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In this paper, the pore structure characteristics of shale samples from the Lower Silurian Longmaxi Formation in South of Sichuan Basin of China were investigated by total organic carbon (TOC) content determination, X-ray diffraction (XRD), scanning electron microscope (SEM), low pressure nitrogen adsorption (LPNA) and high pressure mercury injection (HPMI). The fractal dimension of shale samples was calculated based on Frenkel-Halsey-Hill (FHH) model and thermodynamic relation model. The results showed that the major mineral compositions of shales were quartz and clay content. Organic pores, intergranular pores, intragranular pores, microfractures were widely developed in the shale samples, of which organic pores were the most developed. The pore morphology was mainly ink bottle-shaped pores and slit-shaped pores; the pore size distribution of shale samples was complex with multiple distribution peaks, the pore size between 3 and 40 nm occupied the most of storage space. The fractal dimension Dn1 of pores between 2 nm and 10 nm was 2.7177–2.7933, while fractal dimension Dn2 of pores between 10 nm and 50 nm was 2.2439–2.5468. The fractal dimension Dr of macropores calculated by the thermodynamic model was 2.6401–2.7025.

The L1 cell adhesion molecule (L1CAM) plays important roles in the development and plasticity of the nervous system as well as in tumor formation, progression, and metastasis. New ligands are necessary tools for biomedical research and the detection of L1CAM. Here, DNA aptamer yly12 against L1CAM was optimized to have much stronger binding affinity (10–24 fold) at room temperature and 37 °C via sequence mutation and extension. This interaction study revealed that the optimized aptamers (yly20 and yly21) adopted a hairpin structure containing two loops and two stems. The key nucleotides for aptamer binding mainly located in loop I and its adjacent area. Stem I mainly played the role of stabilizing the binding structure. The yly-series aptamers were demonstrated to bind the Ig6 domain of L1CAM. This study reveals a detailed molecular mechanism for the interaction between yly-series aptamers and L1CAM and provides guidance for drug development and detection probe design against L1CAM.

Desertification, a current serious global environmental problem, has caused ecosystems and the environment to degrade. The total area of desertified land is about 1.72 million km2 in China, which is extensively affected by desertification. Estimating land desertification risks is the top priority for the sustainable development of arid and semi-arid lands in China. In this study, the Mediterranean Desertification and Land Use (MEDALUS) model was used to assess the sensitivity of land desertification in China. Based on multi-source remote sensing data, this study integrated natural and human factors, calculated the land desertification sensitivity index by overlaying four indicators (soil quality, vegetation quality, climate quality, and management quality), and explored the driving forces of desertification using a principal component and correlation analysis. It was found that the spatial distribution of desertification sensitivity areas in China shows a distribution pattern of gradually decreasing from northwest to southeast, and the areas with very high and high desertification sensitivities were about 620,629 km2 and 2,384,410 km2, respectively, which accounts for about 31.84% of the total area of the country. The very high and high desertification sensitivity areas were mainly concentrated in the desert region of northwest China. The principal component and correlation analysis of the sub-indicators in the MEDALUS model indicated that erosion protection, drought resistance, and land use were the main drivers of desertification in China. Furthermore, the aridity index, soil pH, plant coverage, soil texture, precipitation, soil depth, and evapotranspiration were the secondary drivers of desertification in China. Moreover, the desertification sensitivity caused by drought resistance, erosion protection, and land use was higher in the North China Plain region and Guanzhong Basin. The results of the quantitative analysis of the driving forces of desertification based on mathematical statistical methods in this study provide a reference for a comprehensive strategy to combat desertification in China and offer new ideas for the assessment of desertification sensitivity at macroscopic scales.

The acoustic response characteristics of shales were investigated by the acoustic transmission experiment, which is the basis of solving geological and engineering problems using the seismic or logging information during the process of the exploration and development of shale gas reservoirs. Based on the theory of acoustic wave and the background of acoustic transmission experiment, the initial condition, vibration source condition, boundary condition and stability condition were constructed, and the numerical simulation of acoustic transmission experiment of shales were completed through Matlab programming. The results show that under the same bedding angle, the acoustic time and attenuation coefficient of shales shown positive correlation with the bedding density; whereas under the same bedding density, the variation laws of the acoustic time and the attenuation coefficient of shales were more complex with the change of the bedding angle, that is, the acoustic time and attenuation coefficient of shales increased first, then decreased and then increased again with the increase of the bedding angle.

In visual reasoning, the achievement of deep learning significantly improved the accuracy of results. Image features are primarily used as input to get answers. However, the image features are too redundant to learn accurate characterizations within a limited complexity and time. While in the process of human reasoning, abstract description of an image is usually to avoid irrelevant details. Inspired by this, a higher-level representation named semantic representation is introduced. In this paper, a detailed visual reasoning model is proposed. This new model contains an image understanding model based on semantic representation, feature extraction and process model refined with watershed and u-distance method, a feature vector learning model using pyramidal pooling and residual network, and a question understanding model combining problem embedding coding method and machine translation decoding method. The feature vector could better represent the whole image instead of overly focused on specific characteristics. The model using semantic representation as input verifies that more accurate results can be obtained by introducing a high-level semantic representation. The result also shows that it is feasible and effective to introduce high-level and abstract forms of knowledge representation into deep learning tasks. This study lays a theoretical and experimental foundation for introducing different levels of knowledge representation into deep learning in the future.

This paper focuses on a robust continuous sliding mode control (RCSMC) method for manipulator PMSM trajectory tracking system under time-varying uncertain disturbances. The main objective of this study is to improve the trajectory tracking dynamic response and disturbances rejection ability of the manipulator PMSM, and then the manipulator itself, by using the RCSMC method. The RCSMC method consists of two key parts: a terminal continuous sliding mode controller (TCSMC), and an extended state observer (ESO). The TCSMC has been demonstrated to have remarkable capabilities to reduce the chattering phenomenon caused by high frequency switching function in the conventional sliding mode control law, and reject the strong time-varying uncertain disturbances for PMSM velocity loops. However, the high control gain, which could lead high velocity steady state fluctuations, is needed. Therefore, an extended state observer is introduced to estimate the disturbances. The estimated disturbances are further used by the velocity loop controller as a kind of feed-forward compensation to reduce the gain of the TCSMC method. The stability of the PMSM trajectory tracking system with the RCSMC algorithm is guaranteed by the Lyapunov stability criteria. Simulations have been conducted to verify the performance of the proposed RCSMC algorithm. Finally, the proposed RCSMC algorithm is applied in a practical 6-DOF manipulator, and the experimental results exhibit the extraordinary robustness and capabilities in dynamic position tracking characteristics, velocity response and disturbances rejection.

The random distribution of gravels makes the conglomerate reservoir highly heterogeneous. A stress concentration occurs at the gravel-matrix interfaces owing to the embedded gravel and affects the local mechanical response significantly, making it difficult to control and predict hydraulic fracture (HF) propagation. The mechanism of HF propagation in conglomerate reservoirs remains unclear; thus, it is difficult to effectively design and treat hydraulic fracturing. Based on the global pore-pressure cohesive zone element (GPPCZ) model method, a two-dimensional (2D) fracture propagation model with flow-stress-damage (FSD) coupling was established to investigate HF nucleation, propagation, and coalescence in conglomerate reservoirs. This model was experimentally verified, and fractal theory was introduced to quantify the complexity of fracture morphology. The microscale interactions of the gravel, matrix, and interface have been taken into consideration during simulating HF propagation accurately in macroscale. The influence of the mechanical properties of gravel, matrix, matrix-gravel interface, and reservoir stress distribution state, on HF morphology (HF length, stimulated reservoir square, and HF complexity morphology), was investigated. Finally, the main factors affecting fracture propagation were analyzed. It was revealed that the difference between the mechanical properties of the gravel and the matrix in the conglomerate rock will affect the geometry of HF to varying degrees. The local behavior of fracture propagation is obviously dominated by the elastic modulus, tensile strength, and the strength for the matrix-gravel interface. However, the propagation of HF at the whole scale is mainly dominated by the horizontal stress state, including the minimum horizontal stress and horizontal stress difference. In addition, the difference in horizontal stress significantly affects the fracturing patterns (deflection, bifurcation, and penetration) when HF encounters gravel. In this study, a simulation method of HF propagation in conglomerate reservoirs is introduced, and the results provide theoretical support for the prediction of HF propagation morphology and plan design of hydraulic fracturing in conglomerate reservoirs.

Abstract The horizontal well‐staged fracturing technology has been widely used in many oilfields to enhance well production by creating fracture network. Accurate prediction of fracture initiation is significant for successful hydraulic fracturing operation. However, hydraulic fracture initiation in fractured reservoir is highly tricky due to its rich natural fractures and artificial fractures previously created during staged fracturing. These fractures are thought to be major factors in conducting efficient staged fracturing in fractured reservoir. Therefore, in this paper, induced stress from artificial fractures has been analyzed by using two‐dimensional analytical model. Besides, based on the assumption that rock in the formation is composed by rock matrix and fracture plane, considering tensile and shear failure type, failure criterion with multiple natural fracture planes has been developed. By combining impacts from natural fractures and artificial fractures, we establish an analytical model to calculate initial fracture pressure for horizontal staged fracturing in fractured reservoir. These results demonstrate that induced stress is associated with artificial fractures’ location, height, and number. This induced stress leads to increment of initial fracture pressure, restricting fracture initiation. Due to natural fractures, there are three types of initiation, which are tensile failure along rock matrix, tensile failure along natural fracture, and shear failure along natural fracture plane. When rock failure is related to natural fracture, initial fracture pressure decreases and is variable with natural fracture plane occurrence. Especially, with large number of natural fractures, only one initiation type exists, which is tensile failure along natural fracture. Additionally, for horizontal borehole, influencing extent of fracture planes is associated with wellbore trajectory. The case study proves the applicability of this analytical model, meaning it can be used to guide horizontal staged fracturing in oilfield.

Abstract The molecular simulation method was used to investigate the adsorption behaviors of methane on illite. The effects of several factors on methane adsorption, free gas amounts, and the proportions of absorbed gas in the illite nanopores, including the pore size, temperature, and water content, are discussed. The results obtained show that methane adsorption in illite nanopores is due mainly to van der Waals adsorption. With an increase in the pressure or of the pore size, the free gas amounts of methane increase, whereas the free gas amounts decrease with increasing temperature or water content. With increasing pressures or decreasing pore sizes, the methane adsorption capacity of the illite pores increases. When the pressure or pore size increases, the proportion of the adsorbed gas in the pores decreases. As the temperature increases, the methane adsorption capacity of the illite pores decreases, and the proportion of adsorbed gas in the illite pores decreases slightly. The adsorbed phase density decreases with increasing pore size and temperature, whereas the adsorbed phase density increases with increasing pressure. The electrostatic forces and hydrogen bonds have a positive effect on water adsorption in the illite nanopores, while the van der Waals forces have the opposite effect, which causes the water molecules in the illite pores to exist in the form of aggregates. The water molecules occupy the areas near the pore walls in a directional manner and occupy the adsorption space and the adsorption sites of methane, resulting in a decrease in the methane adsorption capacity and a slight reduction in the proportion of adsorbed gas.

Cutaneous T cell lymphoma is a generally indolent disease derived from skin-homing mature T cells. However, in advanced stages, cutaneous T cell lymphoma may manifest aggressive clinical behaviour and lead to a poor prognosis. The mechanism of disease progression in cutaneous T cell lymphoma remains unknown. This study, based on a large clinical cohort, found that IKZF2, an essential transcription factor during T cell development and differentiation, showed stage- dependent overexpression in the malignant T cells in mycosis fungoides lesions. IKZF2 is specifically over- expressed in advanced-stage mycosis fungoides lesions, and correlates with poor prognosis. Mechanistically, overexpression of IKZF2 promotes cutaneous T cell lymphoma progression via inhibiting malignant cell apoptosis and may contribute to tumour immune escape by downregulating major histocompatibility complex II molecules and up-regulating the production of anti-inflammatory cytokine interleukin-10 by malignant T cells. These results demonstrate the important role of IKZF2 in high-risk cutaneous T cell lymphoma and pave the way for future targeted therapy.

Conglomerate reservoir is an important part of unconventional oil and gas resources, which has great developmental potential. However, its sedimentary environment and structural background are complex, and its cementation types, gravel volume fraction and shape are quite different, which leads to its strong heterogeneity. When developing a conglomerate reservoir, it is extremely difficult to drill because of its strong heterogeneity. It is difficult to obtain the mechanical properties and laws of the conglomerate through physical experiments, which further restricts the development process of conglomerate reservoirs. In order to study its failure law, a three-dimensional numerical model of a conglomerate is built based on the discrete element method, and the effects of cementation strength and gravel characteristics on the mechanical properties of the conglomerate are emphatically studied. The results show that the elastic modulus and uniaxial compressive strength of the conglomerate decrease obviously with the decrease in cementation strength. With the increase in cementation strength, the normal contact force of the conglomerate model increases significantly, the distribution of normal contact force changes from cylinder to sphere, and the heterogeneity of the conglomerate decreases. There is a threshold value for the influence of cementation strength on mechanical properties of the conglomerate, and when the threshold is exceeded, the mechanical properties of the conglomerate no longer change obviously. With the increase in gravel content, the uniaxial compressive strength of the conglomerate decreases at first and then increases, the phenomenon of penetrating gravels and bypassing gravels increases, and the single diagonal crack changes into diagonal cross cracks; the cementation strength and gravel content of gravel jointly affect the mechanical properties and fracture morphology of the conglomerate, and its stress–strain relationship is the external macroscopic expression of normal contact force of internal particles.

Most of the 3D reconstruction requirements of microscopic scenes exist in industrial detection, and this scene requires real-time object reconstruction and can get object surface information quickly. However, this demand is challenging to obtain for micro scenarios. The reason is that the microscope’s depth of field is shallow, and it is easy to blur the image because the object’s surface is not in the focus plane. Under the video microscope, the images taken frame by frame are mostly defocused images. In the process of 3D reconstruction, a single sheet or a few 2D images are used for geometric-optical calculation, and the affine transformation is used to obtain the 3D information of the object and complete the 3D reconstruction. The feature of defocus image is that its complete information needs to be restored by a whole set of single view defocus image sequences. The defocused image cannot complete the task of affine transformation due to the lack of information. Therefore, using defocus image sequence to restore 3D information has higher processing difficulty than ordinary scenes, and the real-time performance is more difficult to guarantee. In this paper, the surface reconstruction process based on point-cloud data is studied. A Delaunay triangulation method based on plane projection and synthesis algorithm is used to complete surface fitting. Finally, the 3D reconstruction experiment of the collected image sequence is completed. The experimental results show that the reconstructed surface conforms to the surface contour information of the selected object.

The influence of microbiota on host health and disease has attracted adequate attention, and gut microbiota components and microbiota-derived metabolites affect host immune homeostasis locally and systematically. Some studies have found that gut dysbiosis, disturbance of the structure and function of the gut microbiome, disrupts pulmonary immune homeostasis, thus leading to increased disease susceptibility; the gut-lung axis is the primary cross-talk for this communication. Gut dysbiosis is involved in carcinogenesis and the progression of lung cancer through genotoxicity, systemic inflammation, and defective immunosurveillance. In addition, the gut microbiome harbors the potential to be a novel biomarker for predicting sensitivity and adverse reactions to immunotherapy in patients with lung cancer. Probiotics and fecal microbiota transplantation (FMT) can enhance the efficacy and depress the toxicity of immune checkpoint inhibitors by regulating the gut microbiota. Although current studies have found that gut microbiota closely participates in the development and immunotherapy of lung cancer, the mechanisms require further investigation. Therefore, this review aims to discuss the underlying mechanisms of gut microbiota influencing carcinogenesis and immunotherapy in lung cancer and to provide new strategies for governing gut microbiota to enhance the prevention and treatment of lung cancer.

The Inner Tibetan Plateau (ITP), the central and western part of the Tibetan Plateau (TP), covers about one-fourth of the entire TP and contains more than 800 endorheic lakes larger than 1 km2. These lakes are important water reservoirs and sensitive to TP climate changes. They regulate regional water circulations, and further influence local ecosystems. Many lakes in ITP are surrounded by conspicuous paleoshorelines indicating much higher past lake levels. Previous studies found that lakes in the western ITP (west of ∼86°E) apparently expanded to higher levels than those to the east during the Holocene high lake level stage, however, there is no in-depth study on the reasons for the spatial differences of high lake levels within the ITP. In this study, we first identify Holocene lake level (or lake extent) changes over the ITP by combining published lake level variation data with our reconstruction of Dagze Co lake level variations. We then investigate spatial differences in the magnitude of lake expansions and explore the underlying forces driving these differences using the transient climate evolution of the last 21 ka (TraCE-21ka) and Kiel Climate Model (KCM) simulation results. We find that lakes in the ITP expanded to their highest levels during the early Holocene when the Indian summer monsoon (ISM) greatly intensified. After the mid-Holocene, lake levels fell as a result of the weakening of the ISM. The early Holocene northward shift of the westerly jet and a positive phase of the Atlantic multidecadal oscillation (AMO) resulted in the intensification of southwesterly winds on the southwest TP flank. Concurrently, westerly winds over the TP weakened, causing a differential increase in water vapor transport to the ITP with higher precipitation levels in the southwestern ITP and lower levels to the northeast. These wind-driven differential precipitation levels caused lakes in the southwestern ITP to expand to higher levels than those in the central, northern and northeastern ITP. During the early Holocene, expansion of lakes in the northwestern ITP was enhanced by an increase in glacier melt water besides the increased summer rainfall associated with the intensified ISM.

Small sample learning aims to learn information about object categories from a single or a few training samples. This learning style is crucial for deep learning methods based on large amounts of data. The deep learning method can solve small sample learning through the idea of meta-learning “how to learn by using previous experience.” Therefore, this paper takes image classification as the research object to study how meta-learning quickly learns from a small number of sample images. The main contents are as follows: After considering the distribution difference of data sets on the generalization performance of measurement learning and the advantages of optimizing the initial characterization method, this paper adds the model-independent meta-learning algorithm and designs a multi-scale meta-relational network. First, the idea of META-SGD is adopted, and the inner learning rate is taken as the learning vector and model parameter to learn together. Secondly, in the meta-training process, the model-independent meta-learning algorithm is used to find the optimal parameters of the model. The inner gradient iteration is canceled in the process of meta-validation and meta-test. The experimental results show that the multi-scale meta-relational network makes the learned measurement have stronger generalization ability, which further improves the classification accuracy on the benchmark set and avoids the need for fine-tuning of the model-independent meta-learning algorithm.

The release of Escherichia coli (E. coli) O157:H7 has been widely found in various environments, but little is known about the probable influence of the transient E. coli O157:H7 invasion on the native microbial community. Here, we investigated the temporal response of two bacterial biospheres (abundant and rare) of two marsh sediments against E. coli O157:H7 during a 60-day incubation. The diversity of both biospheres showed no evident response to O157:H7 invasion. Temporal factor exhibited greater effects on bacterial variation than O157:H7 invasion. We found that O157:H7 invasion led to an increase in the niche breadth of the bacterial community while decreasing the efficiency of bacterial interaction of the abundant taxa. Moreover, the rare biosphere exhibited enhanced stability against O157:H7 invasion compared with the abundant biosphere, acting as the backbone in resisting external disturbance. Furthermore, each subcommunity assembly showed different randomness levels. The stochastic events were relatively more important in constraining the abundant taxa assembly after invasion. Collectively, E. coli O157:H7 exhibited diverse tangible impact on both biospheres, which unearthed differential responses of abundant and rare biosphere against transient microbial invasion.

Abstract Clay shale is frequently encountered in drilling. With strong hydration capacity, when clay shale contacts with drilling fluid, rock structural and mechanical property will be affected, causing wellbore instability. Acoustic frequency spectrum is a significant parameter in geophysical logging. The influence of hydration on clay shale can be reflected in acoustic logging. Therefore, in order to identify hydration damage and have precise evaluation for hydration damage, a novel hydration damage index has been built on the basis of acoustic frequency spectrum. Meanwhile, considering the influence of hydration, hydrated constitutive model has been proposed using this new index. Results demonstrate that acoustic frequency spectrum has clear modification due to hydration damage. In the hydration evolutionary process, fracture initiation and propagation happen, decreasing acoustic amplitude and dominant frequency. The whole hydration evolutionary process exhibits S curve with clear three stages. In the initial stage, changing ranges of acoustic amplitude and frequency are small. In the middle stage, clear fracture propagation can be noticed and fracture network is formed, boosting the change of acoustic frequency spectrum. Finally, acoustic frequency spectrum becomes stable, meaning hydration damage has reached its limitation. Hydration damage degree is variable with different conditions, but the tendency still remains typical S curve. Stress‐strain curves simulated from hydrated constitutive model are in good agreement with results of uniaxial compressive test, indicating this model can be used to express shale mechanical property in hydration evolutionary process. Findings of this paper can offer theoretical reference for evaluating hydration damage and are advantageous for drilling operation in clay shale formation.

By using core, thin section, well logging, seismic, well testing and other data, the reservoir grading evaluation parameters were selected, the classification criterion considering multiple factors for carbonate reservoirs in this area were established, and the main factors affecting the development of high quality reservoir were determined. By employing Formation MicroScanner Image (FMI) logging fracture-cavity recognition technology and reservoir seismic waveform classification technology, the spatial distribution of reservoirs of all grades were predicted. On the basis of identifying four types of reservoir space developed in the study area by mercury injection experiment, a classification criterion was established using four reservoir grading evaluation parameters, median throat radius, effective porosity and effective permeability of fracture-cavity development zone, relationship between fracture and dissolution pore development and assemblage, and the reservoirs in the study area were classified into grade I high quality reservoir of fracture and cavity type, grade II average reservoir of fracture and porosity type, grade III poor reservoir of intergranular pore type. Based on the three main factors controlling the development of high quality reservoir, structural location, sedimentary facies and epigenesis, the distribution of the 3 grades reservoirs in each well area and formation were predicted using geophysical response and percolation characteristics. Follow-up drilling has confirmed that the classification evaluation standard and prediction methods established are effective. Key Words: Sichuan Basin, Moxi area, Cambrian Longwangmiao Formation, carbonate rock, fracture-cavity reservoir, reservoir grading evaluation, reservoir prediction

Objectives To develop a model of in-hospital mortality using medical record front page (MRFP) data and assess its validity in case-mix standardisation by comparison with a model developed using the complete medical record data.Design A nationally representative retrospective study.Setting Representative hospitals in China, covering 161 hospitals in modelling cohort and 156 hospitals in validation cohort.Participants Representative patients admitted for acute myocardial infarction. 8370 patients in modelling cohort and 9704 patients in validation cohort.Primary outcome measures In-hospital mortality, which was defined explicitly as death that occurred during hospitalisation, and the hospital-level risk standardised mortality rate (RSMR).Results A total of 14 variables were included in the model predicting in-hospital mortality based on MRFP data, with the area under receiver operating characteristic curve of 0.78 among modelling cohort and 0.79 among validation cohort. The median of absolute difference between the hospital RSMR predicted by hierarchical generalised linear models established based on MRFP data and complete medical record data, which was built as ‘reference model’, was 0.08% (10th and 90th percentiles: −1.8% and 1.6%). In the regression model comparing the RSMR between two models, the slope and intercept of the regression equation is 0.90 and 0.007 in modelling cohort, while 0.85 and 0.010 in validation cohort, which indicated that the evaluation capability from two models were very similar.Conclusions The models based on MRFP data showed good discrimination and calibration capability, as well as similar risk prediction effect in comparison with the model based on complete medical record data, which proved that MRFP data could be suitable for risk adjustment in hospital performance measurement.

Hydraulic fracturing is a necessary technique for shale gas exploitation. In order to have efficient stimulation treatment, a complex fracture network has to be developed, whereas with rich bedding planes and natural fractures, the mechanism of forming a fracture network is not fully understood and it is so tricky to predict propagation and initiation of hydraulic fracture. Therefore, in this paper, considering the strong anisotropy of shale reservoir, numerical simulation has been conducted to analyze fracture propagation and initiation on the basis of finite element and damage mechanics. Simulation results indicate that hydraulic fracture is not merely controlled by in situ stress due to strong anisotropy in shale. With plenty of bedding planes, hydraulic fracture tends to have initiation and propagation along the bedding plane. In particular, this influence becomes stronger with low strength and high development density of bedding planes. Additionally, in combination with natural fracture and bedding plane, the initiation point is usually on a natural fracture plane, causing relatively small breakdown pressure. In the process of fracture propagation, hydraulic fracture connects with natural fractures and bedding planes, forming dendritic bifurcation and more complicated paths. Numerical simulation proves that bedding plane and natural fracture are vital factors of hydraulic fracture. Compared to natural fracture, the bedding plane has a stronger impact on hydraulic fracture propagation. For the initiation of hydraulic fracture, natural fracture is the major effecting factor. The outcome of this study is able to offer theoretical guidance for hydraulic fracturing in shale.

Environmental conditions on the Tibetan Plateau (TP) during the last glacial maximum (LGM) are poorly known. Existing studies of environmental proxies and climate model simulations are contradictory, with interpretations varying between cold-dry and cold-wet environmental conditions which differentially influenced lake volumes, loess deposition and vegetation communities across the TP. Genetic and archaeological studies suggest anatomically modern paleolithic foragers initially occupied the TP between 60 and 30 ka, and may have seasonally occupied the TP during the LGM. Hence, a better understanding for LGM environmental conditions is needed in order to estimate whether paleolithic foragers could have survived on the TP during the extreme LGM cold stage. Here we report the investigation of lacustrine sediments and beach deposits within two paleoshorelines around Dagze Co on the southern TP, ∼22 and ∼42 m higher than the present lake level. Optical age estimates suggest the sediments were deposited during the LGM and mid-Holocene, respectively. TraCE-21 climate model simulation results suggest that net annual LGM precipitation in the Dagze Co basin was lower than the mid-Holocene, but about the same as that of the past 1,000 years. Combining the optical age estimates with TraCE-21 and CAM4 climate model simulation results, we deduce that increased summer precipitation and glacier meltwater supply, combined with decreased lake surface evaporation, produced LGM lake levels ∼22 m higher than present. We also synthesized paleoenvironmental records reported across the TP spanning the LGM. This synthesis suggests that the LGM climate in the northern TP was cold and dry, but that some of the southern TP was cold and wet. These relatively wetter LGM conditions in the southern TP may have favored the growth of cold-resistant plants which, in turn, may have supported larger herbivore populations, and provided food for paleolithic foragers. We conclude that seasonal or short-term human occupation of the TP during the LGM was thus more likely in the southern TP than in the north.

The complexity of hydraulic fractures (HF) significantly affects the success of reservoir reconstruction. The existence of a bedding plane (BP) in shale impacts the extension of a fracture. For shale reservoirs, in order to investigate the interaction mechanisms of HF and BPs under the action of coupled stress-flow, we simulate the processes of hydraulic fracturing under different conditions, such as the stress difference, permeability coefficients, BP angles, BP spacing, and BP mechanical properties using the rock failure process analysis code (RFPA2D-Flow). Simulation results showed that HF spread outward around the borehole, while the permeability coefficient is uniformly distributed at the model without a BP or stress difference. The HF of the formation without a BP presented a pinnate distribution pattern, and the main direction of the extension is affected by both the ground stress and the permeability coefficient. When there is no stress difference in the model, the fracture extends along the direction of the larger permeability coefficient. In this study, the in situ stress has a greater influence on the extension direction of the main fracture when using the model with stress differences of 6 MPa. As the BP angle increases, the propagation of fractures gradually deviates from the BP direction. The initiation pressure and total breakdown pressure of the models at low permeability coefficients are higher than those under high permeability coefficients. In addition, the initiation pressure and total breakdown pressure of the models are also different. The larger the BP spacing, the higher the compressive strength of the BP, and a larger reduction ratio (the ratio of the strength parameters of the BP to the strength parameters of the matrix) leads to a smaller impact of the BP on fracture initiation and propagation. The elastic modulus has no effect on the failure mode of the model. When HF make contact with the BP, they tend to extend along the BP. Under the same in situ stress condition, the presence of a BP makes the morphology of HF more complex during the process of propagation, which makes it easier to achieve the purpose of stimulated reservoir volume (SRV) fracturing and increased production.

General cancer-targeted ligands that can deliver drugs to cells have been given considerable attention. In this paper, a high-affinity DNA aptamer (HG1) generally binding to human tumor cells was evolved by cell-SELEX, and was further optimized to have 35 deoxynucleotides (HG1-9). Aptamer HG1-9 could be taken up by live cells, and its target protein on a cell was identified to be human transferrin receptor (TfR). As a man-made ligand of TfR, aptamer HG1-9 was demonstrated to bind at the same site of human TfR as transferrin with comparable binding affinity, and was proved to cross the epithelium barrier through transferrin receptor-mediated transcytosis. These results suggest that aptamer HG1-9 holds potential as a promising ligand to develop general cancer-targeted diagnostics and therapeutics.

The lack of ideal photosensitizers limits the clinical application of photodynamic therapy (PDT). Here we report the PDT efficiency of dicyanomethylene substituted benzothiazole squaraine derivatives. This class of squaraine derivatives possess strong absorption and long excitation and emission wavelengths (ex/em, 685/720 nm). They show negligible dark toxicity, but can generate singlet oxygen under irradiation resulting in the apoptosis and necrosis of cells (phototoxicity). Changing the side chains of these compounds greatly influences their albumin-binding rate, cellular uptake and their phototoxicity. One of the squaraine derivatives with two methyl butyrate side chains shows high PDT efficiency in a mouse subcutaneous xenograft model under the irradiation of a 690 nm laser. These results show the great potential of dicyanomethylene substituted benzothiazole squaraines to be the leading compound of near-infrared photosensitizers in PDT.

Abstract The G-quadruplex (G4) structures of nucleic acids are considered to play an intrinsic role in gene expression. To this end, the development of new G4 ligands has attracted extensive research interests towards potential applications as G4-targeted drugs and molecular probes. To date, the majority of G4 ligands have been composed of an extended planar aromatic scaffold that interacts with the terminal G-tetrad plane via π-π interactions, and various side chains that interact with the sugar-phosphate backbone, loops or grooves of the G4 structures. The side chains act to modulate the affinity and selectivity of the G4 ligands, alongside influencing their biodistribution. Here, we present a click chemistry methodology to generate a series of squaraine-based G4 ligand derivatives based on our previously reported G4 probe (named CSTS) but with varing side chains. We find that importantly these new G4 ligand derivatives retain the G4 selectivity, optical properties and low cytotoxicity of CSTS, but exhibit different binding behaviors to G4 structures, and distinct cellular uptake efficiencies. Indeed, of these new complexes, several exhibit much higher affinity and cellular uptake than CSTS. Overall, this novel, facile and highly effective strategy has significant future potential for the high-throughput screening of G4 ligands or probes targeted towards in vivo applications.

Abstract Dimerization of proteins occurs frequently and plays integral roles in biological processes. However, no single molecular probe is available for in situ detection of protein dimers on cells and tissues because of the difficulty of isolating complete protein dimers for probe preparation and screening, which has greatly hampered the biomedical study of protein dimers. Herein, a G‐rich DNA aptamer (termed BG2) that only binds alkaline phosphatase (AP) heterodimers rather than monomers is reported. This aptamer is generated by the cell‐SELEX (systematic evolution of ligands by exponential enrichment) technique and proves to fold into a duplex stabilized antiparallel G‐quadruplex structure. Using BG2 as molecular probe, AP heterodimers are found to be expressed on several kinds of cancer cells. As an affinity ligand, BG2 could isolate AP heterodimers from cell lysate. BG2 is also demonstrated to be applicable for tumor imaging in mice xenografted with cells highly expressing AP heterodimers. AP isozymes are found in several tissues and blood throughout the body, but the function and tissue distribution of AP heterodimers are totally unknown; therefore, BG2 could serve as a molecular probe to uncover the mystery of AP heterodimers. The generation of aptameric probes by cell‐SELEX will open up a new situation for the study of protein dimers.

Shale reservoirs are characterized by low permeability and natural fractures. In the process of reservoir development, the working fluid enters the reservoir. This may result in the formation of new fractures or expansion of natural fractures. When shale reservoirs are exploited, the fluid pressure in the fracture or pore is reduced. This destroys the stress balance of the reservoir, produces stress sensitivity damage, and reduces the reservoir permeability. Organic-rich shale from the Yanchang Formation, Chang 7 Member of the Ordos Basin, was selected for core flow experiment with helium. The effects of the type of brine, salinity, and soaking time on the stress sensitivity of an organic-rich shale reservoir were investigated. The acoustic characteristics were also investigated to study the effect of interactions between water and shale on stress sensitivity. The experimental results demonstrate that the interactions of water and shale increase the permeability of shale and reduce its stress sensitivity. Furthermore, when the permeability of the shale is excessively low, the stress sensitivity is high. In the acoustic studies, a higher attenuation coefficient of the acoustic wave corresponds to a larger variation in the shale structure and thus a larger permeability of the shale and smaller stress sensitivity coefficient. Whereas there is no apparent effect of the salt water type on the stress sensitivity, higher salinity levels cause higher stress sensitivity. After reacting with 15000 mg/L brine, the stress sensitivity coefficient of shale did not decrease significantly compared with that before action, all of which were above 0.97. However, after reacting with distilled water or 5000 mg/L brine, the stress sensitivity coefficient of shale decreased significantly, and all of them decreased to less than 0.9. Longer water exposures, corresponding to an increased duration of water-shale interactions, result in higher impacts on the stress sensitivity of shale. After 6 hours of shale-brine interaction, the stress sensitivity coefficient of shale is as high as 0.93, while after 48 hours of shale-brine interaction, the stress sensitivity coefficient of shale is reduced to 0.88. This study provides a highly effective reference with regard to the influence of the working fluid on the reservoir during drilling operations and the study of reservoir characteristics after fracturing.

At underground fluid injection sites with natural faults, understanding how to avoid the subsequent fault reactivation and induced seismicity plays a crucial role in the success of subsurface anthropogenic activities. In this work, with the objective of avoiding risky faults in site selection in the Shengli Oilfield, we investigated the faults that are usually encountered in the target demonstration zone; based on the geophysical observations of fault structures, we designed different fault tectonic scenarios to investigate the different penetration patterns of faults. We used the finite element-based numerical method to assess the influence of the effective lateral and vertical reservoir transmissivity in each fault penetration pattern. Our results indicate that when a permeable fault intersects into the target reservoir, it presents both barrier effect to reservoir transmissivity within the target reservoir and hydraulic connection between reservoirs. The effective lateral reservoir transmissivity is dominated by the barrier effect of the fault, and the effective vertical reservoir transmissivity is dominated by the hydraulic connection between reservoirs. Relatively impermeable faults with less contact with the target aquifer make higher effective lateral reservoir transmissivity and lower effective vertical reservoir transmissivity, which would mitigate the risk of caprock failure and the magnitude of the induced seismicity.

With the development of artificial intelligence, more and more people hope that computers can understand human language through natural language technology, learn to think like human beings, and finally replace human beings to complete the highly difficult tasks with cognitive ability. As the key technology of natural language understanding, sentence representation reasoning technology mainly focuses on the sentence representation method and the reasoning model. Although the performance has been improved, there are still some problems such as incomplete sentence semantic expression, lack of depth of reasoning model, and lack of interpretability of the reasoning process. In this paper, a multi-layer semantic representation network is designed for sentence representation. The multi-attention mechanism obtains the semantic information of different levels of a sentence. The word order information of the sentence is also integrated by adding the relative position mask between words to reduce the uncertainty caused by word order. Finally, the method is verified on the task of text implication recognition and emotion classification. The experimental results show that the multi-layer semantic representation network can promote sentence representation’s accuracy and comprehensiveness.

Research and development of water lock inhibiting measures is very crucial in verifying the link mechanism between the internal factors of water lock and its extent of damage. Based on conventional water-lock physics experiments, however, only the consequence of macro water lock damage can be investigated, while the microscopic mechanism cannot be studied. In this paper, 3D digital cores of low-permeability sandstones were prepared by means of high-resolution micro-CT scan, and their equivalent pore network model was built as well. Virtual “imbibition” experiments controlled by capillary force were carried out by using pore-scale flow simulation. Then the link mechanism between the microscopic internal factors (e.g. wettability, water saturation and pore–throat structure parameters) and the water-lock damage degree was discussed. It is shown that the damage degree of water lock reduces gradually as the wettability transits from water wet to gas wet. Therefore, the water lock damage can be reduced effectively and gas-well productivity can be improved so long as the capillary environment is changed from strong water wettability to weak gas wettability. The more different the initial water saturation is from the irreducible water saturation, the more serious the water lock damage is. The damage degree of water lock is in a negative correlation with the coordinate number, but a positive correlation with the pore–throat ratio. Based on the existing research results, water lock tends to form in the formations composed of medium-sized throats. It is concluded that there is a critical throat radius, at which the water lock is the most serious.

As a serious problem in drilling operation, wellbore instability restricts efficient development of shale gas. The interaction between the drilling fluid and shale with hydration swelling property would have impact on the generation and propagation mechanism of cracks in shale formation, leading to wellbore instability. In order to investigate the influence of the hydration swelling on the crack propagation, mineral components and physicochemical properties of shale from the Lower Silurian Longmaxi Formation (LF) were investigated by using the XRD analysis, cation exchange capabilities (CEC) analysis, and SEM observation, and we researched the hydration mechanism of LF shale. Results show that quartz and clay mineral are dominated in mineral composition, and illite content averaged 67% in clay mineral. Meanwhile, CEC of the LF shale are 94.4 mmol/kg. The process of water intruding inside shale along microcracks was able to be observed through high power microscope, meanwhile, the hydration swelling stress would concentrate at the crack tip. The microcracks would propagate, bifurcate and connect with each other, with increase of water immersing time, and it would ultimately develop into macro-fracture. Moreover, the macrocracks extend and coalesce along the bedding, resulting in the rock failure into blocks. Hydration swelling is one of the major causes that lead to wellbore instability of the LF shale, and therefore improving sealing capacity and inhibition of drilling fluid system is an effective measure to stabilize a borehole.

Because of high cost and pollution of oil-based drilling fluid, the water-based drilling fluid is increasingly used now. However, bedding planes and micro-cracks are rich in shale formation. When water-based drilling fluid contacts formation rock, it causes the propagation of crack and invasion of drilling fluid, which decrease shale strength and cause wellbore instability. In this paper, we analyzed influence of water-based drilling fluid on shale strength and failure mode by mechanics experiment. Based on those experimental results, considering the effect of bedding plane and drilling time, we established modeling of wellbore stability for shale formation. The result from this model indicates that in certain azimuth of horizontal well, collapsing pressure increases dramatically due to shale failure along with bedding plane. In drilling operation, those azimuths are supposed to be avoided. This model is applicable for predication of collapsing pressure in shale formation and offers reference for choosing suitable mud weight.

Pore structure has been widely observed to affect the seismic wave velocity of rocks. Although taking lab measurements on 1.0-inch core plugs is popular, it is not representative of the fractured-vuggy carbonates because many fractures and vugs are on a scale up to several hundred microns (and greater) and are spatially heterogeneous. To overcome this shortage, we carried out the lab measurements on full-diameter cores (about 6.5–7.5 cm in diameter). The micro-CT (micro computed tomography) scanning technique is used to characterize the pore space of the carbonates and image processing methods are applied to filter the noise and enhance the responses of the fractures so that the constructed pore spaces are reliable. The wave velocities of P- and S-waves are determined then and the effects of the pore structure on the velocity are analyzed. The results show that the proposed image processing method is effective in constructing and quantitatively characterizing the pore space of the full-diameter fractured-vuggy carbonates. The porosity of all the collected tight carbonate samples is less than 4%. Fractures and vugs are well-developed and the spatial distributions of them are heterogeneous causing, even the samples having similar porosity, the pore structure characteristics of the samples being significantly different. The pores and vugs mainly contribute to the porosity of the samples and the fractures contribute to the change in the wave velocities more than pores and vugs.

Lycium barbarum L. is a widely used functional food and medicinal herb in Asian countries. L. barbarium polysaccharides (LBP) are considered as one of the major medicinal components of L. barbarium fruit and exhibits a wide range of biological activities. Here, we investigated the immunomodulatory effects of LBP and its uptake behaviors at the cellular level. LBP was prepared by water extraction and ethanol precipitation, and divided into two fractions based on the molecular weight distribution by ultrafiltration (LBP > 10 kDa and LBP < 10 kDa). The physicochemical properties of LBP and LBP fractions were well characterized. The LBP > 10 kDa fraction greatly enhanced the viability of macrophages RAW264.7 cells and induced cell polarization, but had weak effects to other tested tumor cell lines and normal cell line. This fraction could regulate the production of NO, TNF-α, IL-6 and ROS in RAW264.7 cells, suggesting both pro-inflammatory and anti-inflammatory effects. The dye-labeled LBP could be internalized into all tested cell lines and accumulated in lysosomes. The internalization of LBP in RAW264.7 cells is mainly through the clathrin-mediated endocytosis pathway. The Caco-2 intestinal transport experiment demonstrated that the dye labeled LBP could be transported through the Caco-2 cell monolayer (mimic intestinal epithelium) through clathrin-mediated endocytosis. These results demonstrate the immunomodulatory effects of LBP and its effective uptake by macrophages and intestine.

Vicia ramuliflora L. is a widely distributed species in Eurasia with high economic value. For past 200 years, it has evolved a tetraploid cytotype and new subspecies at the diploid level. Based on taxonomy, cytogeography and other lines of evidence, previous studies have provided valuable information about the evolution of V. ramuliflora ploidy level, but due to the limited resolution of traditional methods, important questions remain. In this study, fluorescence in situ hybridization (FISH) and random amplified polymorphic DNA (RAPD) were used to analyze the evolution of V. ramuliflora at the diploid and tetraploid levels. Our aim was to reveal the genomic constitution and parents of the tetraploid V. ramuliflora and the relationships among diploid V. ramuliflora populations. Our study showed that the tetraploid cytotype of V. ramuliflora at Changbai Mountains (M) has identical 18S and 5S rDNA distribution patterns with the diploid Hengdaohezi population (B) and the diploid Dailing population (H). However, UPGMA clustering, Neighbor-Joining clustering and principal coordinates analysis based on RAPD showed that the tetraploid cytotype (M) has more close relationships with Qianshan diploid population T. Based on our results and the fact that interspecific hybridization among Vicia species is very difficult, we think that the tetraploid V. ramuliflora is an autotetraploid and its genomic origin still needs further study. In addition, our study also found that Qianshan diploid population (T) had evolved distinct new traits compared with other diploid populations, which hints that V. ramuliflora evolved further at diploid level. We suggest that diploid population T be re-classified as a new subspecies.

Hydraulic fracture dimension is one of the key parameters affecting stimulated porous media. In actual fracturing, plentiful uncertain parameters increase the difficulty of fracture dimension prediction, resulting in the difficulty in the monitoring of reservoir productivity. In this paper, we established a three-dimensional model to analyze the key factors on the stimulated reservoir volume (SRV), with the response surface method (RSM). Considering the rock properties and fracturing parameters, we established a multivariate quadratic prediction equation. Simulation results show that the interactions of injection rate (Q), Young’s modulus (E) and permeability coefficient (K), and Poisson’s ratio (μ) play a relatively significant role on SRV. The reservoir with a high Young’s modulus typically generates high pressure, leading to longer fractures and larger SRV. SRV reaches the maximum value when E1 and E2 are high. SRV is negatively correlated with K1. Moreover, maintaining a high injection rate in this layered formation with high E1 and E2, relatively low K1, and μ1 at about 0.25 would be beneficial to form a larger SRV. These results offer new perceptions on the optimization of SRV, helping to improve the productivity in hydraulic fracturing.

The fruits, leaves and root barks of L. barbarum plant are widely used as functional foods and as ingredients in traditional Chinese prescriptions and patent medicines. They are considered to have different pharmacological activities and health benefits because of their diverse constituents. Here, the chemical constituents of the extracts from fruits, leaves and root barks of L. barbarum were compared by ultra-high performance liquid chromatography coupled with high resolution mass spectrometry (UPLC-HR-MS). A total of 131 compounds were identified and seven of them were quantified. Among them, 98, 28 and 35 constituents were detected in fruits, leaves and root barks respectively. Dicaffeoylspermidine/spermine derivatives were the most detected compounds (74/131); among them, dicaffeoylspermine isomers and propionyl-dicaffeoylspermidine were found in root barks in very large amounts (e.g., kukoamine B = 10.90 mg/g dry powder); dicaffeoyl-spermidine isomers were detected in fruits/leaves in a high amount, and many of their glycosylated derivatives were mainly detected in fruits. In addition, six saponins from L. barbarum fruits were reported for the first time, and 5,6-dihydrosolasonine was reported for the first time in plants. The activity assays showed that the root bark extract possessed the strongest antioxidative activity and cytotoxicity, which was presumed due to the large amount of dicaffeoylspermine/spermidines in root barks. Fourteen potential bioactive components from fruits were identified by a target cell-based screening method. These results will help to understand the different biological activities of these three parts of L. barbarum plant and will benefit the discovery of new functional components.

The lubricant, perfluoropolyethers (PFPEs), has been modeled and analyzed using molecular dynamics simulations based on a coarse-grained bead-spring model. An ultrathin lubricant film with a thickness of 1-2 nm is coated on a disk to lubricate the head disk interface (HDI) of hard disk drives (HDDs). The retention performance of the lubricant film is studied, which is important to avoid a direct contact between the head and disk. The replenishment performance is also studied, which is essential to repair the lubricant film ruptured by a contact of the head. Finally, the typical phenomenon of touch down-take off hysteresis during the contact between head and disk is confirmed and analyzed because of the nanoscopic interactions in the HDI.

We mainly focus on the Permian, Lower Cambrian, Lower Silurian, and Upper Ordovician Formation; the fractal dimensions of marine shales in southern China were calculated using the FHH fractal model based on the low-pressure nitrogen adsorption analysis. The results show that the marine shales in southern China have the dual fractal characteristics. The fractal dimension D1 at low relative pressure represents the pore surface fractal characteristics, whereas the fractal dimension D2 at higher relative pressure describes the pore structure fractal characteristics. The fractal dimensions D1 range from 2.0918 to 2.718 with a mean value of 2.4762, and the fractal dimensions D2 range from 2.5842 to 2.9399 with a mean value of 2.8015. There are positive relationships between fractal dimension D1 and specific surface area and total pore volume, whereas the fractal dimensions D2 have negative correlation with average pore size. The larger the value of the fractal dimension D1 is, the rougher the pore surface is, which could provide more adsorption sites, leading to higher adsorption capacity for gas. The larger the value of the fractal dimension D2 is, the more complicated the pore structure is, resulting in the lower flow capacity for gas.