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OBJECTIVE: Childhood sensory abnormalities experience has a crucial influence on the structure and function of the adult brain. The underlying mechanism of neurological function induced by childhood sensory abnormalities experience is still unclear. Our study was to investigate whether the GABAergic neurons in the anterior cingulate cortex (ACC) regulate social disorders caused by childhood sensory abnormalities experience. METHODS: We used two mouse models, complete Freund's adjuvant (CFA) injection mice and bilateral whisker trimming (BWT) mice in childhood. We applied immunofluorescence, chemogenetic and optogenetic to study the mechanism of parvalbumin (PV) neurons and somatostatin (SST) neurons in ACC in regulating social disorders induced by sensory abnormalities in childhood. RESULTS: Inflammatory pain in childhood leads to social preference disorders, while BWT in childhood leads to social novelty disorders in adult mice. Inflammatory pain and BWT in childhood caused an increase in the number of PV and SST neurons, respectively, in adult mice ACC. Inhibiting PV neurons in ACC improved social preference disorders in adult mice that experienced inflammatory pain during childhood. Inhibiting SST neurons in ACC improved social novelty disorders in adult mice that experienced BWT in childhood. CONCLUSIONS: Our study reveals that PV and SST neurons of the ACC may play a critical role in regulating social disorders induced by sensory abnormalities in childhood.
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Giro del Cíngulo , Ratones Endogámicos C57BL , Parvalbúminas , Somatostatina , Animales , Ratones , Somatostatina/metabolismo , Masculino , Parvalbúminas/metabolismo , Neuronas GABAérgicas/fisiología , Adyuvante de Freund/toxicidad , Vibrisas/fisiología , Vibrisas/inervación , Neuronas , Trastorno de la Conducta Social/etiología , Ratones TransgénicosRESUMEN
BACKGROUND: Our study investigated the role of FAM53B in regulating macrophage M2 polarization and its potential mechanisms in promoting pancreatic ductal adenocarcinoma (PDAC) metastasis. AIM: To further investigate the role of FAM53B in regulating macrophage M2 polarization and its potential mechanism in promoting PDAC metastasis. Our goal is to determine how FAM53B affects macrophage M2 polarization and to define its underlying mechanism in PDAC metastasis. METHODS: Cell culture and various experiments, including protein analysis, immunohistochemistry, and animal model experiments, were conducted. We compared FAM53B expression between PDAC tissues and healthy tissues and assessed the correlation of FAM53B expression with clinical features. Our study analyzed the role of FAM53B in macrophage M2 polarization in vitro by examining the expression of relevant markers. Finally, we used a murine model to study the role of FAM53B in PDAC metastasis and analyzed the potential underlying mechanisms. RESULTS: Our research showed that there was a significant increase in FAM53B levels in PDAC tissues, which was linked to adverse tumor features. Experimental findings indicated that FAM53B can enhance macrophage M2 polarization, leading to increased anti-inflammatory factor release. The results from the mouse model further supported the role of FAM53B in PDAC metastasis, as blocking FAM53B prevented tumor cell invasion and metastasis. CONCLUSION: FAM53B promotes PDAC metastasis by regulating macrophage M2 polarization. This discovery could lead to the development of new strategies for treating PDAC. For example, interfering with the FAM53B signaling pathway may prevent cancer spread. Our research findings also provide important information for expanding our understanding of PDAC pathogenesis.
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Colorectal cancer (CRC) remains one of the leading causes of cancer-related death worldwide. The poor prognosis of this malignancy is attributed mainly to the persistent activation of cancer signaling for metastasis. Here, we showed that protein tyrosine phosphatase-like A domain containing 1 (PTPLAD1) is down-regulated in highly metastatic CRC cells and negatively associated with poor survival of CRC patients. Systematic analysis reveals that epithelial-to-mesenchymal transition (EMT) and mitochondrial fusion-to-fission (MFT) transition are two critical features for CRC patients with low expression of PTPLAD1. PTPLAD1 overexpression suppresses the metastasis of CRC in vivo and in vitro by inhibiting the Raf/ERK signaling-mediated EMT and mitofission. Mechanically, PTPLAD1 binds with PHB via its middle fragment (141-178 amino acids) and induces dephosphorylation of PHB-Y259 to disrupt the interaction of PHB-Raf, resulting in the inactivation of Raf/ERK signaling. Our results unveil a novel mechanism in which Raf/ERK signaling activated in metastatic CRC induces EMT and mitochondrial fission simultaneously, which can be suppressed by PTPLAD1. This finding may provide a new paradigm for developing more effective treatment strategies for CRC.
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Aminoácidos , Neoplasias del Colon , Humanos , Transición Epitelial-Mesenquimal/genética , Dinámicas Mitocondriales , Prohibitinas , Transducción de Señal , Quinasas rafRESUMEN
Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) caused a large-scale global pandemic between 2020 and 2022. Despite efforts to understand its biological and pathogenic mechanisms, the viral impact on the neurological systems remains unclear. The main goal of this study was to quantify the neurological phenotypes induced by the SARS-CoV-2 spike protein in neurons, as measured by in-vitro multiwell micro-electrode arrays (MEAs). Materials and methods: The authors extracted the whole-brain neurons from the newborn P1 mice and plated them on multiwell MEAs and administered purified recombinant spike proteins (both S1 and S2 subunits) from the SARS-CoV-2 virus. The signals from the MEAs were transmitted from an amplifier to a high-performance computer for recording and analysis using an in-house developed algorithm to quantify neuronal phenotypes. Results: Primary among the phenotypic features analyzed, we discovered that neuronal treatment with spike 1 protein (S1) protein from SARS-CoV-2 decreased the mean burst numbers observed on each electrode, an effect that could be rescued with an anti-S1 antibody. Conversely, this mean burst number decrease was not observed with spike 2 protein (S2) treatment. Finally, our data strongly suggest that the receptor binding domain of S1 is responsible for the reduction in neuronal burst activity. Conclusion: Overall, our results strongly indicate that spike proteins may play an important role in altering neuronal phenotypes, specifically the burst patterns, when neurons are exposed during early development.
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OBJECTIVE: The study aimed to pool and analyze the effects of different forms of exercise on muscle strength (handgrip strength [HGS]), and physical performance (timed up and go test [TUGT], gait speed [GS] and chair stand test [CS]) in older adults with sarcopenia. METHODS: The effect sizes of all studies retrieved and included by the four databases were analyzed using the network meta-analysis and expressed as standardized mean differences (SMD) and the corresponding 95% confidence intervals (CI). RESULTS: Twenty studies were included in this study with 1347 older adults with sarcopenia. Compared with control and other intervention groups, resistance training (RT) improved HGS [SMD=3.8, 95% CI (1.3, 6.0), p<0.05] and TUGT [SMD = -1.99, 95% CI (-2.82, -1.16), p<0.05] significantly. comprehensive training (CT) [SMD = -2.04, 95% CI (-3.05, -1.06), Pp<0.05] and Comprehensive training under self-management (CT_SM) [SMD = -2.01, 95% CI (-3.24, -0.78), p<0.05] improved TUGT significantly. CONCLUSION: In older adults with sarcopenia, RT could improve HGS and TUGT, CT and CT_SM could improve TUGT. There were no significant changes in CS and GS with any of the exercise training modes.
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Sarcopenia , Humanos , Anciano , Sarcopenia/terapia , Fuerza de la Mano/fisiología , Metaanálisis en Red , Equilibrio Postural , Estudios de Tiempo y Movimiento , Fuerza Muscular/fisiología , Ejercicio Físico/fisiologíaRESUMEN
OBJECTIVES: Ferroptosis is a newly discovered cell death mode that has been confirmed to occur in the intestinal epithelial cells in ulcerative colitis (UC). In this study we aimed to elucidate the mechanism of ferroptosis and its association with adenosine monophosphate-activated protein kinase (AMPK) in UC. METHODS: Gene expression profiles of colonic mucosa (GSE87473) were downloaded. Both human colonic samples and dextran sodium sulfate (DSS)-induced colitis murine model were used. The molecular markers of ferroptosis were detected using western blot and immunohistochemistry. Symptoms, iron abundance, and lipid peroxidation level of the mouse model were measured to evaluate the role of AMPK activation in ferroptosis. RESULTS: Both gene and protein expressions of GPX4 and FTH1 were decreased in UC patients compared with the healthy controls. An increased iron abundance and lipid peroxidation level in colon tissues and damaged mitochondria were found in DSS-induced colitis. AMPK expression was decreased in UC patients and correlated with FTH1 and GPX4. Activation of AMPK with metformin inhibited ferroptosis in the colon, improved symptoms, and prolonged the lifespan in DSS-induced colitis mice. CONCLUSIONS: Ferroptosis can be observed in colonic tissues in UC. AMPK activation inhibits ferroptosis in murine colitis model, which may act as a potential target for the treatment of colitis.
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Colitis Ulcerosa , Colitis , Ferroptosis , Humanos , Ratones , Animales , Proteínas Quinasas Activadas por AMP/metabolismo , Sulfato de Dextran/efectos adversos , Sulfato de Dextran/metabolismo , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis/metabolismo , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/metabolismo , Colon/metabolismo , Modelos Animales de Enfermedad , Hierro/efectos adversos , Hierro/metabolismo , Ratones Endogámicos C57BLRESUMEN
Controlled cortical impingement is a widely accepted method to induce traumatic brain injury to establish a traumatic brain injury animal model. A strike depth of 1 mm at a certain speed is recommended for a moderate brain injury and a depth of > 2 mm is used to induce severe brain injury. However, the different effects and underlying mechanisms of these two model types have not been proven. This study investigated the changes in cerebral blood flow, differences in the degree of cortical damage, and differences in motor function under different injury parameters of 1 and 2 mm at injury speeds of 3, 4, and 5 m/s. We also explored the functional changes and mitochondrial damage between the 1 and 2 mm groups in the acute (7 days) and chronic phases (30 days). The results showed that the cerebral blood flow in the injured area of the 1 mm group was significantly increased, and swelling and bulging of brain tissue, increased vascular permeability, and large-scale exudation occurred. In the 2 mm group, the main pathological changes were decreased cerebral blood flow, brain tissue loss, and cerebral vasospasm occlusion in the injured area. Substantial motor and cognitive impairments were found on day 7 after injury in the 2 mm group; at 30 days after injury, the motor function of the 2 mm group mice recovered significantly while cognitive impairment persisted. Transcriptome sequencing showed that compared with the 1 mm group, the 2 mm group expressed more ferroptosis-related genes. Morphological changes of mitochondria in the two groups on days 7 and 30 using transmission electron microscopy revealed that on day 7, the mitochondria in both groups shrank and the vacuoles became larger; on day 30, the mitochondria in the 1 mm group became larger, and the vacuoles in the 2 mm group remained enlarged. By analyzing the proportion of mitochondrial subgroups in different groups, we found that the model mice had different patterns of mitochondrial composition at different time periods, suggesting that the difference in the degree of damage among traumatic brain injury groups may reflect the mitochondrial changes. Taken together, differences in mitochondrial morphology and function between the 1 and 2 mm groups provide a new direction for the accurate classification of traumatic brain injury. Our results provide reliable data support and evaluation methods for promoting the establishment of standard mouse controlled cortical impingement model guidelines.
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Amino acids (AAs) are important metabolites that are related with diabetes. However, their roles in the initiation and development of diabetes mellitus (DM), especially in the treatment of Ginkgo biloba leaves extract (GBE) have not been fully explored. Thus, we investigated the roles that AAs played in the progression and GBE supplementation of DM rat induced by streptozotocin. The rats were randomly divided into a normal control group treated with drug-free solution, a normal control group treated with GBE, a DM group treated with drug-free solution, and DM group treated with GBE; and maintained on this protocol for 9 weeks. Rat plasma was collected from the sixth week to the ninth week and then analyzed with the optimized hydrophilic interaction liquid chromatography coupled with tandem mass spectrometry method. A total of 17 AAs with differential levels were monitored to indicate dysfunction of AAs metabolism to confirm the occurrence and development of DM. Treatment with GBE partially reversed the changes seen in seven AAs including leucine, isoleucine, tyrosine, glutamic acid, asparagines, lysine and alanine in DM rats, indicating that GBE could prevent the occurrence and development of DM by acting on AAs metabolism. The improvement of those AAs metabolism disorders may play a considerable role in the treatment of GBE on the occurrence and development of DM. Those findings potentially promote the understanding of the pathogenic progression of DM and reveal the therapeutic mechanism of GBE against DM.
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Diabetes Mellitus , Ginkgo biloba , Aminoácidos/análisis , Animales , Cromatografía Liquida , Ginkgo biloba/química , Interacciones Hidrofóbicas e Hidrofílicas , Extractos Vegetales/análisis , Hojas de la Planta/química , Ratas , Espectrometría de Masas en TándemRESUMEN
Traditionally, the quality evaluation of Chrysanthemum morifolium (CM) cv. (Juhua) attributes its habitats and processing methods, however, this strategy of neglecting bioactive ingredients usually results in deviation of quality evaluation. This study aims to explore the quality marker (Q-marker) based on spectrum-effect relationship and quality control strategy of CMs. The chromatographic fingerprint of 30 flower head samples of CMs from five different habitats including Hang-baiju, Gongju, Huaiju, Taiju and Boju were constructed by high performance liquid chromatography and analyzed through chemometrics methods such as similarity analysis (SA), cluster analysis (CA) and principal component analysis (PCA). The common peaks were quantified by external standard method and relative correction factor method. The in-vitro radical scavenging capacity assays of DPPH·, ·OH and ABTS were carried out. The Q-marker was explored by the correlation analysis between the contents of common peaks and in-vitro radical scavenging capacity, and then used to evaluate the quality of 30 flower head samples of CMs. A total of eight common peaks were appointed in 30 flower head samples of CMs, and their similarities ranged from 0.640 to 0.956. CA results showed that 30 flower head samples of CMs could be divided into five categories with reference to the Euclidean distance of 5. PCA results showed that common peaks played a major role in differential contribution of CMs. The quantification of common peaks hinted that their contents possessed significant variation whether for different accessions or the same accessions of CMs. The correlation analysis showed that chlorogenic acid, 3,5-O-dicaffeoylquinic acid, unknown peak 1, 4,5-O-dicaffeoylquinic acid and kaempferol-3-O-rutinoside could be used as the Q-markers for the quality evaluation of 30 flower head samples of commercially available CMs. The analysis strategy that combines chromatographic fingerprint analysis, multiple ingredients quantification, in-vitro chemical anti-oxidant activity evaluation and spectrum-effect relationship analysis clarified the therapeutic material basis and discovered the Q-markers, which possibly offers a more comprehensive quality assessment of CMs.
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Rare monogenic disorders often share molecular etiologies involved in the pathogenesis of common diseases. Congenital disorders of glycosylation (CDG) and deglycosylation (CDDG) are rare pediatric disorders with symptoms that range from mild to life threatening. A biological mechanism shared among CDG and CDDG as well as more common neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis, is endoplasmic reticulum (ER) stress. We developed isogenic human cellular models of two types of CDG and the only known CDDG to discover drugs that can alleviate ER stress. Systematic phenotyping confirmed ER stress and identified elevated autophagy among other phenotypes in each model. We screened 1049 compounds and scored their ability to correct aberrant morphology in each model using an agnostic cell-painting assay based on >300 cellular features. This primary screen identified multiple compounds able to correct morphological phenotypes. Independent validation shows they also correct cellular phenotypes and alleviate each of the ER stress markers identified in each model. Many of the active compounds are associated with microtubule dynamics, which points to new therapeutic opportunities for both rare and more common disorders presenting with ER stress, such as Alzheimer's disease and amyotrophic lateral sclerosis.
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Estrés del Retículo Endoplásmico/genética , Modelos Biológicos , Sustancias Protectoras/farmacología , Factor de Transcripción Activador 6/metabolismo , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Línea Celular , Proliferación Celular/efectos de los fármacos , Forma de la Célula/efectos de los fármacos , Trastornos Congénitos de Glicosilación/patología , Evaluación Preclínica de Medicamentos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Humanos , Fenotipo , Reproducibilidad de los Resultados , Proteína 1 de Unión a la X-Box/metabolismoRESUMEN
A sensor array mimicking a chemical nose/tongue based on bovine serum albumin nanoparticles (BSANsn) has been developed for the fluorescence pattern recognition of metal ions in biofluids. Three types of BSANsn (BSANs10, BSANs20, and BSANs40) show the same excitation/emission peak at 478/526 nm. According to the differential fluorescence variation, the sensor array shows particular fluorescence response patterns depending upon metal ions. Upon principal component analysis (PCA), it was found that the sensor array can distinguish 18 metal ions clearly at a concentration of as low as 10 µM. Moreover, different concentrations of metal ions and mixed metal ions of diverse kinds or valence states can be differentiated by the sensor in biofluids. In addition, the results were well consistent with those obtained with the traditional ICP-AES method.
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Técnicas Biosensibles , Nanopartículas del Metal , Nanopartículas , Iones , Metales , Albúmina Sérica BovinaRESUMEN
Sediment samples were collected from 11 typical sites in Hengshui Lake separately in August 2018 and March 2019. Characteristics and ecological risk assessment of typical persistent organic pollutants (POPs), including polycyclic aromatic hydrocarbons (PAHs), organochlorine pesticides (OCPs), and polybrominated diphenyl ethers (PBDEs), in these sediments were analyzed. The results showed that the average content of ΣPAHs in sediments of Hengshui Lake was 875.49 ng·g-1 and 1010.17 ng·g-1 in August 2018 and March 2019, respectively. Compared with other regions in China and abroad, ΣPAHs in sediments from Hengshui Lake were at moderate pollution level. Distribution of ΣPAHs varied between different sites, but the values changed within a narrow range in different seasons. Sources of PAHs in sediments from Hengshui Lake were complex, but combustion of wood and coal was the main source, followed by oil pollution. Generally, the ecological risk of PAHs was at a low level. However, fluorene pollution control should be strengthened. For ΣOCPs, the average values in sediments were 35.57 ng·g-1 and 38.39 ng·g-1 in August and March, respectively. Compared with other regions, the pollution of ΣOCPs was at a moderate level. In addition, the distribution of ΣOCPs varied a small amount between different sites. There were significant differences between the two seasons. The contents of DDTs in sediments were mainly related to the residual DDTs after long-term soil weathering and the input of recent DDTs sources. Contents of HCHs in sediments were influenced by the use of HCHs in industrial history and inputs of agricultural lindane. Generally, the ecological risk of OCPs was at a medium level, but the DDTs pollution control should be strengthened. For ΣPBDEs, the average values were 1.77 ng·g-1 and 1.45 ng·g-1 in the sediments in August 2018 and March 2019, respectively. Compared with other regions, they were at a lower pollution level. The distribution of ΣPBDEs showed small differences between different sites, and did not obviously vary between spring and summer. The PBDEs in sediments were mainly low-bromine PBDEs, which might be contaminated with penta-BDEs from textiles and foams. Additionally, PBDEs were also probably input by distant settlement and migration from the atmosphere, and soil flushing into the lake. PBDEs posed no immediate ecological risk.
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Contaminantes Ambientales , Hidrocarburos Clorados/análisis , Hidrocarburos Policíclicos Aromáticos/análisis , Contaminantes Químicos del Agua/análisis , China , Monitoreo del Ambiente , Sedimentos Geológicos , Lagos , Medición de Riesgo , RíosRESUMEN
Arsenic was recently identified as a pollutant that is a major cause of lung cancer. Since heparin-binding EGF-like growth factor (HB-EGF) was reported to be a promising therapeutic target for lung cancer, we investigated the role and mechanism of HB-EGF during arsenic-induced carcinogenesis and development of lung cancer. HB-EGF expression were upregulated in As-T cells, lung cancer cell lines, and in most lung cancer tissue samples; and HB-EGF activated the EGFR/p-ERK/HIF-1α pathway and induced VEGF by regulating HIF-1α transcription. HIF-1α transcriptional stimulation by HB-EGF was facilitated by PKM2 and played an important role in HB-EGF's effect on cells. An HB-EGF inhibitor(CRM197, cross-reacting material 197) slowed cell proliferation and inhibited migration of As-T and A549 cells, and inhibited tumor growth. PKM2 also played an important role in the proliferation and migration in As-T cells. The positive staining ratios of EGFR phosphorylation (Y1068) and PKM2 were significantly higher in most cases of lung cancer than in paired normal tumor-adjacent lung tissues; and HB-EGF expression levels strongly correlated with p-EGFR expression levels. Thus, HB-EGF drives arsenic-induced carcinogenesis, tumor growth, and lung cancer development via the EGFR/PKM2/HIF-1α pathway.
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This letter reports on a novel cost-efficient and multifunctional barcode-like sensors array (BLSA) printed with a conductive bioinspired smart ink. The conductive ink (P@G ink), which can be further chemically engineered with different organic ligands, was generated via facile one-pot hydrothermal reduction of graphene oxide (GO) in dopamine (DA) as coreductan Usingvarious chemical derivatives of the P@G inks on a flexible substrate (e.g., Kapton), a highly integrated BLSA as well as smart nose/tongue mimic array were generated for simultaneous sensing and distinguishing of complex physical and chemical stimuli, including temperature, light, air pressure, relative humidity, and volatile organic compounds (VOCs). Due to these very attractive features, the reported P@G ink-based BLSA would have the potential for unique opportunities regarding "all-in-one"-yet cost-effective-disposable electronics and sensors.
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Equipos y Suministros Eléctricos , Tinta , Presión del Aire , Biomimética , Dopamina , Grafito , Humedad , Luz , Temperatura , Compuestos Orgánicos VolátilesRESUMEN
Here we present an open-source R package 'meaRtools' that provides a platform for analyzing neuronal networks recorded on Microelectrode Arrays (MEAs). Cultured neuronal networks monitored with MEAs are now being widely used to characterize in vitro models of neurological disorders and to evaluate pharmaceutical compounds. meaRtools provides core algorithms for MEA spike train analysis, feature extraction, statistical analysis and plotting of multiple MEA recordings with multiple genotypes and treatments. meaRtools functionality covers novel solutions for spike train analysis, including algorithms to assess electrode cross-correlation using the spike train tiling coefficient (STTC), mutual information, synchronized bursts and entropy within cultured wells. Also integrated is a solution to account for bursts variability originating from mixed-cell neuronal cultures. The package provides a statistical platform built specifically for MEA data that can combine multiple MEA recordings and compare extracted features between different genetic models or treatments. We demonstrate the utilization of meaRtools to successfully identify epilepsy-like phenotypes in neuronal networks from Celf4 knockout mice. The package is freely available under the GPL license (GPL> = 3) and is updated frequently on the CRAN web-server repository. The package, along with full documentation can be downloaded from: https://cran.r-project.org/web/packages/meaRtools/.
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Potenciales de Acción/fisiología , Biología Computacional/métodos , Neuronas/fisiología , Programas Informáticos , Algoritmos , Animales , Células Cultivadas , Electrofisiología , Ratones , Ratones Noqueados , MicroelectrodosRESUMEN
One-lung ventilation in thoracic surgery provokes profound systemic inflammatory responses and injury related to lung tidal volume changes. We hypothesized that the highly selective a2-adrenergic agonist dexmedetomidine attenuates these injurious responses. Sixty patients were randomly assigned to receive dexmedetomidine or saline during thoracoscopic surgery. There is a trend of less postoperative medical complication including that no patients in the dexmedetomidine group developed postoperative medical complications, whereas four patients in the saline group did (0% versus 13.3%, p = 0.1124). Plasma inflammatory and injurious biomarkers between the baseline and after resumption of two-lung ventilation were particularly notable. The plasma high-mobility group box 1 level decreased significantly from 51.7 (58.1) to 33.9 (45.0) ng.ml-1 (p < 0.05) in the dexmedetomidine group, which was not observed in the saline group. Plasma monocyte chemoattractant protein 1 [151.8 (115.1) to 235.2 (186.9) pg.ml-1, p < 0.05] and neutrophil elastase [350.8 (154.5) to 421.9 (106.1) ng.ml-1, p < 0.05] increased significantly only in the saline group. In addition, plasma interleukin-6 was higher in the saline group than in the dexmedetomidine group at postoperative day 1 [118.8 (68.8) versus 78.5 (58.8) pg.ml-1, p = 0.0271]. We conclude that dexmedetomidine attenuates one-lung ventilation-associated inflammatory and injurious responses by inhibiting alveolar neutrophil recruitment in thoracoscopic surgery.
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Dexmedetomidina/uso terapéutico , Ventilación Unipulmonar/efectos adversos , Neumonía/tratamiento farmacológico , Toracoscopía/efectos adversos , Volumen de Ventilación Pulmonar/fisiología , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neumonía/inmunología , Volumen de Ventilación Pulmonar/efectos de los fármacos , Volumen de Ventilación Pulmonar/inmunologíaRESUMEN
The Flavivirus genus contains several arthropod-borne viruses that pose global health threats, including dengue viruses (DENV), yellow fever virus (YFV), and Zika virus (ZIKV). In order to understand how these viruses replicate in human cells, we previously conducted genome-scale RNA interference screens to identify candidate host factors. In these screens, we identified ribosomal proteins RPLP1 and RPLP2 (RPLP1/2) to be among the most crucial putative host factors required for DENV and YFV infection. RPLP1/2 are phosphoproteins that bind the ribosome through interaction with another ribosomal protein, RPLP0, to form a structure termed the ribosomal stalk. RPLP1/2 were validated as essential host factors for DENV, YFV, and ZIKV infection in two human cell lines: A549 lung adenocarcinoma and HuH-7 hepatoma cells, and for productive DENV infection of Aedes aegypti mosquitoes. Depletion of RPLP1/2 caused moderate cell-line-specific effects on global protein synthesis, as determined by metabolic labeling. In A549 cells, global translation was increased, while in HuH-7 cells it was reduced, albeit both of these effects were modest. In contrast, RPLP1/2 knockdown strongly reduced early DENV protein accumulation, suggesting a requirement for RPLP1/2 in viral translation. Furthermore, knockdown of RPLP1/2 reduced levels of DENV structural proteins expressed from an exogenous transgene. We postulate that these ribosomal proteins are required for efficient translation elongation through the viral open reading frame. In summary, this work identifies RPLP1/2 as critical flaviviral host factors required for translation. IMPORTANCE: Flaviviruses cause important diseases in humans. Examples of mosquito-transmitted flaviviruses include dengue, yellow fever and Zika viruses. Viruses require a plethora of cellular factors to infect cells, and the ribosome plays an essential role in all viral infections. The ribosome is a complex macromolecular machine composed of RNA and proteins and it is responsible for protein synthesis. We identified two specific ribosomal proteins that are strictly required for flavivirus infection of human cells and mosquitoes: RPLP1 and RPLP2 (RPLP1/2). These proteins are part of a structure known as the ribosomal stalk and help orchestrate the elongation phase of translation. We show that flaviviruses are particularly dependent on the function of RPLP1/2. Our findings suggest that ribosome composition is an important factor for virus translation and may represent a regulatory layer for translation of specific cellular mRNAs.
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Infecciones por Flavivirus/metabolismo , Infecciones por Flavivirus/virología , Flavivirus/fisiología , Interacciones Huésped-Patógeno , Fosfoproteínas/metabolismo , Proteínas Ribosómicas/metabolismo , Proteínas Virales/metabolismo , Aedes/virología , Animales , Línea Celular , Virus del Dengue/fisiología , Infecciones por Flavivirus/genética , Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Fosfoproteínas/química , Fosfoproteínas/genética , Unión Proteica , Multimerización de Proteína , Proteínas Ribosómicas/química , Proteínas Ribosómicas/genética , Replicación Viral , Virus de la Fiebre Amarilla/fisiologíaAsunto(s)
Vesícula/complicaciones , Enfisema/complicaciones , Neoplasias Pulmonares/cirugía , Neoplasias Primarias Secundarias/cirugía , Cirugía Torácica Asistida por Video/métodos , Humanos , Pulmón/cirugía , Neoplasias Pulmonares/complicaciones , Masculino , Persona de Mediana Edad , Neoplasias Primarias Secundarias/complicaciones , Resultado del TratamientoRESUMEN
BACKGROUND: Vagus nerve stimulation (VNS) has become the most common non-pharmacological treatment for intractable drug-resistant epilepsy. However, the contribution of VNS to neurological rehabilitation following stroke has not been thoroughly examined. Therefore, we investigated the specific role of acute VNS in the recovery of cognitive functioning and the possible mechanisms involved using a cerebral ischemia/reperfusion (I/R) injury model in rats. METHODS: The I/R-related injury was modeled using occlusion and reperfusion of the middle cerebral artery (MCAO/R) in Sprague-Dawley rats. VNS was concurrently applied to the vagus nerve using a stimulation intensity of 1 mA at a fixed frequency of 20 Hz with a 0.4-ms bipolar pulse width. The stimulation duration and inter-train interval were both 3 s. Next, Morris water maze and shuttle-box behavioral experiments were conducted to assess the effects of VNS on the recovery of learning, memory, and inhibitory avoidance following I/R injury. Intracerebroventricular injection of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4), a selective neurotoxin for noradrenergic neurons, was used to evaluate the role of norepinephrine (NE) as a mediator of therapeutic effects of VNS on cognitive recovery. RESULTS: Compared with the MCAO/R group, the VNS+MCAO/R group had improved spatial memory as indicated by swimming path lengths and escape latencies in the Morris water maze, and fear memory, as indicated by the avoidance conditioned response rate, mean shock duration, and avoidance time in shuttle-box behavior experiments. Compared with the VNS+MCAO/R group, the DSP-4+VNS+MCAO/R group, which had reduced NE levels in cortical and hippocampal brain regions, showed a reversal of the VNS-induced benefits on spatial and fear memory performance. CONCLUSIONS: VNS improves spatial and fear memory in a rat model of MCAO/R injury. However, a reduction in NE from the administration of DSP-4 blocks these protective effects, suggesting that NE may contribute to the influence exhibited by VNS on memory performance in rats with cerebral I/R-related injury.
Asunto(s)
Isquemia Encefálica/complicaciones , Isquemia Encefálica/fisiopatología , Cognición , Daño por Reperfusión/complicaciones , Daño por Reperfusión/fisiopatología , Estimulación del Nervio Vago/métodos , Animales , Bencilaminas/toxicidad , Cognición/efectos de los fármacos , Miedo/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/patología , Infarto de la Arteria Cerebral Media/complicaciones , Infarto de la Arteria Cerebral Media/fisiopatología , Masculino , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Norepinefrina/metabolismo , Ratas Sprague-Dawley , Memoria Espacial/efectos de los fármacosRESUMEN
Effective setting strategies using Monte Carlo simulation are presented to mitigate the irradiation damage in synchrotron radiation microangiography (SRA). A one-dimensional mouse head model and a segmented voxel phantom mouse head were simulated using the EGSnrc/DOSXYZnrc code to investigate the dose enhancement effect of an iodine contrast agent irradiated by a monochromatic synchrotron radiation source. The influence of the iodine concentration, vessel width and depth, protection with and without the skull layer, and various incident X-ray energies were all simulated. The dose enhancement effect and the absolute dose based on the segmented voxel mouse head phantom were evaluated. The dose enhancement ratio depended little on the irradiation depth, but strongly and linearly increasing on iodine concentration. The protection given by the skull layer cannot be ignored in SRA because a 700â µm-thick skull can decrease the dose by 10%. The incident X-ray energy can affect the dose significantly. Compared with a dose of 33.2â keV for 50â mgI ml(-1), a dose of 32.7â keV decreased by 38%, whereas a dose of 33.7â keV increased by 69.2% and the variation strengthened more with enhanced iodine concentration. The segmented voxel mouse head phantom also showed that the average dose enhancement effect and the maximal voxel dose per photon depended little on the iodine voxel volume ratio but strongly on the iodine concentration. To decrease the damage caused by the dose in SRA, a high-Z contrast agent should be used as little as possible and irradiation of the injection site of the contrast agent should be avoided immediately after the injection. The fragile vessel containing iodine should avoid being closely irradiated. Avoiding irradiating through a thin (or no) skull region, or attaching a thin equivalent material on the outside for protection are better methods. An incident X-ray energy as low as possible should be used as long as the SRA image quality is ensured. The use of the synergetic and synchronous shuttering technique in SRA is also very critical in order to effectively shorten the accumulative irradiation time in in vivo animal irradiation experiments.