Novel Markov model of induced pluripotency predicts gene expression changes in reprogramming

<p>Abstract</p> <p>Background</p> <p>Somatic cells can be reprogrammed to induced-pluripotent stem cells (iPSCs) by introducing few reprogramming factors, which challenges the long held view that cell differentiation is irreversible. However, the mechanism of induced pluripotency is still unknown.</p> <p>Methods</p> <p>Inspired by the phenomenological reprogramming model of Artyomov et al (2010), we proposed a novel Markov model, stepwise reprogramming Markov (SRM) model, with simpler gene regulation rules and explored various properties of the model with Monte Carlo simulation. We calculated the reprogramming rate and showed that it would increase in the condition of knockdown of somatic transcription factors or inhibition of DNA methylation globally, consistent with the real reprogramming experiments. Furthermore, we demonstrated the utility of our model by testing it with the real dynamic gene expression data spanning across different intermediate stages in the iPS reprogramming process.</p> <p>Results</p> <p>The gene expression data at several stages in reprogramming and the reprogramming rate under several typically experiment conditions coincided with our simulation results. The function of reprogramming factors and gene expression change during reprogramming could be partly explained by our model reasonably well.</p> <p>Conclusions</p> <p>This lands further support on our general rules of gene regulation network in iPSC reprogramming. This model may help uncover the basic mechanism of reprogramming and improve the efficiency of converting somatic cells to iPSCs.</p

Simulation and Experimental Investigation on the AE Tomography to Improve AE Source Location in the Concrete Structure

Acoustic emission (AE) tomography, which is based on the time-travel tomography with AE events as its signal sources, is a new visualization tool for inspecting and locating the internal damages in the structures. In this paper, AE tomography is applied to examine a man-made damage in a typical heterogeneous concrete structure to validate its effectiveness. Firstly, the finite element (ABAQUS/Explicit) simulation model of the concrete structure with one damaged circle in its center is built, and the simulated AE signals are obtained to establish the AE tomography. The results show that the damaged circle in the created model can be visualized clearly with the AE tomography in its original location. Secondly, the concrete specimen based on the FE model is fabricated, and the pencil lead break (PLB) signal is taken as the exciting source for AE tomography. It is shown that the experimental results have good consistency with the FE simulation results, which also verifies the feasibility of the finite element model for AE tomography. Finally, the damage source location based on AE tomography is compared with the traditional time of arrival (TOA) location method, and the better location accuracy is obtained with the AE tomography. The research results indicate that AE tomography has great potential in the application of structure damage detection.Foundation of China (no. 51175079, no. 51305176) as well as the Fundamental Research Funds for the Central Universities (CXLX12 0079)

Novel albumin-binding multifunctional probe for synergistic enhancement of FL/MR dual-modal imaging and photothermal therapy

The fluorescence/magnetic resonance (FL/MR) dual-modal imaging could provide accurate tumor visualization to guide photothermal therapy (PTT) of cancer, which has attracted widespread attention from scientists. However, facile and effective strategies to synergistically enhance fluorescence intensity, MR contrast and photothermal efficacy have rarely been reported. This study presents a novel multifunctional probe Gd-EB-ICG (GI) for FL/MR dual-modal imaging-guided PTT of cancer. GIs can self-assemble with endogenous albumin to form drug-albumin complexes (GIAs), which exhibit excellent biocompatibility. Albumin can protect GIAs from the recognition and clearance by the mononuclear phagocytic system (MPS). High plasma concentration and long half-life allow GIAs to accumulate continuously in the tumor area through EPR effect and specific uptake of tumor. Because of the prolonged rotational correlation time (τR) of Gd chelates, GIAs exhibited superior MR contrast performance over GIs with more than 3 times enhancement of longitudinal relaxation efficiency (r1). The fluorescence quantum yield and photothermal conversion efficiency of GIAs was also significantly improved due to the constrained geometry, disrupted aggregation and enhanced photothermal stability. This simple and feasible strategy successfully resulted in a synergistic effect for FL/MR dual-modal imaging and photothermal therapy, which can cast a new light for the clinical translation of multifunctional probes

Integrating Phosphorylation Network with Transcriptional Network Reveals Novel Functional Relationships

Phosphorylation and transcriptional regulation events are critical for cells to transmit and respond to signals. In spite of its importance, systems-level strategies that couple these two networks have yet to be presented. Here we introduce a novel approach that integrates the physical and functional aspects of phosphorylation network together with the transcription network in S.cerevisiae, and demonstrate that different network motifs are involved in these networks, which should be considered in interpreting and integrating large scale datasets. Based on this understanding, we introduce a HeRS score (hetero-regulatory similarity score) to systematically characterize the functional relevance of kinase/phosphatase involvement with transcription factor, and present an algorithm that predicts hetero-regulatory modules. When extended to signaling network, this approach confirmed the structure and cross talk of MAPK pathways, inferred a novel functional transcription factor Sok2 in high osmolarity glycerol pathway, and explained the mechanism of reduced mating efficiency upon Fus3 deletion. This strategy is applicable to other organisms as large-scale datasets become available, providing a means to identify the functional relationships between kinases/phosphatases and transcription factors

Etiologic Diagnosis of Lower Respiratory Tract Bacterial Infections Using Sputum Samples and Quantitative Loop-Mediated Isothermal Amplification

Etiologic diagnoses of lower respiratory tract infections (LRTI) have been relying primarily on bacterial cultures that often fail to return useful results in time. Although DNA-based assays are more sensitive than bacterial cultures in detecting pathogens, the molecular results are often inconsistent and challenged by doubts on false positives, such as those due to system- and environment-derived contaminations. Here we report a nationwide cohort study on 2986 suspected LRTI patients across P. R. China. We compared the performance of a DNA-based assay qLAMP (quantitative Loop-mediated isothermal AMPlification) with that of standard bacterial cultures in detecting a panel of eight common respiratory bacterial pathogens from sputum samples. Our qLAMP assay detects the panel of pathogens in 1047(69.28%) patients from 1533 qualified patients at the end. We found that the bacterial titer quantified based on qLAMP is a predictor of probability that the bacterium in the sample can be detected in culture assay. The relatedness of the two assays fits a logistic regression curve. We used a piecewise linear function to define breakpoints where latent pathogen abruptly change its competitive relationship with others in the panel. These breakpoints, where pathogens start to propagate abnormally, are used as cutoffs to eliminate the influence of contaminations from normal flora. With help of the cutoffs derived from statistical analysis, we are able to identify causative pathogens in 750 (48.92%) patients from qualified patients. In conclusion, qLAMP is a reliable method in quantifying bacterial titer. Despite the fact that there are always latent bacteria contaminated in sputum samples, we can identify causative pathogens based on cutoffs derived from statistical analysis of competitive relationship

Reconstructing historical changes in phosphorus inputs to rivers from point and nonpoint sources in a rapidly developing watershed in eastern China, 1980–2010

Quantifying point (PS) and nonpoint source (NPS) phosphorus inputs to rivers is critical for developing effective watershed remediation strategies. This study reconstructed PS and NPS total phosphorus (TP) inputs to the Yongan River in eastern China in 1980-2010 using a load apportionment model (LAM) from paired riverine TP concentrations and river discharge records. Based on the fundamental hydrological differences between PS and NPS pollution, the LAM statistically quantified their individual inputs as a power-law function of river discharge. The LAM-estimated monthly/annual riverine TP loads were in good agreement with results derived from a regression model, Load Estimator (LOADEST). The annual TP load increased from 18.4 to 357.0 Mg yr(-1) between 1980 and 2010. The PS input contributed 7-45% of annual total TP load and increased 23-fold, consistent with a 20-fold increase in flow-adjusted average chloride concentration during the low flow regime (a proxy for wastewater inputs), as well as measured increases in population, poultry, and industrial production. Inferring from observed TP and chloride ratios, as well as total suspended solids (TSS) and river discharge dynamics, temporally retained P load within the river during the low flow regime was estimated to contribute 18-65% of the annual PS input load. NPS inputs consistently dominated the annual riverine TP load (55-93%) and increased 19-fold, consistent with the strong correlation between riverine TP and TSS concentrations, increasing developed land area, improved agricultural drainage systems, and phosphorus accumulation in agricultural soils. Based on our analysis, TP pollution control strategies should be preferentially directed at reductions in NPS loads, especially during summer high-flow periods when the greatest eutrophication risk occurs

Reconstructing historical changes in phosphorus inputs to rivers from point and nonpoint sources in a rapidly developing watershed in eastern China, 1980-2010.

Quantifying point (PS) and nonpoint source (NPS) phosphorus inputs to rivers is critical for developing effective watershed remediation strategies. This study reconstructed PS and NPS total phosphorus (TP) inputs to the Yongan River in eastern China in 1980-2010 using a load apportionment model (LAM) from paired riverine TP concentrations and river discharge records. Based on the fundamental hydrological differences between PS and NPS pollution, the LAM statistically quantified their individual inputs as a power-law function of river discharge. The LAM-estimated monthly/annual riverine TP loads were in good agreement with results derived from a regression model, Load Estimator (LOADEST). The annual TP load increased from 18.4 to 357.0 Mg yr(-1) between 1980 and 2010. The PS input contributed 7-45% of annual total TP load and increased 23-fold, consistent with a 20-fold increase in flow-adjusted average chloride concentration during the low flow regime (a proxy for wastewater inputs), as well as measured increases in population, poultry, and industrial production. Inferring from observed TP and chloride ratios, as well as total suspended solids (TSS) and river discharge dynamics, temporally retained P load within the river during the low flow regime was estimated to contribute 18-65% of the annual PS input load. NPS inputs consistently dominated the annual riverine TP load (55-93%) and increased 19-fold, consistent with the strong correlation between riverine TP and TSS concentrations, increasing developed land area, improved agricultural drainage systems, and phosphorus accumulation in agricultural soils. Based on our analysis, TP pollution control strategies should be preferentially directed at reductions in NPS loads, especially during summer high-flow periods when the greatest eutrophication risk occurs

Etiologic diagnosis of lower respiratory tract bacterial infections using Sputum samples and quantitative loop-mediated isothermal amplification

Etiologic diagnoses of lower respiratory tract infections (LRTI) have been relying primarily on bacterial cultures that often fail to return useful results in time. Although DNA-based assays are more sensitive than bacterial cultures in detecting pathogens, the molecular results are often inconsistent and challenged by doubts on false positives, such as those due to system- and environment-derived contaminations. Here we report a nationwide cohort study on 2986 suspected LRTI patients across P. R. China. We compared the performance of a DNA-based assay qLAMP (quantitative Loop-mediated isothermal AMPlification) with that of standard bacterial cultures in detecting a panel of eight common respiratory bacterial pathogens from sputum samples. Our qLAMP assay detects the panel of pathogens in 1047(69.28%) patients from 1533 qualified patients at the end. We found that the bacterial titer quantified based on qLAMP is a predictor of probability that the bacterium in the sample can be detected in culture assay. The relatedness of the two assays fits a logistic regression curve. We used a piecewise linear function to define breakpoints where latent pathogen abruptly change its competitive relationship with others in the panel. These breakpoints, where pathogens start to propagate abnormally, are used as cutoffs to eliminate the influence of contaminations from normal flora. With help of the cutoffs derived from statistical analysis, we are able to identify causative pathogens in 750 (48.92%) patients from qualified patients. In conclusion, qLAMP is a reliable method in quantifying bacterial titer. Despite the fact that there are always latent bacteria contaminated in sputum samples, we can identify causative pathogens based on cutoffs derived from statistical analysis of competitive relationship. Trial Registration: ClinicalTrials.gov NCT00567827