Synthesis of novel substituted N-aryl benzamides as hA3G stabilizers and their inhibitory activities against hepatitis C virus replication

AbstractA series of novel amino-substituted N-aryl benzamide analogs were synthesized and evaluated for their ability to inhibit hepatitis C virus (HCV) replication in acutely infected Huh7.5 cells. Most of the substituted N-aryl benzamide compounds showed convincing anti-HCV activities. Compounds 1f, 1g and 4c exhibited potent anti-replicative activity at low micromolar levels (IC50=1.0–2.0μM) with selective indices (SI) greater than 40. Mechanistic analysis indicated that the active compounds increased intracellular hA3G protein levels and inhibited HCV replication in a dose-dependent manner. The results demonstrate that this series of substituted N-aryl benzamide compounds warrant further investigation as inhibitors of HCV replication

A nomogram based on genotypic and clinicopathologic factors to predict the non-sentinel lymph node metastasis in Chinese women breast cancer patients

BackgroundSentinel lymph node biopsy (SLNB) is the standard treatment for breast cancer patients with clinically negative axilla. However, axillary lymph node dissection (ALND) is still the standard care for sentinel lymph node (SLN) positive patients. Clinical data reveals about 40-75% of patients without non-sentinel lymph node (NSLN) metastasis after ALND. Unnecessary ALND increases the risk of complications and detracts from quality of life. In this study, we expect to develop a nomogram based on genotypic and clinicopathologic factors to predict the risk of NSLN metastasis in SLN-positive Chinese women breast cancer patients.MethodsThis retrospective study collected data from 1,879 women breast cancer patients enrolled from multiple centers. Genotypic features contain 96 single nucleotide polymorphisms (SNPs) associated with breast cancer susceptibility, therapy and prognosis. SNP genotyping was identified by the quantitative PCR detection platform. The genetic features were divided into two clusters by the mutational stability. The normalized polygenic risk score (PRS) was used to evaluate the combined effect of each SNP cluster. Recursive feature elimination (RFE) based on linear discriminant analysis (LDA) was adopted to select the most useful predictive features, and RFE based on support vector machine (SVM) was used to reduce the number of SNPs. Multivariable logistic regression models (i.e., nomogram) were built for predicting NSLN metastasis. The predictive abilities of three types of model (based on only clinicopathologic information, the integrated clinicopathologic and all SNPs information, and integrated clinicopathologic and significant SNPs information) were compared. Internal and external validations were performed and the area under ROC curves (AUCs) as well as a series of evaluation indicators were assessed.Results229 patients underwent SLNB followed by ALND and without any neo-adjuvant therapy, 79 among them (34%) had a positive axillary NSLN metastasis. The LDA-RFE identified the characteristics including lymphovascular invasion, number of positive SLNs, number of negative SLNs and two SNP clusters as significant predictors of NSLN metastasis. Furthermore, the SVM-RFE selected 29 significant SNPs in the prediction of NSLN metastasis. In internal validation, the median AUCs of the clinical and all SNPs combining model, the clinical and 29 significant SNPs combining model, and the clinical model were 0.837, 0.795 and 0.708 respectively. Meanwhile, in external validation, the AUCs of the three models were 0.817, 0.815 and 0.745 respectively.ConclusionWe present a new nomogram by combining genotypic and clinicopathologic factors to achieve higher sensitivity and specificity comparing with traditional clinicopathologic factors to predict NSLN metastasis in Chinese women breast cancer. It is recommended that more validations are required in prospective studies among different patient populations

A modeling study of the nonlinear response of fine particles to air pollutant emissions in the Beijing-Tianjin-Hebei region

The Beijing–Tianjin–Hebei (BTH) region has been suffering from the most severe fine-particle (PM2:5) pollution in China, which causes serious health damage and economic loss. Quantifying the source contributions to PM2:5 concentrations has been a challenging task because of the complicated nonlinear relationships between PM2:5 concentrations and emissions of multiple pollutants from multiple spatial regions and economic sectors. In this study, we use the extended response surface modeling (ERSM) technique to investigate the nonlinear response of PM2:5 concentrations to emissions of multiple pollutants from different regions and sectors over the BTH region, based on over 1000 simulations by a chemical transport model (CTM). The ERSM-predicted PM2:5 concentrations agree well with independent CTM simulations, with correlation coefficients larger than 0.99 and mean normalized errors less than 1 %. Using the ERSM technique, we find that, among all air pollutants, primary inorganic PM2:5 makes the largest contribution (24–36 %) to PM2:5 concentrations. The contribution of primary inorganic PM2:5 emissions is especially high in heavily polluted winter and is dominated by the industry as well as residential and commercial sectors, which should be prioritized in PM2:5 control strategies. The total contributions of all precursors (nitrogen oxides, NOx ; sulfur dioxides, SO2; ammonia, NH3; non-methane volatile organic compounds, NMVOCs; intermediate-volatility organic compounds, IVOCs; primary organic aerosol, POA) to PM2:5 concentrations range between 31 and 48 %. Among these precursors, PM2:5 concentrations are primarily sensitive to the emissions of NH3, NMVOCCIVOC, and POA. The sensitivities increase substantially for NH3 and NOx and decrease slightly for POA and NMVOCCIVOC with the increase in the emission reduction ratio, which illustrates the nonlinear relationships between precursor emissions and PM2:5 concentrations. The contributions of primary inorganic PM2:5 emissions to PM2:5 concentrations are dominated by local emission sources, which account for over 75% of the total primary inorganic PM2:5 contributions. For precursors, however, emissions from other regions could play similar roles to local emission sources in the summer and over the northern part of BTH. The source contribution features for various types of heavy-pollution episodes are distinctly different from each other and from the monthly mean results, illustrating that control strategies should be differentiated based on the major contributing sources during different types of episodes.publishedVersio

A Survey on Routing Protocols for Large-Scale Wireless Sensor Networks

With the advances in micro-electronics, wireless sensor devices have been made much smaller and more integrated, and large-scale wireless sensor networks (WSNs) based the cooperation among the significant amount of nodes have become a hot topic. “Large-scale” means mainly large area or high density of a network. Accordingly the routing protocols must scale well to the network scope extension and node density increases. A sensor node is normally energy-limited and cannot be recharged, and thus its energy consumption has a quite significant effect on the scalability of the protocol. To the best of our knowledge, currently the mainstream methods to solve the energy problem in large-scale WSNs are the hierarchical routing protocols. In a hierarchical routing protocol, all the nodes are divided into several groups with different assignment levels. The nodes within the high level are responsible for data aggregation and management work, and the low level nodes for sensing their surroundings and collecting information. The hierarchical routing protocols are proved to be more energy-efficient than flat ones in which all the nodes play the same role, especially in terms of the data aggregation and the flooding of the control packets. With focus on the hierarchical structure, in this paper we provide an insight into routing protocols designed specifically for large-scale WSNs. According to the different objectives, the protocols are generally classified based on different criteria such as control overhead reduction, energy consumption mitigation and energy balance. In order to gain a comprehensive understanding of each protocol, we highlight their innovative ideas, describe the underlying principles in detail and analyze their advantages and disadvantages. Moreover a comparison of each routing protocol is conducted to demonstrate the differences between the protocols in terms of message complexity, memory requirements, localization, data aggregation, clustering manner and other metrics. Finally some open issues in routing protocol design in large-scale wireless sensor networks and conclusions are proposed

Body Mass Index Differences in the Gut Microbiota Are Gender Specific

Background: The gut microbiota is increasingly recognized as playing an important role in the development of obesity, but the influence of gender remains elusive. Using a large cohort of Chinese adults, our study aimed to identify differences in gut microbiota as a function of body mass index (BMI) and investigate gender specific features within these differences.Methods: Five hundred fifty-one participants were categorized as underweight, normal, overweight, or obese, based on their BMI. Fecal microbiome composition was profiled via 16S rRNA gene sequencing. Generalized linear model (GLM), BugBase, PICRUSt, and SPIEC-EASI were employed to assess the variabilities in richness, diversity, structure, organism-level microbiome phenotypes, molecular functions, and ecological networks of the bacterial community that associated with BMI and sex.Results: The bacterial community of the underweight group exhibited significantly higher alpha diversity than other BMI groups. When stratified by gender, the pattern of alpha diversity across BMI was maintained in females, but no significant difference in alpha diversity was detected among the BMI groups of males. An enrichment of Fusobacteria was observed in the fecal microbiota of obese males, while obese females demonstrated an increased relative abundance of Actinobacteria. Analysis of microbial community-level phenotypes revealed that underweight males tend to have more anaerobic and less facultatively anaerobic bacteria, indicating a reduced resistance to oxidative stress. Functionally, butyrate-acetoacetate CoA-transferase was enriched in obese individuals, which might favor energy accumulation. PhoH-like ATPase was found to be increased in male obese subjects, indicating a propensity to harvest energy. The microbial ecological network of the obese group contained more antagonistic microbial interactions as well as high-degree nodes.Conclusion: Using a large Chinese cohort, we demonstrated BMI-associated differences in gut microbiota composition, functions, and ecological networks, which were influenced by gender. Results in this area have shown variability across several independent studies, suggesting that further investigation is needed to understand the role of the microbiota in modulating host energy harvest and storage, and the impact of sex on these functions

Particulate matter pollution over China and the effects of control policies

China is one of the regions with highest PM(2.5)concentration in the world. In this study, we review the spatio-temporal distribution of PM2.5 mass concentration and components in China and the effect of control measures on PM2.5 concentrations. Annual averaged PM2.5 concentrations in Central-Eastern China reached over 100 mu g m(-3), in some regions even over 150 mu g m(-3). In 2013, only 4.1% of the cities attained the annual average standard of 35 mu g m(-3). Aitken mode particles tend to dominate the total particle number concentration. Depending on the location and time of the year, new particle formation (NPF) has been observed to take place between about 10 and 60% of the days. In most locations, NPF was less frequent at high PM mass loadings. The secondary inorganic particles (i.e., sulfate, nitrate and ammonium) ranked the highest fraction among the PM2.5 species, followed by organic matters (OM), crustal species and element carbon (EC), which accounted for 6-50%, 15-51%, 5-41% and 2-12% of PM2.5, respectively. In response to serious particulate matter pollution, China has taken aggressive steps to improve air quality in the last decade. As a result, the national emissions of primary PM2.5, sulfur dioxide (SO2), and nitrogen oxides (NOx) have been decreasing since 2005, 2006, and 2011, respectively. The emission control policies implemented in the last decade could result in noticeable reduction in PM2,(5)concentrations, contributing to the decreasing PM2.5 trends observed in Beijing, Shanghai, and Guangzhou. However, the control policies issued before 2010 are insufficient to improve PM2.5 air quality notably in future. An optimal mix of energy-saving and end-of-pipe control measures should be implemented, more ambitious control policies for NMVOC and NH3 should be enforced, and special control measures in winter should be applied. 40-70% emissions should be cut off to attain PM2.5 standard. (C) 2017 Elsevier B.V.All rights reserved.Peer reviewe

Distinct Genotype of Hantavirus Infection in Rodents in Jiangxi Province, China, in 2020–2021

Hantavirus causes hemorrhagic fever with renal syndrome, thus posing a major threat to human health in Jiangxi Province, China. Both Hantaan virus (HTNV) and Seoul virus (SEOV) have been found to be endemic in the province. Rodents were trapped from Gaoan Anyi and Tonggu counties in Jiangxi Province in 2020–2021. Hantavirus specific antibodies in the blood and RNA in the lung samples from the captured mammals were detected and analyzed. A total of 889 small mammals from seven species were collected. Positive detection was observed for hantavirus antibodies in 9.8% (87/889), SEOV RNA in 1% (9/889) and HTNV RNA in 2.6% (23/889). The difference in detection rates between regions was significant. Phylogenetic analysis of the obtained partial sequences of M and S segments revealed that two distinct genotypes of HTNV and three genotypes of SEOV were co-circulating in the captured mammals, with a regionally specific distribution. Multiple distinct genotypes of hantavirus are co-circulating in the province. Further studies in broader areas remain needed to reveal the diversity of hantaviruses

Axons Amplify Somatic Incomplete Spikes into Uniform Amplitudes in Mouse Cortical Pyramidal Neurons

BACKGROUND: Action potentials are the essential unit of neuronal encoding. Somatic sequential spikes in the central nervous system appear various in amplitudes. To be effective neuronal codes, these spikes should be propagated to axonal terminals where they activate the synapses and drive postsynaptic neurons. It remains unclear whether these effective neuronal codes are based on spike timing orders and/or amplitudes. METHODOLOGY/PRINCIPAL FINDINGS: We investigated this fundamental issue by simultaneously recording the axon versus soma of identical neurons and presynaptic vs. postsynaptic neurons in the cortical slices. The axons enable somatic spikes in low amplitude be enlarged, which activate synaptic transmission in consistent patterns. This facilitation in the propagation of sequential spikes through the axons is mechanistically founded by the short refractory periods, large currents and high opening probability of axonal voltage-gated sodium channels. CONCLUSION/SIGNIFICANCE: An amplification of somatic incomplete spikes into axonal complete ones makes sequential spikes to activate consistent synaptic transmission. Therefore, neuronal encoding is likely based on spike timing order, instead of graded analogues

Quantal Glutamate Release Is Essential for Reliable Neuronal Encodings in Cerebral Networks

Background: The neurons and synapses work coordinately to program the brain codes of controlling cognition and behaviors. Spike patterns at the presynaptic neurons regulate synaptic transmission. The quantitative regulations of synapse dynamics in spike encoding at the postsynaptic neurons remain unclear. Methodology/Principal Findings: With dual whole-cell recordings at synapse-paired cells in mouse cortical slices, we have investigated the regulation of synapse dynamics to neuronal spike encoding at cerebral circuits assembled by pyramidal neurons and GABAergic ones. Our studies at unitary synapses show that postsynaptic responses are constant over time, such as glutamate receptor-channel currents at GABAergic neurons and glutamate transport currents at astrocytes, indicating quantal glutamate release. In terms of its physiological impact, our results demonstrate that the signals integrated from quantal glutamatergic synapses drive spike encoding at GABAergic neurons reliably, which in turn precisely set spike encoding at pyramidal neurons through feedback inhibition. Conclusion/Significance: Our studies provide the evidences for the quantal glutamate release to drive the spike encodings precisely in cortical circuits, which may be essential for programming the reliable codes in the brain to manage wellorganize