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Chronic alcohol consumption is a major risk factor for alcoholic steatohepatitis (ASH). Previous studies have shown that direct injury of hepatocytes is the key factor in its occurrence and development. However, our study shows that the role of Kupffer cells in ASH cannot be ignored. We isolated Kupffer cells from the livers of ASH mice and found that alcohol consumption induced Kupffer cell pyroptosis and increased the release of interleukin-1ß (IL-1ß). Furthermore, we screened the related m6A enzyme methyltransferase-like 3 (METTL3) from liver Kupffer cells, and found that silencing METTL3 alleviated inflammatory cytokine eruption by Kupffer cell pyroptosis in ASH mice. In vitro, we silenced METTL3 with lentivirus in BMDMs and RAW264.7 cells and confirmed that METTL3 could reduce pyroptosis by influencing the splicing of pri-miR-34A. Together, our results revealed a critical role of KC pyroptosis in ASH and highlighted the mechanism by which METLL3 relieves cell pyroptosis, which could be a promising therapeutic strategy for ASH.
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Hígado Graso Alcohólico , MicroARNs , Animales , Ratones , Macrófagos del Hígado , Piroptosis , Hepatocitos , MetiltransferasasRESUMEN
A dual-mode fluorescence/visual aptasensor was developed for straightforward and accurate determination of aflatoxin B1 (AFB1) based on an Au/metal-organic framework (Au/MOF) composite. Aptamer-modified Au/Fe3O4 (Apt/Au/Fe3O4) served as the recognition element, and Au/MOF modified with complementary chains and 3,3',5,5'-tetramethylbenzidine (cDNA/TMB/Au/MOF) acted as the fluorescence and visual probes. These components are integrated to form conjugates (Apt/Au/Fe3O4-cDNA/TMB/Au/MOF). Upon the introduction of AFB1, some cDNA/TMB/Au/MOF dissociated from Apt/Au/Fe3O4, enabling the use of detached probes for visual detection. The undecomposed conjugates were isolated magnetically for use in fluorescence detection. As the AFB1 concentration increases, the visual signal intensifies and fluorescence intensity diminishes. Thus, the proposed aptasensor achieves the simultaneous fluorescence and visual determination of AFB1, obviating the need for material and reagent substitutions. The detection limits were established at 0.07 ng mL-1 for the fluorescence mode and 0.08 ng mL-1 for the visual mode. The effectiveness of the aptasensor was further validated by quantifying AFB1 in real samples.
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Aflatoxina B1 , Aptámeros de Nucleótidos , Técnicas Biosensibles , Oro , Límite de Detección , Estructuras Metalorgánicas , Nanocompuestos , Aflatoxina B1/análisis , Oro/química , Aptámeros de Nucleótidos/química , Estructuras Metalorgánicas/química , Técnicas Biosensibles/métodos , Nanocompuestos/química , Espectrometría de Fluorescencia/métodos , Bencidinas/química , Contaminación de Alimentos/análisis , Fluorescencia , Colorantes Fluorescentes/químicaRESUMEN
BACKGROUND: Anti-GQ1b antibody syndrome referred to a clinical spectrum characterized by acute onset of ataxia, ophthalmoplegia and areflexia, while visual deterioration was rarely reported in terms of ocular disorders. This study aimed to describe the clinical characteristics of anti-GQ1b antibody syndrome with visual impairment. METHODS: The database at the First Affiliated Hospital of Sun Yat-sen University was searched from 2014 to 2020. Patients with anti-GQ1b IgG were identified and divided into two groups according to the existence of optic neuropathy. Clinical and laboratory data of these subjects between the two groups were collected and analyzed. All patients were followed up by telephone to assess the outcome. RESULTS: A total of 12 patients with seropositive anti-GQ1b antibody were included, 75% of which got antecedent infection. Of these cases, 3 showed visual deterioration accompanied by abnormal orbital magnetic resonance imaging or visual evoked potentials, and the other 9 didn't show any evidence of vision impairment. Patients in the optic neuropathy group presented prominent visual impairments as initial symptoms and were more likely to suffer from facial weakness. There were 4 patients in normal visual acuity group complaining of blurred vision due to intraocular muscle paralysis, which was distinguished by subsequent examination. The combination of glucocorticoids and intravenous immunoglobulin was applied to treat patients with optic neuropathy. CONCLUSIONS: This study provides strong evidence that anti-GQ1b antibody syndrome can exhibit visual impairment, which helps further expand the clinical spectrum of anti-GQ1b antibody syndrome. More attention should be paid to the physical and supplementary ophthalmological examination to explore the pathogenesis and treatment of anti-GQ1b antibody syndrome.
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Oftalmoplejía , Enfermedades del Nervio Óptico , Potenciales Evocados Visuales , Gangliósidos , Humanos , Oftalmoplejía/complicaciones , Enfermedades del Nervio Óptico/complicaciones , Estudios RetrospectivosRESUMEN
Cardiac shock wave therapy (CSWT) is a novel therapeutic procedure for patients with angina that is refractory to conventional therapy. We investigated the potential mechanism and therapeutic efficacy of non-R-wave-triggered CSWT to attenuate myocardial dysfunction in a large animal model of hypertensive cardiomyopathy. Sustained elevated blood pressure (BP) was induced in adult pigs using a combination of angiotensin-II and deoxycorticosterone acetate (DOCA). Two sessions of non-R-wave-triggered CSWT were performed at 11 and 16 weeks. At 10 weeks, systolic and diastolic blood pressure, LV posterior wall thickness and intraventricular septum thickness significantly increased in both the hypertension and CSWT groups. At 20 weeks, +dP/dt and end-systolic pressure-volume relationship (ESPVR) decreased significantly in the hypertension group but not the CSWT group, as compared with week 10. A significant improvement in end-diastolic pressure-volume relationship (EDPVR) was observed in the CSWT group. The CSWT group exhibited significantly increased microvascular density and vascular endothelial growth factor (VEGF) expression in the myocardium. Cytokine array demonstrated that the CSWT group had significantly reduced inflammation compared with the hypertension group. Our results demonstrate that non-R-wave-triggered CSWT is safe and can attenuate LV systolic and diastolic dysfunction via enhancement of myocardial neovascularization and anti-inflammatory effect in a large animal model of hypertensive cardiomyopathy.
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Cardiomiopatías , Tratamiento con Ondas de Choque Extracorpóreas , Hipertensión , Animales , Porcinos , Tratamiento con Ondas de Choque Extracorpóreas/métodos , Factor A de Crecimiento Endotelial Vascular , Angina de Pecho , Cardiomiopatías/etiología , Cardiomiopatías/terapia , Hipertensión/complicaciones , Hipertensión/terapiaRESUMEN
Herein, a hetero(S,N)-quintuple [9]helicene (SNQ9H) molecule with an azacorannulene core was synthesized, currently representing the highest hetero-helicene reported in the field of multiple [n]helicenes. X-ray crystallography indicated that SNQ9H includes not only a propeller-shaped conformer SNQ9H-1, but also an unforeseen quasi-propeller-shaped conformer SNQ9H-2. Different conformers were observed for the first time in multiple [n≥9]helicenes, likely owing to the doping of heteroatomic sulfurs in the helical skeletons. Remarkably, the ratio of SNQ9H-1 to SNQ9H-2 can be regulated in situ by the reaction temperature. Experimental studies on the photophysical and redox properties of SNQ9H and theoretical calculations clearly demonstrated that the electronic structures of SNQ9H depend on their molecular conformations. The strategy of introducing heteroatomic sulfurs into the helical skeleton may be useful in constructing various conformers of higher multiple [n]helicenes in the future.
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Lesions of the peripheral nerves can lead to lifelong neuropathic pain (NP). Autophagic deficiency in the Schwann cells (SCs) is an early event in the origin of NP chronification. Uncoordinated gene 5H2 (UNC5H2), one of the repulsive netrin receptors, mediated the effect of netrin-1 on autophagic activation and cell survival in endothelial cells. However, its role on autophagy regulation in peripheral nerves during NP process remains unidentified. Chronic constriction injury (CCI) of the left sciatic nerve was induced in Sprague-Dawley rats, and UNC5H2 small interfering RNA was transfected to the ipsilateral sciatic nerve immediately after injury. Mechanical allodynia was assessed. Sciatic UNC5H2 and netrin-1 protein levels were investigated. Autophagy in the ipsilateral sciatic nerves was evaluated by detecting punctate light chain 3(LC3) and autophagosomes, as well as the levels of LC3 II, p62 and phosphorylated UNC51-like kinase (ULK1). After CCI, UNC5H2 of the sciatic nerves was upregulated, exclusively expressed in SCs. Small interfering RNA transfection resulted in significant decrease of UNC5H2 and netrin-1 protein, leading to exaggeration of mechanical allodynia through 14 days after CCI. Autophagy was activated but autophagic influx was interfered within a week after CCI, shown by the elevated levels of both LC3II and p62, which was further deteriorated with UNC5H2 knockdown. In addition, the injury-induced augmentation of phosphorylated ULK1 was significantly diminished by UNC5H2 knockdown. Altogether, the results suggest that local UNC5H2 of the peripheral nerve plays a significant role in the process of injury-induced mechanical allodynia, probably associated to its contribution to autophagic regulation.
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Hiperalgesia , Animales , Autofagia , Células Endoteliales , Netrina-1 , Ratas , Ratas Sprague-Dawley , Regulación hacia ArribaRESUMEN
Recent pre-clinical and clinical studies have suggested that endogenous cardiospheres (eCS) are potentially safe and effective for cardiac regeneration following myocardial infarction (MI). Nevertheless the preparation of autologous eCS requires invasive myocardial biopsy with limited yield. We describe a novel approach to generate induced cardiospheres (iCS) from adult skin fibroblasts via somatic reprogramming. After infection with Sox2, Klf4, and Oct4, iCS were generated from mouse adult skin fibroblasts treated with Gsk3ß inhibitor-(2'Z,3'E)- 6-Bromoindirubin-3'-oxime and Oncostatin M. They resembled eCS, but contained a higher percentage of cells expressing Mesp1, Isl1, and Nkx2.5. They were differentiated into functional cardiomyocytes in vitro with similar electrophysiological properties, calcium transient and contractile function to eCS and mouse embryonic stem cell-derived cardiomyocytes. Transplantation of iCS (1 × 106 cells) into mouse myocardium following MI had similar effects to transplantation of eCS but significantly better than saline or fibroblast in improving left ventricular ejection fraction, increasing anterior/septal ventricular wall thickness and capillary density in the infarcted region 4 weeks after transplantation. No tumor formation was observed. iCS generated from adult skin fibroblasts by somatic reprogramming and a cocktail of Gsk3ß inhibitor-6-Bromoindirubin-3'-oxime and Oncostatin M may represent a novel source for cell therapy in MI. Stem Cells 2016;34:2693-2706.
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Reprogramación Celular , Fibroblastos/metabolismo , Infarto del Miocardio/terapia , Miocitos Cardíacos/trasplante , Regeneración/fisiología , Esferoides Celulares/trasplante , Potenciales de Acción , Animales , Calcio/metabolismo , Diferenciación Celular , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Expresión Génica , Glucógeno Sintasa Quinasa 3 beta/antagonistas & inhibidores , Glucógeno Sintasa Quinasa 3 beta/genética , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Humanos , Indoles/farmacología , Factor 4 Similar a Kruppel , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Ratones , Infarto del Miocardio/genética , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Miocitos Cardíacos/citología , Miocitos Cardíacos/metabolismo , Factor 3 de Transcripción de Unión a Octámeros/genética , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , Oncostatina M/farmacología , Oximas/farmacología , Cultivo Primario de Células , Factores de Transcripción SOXB1/genética , Factores de Transcripción SOXB1/metabolismo , Piel/citología , Piel/efectos de los fármacos , Piel/metabolismo , Esferoides Celulares/citología , Esferoides Celulares/metabolismo , Transducción Genética , Función Ventricular Izquierda/fisiologíaAsunto(s)
Síndrome de Churg-Strauss , Granulomatosis con Poliangitis , Enfermedades del Sistema Nervioso Periférico , Síndrome de Churg-Strauss/complicaciones , Síndrome de Churg-Strauss/diagnóstico , Síndrome de Churg-Strauss/tratamiento farmacológico , Nervios Craneales , Granulomatosis con Poliangitis/complicaciones , Granulomatosis con Poliangitis/diagnóstico , Granulomatosis con Poliangitis/tratamiento farmacológico , Humanos , Inmunoglobulinas Intravenosas , Enfermedades del Sistema Nervioso Periférico/diagnóstico , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/etiologíaRESUMEN
AIMS: Thoracic spinal cord stimulation (SCS) has been shown to improve left ventricular ejection fraction (LVEF) in heart failure (HF). Nevertheless, the optimal duration (intermittent vs. continuous) of stimulation and the mechanisms of action remain unclear. METHODS AND RESULTS: We performed chronic thoracic SCS at the level of T1-T3 (50 Hz, pulse width 0.2 ms) in 30 adult pigs with HF induced by myocardial infarction and rapid ventricular pacing for 4 weeks. All the animals were treated with daily oral metoprolol succinate (25 mg) plus ramipril (2.5 mg), and randomized to a control group (n = 10), intermittent SCS (4 h ×3, n = 10) or continuous SCS (24 h, n = 10) for 10 weeks. Serial measurements of LVEF and +dP/dt and serum levels of norepinephrine and B-type natriuretic peptide (BNP) were measured. After sacrifice, immunohistological studies of myocardial sympathetic and parasympathetic nerve sprouting and innervation were performed. Echocardiogram revealed a significant increase in LVEF and +dP/dt at 10 weeks in both the intermittent and continuous SCS group compared with controls (P < 0.05). In both SCS groups, there was diffuse sympathetic nerve sprouting over the infarct, peri-infarct, and normal regions compared with only the peri-infarct and infarct regions in the control group. In addition, sympathetic innervation at the peri-infarct and infarct regions was increased following SCS, but decreased in the control group. Myocardium norepinephrine spillover and serum BNP at 10 weeks was significantly decreased only in the continuous SCS group (P < 0.05). CONCLUSIONS: In a porcine model of HF, SCS induces significant remodelling of cardiac sympathetic innervation over the peri-infarct and infarct regions and is associated with improved LV function and reduced myocardial norepinephrine spillover.
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Insuficiencia Cardíaca/terapia , Corazón/inervación , Regeneración Nerviosa , Estimulación de la Médula Espinal/métodos , Sistema Nervioso Simpático/fisiopatología , Función Ventricular Izquierda , Animales , Biomarcadores/sangre , Estimulación Cardíaca Artificial , Modelos Animales de Enfermedad , Electrocardiografía , Femenino , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/fisiopatología , Masculino , Infarto del Miocardio/complicaciones , Péptido Natriurético Encefálico/sangre , Norepinefrina/sangre , Distribución Aleatoria , Recuperación de la Función , Volumen Sistólico , Porcinos , Sistema Nervioso Simpático/metabolismo , Sistema Nervioso Simpático/patología , Vértebras Torácicas , Factores de Tiempo , Ultrasonografía , Presión VentricularRESUMEN
In the porcine coronary artery, regenerated endothelium is dysfunctional as regards the responses to endothelium-dependent agonists. The current study aimed to determine the possible involvement of histamine in such dysfunction. Pigs were treated chronically with pyrilamine (H1 receptor inhibitor, 2 mg·kg(-1)·day(-1)) with part of their coronary endothelium and allowed to regenerate for 28 days after balloon denudation. The results showed a reduction in relaxation to bradykinin (Gq protein dependent) only in the pyrilamine-treated group (area under the curve, 269.7 ± 13.4 vs. 142.0 ± 31.0, native endothelium vs. regenerated endothelium) but not in the control group (253.0 ± 22.1 vs. 231.9 ± 29.5, native endothelium vs. regenerated endothelium). The differences in the relaxation to serotonin (Gi protein dependent) between native and regenerated endothelium were not affected by the pyrilamine treatment (control group, 106.3 ± 17.0 vs. 55.61 ± 12.7; and pyrilamine group, 106.0 ± 8.20 vs. 49.30 ± 6.31, native endothelium vs. regenerated endothelium). These findings indicate that during regeneration of the endothelium, the activation of H1 receptors by endogenous histamine may be required to maintain the endothelium-dependent Gq protein-mediated relaxation to bradykinin, suggesting a beneficial role of the monoamine in the process of endothelial regeneration.
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Endotelio Vascular/efectos de los fármacos , Antagonistas de los Receptores Histamínicos H1/farmacología , Relajación Muscular/efectos de los fármacos , Pirilamina/farmacología , Regeneración , Animales , Bradiquinina/farmacología , Vasos Coronarios/lesiones , Endotelio Vascular/metabolismo , Endotelio Vascular/fisiología , Femenino , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/metabolismo , Antagonistas de los Receptores Histamínicos H1/uso terapéutico , Pirilamina/uso terapéutico , Serotonina/farmacología , Porcinos , Vasodilatación , Vasodilatadores/farmacologíaRESUMEN
The breathing rhythm serves as a reference that paces orofacial motor actions and orchestrates active sensing. Past work has reported that pacing occurs solely at a fixed phase relative to sniffing. We re-evaluated this constraint as a function of exploratory behavior. Allocentric and egocentric rotations of the head and the electromyogenic activity of the motoneurons for head and orofacial movements were recorded in free-ranging rats as they searched for food. We found that a change in state from foraging to rearing is accompanied by a large phase shift in muscular activation relative to sniffing, and a concurrent change in the frequency of sniffing, so that pacing now occurs at one of the two phases. Further, head turning is biased such that an animal gathers a novel sample of its environment upon inhalation. In total, the coordination of active sensing has a previously unrealized computational complexity. This can emerge from hindbrain circuits with fixed architecture and credible synaptic time delays.
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Movimiento , Vibrisas , Ratas , Animales , Vibrisas/fisiología , Movimiento/fisiología , Conducta Exploratoria/fisiología , Rombencéfalo , Neuronas Motoras , Movimientos de la Cabeza/fisiologíaRESUMEN
Hate crimes and hateful rhetoric targeting individuals of Asian descent have increased since the outbreak of COVID-19. These troubling trends have heightened concerns about the role of the Internet in facilitating radicalization. This article explores the existence of three warning signs of radicalization-fixation, group identification, and energy bursts-using data from Twitter and Reddit. Data were collected before and after the outbreak of COVID-19 to assess the role of the pandemic in affecting social media behavior. Using computational social science and Natural Language Processing techniques, we looked for signs of radicalization targeting China or Chinese individuals. Results show that fixation on the terms China and Chinese increased on Twitter and Reddit after the pandemic began. Moreover, tweets and posts containing either of these terms became more hateful, offensive, and negative after the outbreak. We also found evidence of individuals identifying more closely with a particular group, or adopting an "us vs. them" mentality, after the outbreak of COVID-19. These findings were especially prominent in subreddits catering to self-identified Republicans and Conservatives. Finally, we detected bursts of activity on Twitter and Reddit following the start of the pandemic. These warning signs suggest COVID-19 may have had a radicalizing effect on some social media users. This work is important because it not only shows the potential radicalizing effect of the pandemic, but also demonstrates the ability to detect warning signs of radicalization on social media. This is critical, as detecting warning signs of radicalization can potentially help curb hate-fueled violence.
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COVID-19 , Racismo , Medios de Comunicación Sociales , Humanos , Pueblo Asiatico , OdioRESUMEN
Eriogynapyretorum Westwood is a notorious defoliator of Camphoraofficinarum Nees that causes large economic and ecological losses in planted forests. To understand the importance of suppressing the population of E.pyretorum on natural parasitoids, a four-years investigation was conducted in the field. Four egg parasitoid species Ooencyrtuskuvanae Howard, Trichogrammachionis Ishii, Telenomus sp. and Anastatusdexingensis Sheng & Wang were captured in the wild. One of these is the dominant endoparasitoid species T.chionis, which has a quicker developmental time (8.33 d), more offspring (8.39/egg) and a greater parasitism rate (89.54%). With different elevation distributions, the parasitism rates for Kriechbaumerellalongiscutellaris Qian & He, Gregopimplahimalayensis (Cameron), Theroniadepressa (Gupta) and Xanthopimplakonowi (Krieger) were 17.29%, 2.10%, 4.23% and 0.83%, respectively. Female longevity (47.75 d), offspring (13.36/pupa) and sex ratio (1.16:1) were compared in four pupal parasitoids and K.longiscutellaris was the most abundant species of E.pyretorum in Fujian Province.
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The complete mitochondrial genomes (mitogenomes) of beetles in the tribe Scolytoplatypodini (genus Scolytoplatypus) were sequenced and annotated. These included Scolytoplatypus raja (15,324 bp), Scolytoplatypus sinensis (15,394 bp), Scolytoplatypus skyliuae (15,167 bp), and Scolytoplatypus wugongshanensis (15,267 bp). The four mitogenomes contained 37 typical genes, including 13 protein-coding genes (PCGs), 22 transfer RNA genes (tRNAs), and 2 ribosomal RNA genes (rRNAs). The gene orientation and arrangement of the four mitogenomes were similar to other Coleoptera mitogenomes. PCGs mostly started with ATN and terminated with TAA. The Ka/Ks ratio of 13 PCGs in the four species revealed that cox1 had the slowest evolutionary rate and atp8 and nad6 had a higher evolutionary rate. All tRNAs had typical cloverleaf secondary structures, but trnS1 lacked dihydrouridine arm. Partial tRNAs lost the discriminator nucleotide. The trnY did not possess the discriminator nucleotide and also lost three bases, showing a special amino-acyl arm. Bayesian inference (BI) and maximum likelihood (ML) methods were conducted for phylogenetic analyses using 13 PCGs. Scolytoplatypodini was clustered with Hylurgini and Hylastini, and the monophyly of Scolytoplatypodini was supported. The four newly sequenced mitogenomes increase understanding of the evolutionary relationships of Scolytoplatypodini and other Scolytinae species.
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Escarabajos , Genoma Mitocondrial , Gorgojos , Animales , Escarabajos/genética , Gorgojos/genética , Filogenia , Teorema de Bayes , ARN de Transferencia/genética , NucleótidosRESUMEN
Introduction: Tumor progression is driven by intrinsic malignant behaviors caused by gene mutation or epigenetic modulation, as well as crosstalk with the components in the tumor microenvironment (TME). Considering the current understanding of the tumor microenvironment, targeting the immunomodulatory stromal cells such as cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) could provide a potential therapeutic strategy. Here, we investigated the effect of sulfatinib, a multi-targeted tyrosine kinase inhibitor (TKI) of FGFR1, CSF1R, and VEGFR1-3, on the treatment of osteosarcoma (OS). Methods: In vitro, the antitumor effect was tested by clony formation assay and apoptosis assay.The inhibition of tumor migration and invasion was detected by Transwell assay, and the de-polarization of macrophage was detected by flow cytometry.In vivo, subcutaneous and orthotopic tumor models were established to verify antitumor effect, and the underlying mechanism was verified by immunohistochemistry(IHC), immunofluorescence(IF) and flow cytometry. Results: Sulfatinib suppressed OS cell migration and invasion by inhibiting epithelial-mesenchymal transition (EMT) by blocking the secretion of basic fibroblast growth factor (bFGF) in an autocrine manner. In addition, it regulated immune TME via inhibition of the migration of skeletal stem cells (SSCs) to the TME and the differentiation from SSCs to CAFs. Moreover, sulfatinib can suppress OS by modulation of the TME by inhibiting M2 polarization of macrophages. Systemic treatment of sulfatinib can reduce immunosuppression cells M2-TAMs, Tregs, and myeloid-derived suppressor cells (MDSCs) and increase cytotoxic T-cell infiltration in tumors, the lungs, and the spleens. Discussion: Our preclinical experiments have shown that sulfatinib can inhibit the proliferation, migration, and invasion of OS by playing a dual role on tumor cells and the tumor microenvironment simultaneously and systematically reverse immunosuppression to immune activation status, which could be translated into clinical trials.
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Orofacial motor actions are movements that, in rodents, involve whisking of the vibrissa, deflection of the nose, licking and lapping with the tongue, and consumption through chewing. These actions, along with bobbing and turning of the head, coordinate to subserve exploration while not conflicting with life-supporting actions such as breathing and swallowing. Orofacial and head movements are comprised of two additive components: a rhythm that can be entrained by the breathing oscillator and a broadband component that directs the actuator to the region of interest. We focus on coordinating the rhythmic component of actions into a behavior. We hypothesize that the precise timing of each constituent action is continually adjusted through the merging of low-level oscillator input with sensory-derived, high-level rhythmic feedback. Supporting evidence is discussed.
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Movimiento , Nariz , Animales , Roedores , Respiración , VibrisasRESUMEN
Despite the extraordinary success of immune checkpoint inhibitors (ICIs) in cancer treatment, their use is associated with a high incidence of immune-related adverse events (IRAEs), resulting from therapy-related autoimmunity against various target organs. ICI-induced myocarditis is one of the most severe forms of IRAE, which is associated with risk of hemodynamic compromise and mortality. Despite increasing recognition and prompt treatment by clinicians, there remain significant gaps in knowledge regarding the pathophysiology, diagnosis and treatment of ICI-induced myocarditis. As the newly emerged disease entity is relatively rare, it is challenging for researchers to perform studies involving patients at scale. Alternatively, mouse models have been developed to facilitate research understanding of the pathogenesis of ICI-induced myocarditis and drug discovery. Transgenic mice with immune checkpoint genes knocked out allow induction of myocarditis in a highly reproducible manner. On the other hand, it has not been possible to induce ICI-induced myocarditis in wild type mice by injecting ICIs monotherapy alone. Additional interventions such as combinational ICI, tumor inoculation, cardiac sarcomere immunization, or cardiac irradiation are necessary to mimic the underlying pathophysiology in human cancer patients and to induce ICI-induced myocarditis successfully. This review focuses on the immunopathogenesis of ICI-induced myocarditis, drawing insights from human studies and animal models, and discusses the potential implications for treatment.
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Endothelial regeneration and dyslipidemia impair endothelium-dependent relaxation, while supplementation with fish oil (FO) prevents it. The genomic impact of different diets was compared in primary cultures derived from native and regenerated endothelial cells. Pigs were fed with high-cholesterol (CHL) or FO-rich diet. Partial in vivo removal of endothelium was performed to induce endothelial regeneration. Native and regenerated cells were harvested, cultured, and prepared for genomic (microarray experiments, real-time PCR) and proteomic (Western blotting) analysis. The analysis identified genomic changes induced by chronic CHL diet in native cultures resembling those induced by in vivo regeneration, as well as those that could be prevented by FO diet. At the protein level, the reduced and increased presences of endothelial nitric oxide synthase and F2, respectively, observed after regeneration combined with CHL diet were alleviated by FO. The comparison of the differential changes induced by regeneration in vivo in endothelial cells from both diet groups revealed a limited number of genes as the most likely contributors to reduction in endothelium-dependent relaxations in porcine coronary arteries lined with regenerated endothelium.
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Dieta , Células Endoteliales/metabolismo , Genómica/métodos , Porcinos/genética , Animales , Western Blotting , Peso Corporal/efectos de los fármacos , Células Cultivadas , Colesterol en la Dieta/administración & dosificación , Colesterol en la Dieta/farmacología , Vasos Coronarios/metabolismo , Endotelio Vascular/citología , Endotelio Vascular/fisiología , Ácidos Grasos Insaturados/administración & dosificación , Ácidos Grasos Insaturados/farmacología , Femenino , Perfilación de la Expresión Génica , Lípidos/sangre , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteómica/métodos , Distribución Aleatoria , Regeneración , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Porcinos/metabolismo , Transcriptoma/efectos de los fármacosRESUMEN
BACKGROUND: Prior experimental studies show that thoracic spinal cord stimulation (SCS) improves left ventricular (LV) ejection fraction (LVEF). The mechanism of this improvement in the LV contractile function after SCS and its effects on the myocardial oxygen consumption remains unknown. METHODS AND RESULTS: We performed thoracic SCS (T1-T2 level) followed by 4 weeks of rapid ventricular pacing in 9 adult pigs with ischemic heart failure (HF) induced by myocardial infarction (MI). At 24 hours off-pacing, detailed echocardiogram and invasive hemodynamic assessment were performed to determine LV contractile function and myocardial oxygen consumption. Serum norepinephrine level was measured before and after SCS. SCS was performed on 2 occasions for 15 minutes, 30 minutes apart (recovery) with 50 Hz frequency (pulse width 0.2 millisecond, 90% of motor threshold at 2 Hz output). Echocardiogram revealed significant decrease in LVEF (33.8 ± 1.8% vs 66.5 ± 1.7%, P < 0.01) after induction of MI and HF. Compared with MI and HF, acute SCS significantly increased LVEF and +dP/dt (all P < 0.05). Withdrawal of SCS during recovery decreased +dP/dt, but not LVEF that increased again with repeated SCS. Myocardial oxygen consumption also significantly decreased during SCS compared with MI and HF (P = 0.006) without any change in serum norepinephrine level (P = 0.9). Speckle tracking imaging showed significant improvement in global and regional circumferential strains over the infarcted mid and apical regions, decreased in time to peak circumferential strain over the lateral and posterior wall after SCS, and the degree of intraventricular dyssynchrony during SCS compared with MI and HF (P < 0.05). CONCLUSIONS: In a porcine model of ischemic HF, acute SCS improved global and regional LV contractile function and intraventricular dyssynchrony, and decreased myocardial oxygen consumption without elevation of norepinephrine level.
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Terapia por Estimulación Eléctrica/métodos , Insuficiencia Cardíaca/terapia , Contracción Miocárdica , Isquemia Miocárdica/complicaciones , Miocardio/metabolismo , Consumo de Oxígeno , Médula Espinal , Disfunción Ventricular Izquierda/terapia , Función Ventricular Izquierda , Animales , Biomarcadores/sangre , Cateterismo Cardíaco , Modelos Animales de Enfermedad , Ecocardiografía Doppler , Femenino , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/fisiopatología , Norepinefrina/sangre , Recuperación de la Función , Volumen Sistólico , Porcinos , Vértebras Torácicas , Factores de Tiempo , Disfunción Ventricular Izquierda/diagnóstico , Disfunción Ventricular Izquierda/etiología , Disfunción Ventricular Izquierda/metabolismo , Disfunción Ventricular Izquierda/fisiopatologíaRESUMEN
This study describes two new species, Scolytoplatypuswugongshanensis Liao, Lai & Beaver, sp. nov. and S.skyliuae Liao, Lai & Beaver, sp. nov., reinstates S.sinensis (Tsai & Huang, 1965) from synonymy with S.mikado (Blandford, 1893), and records five species for the first time from China, S.brahma Blandford, 1898, S.curviciliosus Gebhardt, 2006, S.minimus Hagedorn, 1904, S.ruficauda Eggers, 1939, S.samsinghensis Maiti & Saha, 2009, and three from mainland China, S.blandfordi Gebhardt, 2006, S.calvus Beaver & Liu, 2007, S.pubescens Hagedorn, 1904. A key to the males of Scolytoplatypus species in China is given. Genetic data from four genes indicate a rather isolated position for both new species, although their genetic relationship to each other was close.