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BackgroundStage II colorectal cancer(CRC) patients after surgery alone have a five-year survival rate of ~60-80%; the incremental benefit of adjuvant chemotherapy is

Objective To investigate the differential expression of piRNAs in brain tissues from patients with Alzheimer's disease (AD), and to study the roles of these piRNAs related to AD. Methods With age and sex matching, 6 AD (pathological AD) and 7 control subjects were selected. RNAs were converted into piRNAs after extracting from the prefrontal lobe brain tissues, then piRNAs were reversed transcription into cDNA. Based on preliminary results, 10 piRNAs expressed in brain tissues were selected: DQ571030, DQ597973, DQ576872, DQ597479, DQ586404, DQ590835, DQ600318, DQ581610, DQ586113 and DQ571669. The expression of piRNAs was detected by real-time PCR. Those mRNA related with piRNAs of significant differences were further studied. Results A trend of decrease was found in the expression of all the 10 piRNAs in the AD group. The expression of 4 piRNAs DQ597973, DQ576872, DQ597479 and DQ600318 were significantly decreased in the AD group(P＜0.05). The related mRNA LRRC37A3 of DQ600318 was further studied. DQ600318 showed the most significant difference in expression. The expression of LRRC37A3 was also significantly decreased in the AD group (P＜0.01). Conclusions The decreasing expression of DQ600318 and LRRC37A3 is potentially related to AD, and the detection of DQ600318 may function as a marker of AD pathogenesis.

Abstract The ultrafast monitoring of deoxyribonucleic acid (DNA) dynamic structural changes is an emerging and rapidly growing research topic in biotechnology. The existing optical spectroscopy used to identify different dynamical DNA structures lacks quick response while requiring large consumption of samples and bulky instrumental facilities. It is highly demanded to develop an ultrafast technique that monitors DNA structural changes with the external stimulus or cancer‐related disease scenarios. Here, we demonstrate a novel photonic integrated graphene‐optofluidic device to monitor DNA structural changes with the ultrafast response time. Our approach is featured with an effective and straightforward design of decoding the electronic structure change of graphene induced by its interactions with DNAs in different conformations using ultrafast nanosecond pulse laser and achieving refractive index sensitivity of ~3 × 10−5 RIU. This innovative technique for the first time allows us to perform ultrafast monitoring of the conformational changes of special DNA molecules structures, including G‐quadruplex formation by K+ ions and i‐motif formation by the low pH stimulus. The graphene‐optofluidic device as presented here provides a new class of label‐free, ultrafast, ultrasensitive, compact, and cost‐effective optical biosensors for medical and healthcare applications.

BACKGROUND Vesicular structure of volcanic rocks records the processes of the dissolution, expansion and escape of volatile gases in the ascending magma. The detailed study of characteristics of vesicles in volcanic rocks will be helpful to understand volatile content of magma and the ascent and erupting process of magma. Although a number of methods have been developed in the last decades to study the vesicle characteristics of volcanic rocks, they generally have the problems of low efficiency, less data collection, and sample destruction. OBJECTIVES To quantitatively characterize the content and size distribution of vesicles in volcanic rocks. METHODS On the basis of three-dimensional reconstruction of vesicular basalt by X-ray computed tomography, the content and size distribution of vesicles were calculated with three software programs (VG Studio MAX, ImageJ, Matlab), and an improved method for conversion of vesicle volume to volatile mass fraction in volcanic rock was also proposed. RESULTS The vesicle content in three-dimensional space for a basalt sample from the South China Sea in water depth of 1488 meter was 12.32%, and the vesicle size showed a lognormal distribution. The majority of vesicles were 180-200μm in equivalent sphere diameter and 340-360μm in maximum diameter. The content of vesicles in the two-dimensional slices on the profile varied greatly, but the amplitude of each value around the volume fraction fluctuated little, and there was a significant positive correlation with the number density of vesicles. Based on the known vesicle content, the calculated mass fractions of CO2 and H2O in the sample were 0.233% and 0.099%, respectively. CONCLUSIONS The study demonstrates that industrial CT scanning combined with image processing software can produce non-destructive rapid statistics and analysis of volcanic vesicles. The proposed method will be an efficient tool to study the genesis of volcanic rocks and their magmatic processes.

Background: The MSI/MSS status does not fully explain cancer immunotherapy response in colorectal cancer. Thus, we developed a colorectal cancer-specific method that predicts cancer immunotherapy response.Methods: We used gene expression data of 454 samples (MSI = 131, MSI-L = 23, MSS = 284, and Unknown = 16) and developed a TMEPRE method that models signatures of CD8+ T-cell infiltration and CD8+ T-cell exhaustion states in the tumor microenvironment of colorectal cancer. TMEPRE model was validated on three RNAseq datasets of melanoma patients who received pembrolizumab or nivolumab and one RNAseq dataset of purified CD8+ T cells in different exhaustion states.Results: TMEPRE showed predictive power in three datasets of anti-PD1-treated patients (p = 0.056, 0.115, 0.003). CD8+ T-cell exhaustion component of TMEPRE model correlates with anti-PD1 responding progenitor exhausted CD8+ T cells in both tumor and viral infection (p = 0.048, 0.001). The global pattern of TMEPRE on 454 colorectal cancer samples indicated that 10.6% of MSS patients and 67.2% of MSI patients show biological characteristics that can potentially benefit from anti-PD1 treatment. Within MSI nonresponders, approximately 50% showed insufficient tumor-infiltrating CD8+ T cells and 50% showed terminal exhaustion of CD8+ T cells. These terminally exhausted CD8+ T cells coexisted with signatures of myeloid-derived suppressor cells in colorectal cancer.Conclusion: TMEPRE is a colorectal cancer-specific method. It captures characteristics of CD8+ T-cell infiltration and CD8+ T-cell exhaustion state and predicts cancer immunotherapy response. A subset of MSS patients could potentially benefit from anti-PD1 treatment. Anti-PD1 resistance MSI patients with insufficient infiltration of CD8+ T cells or terminal exhaustion of CD8+ T cells need different treatment strategies.

To more accurately and effectively solve the problem of comprehensive reliability of multi-failure mode with the thermal creep, dual response surface method（DRSM） was adopted to implement the reliability of aero-engine turbine blisk. The numerical characteristics of the material parameters were obtained through the creep test data. The gas temperature, material density, elastic modulus and working rotation speed of the blisk structure were select as input variables. By constructing the finite element model of the blisk and the thermal-structural coupling analysis method, the stress and strain of turbine blisk were obtained. The mathematical model of dual response surface for stress and strain of turbine blisk was established by using the Latin hypercube small sampling technique. The comprehensive reliability analysis of the blisk was completed by using Monte Carlo method with linkage sampling of dual response surface model. The results indicate that the comprehensive reliability of blisk with thermal creep is 0.985 6. The comparison of method shows that dual response surface method can significantly improve computational efficiency without the loss of accuracy.

Coccinella septempunctata (ladybird) is one of the foremost natural predators that feed on aphids. Thus, C. septempunctata serves as an effective biological control agent in integrated pest management (IPM) programs. To supplement the activity of biological control agents, IPM programs often incorporate chemical pesticides to bolster crop protection. To evaluate the effects of a potent insecticide, tolfenpyrad, on C. septempunctata, we tested the sublethal effects of tolfenpyrad on all developmental stages of the life cycle of C. septempunctata and its effects on the next generation. For sublethal testing of the parent generation, the LR50 of tolfenpyrad for C. septempunctata was determined to range from 1.04 to 8.43 g a.i. /hm2 within a set exposure period, while the hazard quotient (HQ) values were above our threshold value of 2 during the entire observation period. These data indicated a potential toxicity risk from tolfenpyrad exposure. The no observed effect application rates (NOERs) of tolfenpyrad on parents (F0) were determined for survival (0.485 g a.i. /hm2), developmental time of pupation (0.242 g a.i. /hm2), and fecundity (0.485 g a.i. /hm2). Application of sublethal doses to unexposed progeny (F1) of exposed parents, prolonged the L1 (1st instar of larvae) and L2 (2nd instar of larvae) stage, while the total longevity, intrinsic rate of increase (r), finite rate of increase (γ), net reproductive rate (R0), and mean generation time (T) were significantly reduced. These results demonstrated the negative influence of sublethal concentrations of tolfenpyrad on C. septempunctata and its persistent effects on subsequent generations.

Persistent antigen exposure in chronic infection and cancer has been proposed to lead to cytotoxic T lymphocyte (CTL) “exhaustion”, i.e., loss of effector function and disease control. Recent work identifies a population of poorly differentiated TCF-1+PD-1+ CD8+ T cells as precursors of the terminally exhausted CTL pool. These “predysfunctional” CTLs are suggested to respond to PD-1 targeted therapy by giving rise to a pool of functional CTLs. Supported by gene expression analyses, we present a model in which lack of CD4+ T cell help during CD8+ T cell priming results in the formation of predysfunctional CTLs. Our model implies that predysfunctional CTLs are formed during priming and that the remedy for CTL dysfunction is to provide “help” signals for generation of optimal CTL effectors. We substantiate that this may be achieved by engaging CD4+ T cells in new CD8+ T cell priming, or by combined PD-1 blocking and CD27 agonism with available immunotherapeutic antibodies.

The integrated navigation system is used to estimate the position, velocity, and attitude of a vehicle with the output of inertial sensors. This paper concentrates on the problem of the INS/GPS integrated navigation system design and simulation. The structure of the INS/GPS integrated navigation system is made up of four parts: 1) GPS receiver, 2) Inertial Navigation System, 3) Extended Kalman filter, and 4) Integrated navigation scheme. Afterwards, we illustrate how to simulate the integrated navigation system with the extended Kalman filter by measuring position, velocity and attitude. Particularly, the extended Kalman filter can estimate states of the nonlinear system in the noisy environment. In extended Kalman filter, the estimation of the state vector and the error covariance matrix are computed by steps: 1) time update and 2) measurement update. Finally, the simulation process is implemented by Matlab, and simulation results prove that the error rate of statement measuring is lower when applying the extended Kalman filter in the INS/GPS integrated navigation system.

This article sorts out the development of China’s new energy vehicle industry from three levels of policy, market and technology, and judges the development trend. At the policy level, R&D and innovation support policies, promotion fee policies, and going out policies will become development trends. At the market level, the future automobile market will gradually pick up and maintain a steady development trend. At the technical level, the level of three-electric technology and intelligent network technology will be further improved. On this basis, the company’s development strategy is analyzed in order to provide a reference for the development of new energy automobile companies.

FurinDB (freely available online at http://www.nuolan.net/substrates.html) is a database of furin substrates. This database includes experimentally verified furin cleavage sites, substrates, species, experimental methods, original publications of experiments and associated drugs targeting furin substrates. The current database release contains 126 furin cleavage sites from three species: mammals, bacteria and viruses. A main feature of this database is that all furin cleavage sites are recorded as a 20-residue motif, including one core region (eight amino acids, P6–P2’) and two flanking solvent accessible regions (eight amino acids, P7–P14, and four amino acids, P3’–P6’), that represent our current understanding of the molecular biology of furin cleavage. This database is important for understanding the molecular evolution and relationships between sequence motifs, 3D structures, cellular functions and physical properties required by furin for cleavage, and for elucidating the molecular mechanisms and the progression of furin cleavage associated human diseases, including pathogenic infections, neurological disorders, tumorigenesis, tumor invasion, angiogenesis, and metastasis. FurinDB database will be a solid addition to the publicly available infrastructure for scientists in the field of molecular biology.

Proprotein convertases are enzymes that proteolytically cleave protein precursors in the secretory pathway to yield functional proteins. Seven mammalian subtilisin/Kex2p-like proprotein convertases have been identified: furin, PC1, PC2, PC4, PACE4, PC5 and PC7. The binding pockets of all seven proprotein convertases are evolutionarily conserved and highly similar. Among the seven proprotein convertases, the furin cleavage site motif has recently been characterized as a 20-residue motif that includes one core region P6-P2´ inside the furin binding pocket. This study extended this information by examining the 3D structural environment of the furin binding pocket surrounding the core region P6-P2´ of furin substrates. The physical properties of mutations in the binding pockets of the other six mammalian proprotein convertases were compared. The results suggest that: 1) mutations at two positions, Glu230 and Glu257, change the overall density of the negative charge of the binding pockets, and govern the substrate specificities of mammalian proprotein convertases; 2) two proprotein convertases (PC1 and PC2) may have reduced sensitivity for positively charged residues at substrate position P5 or P6, whereas the substrate specificities of three proprotein convertases (furin, PACE4, and PC5) are similar to each other. This finding led to a novel design of a short peptide pattern for small molecule inhibitors: [K/R]-X-V-X-K-R. Compared with the widely used small molecule dec-RVKR-cmk that inhibits all seven proprotein convertases, a finely-tuned derivative of the short peptide pattern [K/R]-X-V-X-K-R may have the potential to more effectively inhibit five of the proprotein convertases (furin, PC4, PACE4, PC5 and PC7) compared to the remaining two (PC1 and PC2). The results not only provide insights into the molecular evolution of enzyme function in the proprotein convertase family, but will also aid the study of the functional redundancy of proprotein convertases and the development of therapeutic applications.

In this manuscript, carrier transport simulation methods are proposed for devices with the coexistence of quantum transport and diffusive transport by combining the nonequilibrium Green's function method with the drift-diffusion transport simulation method. Current continuity between quantum transport and drift-diffusion transport is ensured by setting quantum transport current as the connection boundary condition of drift-diffusion simulation or by introducing quantum transport-induced carrier generation rates to drift-diffusion simulation. A comprehensive study of our method and the method combining the Wentzel–Kramers–Brillouin (WKB) method with the drift-diffusion transport simulation method is performed for n-type tunnel oxide passivating contact solar cell to investigate their applicable conditions and balance the accuracy and computational cost. As the oxide barrier width, barrier height, and electron effective mass increase, or the doping concentration in the electron transport layer decreases to the extent that the blocking effect of the oxide barrier on light-generated electrons becomes significant, method I is more accurate since the transmission coefficient near the conduction band edge calculated by WKB is overestimated; otherwise, method II is more suitable due to its low computational cost without the loss of accuracy. In addition, the differences between current densities, carrier densities, and Shockley–Read–Hall recombination rates simulated under the two current continuity conditions for the solar cell with different carrier mobilities are also further explored and analyzed. [ABSTRACT FROM AUTHOR]

Background MammaPrint was developed as a diagnostic tool to predict risk of breast cancer metastasis using the expression of 70 genes. To better understand the tumor biology assessed by MammaPrint, we interpreted the biological functions of the 70-genes and showed how the genes reflect the six hallmarks of cancer as defined by Hanahan and Weinberg. Results We used a bottom-up system biology approach to elucidate how the cellular processes reflected by the 70-genes work together to regulate tumor activities and progression. The biological functions of the genes were analyzed using literature research and several bioinformatics tools. Protein-protein interaction network analyses indicated that the 70-genes form highly interconnected networks and that their expression levels are regulated by key tumorigenesis related genes such as TP53, RB1, MYC, JUN and CDKN2A . The biological functions of the genes could be associated with the essential steps necessary for tumor progression and metastasis, and cover the six well-defined hallmarks of cancer, reflecting the acquired malignant characteristics of a cancer cell along with tumor progression and metastasis-related biological activities. Conclusion Genes in the MammaPrint gene signature comprehensively measure the six hallmarks of cancer-related biology. This finding establishes a link between a molecular signature and the underlying molecular mechanisms of tumor cell progression and metastasis.