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Panax quinquefolium is a perennial herbaceous plant that contains many beneficial ginsenosides with diverse pharmacological effects. 24(R)-pseudoginsenoside F11 is specific to P. quinquefolium, a useful biomarker for distinguishing this species from other related plants. However, because of its nonconjugated property and the complexity of existing detection methods, this biomarker cannot be used as the identification standard. We herein present a stable 24(R)-pseudoginsenoside F11 fingerprint spectrum in the terahertz band, thereby proving that F11 can be detected and quantitatively analyzed via terahertz spectroscopy. We also analyzed the sample by high-performance liquid chromatography-triple quadrupole mass spectrometry. The difference between the normalized data for the two analytical methods was less than 5%. Furthermore, P. quinquefolium from different areas and other substances can be clearly distinguished based on these terahertz spectra with a standard principal component analysis. Our method is a fast, simple, and cost-effective approach for identifying and quantitatively analyzing P. quinquefolium.

5-Methylcytosine (m5C) is a kind of methylation modification that occurs in both DNA and RNA and is present in the highly abundant tRNA and rRNA. It has an important impact on various human diseases including cancer. The function of m5C is modulated by regulatory proteins, including methyltransferases (writers) and special binding proteins (readers). This study aims at comprehensive study of the m5C RNA methylation-related genes and the main pathways under m5C RNA methylation in gastrointestinal (GI) cancer. Our result showed that the expression of m5C writers and reader was mostly up-regulated in GI cancer. The NSUN2 gene has the highest proportion of mutations found in GI cancer. Importantly, in liver cancer, higher expression of almost all m5C regulators was significantly associated with lower patient survival rate. In addition, the expression level of m5C-related genes is significantly different at various pathological stages. Finally, we have found through bioinformatics analysis that m5C regulatory proteins are closely related to the ErbB/PI3K–Akt signaling pathway and GSK3B was an important target for m5C regulators. Besides, the compound termed streptozotocin may be a key candidate drug targeting on GSK3B for molecular targeted therapy in GI cancer.

Background: Oxidative stress plays a critical role in pulmonary fibrosis after acute lung injury (ALI), and epithelial-mesenchymal transition (EMT) events are involved in this process. The purpose of this study was to investigate the protective effects of melatonin, a natural antioxidant, on lipopolysaccharide (LPS)-induced EMT in human alveolar epithelial cells. Methods: Human type II alveolar epithelial cell-derived A549 cells were incubated with LPS and melatonin alone or in combination for up to 24 h. The morphological changes of the treated cells were evaluated as well as indexes of oxidative stress. EMT-related proteins and the Nrf2 signaling pathway were detected by western blot analysis and immunofluorescence staining, respectively. To further investigate the underlying mechanisms, the effects of melatonin on cells transfected Nrf2 short hairpin RNA (shRNA) and the PI3K / GSK-3β signaling pathway were evaluated. Results: Treatment with melatonin upregulated Nrf2 expression, inhibited LPS-induced cell morphological change, reversed the expressions of EMT-related proteins, and reduced reactive oxygen species (ROS) production in A549 cells, as well as the levels of malondialdehyde (MDA) and anti-oxidative enzymes. Yet, the effects of melatonin were almost completely abolished in cells transfected Nrf2 shRNA. Furthermore, the data demonstrated that melatonin could activate the PI3K/AKT signaling pathway, resulting in phosphorylation of GSK-3β (Ser9) and upregulation of the Nrf2 protein in A549 cells, which ultimately attenuated LPS-induced EMT. Conclusion: The present study is the first to demonstrate that melatonin can protect human alveolar epithelial cells against oxidative stress by effectively inhibiting LPS-induced EMT, which was mostly dependent on upregulation of the Nrf2 pathway via the PI3K/GSK-3β axis. Further studies are warranted to investigate the role of melatonin for the treatment of oxidative stress-associated diseases, as well as pulmonary fibrosis after ALI.

Engineering rock mass is normally subject to cyclic–dynamic disturbances from excavation, blasting, drilling, and earthquakes. Natural fractures in rock masses can be reactivated and propagated under dynamic and static loadings, which affects the stability of rock mass engineering. However, fractured rock mass failure induced by cyclic-impact disturbances is far from clear, especially considering varying angles between the rock mass and the direction of impact loadings. This work investigated rock deformation and failure characteristics through cyclic impact tests on granite samples with cracks of different angles. A Hopkinson bar was employed for uniaxial cyclic impact tests on granite samples with the crack inclination angles of 0–90°. The magnetic resonance imaging technique was used to determine rocks’ porosity after cyclic impacts. The stress–strain curves, porosity, strength, deformation modulus, failure modes, and energy density of samples were obtained and discussed. Results showed that the crack inclination angles significantly affected the damage evolution and crack morphology of rocks. Under the constant cyclic impact, the dynamic deformation modulus and dynamic strength of rock samples first increased and then decreased with the increase in crack inclination angle. The failures of granite samples for inclination angles of 0 and 90° were dominated by tensile cracking, while those for the inclination angles of 30–60° were dominated by shear cracking. The energy density per unit time gradually decreased with the increase in impact cycles. The results can provide references for the stability analysis and cyclic-impact-induced failure prediction of fractured rock masses.

In power systems, the destruction of some important nodes may cause cascading faults. If the most important node in the power system can be found, the important node can be protected in advance, thereby avoiding a blackout accident. At present, the evaluation algorithm of node importance is calculated based on the power flow of the power grid, so the calculation results must be lagging behind, and it does not have the ability to provide early warning for the power grid to provide protection signals. Therefore, it is necessary to predict the importance of nodes in the power system. After using a reasonable prediction model to predict the importance of nodes, we can simulate the future state of power system operation and avoid accidents for the dispatching agency of the power grid company according to the prediction results. This paper proposes a prediction model based on convolutional long short-term memory (ConvLSTM) to predict the importance of nodes. This method has obvious advantages over the long short-term memory (LSTM) network. The convolution operation is used to replace the original full connection operation of the LSTM network, which not only utilizes the advantages of convolution to extract spatial features but also retains the ability of LSTM to process time-series features. The simulation results show that the prediction of node importance using the ConvLSTM network is much more accurate than LSTM. Using statistical indicators to compare and analyze the prediction results, it can be seen that ConvLSTM has higher prediction accuracy. Therefore, using the ConvLSTM model to predict node importance has certain significance for grid dispatching agencies to accurately simulate the future state of the power system and avoid risks in advance.

In this paper, mechanical property tests of sandstone with multiple shapes of prefabricated fractures (single, T-shaped, and Y-shaped fractures) are carried out through the MTS815 rock mechanics testing machine and the Teledyne ISCO D-Series Pumps system. Considering the hydro-mechanical coupling effects, the experiments reveal the key thresholds, strength characteristics and deformation laws of multi-shape fractured sandstones during the progressive failure process. According to the elastic-plastic theory, the continuous damage theory and the statistical damage theory, a new damage model is constructed, which fully reflects the coupled effects among water, micro flaws and macroscopic prefabricated fractures. The crack closure stress σcc, crack initiation stress σci and damage stress σcd of multi-shape fractured sandstone samples are determined by the proposed volumetric strain response method. In the range of 0–90°, the σcc and σci of the multi-shape fractured sandstone samples are different, as well as the angles when the σcd and peak strength (σc) reach their peak values. The stress ratios (the σcc/σc, σci/σc, and σcd/σc are collectively referred to as stress ratios) are hardly affected by the shape and inclination of the fractures inside the rock. According to strength analysis and deformation characteristics, the weakening effect of water has less of an influence on the strength than prefabricated fractures. The stress–strain curve obtained, based on the hydro-mechanical coupling test, is in good agreement with the theoretical curve generated by the damage constitutive model, verifying the rationality of the damage constitutive model. In addition, the fracture inclination only affects the numerical value of the total damage variable of multi-shape fractured sandstone samples, and has minor effects on its variation trend.

Rapeseed (Brassica napus L.) is mainly used for oil production and industrial purposes. A high photosynthetic efficiency is the premise of a high yield capable of meeting people’s various demands. Chlorophyll-deficient mutants are ideal materials for studying chlorophyll biosynthesis and photosynthesis. In a previous study, we obtained the mutant yl1 for leaf yellowing throughout the growth period by ethyl methanesulfonate mutagenesis of B. napus. A genetic analysis showed that the yl1 chlorophyll-deficient phenotype was controlled by one incompletely dominant gene, which was mapped on chromosome A03 by a quantitative trait loci sequencing analysis and designated as BnA03.Chd in this study. We constructed an F2 population containing 5256 individuals to clone BnA03.Chd. Finally, BnA03.Chd was fine-mapped to a 304.7 kb interval of the B. napus ‘ZS11’ genome containing 58 annotated genes. Functional annotation, transcriptome, and sequence variation analyses confirmed that BnaA03g0054400ZS, a homolog of AT5G13630, was the most likely candidate gene. BnaA03g0054400ZS encodes the H subunit of Mg-chelatase. A sequence analysis revealed a single-nucleotide polymorphism (SNP), causing an amino-acid substitution from glutamic acid to lysine (Glu1349Lys). In addition, the molecular marker BnaYL1 was developed based on the SNP of BnA03.Chd, which perfectly cosegregated with the chlorophyll-deficient phenotype in two different F2 populations. Our results provide insight into the molecular mechanism underlying chlorophyll synthesis in B. napus.

In this research, we successfully developed a green, economical and effective one–step hydrothermal method for the synthesis of fluorescent nitrogen–doped carbon dots (N–CDs) by utilizing fresh tea leaves and urea as the carbon and nitrogen sources, respectively. The obtained N–CDs were characterized by TEM, XPS and FT–IR. We found that the N–CDs were near–spherical with an average size of about 2.32 nm, and contained abundant oxygen and nitrogen functional groups. The N–CDs exhibited bright blue fluorescence under ultraviolet illumination, with the maximum emission at 455 nm. Meanwhile, the as–prepared N–CDs could be selectively quenched by Fe3+ ions. The quenching of N–CDs is linearly correlated with the concentration of Fe3+ in the range of 0.1–400 μM with a low detection limit of 0.079 μM. Significantly, the N–CDs present excellent biocompatibility and high photostability. The results also depict that multicolor fluorescence is displayed under a fluorescence microscope and successfully applied for the detection of intracellular Fe3+. To sum up, the fluorescent N–CDs are expected to be a sensitive detection probe for Fe3+ in biological systems.

Industrial solid waste refers to the solid waste that is produced in industrial production activities. Without correct treatment and let-off, industrial solid waste may cause environmental pollution due to a variety of pollutants and toxic substances that are contained in it. Conventional detection methods for identifying harmful substances are high performance liquid chromatography (HPLC) and gas chromatography-mass spectrometry (GC-MS), which are complicated, time-consuming, and highly demanding for the testing environment. Here, we propose a method for the quantitative analysis of harmful components in industrial solid waste by using terahertz (THz) spectroscopy combined with chemometrics. Pyrazinamide, benazepril, cefprozil, and bisphenol A are four usual hazardous components in industrial solid waste. By comparing with the Raman method, the THz method shows a much higher accuracy for their concentration analysis (90.3–99.8% vs. 11.7–86.9%). In addition, the quantitative analysis of mixtures was conducted, and the resulting prediction accuracy rate was above 95%. This work has high application value for the rapid, accurate, and low-cost detection of industrial solid waste.

This work focused on the nonlinear seepage behaviors of flow in pore-fracture media. Natural sandstones were selected to prefabricate single-fracture specimens with different inclinations (0–90°). Seepage tests of combined media were performed under different confining pressures (8–10 MPa) and different water pressures (3–7 MPa) in a triaxial pressure chamber. The fitting analysis of experimental data showed that Forchheimer’s law described the nonlinear characteristics of flow in the pore-fracture media. Linear term coefficient a and nonlinear term coefficient b of the sandstone samples with different inclinations changed more obviously with the increased inclination. When the fracture inclination was greater than 30°, a and b values had a sudden jump. The nonlinear inertial-parameter equation of fluid flow in pore-fracture media was proposed based on non-Darcy flow coefficient β and inherent permeability k. The applicability of the following methods to evaluate Darcy’s law was discussed, including normalized hydraulic conductivity, pressure gradient ratio, and discharge ratio. The three methods were able to determine critical parameters and distinguish linear and nonlinear flow. Furthermore, it was specified for the first time that when β was negative, critical nonlinear effect E was −0.1, and Forchheimer’s coefficient F0 was −0.091. In the −∇P-Q relationship, the fitting curve was convex to the −∇P axis, and the increase of Q was higher than the linear increase, presenting the nonlinearity of overflow. On the one hand, the fractures and pores were compressed under the confining pressure due to the prefabricated fractures of different shapes and different inclinations. A higher seepage water pressure was needed to stabilize the seepage system with the excessive flow rate. On the other hand, the barrier effect of the fluid inside the rock was completely lost because the fluid expanded the seepage channel. Its permeability was changed, leading to seepage instability.

Docetaxel is a major treatment for advanced prostate cancer (PCa); however, its resistance compromises clinical effectiveness. Estrogen receptor-related receptor alpha (ERRα) belongs to an orphan nuclear receptor superfamily and was recently found to be closely involved in cancer. In the present study, we found that ERRα was involved in docetaxel resistance in PCa. Overexpression of ERRα conferred docetaxel resistance in PCa cell lines, and cells with ERRα downregulation were more sensitive to docetaxel. Among the drug resistance-related genes, ABCC4 demonstrated synchronous expression after ERRα manipulation in cells. Moreover, both ERRα and ABCC4 were overexpressed in the docetaxel-resistant cell, which could be reversed by ERRα knockdown. The knockdown of ERRα also reversed the reduced drug accumulation in the docetaxel-resistant cell. We also demonstrated for the first time that ABCC4 was a direct target of ERRα as determined by the CHIP and luciferase assays. Bioinformatics analysis revealed high expression of ERRα and ABCC4 in PCa patients, and a number of potential ERRα/ABCC4 targets were predicted. In conclusion, our study demonstrated a critical role for ERRα in docetaxel resistance by directly targeting ABCC4 and stressed the importance of ERRα as a potential therapeutic target for drug-resistant PCa.

The development of chemotherapy resistance significantly impairs the efficiency of chemotherapy, but the underlying mechanisms of chemotherapy resistance in gastric cancer (GC) are complicated and still need to be further explored. Here, we aimed to reveal the effects of miR-4290/PDK1 (pyruvate dehydrogenase kinase 1) axis on chemotherapy resistance of GC in vitro. The expression patterns of miR-4290 in GC tissues and cell lines were determined by real-time quantitative PCR. Kaplan-Meier was used to assess the relationship between miR-4290 expression levels and patients' overall survival. CCK-8 and flow cytometry technologies were applied to detect cell proliferation and apoptosis. The luciferase gene reporter assay was used to evaluate the interaction between miR-4290 and PDK1. miR-4290 was lowly expressed in GC tissues and cell lines, which was closely associated with the shorter overall survival of GC patients. miR-4290 mimics significantly inhibited cell proliferation and induced cell apoptosis, as well as induced a significant reduction in the expression of PDK1. Moreover, miR-4290 significantly inhibited glycolysis and decreased the IC50 value to cisplatin in SGC7901 cells, whereas these effects were abolished and cell apoptosis was promoted when PDK1 was overexpressed. In conclusion, this study revealed that miR-4290 suppressed PDK1-mediated glycolysis to enhance the sensitivity of GC cells to cisplatin.

The monocarboxylate transporters (MCTs) MCT1, MCT2, and MCT4 are essential components of the astrocyte-neuron lactate shuttle (ANLS), which is a fundamental element of brain energetics. Decreased expression of MCTs can induce cognitive dysfunction of the brain. In the present study, we established a mouse model of long-term ketamine administration by subjecting mice to a 6-month course of a daily intraperitoneal injection of ketamine. These mice demonstrated learning and memory deficits and a significant decline in MCT1 and MCT4 proteins in the hippocampal membrane fraction, while cytoplasmic MCT1 and MCT4 protein levels were significantly increased. In contrast, the levels of global MCT2 protein were significantly increased. Analysis of mRNA levels found no changes in MCT1/4 transcripts, although the expression of MCT2 mRNA was significantly increased. We suggest that redistribution of hippocampal MCT1 and MCT4, but not MCT2 up-regulation, may be related to learning and memory deficits induced by long-term ketamine administration.

Breast cancer is the most common type of cancer among women. Therefore, discovery of new and effective drugs with fewer side effects is necessary to treat it. Sulforaphane (SFN) is an organosulfur compound obtained from cruciferous plants, such as broccoli and mustard, and it has the potential to treat breast cancer. Hence, it is vital to find out how SFN targets certain genes and cellular pathways in treating breast cancer. In this review, molecular targets and cellular pathways of SFN are described. Studies have shown SFN inhibits cell proliferation, causes apoptosis, stops cell cycle and has anti-oxidant activities. Increasing reactive oxygen species (ROS) produces oxidative stress, activates inflammatory transcription factors, and these result in inflammation leading to cancer. Increasing anti-oxidant potential of cells and discovering new targets to reduce ROS creation reduces oxidative stress and it eventually reduces cancer risks. In short, SFN effectively affects histone deacetylases involved in chromatin remodeling, gene expression, and Nrf2 anti-oxidant signaling. This review points to the potential of SFN to treat breast cancer as well as the importance of other new cruciferous compounds, derived from and isolated from mustard, to target Keap1 and Akt, two key regulators of cellular homeostasis.

Background: The aim of the present study was to investigate the synergistic effects and interactive mechanisms of Shufeng Jiedu Capsule (SFJDC) combined with oseltamivir in the treatment of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) induced by the influenza A virus (IAV). Methods: The extraction of SFJDC was analyzed by UHPLC/ESI Q-Orbitrap Mass Spectrometry. Human bronchial epithelial cells were isolated from COPD (DHBE) bronchial tissues, co-cultured with IAV for 24 h, and were subsequently treated with SFJDC and/or oseltamivir. Cell viability was detected by MTT assay. A rat model of COPD with IAV infection was established and treated with SFJDC and/or oseltamivir. Interleukin (IL)-1β and IL-18 in serum and bronchoalveolar lavage fluid (BALF) were measured by ELISA. Additionally, mRNA and protein levels of NLRP3 inflammasome pathway were measured by quantitative real-time PCR and Western blotting, respectively. Results: SFJDC and/or oseltamivir, at their optimal concentrations, had no significant cytotoxicity against DHBEs. The levels of NLRP3-inflammasome-associated components were significantly elevated after cells were inoculated with IAV, whereas the mRNA and protein levels of these components were significantly decreased after treatment with SFJDC and/or oseltamivir in vitro. Moreover, in vivo, the combination of SFJDC and oseltamivir improved survival rates, attenuated clinical symptoms, induced weight gain, alleviated lung damage, and significantly reduced IL-1β and IL-18 levels in serum and BALF, as well as reduced the expression levels of NLRP3-associated components and viral titers in lung homogenates. Conclusion: SFJDC combined with oseltamivir treatment significantly attenuated IAV-induced airway inflammation and lung viral titers. Hence, our findings may provide a novel therapeutic strategy for IAV-induced respiratory infection.

Terahertz (THz) waves are electromagnetic waves with frequency in the range from 0.1 to 10 THz. THz waves have great potential in the biomedical field, especially in cancer diagnosis, because they exhibit low ionization energy and can be used to discern most biomolecules based on their spectral fingerprints. In this paper, we review the recent progress in two applications of THz waves in cancer diagnosis: imaging and spectroscopy. THz imaging is expected to help researchers and doctors attain a direct intuitive understanding of a cancerous area. THz spectroscopy is an efficient tool for component analysis of tissue samples to identify cancer biomarkers. Additionally, the advantages and disadvantages of the developed technologies for cancer diagnosis are discussed. Furthermore, auxiliary techniques that have been used to enhance the spectral signal-to-noise ratio (SNR) are also reviewed.

Sepsis and intestinal injury triggered by sepsis are common in intensive care units, which can contribute to a high mortality. lncRNAs can modulate gene expression, and they are closely involved in multiple diseases, including sepsis. In our present study, we investigated the biological function of MEG3 in sepsis, especially during the intestinal injury. Currently, we observed that in LPS-induced sepsis mouse models, the intestinal injury was triggered. Meanwhile, we reported that MEG3 was greatly decreased in vivo, with an increase of miR-129-5p and inhibition of SP-D. Then, MEG3 was overexpressed, and we found that its overexpression repressed the intestinal injury via downregulating miR-129-5p in sepsis mice. Moreover, TNF-α and IL-6 expression was elevated in intestinal tissues compared to the control groups. MEG3 restrained the activation of TNF-α and IL-6, in sepsis models. Subsequently, to induce the inflammatory injury of sepsis, human colorectal Caco2 cells were treated with 10 ng/ml LPS. 10 ng/ml LPS significantly inhibited Caco2 cell proliferation and increased the apoptosis. Additionally, MEG3 was decreased whereas miR-129-5p was obviously increased in Caco2 cells incubated with LPS. Interestingly, we showed that MEG3 repressed cell apoptosis partly and enhanced Caco2 cell proliferation. miR-129-5p overexpression could reverse the effect of MEG3 in vitro. Previously, we proved SP-D was reduced in sepsis and it depressed the intestinal injury in vivo. Finally, the correlation among MEG3, miR-129-5p, and SP-D was predicted and confirmed in our investigation. These findings indicated that MEG3 might be a potential target for intestinal damage caused by sepsis via regulating miR-129-5p and SP-D.

Sepsis is a severe disease, which results from the excessive inflammatory response to the infection. Dysfunction of intestinal barrier is a crucial problem in various pathological conditions. Meanwhile, microRNAs exhibit significant roles in the modulation of many diseases, including sepsis. Multiple investigations indicate that miR-199a-5p participates in different human diseases. Nevertheless, little is known on the roles of miR-199a-5p in sepsis. Herein, we evaluated the mechanism of miR-199a-5p on the intestinal barrier dysfunction in sepsis. Intestinal mucosa permeability indicators including D-lactic acid, DAO, and FD-40 levels were determined, and they were greatly increased in sepsis. Then, we proved that miR-199a-5p was induced in sepsis mice tissues and isolated intestinal epithelial cells. Moreover, miR-199a-5p increased D-lactic acid, DAO, and FD-40 while inhibition of miR-199a-5p exhibited a reversed process. Additionally, we observed that miR-199a-5p affected the oxidative damage and inflammation in the intestine tissues from sepsis mice. The content of MDA was elevated whereas SOD was remarkably repressed in the miR-199a-5p mimic group. IL-6, IL-1β, and TNF-α were induced by miR-199a-5p overexpression while IL-10 was reduced by miR-199a-5p. Subsequently, surfactant protein D (SP-D) was predicted as the target of miR-199a-5p. The activation of NF-κB has been identified in sepsis. Herein, we demonstrated that inhibitor of miR-199a-5p contributed to IEC injury via targeting SP-D and inactivating the NF-κB pathway. These revealed miR-199a-5p exacerbated the intestinal barrier dysfunction via inhibiting SP-D and activating the NF-κB pathway in sepsis.

Prediction of rock fracture is essential to understand the rock failure mechanism. The three-point bending test has been one of the most popular experiments for the determination of rock fracture parameters. However, the crack initiation and propagation of rock beam with the center notch and offset notch have not been fully understood. This paper develops a numerical method for modelling the notched beam cracking based on nonlocal extended finite element method (i.e., XFEM) and mixed mode rock fracture model. An example is worked out to demonstrate the application of the numerical method and verified with experimental results. The crack length development, crack pattern, crack opening and slipping displacements, and the load-crack mouth of displacement (P-CMOD) curve are obtained. The effects of offset notch location and mechanical properties on the crack length development, P-CMOD curve, and crack pattern are investigated and discussed. It has been found that the peak load of the notched beam nearly linearly increases with the increase of the notch offset ratio. The cracking of rock beam with offset notch is dominated by mode I fracture, but mode II fracture contributes more when crack deflection occurs. The fracture energy significantly affects the peak load, while it has little effect on the prepeak and postpeak slopes in the P-CMOD curve.

Conjugate joint is one of the most common joint forms in natural rock mass, which is produced by different tectonic movements. To better understand the preexisting flaws, it is necessary to investigate joint development and its effect on the deformation and strength of the rock. In this study, uniaxial compression tests of granite specimens with different conjugate joints distribution were performed using the GAW-2000 compression-testing machine system. The PCI-2 acoustic emission (AE) testing system was used to monitor the acoustic signal characteristics of the jointed specimens during the entire loading process. At the same time, a 3D digital image correlation (DIC) technique was used to study the evolution of stress field before the peak strength at different loading times. Based on the experimental results, the deformation and strength characteristics, AE parameters, damage evolution processes, and energy accumulation and dissipation properties of the conjugate jointed specimens were analyzed. It is considered that these changes were closely related to the angle between the primary and secondary joints. The results show that the AE counts can be used to characterize the damage and failure of the specimen during uniaxial compression. The local stress field evolution process obtained by the DIC can be used to analyze the crack initiation and propagation in the specimen. As the included angle increases from 0° to 90°, the elastic modulus first decreases and then increases, and the accumulative AE counts of the peak first increase and then decrease, while the peak strength does not change distinctly. The cumulative AE counts of the specimen with an included angle of 45° rise in a ladder-like manner, and the granite retains a certain degree of brittle failure characteristics under the axial loading. The total energy, elastic energy, and dissipation energy of the jointed specimens under uniaxial compression failure were significantly reduced. These findings can be regarded as a reference for future studies on the failure mechanism of granite with conjugate joints.

Natural joints existing in rock significantly affect the stability of long-term served subsurface engineering. In this paper, granite specimens with two orthogonal cracks were made for uniaxial compressive tests. The acoustic emission monitoring (AE) and digital image correlation techniques were employed to record the acoustic events and cracking of rock. The stress, ring-down count, and cumulative ring-down count of AE during the tests were obtained. The b-value of AE was calculated based on the magnitude and number of AE events. The relationship between the b-value and rock cracking for the specimens with orthogonal cracks was discussed. Further, the effects of orthogonal cracks distribution on the b-value and rock cracking were investigated. Experimental results show that the specimens with orthogonal cracks would undergo multiple cycles of energy accumulation-release-reaccumulation-rerelease under the uniaxial compression. For the specimens with orthogonal cracks, the b-value of AE was volatile but generally decreased until complete failure. Every cracking event during the loading made the b-value drop and then the reaccumulation of energy made the b-value increase or stable. The specimen with orthogonal cracks was more prone to initial cracking than the intact rock. The orientation of cracks had effects on the b-value evolution and crack patterns. The b-value reaching about 1.5 can be used as the failure precursor of specimens with orthogonal cracks.

To investigate the deformation and stability of the rock surrounding a tunnel excavated through layered rock, a three-dimensional numerical simulation was conducted to compare and analyze the right line of the YD2K100+560–630 two-stage docking cross-section of the Yuelongmen Tunnel using a ubiquitous joint model. Based on 3-D numerical simulations, the following conclusions were drawn: (1) The excavation on the construction entrance side significantly disturbed the construction exit side, and the exit side was more disturbed in the steeply dipping layer than in the gently dipping layer. (2) The influence of the dip angle of the laminae on the uplift of the tunnel invert was greater than the influence on the tunnel vault settlement when the laminae were oriented perpendicular to the trend of the tunnel and two-stage docking excavation was used. (3) When two-stage excavation was applied to gently inclined laminated rock, there was an obvious disturbance to both the top of the tunnel (less than one time the diameter of the through face; and to the bottom of the tunnel within 0.5 time the diameter of the through face on the side with the stopping construction exit side during the tunnelling process. When tunnel excavation was conducted against the trend of the layer, there was obvious disturbance to the top of the tunnel within 0.5 time the diameter of the through face and to the bottom of the tunnel within one time the diameter of the entrance face) on the construction exit side during the tunnelling process due to the presence of laminae. The excavation on the construction entrance side significantly disturbed the construction exit side. When docking and penetrating layered rock tunnels, priority should be given to docking and penetrating in the direction corresponding to the layers, and temporary support on the exit side should be strengthened to ensure the deformation stability of the surrounding rock mass.

This paper presents a temperature-insensitive wideband cryogenic amplifier for superconducting nanowire single-photon detectors (SNSPD). With a proposed folded diode-connected transistor load to realize a good device-tracking feature, the theoretical derivations the simulations and test results prove that the amplifier-gain cell has a stable gain performance over a wide temperature range, solving the issues of a lack of the accurate cryogenic device models. The amplifier achieves a gain of 26 dB from 100 kHz to 1 GHz at 4.2 K, consuming only 1.8 mW from a 1.8 V supply. With a 0.13-μm SiGe BiCMOS process, the chip area is 0.5 mm².

Psychoactive substances are a class of chemical substances which could cause public health threats. Cognitive disorders are a category of mental health disorders that primarily affect cognitive abilities. Tau protein could maintain neuronal cytoskeleton stabilization. Post-translational modification of tau, especially phosphorylation, is an important way to regulate the structure and function of tau and phosphorylated tau is closely related to cognitive function. Lots of studies have reported the phenomenon that psychoactive substances can cause cognitive function impairment. We reviewed recent related studies and discussed them by drug classification. We mainly focused on cognitive disorders caused by acute or chronic exposure of each drugs, animal experiments and the mechanisms associated with tau phosphorylation, then compared the similarities and differences among them, trying to find out the common rules. The results suggested that tau phosphorylation is involved in psychoactive substance-induced cognitive disorder and different psychoactive substances may act by affecting amount or activity of different kinases and phosphatases in the metabolic pathway of tau. We demonstrated that tau protein is a potential target for psychoactive substances induced cognitive disorder treatments.

Abstract Recent studies have shown that on one hand, tumors need to obtain a sufficient energy supply, and on the other hand they must evade the body’s immune surveillance. Because of their metabolic reprogramming characteristics, tumors can modify the physicochemical properties of the microenvironment, which in turn affects the biological characteristics of the cells infiltrating them. Regulatory T cells (Tregs) are a subset of T cells that regulate immune responses in the body. They exist in large quantities in the tumor microenvironment and exert immunosuppressive effects. The main effect of tumor microenvironment on Tregs is to promote their differentiation, proliferation, secretion of immunosuppressive factors, and chemotactic recruitment to play a role in immunosuppression in tumor tissues. This review focuses on cell metabolism reprogramming and the most significant features of the tumor microenvironment relative to the functional effects on Tregs, highlighting our understanding of the mechanisms of tumor immune evasion and providing new directions for tumor immunotherapy.

Rising demand for ruminant meat and dairy products in developing nations drives increasing GHG and ammonia emissions from livestock. Authors show here that only long-term adoption of global best-practice in sustainable intensification buffered by a short-term coping strategy of green-source trading can offer a way forward.

Abstract Background Actin filament-associated protein 1 antisense RNA 1 (AFAP1-AS1), a long noncoding RNA, is significantly highly expressed and associated with metastasis and poor prognosis in many cancers, including nasopharyngeal carcinoma (NPC). In this study, we aim to identify the role of AFAP1-AS1 acting as an oncogenic lncRNA to promote NPC metastasis. Methods The role of AFAP1-AS1, miR-423-5p, and FOSL2 in NPC metastasis was investigated in vitro and in vivo. Bioinformatics analysis and luciferase activity assays were used to identify the interaction between AFAP1-AS1, miR-423-5p, and FOSL2. Additionally, real-time PCR and western blotting were used to assess the function of AFAP1-AS1 acting as an oncogenic lncRNA to promote NPC progression by regulating miR-423-5p and the downstream Rho/Rac pathway. Results In this study, we determined that AFAP1-AS1 functions as a competing endogenous RNA in NPC to regulate the Rho/Rac pathway through miR-423-5p. These interactions can mediate the expression of RAB11B, LASP1, and FOSL2 and accelerate cell migration and invasion via the Rho/Rac signaling pathway or FOSL2. AFAP1-AS1 and FOSL2 could competitively bind with miR-423-5p to regulate several molecules, including RAB11B and LASP1 of the Rho/Rac signaling pathway. AFAP1-AS1 can also regulate the expression of LASP1, which was transcriptionally regulated by FOSL2, resulting in increased migration and invasion of NPC cells via the Rho/Rac signaling pathway. Conclusions The observations in this study identify an important role for AFAP1-AS1 as a competing endogenous RNA (ceRNA) in NPC pathogenesis and indicate that it may serve as a potential target for cancer diagnosis and treatment.

Background: MiR-195 plays an important role in metastasis and invasion of esophageal cancer (EC). However, the specific mechanism is not clear. The aim of this study was to explore the pathways how miR-195 controls EC cell proliferation. Method: Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was applied to detect theexpression of miR-195 in 25 cases of EC tissues and matched adjacent normal tissues in EC patients. MTT, colony formation and flow cytometry were performed to evaluate the effects of miR-195 on cell proliferation, respectively. Dual luciferase reporter assay was used to verify that cyclin D1 and cdc42 were targets of miR-195. qRT-PCR and western blot analysis were performed to analyze mRNA and protein expression. Result: In this study, we observed that miR-195 was repressed in EC tissue than in normal tissue. Similarly, miR-195 also showed lower expressions in EC cell lines (ECA109, TE-1, TE-8 and TE-13) than in the primary human esophageal epithelial cell (HEEC). Overexpression of miR-195 inhibited EC cell proliferation while treatment of antagomir promoted EC cell proliferationby suppressed Cdc42 and cyclin D1. Conclusion: Our result indicated miR-195 suppresses cyclin D1 and Cdc42 to inhibit EC cell proliferation, and Cdc42 may via regulating both cyclin D1-dependent and independent pathways to control EC cell proliferation.

Summary: Uveal melanoma (UM), the most common ocular malignancy, is characterized by GNAQ/11 mutations. Hippo/YAP and Ras/mitogen-activated protein kinase (MAPK) emerge as two important signaling pathways downstream of G protein alpha subunits of the Q class (GαQ/11)-mediated transformation, although whether and how they contribute to UM genesis in vivo remain unclear. Here, we adapt an adeno-associated virus (AAV)-based ocular injection method to directly deliver Cre recombinase into the mouse uveal tract and demonstrate that Lats1/2 kinases suppress UM formation specifically in uveal melanocytes. We find that genetic activation of YAP, but not Kras, is sufficient to initiate UM. We show that YAP/TAZ activation induced by Lats1/2 deletion cooperates with Kras to promote UM progression via downstream transcriptional reinforcement. Furthermore, dual inhibition of YAP/TAZ and Ras/MAPK synergizes to suppress oncogenic growth of human UM cells. Our data highlight the functional significance of Lats-YAP/TAZ in UM initiation and progression in vivo and suggest combination inhibition of YAP/TAZ and Ras/MAPK as a new therapeutic strategy for UM. : Li et al. utilize an AAV-based ocular injection method to specifically manipulate Hippo/YAP and Ras signaling in mouse uveal melanocytes. They reveal the role of YAP/TAZ in uveal melanoma formation and suggest that the Hippo/YAP-Ras/MAPK interaction during tumor growth can be exploited to develop a therapeutic strategy for uveal melanoma. Keywords: uveal melanoma, Hippo/YAP, Ras/MAPK, tumor initiation, tumor progression, dual inhibition, mouse model, AAV ocular injection

Abstract Background Idiopathic pulmonary fibrosis (IPF), a chronic, progressive, fibrosing interstitial lung disease, is associated with extremely poor prognosis, and lacks effective treatment. The frequently used immunosuppressive therapies such as dexamethasone (DEX) are often associated with side effects. Recently, combination of two Chinese herbal medicine preparations, Salvia miltiorrhiza and ligustrazine (SML), serves as an alternative medicine for treatment of IPF in clinical practices in China. The aim of this study is to compare the anti-fibrotic effect of SML with that of DEX and to investigate the underlying mechanisms. Methods A rat model of bleomycin (BLM) induced pulmonary fibrosis was used in this study. Ninety rats were assigned to six groups: control group; BLM-group; BLM and dexamethasone group (BLM + DEX); BLM + low-dose SML; BLM + medium-dose SML and BLM + high-dose SML. Rats were sacrificed on day 7, 14 and 28 after treatment. The extent of alveolitis and fibrosis was observed by H&E and Masson’s trichrome staining. The expressions of TNF-α, TGF-β1 and SMAD4 were determined and quantified by immunohistochemical analysis. The serum levels of TNF-α and TGF-β1 were further quantified by ELISA kits. Results Both DEX and SML treatment attenuated BLM-induced lung injury and pathological collagen deposition in rats, showing improved alveolitis and fibrosis scores on day 7, 14, 28, compared to the BLM group (p

Variable stiffness design (VSD) has been paid more attention for its capability of further exploiting the potential of fiber-reinforced composite in composite structure design. VSD under different mechanical property indexes is reviewed in this paper. The review mostly focuses on strength, buckling, frequency, and other more common mechanical indices. Subsequently, the usage of VSD method for several years is briefly summarized. Some successful tests about variable stiffness composite parts are introduced and the experiment results are also addressed. The article summarizes the research situation from both perspectives based on a number of papers about the VSD of composite materials in recent years and provides theoretical reference and basic knowledge to new researchers.

Background To evaluate the effects of miR-99a on the migration and proliferation of glioma cells. Materials and Methods: Glioma cell line LN229 with stable up-regulation of miR-99a was constructed by transfection of hsa-miR-99a mimics, and cells with stable miR-99a knock-down were established by transfection of hsa-miR-99a inhibitor. The proliferation capacities of two groups were detected by the MTT assay, and their migration capacities were detected by the scratch assay. Results: LN229 cells with stable up-regulation and knock-down of miR-99a were successfully constructed. Up-regulating miR-99a inhibited the proliferation and migration of glioma cells, but knocking down this gene promoted their proliferation and migration. Conclusion: MiR-99a significantly affected the proliferation and migration of glioma cells, as a potentially eligible target for glioma therapy.

Abstract Circular RNAs (circRNAs) are connected at the 3′ and 5′ ends by exon or intron cyclization, forming a complete ring structure. circRNA is more stable and conservative than linear RNA and abounds in various organisms. In recent years, increasing numbers of reports have found that circRNA plays a major role in the biological functions of a network of competing endogenous RNA (ceRNA). circRNAs can compete together with microRNAs (miRNAs) to influence the stability of target RNAs or their translation, thus, regulating gene expression at the transcriptional level. circRNAs are involved in biological processes such as tumor cell proliferation, apoptosis, invasion, and migration as ceRNAs. circRNAs, therefore, represent promising candidates for clinical diagnosis and treatment. Here, we review the progress in studying the role of circRNAs as ceRNAs in tumors and highlight the participation of circRNAs in signal transduction pathways to regulate cellular functions.

Abstract As a major driving element of the structure and function of arid and semiarid ecosystems, rainfall is the essential factor limiting plant biological processes. To clarify the characteristics of transpiration and responses to summer rainfall, sap flow density (Fd) of Pinus tabulaeformis and Hippophae rhamnoides was monitored using thermal dissipation probes. In addition, midday leaf water potential (ψm) and leaf stomatal conductance (Gs) were also analyzed to determine water use strategies. The results indicated that the diurnal variation in the normalized Fd values exhibited a single‐peak curve for P. tabulaeformis, while H. rhamnoides showed multiple peaks. The normalized Fd for P. tabulaeformis remained relatively stable regardless of rainfall events. However, there was also a significant increase in the normalized Fd for H. rhamnoides in response to rainfall in June and August (p

This paper presents a two-channel (I+Q) variable gain amplifier (VGA) for low power 60-GHz wireless receiver. The VGA consists of four-stage gain cells, an efficient DC-offset cancelling circuit and an output buffer for test purposes. To achieve wide bandwidth and low power consumption, a modified Cherry-Hooper amplifier gain cell is used. With a tunable transistor and its parasitic capacitance, a dB-linear characteristic and a flat gain response are achieved without any additional exponential circuit. The DC-offset is cancelled effectively with two proposed feedback loops. The measurement results show that the VGA achieves a gain range of 6 to 44 dB, an OP1dB of 1 dBm, and a 3-dB bandwidth of over 1 GHz with an excellent flat gain response. Fabricated in a 65-nm CMOS technology, the two-channel VGA core occupies a silicon area of only 0.055 mm2 and consumes only 10 mA from a 1.2 V power supply.

Abstract Processing (Paozhi) represents a unique Chinese pharmaceutic technique to facilitate the use of Chinese herbal medicines (CHMs) for a specific clinical need in the guidance of Traditional Chinese Medicine (TCM) theory. Traditionally, most CHMs require a proper processing to meet the needs of specific clinical syndromes before being prescribed by TCM practitioners. During processing, significant changes in chemical profiles occur, which inevitably influence the associated pharmacological properties of a CHM. However, although processing is formed in a long-term practice, the underlying mechanisms remain unclear for most CHMs. The deepening understanding of the mechanism of processing would provide scientific basis for standardization of processing. This review introduced the role of processing in TCM and several typical methods of processing. We also summarized the up-to-date efforts on the mechanistic study of CHM processing. The processing mechanisms mainly include the following aspects: (i) directly reducing contents of toxic constituents; (ii) structural transformation of constituents; (iii) improving solubility of constituents; (iv) physically changing the existing form of constituents; (v) and influence by excipients. These progress may give new insights into future researches.

Mixed-species tree plantations have additional ecological benefits over single-species tree plantations, such as habitat restoration and increasing biodiversity. However, changes in the soil carbon, nitrogen, and phosphorus storages and stoichiometry after mixed afforestation with the N-fixing tree species under the “Grain for Green Project” in the Loess Plateau of China are not well understood. Typical restoration types, including the mixed plantations of Pinus tabuliformis with Hippophae rhamnoides (HrPt) and Robinia pseudoacacia with H. rhamnoides (HrRp), as well as the pure forests of P. tabuliformis (Pt) and R. pseudoacacia (Rp), were chosen to examine changes in the storages and stoichiometry of soil organic carbon (SOC), total nitrogen (TN), and total phosphorus (TP) in 0–100 cm soil layers. The results showed that compared with the corresponding pure forest, HrRp significantly increased the SOC content in the 0–20 cm soil layer and the SOC storage in the 0–100 cm layer, while HrPt significantly increased the SOC content in the 0–10 cm layer, but there was no significant difference for SOC storage in the 0–100 cm layer between Pt and HrPt. Similarly, HrRp significantly increased the TN content in the 0–10 cm layer and the TN storage in the 0–100 cm layer, but there was no significant difference in TN storage between Pt and HrPt. Furthermore, HrRp significantly increased the TP content in the 0–100 cm layer and TP storage was higher than that of Rp, while there were no significant differences in TP content and storage between Pt and HrPt. In the 0–10 cm soil layer, HrRp significantly reduced C:N and increased N:P, but HrPt significantly increased C:P. In addition, compared with the pure forest, the soil physical and chemical properties had a stronger control effect on the soil storages and stoichiometric ratios in the mixed forests. In summary, compared with P. tabuliformis, the introduction of N-fixing tree species into the R. pseudoacacia forest was more conducive to the accumulation of SOC, TN, and TP reserves and the improvement of the N and P utilization efficiency. These results have important implications for the restoration of degraded vegetation and scientific management of mixed plantations on the Loess Plateau and can provide basic data for the assessment of soil quality at the regional scale.

Biological processes have high removal efficiencies and low operational costs, but the secondary effluent of coking wastewater (CWW), even at a low concentration, is difficult for microorganisms to degrade directly. In this study, glucose was used as a carbon source and co-metabolic substrate for microbial acclimation in order to enhance the advanced treatment of coking wastewater (CWW). The removal performance of the pollutants, especially recalcitrant compounds, was studied and the changes in the microbial community structure after activated sludge acclimation were analyzed. The effect of glucose addition on the secondary biochemical effluent of coking wastewater (SBECW) treatment by the acclimated sludge was further studied by a comparison between the performance of two parallel reactors seeded with the acclimated sludge. Our results showed that the concentrations of chemical oxygen demand (COD), total organic carbon (TOC), and UV absorption at 254 nm (UV254) of the wastewater decreased in the acclimation process. Refractory organic matter, such as polycyclic aromatic hydrocarbons and nitrogen-containing heterocyclics, in the SBECW was effectively degraded by the acclimated sludge. High-throughput sequencing revealed that microbes with a strong ability to degrade recalcitrant compounds were enriched after acclimation, such as Thauera (8.91%), Pseudomonas (3.35%), and Blastocatella (10.76%). Seeded with the acclimated sludge, the reactor with the glucose addition showed higher COD removal efficiencies than the control system without glucose addition (p < 0.05). Collectively, glucose addition enhanced the advanced treatment of coking wastewater (CWW).

Oilseed–vegetable-dual-purpose (OVDP) rapeseed can effectively alleviate the land contradiction between crops and it supplements vegetable supplies in winter or spring. The soluble solids content (SSC) is an important index that is used to evaluate the quality and sugar content of fruits and vegetables. However, the genetic architecture underlying the SSC in Brassica napus shoots is still unclear. Here, quantitative trait loci (QTLs) for the SSC in B. napus shoots were investigated by performing linkage mapping using a recombinant inbred line population containing 189 lines. A germplasm set comprising 302 accessions was also used to conduct a genome-wide association study (GWAS). The QTL mapping revealed six QTLs located on chromosomes A01, A04, A08, and A09 in two experiments. Among them, two major QTLs, qSSC/21GY.A04-1 and qSSC/21NJ.A08-1, accounted for 12.92% and 10.18% of the phenotypic variance, respectively. In addition, eight single-nucleotide polymorphisms with phenotypic variances between 5.62% and 10.18% were identified by the GWAS method. However, no locus was simultaneously identified by QTL mapping and GWAS. We identified AH174 (7.55 °Brix and 7.9 °Brix), L166 (8.9 °Brix and 8.38 °Brix), and L380 (8.9 °Brix and 7.74 °Brix) accessions can be used as superior parents. These results provide valuable information that increases our understanding of the genetic control of SSC and will facilitate the breeding of high-SSC B. napus shoots.

The spatio-temporal variation of precipitation under global warming had been a research hotspot. Snowfall is an important part of precipitation, and its variabilities and trends in different regions have received great attention. In this paper, the Haihe River Basin is used as a case, and we employ the K-means clustering method to divide the basin into four sub-regions. The double temperature threshold method in the form of the exponential equation is used in this study to identify precipitation phase states, based on daily temperature, snowfall, and precipitation data from 43 meteorological stations in and around the Haihe River Basin from 1960 to 1979. Then, daily snowfall data from 1960 to 2016 are established, and the spatial and temporal variation of snowfall in the Haihe River Basin are analyzed according to the snowfall levels as determined by the national meteorological department. The results evalueted in four different zones show that (1) the snowfall at each meteorological station can be effectively estimated at an annual scale through the exponential equation, for which the correlation coefficient of each division is above 0.95, and the relative error is within 5%. (2) Except for the average snowfall and light snowfall, the snowfall and snowfall days of moderate snow, heavy snow, and snowstorm in each division are in the order of Zones III > IV > I > II. (3) The snowfall and the number of snowfall days at different levels both show a decreasing trend, except for the increasing trend of snowfall in Zone I. (4) The interannual variation trend in the snowfall at the different levels are not obvious, except for Zone III, which shows a significant decreasing trend.

Carbon nano-tubes as a kind of novel nanometer material have been extensively applied in cement-based composite materials to improve their properties. This study prepared carbon nano-tubes cement based composite materials by evenly scattering carbon nano-tubes in cement materials using ultrasonic method and emphatically investigation the improvement of the mechanical property. The results demonstrated that, the addition of carbon nano-tubes could significantly relieve the mechanical properties of cement based composite materials. When the mixing amount of carbon nano-tubes reached the optimal value, i.e., 0.1%, the improvement of the mechanical property of the carbon nano-tubes cement based composite materials was the best. The microstructure analysis using scanning electron microscope suggested that, carbon nano-tubes produced bridging and pullout effects in the cement-based materials, which enhanced the damage resistance of the cement based materials.

In this paper, we have achieved a high repetition rate and tunable pulse generation near ∼2 μm through an all-optical actively mode-locked fiber laser. The performances of the fiber laser have been systematically investigated through numerical simulations. The thulium-doped fiber laser cavity is modulated by the optical injection at 1.55 μm via a nonlinear optical loop mirror in which a specially-designed group-velocity-matching highly nonlinear fiber is incorporated. According to the simulation results, up to 40-GHz pulse train with picosecond tunable pulse width and peak power can be produced. Moreover, the repetition rate can be further enlarged with the help of higher gain. The impacts of gain coefficient, cavity length, and repetition rate on the output are studied in details. The proposed mode-locked fiber laser can be potentially used for future 2- μm fiber communication.

Abstract Background Mismatch‐repair genes (MMRs) ensure high fidelity in genome editing. Loss of function mutation of MMRs will lead to instability of the genome and increase the incidence of cancers. Human mutL homolog 1 (MLH1) is a member of the MMRs, and its mutation is found in Lynch syndrome (LS). In addition to the high incidence of colorectal cancer, LS patients often have other primary cancers. Here, a case of LS‐associated lung and gastric double primary cancer was reported. Methods Diagnosis of lung and gastric double primary cancer was mainly based on clinical findings, imaging examination, and histopathological data. The tumor tissues and blood samples were collected, and then genomic DNA was extracted and 450 cancer‐related gene alteration screening was conducted by next‐generation sequencing and the functional verification of a mutant gene was carried out using the PCR method. Results We detected the epidermal growth factor receptor L858R, MSH2 R929* and telomerase reverse transcriptase amplification in the lung cancer specimen; CDH1 c.1320+1G>T mutation in the gastric cancer (GC) specimen; and MLH1 c.1896+5G>A germline mutation in the lung and GC specimens by 450 cancer‐related gene mutations detection using next‐generation sequencing technology. MLH1c.1896+5G>A is a novel germline mutation, and it was verified by the PCR subsequently. It was found that it could affect the splicing of intron 16. Nine relatives of three‐generation of the patient were examined and the MLH1 c.1896+5G>A mutation and pedigree analysis were performed. The father's sister without cancer also carries this mutation. Conclusion Diagnosis of LS was mainly depended on the following: the cancer histories of his relatives, multi‐primary cancers of lung and stomach in his own body, MLH1 and MSH2 gene mutations detected in the cancer tissues. The clinical significance of this new MLH1 c.1896+5G>A germline mutation detected in the LS‐associated double primary cancer patient needed further study.

Background: We previously demonstrated that a Danshensu-Tetramethylpyrazine conjugate DT-010 enhanced anticancer effect of doxorubicin (Dox) in Dox-sensitive human breast cancer cells, and protected against Dox-induced cardiotoxicity. This work was designed to see whether DT-010 overcomes Dox resistance in resistant human breast cancer cells.Methods: The effects of DT-010, Dox or their combination on cell viability of Dox-resistant human breast cancer MCF-7/ADR cells were conducted using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was examined by flow cytometry after Annexin V-FITC/PI co-staining. Dox accumulation in MCF-7/ADR cells was detected by flow cytometry and fluorescence microscopy. A fluorometric multidrug resistance (MDR) assay kit was used to evaluate the effect of DT-010 on MDR transporter activity. P-glycoprotein (P-gp) expression and activity were analyzed by Western blot and rhodamine 123 (Rh123) efflux assay, respectively. The effects of DT-010 on glycolysis and mitochondrial stress were detected using an Extracellular Flux Analyzer. A Succinate Dehydrogenase Activity Assay kit was used to measure mitochondrial complex II activity.Results: At non-cytotoxic concentrations, DT-010 in combination with Dox led to a significant growth inhibition of MCF-7/ADR cells, suggesting a synergy between DT-010 and Dox to reverse Dox resistance. DT-010 restored Dox-mediated apoptosis and p53 induction in MCF-7/ADR cells. DT-010 increased Dox accumulation in MCF-7/ADR cells via inhibiting P-gp activity, but without changing P-gp expression. Further studies showed that DT-010 significantly inhibited glycolysis and mitochondrial function of MCF-7/ADR cells. Mitochondrial complex II activity was inhibited by DT-010 or DT-010/Dox combination, but not by Dox. The DT-010-mediated suppression of metabolic process may render cells more vulnerable to Dox treatment and thus result in enhanced efficacy.Conclusions: The results indicate that DT-010 overcomes Dox resistance in human breast cancer cells through a dual action via simultaneously inhibiting P-gp-mediated drug efflux and influencing metabolic process.

Tau protein is known to play an important role in maintaining microtubule assembly and stabilization, and maintaining the normal morphology of neurons, but several studies have found that chronic stress leads to Tau hyperphosphorylation. A large number of clinical trials have found that ketamine, which is an N-methyl-D-aspartate receptor antagonist, produces a rapid, long-lasting, and potent antidepressant effect in patients suffering from major depression. This rapid antidepressant effect of ketamine, which involves many mechanisms, has attracted wide attention. However, the relationship between ketamine’s antidepressant effects and Tau protein has rarely been examined. We used C57BL/6 and Tau KO mice exposed to 42 days of chronic unpredictable mild stress (the CUMS model) to investigate the effect of ketamine on behavioral changes and synaptic functioning of the hippocampus. The results showed that a single treatment of ketamine rapidly relieved the CUMS-induced anhedonia, depression-like, and anxious behaviors of the C57BL/6 mice. The abnormal behaviors were accompanied by increased levels of specific alterations of hyperphosphorylated Tau protein in cytoplasm and synapse in the hippocampus of the C57BL/6 mice, but ketamine reduced the aggregation of hyperphosphorylated Tau protein only in the synapse. We also found that CUMS exposure reduced the levels of GluA1 and PSD95 in the hippocampus of the C57BL/6 mice and that these deficits were reversed by ketamine. However, the Tau KO mice did not develop any stress-induced depressive behaviors or deficits of hippocampal function. The antidepressant effect of ketamine may decrease the levels of hyperphosphorylated Tau protein in synapse of C57BL/6 mice.

The introduction of targeted therapy is the biggest success in the treatment of cancer in the past few decades. However, heterogeneous cancer is characterized by diverse molecular alterations as well as multiple clinical profiles. Specific genetic mutations in cancer therapy targets may increase drug sensitivity, or more frequently result in therapeutic resistance. In the past 3 years, several novel targeted therapies have been approved for cancer treatment, including drugs with new targets (i.e., anti-PD1/PDL1 therapies and CDK4/6 inhibitors), mutation targeting drugs (i.e., the EGFR T790M targeting osimertinib), drugs with multiple targets (i.e., the EGFR/HER2 dual inhibitor neratinib) and drug combinations (i.e., encorafenib/binimetinib and dabrafenib/trametinib). In this perspective, we focus on the most up-to-date knowledge of targeted therapy and describe how genetic mutations influence the sensitivity of targeted therapy, highlighting the challenges faced within this era of precision medicine. Moreover, the strategies that deal with mutation-driven resistance are further discussed. Advances in these areas would allow for more targeted and effective therapeutic options for cancer patients.

Deformation and failure of rock are very important to underground space engineering. In this paper, a new three-dimensional multicomponent bonded-particle model is developed for heterogeneous rocks. Granite samples from the Sanshandao Gold Mine are first analyzed using a microscope. Cylindrical and disc models consisting of four minerals (i.e., plagioclase, potash feldspar, quartz, and biotite) are built to simulate the behavior of the granite under compressive and tensile tests. To improve the calibration efficiency, a new method for determining the microparameters of minerals is proposed. Uniaxial compression, triaxial compression, and Brazilian tests are carried out in the lab. The failure pattern and stress-strain curves are obtained from numerical simulations and verified with those observed in the experiments. Furthermore, the Mohr–Coulomb and Hoek–Brown strength parameters are obtained and compared with the experimental results. The multicomponent particle model is shown to well reproduce the behavior of granite under the compressive and tensile tests. The multicomponent bonded-particle model significantly improves the accuracy of three parameters: the ratio of tensile strength to uniaxial compressive strength, the friction angle, and the parameter mi of the Hoek–Brown criterion. The linear fitting calibration method provides a fast and efficient way to determine the microparameters of particles in heterogeneous rocks.

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-23418-z

Seasonal variations in stoichiometry are a crucial regulatory mechanism for plant communities that respond to environmental changes. However, the seasonal characteristics of stoichiometry in plants, litter, and soil are poorly understood, especially in plantation ecosystems. Therefore, we explored the seasonal variations of C, N, and P contents and ratios between plants, litter, and soil of a Robinia pseudoacacia plantation on the Loess Plateau in China in 2017. The results indicate that the C, N, P contents and ratios in plants, litter and soil showed different seasonal patterns. The N and P contents of tree and shrub leaves substantially decreased over the growing season, while the C:N, C:P, and N:P ratios exhibited the opposite trend. The utilization efficiency of the N and P elements by trees and shrubs gradually increased with the change of the growing season. These results suggest that the C:N:P stoichiometry of plants was more sensitive to seasonal changes than the litter and soil; therefore, the potential impacts of time should be considered when using stoichiometry to explore the utilization of plant nutrients. Additionally, the P content between tree leaves and soil and the N content between herb leaves and soil were significantly positively correlated, indicating that the growth of the tree and herb layer in the R. pseudoacacia plantation in the area was restricted by P and N, respectively. Meanwhile, the N content in the leaves between trees and herbs showed a significant negative correlation, indicating that N competition existed between R. pseudoacacia and understory herbs, which was not conducive to the effective use of environmental resources by the R. pseudoacacia plantation ecosystem. This study contributes to vegetation restoration and plantation management on the Loess Plateau and provides basic information for global stoichiometric analyses.