RGS5 augments astrocyte activation and facilitates neuroinflammation via TNF signaling.

Astrocytes contribute to chronic neuroinflammation in a variety of neurodegenerative diseases, including Parkinson's disease (PD), the most common movement disorder. However, the precise role of astrocytes in neuroinflammation remains incompletely understood. Herein, we show that regulator of G-protein signaling 5 (RGS5) promotes neurodegenerative process through augmenting astrocytic tumor necrosis factor receptor (TNFR) signaling. We found that selective ablation of Rgs5 in astrocytes caused an inhibition in the production of cytokines resulting in mitigated neuroinflammatory response and neuronal survival in animal models of PD, whereas overexpression of Rgs5 had the opposite effects. Mechanistically, RGS5 switched astrocytes from neuroprotective to pro-inflammatory property via binding to the receptor TNFR2. RGS5 also augmented TNFR signaling-mediated pro-inflammatory response by interacting with the receptor TNFR1. Moreover, interrupting RGS5/TNFR interaction by either RGS5 aa 1-108 or small molecular compounds feshurin and butein, suppressed astrocytic cytokine production. We showed that the transcription of astrocytic RGS5 was controlled by transcription factor early B cell factor 1 whose expression was reciprocally influenced by RGS5-modulated TNF signaling. Thus, our study indicates that beyond its traditional role in G-protein coupled receptor signaling, astrocytic RGS5 is a key modulator of TNF signaling circuit with resultant activation of astrocytes thereby contributing to chronic neuroinflammation. Blockade of the astrocytic RGS5/TNFR interaction is a potential therapeutic strategy for neuroinflammation-associated neurodegenerative diseases.

The risk factor assessment of the spread of foot-and-mouth disease in mainland China.

In China, foot-and-mouth disease (FMD) serotype O remains prevalent, and its main host is pigs. Infected but undiscovered pigs can carry foot-and-mouth disease virus (FMDV) for a longtime. And, the virus can spread among farms through pig trade. Although individual vaccination at least 2 times a year and monthly monitoring disease and culling all individual in same group for pigs are adopted vigorously in China, the epidemic remains prevalent. Therefore, in this paper, based on these propagation characteristics and control measures of the epidemic in China, we take the pig farms as research individuals, the trade among farms as transmission routes to establish a dynamic model with nonlinear incidence. In addition, we use this model to assess the impact of trade and transport of pigs among farms on the spread of foot-and-mouth disease virus (FMDV), and to assess the effect of the immunization, monitoring and culling adopted presently in China on the control of the epidemic. By the dynamical analysis of the model, it is found that there will appear backward branching under some conditions, which means that there are two spreading thresholds for the disease, and the disease development trend is also related to the current epidemic situation. Besides, we give the threshold conditions of key parameters to control the spread of FMD. By carrying out data fitting and parameter estimation, we confirm the model rationality, and give four evaluation indexes: the basic reproduction number R0 of FMD serotype O in China, the value of the infected farms at the equilibria, annual probability of a susceptible farm being infected and annual transmission intensity of an infected farm. By carrying out the sensitivity analysis of key parameters on four evaluation indexes, the effect of parameters on the spread of the disease can be intuitively observed. All these can provide a theoretical basis for understanding of the trading-based transmission mechanism, control and prevention of foot-and-mouth disease in pigs in China.

Discovery of 4,6-Disubstituted Pyrimidine Derivatives as Novel Dual VEGFR2/FGFR1 Inhibitors.

Abnormalities in the FGFRs signaling pathway and VEGFR2 amplification often occur in a variety of tumors, and they synergistically promote tumor angiogenesis. Studies have shown that the up-regulation of FGF-2 is closely related to the resistance of VEGFR2 inhibitors. Activation of the FGFRs signal is a signal of compensatory angiogenesis after VEGFR2 resistance. Dual VEGFR2/FGFR1 inhibitors contribute to overcoming the resistance of VEGFR2 inhibitors and inhibit tumor growth significantly. Based on this, we designed and synthesized a series of 4,6-disubstituted pyrimidine derivatives as dual VEGFR2/FGFR1 inhibitors by the molecular hybridization strategy. 3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-{6-[(4-methoxyphenyl)amino]pyrimidin-4-yl}-1-methylurea (8b) had the best inhibitory activities against VEGFR2 and FGFR1 at 10 µM (82.2 % and 101.0 %, respectively), it showed moderate antiproliferative activities against A549 and KG-1 cell lines as well. Besides, molecular docking was also carried out to study the binding mode of 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-{6-[(4-methoxyphenyl)-amino]-pyrimidin-4-yl}-1-methylurea (8b) with VEGFR2 and FGFR1. These studies reveal that this series of compounds deserve further optimization.

Transmission dynamics of COVID-19 in Wuhan, China: effects of lockdown and medical resources.

Due to the strong infectivity of COVID-19, it spread all over the world in about three months and thus has been studied from different aspects including its source of infection, pathological characteristics, diagnostic technology and treatment. Yet, the influences of control strategies on the transmission dynamics of COVID-19 are far from being well understood. In order to reveal the mechanisms of disease spread, we present dynamical models to show the propagation of COVID-19 in Wuhan. Based on mathematical analysis and data analysis, we systematically explore the effects of lockdown and medical resources on the COVID-19 transmission in Wuhan. It is found that the later lockdown is adopted by Wuhan, the fewer people will be infected in Wuhan, and nevertheless it will have an impact on other cities in China and even the world. Moreover, the richer the medical resources, the higher the peak of new infection, but the smaller the final scale. These findings well indicate that the control measures taken by the Chinese government are correct and timely.

[The Function of Neuroinflammation in Parkinson Disease].

Parkinson disease (PD) is the second most common neurodegenerative disorder, characterized by a progressive loss of dopaminergic neurons in the substantia nigra (SN). The pathology of PD remains unclear. Recent findings suggests neuroinflammation plays a critical role in PD. Occurrence of neuroinflammation, including microglia and astrocyte activation, T lymphocyte infiltration and blood-brain barrier disruption, has been identified in PD. However, the mechanism of neuroinflammation regulation in PD is not fully deciphered. In this review, we focus on the cutting edge in researches of neuroinflammation in PD, which may provide us new ideas in prevention and recovery of PD.

Forecast of peak infection and estimate of excess deaths in COVID-19 transmission and prevalence in Taiyuan City, 2022 to 2023.

In this paper, with the method of epidemic dynamics, we assess the spread and prevalence of COVID-19 after the policy adjustment of prevention and control measure in December 2022 in Taiyuan City in China, and estimate the excess population deaths caused by COVID-19. Based on the transmission mechanism of COVID-19 among individuals, a dynamic model with heterogeneous contacts is established to describe the change of control measures and the population's social behavior in Taiyuan city. The model is verified and simulated by basing on reported case data from November 8th to December 5th, 2022 in Taiyuan city and the statistical data of the questionnaire survey from December 1st to 23rd, 2022 in Neijiang city. Combining with reported numbers of permanent residents and deaths from 2017 to 2021 in Taiyuan city, we apply the dynamic model to estimate theoretical population of 2022 under the assumption that there is no effect of COVID-19. In addition, we carry out sensitivity analysis to determine the propagation character of the Omicron strain and the effect of the control measures. As a result of the study, it is concluded that after adjusting the epidemic policy on December 6th, 2022, three peaks of infection in Taiyuan are estimated to be from December 22nd to 31st, 2022, from May 10th to June 1st, 2023, and from September 5th to October 13th, 2023, and the corresponding daily peaks of new cases can reach 400 000, 44 000 and 22 000, respectively. By the end of 2022, excess deaths can range from 887 to 4887, and excess mortality rate can range from 3.06% to 14.82%. The threshold of the infectivity of the COVID-19 variant is estimated 0.0353, that is if the strain infectivity is above it, the epidemic cannot be control with the previous normalization measures.

Dynamic analysis of rabies transmission and elimination in mainland China.

Rabies is an acute zoonotic infectious disease caused by rabies virus. In 2015, the World Health Organization proposed the goal of eliminating dog-induced human rabies by 2030. In response to this goal positively, China has been dedicated to the control and elimination of rabies mainly caused by dogs, for nearly 10 years. By applying infectious disease dynamics, in this paper, we establish a dog-human rabies transmission model to forecast future epidemic trends of rabies, assess whether the goal of eliminating dog-induced human rabies cases in China can be achieved in 2030, and further evaluate and suggest the follow-up sustained preventive measures after the elimination of human rabies. By analyzing and simulating above dynamic model, it is concluded that rabies has been well controlled in China in recent years, but dog-induced human rabies cannot be eliminated by 2030 according to current situation. In addition, we propose to improve rabies control efforts by increasing the immunization coverage rate of rural domestic dogs, controlling the number of stray dogs and preventing the import of rabies virus in wild animals. Immunization coverage rate of rural domestic dogs which is currently less than 10% is far from requirement, and it needs to reach 50%-60% to meet the goal of 2030. Since it is difficult to immunize stray dogs, we suggest to control the number of stray dogs below 15.27 million to achieve the goal. If the goal of eliminating human rabies is reached in 2030, the essential immunization coverage needs to be maintained for 18 years to reduce the number of canine rabies cases to zero. Lastly, to prevent transmission of rabies virus from wild animals to dogs, the thresholds of the number of dogs and the immunization coverage rate of dogs after eliminating canine rabies cases are also discussed.

Single-Channel Selection for EEG-Based Emotion Recognition Using Brain Rhythm Sequencing.

Recently, electroencephalography (EEG) signals have shown great potential for emotion recognition. Nevertheless, multichannel EEG recordings lead to redundant data, computational burden, and hardware complexity. Hence, efficient channel selection, especially single-channel selection, is vital. For this purpose, a technique termed brain rhythm sequencing (BRS) that interprets EEG based on a dominant brain rhythm having the maximum instantaneous power at each 0.2 s timestamp has been proposed. Then, dynamic time warping (DTW) is used for rhythm sequence classification through the similarity measure. After evaluating the rhythm sequences for the emotion recognition task, the representative channel that produces impressive accuracy can be found, which realizes single-channel selection accordingly. In addition, the appropriate time segment for emotion recognition is estimated during the assessments. The results from the music emotion recognition (MER) experiment and three emotional datasets (SEED, DEAP, and MAHNOB) indicate that the classification accuracies achieve 70-82% by single-channel data with a 10 s time length. Such performances are remarkable when considering minimum data sources as the primary concerns. Furthermore, the individual characteristics in emotion recognition are investigated based on the channels and times found. Therefore, this study provides a novel method to solve single-channel selection for emotion recognition.

[Proteomic analysis between keloid and normal skin].

OBJECTIVE: To investigate and search correlative proteins of keloid by comparing the results of differential proteomic analysis between keloid and normal skin. METHODS: From January 2010 to June 2010 two-dimensional gel electrophoresis was used to define patterns of protein expression in keloid skin from 8 patients and matched normal skin from 3 patients. Differential expression protein spots were showed and analyzed by matrix-assisted laser desorption ionization-time of flying/time of flying (MALDI-TOF/TOF) mass spectrometry. RESULTS: This study succeeded to provide a two-dimensional protein profiling comparison between normal skin and keloid. Gel-analysis software identified an average of 2978 spots in keloid while 3053 spots in normal skin and statistical filtering yielded 40 spots of a 4-fold change, 32 of which were identified by using mass spectrometry, 20 were up-regulated and 12 were down-regulated. Functional analysis revealed that these proteins could be fractionated to carrier proteins (3 proteins), signal transduction proteins (4 proteins), proliferation and apoptosis related proteins (2 proteins), cytoskeleton proteins (6 proteins), extracellular matrix proteins (8 proteins), immunity related proteins (3 proteins), tumor related proteins (2 proteins), and function unknown protein (4 proteins). CONCLUSIONS: Proteomic analysis can identify the proteins with variance of keloid versus normal skin. The further research to these differential proteins may help reveal the pathogenesis of keloid and provide new treatments for keloid.

Transmission analysis of COVID-19 with discrete time imported cases: Tianjin and Chongqing as cases.

In 2020, an unexpectedly large outbreak of the coronavirus disease 2019 (COVID-19) epidemic was reported in mainland China. As we known, the epidemic was caused by imported cases in other provinces of China except for Hubei in 2020. In this paper, we developed a differential equation model with tracing isolation strategy with close contacts of newly confirmed cases and discrete time imported cases, to perform assessment and risk analysis for COVID-19 outbreaks in Tianjin and Chongqing city. Firstly, the model behavior without imported cases was given. Then, the real-time regeneration number in Tianjin and Chongqing city revealed a trend of rapidly rising, and then falling fast. Finally, sensitivity analysis demonstrates that the earlier with Wuhan lock-down, the fewer cases in these two cities. One can obtain that the tracing isolation of close contacts of newly confirmed cases could effectively control the spread of the disease. But it is not sensitive for the more contact tracing isolation days on confirmed cases, the fewer cases. Our investigation model could be potentially helpful to provide model building technology for the transmission of COVID-19.

EEG-based Emotion Recognition Using Similarity Measure of Brain Rhythm Sequencing.

The similarity is a fundamental measure from the homology theory in bioinformatics, and the biological sequence can be classified based on it. However, such an approach has not been utilized for electroencephalography (EEG)-based emotion recognition. To this end, the sequence generated by choosing the dominant brain rhythm owning maximum instantaneous power at each 0.2 s timestamp of the EEG signal has been proposed. Then, to recognize emotional arousal and valence, the similarity measures between pairwise sequences have been performed by dynamic time warping (DTW). After evaluations, the sequence that provides the highest accuracy has been obtained. Thus, the representative channel has been found. Besides, the appropriate time segment for emotion recognition has been estimated. Those findings helpfully exclude redundant data for assessing emotion. Results from the DEAP dataset displayed that the classification accuracies between 72%-75% can be realized by applying the single-channel data with a 5 s length, which is impressive when considering fewer data sources as the primary concern. Hence, the proposed idea would open a new way that uses the similarity measures of sequences for EEG-based emotion recognition.

Profiling protein markers associated with lymph node metastasis in prostate cancer by DIGE-based proteomics analysis.

Current predictive tools and imaging modalities are not accurate enough for preoperative diagnosis of lymph node metastatic prostate cancer (LNM PCa). Proteomic analysis is introduced to screen potential biomarkers for early detection of LNM PCa. In our initial study, protein samples from localized and LNM PCa as well as benign prostatic hyperplasia tissues were analyzed using two-dimensional fluorescence difference in gel electrophoresis (2-D DIGE) coupled with MALDI-TOF/TOF MS. We identified 58 proteins that were differentially expressed in the LNM PCa group relative to the localized PCa group. Six of these proteins, e-FABP5, MCCC2, PPA2, Ezrin, SLP2, and SM22, are functionally relevant to cancer metastasis. Expression of these proteins was therefore further validated in tissue samples from the original cohort and also from a larger, independent cohort of patients using real time PCR, Western blotting, and immunohistochemistry staining. In addition, the serum levels of e-FABP5 were also examined by ELISA. Relative to localized PCa tissues, LNM PCa tissues had increased expression of e-FABP5, MCCC2, PPA2, Ezrin, and SLP2 and decreased expression of SM22. Patients with LNM PCa had significantly higher levels of serum e-FABP5. This study presents evidence that increased expression of e-FABP5, MCCC2, PPA2, Ezrin, and SLP2 and decreased expression of SM22 are useful diagnostic markers for the existence of LNM PCa.

Transmission dynamics of brucellosis: Mathematical modelling and applications in China.

Brucellosis, the most common zoonotic disease worldwide, represents a great threat to animal husbandry with the potential to cause enormous economic losses. Meanwhile, brucellosis is one of the major public-health problems in China, and the number of human brucellosis cases has increased dramatically in recent years. In order to show the main features of brucellosis transmission in China, we give a systematic review on the transmission dynamics of brucellosis including a series of mathematical models and their applications in China. For different situations, dynamical models of brucellosis transmission in single population and multiple populations are devised based on ordinary differential equations. Furthermore, we revealed the spatial-temporal characteristics and effective control measures of brucellosis transmission. The results may provide new perspectives for the prevention and control of other types of zoonoses.

Mathematical modeling of COVID-19 transmission: the roles of intervention strategies and lockdown.

An outbreak of rapidly spreading coronavirus established human to human transmission and now became a pandemic across the world. The new confirmed cases of infected individuals of COVID-19 are increasing day by day. Therefore, the prediction of infected individuals has become of utmost important for health care arrangements and to control the spread of COVID-19. In this study, we propose a compartmental epidemic model with intervention strategies such as lockdown, quarantine, and hospitalization. We compute the basic reproduction number (R0), which plays a vital role in mathematical epidemiology. Based on R0, it is revealed that the system has two equilibrium, namely disease-free and endemic. We also demonstrate the non-negativity and boundedness of the solutions, local and global stability of equilibria, transcritical bifurcation to analyze its epidemiological relevance. Furthermore, to validate our system, we fit the cumulative and new daily cases in India. We estimate the model parameters and predict the near future scenario of the disease. The global sensitivity analysis has also been performed to observe the impact of different parameters on R0. We also investigate the dynamics of disease in respect of different situations of lockdown, e.g., complete lockdown, partial lockdown, and no lockdown. Our analysis concludes that if there is partial or no lockdown case, then endemic level would be high. Along with this, the high transmission rate ensures higher level of endemicity. From the short time prediction, we predict that India may face a crucial phase (approx 6000000 infected individuals within 140 days) in near future due to COVID-19. Finally, numerical results show that COVID-19 may be controllable by reducing the contacts and increasing the efficacy of lockdown.

Analysis of COVID-19 transmission in Shanxi Province with discrete time imported cases.

Since December 2019, an outbreak of a novel coronavirus pneumonia (WHO named COVID-19) swept across China. In Shanxi Province, the cumulative confirmed cases finally reached 133 since the first confirmed case appeared on January 22, 2020, and most of which were imported cases from Hubei Province. Reasons for this ongoing surge in Shanxi province, both imported and autochthonous infected cases, are currently unclear and demand urgent investigation. In this paper, we developed a SEIQR difference-equation model of COVID-19 that took into account the transmission with discrete time imported cases, to perform assessment and risk analysis. Our findings suggest that if the lock-down date in Wuhan is earlier, the infectious cases are fewer. Moreover, we reveal the effects of city lock-down date on the final scale of cases: if the date is advanced two days, the cases may decrease one half (67, 95% CI: 66-68); if the date is delayed for two days, the cases may reach about 196 (95% CI: 193-199). Our investigation model could be potentially helpful to study the transmission of COVID-19, in other provinces of China except Hubei. Especially, the method may also be used in countries with the first confirmed case is imported.

Hemodynamic changes in superficial arteriovenous malformation surgery measured by intraoperative ICG fluorescence videoangiography with FLOW 800 software.

BACKGROUND: Arteriovenous malformation(AVM) have long-term "blood stealing" characteristics, which result in complicated hemodynamic features. To analyze the application of intraoperative indocyanine green angiography with FLOW 800 software in AVM surgeries. METHODS: Data on 17 patients undergoing surgery with ICG fluorescence were collected in Beijing Tiantan Hospital. To analyze the hemodynamic features of AVM and the influence on the peripheral cortex of AVM resection, we assessed the following hemodynamic parameters: maximum intensity, slope of rise, time to half-maximal fluorescence, and transit time from arteries to veins. RESULTS: In the 17 superficial AVMs studied, the time-delay color mode of the FLOW 800 software was superior to the traditional playback mode for identifying feeding arteries, draining veins, and their relation to normal cortical vessels. The maximum fluorescence intensity and slope of the ICG fluorescence curve of feeder arteries and draining veins were higher than those of normal peripheral vessels (P < 0.05). The transit times in AVMs were significantly shorter than those in normal peripheral vessels (P < 0.05). After AVM resection, cerebral flow increased in the cortex, and local cycle time becomes longer, although the differences were not significant (P > 0.05). CONCLUSIONS: Hemodynamic parameter analysis provided quality guidance for the resection of AVMs and could also be used in estimating changes in blood flow in the local cortex to identify abnormal hyperperfusion and residual nidus.

Schistosoma japonicum: proteomics analysis of differentially expressed proteins from ultraviolet-attenuated cercariae compared to normal cercariae.

Schistosomiasis is considered the most important human helminthiasis in terms of morbidity and mortality. In this study, comparative soluble proteomic analysis of normal cercariae and ultraviolet-irradiated attenuated cercariae (UVAC) from Schistosoma japonicum were carried out in view of the high efficiency of irradiation-attenuated cercariae vaccine. The results revealed that some proteins showed significant differential expression in the parasite after treatment with ultraviolet light. Total 20 protein spots were identified by mass spectrometry, corresponded to five groups according to their functions in the main that were structural and motor proteins (actin, et al.), energy metabolism associated enzymes (glyceraldehydes-3-phosphage dehydrogenase, et al.), signaling transduction pathway-associated molecules (14-3-3 protein, et al.), heat shock protein families (HSP 70 family, et al.), and other functional proteins (20S proteasome). Furthermore, our results indicated that the differential expression of the proteins by ultraviolet irradiation may be, at least partially, acquired by regulating the mRNA levels of corresponding proteins. These results may provide new clues for further exploring the mechanism of protective immunity induced by UVAC and may shed some light on the development of vaccines against schistosomiasis.

Asymptotic analysis of endemic equilibrium to a brucellosis model.

Brucellosis is one of the worlds major infectious and contagious bacterial disease. In order to study different types of brucellosis transmission models among sheep, we propose a deterministic model to investigate the transmission dynamics of brucellosis with the flock of sheep divided into basic ewes and other sheep. The global dynamical behavior of this model is given: including the basic repro-duction number, the existence and uniqueness of positive equilibrium, the global asymptotic stability of the equilibrium. We prove the uniqueness of positive endemic equilibrium through using proof by contradiction, and the global stability of endemic equilibrium by using Lyapunov function. Especially, we give the specific coefficients of global Lyapunov function, and show the calculation method of these specific coefficients. By running numerical simulations for the cases with the basic reproduction number to demonstrate the global stability of the equilibria and the unique endemic equilibrium, re-spectively. By some sensitivity analysis of the basic reproduction number on parameters, we find that vaccination rate of sheep and seropositive detection rate of recessive infected sheep are very important factor for brucellosis.

[Detection of serum biomakers of osteosarcoma by proteomic profiling].

OBJECTIVE: To detect differentially expressed proteins in serum of patient with osteosarcoma. METHODS: 8 serum protein samples were recruited (4 cases of osteosarcoma and 4 cases of normal adults), cross-labeled with variant CyDye, followed by two-dimensional differential in-gel electrophoresis (2-D DIGE), image analysis, and identified by matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS). RESULTS: 24 protein spot-features were significantly increased, and 34 were significantly decreased in the serum from patients with osteosarcoma relative to the controls. The mass spectrometry analysis revealed 18 unique proteins that were increased, and 25 unique proteins decreased in the serum of patients with osteosarcoma. Gelsolin was down-regulated in osteosarcoma, and Western blotting also confirmed a decreased level of gelsolin in the serum of patients with osteosarcoma. CONCLUSION: Our results indicate that gelsolin may have great potential as a biomarker of osteosarcoma and as a potential target for therapy. These preliminary data suggest that incorporation of more samples and new datasets will permit the identification of serum biomarkers for osteosarcoma.

Age-dependent alpha-synuclein accumulation and aggregation in the colon of a transgenic mouse model of Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is one of the most common neurodegenerative diseases, neuropathologically characterized by misfolded protein aggregation, called Lewy bodies and Lewy neurites. PD is a slow-progressive disease with colonic dysfunction appearing in the prodromal stage and lasting throughout the course of the disease. METHODS: In order to study PD pathology in the colon, we examined the age-dependent morphological and pathological changes in the colon of a PD mouse model expressing human wildtype α-synuclein (α-syn) fused with the green fluorescent protein (GFP), under the endogenous mouse α-syn promoter. RESULTS: We observed an age-dependent progressive expression and accumulation of α-syn-GFP in the enteric neurons of Meissner's (submucosal) and Auerbach's (myenteric) plexuses of the colon. Additionally, the phosphorylation of α-syn at serine 129 also increased with age and the aggregation of α-syn-GFP coincided with the appearance of motor deficits at 9 months of age. Furthermore, α-syn (-GFP) distinctly co-localized with different subtypes of neurons, as identified by immunohistochemical labeling of vasoactive intestinal peptide (VIP), neuronal nitric oxide synthase (nNOS), and calretinin. CONCLUSIONS: Our results show the development of α-syn pathology in the enteric neurons of the colon in a PD mouse model, which coincide with the appearance of motor deficits. Our mouse model possesses the potential and uniqueness for studying PD gastrointestinal dysfunction.