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Abstract The incident angle of seismic waves influences the dynamic response of rock slopes. However, the relationship between the back-slope effect in strong earthquake areas and the incident angle has not been well-explained. Based on the equivalent nodal force method and the viscoelastic artificial boundary theory, the oblique incidence of seismic P-wave and SV-wave are carried out in FLAC3D software. The accuracy of the proposed method is verified by comparing it with the results of the theoretical solution and another numerical result. The dynamic response of trapezoidal canyon slope under oblique incidence of P-waves and SV-waves was studied, and the effects of different slope angles and canyon widths were analyzed. The study reveals a pronounced back-slope effect under the action of the P-wave and SV-wave, and the slope’s horizontal direction dynamic response plays an important role. At the same location on the slope surface, the relative horizontal acceleration of the slope increases with the incident angle of P-waves and SV-waves, and the maximum value on the back-slope side is approximately 19 times and 6.8 times that of the front-slope side, respectively. Slope angle significantly affects the back-slope side’s dynamic response, showing an increase with increasing slope angle, while canyon width has a limited impact.

Abstract Studying crystal anisotropy is of great importance for understanding the thermal–mechanical coupling behavior of crystalline rocks in deep underground engineering. In this study, a microscopic parameter calibration method incorporating the size effect is proposed. Subsequently, a thermal–mechanical coupling model accounting for the quartz crystal anisotropy is established to investigate the thermal–mechanical coupling behavior of monomineral quartzite. The results show that thermal-induced microcracks are exclusively distributed along crystal boundaries, and initiate preferentially from crystal boundaries with a larger average linear thermal expansion coefficient, eventually leading to the formation of a crack network. With the increase in temperature, the peak strength of monomineral quartzite increases slightly at first and then decreases rapidly, and the transition threshold temperature is 200 °C. Both elastic modulus and Poisson’s ratio show a monotonic pattern, with abrupt changes occurring at 200 and 300 °C, respectively. The monomineral quartzite exhibits a significant compaction stage under uniaxial compression, and the ductile strengthening critical temperature for monomineral quartzite are between 400 and 500 °C. The quartz crystal anisotropy leads to an anisotropic distribution of inclination angles for tensile microcracks under high temperatures while having no obvious effect on the shear microcracks. In addition, the average size of fragments generated under uniaxial compression is influenced by thermal cracking, demonstrating an initial decrease followed by an increase, and the distribution of fragment sizes is solely correlated with the temperature, which is more concentrated with the increase in temperature.

Background Prognostic markers and biological pathways linked to detrimental clinical outcomes in heart failure with preserved ejection fraction (HFpEF) remain incompletely defined. Methods and Results We measured serum levels of 4123 unique proteins in 1117 patients with HFpEF enrolled in the PARAGON‐HF (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction) trial using a modified aptamer proteomic assay. Baseline circulating protein concentrations significantly associated with the primary end point and the timing and occurrence of total heart failure hospitalization and cardiovascular death were identified by recurrent events regression, accounting for multiple testing, adjusted for age, sex, treatment, and anticoagulant use, and compared with published analyses in 2515 patients with heart failure with reduced ejection fraction from the PARADIGM‐HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and ATMOSPHERE (Efficacy and Safety of Aliskiren and Aliskiren/Enalapril Combination on Morbidity–Mortality in Patients With Chronic Heart Failure) clinical trials. We identified 288 proteins that were robustly associated with the risk of heart failure hospitalization and cardiovascular death in patients with HFpEF. The baseline proteins most strongly related to outcomes included B2M (β‐2 microglobulin), TIMP1 (tissue inhibitor of matrix metalloproteinase 1), SERPINA4 (serpin family A member 4), and SVEP1 (sushi, von Willebrand factor type A, EGF, and pentraxin domain containing 1). Overall, the protein–outcome associations in patients with HFpEF did not markedly differ as compared with patients with heart failure with reduced ejection fraction. A proteomic risk score derived in patients with HFpEF was not superior to a previous proteomic score derived in heart failure with reduced ejection fraction nor to clinical risk factors, NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), or high‐sensitivity cardiac troponin. Conclusions Numerous serum proteins linked to metabolic, coagulation, and extracellular matrix regulatory pathways were associated with worse HFpEF prognosis in the PARAGON‐HF proteomic substudy. Our results demonstrate substantial similarities among serum proteomic risk markers for heart failure hospitalization and cardiovascular death when comparing clinical trial participants with heart failure across the ejection fraction spectrum. Registration URL: https://www.clinicaltrials.gov; Unique Identifiers: NCT01920711, NCT01035255, NCT00853658.

Rock avalanche disasters in alpine and gorge regions are frequent and large in scale and cause severe damage. The movement of a rock avalanche is complex and has not been fully studied. The deposits of a rock avalanche can provide valuable insights into its movement process, which is crucial in understanding the rock fragmentation mechanism and predicting disaster-affected areas. Taking the Wangjiapo rock avalanche in Yunnan Province of China as an example, the size, shape and distribution characteristics of the deposit were analyzed based on field surveys, unmanned aerial vehicle (UAV) photography and image recognition technology. Initially, 3062 deposited rock blocks were manually measured in the field. Subsequently, the Particles/Pores and Cracks Analysis System (PCAS) was employed to identify 11,357 rock blocks with an area greater than 0.1 m2 from UAV orthophotos. By comparing the characteristics of the rock blocks obtained through image recognition and manual measurement, the statistical analysis of UAV aerial imagery combined with PACS proved feasible in studying the Wangjiapo rock avalanche. The results showed that the rock block movement was accompanied by fragmentation and sorting processes; furthermore, the roundness increased with the migration distance. Small blocks were more prevalent at the foot of the slope, while irregularly shaped, large blocks dominated in source areas. The movement of huge blocks was characterized by significant potential energy-driven features and inertia advantages, allowing them to travel farther than smaller blocks, and they tended to be concentrated in the central area of the deposit. Additionally, affected by the cementation degree of breccia and the topography, the blocks in the eastern and western deposit areas exhibited different fragmentation and deposition characteristics.

Despite the considerable efforts devoted to the toxicological assessment of nanoplastics, the effect of UV-irradiation induced aging, a realistic environmental process, on the toxicity of nanoplastics toward microalgae and its underlying mechanisms remain largely unknown. Herein, this study comparatively investigated the toxicities of polystyrene nanoplastics (nano-PS) and the UV-aged nano-PS on the eukaryotic alga Chlorella vulgaris, focusing on evaluating their inhibitory effects on carbon fixation. Exposure to environmentally relevant concentrations (0.1–10 mg/L) of nano-PS caused severe damage to chloroplast, inhibited the photosynthetic efficiency and electron transport, and suppressed the activities of carbon fixation related enzymes. Multi-omics results revealed that nano-PS interfered with energy supply by disrupting light reactions and TCA cycle and hindered the Calvin cycle, thereby inhibiting the photosynthetic carbon fixation of algae. The above alterations partially recovered after a recovery period. The aged nano-PS were less toxic than the pristine ones as evidenced by the mitigated inhibitory effect on algal growth and carbon fixation. The aging process introduced oxygen-containing functional groups on the surface of nano-PS, increased the hydrophilicity of nano-PS, limited their attachment on algal cells, and thus reduced the toxicity. The findings of this work highlight the potential threat of nanoplastics to the global carbon cycle.

Block-in-matrix-soils (bimsoils) are geological mixtures that have distinct structures consisting of relatively strong rock blocks and weak matrix soils. It is still a challenge to evaluate the mechanical behaviors of bimsoils because of the heterogeneity, chaotic structure, and lithological variability. As a result, only very limited laboratory studies have been reported on the evolution of their internal deformation. In this study, the deformation evolution of bimsoils under uniaxial loading is investigated using real-time X-ray computed tomography (CT) and image correlation algorithm (with a rock block percentage (RBP) of 40%). Three parameters, i.e. heterogeneity coefficient (K), correlation coefficient (CC), and standard deviation (STD) of displacement fields, are proposed to quantify the heterogeneity of the motion of the rock blocks and the progressive deformation of the bimsoils. Experimental results show that the rock blocks in bimsoils are prone to forming clusters with increasing loading, and the sliding surface goes around only one side of a cluster. Based on the movement of the rock blocks recorded by STD and CC, the progressive deformation of the bimsoils is quantitatively divided into three stages: initialization of the rotation of rock blocks, formation of rock block clusters, and formation of a shear band by rock blocks with significant rotation. Moreover, the experimental results demonstrate that the meso-motion of rock blocks controls the macroscopic mechanical properties of the samples.

Natural gas hydrate (NGH) is considered as a type of clean energy to replace coal and oil. During exploitation, permeability is one of the key parameters controlling production efficiency, reservoir stability, and greenhouse gas sequestration. Limited by experimental and numerical simulation tools, in current research, the directionality of permeability is usually ignored. In this work, a DEM–CFD coupling simulation method is developed to compute the anisotropic permeability. The sedimentary process of reservoir sediments is reconstructed, enabling the acquisition of numerical models that possess pore structures consistent with the actual fabric characteristics. The fluid transport process in various directions can be simulated with a finite element method. Taking the natural gas hydrate reservoir in the Shenhu area of the South China Sea as an example, the proposed method is validated and applied to explore the effect of compaction stress on permeability anisotropy. With the increase in compaction stress, the permeability anisotropy exhibited a rapid initial increase, followed by a sustained stabilization. The primary cause is the rearrangement of sediment particles. The non-spherical particles are driven to align in a predominantly horizontal orientation, thereby enhancing anisotropy. The proposed method provides a tool for the efficient exploitation of hydrate resources.

Considerable research has been conducted on single-ion conductive polymeric electrolytes with high lithium ion transference numbers. However, low ionic conductivity is a long-standing challenge for lithium metal batteries, hindering the development of extending their cycle life. In this study, we synthesized a novel fluorine-containing single-ion polymeric electrolyte, LiP(VDF-co-MAF)BB (Polyvinylidene fluoride trifluoromethyl acrylate lithium borate polymer; subsequently referred to as PPMBB), exhibiting a room temperature conductivity of 1.03 × 10−3 S/cm. This electrolyte demonstrates a high lithium ion transference number of 0.7901 and an extended electrochemical stability window of 5.5 V. Under a 2 C discharge rate, it manifests a remarkable discharge specific capacity of 146.8 mAh/g. Moreover, even after 364 cycles, the capacity retention remains at 76%. The single-ion polymeric gel electrolyte designed in this work provides a promising strategy for the prolonged cycling performance of lithium metal batteries.

Abstract The pathogenesis and clinical heterogeneity of Parkinson’s disease (PD) have been evaluated from molecular, pathophysiological, and clinical perspectives. High-throughput proteomic analysis of cerebrospinal fluid (CSF) opened new opportunities for scrutinizing this heterogeneity. To date, this is the most comprehensive CSF-based proteomics profiling study in PD with 569 patients (350 idiopathic patients, 65 GBA + mutation carriers and 154 LRRK2 + mutation carriers), 534 controls, and 4135 proteins analyzed. Combining CSF aptamer-based proteomics with genetics we determined protein quantitative trait loci (pQTLs). Analyses of pQTLs together with summary statistics from the largest PD genome wide association study (GWAS) identified 68 potential causal proteins by Mendelian randomization. The top causal protein, GPNMB, was previously reported to be upregulated in the substantia nigra of PD patients. We also compared the CSF proteomes of patients and controls. Proteome differences between GBA + patients and unaffected GBA + controls suggest degeneration of dopaminergic neurons, altered dopamine metabolism and increased brain inflammation. In the LRRK2 + subcohort we found dysregulated lysosomal degradation, altered alpha-synuclein processing, and neurotransmission. Proteome differences between idiopathic patients and controls suggest increased neuroinflammation, mitochondrial dysfunction/oxidative stress, altered iron metabolism and potential neuroprotection mediated by vasoactive substances. Finally, we used proteomic data to stratify idiopathic patients into “endotypes”. The identified endotypes show differences in cognitive and motor disease progression based on previously reported protein-based risk scores.Our findings not only contribute to the identification of new therapeutic targets but also to shape personalized medicine in CNS neurodegeneration.

The permeability of natural gas hydrate (NGH) turbidite reservoirs typically exhibits significant anisotropy, with anisotropy being a crucial basis for evaluating reservoir production. The presence of hydrates, as a crucial constituent of the solid framework, not only impacts the overall permeability but also influences the permeability anisotropy. To investigate the saturation sensitivity of permeability anisotropy, a series of simulations are performed by integrating particle flow and computational fluid dynamics methods to construct the homogeneous and layered numerical samples and compute the evolution of permeability anisotropy. It is shown that the permeability is isotropic for homogeneous sediments and the isotropy remains unchanged regardless of variations in hydrate saturation. The permeability of layered sediments, in contrast, exhibits significant anisotropy due to the presence of dominant channels within the coarse layer. For uniformly distributed hydrates, the more effective blockage in coarse layers results in a reduction in anisotropy. While for preferentially distributed hydrates, the excess blocking of coarse layers makes the dominant channels transfer to the fine layers, the further blocking causes a U-shaped anisotropy–saturation curve characterized by a decrease–increase transformation. During the reservoir production process, the preponderance channels blocked by hydrates will be cleared and the horizontal permeability will significantly increase. As a result, the production efficiency of horizontal wells may exceed expectations. The findings offer a parameter support for production estimation and environmental assessment.

Three strong storms that occurred on July 21, 2012, July 20, 2016, and July 16, 2018 caused severe flooding and debris flows in the mountain areas of Beijing. The detailed records of these storms and the actual occurrence time of the debris flows provide an opportunity for evaluating the thresholds derived from different types of rainfall intensities. Herein, a new rainfall threshold of debris flows is derived from the real-time rainfall intensities in Beijing. In addition, the thresholds are estimated based on the average rainfall intensities over the interval from the beginning of the rainfall to the debris flow occurrence and over the entire rainfall duration. The results show that the various types of rainfall thresholds display significantly different capabilities in terms of separating the storms with positive debris-flow response from those with negative debris-flow response, and the real-time rainfall threshold exhibits the best performance. Moreover, our data indicate that the debris flows in Beijing are triggered by the combined work of rainfall intensity and cumulative precipitation. A debris flow is initiated only when the cumulative precipitation and rainfall intensity simultaneously reach a threshold level.

Abstract Background It is worrisome that several pollutants can enhance the abundance of antibiotic resistance genes (ARGs) in the environment, including agricultural fungicides. As an important bioindicator for environmental risk assessment, earthworm is still a neglected focus that the effects of the fungicide carbendazim (CBD) residues on the gut microbiome and resistome are largely unknown. In this study, Eisenia fetida was selected to investigate the effects of CBD in the soil-earthworm systems using shotgun metagenomics and qPCR methods. Results CBD could significantly perturb bacterial community and enrich specific bacteria mainly belonging to the phylum Actinobacteria. More importantly, CBD could serve as a co-selective agent to elevate the abundance and diversity of ARGs, particularly for some specific types (e.g., multidrug, glycopeptide, tetracycline, and rifamycin resistance genes) in the earthworm gut. Additionally, host tracking analysis suggested that ARGs were mainly carried in some genera of the phyla Actinobacteria and Proteobacteria. Meanwhile, the level of ARGs was positively relevant to the abundance of mobile genetic elements (MGEs) and some representative co-occurrence patterns of ARGs and MGEs (e.g., cmx-transposase and sul1-integrase) were further found on the metagenome-assembled contigs in the CBD treatments. Conclusions It can be concluded that the enhancement effect of CBD on the resistome in the earthworm gut may be attributed to its stress on the gut microbiome and facilitation on the ARGs dissemination mediated by MGEs, which may provide a novel insight into the neglected ecotoxicological risk of the widely used agrochemicals on the gut resistome of earthworm dwelling in soil. Video abstract Graphical Abstract

Reservoir landslide is a common geological disaster during the operation of hydropower projects. The fluctuation of reservoir water level is an important factor that induces slope instability. The natural slope will gradually lose stability under the rapid rise and fall of reservoir water level. A variety of landslide examples show that, on the premise of not suffering from extreme environmental conditions, the reservoir landslide often occurs after the rapid fluctuation of the reservoir water level for a period of time, and there is a certain time difference between its instability failure and the rapid rise and fall of the reservoir water level. In order to study the hysteresis effect between the stability change of the reservoir slope and the fluctuation of the reservoir water level, taking the Chana landslide in the reservoir area of Longyangxia Hydropower Station as an example, combining the field survey, geological survey data, and the actual change of the reservoir water level, the finite element simulation software is used to restore the actual working condition, and the research is carried out from three aspects of slope seepage field, displacement field, and stability. The results show the following: (1) The hysteresis of slope seepage change during the rising period of reservoir water level is more obvious than that during the falling period of reservoir water level. The deformation potential of Chana landslide is greater during the falling period of reservoir water level, while the deformation is restrained during the rising period of reservoir water level. (2) The incremental displacement simulation results of Chana landslide show that there are deformation incubation period and deformation release period of Chana landslide. The deformation incubation period occurs during the rapid rise and fall of reservoir water level, and the deformation release period occurs during the stable change of reservoir water level. (3) The incremental displacement produced during the deformation release period of the slope is large, but the slope remains stable, which reflects the existence of the internal antisliding mechanism of the landslide from the side. (4) The stability coefficient of Chana landslide changes greatly during the drawdown period. When the drawdown rate of water level is kept at 0.03~0.07 m/d, the stability coefficient of Chana landslide changes slightly and the slope is relatively stable.

The mechanical characteristics of gas hydrate-bearing sediments (HBS) are important for evaluating reservoir stability. The interbedded formation of HBS is common in target mining reservoirs. Existing studies on the triaxial mechanical properties of HBS are primarily based on homogeneous and isotropic samples. Therefore, the stress–strain law of the target mining reservoirs cannot be predicted accurately. In this study, a series of sediment models with interlayers of coarse and fine mineral grains were established based on the PFC3D code, and the influence of the layered distribution characteristics of sediment particles and hydrates on the macroscopic mechanical behaviour of the reservoir was comprehensively analysed. The triaxial compression simulation results indicate that the peak strength, deformation modulus, and cohesion of the layered HBS are significantly lower than those of the homogeneous model. The deformation modulus of the reservoir is mainly affected by the fine-grained layer without hydrates. When the coarse and fine grains correspond to different mineral components, the two minerals are heterogeneous in terms of their micromechanical parameters, which can further reduce the macroscopic mechanical parameters of the HBS. In addition, the layered distribution of hydrate results in significant anisotropy of the reservoir. This study constitutes a reference regarding the control mechanism of gas hydrate reservoir strength.

Disconnected (disco)-interacting protein 2 homolog B (Dip2B) is a member of the Dip2 superfamily and plays an essential role in axonal outgrowth during embryogenesis. In adults, Dip2B is highly expressed in different brain regions, as shown by in situ analysis, and may have a role in axon guidance. However, the expression and biological role of Dip2B in other somatic tissues remain unknown. To better visualize Dip2B expression and to provide insight into the roles of Dip2B during postnatal development, we used a Dip2btm1a(wtsi)komp knock-in mouse model, in which a LacZ-Neo fusion protein is expressed under Dip2b promoter and allowed Dip2B expression to be analyzed by X-gal staining. qPCR analyses showed that Dip2b mRNA was expressed in a variety of somatic tissues, including lung and kidney, in addition to brain. LacZ staining indicated that Dip2B is broadly expressed in neuronal, reproductive, and vascular tissues as well as in the kidneys, heart, liver, and lungs. Moreover, neurons and epithelial cells showed rich staining. The broad and intense patterns of Dip2B expression in adult mice provide evidence of the distribution of Dip2B in multiple locations and, thereby, its implication in numerous physiological roles.

Soil and rock mixture (SRM) consists of high-strength rock blocks and small-grained soils, which depend seriously on the rock size and the heterogeneity of structure. Because of inhomogeneous cementation between rock blocks, complex granulometric composition, and random distribution of rock blocks, these SRMs usually cause problems. Investigation of the localized deformation is critical for successful engineering designs, engineering safety assessment. In this work, uniaxial compression testing on the SRM with a rock block percentage of 40% (mass ratio) is performed under real-time computed tomography (CT) combined with digital image correlation (DIC) technology. Based on radial strain fields and shear fields, heterogeneity of strain fields and rock block motion is analyzed quantitatively by semi-variance. The results show that rock block is the main factor controlling the shear band geometry distribution. A localization strain band usually occurs along the soil and rock interfaces. From the experimental results by the DIC method, the damage factor is presented to describe the damage evolution of the SRM under uniaxial compression. The method proposed in this study can be used to quantitatively analyze the deformation characteristics of the SRM sample.

Disco-interacting protein 2 homolog B (Dip2B) is a member of Dip2 family encoded by Dip2b gene. Dip2B has been reported to regulate murine epithelial KIT+ progenitor cell expansion and differentiation epigenetically via exosomal miRNA targeting during salivary gland organogenesis. However, its molecular functions, cellular activities and biological process remain unstudied. Here, we investigated the transcriptome of Dip2B-deficient mouse embryonic lung fibroblasts (MELFs) isolated from E14.5 embryos by RNA-Seq. Expression profiling identified 1369 and 1104 differentially expressed genes (DEGs) from Dip2b−/− and Dip2b+/− MELFs in comparisons to wild-type (Dip2b+/+). Functional clustering of DEGs revealed that many gene ontology terms belong to membrane activities such as ‘integral component of plasma membrane’, and ‘ion channel activity’, suggesting possible roles of Dip2B in membrane integrity and membrane function. KEGG pathway analysis revealed that multiple metabolic pathways are affected in Dip2b−/− and Dip2b+/− when compared to Dip2b+/+ MELFs. These include ‘protein digestion and absorption’, ‘pancreatic secretion’ and ‘steroid hormone synthesis pathway’. These results suggest that Dip2B may play important roles in metabolism. Molecular function analysis shows transcription factors including Hox-genes, bHLH-genes, and Forkhead-genes are significantly down-regulated in Dip2b−/− MELFs. These genes are critical in embryo development and cell differentiation. In addition, Dip2B-deficient MELFs demonstrated a reduction in cell proliferation and migration, and an increase in apoptosis. All results indicate that Dip2B plays multiple roles in cell proliferation, migration and apoptosis during embryogenesis and may participate in control of metabolism. This study provides valuable information for further understanding of the function and regulatory mechanisms of Dip2B.

Objectives To investigate the demographics and motivations of whole-body donors in China, and help suggest a solution to the problem of low body donation numbers.Design A cross-sectional study on body donors in China. Demographic analysis of the donating information of deceased donors and in-depth interviews of potential body donors.Setting Eleven districts in Nanjing, China.Participants Deceased whole-body donors who had donated their bodies to the body donation receiving station of Nanjing Medical University between 1 July 2009 and 30 June 2019 (n=835), and living registered whole-body donors (n=68).Results Among the whole-body donor population, the numbers of males, people older than 65 years and those working as teachers, government officials, medical staff and farmers were significantly higher than those of the general Nanjing population. Donors with an education level of college or above accounted for nearly half of the deceased donors, and considered donating their bodies earlier in their lives than others. Cancer and heart disease were the major causes of death among donors. Interviews of the 68 living donors revealed the following major motivations for the decision to donate: to support medical education; to reduce their children’s funeral burden; no longer holding traditional Chinese views on life and death; influence by role models and annoyance at complex funeral ceremonies.Conclusions Older people, people with an education level of college or above, labourers, teachers, government officials and farmers are the major groups that donate their bodies. Although people’s motivations for donation are complex, their desire to support medical education is the most prevalent motivation. By helping focus on target groups for promotional messaging and identifying their prime motivations, this study’s findings can provide a reference for promoting body donation in China.

Long-term stability of large-span caverns is a challenging issue for design and construction of underground rock engineering. The Heidong cavern group consisting of 21 caverns was constructed about 1400 years ago for quarrying in massive Cretaceous tuff. The cavern No. 5 of the Heidong cavern group is characterized by an unsupported span up to 92 m, with the overburden thickness of only 3–25 m. To analyze its long-term stability, a detailed investigation was conducted to obtain its geometry and rock mass characteristics, and to monitor surrounding rock displacements. Based on field survey and laboratory tests, numerical simulations were performed using the finite difference code FLAC3D. The analysis results revealed that for the long-term stability of the cavern No. 5, some major factors should be carefully considered, such as cavern excavation method in hard massive rocks, site investigation using trial pits, tools like short iron chisel and hammer for manual excavation, geometric dome roof, and waste rocks within abutment or on the floor. The highlights of the technologies obtained from this large-scale ancient underground project can provide reference for other similar project excavations in practice.

Hydraulic fracturing is a key technical means for stimulating tight and low permeability reservoirs to improve the production, which is widely employed in the development of unconventional energy resources, including shale gas, shale oil, gas hydrate, and dry hot rock. Although significant progress has been made in the simulation of fracturing a single well using two-dimensional Particle Flow Code (PFC2D), the understanding of the multi-well hydraulic fracturing characteristics is still limited. Exploring the mechanisms of fluid-driven fracture initiation, propagation and interaction under multi-well fracturing conditions is of great theoretical significance for creating complex fracture networks in the reservoir. In this study, a series of two-well fracturing simulations by a modified fluid-mechanical coupling algorithm were conducted to systematically investigate the effects of injection sequence and well spacing on breakdown pressure, fracture propagation and stress shadow. The results show that both injection sequence and well spacing make little difference on breakdown pressure but have huge impacts on fracture propagation pressure. Especially under hydrostatic pressure conditions, simultaneous injection and small well spacing increase the pore pressure between two injection wells and reduce the effective stress of rock to achieve lower fracture propagation pressure. The injection sequence can change the propagation direction of hydraulic fractures. When the in-situ stress is hydrostatic pressure, simultaneous injection compels the fractures to deflect and tend to propagate horizontally, which promotes the formation of complex fracture networks between two injection wells. When the maximum in-situ stress is in the horizontal direction, asynchronous injection is more conducive to the parallel propagation of multiple hydraulic fractures. Nevertheless, excessively small or large well spacing reduces the number of fracture branches in fracture networks. In addition, the stress shadow effect is found to be sensitive to both injection sequence and well spacing.

The design of core-shell structure is considered as a facile approach to obtain polymer composites with excellent dielectric properties and high breakdown strength (Eb). In this work, thiol-terminated poly(vinylidene fluoride) (PVDF-SH) and polystyrene (PS-SH) are synthesized by a two-step process. The as-prepared polymers are applied to modify BaTiO3 (BT) nanoparticles. The subsequent morphologies, dielectric properties, and Eb of PVDF-based composites are investigated systematically. PVDF encapsulated BT (PVDF@BT) fillers carries more desirable compatibility with matrix compared with PS encapsulated BT (PS@BT) and raw BT. For instance, the Eb of the 30 vol% PVDF@BT composites slightly decreased from 150.6 to 117 kV/mm for PVDF matrix, as compared to the raw and PS@BT composites, for those the values intensively reduced to 58.5 kV/mm and 107 kV/mm, respectively. It is also observed that PVDF polymer shells play a significant role in the improvement of composites dielectric constant (εr). Moreover, the design of the polymer shell also contributes to the suppression of dielectric loss. The results are of great importance for understanding the effect of polymer shells and fluorinated filler on composite properties. This study provides a strategy for preparing composites with high εr while maintaining high Eb for the next generation of dielectric capacitors. Keywords: Dielectric nanocomposites, PVDF shell, Breakdown strength, Dielectric constant

Disconnected interacting protein 2 homolog A (DIP2A) is highly expressed in nervous system and respiratory system of developing embryos. However, genes regulated by Dip2a in developing brain and lung have not been systematically studied. Transcriptome of brain and lung in embryonic 19.5 day (E19.5) were compared between wild type and Dip2a-/- mice. An average of 50 million reads per sample was mapped to the reference sequence. A total of 214 DEGs were detected in brain (82 up and 132 down) and 1900 DEGs in lung (1259 up and 641 down). GO enrichment analysis indicated that DEGs in both Brain and Lung were mainly enriched in biological processes 'DNA-templated transcription and Transcription from RNA polymerase II promoter', 'multicellular organism development', 'cell differentiation' and 'apoptotic process'. In addition, COG classification showed that both were mostly involved in 'Replication, Recombination, and Repair', 'Signal transduction and mechanism', 'Translation, Ribosomal structure and Biogenesis' and 'Transcription'. KEGG enrichment analysis showed that brain was mainly enriched in 'Thyroid cancer' pathway whereas lung in 'Complement and Coagulation Cascades' pathway. Transcription factor (TF) annotation analysis identified Zinc finger domain containing (ZF) proteins were mostly regulated in lung and brain. Interestingly, study identified genes Skor2, Gpr3711, Runx1, Erbb3, Frmd7, Fut10, Sox11, Hapln1, Tfap2c and Plxnb3 from brain that play important roles in neuronal cell maturation, differentiation, and survival; genes Hoxa5, Eya1, Errfi1, Sox11, Shh, Igf1, Ccbe1, Crh, Fgf9, Lama5, Pdgfra, Ptn, Rbp4 and Wnt7a from lung are important in lung development. Expression levels of the candidate genes were validated by qRT-PCR. Genome wide transcriptional analysis using wild type and Dip2a knockout mice in brain and lung at embryonic day 19.5 (E19.5) provided a genetic basis of molecular function of these genes.

[This corrects the article DOI: 10.1371/journal.pone.0213702.].

With the accelerated development of urbanization, waste disposal has become a tough problem. If waste cannot be disposed properly, it will lead to environment pollution and waste of resources. Since the energy utilization of the Waste Processing Base (WPB) has not been considered thoroughly, optimal planning of the Multi-Energy Circular System (MECS) coupled with the WPB is studied in this paper. Based on a typical WPB, this paper adds Power to Gas (P2G) and energy storage equipment, and applies a bi-level optimization model to optimize energy utilization. The minimum of total annual cost is the objective of the upper model, whose decision variables are the capacity of each equipment. The minimum annual operating cost is the lower model’s objective whose decision variables are the control parameters of certain energy equipment. Finally, a practical WPB is used for the demonstration and simulation of the proposed planning scheme. The analysis of the simulation results indicates that the collaborative optimization of the MECS coupled with WPB is effective, and improves the benefits of energy, economy, and environment enormously.

Rock is an aggregate of mineral grains, and the grain shape has an obvious influence on rock mechanical behaviors. Current research on grain shape mostly focuses on loose granular materials and lacks standardized quantitative methods. Based on the CLUMP method in the two-dimensional particle flow code (PFC2D), three different grain groups were generated: strip, triangle, and square. Flatness and roughness were adopted to describe the overall contour and the surface morphology of the mineral grains, respectively. Simulated results showed that the grain shape significantly affected rock porosity and further influenced the peak strength and elastic modulus. The peak strength and elastic modulus of the model with strip-shaped grains were the highest, followed by the models with triangular and square grains. The effects of flatness and roughness on rock peak strength were the opposite, and the peak strength had a significant, positive correlation with cohesion. Tensile cracking was dominant among the generated microcracks, and the percentage of tensile cracking was maximal in the model with square grains. At the postpeak stage, the interlocking between grains was enhanced along with the increased surface roughness, which led to a slower stress drop.

The seismic waves do not arrive with a vertical incidence for near-fault rock slopes, which highlights the importance of investigating the topographic effect under oblique incidence seismic waves. The equivalent nodal force method was employed to simulate seismic P waves with oblique incidence, by utilizing the finite difference method and viscoelastic artificial boundary. The accuracy of the method was verified by comparing it with the analytical solution of the free field in half-space, and the error is within 5%. Furthermore, the influence of slope heights, angles, and shapes on the dynamic response of rock slopes is analysed under the different incidence angles of seismic waves. The results show that the critical height of the rock slope varies with the incident angle, and the greater the incidence angle, the lower the critical height of the slope. The maximum value of the acceleration amplification coefficient is 8.5 in the slope shoulder when both the slope angle and incident angle are 75°. Additionally, the location of the strong acceleration response area of the concave and linear slopes is almost not affected by the incident angle, whereas the convex slopes move from the slope shoulder towards the convex position with increasing incident angle.

Mechanisms underlying the vein development remain largely unknown. Tie2 signaling mediates endothelial cell (EC) survival and vascular maturation and its activating mutations are linked to venous malformations. Here we show that vein formation are disrupted in mouse skin and mesentery when Tie2 signals are diminished by targeted deletion of Tek either ubiquitously or specifically in embryonic ECs. Postnatal Tie2 attenuation resulted in the degeneration of newly formed veins followed by the formation of haemangioma-like vascular tufts in retina and venous tortuosity. Mechanistically, Tie2 insufficiency compromised venous EC identity, as indicated by a significant decrease of COUP-TFII protein level, a key regulator in venogenesis. Consistently, angiopoietin-1 stimulation increased COUP-TFII in cultured ECs, while Tie2 knockdown or blockade of Tie2 downstream PI3K/Akt pathway reduced COUP-TFII which could be reverted by the proteasome inhibition. Together, our results imply that Tie2 is essential for venous specification and maintenance via Akt mediated stabilization of COUP-TFII.

A modified fluid-mechanically coupled algorithm in PFC2D was adopted in this article to study the influence of grain size heterogeneity and in-situ stress on hydraulic fracturing behavior. Simulated results showed that the in-situ stress and grain size heterogeneity significantly affect the initiation, growth, and spatial distribution of the hydraulic fractures: (1) the initiation and breakdown pressure are gradually reduced with the increase of the grain size heterogeneity; (2) with increased in-situ stress, the initiation and breakdown pressure increase, and the reduction effect of grain size heterogeneity on the breakdown pressure becomes more obvious; (3) in grain size homogeneous rock, the initiation pressure decreases with increasing in-situ stress ratio, however, the initiation pressure of grain size heterogeneous rock is almost unaffected by the in-situ stress ratio; (4) The in-situ stress ratio and grain size heterogeneity affect the spatial distribution of hydraulic fractures simultaneously. When the in-situ stress ratio is larger than 1, the hydraulic fractures propagate substantially along the direction of the maximum principal stress. When the in-situ stress ratio is 1, the initiation position and extension direction of hydraulic fractures are random and complex fracture networks can easily develop in a grain size homogeneous model.

Disconnected (disco)-interacting protein 2 homolog A is a member of the DIP2 protein family encoded by Dip2a gene. Dip2a expression pattern has never been systematically studied. Functions of Dip2a in embryonic development and adult are not known. To investigate Dip2a gene expression and function in embryo and adult, a Dip2a-LacZ mouse model was generated by insertion of β-Gal cDNA after Dip2a promoter using CRISPR/Cas9 technology. Dip2a-LacZ mouse was designed to be a lacZ reporter mouse as well as a Dip2a knockout mouse. Heterozygous mice were used to study endogenous Dip2a expression and homozygotes to study DIP2A-associated structure and function. LacZ staining indicated that Dip2a is broadly expressed in neuronal, reproductive and vascular tissues, as well as in heart, kidney, liver and lung. Results demonstrate that Dip2a is expressed in ectoderm-derived tissues in developing embryos. Adult tissues showed rich staining in neurons, mesenchymal, endothelial, smooth muscle cells and cardiomyocytes by cell types. The expression pattern highly overlaps with FSTL1 and supports previous report that DIP2A to be potential receptor of FSTL1 and its protective roles of cardiomyocytes. Broad and intense embryonic and adult expression of Dip2a has implied their multiple structural and physiological roles.

ZFN, TALENs and CRISPR/Cas9 system have been used to generate point mutations and large fragment deletions and insertions in genomic modifications. CRISPR/Cas9 system is the most flexible and fast developing technology that has been extensively used to make mutations in all kinds of organisms. However, the most mutations reported up to date are small insertions and deletions. In this report, CRISPR/Cas9 system was used to make large DNA fragment deletions and insertions, including entire Dip2a gene deletion, about 65kb in size, and β-galactosidase (lacZ) reporter gene insertion of larger than 5kb in mouse. About 11.8% (11/93) are positive for 65kb deletion from transfected and diluted ES clones. High targeting efficiencies in ES cells were also achieved with G418 selection, 46.2% (12/26) and 73.1% (19/26) for left and right arms respectively. Targeted large fragment deletion efficiency is about 21.4% of live pups or 6.0% of injected embryos. Targeted insertion of lacZ reporter with NEO cassette showed 27.1% (13/48) of targeting rate by ES cell transfection and 11.1% (2/18) by direct zygote injection. The procedures have bypassed in vitro transcription by directly co-injection of zygotes or co-transfection of embryonic stem cells with circular plasmid DNA. The methods are technically easy, time saving, and cost effective in generating mouse models and will certainly facilitate gene function studies.

Hydraulic fracturing technology is usually used to stimulate tight gas reservoirs for increasing gas production. The stimulated volume depends in part on the pre-existing natural fractures in a reservoir. The mechanisms influencing the interaction between hydraulic fractures and natural fractures have to be well understood in order to achieve a successful application of hydraulic fracturing. In this paper, hydraulic fracturing simulations were performed based on a two-dimensional Particle Flow Code with an embedded Smooth Joint Model to investigate the interactions between hydraulic fractures and natural fractures and compare these against laboratory experimental results and analytical models. Firstly, the ability of the Smooth Joint Model to mimic the natural rock joints was validated. Secondly, the interactions between generated hydraulic fractures and natural fractures were simulated. Lastly, the influence of angle of approach, in situ differential stress, and the permeability of natural fractures was studied. It is found that the model is capable of simulating the variety of interactions between hydraulic fractures and natural fractures such as Crossed type, Arrested type and Dilated type, and the modeling examples agree well with the experimental results. Under high approach angles and high differential stresses, the hydraulic fractures tend to cross pre-existing natural fractures. Under contrary conditions, a hydraulic fracture is more likely to propagate along the natural fracture and re-initiate at a weak point or the tip of the natural fracture. Moreover, these numerical results are in good agreement compared with Blanton’s criterion. The variety of permeability of natural fractures has a great effect on their interactions, which should not be overlooked in hydraulic fracturing studies.

In this work, a thermo-responsive and cross-linked fluoropolymer poly(2,2,2-Trifluoroethyl) methacrylate (PTFEMA) was successfully prepared by reversible addition-fragmentation chain transfer (RAFT) mediated aqueous polymerization with a thermo-responsive diblock poly(dimethylacrylamide-b-N-isopropylacrylamide) (PDMA-b-PNIPAM) that performed a dual function as both a nanoreactor and macro-RAFT agent. The cross-linked polymer particles proved to be in a spherical-like structure of about 50 nm in diameter and with a relatively narrow particle size distribution. 1H-NMR and 19F-NMR spectra showed that thermo-responsive diblock P(DMA-b-NIPAM) and cross-linked PTFEMA particles were successfully synthesized. Influence of the amount of ammonium persulfate (APS), the molar ratio of monomers to RAFT agent, influence of the amount of cross-linker on aqueous polymerization and thermo-responsive characterization of the particles are investigated. Monomer conversion increased from 44% to 94% with increasing the molar ratio of APS and P(DMA-b-NIPAM) from 1:9 to1:3. As the reaction proceeded, the particle size increased from 29 to 49 nm due to the consumption of TFEMA monomer. The size of cross-linked nanoparticles sharply decreased from 50.3 to 40.5 nm over the temperature range 14–44 °C, suggesting good temperature sensitivity for these nanoparticles.

Uterus development during pre-implantation stage affects implantation process and embryo growth. Aberrant uterus development is associated with many human reproductive diseases. Among the factors regulating uterus development, vascular remodeling promoters are critical for uterus function and fertility. Vascular endothelial growth factor (VEGF), as one of the major members, has been found to be important in endothelial cell growth and blood vessel development, as well as in non-endothelial cells. VEGF mediation in reproduction has been broadly studied, but VEGF-induced transcriptional machinery during implantation window has not been systematically studied. In this study, a genetically repressed VEGF mouse model was used to analyze uterus transcriptome at gestation 2.5 (G2.5) by Solexa/Illumina's digital gene expression (DGE) system. A number of 831 uterus-specific and 2398 VEGF-regulated genes were identified. Gene ontology (GO) analysis indicated that genes actively involved in uterus development were members of collagen biosynthesis, cell proliferation and cell apoptosis. Uterus-specific genes were enriched in activities of phosphatidyl inositol phosphate kinase, histone H3-K36 demethylation and protein acetylation. Among VEGF-regulated genes, up-regulated were associated with RNA polymerase III activity while down-regulated were strongly related with muscle development. Comparable numbers of antisense transcripts were identified. Expression levels of the antisense transcripts were found tightly correlated with their sense expression levels, an indication of possibly non-specific transcripts generated around the active promoters and enhancers. The antisense transcripts with exceptionally high or low expression levels and the antisense transcripts under VEGF regulation were also identified. These transcripts may be important candidates in regulation of uterus development. This study provides a global survey on genes and antisense transcripts regulated by VEGF in the pre-implantation stage. Results will contribute to further study the candidate genes and pathways in regulating implantation process and related diseases.

Hydraulic fracturing is a useful tool for enhancing rock mass permeability for shale gas development, enhanced geothermal systems, and geological carbon sequestration by the high-pressure injection of a fracturing fluid into tight reservoir rocks. Although significant advances have been made in hydraulic fracturing theory, experiments, and numerical modeling, when it comes to the complexity of geological conditions knowledge is still limited. Mechanisms of fluid injection-induced fracture initiation and propagation should be better understood to take full advantage of hydraulic fracturing. This paper presents the development and application of discrete particle modeling based on two-dimensional particle flow code (PFC2D). Firstly, it is shown that the modeled value of the breakdown pressure for the hydraulic fracturing process is approximately equal to analytically calculated values under varied in situ stress conditions. Furthermore, a series of simulations for hydraulic fracturing in competent rock was performed to examine the influence of the in situ stress ratio, fluid injection rate, and fluid viscosity on the borehole pressure history, the geometry of hydraulic fractures, and the pore-pressure field, respectively. It was found that the hydraulic fractures in an isotropic medium always propagate parallel to the orientation of the maximum principal stress. When a high fluid injection rate is used, higher breakdown pressure is needed for fracture propagation and complex geometries of fractures can develop. When a low viscosity fluid is used, fluid can more easily penetrate from the borehole into the surrounding rock, which causes a reduction of the effective stress and leads to a lower breakdown pressure. Moreover, the geometry of the fractures is not particularly sensitive to the fluid viscosity in the approximate isotropic model.

CD97 is over-expressed in the majority of gastric adenocarcinomas and is associated with its dedifferentiation and aggressiveness. Our previous results demonstrated that out of three CD97 isoforms tested, only the small one was able to promote increased invasiveness in vitro. Based on these data we further aimed to investigate the role of CD97 small isoform in gastric cancer progression in vivo by employing the cells with a stable CD97 small isoform knock-down and an orthotopic gastric cancer mouse model. We could demonstrate that the knock down of CD97/EGF1,2,5, led to a significant decrease in the number of cells penetrating the gelatin coated membrane as compared with control cells. In the gastric cancer mouse model, both the hypodermic and the orthotopic yielded tumor masses of the CD97/EGF1,2,5kd group and were significantly smaller than the control. Metastatic tumor cell number in early metastatic regional lymph nodes on post-operative day 42 was distinctly decreased in the CD97/EGF1,2,5kd group as compared with the SGC-NS group, and was accompanied with the downregulation of CD44, VEGFR, CD31 and CD97. We concluded in this study that CD97 small isoform not only supported gastric cancer local growth, but also promoted metastatic spread in orthotopically implanted mouse model suggesting involvement of the CD97 small isoform in the preparation of (pre)metastatic niche.