ± 7.7 mm2, p = 0.004), mean wall thickness (1.3 ± 0.2 mm vs. 1.2 ± 0.2 mm, p = 0.001), maximum normalized wall index (NWI)(63.9% ± 6.0% vs. 62.2% ± 5.9%, p = 0.023) and %volume of LRNC (9.7% ± 8.2% vs. 7.4% ± 7.9%, p = 0.025) in the carotid arteries compared to those with TIA. After adjustment for clinical factors, above characteristics of carotid arteries were significantly associated with the type of ischemic events. After further adjustment for maximum NWI, this association remained statistically significant (OR, 1.41; CI, 1.01-1.96; p = 0.041). CONCLUSIONS: Ischemic stroke patients had larger plaque burden and greater proportion of LRNC in carotid plaques compared to those with TIA. This study suggests that ischemic stroke patients had more vulnerable plaques compared to those with TIA.
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Estenosis Carotídea , Ataque Isquémico Transitorio , Accidente Cerebrovascular Isquémico , Placa Aterosclerótica , Accidente Cerebrovascular , Arterias Carótidas/diagnóstico por imagen , Arterias Carótidas/patología , Estenosis Carotídea/complicaciones , Humanos , Ataque Isquémico Transitorio/diagnóstico por imagen , Ataque Isquémico Transitorio/etiología , Imagen por Resonancia Magnética , Placa Aterosclerótica/complicaciones , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/etiologíaRESUMEN
An electro-absorption modulator (EAM) integrated widely tunable distributed Bragg reflector (DBR) laser working at 1.5â µm is reported. By utilizing the RF resonance between the bonding wire and the EAM, a 28â GHz modulation bandwidth is obtained. The device is modulated with up to 50 Gb/s NRZ data. At 28 Gb/s, the power penalty to obtain a 10-10 bit error rate (BER) after a 5 Km standard single mode fiber transmission is less than 0.7â dB. Because the DBR material has a long bandgap wavelength, the wavelength tuning range of the laser is larger than 12â nm. The DBR laser is a promising low cost tunable light source for future high capacity wavelength division multiplexing (WDM) optical communication systems.
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BACKGROUND: Carotid vulnerable plaque is a major cause of stroke and differs between men and women. Few studies have investigated the differences in carotid plaque features between sexes in a Chinese population. PURPOSE: To compare carotid atherosclerotic plaque features between men and women in a Chinese population using magnetic resonance imaging. STUDY TYPE: Cross-sectional. SUBJECTS: A total of 567 patients (mean age: 61.5 ± 10.1 years; 404 men) who had recent stroke or transient ischemia attack and atherosclerotic plaque in at least one carotid artery. FIELD STRENGTH: A 3.0 T. SEQUENCE: T1- and T2-weighted turbo spin echo, three-dimensional time-of-flight (TOF) fast field echo and magnetization-prepared rapid acquisition gradient echo sequences. ASSESSMENT: Plaque characteristics including lumen area (LA), wall area (WA), total vessel area (TVA), mean wall thickness (MWT), and mean normalized wall index (NWI); presence of calcification, lipid-rich necrotic core (LRNC), intraplaque hemorrhage (IPH), and fibrous cap rupture (FCR); and percent composition area (%area) were evaluated and compared between men and women. STATISTICAL TESTS: Independent-sample t test, Mann-Whitney U test, chi-square test, and multiple linear and logistic regressions. RESULTS: In symptomatic arteries, men had significantly greater LA (46.2 ± 15.6 mm2 vs. 40.7 ± 12.9 mm2 , P < 0.05), WA (33.9 ± 11.5 mm2 vs. 26.3 ± 7.5 mm2 , P < 0.05), and TVA (80.1 ± 20.4 mm2 vs. 67.0 ± 18.0 mm2 , P < 0.05); higher MWT (1.2 ± 0.4 mm vs. 1.0 ± 0.2 mm, P < 0.05); and higher prevalence of LRNC (72.3% vs. 46.0%, P < 0.05) and IPH (18.6% vs. 4.9%, P < 0.05) compared with women. In asymptomatic arteries, men had significantly greater LA (48.3 ± 16.9 mm2 vs. 42.1 ± 12.6 mm2 , P < 0.05), WA (32.9 ± 11.0 mm2 vs. 25.8 ± 6.1 mm2 , P < 0.05), and TVA (81.2 ± 22.1 mm2 vs. 67.9 ± 16.5 mm2 , P < 0.05); higher MWT (1.2 ± 0.3 mm vs. 1.0 ± 0.2 mm, P < 0.05); higher prevalence of LRNC (67.8% vs. 42.9%, P < 0.05), IPH (14.9% vs. 1.2%, P < 0.05), and FCR (6.4% vs. 1.2%, P < 0.05); and higher %LRNC area (24.8 ± 17.2% vs. 17.8 ± 14.1%, P < 0.05) compared with women. DATA CONCLUSION: Men have similar plaque burden but more vulnerable atherosclerotic plaques compared with women in both symptomatic and asymptomatic carotid arteries in a Chinese population. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 3.
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Aterosclerosis , Estenosis Carotídea , Placa Aterosclerótica , Anciano , Aterosclerosis/diagnóstico por imagen , Aterosclerosis/epidemiología , Arterias Carótidas/diagnóstico por imagen , Estenosis Carotídea/diagnóstico por imagen , Estenosis Carotídea/epidemiología , China/epidemiología , Estudios Transversales , Femenino , Humanos , Imagen por Resonancia Magnética , Espectroscopía de Resonancia Magnética , Masculino , Persona de Mediana Edad , Placa Aterosclerótica/diagnóstico por imagenRESUMEN
Background: The poor outcome of advanced renal cell carcinoma (RCC) necessitates new treatments. Cobimetinib is a MEK inhibitor and approved for the treatment of melanoma. This work investigated the efficacy of cobimetinib alone and in combination with anti-RCC drugs. Methods: Proliferation and apoptosis assays were performed, and combination index was analyzed on RCC cell lines (CaKi-2, 786-O, A-704, ACHN and A489) and xenograft models. Immunoblotting analysis was conducted to investigate the MAPK pathway. Results: Cobimetinib was active against RCC cells, with IC50 at 0.006-0.8µM, and acted synergistically with standard-of-care therapy. Cobimetinib at nontoxic doses prevented tumor formation, inhibited tumor growth and enhanced efficacy of 5-fluorouracil, sorafenib and sunitinib via suppressing Raf/MEK/ERK, leading to MAPK pathway inhibition. Conclusion: Our findings demonstrate the potent anti-RCC activity of cobimetinib and its synergism with RCC standard-of-care drugs, and confirm the underlying mechanism of the action of cobimetinib.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Azetidinas/farmacología , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Piperidinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apoptosis/efectos de los fármacos , Azetidinas/uso terapéutico , Carcinoma de Células Renales/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Sinergismo Farmacológico , Fluorouracilo/farmacología , Fluorouracilo/uso terapéutico , Humanos , Neoplasias Renales/patología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Ratones , Piperidinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Sorafenib/farmacología , Sorafenib/uso terapéutico , Sunitinib/farmacología , Sunitinib/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The outbreak of coronavirus (COVID-19) in early 2020 posed a significant threat to people's health and economic sustainability in China and worldwide. This study investigated whether the lockdown measures precipitated by the COVID-19 pandemic affected air pollutants in the short term. Moreover, we investigated the impact of the heterogeneity of cities and regions. Using city-level daily panel data for the 2018-2020 lunar calendar, we employed a two-way fixed effects model and interrupted time-series analysis to inspect the effects of the lockdown measures. Interesting empirical findings emerged from our analysis. First, compared with the base period from 2018 to 2019, the COVID-19 lockdown measures significantly reduced air pollutants. In 2020, compared to 2018, PM10 and SO2 dropped by 15.28 µg/m3 and 6.55 µg/m3, and compared to 2019, PM2.5, PM10, and SO2 declined by 7.4 µg/m3, 19.34 µg/m3, and 1.41 µg/m3, respectively. Second, our dynamic analysis showed that as more time elapsed since the start of the lockdown, the associated reduction in air pollution became more significant. Third, the proportion of secondary industries and the cumulative number of confirmed cases had a considerable heterogeneity impact on lockdown measures. Policymakers should encourage investment in new infrastructure and initiatives to boost efficiency and enhance environmental outcomes.
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We report a novel single-cavity dual-wavelength laser that has two distributed Bragg reflector (DBR) gratings at each side of a gain section for THz communication applications. By varying the inject current of one of the DBR gratings, the optical beat frequency of the laser can be widely tuned. In the device, a high-speed electro-absorption modulator (EAM) is also integrated and can be used for up to 25 Gb/s data modulation.
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BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNAs about 22 nucleotides in length, which play an important role in gene regulation of both eukaryotes and viruses. They can promote RNA cleavage and repress translation via base-pairing with complementary sequences within mRNA molecules. MAIN BODY: Human cytomegalovirus (HCMV) encodes a large number of miRNAs that regulate transcriptions of both host cells and themselves to favor viral infection and inhibit the host's immune response. To date, ~ 26 mature HCMV miRNAs have been identified. Nevertheless, their roles in viral infection are ambiguous, and the mechanisms have not been fully revealed. Therefore, we discuss the methods used in HCMV miRNA research and summarize the important roles of HCMV miRNAs and their potential mechanisms in infection. CONCLUSIONS: To study the miRNAs encoded by viruses and their roles in viral replication, expression, and infection will not only contribute to the planning of effective antiviral therapies, but also provide new molecular targets for the development of antiviral drugs.
Asunto(s)
Infecciones por Citomegalovirus/virología , Citomegalovirus/genética , Interacciones Huésped-Patógeno/genética , MicroARNs/genética , Línea Celular , Citomegalovirus/fisiología , Regulación Viral de la Expresión Génica , Interacciones Huésped-Patógeno/inmunología , Humanos , ARN Viral/genética , Replicación Viral/genéticaRESUMEN
The above article was published online with incorrect presentation of author name. Mingming is the given name and Lu is the family name. The presentation of the author name has been corrected above.