DeepCBS: shedding light on the impact of mutations occurring at CTCF binding sites

CTCF-mediated chromatin loops create insulated neighborhoods that constrain promoter-enhancer interactions, serving as a unit of gene regulation. Disruption of the CTCF binding sites (CBS) will lead to the destruction of insulated neighborhoods, which in turn can cause dysregulation of the contained genes. In a recent study, it is found that CTCF/cohesin binding sites are a major mutational hotspot in the cancer genome. Mutations can affect CTCF binding, causing the disruption of insulated neighborhoods. And our analysis reveals a significant enrichment of well-known proto-oncogenes in insulated neighborhoods with mutations specifically occurring in anchor regions. It can be assumed that some mutations disrupt CTCF binding, leading to the disruption of insulated neighborhoods and subsequent activation of proto-oncogenes within these insulated neighborhoods. To explore the consequences of such mutations, we develop DeepCBS, a computational tool capable of analyzing mutations at CTCF binding sites, predicting their influence on insulated neighborhoods, and investigating the potential activation of proto-oncogenes. Futhermore, DeepCBS is applied to somatic mutation data of liver cancer. As a result, 87 mutations that disrupt CTCF binding sites are identified, which leads to the identification of 237 disrupted insulated neighborhoods containing a total of 135 genes. Integrative analysis of gene expression differences in liver cancer further highlights three genes: ARHGEF39, UBE2C and DQX1. Among them, ARHGEF39 and UBE2C have been reported in the literature as potential oncogenes involved in the development of liver cancer. The results indicate that DQX1 may be a potential oncogene in liver cancer and may contribute to tumor immune escape. In conclusion, DeepCBS is a promising method to analyze impacts of mutations occurring at CTCF binding sites on the insulator function of CTCF, with potential extensions to shed light on the effects of mutations on other functions of CTCF

Flexible surface acoustic wave resonators built on disposable plastic film for electronics and lab-on-a-chip applications

Flexible electronics are a very promising technology for various applications. Several types of flexible devices have been developed, but there has been limited research on flexible electromechanical systems (MEMS). Surface acoustic wave (SAW) devices are not only an essential electronic device, but also are the building blocks for sensors and MEMS. Here we report a method of making flexible SAW devices using ZnO nanocrystals deposited on a cheap and bendable plastic film. The flexible SAW devices exhibit two wave modes - the Rayleigh and Lamb waves with resonant frequencies of 198.1 MHz and 447.0 MHz respectively, and signal amplitudes of 18 dB. The flexible devices have a high temperature coefficient of frequency, and are thus useful as sensitive temperature sensors. Moreover, strong acoustic streaming with a velocity of 3.4 cm/s and particle concentration using the SAW have been achieved, demonstrating the great potential for applications in electronics and MEMS

Abnormal RNA Stability in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) share key features, including accumulation of the RNA-binding protein TDP-43. TDP-43 regulates RNA homeostasis, but it remains unclear whether RNA stability is affected in these disorders. We use Bru-seq and BruChase-seq to assess genome-wide RNA stability in ALS patient-derived cells, demonstrating profound destabilization of ribosomal and mitochondrial transcripts. This pattern is recapitulated by TDP-43 overexpression, suggesting a primary role for TDP-43 in RNA destabilization, and in postmortem samples from ALS and FTD patients. Proteomics and functional studies illustrate corresponding reductions in mitochondrial components and compensatory increases in protein synthesis. Collectively, these observations suggest that TDP-43 deposition leads to targeted RNA instability in ALS and FTD, and may ultimately cause cell death by disrupting energy production and protein synthesis pathways

A Computational Method Based on the Integration of Heterogeneous Networks for Predicting Disease-Gene Associations

The identification of disease-causing genes is a fundamental challenge in human health and of great importance in improving medical care, and provides a better understanding of gene functions. Recent computational approaches based on the interactions among human proteins and disease similarities have shown their power in tackling the issue. In this paper, a novel systematic and global method that integrates two heterogeneous networks for prioritizing candidate disease-causing genes is provided, based on the observation that genes causing the same or similar diseases tend to lie close to one another in a network of protein-protein interactions. In this method, the association score function between a query disease and a candidate gene is defined as the weighted sum of all the association scores between similar diseases and neighbouring genes. Moreover, the topological correlation of these two heterogeneous networks can be incorporated into the definition of the score function, and finally an iterative algorithm is designed for this issue. This method was tested with 10-fold cross-validation on all 1,126 diseases that have at least a known causal gene, and it ranked the correct gene as one of the top ten in 622 of all the 1,428 cases, significantly outperforming a state-of-the-art method called PRINCE. The results brought about by this method were applied to study three multi-factorial disorders: breast cancer, Alzheimer disease and diabetes mellitus type 2, and some suggestions of novel causal genes and candidate disease-causing subnetworks were provided for further investigation

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Stress sensitivity evaluation of ultra-low permeability sandstone reservoir and its influence on oilfield development

Luohe ultra-low permeability sandstone reservoir is a hot block in Yanchang oilfield, which is a potential point for increasing production and reservoir. In view of the current situation that there is no unified stress sensitivity evaluation standard for ultra-low permeability sandstone in the study area, taking the ultra-low permeability sandstone in Luohe district as the research object, the stress sensitivity evaluation of ultra-low permeability sandstone is carried out by using experimental analysis as the main means. The results show that it is more accurate to evaluate porosity by using pore stress sensitivity coefficient instead of pore compressibility coefficient. With the increase of net overburden pressure, the porosity stress sensitivity decreases gradually; the permeability stress sensitivity is evaluated by variable confining pressure. With the increase of confining pressure, the permeability damage decreases. With the decrease of confining pressure, the permeability damage increases, but it can not recover to the original value, so the permeability damage is irreversible; in the low bottom hole pressure stage, stress sensitivity has a greater impact on oil well productivity, while in the high bottom hole pressure stage, stress sensitivity has a smaller impact on oil well productivity; advanced water injection can reduce the adverse effect of stress sensitivity on the development of ultra-low permeability sandstone and maximize the economic benefits. The research results clarify the method of stress sensitivity evaluation, and provide guidance for efficient water injection in the next step

Study on shaping slope stability of dump in eastern grassland open-pit mine

The dumps in the open-pit mining area in the eastern grassland are prone to landslides due to the fragile ecological environment, so it is inevitable to reshape the dump slopes. In order to explore a more scientific method for slope shaping of open-pit mine dump, slope stability analysis were used to compare effect of three types of slope-type (wave-shaped, slope-shaped and step-shaped slope shaping method)in outside dumping site of Baori Hiller open-pit mine. The results show that the slope stability is negatively correlated with the slope angle, and the stability of different shaping slopes is realized as wave-shaped slope (F=2.711)> Slope-shaped slope(F=2.513)>Step-shaped slope(F=1.047), in which the wave type and slope type are all within the safe range, but the step type slope is unstable; in consideration of cost, stability and erosion resistance, it is better to set the slope angle of the dump to 15°.The wave-shaped shaping method of the natural dumping of the excavation field outside the Baori Hiller open-pit mine has the best effect and is worth promoting

Carbon Emission Pattern of Driving Car on Vertical Curves of Highway

Low carbon road design has always been a research hotspot for scholars. One of the primary road variables affecting the carbon emission of automobiles is vertical curve, which serves as the primary geometric alignment of the longitudinal portion of the road. The instantaneous speed and acceleration data of cars on various vertical curve sections are gathered for this study by combining simulation and real vehicle experiment methods. This study then built a database of carbon emissions for cars on various vertical curve sections based on the Motor Vehicle Emission Simulator (MOVES) model, used Statistical Product and Service Solutions (SPSS) to analyze the data, and developed a carbon emission model for cars on various vertical curve sections. Finally, it was found that the average error of the carbon emission model for different vertical curve sections was 8.37%, and the accuracy of carbon emission modelling could meet the requirements. The results show that the main influencing factor of carbon emission of cars on vertical curve sections is the radius of vertical curve, and the carbon emission of cars is inversely proportional to the radius of vertical curve. The smaller the value of vertical curve radius is, the more the engine output increases and the greater the carbon emission level will be. This research will provide reference and theoretical support for low-carbon design of highway longitudinal slope sections