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BACKGROUND/AIMS: Metabolic-associated fatty liver disease (MAFLD) is a common cause of chronic liver disease worldwide. However, there is currently no recognized effective drugs for treating it. MATERIALS AND METHODS: In this study, we investigated the efficacy of Honokiol (HNK) in vitro for mitigating MAFLD. Then, 0.4 mM palmitic acid (PA) and LO2 cells were used to establish the MAFLD model. The protective effect of HNK on MAFLD was confirmed by Oil Red O staining and cell counting kit (CCK-8) assay in LO2 cell line. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were carried out to analyze the regulatory role of HNK on Nrf2 and RIPK3 signaling pathways. The effect of HNK and its downstream signaling pathways on oxidative stress were verified by the detection of reactive oxygen species (ROS), malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD). The concentration of IL-1ß, IL-6L, and TNF-α was assessed by enzyme-linked immunosorbent assay (ELISA). RESULTS: The middle concentration of HNK (50 µmol/L) was selected as the best option for inhibiting lipidosis and oxidative stress in MAFLD models. Honokiol mitigates MAFLD via activation of nuclear factor E2-related factor 2 (Nrf2) signaling pathways in vitro. Honokiol suppressed MAFLD via activating the Nrf2 signaling pathway to play an antioxidant and anti-inflammatory role. Also, HNK regulates Nrf2 and RIPK3 signaling pathways to mitigate MAFLD. CONCLUSION: Our results showed that HNK may suppress the oxidative stress and inflammation in MAFLD via activation of Nrf2 signaling pathway.
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Compostos de Bifenilo , Lignanas , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , Proteína Serina-Treonina Quinases de Interação com Receptores , Transdução de Sinais , Lignanas/farmacologia , Lignanas/uso terapêutico , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Humanos , Compostos de Bifenilo/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Linhagem Celular , Espécies Reativas de Oxigênio/metabolismo , Ácido Palmítico/farmacologia , Compostos Alílicos , FenóisRESUMO
This paper presents the development of path-tracking control strategies for an over-actuated autonomous electric vehicle. The vehicle platform is equipped with four-wheel steering (4WS) as well as torque vectoring (TV) capabilities, which enable the control of vehicle dynamics to be enhanced. A nonlinear model predictive controller is proposed taking into account the nonlinearities in vehicle dynamics at the limits of handling as well as the crucial actuator constraints. Controllers with different actuation formulations are presented and compared to study the path-tracking performance of the vehicle with different levels of actuation. The controllers are implemented in a high-fidelity simulation environment considering scenarios of vehicle handling limits. According to the simulation results, the vehicle achieves the best overall path-tracking performance with combined 4WS and TV, which illustrates that the over-actuation topology can enhance the path-tracking performance during conditions under the limits of handling. In addition, the performance of the over-actuation controller is further assessed with different sampling times as well as prediction horizons in order to investigate the effect of such parameters on the control performance, and its capability for real-time execution. In the end, the over-actuation control strategy is implemented on a target machine for real-time validation. The control formulation proposed in this paper is proven to be compatible with different levels of actuation, and it is also demonstrated in this work that it is possible to include the particular over-actuation formulation and specific nonlinear vehicle dynamics in real-time operation, with the sampling time and prediction time providing a compromise between path-tracking performance and computational time.
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We demonstrate the first ten-watt-level eye-safe intracavity crystalline Raman laser, to the best of our knowledge. The efficient high-power eye-safe Raman laser is intracavity-pumped by an acousto-optically Q-switched 1314â nm two-crystal Nd:YLF laser. Benefiting from the unique bi-axial properties of KGW crystal, two sets of eye-safe dual-wavelength Raman lasers operating at 1461, 1645â nm and 1490, 1721nm are achieved by rotating the Raman crystal. Under the launched pump power of 84.9 W and the repetition rate of 4 kHz, the maximum first-Stokes output powers of 7.9 W at 1461â nm and 8.2 W at 1490â nm are acquired with the second-Stokes output powers of 1.4 W at 1645â nm and 1.5 W at 1721nm, respectively, leading to the eye-safe dual-wavelength Raman output powers of up to 9.3 and 9.7 W. Meanwhile, the pulse durations at the wavelengths of 1461, 1490, 1645, 1721nm are determined to be 4.8, 5.5, 4.3, and 3.6â ns, respectively, which give rise to the peak powers approaching about 410, 370, 80, 100â kW. These Stokes emissions are found to be near diffraction limited with M2 < 1.6 across the entire output power range.
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A highly powerful nanosecond pulsed deep-red laser was demonstrated by intracavity second-harmonic generation of an actively Q-switched Nd:YLF dual-crystal-based KGW Raman laser in a critically phase-matched lithium triborate (LBO) crystal. The first-Stokes fields at 1461 and 1490â nm driven by the 1314â nm fundamental laser were firstly produced by accessing the Raman shifts of 768 and 901â cm-1 in the KGW crystal, respectively, and thereafter converted to the deep-red emission lines at 731 and 745â nm by finely tuning the phase-matching angle of the LBO crystal and carefully realigning the resonator. Integrating the benefits of the Nd:YLF dual-crystal configuration and the meticulously designed L-shaped resonator, this deep-red laser system delivered the maximum average output powers of 5.2 and 7.6â W with the optical power conversion efficiencies approaching 6.3% and 9.2% under the optimal pulse repetition frequency of 4â kHz, respectively. The pulse durations of 6.7 and 5.5â ns were acquired with the peak powers up to approximately 190 and 350â kW, respectively, and the resultant beam qualities were determined to be near-diffraction-limited with M2 ≈ 1.5.
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We report on a high-repetition-rate and high-beam-quality all-solid-state nanosecond pulsed deep-red laser source by intracavity second harmonic generation of the actively Q-switched Nd:YVO4/KGW Raman laser. The polarization of the 1342â nm fundamental laser was aligned with the Ng and Nm axes of KGW crystal for accessing the eye-safe Raman lasers at 1496 and 1526â nm, respectively. With the aid of the elaborately designed V-shaped resonator and the composite Nd:YVO4 crystal, excellent mode matching and good thermal diffusion have been confirmed. Under an optimal pulse repetition frequency of 25 kHz, the average output powers of the Raman lasers at 1496 and 1526â nm were measured to be 3.7 and 4.9 W with the superior beam quality factor of M2 = 1.2, respectively. Subsequently, by incorporating a bismuth borate (BIBO) crystal, the deep-red laser source was able to lase separately two different spectral lines at 748 and 763â nm, yielding the maximum average output powers of 2.5 and 3.2 W with the pulse durations of 15.6 and 11.3â ns, respectively. The resulting beam quality was determined to be near-diffraction-limited with M2 = 1.28.
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We demonstrate an efficient wavelength-selectable output in the attractive deep-red spectral region from an intracavity frequency converted Nd:YLF/KGW Raman laser. Driven by an acousto-optic Q-switched 1314â nm Nd:YLF laser, two first-Stokes waves at 1461 and 1490â nm were generated owing to the bi-axial properties of KGW crystal. By incorporating intracavity sum-frequency generation and second-harmonic generation with an angle-tuned bismuth borate (BIBO) crystal, four discrete deep-red laser emission lines were yielded at the wavelengths of 692, 698, 731, and 745â nm. Under the incident pump power of 50 W and the repetition rate of 4 kHz, the maximum average output powers of 2.4, 2.7, 3.3, and 3.6 W were attained with the pulse durations of 3.4, 3.2, 4.3, and 3.7â ns, respectively, corresponding to the peak powers up to 177, 209, 190, and 245â kW. The results indicate that the Nd:YLF/KGW Raman laser combined with an angle-adjusted BIBO crystal provides a reliable and convenient approach to achieve the selectable multi-wavelength deep-red laser with short pulse duration and high peak power.
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Automated vehicles are expected to push towards the evolution of the mobility environment in the near future by increasing vehicle stability and decreasing commute time and vehicle fuel consumption. One of the main limitations they face is motion sickness (MS), which can put their wide impact at risk, as well as their acceptance by the public. In this direction, this paper presents the application of motion planning in order to minimise motion sickness in automated vehicles. Thus, an optimal control problem is formulated through which we seek the optimum velocity profile for a predefined road path for multiple fixed journey time (JT) solutions. In this way, a Pareto Front will be generated for the conflicting objectives of MS and JT. Despite the importance of optimising both of these, the optimum velocity profile should be selected after taking into consideration additional objectives. Therefore, as the optimal control is focused on the MS minimisation, a sorting algorithm is applied to seek the optimum solution among the pareto alternatives of the fixed time solutions. The aim is that this solution will correspond to the best velocity profile that also ensures the optimum compromise between motion comfort, safety and driving behaviour, energy efficiency, journey time and riding confidence.
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Condução de Veículo , Enjoo devido ao Movimento , Algoritmos , Humanos , Movimento (Física) , Meios de TransporteRESUMO
The present study examined neural substrates underlying turn-based cooperation and competition in a real two-person situation. We simultaneously measured pairs of participants' activations in their bilateral frontal, temporal, and parietal regions using a 96-channel near-infrared spectroscopy (NIRS) system, when participants played a turn-taking disk-game on a computer. NIRS data demonstrated significant inter-brain neural synchronization (INS) across participant pairs' right posterior superior temporal sulcus (pSTS) in both the cooperation and competition conditions, and the competition condition also involved significant INS in the right inferior parietal lobule (IPL). In addition, competitive dyads' INS in the bilateral inferior frontal gyrus (IFG) may play as a role of mediation in relationship between their empathy score and disk-manipulation latency, but cooperative dyads' INS did not. These results suggest that first the right pSTS may be commonly involved in both cooperation and competition due to task demands of joint attention and intention understanding, while the right IPL may be more important for competition due to additional requirements of mentalizing resources in competing contexts. Second, participants' empathy may promote INS in the bilateral IFG across competitors, and in turn affect their competitive performance.
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Mapeamento Encefálico , Encéfalo/fisiologia , Comportamento Competitivo , Comportamento Cooperativo , Vias Neurais , Espectroscopia de Luz Próxima ao Infravermelho , Análise de Variância , Fenômenos Eletrofisiológicos , Empatia , Feminino , Humanos , Masculino , Reprodutibilidade dos TestesRESUMO
OBJECTIVE: To investigate the effect of metronomic chemotherapy of low dose phosphoramide combined with prednisolone (CP metronomic chemotherapy) on proliferation and apoptosis of RPMI 8226 cells, and to explore its regulating effect on Notch1/NF-κB signaling pathways. METHODS: Experiment was divided into the DMSO control group, and the phosphoramide mustard (PM) group, the prednisolone group, the phosphoramide mustard plus prednisolone group (the CP group). RPMI 8226 cells were treated with different drugs, CCK-8 method was used to detect cell proliferation, flow cytometry was used to detect the cell cycle and apoptosis, reverse transcription PCR was used to detect Notch1 and NF-κB mRNA expression level. RESULTS: Compared with DMSO control group, RPMI8226 cell proliferation inhibition rate in all the PM, prednisolone and CP groups increased significantly with prolonging of time (r of 0.994,0.996,0.999, respectively, P<0.001). And at the same time, the inhibitory rate of cell proliferation was significantly different; the cell inhibitory rate in PM group was lowest, that in CP group was highgest, that in prednissone group was intermediate (P<0.01). After 48 hours, compared with the DMSO control group, the G1/G0 cell proportion in treatment group increased significantly, S phase cell proportion decreased significantly, especially in PM and CP groups. The G2/M phase cell proportion increased in PM group, while reduced in the prednisolone and the CP groups. After 48 hours, compared with the DMSO control group, RPMI 8226 cell apoptosis rate increased as follow: in PM, pre-dnisolone and CP group(P<0.01). After 48 hours, compared with the DMSO control group, Notch1 and NF-κB mRNA expression in the prednisolone, the PM and the CP group decreased significantly(P<0.001). CONCLUSION: CP metronomic chemotherapy can significantly reduce RPMI 8226 cell proliferation, promote RPMI 8226 cell apoptosis, arrest RPMI 8226 cells mainly in the G1/G0 phase, and significantly reduce Notch1 and NF-κB expression levels. It is suggested that Notch1/NF-κB signaling pathways is involved in CP metronomic chemotherapy for MM.
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Transdução de Sinais , Antineoplásicos , Apoptose , Contagem de Células , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Humanos , NF-kappa B , Receptor Notch1 , Fator de Transcrição RelARESUMO
OBJECTIVE: To investigate effects of low-dose cyclophosphamide and prednisone (CP) metronomic chemotherapy on microvessel density of bone marrow, serum vascular endothelial growth factor (VEGF) and platelet derived growth factor BB (PDGF-BB)in multiple myeloma (MM) patients. METHODS: 54 refractory or relapsed MM patients were treated with CP metronomic chemotherapy consisted of oral cyclophosphamide (CTX, 50 mg/d) and prednisone (Pred, 15 mg/d). Bone marrow and peripheral blood of each patient were collected before and 2, 4, 6 months after treatment. Among the 37 assessable patients, 30 cases were responsive with the response rate of 81.08%. Another 17 cases were follow-uped less than 6 months or failure to obtain serum samples or lost to follow-up. Microvessel density of bone marrow was measured by immunohistochemistry and serum VEGF/PDGF-BB expression was analyzed by ELISA in the 37 assessable patients. RESULTS: 2, 4, 6 months following CP metronomic chemotherapy, microvessel densities of bone marrow in the responders were 33.1 ± 4.8/HP, 24.8 ± 3.7/HP, 19.7 ± 2.1/HP respectively; the expressions of VEGF were (394 ± 57) ng/L, (268 ± 32) ng/L and (217 ± 20) ng/L respectively; the expressions of PDGF-BB were (304 ± 31) ng/L, (274 ± 31) ng/L and (196 ± 22) ng/L respectively. After CP metronomic chemotherapy, there were significantly lower of microvessel density, VEGF and PDGF-BB levels than pretreatment \[MVD 48.5 ± 5.9/HP, VEGF (517 ± 60) ng/L, PDGF-BB (484 ± 60) ng/L\]in the responders (P < 0.01). While in the non-responders, after treated by CP metronomic chemotherapy for 2 months, microvessel density, the expression of VEGF and the expression of PDGF-BB were 32.5 ± 4.7/HP, 512 ± 39 ng/L and (452 ± 39) ng/L respectively. There were no significant changes of MVD, VEGF and PDGF-BB levels compared with pretreatment \[MVD 33.2 ± 5.6/HP,VEGF (498 ± 55) ng/L, PDGF-BB (488 ± 44) ng/L\] (P > 0.05). CONCLUSIONS: Our findings suggested that continuous low-dose CP metronomic chemotherapy could decrease microvessel density of bone marrow in MM patients. Furthermore, it down-regulated expression of serum VEGF and PDGF-BB to exert its anti-angiogenesis in MM.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/irrigação sanguínea , Mieloma Múltiplo/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/administração & dosagem , Becaplermina , Ciclofosfamida/administração & dosagem , Feminino , Humanos , Masculino , Microvasos/efeitos dos fármacos , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Prednisona/administração & dosagem , Proteínas Proto-Oncogênicas c-sis/sangue , Fator A de Crescimento do Endotélio Vascular/sangueRESUMO
The mechanism of idiopathic ventricular tachycardia originating from the right ventricular outflow tract (RVOT) is not clear. Many clinical reports have suggested a mechanism of triggered activity. However, there are few studies investigating this because of the technical difficulties associated with examining this theory. The L-type calcium current (I (Ca-L)), an important inward current of the action potential (AP), plays an important role in arrhythmogenesis. The aim of this study was to explore differences in the APs of right ventricular (RV) and RVOT cardiomyocytes, and differences in electrophysiological characteristics of the ICa-L in these myocytes. Rabbit RVOT and RV myocytes were isolated and their AP and I (Ca-L) were investigated using the patch-clamp technique. RVOT cardiomyocytes had a wider range of AP duration (APD) than RV cardiomyocytes, with some markedly prolonged APDs and markedly shortened APDs. The markedly shortened APDs in RVOT myocytes were abolished by treatment with 4-AP, an inhibitor of the transient outward potassium current, but the markedly prolonged APDs remained, with some myocytes with a long AP plateau not repolarizing to resting potential. In addition, early afterdepolarization (EAD) and second plateau responses were seen in RVOT myocytes but not in RV myocytes. RVOT myocytes had a higher current density for I (Ca-L) than RV myocytes (RVOT (13.16±0.87) pA pF(-1), RV (8.59±1.97) pA pF(-1); P<0.05). The I (Ca-L) and the prolonged APD were reduced, and the EAD and second plateau response disappeared, after treatment with nifedipine (10 µmol L(-1)), which blocks the I (Ca-L). In conclusion, there was a wider range of APDs in RVOT myocytes than in RV myocytes, which is one of the basic factors involved in arrhythmogenesis. The higher current density for I (Ca-L) is one of the factors causing prolongation of the APD in RVOT myocytes. The combination of EAD with prolonged APD may be one of the mechanisms of RVOT-VT generation.
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Canais de Cálcio Tipo L/metabolismo , Ventrículos do Coração/metabolismo , Miócitos Cardíacos/metabolismo , Potenciais de Ação/fisiologia , Animais , Ventrículos do Coração/fisiopatologia , Humanos , Masculino , Miócitos Cardíacos/citologia , Técnicas de Patch-Clamp , Coelhos , Taquicardia Ventricular/fisiopatologiaRESUMO
A 19-year-old woman with skeletal Class III malocclusion, paranasal depression, and a low mandibular plane angle was treated with orthodontics and orthognathic surgery. Dental decompensation and protraction of maxillary right third molar to replace maxillary right second molar were performed before surgery. Clockwise rotation of maxillo-mandibular complex was applied by Le Fort I osteotomy and bilateral sagittal split osteotomies to achieve facial balance. The active treatment period was 12 months. The stable occlusion and skeletal relationship were observed after a 10-month follow-up period.
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Má Oclusão Classe III de Angle/cirurgia , Mandíbula/cirurgia , Maxila/cirurgia , Procedimentos Cirúrgicos Ortognáticos/métodos , Cefalometria/métodos , Feminino , Seguimentos , Humanos , Má Oclusão Classe III de Angle/terapia , Osteotomia de Le Fort/métodos , Osteotomia Sagital do Ramo Mandibular/métodos , Sobremordida/cirurgia , Sobremordida/terapia , Planejamento de Assistência ao Paciente , Prognatismo/cirurgia , Prognatismo/terapia , Rotação , Técnicas de Movimentação Dentária/métodos , Resultado do Tratamento , Dimensão Vertical , Adulto JovemRESUMO
PURPOSE: The purpose of this study was to evaluate the efficacy and tolerability of continuous low-dose cyclophosphamide and prednisone (CP) as a salvage therapy for multiple myeloma (MM). PATIENTS AND METHODS: A total of 27 consecutive patients with MM received a treatment regimen that consisted of oral cyclophosphamide 50 mg and prednisone 15 mg daily. Nineteen patients had severe comorbid conditions; 8 were unwilling to continue conventional chemotherapy as a result of severe infection associated with the conventional chemotherapy. Patients had received 1 to 4 chemotherapeutic regimens before the enrollment. RESULTS: The overall response rate (complete remission, very good partial response, and partial response) was 66.7%. The median time to response was 2 months. In the patients who responded to the treatment, the median progression-free survival (PFS) has not been reached. In the nonresponding patients, the median PFS was 4 months. CONCLUSION: Continuous low-dose CP is an effective and well-tolerated salvage therapy for MM.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Humanos , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Terapia de SalvaçãoRESUMO
Metal-responsive transcription factor, MTF-1 is a zinc finger protein, shown to be essential for embryonic development. Homozygous knockout mouse embryos for MTF-1 die in utero at day 14 of gestation, due to liver decay. In the present study, we report the complete nucleotide sequence of cDNA encoding zebrafish MTF-1 and the amino acid sequence similarity with that of mouse, human, fish and Drosophila. The size of the zebrafish MTF-1 cDNA is 3,379 bp and the coding region (1,779 bp) encodes a polypeptide of 593 amino acids. The putative zinc finger and transactivation domains comprised by zebrafish MTF-1 were also determined. The zebrafish MTF-1 shows high identity of 97, 93, 93 and 67% in the DNA binding zinc finger domain and 51, 44, 48 and 20% overall identity with fugu, human, mouse and Drosophila, respectively. RT-PCR results show the maternal expression of MTF-1 transcripts. The pattern of MTF-1 gene expression during embryonic and early larval development was studied by whole-mount in situ hybridization using DIG-labeled anti-sense RNA probe. Stronger and ubiquitous expression was observed during the embryonic stages whereas, specific expression, especially in the neural parts, was observed throughout the stages studied after hatching.