Overexpression of β1 integrin contributes to polarity reversal and a poor prognosis of breast invasive micropapillary carcinoma

© Liu et al. Invasive micropapillary carcinoma (IMPC) of the breast is a highly aggressive breast cancer. Polarity reversal exemplified by cluster growth is hypothesized to contribute to the invasiveness and metastasis of IMPC. In this study, we demonstrate that levels of β1 integrin and Rac1 expression were greater in breast IMPC than in invasive breast carcinoma of no specific type and paraneoplastic benign breast tissue. We show that silencing β1 integrin expression using the β1 integrin inhibitor AIIB2 partially restored polarity in IMPC primary cell clusters and downregulated Rac1. Thus, overexpression of β1 integrin upregulates Rac1. Univariate analysis showed that overexpression of β1 integrin and Rac1 was associated with breast cancer cell polarity reversal, lymph node metastasis, and poor disease-free survival in IMPC patients. Multivariate analysis revealed that polarity reversal was an independent predictor of poor disease-free survival. These findings indicate that overexpression of β1 integrin and the resultant upregulation of Rac1 contribute to polarity reversal and metastasis of breast IMPC, and that β1 integrin and Rac1 could be potential prognostic biomarkers and targets for treatment of breast IMPC

Optimizing medium for producing ethanol from industrial crop Jerusalem artichoke by one- step fermentation and recombinant Saccharomyces cerevisiae

In order to obtain a high ethanol yield from the Jerusalem artichoke raw extract and reduce the fermentation cost, we have engineered a new recombinant Saccharomyces cerevisiae strain that could produce ex-inulinase. The response surface methodology based on Plackett-Burman and Box-Behnken design was used to optimize the medium for the ethanol production from the Jerusalem artichoke raw extracts by the recombinant strain. In the first optimization step, Plackett-Burman design was employed to select significant factors, including concentrations of yeast extract, inoculum, and MgSO(4)7H(2)O. In the second step, the steepest ascent experiment was carried out to determine the center point with the three significant factors; the selected combinations were further optimized using the Box-Behnken design. The maximum ethanol production rate was predicted at 91.1g/l, which was based on a medium consisting of yeast extract 9.24g/l, inoculum 39.8ml/l, and MgSO(4)7H(2)O 0.45g/l. In the validating experiment, the ethanol fermentation rate reached 102.1g/l, closely matching the predicted rate.In order to obtain a high ethanol yield from the Jerusalem artichoke raw extract and reduce the fermentation cost, we have engineered a new recombinant Saccharomyces cerevisiae strain that could produce ex-inulinase. The response surface methodology based on Plackett-Burman and Box-Behnken design was used to optimize the medium for the ethanol production from the Jerusalem artichoke raw extracts by the recombinant strain. In the first optimization step, Plackett-Burman design was employed to select significant factors, including concentrations of yeast extract, inoculum, and MgSO(4)7H(2)O. In the second step, the steepest ascent experiment was carried out to determine the center point with the three significant factors; the selected combinations were further optimized using the Box-Behnken design. The maximum ethanol production rate was predicted at 91.1g/l, which was based on a medium consisting of yeast extract 9.24g/l, inoculum 39.8ml/l, and MgSO(4)7H(2)O 0.45g/l. In the validating experiment, the ethanol fermentation rate reached 102.1g/l, closely matching the predicted rate

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Erratum to: 36th International Symposium on Intensive Care and Emergency Medicine

[This corrects the article DOI: 10.1186/s13054-016-1208-6.]

Diffusion in Liquids: Equilibrium Molecular Simulations and Predictive Engineering Models

The aim of this thesis is to study multicomponent diffusion in liquids using Molecular Dynamics (MD) simulations. Diffusion plays an important role in mass transport processes. In binary systems, mass transfer processes have been studied extensively using both experiments and molecular simulations. From a practical point of view, systems consisting more than two components are more interesting. However, experimental and simulation data on transport diffusion for such systems are scarce. Therefore, a more detailed knowledge on mass transfer in multicomponent systems is required. The presence of multiple components in a system introduces difficulties in studying diffusion in experiments. Investigating the concentration dependence of diffusion coefficients seriously increases the required experimental effort. In this thesis, we will use MD simulation based on classical force fields to study multicomponent diffusion in liquids. Diffusion can be described using both Fick and Maxwell- Stefan (MS) diffusion coefficients. Experiments provide Fick diffusion coefficients while simulations usually provide MS diffusion coefficients. Fick and MS diffusivities are related via the matrix of thermodynamic factors. A brief survey on methods for studying liquid diffusion and their limitations is presented in chapter 1 In chapter 2, we study the diffusion in the ternary system n-hexane-cyclohexanetoluene. The existing models for predicting MS diffusivities at finite concentrations (i:e: the Vignes equation) as well as the predictions at infinite dilution (i:e: predictions of Ðxk!1 i j using the so-called WK, KT, VKB, DKB and RS models) are tested using MD simulations. We find that (1) the Vignes equation only results in reasonable predictions for MS diffusivities yielding differences of 13% compared to the actual diffusion coefficients; (2) the best predictive model (the KT model) for calculating MS diffusivities at infinite dilution results in differences of 8% compared to the actual diffusion coefficients. It is important to note that the differences of 8% can be a coincidence since KT model is empirical and does not have a theoretical basis. This limitation makes KT model unreliable for other systems. To overcome the difficulties in predicting ternary MS diffusivities at infinite dilution (i:e: Ðxk!1 i j ), we derive the so-called LBV model based on the Onsager relations. MS diffusivities at infinite dilution can be expressed in terms of binary and pure component self-diffusivities and integrals over velocity cross-correlation functions. By neglecting the latter terms, we obtain the LBV model. In chapter 3, the LBV model is validated for WCA fluids and the ternary systems n-hexane-cyclohexane-toluene and methanol-ethanol-water. We find that: (1) for ideal mixtures i:e: the WCA system, as well as the n-hexane-cyclohexane-toluene system, the LBV model is accurate and superior compared to the existing models for predicting ternary MS diffusivities at infinite dilution (i:e: the WK, KT, VKB, DKB and RS models); (2) in mixtures containing associating components, i:e: the ethanol-methanol-water system, the LBV model indicates that in this system the integrals over velocity cross-correlation functions are important and cannot be neglected. Moreover, the LBV model provides an explanation why the MS diffusivity describing the friction between adsorbed components in a porous material is usually very large. In chapter 4, we focus on describing the values of MS diffusivities at finite concentration. A multicomponent Darken model for describing the concentration dependence of MS diffusivities is derived from linear response theory and the Onsager relations. In addition, a predictive model for the required self-diffusivities in the mixture is proposed leading to the so-called predictive Darken-LBV model. We compare our novel models to the existing generalized Vignes equation and the generalized Darken equation. Two systems are considered: (1) ternary and quaternary WCA systems; (2) the ternary system n-hexane-cyclohexane-toluene. Our results show that in all studied systems, our predictive Darken-LBV equation describes the concentration dependence better than the existing models. The physically-based Darken-LBV model provides a sound and robust framework for prediction of MS diffusion coefficients in multicomponent mixtures. In chapter 5, diffusion in more complex ionic liquid (IL) systems are investigated. Previous research reported in literature has largely focused on self-diffusion in ILs. For practical applications, mutual (transport) diffusion is by far more important than self-diffusion. We compute the MS diffusivities in binary systems containing 1-alkyl- 3- methylimidazolium chloride (CnmimCl), water and/or dimethyl sulfoxide (DMSO). The dependence of MS diffusivities on mixture composition are investigated. Our results show that: (1) For solutions of ILs in water and DMSO, self-diffusivities decrease strongly with increasing IL concentration. For the system DMSO-IL, an exponential decay is observed for this; (2) For both water-IL and DMSO-IL, MS diffusivities vary by a factor of 10 within the concentration range which is still significantly smaller than the variation of the self diffusivities; (3) The MS diffusivities of the investigated IL are almost independent of the alkyl chain length; (4) ILs stay in a form of isolated ions in CnmimCl-H2O mixtures, however, dissociation into ions is much less observed in CnmimCl-DMSO systems. This has a large effect on the concentration dependence of MS diffusivities; (5) The LBV model for predicting the MS diffusivity at infinite dilution described in chapter 3 suggests that velocity cross-correlation functions in ionic liquids cannot be neglected and that the dissociation of ILs into ion pairs has a very strong influence on diffusion. In experiments, Fick diffusion coefficients are measured and molecular simulation usually provides MS diffusivities. These approaches are related via the matrix of thermodynamic factors which is usually known only with large uncertainties. This leaves a gap between theory and application. In chapter 6, we introduce a consistent and efficient framework for the determination of Fick diffusivities in liquid mixtures directly from equilibrium MD simulations by calculating both the thermodynamic factor and the MS diffusivity. This provides the missing step to extract Fick diffusion coefficients directly from equilibrium MD simulations. The computed Fick diffusivities of acetone-methanol and acetone-tetrachloromethane mixtures are in excellent agreement with experimental values. The suggested framework thus provides an efficient route to model diffusion in liquids based on a consistent molecular picture. In chapter 7, we validate our method for computing Fick diffusivities using equilibrium MD simulations for the ternary system chloroform - acetone - methanol. Even though a simple molecular model is used (i:e: rigid molecules that interact by Lennard-Jones and electrostatic interactions), the computed thermodynamic factors are in close agreement with experiments. Validation data for diffusion coefficients is only available for two binary sub-systems. In these binary systems, MD results and experiments do agree well. For the ternary system, the computed thermodynamic factors using Molecular Dynamics simulation are in excellent agreement with experimental data and better than the ones obtained from COSMO-SAC calculations. Therefore, we expect that the computed Fick diffusivities should also be comparable with experiments. Our results suggest that the presented approach allows for an efficient and consistent prediction of multicomponent Fick diffusion coefficients from MD simulations. Now, a tool for guiding experiments and interpreting multicomponent mass transfer is available.Process & EnergyMechanical, Maritime and Materials Engineerin

Anomaly Detection on the Digital Video Braodcasting System

Electrical Engineering, Mathematics and Computer ScienceIntelligent System

Efficiency in Deep Learning: Image and Video Deep Model Efficiency

Deep learning is the core algorithmic tool for automatically processing large amounts of data. Deep learning models are defined as a stack of functions (called layers) with millions of parameters, that are updated during training by fitting them to data. Deep learning models have show remarkable accuracy gains on visual problems in video and images. Yet at the same time, this comes at a considerable computational cost that raises concerns about energy consumption. The escalation in the number of parameters and the surging demand for extensive data exacerbate these concerns. This thesis delves into the core of these concerns, proposing innovative techniques to enhance the efficiency of deep learning models. This thesis starts with exploring efficient deep learning models for video data, followed by efficient models for image data.....Pattern Recognition and Bioinformatic

How to Preserve Historic Districts in Harbin: A Study in Transplanting European Experiences

Historic preservation is always a hot topic in contemporary city development. The heritage witnessed how human life evolved and how the city developed. The high historical value assembles the city’s spirit and it brings to the human a sense of belonging. However, with urbanization and modernization, the heritages are easily under the risks of being damaged. Since 1980s, China started to pay attention on heritage preservation. The historic buildings, sites and historic cities are continuously added into the preservation objectives. Harbin city is a Chinese city with influences of western culture in its architecture due to its history. The government took actions to preserve these heritages since late 1980s. But facing countless historic remaining, the process of historic preservation planning has many problems which lead to a dissatisfaction of Harbin city. So far, there are 22 legally listed historic cultural districts. Based on their functions, they are divided into 5 types. The three districts having the most problems regarding preservation are covered in this research while the other two with better conditions are left for further study. The main difficulties in historic preservation are stated to provide sufficient knowledge on what is happening in Harbin, namely the decay of historic cultural value, the extensive influence of the government and commercial developers over other actors, and the lack of funding on preservation projects. In order to improve the historic preservation planning system for Harbin, the research deeps into the current situation of Harbin and analyzes two European cases in order to draw lessons. Three main parts in the body of the analysis are inspiration phase, learning phase and the transplantation phase. The inspiration phase contains the current situation and the case introductions, the learning phase contains the case analysis and the transplantation phase is focusing on transferring the merits from cases to Harbin. Five aspects are found to be essential in historic preservation. These are guidance of operation, public participation, supervision in process, coordination with other organizations and money source. The activities of these aspects are discussed in the case studies. And in order to improve the historic preservation planning system in Harbin, together with the local situation and resources, this research recommends five mechanisms. According to Richard Rose’s theories on the alternatives of treating lessons learning, they are adapted to increase the suitability and effectiveness: The research suggests that the experts should come up with a clear and detailed operating guidance for the operators in real work. The public’s involvement and other organizations should be encouraged and stimulated to coordinate in the preserving process. The funding problem can be solved by getting support from central government and the society including rich groups and donations. The mass media should monitor the process in order to ensure the fairness of the process.Policy, Organisation, Law and GamingMulti Actor SystemsTechnology, Policy and Managemen

Development of Condition Monitoring System for Railway Crossings: Condition Assessment and Degradation Detection for Guided Maintenance

Railway crossings are essential components of the railway track system that allow trains to switch from one track to another. Due to the complex wheel-rail interaction in the crossing panel, crossings are vulnerable elements of railway infrastructure and usually have short service lives. The crossing damage not only results in substantial maintenance efforts but also leads to traffic disruptions and can even affect traffic safety. In the Netherlands, the annual maintenance cost on railway crossings is more than 50 million euros. Due to the lack of monitoring systems, the real-time information on crossing condition is limited. As a result, the present maintenance actions on railway crossings are mainly reactive that take place only after the occurrence of visible damage. Usually, such actions (repairs) are carried out too late and result in unplanned disruptions that negatively affect track availability. In the Netherlands, around 100 crossings are urgently replaced every year, accompanied by traffic interruptions. Also, there is a considerable number of crossings with the service life of only 2-3 years. The maintenance methods used by the contractors on such crossings are somewhat limited and usually ended up with ballast tamping. In this case, the root causes of the fast crossing degradation are usually not resolved, and the crossings are still operated in degraded conditions after the maintenance. In order to improve the efficiency of the current maintenance of railway crossings aiming for better crossing performance, the goal of this study is to develop a monitoring system for railway crossings using which the crossing condition can be assessed, and the sources of the degradation can be detected. Using such a system timely and proper maintenance on railway crossings can be provided. The main steps in achieving this goal were as follows: Based on the measured dynamic responses of railway crossings due to passing trains, several condition indicators were proposed; To provide the fundamental basis for the proposed indicators a numerical model for the analysis of vehicle-crossing interaction was developed; The effectiveness of the proposed indicators was demonstrated using the data from long-term monitoring of 1:9 and 1:15 crossings. The railway crossing conditions can be reflected in the changes in the dynamic responses due to passing trains. In this study, the responses were obtained from the crossing instrumentation and wayside monitoring system. The responses reflect the wheel-rail interaction, which consists of the wheel impact accelerations, impact locations and the rail displacements due to the impacts, etc. Based on the correlation analysis of the responses, the indicators related to the wheel impact, fatigue area and ballast support were proposed. The indicators form a basis for the structural health monitoring (SHM) system for the railway crossings. To verify the effectiveness of the proposed indicators, and to explain the experimental findings, a numerical vehicle-crossing model is developed using the multi-body system (MBS) method. The model is validated using the measurement results and further verified using the finite element (FE) model. The proposed indicators and the MBS model were applied to the condition stage identification and damage source detection of the crossings. The main outcomes are presented below. In the condition monitoring of normally degraded crossings, the proposed indicators were capable to catch the main degradation stages of the railway crossing ranging from newly installed to damaged and repaired ones. With the assistance of these indicators, the maintenance actions can be timely applied before the occurrence of severe damage. The proposed indicators can also be used for assessing the effectiveness of the performed maintenance (repair welding and grinding, ballast tamping, etc.). It was demonstrated that ballast tamping has no positive effect on the performance of the monitored 1:9 crossing. The proposed indicators can also help to detect the root causes of the crossing damage. In some cases, the degradation is caused by adjacent structures, and therefore the maintenance should be performed not on the crossing itself but of the track nearby. In this study, the fast degradation of the monitored 1:9 crossing was found to be caused by the lateral track deformation in front of the crossing. The numerical results confirmed the phenomenon that the train hunting motion activated by the track deviation. It was the source of the extremely high impacts recorded by the monitoring system that ultimately resulted in the fast crossing degradation. By knowing the damage sources, proper maintenance can be performed rather than the currently used ineffective ballast tamping. Additionally, it was found that crossing degradation can also result from external disturbances. It was proven that highly increased rail temperature due to the long duration of sunshine would amplify the existed geometry deviation in turnout. Considering the high sensitivity of wheel-rail interaction in the crossing, higher standards for crossing maintenance and construction are required for better crossing performance. This study contributes to the development of the condition monitoring system for railway crossings. The application of the condition indicators is a big step forward for the current maintenance philosophies from damage repair to predictive maintenance, and from “failure reactive” to “failure proactive”. The outcomes in this study will contribute to the better performance of railway crossings.Railway Engineerin

Demonstration of 2 x 2 heterodyne receiver array at 1.4THz using HEB mixers and Fourier phase grating LO

This master thesis demonstrates the realization of a 2×2 heterodyne receiver array at 1.4 THz based on superconducting hot electron bolometer (HEB) mixers and a Fourier phase grating local oscillator (LO). This is the first time to build a heterodyne receiver array based on these two techniques at such a high frequency. The theoretical knowledge of two key components in this receiver array, HEB mixer and Fourier phase grating, have been elaborated in this thesis. The Fourier phase grating is further used in designing LO optical path to fit the array configuration. We also characterize the overall performances of this receiver array, including the required optimal pumped LO power, noise temperature, IF bandwidth and stability. Based on the fact that the phase grating duplicate the incoming single LO source, we suggest an idea of stabilizing two pixels using one stabilization circuit for the first time. This can reduce the complexity in designing large array. This 1.4 THz receiver array can also be served as a prototype for developing future 4.7 THz array in GUSSTO project, which is proposed to flight by NASA.TelecommunicationMicroelectronics & Computer EngineeringElectrical Engineering, Mathematics and Computer Scienc