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Speech recognition crucially relies on slow temporal modulations (<16 Hz) in speech. Recent studies, however, have demonstrated that the long-delay echoes, which are common during online conferencing, can eliminate crucial temporal modulations in speech but do not affect speech intelligibility. Here, we investigated the underlying neural mechanisms. MEG experiments demonstrated that cortical activity can effectively track the temporal modulations eliminated by an echo, which cannot be fully explained by basic neural adaptation mechanisms. Furthermore, cortical responses to echoic speech can be better explained by a model that segregates speech from its echo than by a model that encodes echoic speech as a whole. The speech segregation effect was observed even when attention was diverted but would disappear when segregation cues, i.e., speech fine structure, were removed. These results strongly suggested that, through mechanisms such as stream segregation, the auditory system can build an echo-insensitive representation of speech envelope, which can support reliable speech recognition.
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Córtex Auditivo , Percepção da Fala , Humanos , Percepção da Fala/fisiologia , Inteligibilidade da Fala/fisiologia , Encéfalo , Córtex Auditivo/fisiologia , Atenção , Estimulação AcústicaRESUMO
Invasive candidiasis caused by non-albicans species has been on the rise, with Candida glabrata emerging as the second most common etiological agent. Candida glabrata possesses an intrinsically lower susceptibility to azoles and an alarming propensity to rapidly develop high-level azole resistance during treatment. In this study, we have developed an efficient piggyBac (PB) transposon-mediated mutagenesis system in C. glabrata to conduct genome-wide genetic screens and applied it to profile genes that contribute to azole resistance. When challenged with the antifungal drug fluconazole, PB insertion into 270 genes led to significant resistance. A large subset of these genes has a role in the mitochondria, including almost all genes encoding the subunits of the F1F0 ATPase complex. We show that deleting ATP3 or ATP22 results in increased azole resistance but does not affect susceptibility to polyenes and echinocandins. The increased azole resistance is due to increased expression of PDR1 that encodes a transcription factor known to promote drug efflux pump expression. Deleting PDR1 in the atp3Δ or atp22Δ mutant resulted in hypersensitivity to fluconazole. Our results shed light on the mechanisms contributing to azole resistance in C. glabrata. This PB transposon-mediated mutagenesis system can significantly facilitate future genome-wide genetic screens.
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Candida glabrata , Fluconazol , Fluconazol/metabolismo , Candida glabrata/genética , Farmacorresistência Fúngica/genética , Antifúngicos/farmacologia , Azóis , ATPases Translocadoras de Prótons/metabolismo , Testes de Sensibilidade MicrobianaRESUMO
The proportion of lung cancer in never smokers is rising, especially among Asian women, but there is no effective early detection tool. Here, we developed a polygenic risk score (PRS), which may help to identify the population with higher risk of lung cancer in never-smoking women. We first performed a large GWAS meta-analysis (8595 cases and 8275 controls) to systematically identify the susceptibility loci for lung cancer in never-smoking Asian women and then generated a PRS using GWAS datasets. Furthermore, we evaluated the utility and effectiveness of PRS in an independent Chinese prospective cohort comprising 55 266 individuals. The GWAS meta-analysis identified eight known loci and a novel locus (5q11.2) at the genome-wide statistical significance level of P < 5 × 10-8 . Based on the summary statistics of GWAS, we derived a polygenic risk score including 21 variants (PRS-21) for lung cancer in never-smoking women. Furthermore, PRS-21 had a hazard ratio (HR) per SD of 1.29 (95% CI = 1.18-1.41) in the prospective cohort. Compared with participants who had a low genetic risk, those with an intermediate (HR = 1.32, 95% CI: 1.00-1.72) and high (HR = 2.09, 95% CI: 1.56-2.80) genetic risk had a significantly higher risk of incident lung cancer. The addition of PRS-21 to the conventional risk model yielded a modest significant improvement in AUC (0.697 to 0.711) and net reclassification improvement (24.2%). The GWAS-derived PRS-21 significantly improves the risk stratification and prediction accuracy for incident lung cancer in never-smoking Asian women, demonstrating the potential for identification of high-risk individuals and early screening.
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Neoplasias Pulmonares , Humanos , Feminino , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/genética , Estratificação de Risco Genético , Predisposição Genética para Doença , Estudos de Coortes , Estudos Prospectivos , Estudo de Associação Genômica Ampla , Fatores de Risco , Fumar/genética , Fumar/epidemiologia , ChinaRESUMO
Parkinson's disease (PD) is a degenerative disorder of the nervous system characterized by the loss of dopaminergic neurons and damage of neurons in the substantia nigra (SN) and striatum, resulting in impaired motor functions. This study aims to investigate how extracellular vesicles (EVs) derived from human umbilical cord mesenchymal stem cells (HucMSC) regulate Special AT-rich sequence-binding protein-1 (SATB 1) and influence Wnt/ß-catenin pathway and autophagy in PD model. The PD model was induced by damaging SH-SY5Y cells and mice using 6-OHDA. According to the study, administering EVs every other day for 14 days improved the motor behavior of 6-OHDA-induced PD mice and reduced neuronal damage, including dopaminergic neurons. Treatment with EVs for 12 hours increased the viability of 6-OHDA-induced SH-SY5Y cells. The upregulation of SATB 1 expression with EV treatment resulted in the activation of the Wnt/ß-catenin pathway in PD model and led to overexpression of ß-catenin. Meanwhile, the expression of LC3 II was decreased, indicating alterations in autophagy. In conclusion, EVs could mitigate neuronal damage in the 6-OHDA-induced PD model by upregulating SATB 1 and activating Wnt/ß-catenin pathway while also regulating autophagy. Further studies on the potential therapeutic applications of EVs for PD could offer new insights and strategies.
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The inscription of a helical-sampled fiber Bragg grating (HSFBG) in a ring core fiber (RCF) using a low repetition rate femtosecond laser point-by-point technique is demonstrated. The reflection spectrum exhibits several peak groups attributed to the helical-sampled structure, with the wavelength interval between different groups determined by the helical pitch. Meanwhile, the number and spacing of the peaks within each group are dictated by the RCF. An investigation into the effects of helical pitch, helical radius, and grating length of the HSFBG on the reflection spectra is conducted. Furthermore, thermal annealing experiments demonstrate that this HSFBG can survive at the temperatures up to 800°C.
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A multifunctional single-atom nanozyme, denoted as 3D Ni,N-codoped porous carbon (Ni-NPC), was devised that exhibits remarkable adsorption capabilities and a repertoire of enzyme mimetic functions (oxidase- and peroxidase-like). These attributes stem from the distinctive mesoporous thin-shell structure and well-dispersed Ni sites. The efficient adsorption capacity of Ni-NPC was assessed with respect to three carbamate pesticides (CMPs): metolcarb, carbaryl, and isoprocarb. Moreover, a colorimetric detection method for CMP was established based on its robust peroxidase-like catalytic activity and sequential catalytic interactions with acetylcholinesterase. Furthermore, a portable colorimetric sensor based on a hydrogel sphere integrated with a smartphone platform was devised. This sensor enables rapid, on-site, and quantitative assessment of CMP, boasting an extraordinarily low detection limit of 1.5 ng mL-1. Notably, this sensor was successfully applied to the analysis of CMP levels in lake water and vegetable samples (pakchoi and rape), propelling the progress of real-time detection technologies in food and environment monitoring.
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Praguicidas , Smartphone , Acetilcolinesterase , Praguicidas/análise , Carbamatos/química , Peroxidase , Peroxidases , ColorimetriaRESUMO
Superlattices constructed with the wide-band-gap semiconductor ZnO and magnetic oxide FeO, both in the wurtzite structure, have been investigated using spin-polarized first-principles calculations. The structural, electronic and magnetic properties of the (ZnO)n/(w-FeO)n superlattices were studied in great detail. Two different interfaces in the (ZnO)n/(w-FeO)n superlattices were identified and they showed very different magnetic and electronic properties. Local symmetry-driven interfacial magnetization and electronic states can arise from different Fe/Zn distributions at different interfaces or spin ordering of Fe in the superlattice. The local symmetry-driven interfacial magnetization and electronic states, originating either from different Fe/Zn distribution across interfaces I and II, or by spin ordering of Fe in the superlattice, can be identified. It was also found that, in the case of the ferromagnetic phase, the electrons are more delocalized for the majority spin but strongly localized for the minority spin, which resulted in interesting spin-dependent transport properties. Our results will pave the way for designing novel spin-dependent electronic devices through the construction of superlattices from semiconductors and multiferroics.
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When listening to speech, cortical activity can track mentally constructed linguistic units such as words, phrases, and sentences. Recent studies have also shown that the neural responses to mentally constructed linguistic units can predict the outcome of patients with disorders of consciousness (DoC). In healthy individuals, cortical tracking of linguistic units can be driven by both long-term linguistic knowledge and online learning of the transitional probability between syllables. Here, we investigated whether statistical learning could occur in patients in the minimally conscious state (MCS) and patients emerged from the MCS (EMCS) using electroencephalography (EEG). In Experiment 1, we presented to participants an isochronous sequence of syllables, which were composed of either 4 real disyllabic words or 4 reversed disyllabic words. An inter-trial phase coherence analysis revealed that the patient groups showed similar word tracking responses to real and reversed words. In Experiment 2, we presented trisyllabic artificial words that were defined by the transitional probability between words, and a significant word-rate EEG response was observed for MCS patients. These results suggested that statistical learning can occur with a minimal conscious level. The residual statistical learning ability in MCS patients could potentially be harnessed to induce neural plasticity.
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Aprendizagem , Estado Vegetativo Persistente , Humanos , Aprendizagem/fisiologia , Eletroencefalografia/métodos , Idioma , Percepção AuditivaRESUMO
BACKGROUND AND STUDY AIMS: Gastrointestinal stromal tumors (GIST) carry a potential risk of malignancy, and the treatment of GIST varies for different risk levels. However, there is no systematic preoperative assessment protocol to predict the malignant potential of GIST. The aim of this study was to develop a reliable and clinically applicable preoperative nomogram prediction model to predict the malignant potential of gastric GIST. PATIENTS AND METHODS: Patients with a pathological diagnosis of gastric GIST from January 2015 to December 2021 were screened retrospectively. Univariate and multivariate logistic analyses were used to identify independent risk factors for gastric GIST with high malignancy potential. Based on these independent risk factors, a nomogram model predicting the malignant potential of gastric GIST was developed and the model was validated in the validation group. RESULTS: A total of 494 gastric GIST patients were included in this study and allocated to a development group (n = 345) and a validation group (n = 149). In the development group, multivariate logistic regression analysis revealed that tumor size, tumor ulceration, CT growth pattern and monocyte-to- lymphocyte ratio (MLR) were independent risk factors for gastric GIST with high malignancy potential. The AUC of the model were 0.932 (95% CI 0.890-0.974) and 0.922 (95% CI 0.868-0.977) in the development and validation groups, respectively. The best cutoff value for the development group was 0.184, and the sensitivity and specificity at this value were 0.895 and 0.875, respectively. The calibration curves indicated good agreement between predicted and actual observed outcomes, while the DCA indicated that the nomogram model had clinical application. CONCLUSIONS: Tumor size, tumor ulceration, CT growth pattern and MLR are independent risk factors for high malignancy potential gastric GIST, and a nomogram model developed based on these factors has a high ability to predict the malignant potential of gastric GIST.
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Tumores do Estroma Gastrointestinal , Neoplasias Gástricas , Humanos , Nomogramas , Tumores do Estroma Gastrointestinal/patologia , Estudos Retrospectivos , Neoplasias Gástricas/cirurgia , Neoplasias Gástricas/patologia , Fatores de RiscoRESUMO
Perkinsus, a parasitic pathogen of marine bivalves, is widely distributed among various mollusks in numerous countries. However, the prevalence and diversity of Perkinsus species in the two economically important mussels, Mytilus coruscus and M. galloprovincialis, in China remain unknown. The presence of the Perkinsus species was identified in the two mussels sampled along the coast of the East China Sea and the Yellow Sea, using both the alternative Ray's fluid thioglycolate medium (ARFTM) and conventional polymerase chain reaction (PCR). The ARFTM test indicated the presence of Perkinsus-like hypnospores in the two mussels. The diameter of the hypnospores in M. coruscus was significantly smaller than that in M. galloprovincialis. The prevalence of Perkinsus in M. galloprovincialis and M. coruscus ranged from 0 to 37.5% and 0 to 25%, respectively. The mean intensity of Perkinsus in M. galloprovincialis and M. coruscus ranged from 0 to 5.14 and 0 to 4.92, respectively. The PCR assay showed that the prevalence of Perkinsus spp. in M. galloprovincialis and M. coruscus was 0 to 25.0% and 0 to 12.5%, respectively. The homology analysis of the newly obtained internal transcribed spacer (ITS) sequences of Perkinsus revealed the highest identity of 100% with P. beihaiensis. The phylogenetic analysis indicated that the Perkinsus isolates from the two mussels were clustered with P. beihaiensis. The results of the molecular biology indicated that only P. beihaiensis was detected in the two mussels. The highest prevalence of P. beihaiensis was observed in Liaoning province (Dalian, 20.83%), followed by Shandong province, Zhejiang province and Fujian province. Consequently, it is recommended that surveillance should be conducted in Dalian, where the prevalence and mean intensity of P. beihaiensis in M. galloprovincialis are the highest.
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Mytilus , Animais , Mytilus/parasitologia , China/epidemiologia , Filogenia , Reação em Cadeia da Polimerase , Análise de Sequência de DNA , Alveolados/genética , Alveolados/isolamento & purificação , Alveolados/classificação , DNA de Protozoário/genética , Dados de Sequência Molecular , Prevalência , Oceanos e MaresRESUMO
To address the limitations of LiDAR dynamic target detection methods, which often require heuristic thresholding, indirect computational assistance, supplementary sensor data, or postdetection, we propose an innovative method based on multidimensional features. Using the differences between the positions and geometric structures of point cloud clusters scanned by the same target in adjacent frame point clouds, the motion states of the point cloud clusters are comprehensively evaluated. To enable the automatic precision pairing of point cloud clusters from adjacent frames of the same target, a double registration algorithm is proposed for point cloud cluster centroids. The iterative closest point (ICP) algorithm is employed for approximate interframe pose estimation during coarse registration. The random sample consensus (RANSAC) and four-parameter transformation algorithms are employed to obtain precise interframe pose relations during fine registration. These processes standardize the coordinate systems of adjacent point clouds and facilitate the association of point cloud clusters from the same target. Based on the paired point cloud cluster, a classification feature system is used to construct the XGBoost decision tree. To enhance the XGBoost training efficiency, a Spearman's rank correlation coefficient-bidirectional search for a dimensionality reduction algorithm is proposed to expedite the optimal classification feature subset construction. After preliminary outcomes are generated by XGBoost, a double Boyer-Moore voting-sliding window algorithm is proposed to refine the final LiDAR dynamic target detection accuracy. To validate the efficacy and efficiency of our method in LiDAR dynamic target detection, an experimental platform is established. Real-world data are collected and pertinent experiments are designed. The experimental results illustrate the soundness of our method. The LiDAR dynamic target correct detection rate is 92.41%, the static target error detection rate is 1.43%, and the detection efficiency is 0.0299 s. Our method exhibits notable advantages over open-source comparative methods, achieving highly efficient and precise LiDAR dynamic target detection.
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The development of high-efficiency organic solar cells (OSCs) processed from non-halogenated solvents is crucially important for their scale-up industry production. However, owing to the difficulty of regulating molecular aggregation, there is a huge efficiency gap between non-halogenated and halogenated solvent processed OSCs. Herein, we fabricate o-xylene processed OSCs with approaching 20 % efficiency by incorporating a trimeric guest acceptor named Tri-V into the PM6:L8-BO-X host blend. The incorporation of Tri-V effectively restricts the excessive aggregation of L8-BO-X, regulates the molecular packing and optimizes the phase-separation morphology, which leads to mitigated trap density states, reduced energy loss and suppressed charge recombination. Consequently, the PM6:L8-BO-X:Tri-V-based device achieves an efficiency of 19.82 %, representing the highest efficiency for non-halogenated solvent-processed OSCs reported to date. Noticeably, with the addition of Tri-V, the ternary device shows an improved photostability than binary PM6:L8-BO-X-based device, and maintains 80 % of the initial efficiency after continuous illumination for 1380â h. This work provides a feasible approach for fabricating high-efficiency, stable, eco-friendly OSCs, and sheds new light on the large-scale industrial production of OSCs.
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Sulfated aluminum oxide (SAO), a high surface area material containing sulfate anions that behave like weakly coordinating anions, reacts with Ta(âCHtBu)(CH2tBu)3 to form [Ta(CH2tBu)2(O-)2][SAO] (1). Subsequent treatment with H2 forms Ta-H+ sites supported on SAO that are active in hydrogenolysis and alkane metathesis reactions. In both reactions Ta-H+ is more active than related neutral Ta-H sites supported on silica. This reaction chemistry extends to melts of high-density polyethylene (HDPE), where Ta-H+ converts 30% of a low molecular weight HDPE (Mn = 2.5 kg mol-1; D = 3.6) to low molecular weight paraffins under hydrogenolysis conditions. Under alkane metathesis conditions Ta-H+ converts this HDPE to a high MW fraction (Mn = 6.2 kDa; D = 2.3) and low molecular weight alkane products (C13-C32). These results show that incorporating charge as a design element in supported d0 metal hydrides is a viable strategy to increase the reaction rate in challenging reactions involving reorganization of C-C bonds in alkanes.
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BACKGROUND & AIMS: Physical activity, sedentary behaviour, and genetic variants have been associated with the nonalcoholic fatty liver disease (NAFLD). However, whether and how the degree of healthy activity patterns may modify the impact of genetic susceptibility on NAFLD remains unknown. METHODS: Behaviour activity factors were determined according to total physical activity (TPA) and sedentary time. The polygenic risk score (PRS) was calculated by variants in PNPLA3, TM6SF2, MBOAT7, and GCKR. Cox regression was used to analyse the associations of genetic and behaviour activity factors with incident NAFLD in the UK Biobank (N = 338 087). RESULTS: During a median follow-up of 12.4 years, 3201 incident NAFLD cases were ascertained. Analyses of TPA and sedentary time simultaneously showed a dose-response association with the risk of NAFLD (ptrend < .001). The association of behaviour activity patterns with NAFLD varied by genetic variants. Of the subjects with high genetic risk, we observed a null protective effect of moderate or high TPA on NAFLD risk, while sitting less than three hours a day significantly decreased the risk of NAFLD (p = 3.50 × 10-4 ). The high genetic risk of NAFLD can also be offset by the combination of moderate physical activity and shorter sedentary time. Moreover, the high genetic risk group has the greatest reduction of 10-year absolute risk (6.95 per 1000 person-years) if reaching both healthy activities. CONCLUSIONS: Moderate-to-high physical activity and favourable sedentary behaviour may be lifestyle modifications in preventing NAFLD, which could offset the harmful effect of predisposing genetic factors.
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Hepatopatia Gordurosa não Alcoólica , Humanos , Bancos de Espécimes Biológicos , Predisposição Genética para Doença , Fígado , Proteínas de Membrana/genética , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/genética , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Fatores de Risco , Reino Unido/epidemiologiaRESUMO
BACKGROUND AND STUDY AIMS: The optimal treatment modality for T1-2N0M0 duodenal neuroendocrine tumors (DNETs) is still controversial. In this study, long-term survival outcomes were compared between the endoscopic therapy and surgical therapy for T1-2N0M0 DNETs using the Surveillance, Epidemiology, and End Results (SEER) database. PATIENTS AND METHODS: Patients with DNETs from the SEER database were selected from 2004 to 2015. We used the Kaplan-Meier method and log-rank test to compare long-term survival results between the endoscopic therapy and surgical therapy. An analysis of the multivariable Cox proportional hazards model was performed to identify risk factors for patient prognoses. The 1:1 propensity score matching (PSM) was performed to balance baseline data. RESULTS: A total of 816 patients with DNETs were included, of which 578 patients (70.8%) received endoscopic therapy and 238 patients (29.2%) received surgical therapy. Before the PSM, there was no difference between the two groups of patients with DNETs on long-term survival [5-year OS (86.1% vs. 87.9%, P = 0.45), 10-year OS (72.5% vs. 72.3%, P = 0.45)]. After adjusting covariates, we found endoscopic therapy and surgical therapy groups had comparable risks of overall survival (HR 0.86, 95% CI 0.60-1.23, P = 0.409) and cancer-specific survival (HR 1.68, 95% CI 0.74-3.83, P = 0.214). In the post-PSM analysis, there was no discernible difference between the endoscopic therapy and surgical therapy group. CONCLUSIONS: Our study found that for T1-2N0M0 DNETs patients, whose long-term OS and CSS results were similar for the endoscopic and surgical therapy groups. For these patients, endoscopic resection might be an optimal therapy modality.
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Endoscopia , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Humanos , Tumores Neuroendócrinos/cirurgia , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/patologia , Prognóstico , Programa de SEERRESUMO
The silylium-like surface species [i Pr3 Si][(RF O)3 Al-OSi≡)] activates (N^N)Pd(CH3 )Cl (N^N=Ar-N=CMeMeC=N-Ar, Ar=2,6-bis(diphenylmethyl)-4-methylbenzene) by chloride ion abstraction to form [(N^N)Pd-CH3 ][(RF O)3 Al-OSi≡)] (1). A combination of FTIR, solid-state NMR spectroscopy, and reactions with CO or vinyl chloride establish that 1 shows similar reactivity patterns as (N^N)Pd(CH3 )Cl activated with Na[B(ArF )4 ]. Multinuclear 13 C{27 Al} RESPDOR and 1 H{19 F} S-REDOR experiments are consistent with a weakly coordinated ion-pair between (N^N)Pd-CH3 + and [(RF O)3 Al-OSi≡)]. 1 catalyzes the polymerization of ethylene with similar activities as [(N^N)Pd-CH3 ]+ in solution and incorporates up to 0.4 % methyl acrylate in copolymerization reactions. 1 produces polymers with significantly higher molecular weight than the solution catalyst, and generates the highest molecular weight polymers currently reported in copolymerization reactions of ethylene and methylacrylate.
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Cardiac hypertrophy (CH) is a common risk factor for heart failure and even sudden cardiac death. Molecules have emerged as vital regulators in cardiac disorders. LIM domain kinase 1 (Limk1) is reported as a pro-fibrotic mediator in patients with permanent atrial fibrillation and it has also been suggested to aggravate cardiac dysfunction in rats with chronic heart failure. The present study observed that Limk1 was significantly upregulated in the in vitro model of CH induced by angiotensin II (Ang-II). Interestingly, silencing Limk1 led to inhibition of the hypertrophic phenotypes in Ang-II-treated cardiomyocytes. Next, through a series of mechanistic assays including RIP assay, RNA pull-down assay, and luciferase reporter assay, miR-93-5p was verified to target Limk1. Furthermore, circ-Zfp644 was validated as the sponge of miR-93-5p. Circ-Zfp644 functioned as a ceRNA to upregulate Limk1 expression via sequestering miR-93-5p in Ang-II-treated cardiomyocytes. Finally, a range of rescue assays revealed that circ-Zfp644 stimulated hypertrophic effects in Ang-II-treated cardiomyocytes via upregulating Limk1 while miR-93-5p exerted the opposite effects via its inhibition on Limk1. On the whole, the present study revealed that circ-Zfp644 aggravated CH through modulating the miR-93-5p/Limk1 axis. The findings observed on the in vitro model of CH provided new potential for developing CH treatment.
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Cardiomegalia/metabolismo , Quinases Lim/fisiologia , MicroRNAs/metabolismo , Animais , Linhagem Celular , Miócitos Cardíacos , RatosRESUMO
Autonomous and accurate acquisition of the position and azimuth of the vehicle is critical to the combat effectiveness of land-fighting vehicles. The integrated navigation system, consisting of a strap-down inertial navigation system (SINS) and odometer (OD), is commonly applied in vehicles. In the SINS/OD integrated system, the odometer is installed around the vehicle's wheel, while SINS is usually installed on the base of the vehicle. The distance along SINS and OD would cause a velocity difference when the vehicle maneuvers, which may lead to a significant influence on the integration positioning accuracy. Furthermore, SINS navigation errors, especially azimuth error, would diverge over time due to gyro drifts and accelerometer biases. The azimuth error would cause the divergence of dead-reckoning positioning errors with the distance that the vehicle drives. To solve these problems, an integrated positioning and orientation method based on the configuration of SINS and couple odometers was proposed in this paper. The proposed method designed a high precision integrated navigation algorithm, which compensated the lever arm effect to eliminate the velocity difference between SINS and odometers. At the same time, by using the measured information of couple odometers, azimuth reference was calculated and used as an external measurement to suppress SINS azimuth error's divergence over time, thus could further improve the navigation precision of the integrated system, especially the orientation accuracy. The performance of the proposed method was verified by simulations. The results demonstrated that SINS/2ODs integrated system could achieve a positioning accuracy of 0.01% D (total mileage) and orientation accuracy of ±30â³ by using SINS with 0.01°/h Fiber-Optic Gyroscope (FOGs) and 50 µg accelerometers.
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The movement disorder Parkinson's disease (PD) is the second most frequently diagnosed neurodegenerative disease, and is associated with aging, the environment, and genetic factors. The intracellular aggregation of α-synuclein and the loss of dopaminergic neurons in the substantia nigra pars compacta are the pathological hallmark of PD. At present, there is no successful treatment for PD. Maackiain (MK) is a flavonoid extracted from dried roots of Sophora flavescens Aiton. MK has emerged as a novel agent for PD treatment that acts by inhibiting monoamine oxidase B. In this study, we assessed the neuroprotective potential of MK in Caenorhabditis elegans and investigated possible mechanism of this neuroprotection in the human SH-SY5Y cell line. We found that MK significantly reduced dopaminergic neuron damage in 6-hydroxydopamine (6-OHDA)-exposed worms of the BZ555 strain, with corresponding improvements in food-sensing behavior and life-span. In transgenic worms of strain NL5901 treated with 0.25 mM MK, the accumulation of α-synuclein was diminished by 27% (p < 0.01) compared with that in untreated worms. Moreover, in worms and the SH-SY5Y cell line, we confirmed that the mechanism of MK-mediated protection against PD pathology may include blocking apoptosis, enhancing the ubiquitin-proteasome system, and augmenting autophagy by increasing PINK1/parkin expression. The use of small interfering RNA to downregulate parkin expression in vivo and in vitro could reverse the benefits of MK in PD models. MK may have considerable therapeutic applications in PD.
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Caenorhabditis elegans/efeitos dos fármacos , Neuroblastoma/tratamento farmacológico , Oxidopamina/toxicidade , Doença de Parkinson/tratamento farmacológico , Proteínas Quinases/metabolismo , Pterocarpanos/farmacologia , Ubiquitina-Proteína Ligases/metabolismo , alfa-Sinucleína/toxicidade , Adrenérgicos/toxicidade , Animais , Apoptose , Autofagia , Caenorhabditis elegans/crescimento & desenvolvimento , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Neuroblastoma/etiologia , Neuroblastoma/patologia , Doença de Parkinson/etiologia , Doença de Parkinson/patologia , Proteínas Quinases/genética , Ubiquitina-Proteína Ligases/genéticaRESUMO
A smart theranostic prodrug IMC-FDU-TZBC-NO2, releasing active drug on-demand based on hypoxia-activated and indomethacin-mediated, for solid tumor imaging and efficient therapy was designed. This prodrug was constructed by conjugating chemotherapy drug 5-fluoro-2-deoxyuridine (FDU), targeting moiety indomethacin (IMC), and the hypoxic trigger 4-nitrobenzyl group to a fluorescent dye precursor, which was mediated by IMC and activated by NTR under hypoxic conditions. The fluorescent dye IMC-TZBCM was generated and FDU was released at the same time in tumor cells. The rates and amounts of FDU release and IMC-TZBCM generation were regulated by hypoxia status, and increased with increasing degree of hypoxia. Nevertheless, it is "locked" in normal cells. It combined the advantages of tumor targeting, diagnosis, and chemotherapy functions, showed excellent targeting ability to cancer cells, excellent stability in physiological conditions, high cellular uptake efficiency, and on-demand drug release behavior. The in vitro and in vivo assays demonstrated that IMC-FDU-TZBC-NO2 exhibits enhanced anticancer potency and low side effects. The novel targeted theranostic prodrug activated by hypoxia shows a great potential in cancer therapy.