Decoding the Cellular Trafficking of Prion-like Proteins in Neurodegenerative Diseases.

The accumulation and spread of prion-like proteins is a key feature of neurodegenerative diseases (NDs) such as Alzheimer's disease, Parkinson's disease, or Amyotrophic Lateral Sclerosis. In a process known as 'seeding', prion-like proteins such as amyloid beta, microtubule-associated protein tau, α-synuclein, silence superoxide dismutase 1, or transactive response DNA-binding protein 43 kDa, propagate their misfolded conformations by transforming their respective soluble monomers into fibrils. Cellular and molecular evidence of prion-like propagation in NDs, the clinical relevance of their 'seeding' capacities, and their levels of contribution towards disease progression have been intensively studied over recent years. This review unpacks the cyclic prion-like propagation in cells including factors of aggregate internalization, endo-lysosomal leaking, aggregate degradation, and secretion. Debates on the importance of the role of prion-like protein aggregates in NDs, whether causal or consequent, are also discussed. Applications lead to a greater understanding of ND pathogenesis and increased potential for therapeutic strategies.

[Application and development of systems biology in computer-aided drug design].

With the advances in medicine, people have deeply understood the complex pathogenesis of diseases. Revealing the mechanism of action and therapeutic effect of drugs from an overall perspective has become the top priority of drug design. However, the traditional drug design methods cannot meet the current needs. In recent years, with the rapid development of systems biology, a variety of new technologies including metabolomics, genomics, and proteomics have been used in drug research and development. As a bridge between traditional pharmaceutical theory and modern science, computer-aided drug design(CADD) can shorten the drug development cycle and improve the success rate of drug design. The application of systems biology and CADD provides a methodological basis and direction for revealing the mechanism and action of drugs from an overall perspective. This paper introduces the research and application of systems biology in CADD from different perspectives and proposes the development direction, providing reference for promoting the application.

ASC specks exacerbate α­synuclein pathology via amplifying NLRP3 inflammasome activities.

BACKGROUND: Inflammasome activation has a pathogenic role in Parkinson's disease (PD). Up-regulated expressions of inflammasome adaptor apoptosis-associated speck-like protein containing a CARD (ASC) and assembly of ASC specks have been observed in postmortems of human PD brains and experimental PD models. Extracellular ASC specks behave like danger signals and sustain prolonged inflammasome activation. However, the contribution of ASC specks in propagation of inflammasome activation and pathological progression in PD has not been fully established. METHODS: Herein, we used human A53T mutant α-synuclein preformed fibrils (PFFs)-stimulated microglia in vitro and unilateral striatal stereotaxic injection of PFFs-induced mice model of PD in vivo, to investigate the significance of ASC specks in PD pathological progression. Rotarod and open-field tests were performed to measure motor behaviors of indicated mice. Changes in the molecular expression were evaluated by immunofluorescence and immunoblotting (IB). Intracellular knockdown of the ASC in BV2 cells was performed using si-RNA. Microglial and neuronal cells were co-cultured in a trans-well system to determine the effects of ASC knockdown on cytoprotection. RESULTS: We observed a direct relationship between levels of ASC protein and misfolded α­synuclein aggregates in PD mice brains. ASC specks amplified NLRP3 inflammasome activation driven by α-synuclein PFFs stimulation, which aggravated reactive microgliosis and accelerated α­synuclein pathology, dopaminergic neurodegeneration and motor deficits. Endogenous ASC knockdown suppressed microglial inflammasome activation and neuronal α­synuclein aggregation. CONCLUSIONS: In conclusion, our study elucidated that ASC specks contribute to the propagation of inflammasome activation-associated α­synuclein pathology in PD, which forms the basis for targeting ASC as a potential therapy for PD.

High-Precision ADC Spectrum Testing under Non-Coherent Sampling Conditions.

Realizing coherent sampling is one of the major bottlenecks in high-precision ADC spectrum testing. In spectrum analysis, if coherent sampling is not implemented, spectral leakage will result, which in turn leads to inaccurate test results. In this paper, a combined four-parameter sine-curve-fitting algorithm is proposed incorporating non-coherent sampling, with the amplitude, initial phase, and frequency parameters of the sine wave being obtained by fitting. The corresponding coherent sine wave is then calculated and replaced according to the obtained sine wave to reconstruct the new test data, eliminating the requirement of coherent sampling. Numerous simulations demonstrated the functionality and robustness of the algorithm, which was then used to process and analyze the measured data of two commercial high-precision ADCs. The results show that our algorithm can achieve accurate testing of ADC parameters under relaxed test conditions, which verifies the effectiveness and superiority of the scheme.

Improved Multiple-Model Adaptive Estimation Method for Integrated Navigation with Time-Varying Noise.

The accurate noise parameter is essential for the Kalman filter to obtain optimal estimates. However, problems such as variations in the noise environment and measurement anomalies can cause degradation of estimation accuracy or even divergence. The adaptive Kalman filter can simultaneously estimate state and noise parameters, while its performance will also be degraded in complex noise. To address the problem of estimation accuracy degradation and result divergence of the integrated navigation system in a complex time-varying noise environment, an improved multiple-model adaptive estimation (MMAE) that combines the Sage-Husa adaptive unscented Kalman filter with the MMAE is proposed in this paper. The forgetting factor is included as an unknown parameter of MMAE so that the algorithm can adjust the value of the forgetting factor according to different system states. In addition, we improve the hypothesis testing algorithm of classical MMAE to deal with the competition problem of undesirable models that severely impacts the performance of variable-parameter MMAE and enhance the algorithm's parameter identification capability. Simulation results show that this method enhances the system's robustness to noises of different statistical properties and improves the estimation accuracy of the filter in time-varying noise environments.

Optimal Rotational Angular Velocity Determination Method Based on Compound Rotary Semi-Strapdown Inertial Navigation System.

Single-axis rotation modulation (SRM) still accumulates errors in the roll axis direction, which leads to the navigation accuracy not meeting the requirements of guided missiles. Compound rotation modulation (CRM) superimposes one-dimensional rotation on the basis of SRM, so that the error of the projectile in the direction of the roll axis is also modulated. However, the error suppression effect of CRM is not only affected by the error of the IMU itself, but also related to the modulation angular velocity. In order to improve the accuracy of rotary semi-strapdown inertial navigation system (RSSINS), this paper proposes an optimal rotation angular velocity determination method. Firstly, the residual error in CRM scheme is analyzed; then, the relationship between the incomplete modulation error and the modulation angular velocity in CRM is discussed; finally, a method for determining the optimal modulation angular velocity is proposed (K-value method). The analysis of the results shows that the navigation accuracy of the guided projectile is effectively improved with the rotation scheme set at the modulation angular velocity determined by the K-value method.

Effects of dietary supplementation with dandelion tannins or soybean isoflavones on growth performance, antioxidant function, intestinal morphology, and microbiota composition in Wenchang chickens.

Many benefits have been found in supplementing tannins or soybean isoflavones to poultry, including increased body weight gain, antioxidant activity, and better intestinal morphology. However, few studies tested the influence of dandelion tannins or soybean isoflavones supplementation on Wenchang chickens. This study investigates the effects of dietary supplementation with dandelion tannins or soybean isoflavones on the growth performance, antioxidant function, and intestinal health of female Wenchang chickens. A total of 300 chickens were randomly divided into five groups, with six replicates per group and 10 broilers per replicate. The chickens in the control group (Con) were fed a basal diet; the four experimental groups were fed a basal diet with different supplements: 300 mg/kg of dandelion tannin (DT1), 500 mg/kg of dandelion tannin (DT2), 300 mg/kg of soybean isoflavone (SI1), or 500 mg/kg of soybean isoflavone (SI2). The experiment lasted 40 days. The results showed that the final body weight (BW) and average daily gain (ADG) were higher in the DT2 and SI1 groups than in the Con group (P < 0.05). In addition, dietary supplementation with dandelion tannin or soybean isoflavone increased the level of serum albumin (P <0.05); the concentrations of serum aspartate aminotransferase and glucose were significantly higher in the SI1 group (P < 0.05) than in the Con group and the concentration of triglycerides in the DT1 group (P < 0.05). The serum catalase (CAT) level was higher in the DT1 and SI1 groups than in the Con group (P < 0.05). The ileum pH value was lower in the DT2 or SI1 group than in the Con group (P < 0.05). The jejunum villus height and mucosal muscularis thickness were increased in the DT2 and SI1 groups (P < 0.05), whereas the jejunum crypt depth was decreased in the DT1 or DT2 group compared to the Con group (P < 0.05). In addition, the messenger RNA (mRNA) expression level of zonula occludens 1 (ZO-1) in the duodenum of the SI1 group and those of occludin, ZO-1, and claudin-1 in the ileum of the DT2 and SI1 groups were upregulated (P < 0.05) compared to the Con group. Moreover, the DT2 and SI1 groups exhibited reduced intestinal microbiota diversity relative to the Con group, as evidenced by decreased Simpson and Shannon indexes. Compared to the Con group, the relative abundance of Proteobacteria was lower and that of Barnesiella was higher in the DT2 group (P < 0.05). Overall, dietary supplementation with 500 mg/kg of dandelion tannin or 300 mg/kg of soybean isoflavone improved the growth performance, serum biochemical indexes, antioxidant function, and intestinal morphology and modulated the cecal microbiota composition of Wenchang chickens.

An E-nose and Convolution Neural Network based Recognition Method for Processed Products of Crataegi Fructus.

BACKGROUND: The manual identification of Fructus Crataegi processed products is inefficient and unreliable. Therefore, efficient identification of the Fructus Crataegis' processed products is important. OBJECTIVE: In order to efficiently identify Fructus Crataegis processed products with different odor characteristics, a new method based on an electronic nose and convolutional neural network is proposed. METHODS: First, the original smell of Fructus Crataegis processed products is obtained by using the electronic nose and then preprocessed. Next, feature extraction is carried out on the preprocessed data through convolution pooling layer LCP1, convolution pooling layer LCP2 and a full connection layer LFC. Thus, the feature vector of the processed products can be obtained. Then, the recognition model for Fructus Grataegis processed products is constructed, and the model is trained to obtain the optimized parameters: filters F1 and F2, bias vectors B1, B2, B3, and B4, matrices M1 and M2. Finally, the features of the target processed products are extracted through the trained parameters to achieve accurate prediction. RESULTS: The experimental results show that the proposed method has higher accuracy for the identification of Fructus Crataegis processed products, and is competitive with other machine learning based methods. CONCLUSION: The method proposed in this paper is effective for the identification of Fructus Crataegi processed products.

Roll Angular Rate Measurement for High Spinning Projectiles Based on Redundant Gyroscope System.

Precision-guided projectiles, which can significantly improve the accuracy and efficiency of fire strikes, are on the rise in current military engagements. The accurate measurement of roll angular rate is critical to guide a gun-launched projectile. However, Micro-Electro-Mechanical System (MEMS) gyroscope with low cost and large range cannot meet the requirement of high precision roll angular rate measurement due to the limitation by the current technology level. Aiming at the problem, the optimization-based angular rate estimation (OBARS) method specific for projectiles is proposed in this study. First, the output angular rate model of redundant gyroscope system based on the autoregressive integrated moving average (ARIMA) model is established, and then the conventional random error model is improved with the ARIMA model. After that, a Sage-Husa Adaptive Kalman Filter (SHAKF) algorithm that can suppress the time-varying process and measurement noise under the flight condition of the high dynamic of the projectile is designed for the fusion of dynamic data. Finally, simulations and experiments have been carried out to validate the performance of the method. The results demonstrate the proposed method can effectively improve the angular rate accuracy more than the related traditional methods for high spinning projectiles.

The Optimal Design of Modulation Angular Rate for MEMS-Based Rotary Semi-SINS.

In previous studies, the semi-strapdown inertial navigation system (SSINS), based on microelectromechanical system (MEMS) sensors, had realized cross-range measurement of attitude information of high-spinning projectiles through construction of a "spin reduction" platform of the roll axis. However, further improvement of its measurement accuracy has been difficult, due to the inertial sensor error. In order to enhance the navigational accuracy, a periodically rotating method is utilized to compensate for sensor error, which is called rotation modulation. At present, the rotation scheme, as one of the core technologies, has been studied by a lot of researchers. It is known that the modulation angular rate is the main factor affecting the effectiveness of error modulation. Different from the long-endurance and low-dynamic motion characteristics of ships, however, the short-endurance and high-dynamic characteristics of the high-spinning projectile not only require the modulation angular rate to be as fast as possible but, also, the influence of the rotation speed error caused by rotating mechanism errors cannot be ignored. Combined with the rotation speed error of the rotating mechanism, this paper explored the relationship between modulation angular rate, device error, and the navigation error, and then proposed a design method for optimal modulation angular rate. Experiments were carried out to validate the performance of the method. In addition, the proposed method is applicable for rotation modulation systems with different types of motors as the rotating mechanism.

Analyzing hedyotis diffusa mechanisms of action from the genomics perspective.

BACKGROUND AND OBJECTIVE: Hedyotis diffusa is an herb used for anti-cancer, anti-oxidant, anti-inflammatory, and anti-fibroblast treatment in the clinical practice of Traditional Chinese Medicine. However, its pharmacological mechanisms have not been fully established and there is a lack of modern scientific verification. One of the best ways to further understand Hedyotis diffusa's mechanisms of action is to analyze it from the genomics perspective. METHODS: In this study, we used network pharmacology approaches to infer the herb-gene interactions, the herb-pathway interactions, and the gene families. We then analyzed Hedyotis diffusa's mechanisms of action using the genomics context combined with the Traditional Chinese Medicine clinical practice and the pharmacological research. RESULTS: The results obtained in the pathway and gene family analysis were consistent with the Traditional Chinese Medicine clinical experience and the pharmacological activities of Hedyotis diffusa. CONCLUSIONS: Our approach can identify related genes and pathways correctly with little a priori knowledge, and provide potential directions to facilitate further research.

Genome-wide regulation of electro-acupuncture on the neural Stat5-loss-induced obese mice.

Acupuncture is reported to be effective in treating obesity related illnesses, but its mechanism is still unclear. To investigate this mechanism we applied electro-acupuncture (EA) in a mouse model of obesity and used RNA-seq to identify molecular consequences. Deletion of the transcription factor STAT5 from neurons (Stat5NKO) led to obesity. Acupuncture, in turn, reduced body weight and the ratio of epididymal white adipose tissue (Epi-WAT) to body weight, and it also decreased plasma concentrations of glucose, triglyceride, and cholesterol. In addition, EA increased cold endurance of Stat5NKO obese mice. EA reversed altered gene expressions in the hypothalamus and Epi-WAT, especially in the hypothalamus in Stat5NKO obese mice. This study provides, for the first time, insight into genomic networks of obesity and their modulation by electro-acupuncture, which in turn reveals potential mechanisms that explain acupuncture-induced weight-loss.

A protocol of histone modification-based mechanistic study of acupuncture in patients with stable angina pectoris.

BACKGROUND: Angina pectoris (Angina) is a medical condition related to myocardial ischemia. Although acupuncture has been widely accepted as a clinical approach for angina, there is no sufficient evidence of its effectiveness against this syndrome, and its mechanisms have not yet been well elucidated. We develop this protocol to confirm the clinical efficacy of electro-acupuncture on stable angina pectoris by needling on acupoint Neiguan (PC6). Furthermore, we employ high-throughput sequencing technology to investigate the gene expression profiling and determine involvement of histone modifications in the regulation of genes after electro-acupuncture treatment. METHODS/DESIGN: A randomized, controlled, double-blinded (assessor and patients) trial will be carried out. Sixty participants will be randomly assigned to two acupuncture treatment groups and one control group in a 1:1:1 ratio. Participants in acupuncture groups will receive 12 sessions of electro-acupuncture treatment across 4 weeks, followed by a 12-week randomization period. The acupuncture groups are divided into Neiguan (PC6) on Pericardium Meridian of Hand-jueyin or a non-acupoint. The primary clinical measure of effect is the frequency of angina attacks between these groups for four weeks after randomization. RNAs are extracted from peripheral neutrophils collected from all participants on day 0, day 30, and week 16, and are processed to RNA-Seq. We then investigate profiles of histone modifications by ChIP-Seq, for H3 Lysine 4 (H3K4me) and acetylation of H3 Lysine 27 (H3K27ac), in the presence or absence of acupuncture treatment. DISCUSSION: This study determines the efficacy and mechanisms of electro-acupuncture on stable angina pectoris. We focus on effectiveness of acupuncture on alleviating symptoms of myocardial ischemia and the gene regulation and the chromatin remodeling marks, including H3K4me1, H3K4me2, and H3K27ac, which could be key factors for regulating gene expressions caused by electro-acupuncture treatment at Neiguan. This is the first genome-wide study of electro-acupuncture treatment in angina patients, and will provide valuable information for future studies in the fields of acupuncture and its underlying mechanisms. Fourteen patients have been recruited since recruitment opened in November of 2012. This study is scheduled to end in November of 2014. TRIALS REGISTRATION: ChiCTR-TRC-12002668.

Electro-acupuncture at Neiguan pretreatment alters genome-wide gene expressions and protects rat myocardium against ischemia-reperfusion.

This study investigated genome-wide gene expressions and the cardioprotective effects of electro-acupuncture pretreatment at the PC6 Neiguan acupoint on myocardial ischemia reperfusion (I/R) injury. Male SD rats were randomly divided into four groups: sham operation (SO), I/R, electro-acupuncture at the PC6 Neiguan acupoint pretreatment (EA) and electro-acupuncture at non-acupoint pretreatment (NA). Compared with the I/R group, the survival rate of the EA group was significantly increased, the arrhythmia score, infarction area, serum concentrations of CK, LDH and CK-Mb and plasma level of cTnT were significantly decreased. RNA-seq results showed that 725 genes were up-regulated and 861 genes were down-regulated under I/R conditions compared to the SO group; both EA and NA reversed some of these gene expression levels (592 in EA and 238 in NA group). KEGG pathway analysis indicated that these genes were involved in multiple pathways, including ECM, MAPK signaling, apoptosis, cytokine and leukocyte pathways. In addition, some pathways were uniquely regulated by EA, but not NA pretreatment, such as oxidative stress, cardiac muscle contraction, gap junction, vascular smooth muscle contraction, hypertrophic, NOD-like receptor, and P53 and B-cell receptor pathways. This study was first to reveal the gene expression signatures of acute myocardial I/R injury and electro-acupuncture pretreatment in rats.

Acupuncture promotes angiogenesis after myocardial ischemia through H3K9 acetylation regulation at VEGF gene.

BACKGROUND: Acupuncture exerts cardioprotective effects on several types of cardiac injuries, especially myocardial ischemia (MI), but the mechanisms have not yet been well elucidated. Angiogenesis mediated by VEGF gene expression and its modification through histone acetylation has been considered a target in treating myocardial ischemia. This study aims to exam whether modulation of angiogenesis through H3K9 acetylation regulation at VEGF gene is one possible cardioprotective mechanism of acupuncture. RESULTS: We generated rat MI models by ligating the left anterior descending coronary artery and applied electroacupuncture (EA) treatment at the Neiguan (PC6) acupoint. Our results showed that acupuncture reversed the S-T segment change, reduced Q-wave area, decreased CK, CK-MB, LDH levels, mitigated myocardial remodeling, and promoted microvessel formation in the MI heart. RNA-seq analysis showed that VEGF-induced angiogenesis signaling was involved in the modulation of EA. Western blot results verified that the protein expressions of VEGF, Ras, phospho-p44/42 MAPK, phospho-p38 MAPK, phospho-SAPK/JNK and Akt, were all elevated significantly by EA treatment in the MI heart. Furthermore, increased H3K9 acetylation was also observed according with the VEGF. ChIP assay confirmed that EA treatment could notably stimulate the recruitment of H3K9ace at the VEGF promoter. CONCLUSIONS: Our study demonstrates for the first time that acupuncture can effectively up-regulate VEGF expression through H3K9 acetylation modification directly at the VEGF promoter and hence activate VEGF-induced angiogenesis in rat MI models. We employed high throughput sequencing in this study and, for the first time, generated genome-wide gene expression profiles both in the rat MI model and in acupuncture treatment.