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Abstract Background and purpose In recent years, there has been extensive research on the role of exercise as an adjunctive therapy for cancer. However, the potential mechanisms underlying the anti-tumor therapy of exercise in lung cancer remain to be fully elucidated. As such, our study aims to confirm whether exercise-induced elevation of epinephrine can accelerate CD8+ T cell recruitment through modulation of chemokines and thus ultimately inhibit tumor progression. Method C57BL/6 mice were subcutaneously inoculated with Lewis lung cancer cells (LLCs) to establish a subcutaneous tumor model. The tumor mice were randomly divided into different groups to performed a moderate-intensity exercise program on a treadmill for 5 consecutive days a week, 45 min a day. The blood samples and tumor tissues were collected after exercise for IHC, RT-qPCR, ELISA and Western blot. In addition, another group of mice received daily epinephrine treatment for two weeks (0.05 mg/mL, 200 µL i.p.) (EPI, n = 8) to replicate the effects of exercise on tumors in vivo. Lewis lung cancer cells were treated with different concentrations of epinephrine (0, 5, 10, 20 µM) to detect the effect of epinephrine on chemokine levels via ELISA and RT-qPCR. Results This study reveals that both pre- and post-cancer exercise effectively impede the tumor progression. Exercise led to an increase in EPI levels and the infiltration of CD8+ T cell into the lung tumor. Exercise-induced elevation of EPI is involved in the regulation of Ccl5 and Cxcl10 levels further leading to enhanced CD8+ T cell infiltration and ultimately inhibiting tumor progression. Conclusion Exercise training enhance the anti-tumor immunity of lung cancer individuals. These findings will provide valuable insights for the future application of exercise therapy in clinical practice.

IntroductionGoose astrovirus (GAstV) is a newly emerging pathogen that is currently widespread among geese, causing visceral gout and leading to substantial gosling mortalities, posing a severe threat to the waterfowl industry. GAstV II is the predominant epidemic strain, characterized by its high morbidity and mortality rate. Consequently, there is an urgent necessity to develop an effective diagnostic approach to control the dissemination of GAstV II, particularly in clinical farms with limited laboratory resources.MethodsIn this study, a novel multi-enzyme isothermal rapid amplification (MIRA) and lateral flow dipstick (LFD) combined assay was developed. Different primers designed specific targeting a highly conserved region within the viral RdRp gene for the detection of GAstV II. Primers optimized and MIRA-LFD assay analyzed its performance regarding limits of detection, specificity, and efficiency of detection.ResultsThe developed MIRA amplification is conducted at a constant temperature and accomplished within 10 minutes. Subsequent naked-eye observation of the LFD strips merely takes 5 minutes. The established MIRA-LFD method exhibits high specificity, with no cross-reaction with other pathogens and attains a detection sensitivity of 1 copy/μl, which is consistent with the reverse transcription quantitative PCR (RT-qPCR) assay. Further evaluation with clinical samples indicates that the accuracy of this MIRA-LFD method correlates well with RT-qPCR for the detection of GAstV II. ConclusionIn summary, the convenience, sensitivity, and rapidity of this newly developed detection method offer a significant advantage for on-site diagnosis of GAstV II.

Abstract The cGAS-STING pathway plays a crucial role in anti-tumoral responses by activating inflammation and reprogramming the tumour microenvironment. Upon activation, STING traffics from the endoplasmic reticulum (ER) to Golgi, allowing signalling complex assembly and induction of interferon and inflammatory cytokines. Here we report that cGAMP stimulation leads to a transient decline in ER cholesterol levels, mediated by Sterol O-Acyltransferase 1-dependent cholesterol esterification. This facilitates ER membrane curvature and STING trafficking to Golgi. Notably, we identify two cholesterol-binding motifs in STING and confirm their contribution to ER-retention of STING. Consequently, depletion of intracellular cholesterol levels enhances STING pathway activation upon cGAMP stimulation. In a preclinical tumour model, intratumorally administered cholesterol depletion therapy potentiated STING-dependent anti-tumoral responses, which, in combination with anti-PD-1 antibodies, promoted tumour remission. Collectively, we demonstrate that ER cholesterol sets a threshold for STING signalling through cholesterol-binding motifs in STING and we propose that this could be exploited for cancer immunotherapy.

Abstract DNA is a danger signal sensed by cGAS to engage signaling through STING to activate innate immune functions. The best-studied downstream responses to STING activation include expression of type I interferon and inflammatory genes, but STING also activates other pathways, including apoptosis. Here, we report that STING-dependent induction of apoptosis in macrophages occurs through the intrinsic mitochondrial pathway and is mediated via IRF3 but acts independently of gene transcription. By intersecting four mass spectrometry datasets, we identify SAM68 as crucial for the induction of apoptosis downstream of STING activation. SAM68 is essential for the full activation of apoptosis. Still, it is not required for STING-mediated activation of IFN expression or activation of NF-κB. Mechanistic studies reveal that protein trafficking is required and involves SAM68 recruitment to STING upon activation, with the two proteins associating at the Golgi or a post-Golgi compartment. Collectively, our work identifies SAM68 as a STING-interacting protein enabling induction of apoptosis through this DNA-activated innate immune pathway.

BackgroundThe present study aimed to investigate the drug–drug interaction and initial dosage optimization of aripiprazole in patients with schizophrenia based on population pharmacokinetics.Research design and methodsA total of 119 patients with schizophrenia treated with aripiprazole were included to build an aripiprazole population pharmacokinetic model using nonlinear mixed effects.ResultsThe weight and concomitant medication of fluoxetine influenced aripiprazole clearance. Under the same weight, the aripiprazole clearance rates were 0.714:1 in patients with or without fluoxetine, respectively. In addition, without fluoxetine, for the once-daily aripiprazole regimen, dosages of 0.3 and 0.2 mg kg−1 day−1 were recommended for patients with schizophrenia weighing 40–95 and 95–120 kg, respectively, while for the twice-daily aripiprazole regimen, 0.3 mg kg−1 day−1 was recommended for those weighing 40–120 kg. With fluoxetine, for the once-daily aripiprazole regimen, a dosage of 0.2 mg kg−1 day−1 was recommended for patients with schizophrenia weighing 40–120 kg, while for the twice-daily aripiprazole regimen, 0.3 and 0.2 mg kg−1 day−1 were recommended for those weighing 40–60 and 60–120 kg, respectively.ConclusionThis is the first investigation of the effects of fluoxetine on aripiprazole via drug–drug interaction. The optimal aripiprazole initial dosage is recommended in patients with schizophrenia.

Broken coal and rock (BCR) are an important component medium of the caving zone in the goaf (or gob), as well as the main filling material of fault fracture zone and collapse column. The compaction seepage characteristics of BCR directly affect the safe and efficient mining of coal mines. Thus, numerous laboratory studies have focused on the compaction seepage characteristics of BCR. This paper first outlines the engineering problems involved in the BCR during coal mining including the air leakage, the spontaneous combustion, the gas drainage, and the underground reservoirs in the goaf. Water inrush related to tectonics such as faults and collapse columns and surface subsidence related to coal gangue filling and mining also involve the compaction seepage characteristics of BCR. Based on the field problems of BCR, many attempts have been made to mimic field environments in laboratory tests. The experimental equipment (cavity size and shape, acoustic emission, CT, etc.) and experimental design for the BCR were firstly reviewed. The main objects of laboratory analysis can be divided into compression tests and seepage test. During the compaction test, the main research focuses on the bearing deformation characteristics (stress-strain curve), pore evolution characteristics, and re-crushing characteristics of BCR. The seepage test mainly uses gas or water as the main medium to study the evolution characteristics of permeability under different compaction stress conditions. In the laboratory tests, factors such as the type of coal and rock mass, particle size, particle shape, water pressure, temperature, and stress path are usually considered. The lateral compression test of BCR can be divided into three stages, including the self-adjustment stage, the broken stage, and the elastic stage or stable stage. At each stage, stress, deformation, porosity, energy, particle size and breakage rate all have their own characteristics. Seepage test regarding the water permeability experiment of BCR is actually belong to variable mass seepage. While the experimental test still focuses on the influence of stress on the pore structure of BCR in terms of gas permeability. Finally, future laboratory tests focus on the BCR related coal mining including scaling up, long term loading and water immersion, mining stress path matching were discussed.

Layered composite roofs are characterized by developed bedding fissures, resulting in severe deformation and damage of rock bolts at the top of the roadway, as well as a poor roadway support effect. Increasing pretension force is an effective way to enhance the stiffness of the rock bolt support system. To clarify the influence and mechanism of the pretension force on the support effect of rock bolts in the layered roof, a roadway model of the layered roof was established using the interface unit of FLAC3D, and the simulation rock bolts were constructed using the pile unit, which can simulate the mechanical behaviors of rock bolts, such as tension, shear, bending, fracture, and anchor failure, and the pretension force was applied. On this basis, the deformation and failure characteristics and influencing factors of rock bolts in the layered roadway roof under different surrounding rock conditions were simulated and analyzed. The research shows the following: ① Field measurements showed minor shear deformation in the rock bolts at the center of the roadway roof, with lateral displacements of 5.7 cm and 5.3 cm. Significant shear deformation occurred in the rock bolts at the roof corners, with lateral displacements of 18.2 cm and 17.6 cm. ② Simulations of rock bolt deformation characteristics matched the field measurements closely, confirming the reliability of the simulation method, parameter selection, and calculation sequence. ③ The primary factors affecting rock bolt deformation are the structural plane strength and surrounding rock strength. Rock bolts are most susceptible to lateral displacement when the structural plane strength is low, the strength difference between rock layers is large, and the weaker layer is below the structural plane. The presented research can provide a reference for the instability mechanism and support treatment of the layered composite roof roadway.

BackgroundThe appropriate initial dosage of tacrolimus is undefined in Chinese pediatric lung transplant patients with normal hematocrit values. The purpose of this study is to optimize the initial dose of tacrolimus in Chinese children who are undergoing lung transplantation and have normal hematocrit levels.MethodsThe present study is based on a published population pharmacokinetic model of tacrolimus in lung transplant patients and uses the Monte Carlo simulation to optimize the initial tacrolimus dosage in Chinese children with lung transplantation within normal hematocrit levels.ResultsWithin normal hematocrit levels, for children with lung transplantation who do not carry the CYP3A5*1 gene and have no coadministration with voriconazole, it is recommended to administer tacrolimus at a dosage of 0.02 mg/kg/day, divided into two doses, for children weighing 10–32 kg, and a dosage of 0.03 mg/kg/day, also divided into two doses, for children weighing 32–40 kg. For children with lung transplantation who carry the CYP3A5*1 gene and have no coadministration with voriconazole, tacrolimus dosages of 0.02, 0.03, and 0.04 mg/kg/day split into two doses are recommended for children weighing 10–15, 15–32, and 32–40 kg, respectively. For children with lung transplantation who do not carry the CYP3A5*1 gene and have coadministration with voriconazole, tacrolimus dosages of 0.01 and 0.02 mg/kg/day split into two doses are recommended for children weighing 10–17 and 17–40 kg, respectively. For children with lung transplantation who carry the CYP3A5*1 gene and have coadministration with voriconazole, a tacrolimus dosage of 0.02 mg/kg/day split into two doses is recommended for children weighing 10–40 kg.ConclusionsIt is the first time to optimize the initial dosage of tacrolimus in Chinese children undergoing lung transplantation within normal hematocrit.

Highlights (1) This paper reviews the water weakening on rock strength and its influencing factors. (2) Various microscopic methods for studying the pore characterization and weakening mechanism of WRI are compared and analyzed. (3) We study the weakening mechanism of WRIs using microscopic methods. (4) Future works on WRI laboratory tests were suggested.

Abstract With annually increased coal mining depth, gas extraction becomes more and more problematic. The gas extraction effect depends on coal seam permeability, which, in turn, is affected by many factors, including loading and unloading stresses and strains in the coal seam. Stresses induce internal cracks, resulting in cleats and gas emission channels, the coal seam permeability permanently changes accordingly. To clarify the stress-induced effects on coal seam permeability, this survey summarized the available approaches used to link the stress path and seepage law in the coal body seepage law, which can be classified into two design methods: single load variation and combined field mining method. The characterization methods used to observe the surface of coal samples and three-dimensional reconstruction include electron microscopy, CT scanning, and Nuclear Magnetic Resonance (NMR). According to the stress paths designed by the above two approaches, the seepage laws and similarities of three kinds of coal samples with the fractured structure were summarized in this paper. The following directions are recommended to study the seepage law of coal bodies with three kinds of fractured structures under stress. Firstly, the stress path of the experimental coal body should be designed by the combined field mining method. The stressed environment of a deep coal seam is complicated, and the axial and confining pressures change simultaneously. Therefore, one cannot fully reflect the real situation on-site by studying permeability evolution alone. Secondly, during the coal seam mining, the stressed state changes from time to time, and the development of coal seam fractures is affected by mining. When studying the stress effect on seepage of coal samples, the fractured structure of coal samples should be considered. Finally, the available structural characterization methods of coal samples can be combined with the 3D printing technology, which would produce artificial samples with the fractured structure characteristics of natural coal.

Abstract Background Long non-coding RNAs (lncRNAs) are closely related to the occurrence and development of cancer. Abnormally expressed lncRNA can be used as a diagnostic marker for cancer. In this study, we aim to investigate the clinical significance of MIR99AHG expression in lung adenocarcinoma (LUAD), and its biological roles in LUAD progression. Methods The relative expression of MIR99AHG in LUAD tissues and cell lines was analyzed using public databases and RT-qPCR. The biological functions of MIR99AHG were investigated using a loss-of-function approach. The effect of MIR99AHG on lung fibrosis was assessed by scratch assay, invasion assay and lung fibrosis rat model. FISH, luciferase reporter assay and immunofluorescence were performed to elucidate the underlying molecular mechanisms. Results LncRNA MIR99AHG expression level was downregulated in LUAD tissues and cell lines. Low MIR99AHG levels were associated with poorer patient overall survival. Functional analysis showed that MIR99AHG is associated with the LUAD malignant phenotype in vitro and in vivo. Further mechanistic studies showed that, MIR99AHG functions as a competitive endogenous RNA (ceRNA) to antagonize miR-136-5p-mediated ubiquitin specific protease 4 (USP4) degradation, thereby unregulated the expression of angiotensin-converting enzyme 2 (ACE2), a downstream target gene of USP4, which in turn affected alveolar type II epithelial cell fibrosis and epithelial–mesenchymal transition (EMT). In summary, the MIR99AHG/miR-136-5p/USP4/ACE2 signalling axis regulates lung fibrosis and EMT, thus inhibiting LUAD progression. Conclusion This study showed that downregulated MIR99AHG leads to the development of pulmonary fibrosis. Therefore, overexpression of MIR99AHG may provide a new approach to preventing LUAD progression.

Abstract Characterizing the permeability evolution and methane release is of great significance for the safe mining of the high gas outburst seams, as well as coal and gas simultaneous extraction. It contributes to reduce methane emissions from coal mining for greenhouse effect control. Theoretical analysis, laboratory testing, and numerical simulation are widely used methods to characterize the permeability and methane release with the treatment process of pressure-relief mining. However, these methods cannot fully reflect the complexity of filed practice. In this study, we report the effectiveness of protective coal seam (PCS) mining and the pressure-relief area in the protected coal seam (PDCS) based on detailed and integrated field measurements in a Chinese coal mine. To the best of our knowledge, it is the first time to measure the permeability coefficient and gas pressure evolution in the PDCS during the process of PCS longwall mining. The evolution of the permeability coefficient in the pressure-relief area during PCS mining can be divided into four stages: slowly decreasing, sharply increasing, gradually decreasing, and basically stable. The maximum permeability coefficient is 322 times of the initial value and stabilized at 100 times after the goaf compacted. The gas pressure evolution in the PDCS indicates that the strike pressure relief angle is 52.2° at the active longwall face zone, and 59.3° at the installation roadway side. The inclined pressure relief angles at the lower and upper sides of the longwall face are 75° and 78.9°, respectively. The residual gas content and gas pressure of the PDCS in the pressure-relief area are reduced to less than 6 m3/t and within 0.4 MPa, respectively. The field measurements further prove that pressure-relief mining can prevent coal and gas outbursts in PDCSs. The field observations in this paper can serve as benchmark evidence for theoretical analysis and numerical simulations, and also provide insights into realizing safety mining in similar conditions.

Abstract This study presents an example illustrating the role of in situ 3D stress path method in simulating the roof damage development observed in the Mine-by tunnel at Underground Research Laboratory (URL) located in Manitoba, Canada. The 3D stress path, at the point 1 cm in the crown of the Mine-by tunnel, was applied to a cubic Lac du Bonnet (LdB) granite sample to further understand the roof damage process and the associated seismicity. After careful calibrations, a numerical model was used to reproduce the experiment, which produced similar seismicity processes and source mechanisms. Acoustic emission (AE) events obtained from laboratory and numerical modeling were converted to locations in relation to the tunnel face and were compared to the field microseismicity (MS) occurring in the upper notch region of the Mine-by tunnel. The crack development and damage mechanism are carefully illustrated. The difference between tests and field monitoring was discussed. The intermediate principal stress (σ 2) unloading process was carried out in numerical simulation to investigate its role in rock damage development. The results clearly showed σ 2 could play a significant role both in damage development and failure mode. It should be considered when predicting the damage region in underground excavations. This study highlights the potential role of laboratory and numerical stress path tests to investigate fracture processes and mechanisms occurring during engineering activities such as tunnel excavation.

The longitudinal dynamic response of a large-diameter-bored pile is investigated considering the bottom sediment and the radial unloading of the surrounding soil. First, the sediment between the pile tip and the bedrock is treated as a fictitious soil pile with a cross-sectional area similarto that of the pile tip. The large-diameter-bored pile (including the fictitious soil pile) is considered as a Rayleigh–Love rod and is divided into finite segments. Under theseconditions, the three-dimensional (3D) effect of the wave propagation along the pile is indirectly simulated by considering the transverse inertia of the pile to avoid complicated calculations. Meanwhile, the surrounding soil is divided into finite annular zones in the radial direction, with the soil properties varying radially as well to simulate the radial unloading of the surrounding soil during construction. The governing equation for each soil zone is built and solved, from zone to zone, to obtain the shear stress acting on the pile. Then, the governing equation for the fictitious soil pile (i.e., the sediment) is solved to derive the dynamic action at the pile tip. In a similar manner to that ofthe fictitious soil pile and together with the recursion method, the governing equation for the pile is solved to obtain the pile’s complex impedance and velocity response. The proposed solution is verified and then introduced to portray the coupling effect of the sediment, pile parameters and radial unloading of the surrounding soil on the longitudinal dynamic response of the large-diameter-bored pile.

Pyrite is widely distributed in the Earth’s crust and oceanic systems, and it generally occurs as pentagonal dodecahedra, cubic, octahedral, idiomorphic crystals, or dense, massive, granular, and nodular aggregates. In this study, representative pyrite samples from Hunan, Fujian, Jiangxi, Anhui in China and from Peru were collected. By utilizing a range of analytical techniques, including petrography, X-ray diffraction, infrared spectrum, Raman spectrum, major and trace element analysis, as well as sulfur stable isotope analysis, we comprehensively depict the mineralogical and spectroscopic characteristics of pyrite, and the evolution processes of the physical and chemical conditions of mineralization can be qualitatively constrained. The spectroscopic results indicate all samples show a relatively narrow absorption band with weak to moderate intensity in the vicinity of 343 cm−1, which represents the bending vibration of the Fe-[S2]2− molecular bond. The Co content of pyrite exhibits the characteristics of a positive correlation with temperature and a negative correlation with oxygen fugacity, respectively. The δ34S isotopic compositions of colloidal pyrite are in the range of 0.03 to 0.67, which are close to meteoric sulfur and mantle sulfur compositions, while the δ34S values of nodular pyrite fall within the range of granite, indicating the characteristics of mixtures of sulfur sources are mainly related to magmatic activity. Our results provide insight into the formation mechanisms of pyrite in different environments, its mineralization, and the ore genesis of deposits. Moreover, the integrated analytical methods for pyrite are provided, which can define theoretical guidance for the exploration and development of mineral resources.

Graphite usually occurs in mineral/rock associations in the form of solid inclusions and plays an important role in tracing regional metamorphic degree, ore-forming temperature, fluid evolution, as well as the deep carbon cycle of the Earth. In this study, we investigate the placer black nephrite jade where the co-occurrence of abundant graphite inclusions and jade remains extraordinary. By employing petrographic, mineral-chemical, and Raman spectroscopic methods, we characterize the textures and crystallinity of graphite inclusions that exist in nephrite jade. EPMA and petrological data indicate that the main constituents of black jade are tremolite and graphite, with minor phases of diopside, calcite, dolomite, epidote, and apatite. Micro-Raman spectroscopic thermometry of carbonaceous material shows that most of the formation temperatures of graphite inclusions are between 378 and 556 °C, and only a few temperatures may be above 650 °C, indicating that graphite inclusions were formed at medium- to high-temperature metamorphic facies. The petrologic and spectral investigations of graphite inclusions in these nephrite jade samples show major metamorphic signatures with mixed features associated with fluid precipitation. Our results allow us to propose that primary nephrite jade was formed under multi-stage tectonic evolution conditions, and regional temperatures were predominately driven by the late continent–continent collision, while the ore-controlling temperatures of nephrite jade formation were found in a medium- to high-temperature environment.

The jadeite jade in Guatemala exerts remarkable commercial quality, which has attracted wide attention. Guatemalan jadeite jade displays a rich variety of colors; however, the color formation of this jadeite jade has not been systematically investigated to date. In this paper, we study different colors of jade samples to trace the compositions and color-causing mechanisms through petrography, X-ray fluorescence spectroscopy (XRF), Fourier transform infrared spectroscopy (FTIR), laser Raman spectroscopy (LRS), and UV-visible absorption spectroscopy (UV-Vis), as well as electron probe microanalysis (EPMA). The results show that jadeite and omphacite are the main mineral compositions of Guatemalan jadeite jade, together with minor albite and other impurities. The color of Guatemala jadeite jade is mainly related to Cr3+, Fe2+, and Fe3+, of which a small amount of Cr3+ causes the jadeite jade to be emerald green. Moreover, 1~2% FeO contents can lead to the blue or gray color of the samples, while the Fe3+ makes the sample dark green. The green color of some Cr3+-free jadeite is caused by the electron transition between bands of Fe3+, and the green color is related to the iron content. Moreover, the chemical composition analysis shows that some metallic elements existed in Guatemalan jadeite jade, such as Ca, Ti, Al, Si, Ni, Fe, Mn, Cr, Na, Mg, and Sr, and some trace elements were lost or unevenly distributed, which may lead to the heterogeneity of the color of the samples. Our present investigation provides insights into color discrimination, quality evaluation, and identification of Guatemala jadeite jade.

Abstract Cancer has intensively threatened the health and life of human beings across the world. Drug delivery systems (DDSs) can protect the packaged cargoes from degradation; effectively delivery cargoes to specific tissues. Most DDSs are based on functional nanomaterials. As natural nanomaterials, exosomes are secreting by mammalian cells through the multivesicle bodies route. Usually, exosomes possess uniform size ranging from 50 to 150 nm, their membrane surface has many functional proteins and cavity contains RNA, DNA similar to maternal cells. Owing to the high biocompatibility, excellent penetration capability as well as ease to be engineered, exosomes have shown outstanding potentials in delivering therapeutic molecules for cancer diagnosis and treatment. This review summarizes the unique characteristics which makes exosomes promising nanocarrier for cancer treatment. The future developments of exosomes based biomedical applications towards cancer are also outlined. We expect the review will help readers understand the potential value of exosomes based nanocarrier, and also try to elaborate their promising applications.

Abstract In the process of pressure‐relief mining in high gas coal seams and hydraulic fracturing of deep coalbed methane, a large number of irregular fractures are generated inside the coal, which becomes the main path for gas migration. The stress sensitivity of fractures directly affects the gas migration characteristics in the coal. For better matching stress‐permeability test results, a fluid–solid coupling simulation method with the joint stiffness changing method (JSCM), which accommodates fracture (or joint) stiffness through the stress acting on the fracture, is proposed. The stress sensitivity of permeability under different stress states was matched in a simulation and compared with a laboratory experiment. This method has the following advantages compared with the traditional joint stiffness fixing method (JSFM). (1) The JSCM does not need to set the residual joint aperture, which can match a wider range of stresses, so there is no upper limit in principle. (2) The JSCM can match the laboratory test results better than the JSFM. A parameter‐determining method for the JSCM is given for the flow test results. Based on the JSCM, the flow in an irregular fracture under different confining and axial stresses was determined. The results show that the occurrence of segmental fractures with different dip angles in persistent fractures determines the stress sensitivity of the fracture flow. With the increase in axial stress, the fracture aperture of the horizontal section is reduced, causing the decrease in horizontal section seepage capacity. It determines the whole flow of the persistent fracture. While with the increase in confining stress, the fracture aperture of vertical section is greatly reduced and causing flow rate of the whole fracture reducing greatly.

The nephrite jade deposits of different tectonic units in China exert significant commercial quality, which have attracted wide attention. However, these deposits have not been systematically summarized to date. Here, we investigate the major nephrite jade deposits in China to decipher their gemological and mineralogical characteristics, spatial-temporal distribution, and mineralization processes as well as to identify their geological settings and gemological properties, via integrating published geochronology, major and trace elements as well as H-O isotopes. The compiled data suggest that the major nephrite jade deposits in China can also be generally divided into green jade-type (GJ-type) and white jade-type (WJ-type) which covers different species, but most of them belong to the latter. The GJ-type nephrite deposits predominantly occur in ophiolite/ophiolitic mélange suites or are embedded into ultramafic serpentine jade orebodies. This type of nephrite jade mainly formed through the late auto-metamorphic metasomatism of serpentine or the spontaneous crystallization/precipitation along suture/shear zones that acted as pathways to migrate Ca-rich fluids during orogeny. In contrast, the orebodies of WJ-type nephrite jade are usually hosted at the contact zones between the dolomitic marbles and intermediate-felsic or mafic intrusive rocks, which were produced through metamorphism-metasomatism during post continent-continent collision, such as the Kunlun orogenic belt with about ∼1,300 km Hetian nephrite belt, and the eastern nephrite jade deposits along the Pacific Ocean. Our study highlights that the nephrite jade deposits in China originally formed during multiple tectonic stages related to the interactions between hydrothermal fluids and metamorphism under subduction accretion- and collision orogenesis-related settings. In addition, this study also provides insights into the genetic discrimination, mineral exploration, and occurrence characteristics of nephrite jade deposits as well as the evaluation and identification of nephrite jade quality.

Dapagliflozin has been used to treat patients with type 1 diabetes mellitus; however, the actual drug efficacy of dapagliflozin on glycated hemoglobin (HbA1c) and whether there is a rebound from dapagliflozin efficacy on HbA1c remain unknown. The present study aimed to explore the actual therapeutic effect and rebound situation of dapagliflozin on HbA1c in type 1 diabetes mellitus patients. A total of 1,594 type 1 diabetes mellitus patients were enrolled for analysis using a non-linear mixed effect model from randomized controlled trials from published literature works including two 5 mg/day dapagliflozin dosage groups and three 10 mg/day dapagliflozin dosage groups. The change rate of HbA1c from a baseline value was chosen as a dapagliflozin pharmacodynamic evaluation index. After deducting control group effects, the therapeutic effect of 5 and 10 mg/day dapagliflozin on HbA1c in type 1 diabetes mellitus patients had no significant difference. In addition, the actual maximal efficacy (AEmax) of dapagliflozin on HbA1c was -6.24% at week 9. When it reached the AEmax, the dapagliflozin pharmacodynamic rebound on HbA1c occurred, and when the treatment was continued for 0.5 and 1 year, the actual efficacies were -4.70% (75% AEmax) and -3.27% (52% AEmax), respectively. This was the first time to clarify the actual therapeutic effect and rebound situation of dapagliflozin on HbA1c in type 1 diabetes mellitus patients, providing a reference value for clinical practices.

Ground fissures are generated during the coal mining process due to overlying strata migration, which provides gas and water seepage channels and usually contributes to coal mining accidents in shallow buried coal seams with larger mining height working faces. Thus, the evolution features of ground fissures in large mining height working faces and shallow buried coal seams were explored by considering field observation data, similar simulation, and numerical simulations. The results show that the weathered rock layer above the thin bedrock inhibits fracture growth caused by coal mining. Overlying strata fracture expansion can be quantitatively divided into three stages based on fractal dimension: the overburden fracture formation stage, the overburden deformation fracture expansion stage, and the overburden fracture stable development stage. The movement deformation region of the ground fissure can be described by three characteristic zones: the boundary tension zone, the central compression zone, and the central dynamic tension and compression zone. Central dynamic fissures usually have 3–5 fissure counts with 2–5 m intervals between each group of fissures; central fissures develop twice from open to closed widths; the time period for two central fissures to reach their with maximum widths is 11–20 days; and border fissures expand rapidly with maximum values in a time period of 5–6 days.

ABSTRACT The novel duck reovirus (NDRV) is an emerging pathogen that causes disease in various waterfowl species. Since the outbreak, it has caused huge economic losses to the duck industry in China. A rapid, reliable, and high-throughput method is required for epidemiological investigation and evaluation of vaccine immunogenicity. A good first step would be establishing an enzyme-linked immunosorbent assay (ELISA) that could detect NDRV antibodies in different breeds of ducks and geese from the serum and egg yolk. This study used a recombinant NDRV σB protein and a corresponding horseradish peroxidase (HRP)-labeled monoclonal antibody to develop a blocking ELISA (B-ELISA). The cutoff value of the B-ELISA was 37.01%. A total of 212 serum samples were tested by the B-ELISA, and the virus neutralization test (VNT) was the gold standard test. The sensitivity and specificity of the B-ELISA were 92.17% (106/115) and 97.94% (95/97), respectively. The agreement rates between the B-ELISA and VNT were 94.81% (kappa value, 0.896). The B-ELISA could specifically recognize anti-NDRV sera without cross-reacting with other positive serums for other major diseases in ducks and geese. The inter- and intra-assay coefficients of variation (CVs) of the B-ELISA and VNT assays were acceptable. In conclusion, the novel B-ELISA could be a rapid, simple, safe, and economically attractive alternative to the VNT in assessing duck flocks’ immunity status and in epidemiological surveillance in multiple waterfowl species. IMPORTANCE NDRV disease is a new epidemic disease in waterfowl that first appeared in China. Compared with the classical DRV (CDRV), NDRV is associated with more severe symptoms, a higher mortality rate, and a broader host range. NDRV has become the prevalent genotype in China. At present, there are no commercially available diagnostic products for the NDRV disease. VNT, as the gold standard serologic test, is not only time-consuming and laborious, but also has high requirements for facilities and equipment, which is not suitable for clinical application. Conventional ELISA requires specific antispecies conjugates that are not currently available. B-ELISA not only has the advantage of higher analysis specificity, but also can be used to test specific antibodies against different waterfowl species, because no species-specific conjugates are required in such detection. Therefore, it is necessary to establish a B-ELISA for the detection of antibodies against NDRV in waterfowl species.

Body-protective compound (BPC) 157 demonstrates protective effects against damage to various organs and tissues. For future clinical applications, we had previously established a solid-phase synthesis process for BPC157, verified its biological activity in different wound models, and completed preclinical safety evaluations. This study aimed to investigate the pharmacokinetics, excretion, metabolism, and distribution profiles of BPC157. After a single intravenous (IV) administration, single intramuscular (IM) administrations at three doses in successive increments along with repeated IM administrations, the elimination half-life (t1/2) of prototype BPC157 was less than 30 min, and BPC157 showed linear pharmacokinetic characteristics in rats and beagle dogs at all doses. The mean absolute bioavailability of BPC157 following IM injection was approximately 14%–19% in rats and 45%–51% in beagle dogs. Using [3H]-labeled BPC157 and radioactivity examination, we proved that the main excretory pathways of BPC157 involved urine and bile. [3H]BPC157 was rapidly metabolized into a variety of small peptide fragments in vivo, thus forming single amino acids that entered normal amino acid metabolism and excretion pathways. In conclusion, this study provides the first analysis of the pharmacokinetics of BPC157, which will be helpful for its translation in the clinic.

The aim of the present study is to investigate the quantitative effects of sodium–glucose cotransporter-2 (SGLT-2) inhibitors on the quality of life in heart failure (HF) patients. A total of 14,674 HF patients from two dapagliflozin and three empagliflozin studies is included for analysis via the nonlinear mixed-effect modeling (NONMEM) software, among which the change rate of the Kansas City Cardiomyopathy Questionnaire (KCCQ) score is used as the evaluation index. There is no significant difference in the pharmacodynamics influencing the quality of life in HF patients between the SGLT-2 inhibitors: 10 mg/day dapagliflozin and 10 mg/day empagliflozin. For the clinical summary score (CSS), total symptom score (TSS), and overall summary score (OSS), the Emax of the SGLT-2 inhibitors on the quality of life in HF patients is 3.74%, 4.43%, and 4.84%, respectively, and ET50 is 2.23, 4.37, and 7.15 weeks, respectively. In addition, the time duration of achieving 25%, 50%, 75%, and 80% Emax is 0.75, 2.23, 6.69, and 8.92 weeks for the CSS; 1.46, 4.37, 13.11, and 17.48 weeks for the TSS; and 2.39, 7.15, 21.45, and 28.6 weeks for the OSS, respectively. Therefore, to reach the plateau period (80% of Emax) of SGLT-2 inhibitors on the CSS, TSS, and OSS, 10 mg/day dapagliflozin (or 10 mg/day empagliflozin) is required to be taken for 8.92 weeks, 17.48 weeks, and 28.6 weeks, respectively. This is the first time that the quantitative effects of SGLT-2 inhibitors on the quality of life in HF patients are being explored.

The macroscopic failure of concrete used to form an artificial dam in an underground coal mine reservoir is the final manifestation of crack propagation and penetration: the mode of crack propagation is key to the safety evaluation of concrete structures. To improve the performance of concrete in such an artificial dam forming an underground coal mine reservoir, many scholars have investigated nano-modified concrete, but the effects of nanomaterials on the crack propagation mode and failure mode of saturated concrete are not yet fully understood. In the present research, uniaxial compression and acoustic emission (AE) experiments were conducted on saturated concrete specimens containing different types and amounts of nanomaterials, and the crack propagation mode, failure mode, and bearing capacity of different saturated concrete specimens were compared and studied. The results show that: the failure mode, crack propagation mode, and bearing capacity of saturated concrete can be modified by adding nanomaterials, and the type and content thereof can affect the modification effect provided. Considering the strength, bearing capacity, and crack-propagation mode, saturated concrete specimens containing 3 wt% nano-Al 2 O 3 exhibit the best performance, with characteristics of high strength, high bearing capacity, steady crack propagation, and small-scale cracking. The results have guiding significance for damage-warning and safety assessment of hydraulic structures.

Subcortical ischemic vascular disease (SIVD) is one of the important causes of cognitive dysfunction, altered amyloid-beta (Aβ) and cerebral perfusion may be involved in the pathophysiological mechanism of SIVD and are closely related to cognitive function. We aimed to investigate altered serum Aβ and cerebral perfusion in patients with SIVD and their correlation with cognitive function. Seventy-four healthy controls (HCs) and 74 SIVD patients, including 38 SIVD patients with no cognitive impairment (SIVD-NCI) and 36 SIVD patients with mild cognitive impairment (SIVD-MCI) underwent the measurement of serum Aβ40 and Aβ42 levels, pseudo-continuous arterial spin labeling MRI scanning, and cognitive evaluation. Compared to the healthy controls (HCs), the level of serum Aβ40 and Aβ40/42 ratio increased and Aβ42 decreased in SIVD patients. The serum Aβ40 level and Aβ40/42 ratio in patients with SIVD-MCI were significantly higher than those in the HCs and SIVD-NCI, and the level of Aβ42 in the SIVD-MCI was lower than the HCs. In addition, the serum Aβ40/42 ratio provided high diagnostic accuracy for SIVD and SIVD-MCI, it was further identified as an independent risk factor for cognitive impairment. Patients with SIVD-NCI and SIVD-MCI exhibited both increased and decreased cerebral blood flow (CBF) in regional. The Aβ40/42 ratio was associated with global CBF, while altered global and regional CBF was associated with cognitive deficits. In addition, white matter hyperintensities volume (WMHV) correlated with Aβ40/42 ratio, CBF, and cognition. The relationship between Aβ40/42 ratio and cognition was partially mediated by altered CBF. Based on these results, we conclude that the serum Aβ40/42 ratio may be a potential biomarker that can complement current methods for the prediction and diagnosis of cognitive impairment in SIVD patients. In addition, serum Aβ may play a role in cognitive function by regulating CBF, which provides new insights into the intervention, treatment, and prevention of cognitive impairment in SIVD.

Abstract Background Hypoxia has been shown to be able to induce tenogenic differentiation and proliferation of mesenchymal stem cells (MSCs) which lead hypoxia-induced MSCs to be a potential treatment for tendon injury. However, little is known about the mechanism underlying the tenogenic differentiation and proliferation process of hypoxic MSCs, which limited the application of differentiation-inducing therapies in tendon repair. This study was designed to investigate the role of Mohawk homeobox (Mkx) in tenogenic differentiation and proliferation of hypoxic MSCs. Methods qRT-PCR, western blot, and immunofluorescence staining were performed to evaluate the expression of Mkx and other tendon-associated markers in adipose-derived MSCs (AMSCs) and bone marrow-derived MSCs (BMSCs) under hypoxia condition. Small interfering RNA technique was applied to observe the effect of Mkx levels on the expression of tendon-associated markers in normoxic and hypoxic BMSCs. Hypoxic BMSCs infected with Mkx-specific short hair RNA (shRNA) or scramble were implanted into the wound gaps of injured patellar tendons to assess the effect of Mkx levels on tendon repair. In addition, cell counting kit-8 assay, colony formation unit assay, cell cycle analysis, and EdU assay were adopted to determine the proliferation capacity of normoxic or hypoxic BMSCs infected with or without Mkx-specific shRNA. Results Our data showed that the expression of Mkx significantly increased in hypoxic AMSCs and increased much higher in hypoxic BMSCs. Our results also detected that the expression of tenogenic differentiation markers after downregulation of Mkx were significantly decreased not only in normoxic BMSCs, but also in hypoxic BMSCs which paralleled the inferior histological evidences, worse biomechanical properties, and smaller diameters of collagen fibrils in vivo. In addition, our in vitro data demonstrated that the optical density values, the clone numbers, the percentage of cells in S phage, and cell proliferation potential of both normoxic and hypoxic BMSCs were all significantly increased after knockdown of Mkx and were also significantly enhanced in both AMSCs and BMSCs in hypoxia condition under which the expression of Mkx was upregulated. Conclusions These findings strongly suggested that Mkx mediated hypoxia-induced tenogenic differentiation of MSCs but could not completely repress the proliferation of hypoxic MSCs.

The Duck Tembusu virus (DTMUV), a pathogenic flavivirus, has been causing significant economic losses in the Chinese poultry industry since 2010. This virus can severely decrease egg production and inhibit the growth of laying ducks and ducklings. While many vaccines have been developed to prevent DTMUV infection, fresh outbreaks continue to occur, as few effective vaccines are available. The E glycoprotein of DTMUV is the primary target for inducing protective immunity in the natural host. Therefore, we conducted an investigation and successfully developed a recombinant baculovirus containing the DTMUV E gene. Ducklings were then vaccinated with the purified protein derived from this virus as a potential vaccine candidate. Our findings demonstrated that the E glycoprotein of DTMUV was highly expressed in Sf9 cells. The vaccination of ducklings with the recombinant baculovirus Bac-E resulted in the induction of strong humoral and cellular immune responses. Most significantly, we observed that the vaccine provided 100% protective immunity against lethal challenges with the DTMUV YY5 strain.

Abstract Background To observe the effects of vitamin D on the apoptotic human nucleus pulposus cells under tumor necrosis factor-α (TNF-α) treatment. Methods The gene expression data was downloaded from the NCBI Gene Expression Omnibus (GEO) database ( https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE34095 ). Differentially expressed genes between degenerative disc and non-degenerative disc were performed by R software. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) pathway enrichment analyses were performed using The Database for Annotation, Visualization and Integrated Discovery (DAVID). Then, the human nucleus pulposus tissue was harvested from 12 patients according to the modified Pfirrmann classification and human nucleus pulposus cells were obtained from digestion of herniated nucleus pulposus tissue. The collected nucleus pulposus cells were treated with different concentration of TNF-α, and cellular apoptosis was measured by flow cytometry. Then, human nucleus pulposus cells were divided into following groups: normal culture medium, TNF-α treated, TNF-α, and vitamin D-treated groups. Cellular apoptosis rate was quantified by flow cytometry. Protein expression of p-p65, p65, and IkBa was detected with western blot analysis. Results A total of 536 differentially expressed genes were identified through bioinformatic analysis. KEGG pathway revealed that NF-kB signaling pathway was involved in the process of disc degeneration. In the NP cell cultures, vitamin D significantly increased cell proliferation potency. Furthermore, vitamin D inhibited TNF-α induced apoptosis of human nucleus pulposus cells. Vitamin D reduced the phospho-NF-κB/p65 expression in the TNF-α-treated NP cells. Conclusion Vitamin D can attenuate TNF-α-induced NP cells apoptosis through interfering with the NF-κB pathway.

Sorafenib is one of the few effective first-line drugs approved for the treatment of advanced hepatocellular carcinoma (HCC). However, the development of drug resistance is common among individuals with HCC. Recent evidence indicated that the anticancer activity of sorafenib mainly relies on the induction of ferroptosis. Furthermore, in our study, genes that suppress ferroptosis, especially GPX4 and DHODH, were enriched in sorafenib-resistant cells and primary tissues and were associated with poor prognosis of HCC patients who received sorafenib treatment. Therefore, a new ferroptosis inducer comprising a multiplex small interfering RNA (multi-siRNA) capable of simultaneously silencing GPX4 and DHODH was created. Then, exosomes with high multi-siRNA loading and HCC-specific targeting were established by fusing the SP94 peptide and the N-terminal RNA recognition motif (RRM) of U1-A with the exosomal membrane protein Lamp2b. The results from the in vitro and in vivo experiments indicate that this tumor-targeting nano-delivery system (ExoSP94-lamp2b-RRM-multi-siRNA) could enhance sorafenib-induced ferroptosis and overcome sorafenib resistance. Taken together, HCC-targeted exosomes (ExoSP94-Lamp2b-RRM) could specifically deliver multi-siRNA to HCC tissues, enhance sorafenib-induced ferroptosis by silencing GPX4 and DHODH expression and consequently increase HCC sensitivity to sorafenib, which opens a new avenue for clinically overcoming sorafenib resistance from the perspective of ferroptosis.

Rock reinforcement is significant in maintaining the stability of excavated structures, such as tunnels and underground roadways. However, shear failure in the rock reinforcement system, especially the shear failure at the rock reinforcement bolt surface, induces a threat to the rock reinforcement system. To reveal the shear stress (SS) propagation mechanism in the rock reinforcement system, this article conducted a literature review. First, the investigation approaches that were used by previous researchers to study the SS propagation were summarized. The advantages and disadvantages of experimental tests, analytical simulation, and numerical simulation were compared and analyzed. Then, the SS propagation process in the rock reinforcement system was presented. Two typical SS propagation modes were explained. More attention was given to the SS propagation mode in which the maximum SS propagates from the external end of rock reinforcement bolts to the internal end of rock reinforcement bolts. After that, a discussion section was given. In the discussion section, the significance of the SS propagation was further emphasized. Moreover, the limitations in the analytical simulation and numerical simulation were indicated. It is concluded that when studying the SS propagation mechanism of rock reinforcement bolts, combining experimental tests, analytical simulation, and numerical simulation is a better choice. This study is beneficial for revealing the SS propagation mechanism of the rock reinforcement system.

This study investigated the development of lexical complexity, sentence complexity, accuracy, and fluency in the English writing of 22 Chinese university students from the perspective of Complex Dynamic Systems Theory (CDST). Compositions were assigned 30 times over the course of one academic year through Pigaiwang, an online platform that automatically evaluates writing. A modified retrodictive modeling approach was adopted. Specifically, a longitudinal cluster analysis was used to examine emergent prototypes. A moving correlation analysis and retrodictive interviews were conducted to study the signature dynamics that produce each prototype. At each collection, the 22 student compositions were classified into two clusters. One cluster contained those students who performed better than average in accuracy, but worse in the other three variables. The other cluster comprised those students with the opposite performance. Students moved continuously between the two clusters; and their change trajectories can be categorized into three prototypes: a continuously stable type, an initially variable and then stable type, and a continuously variable type. Case studies of three students representing the three emergent prototypes indicated that the signature dynamics for the three prototypes were related to dynamic interactions among different variables and dynamic changes in affect-related elements in the form of writing interests, motivation, and strategies. The initial conditions and the feedback from Pigaiwang acted as key control parameters in shaping the prototypes. The continuously variable prototype developed their writing proficiency to the greatest extent and had the most variability. Based upon the findings, implications for teaching L2 writing are discussed.

Abstract Streptococcus suis (S. suis) is an important zoonotic pathogen that causes septicaemia, meningitis and streptococcal toxic shock-like syndrome in its host, and recent studies have shown that S. suis could be competent for natural genetic transformation. Transformation is an important mechanism for the horizontal transfer of DNA, but some elements that affect the transformation process need to be further explored. Upon entering the competent state, Streptococcus species stimulate the transcription of competence-related genes that are responsible for exogenous DNA binding, uptake and processing. In this study, we performed conserved promoter motif and qRT-PCR analyses and identified CrfP as a novel murein hydrolase that is widespread in S. suis and stimulated with a peptide pheromone in the competent state through a process controlled by ComX. A bioinformatics analysis revealed that CrfP consists of a CHAP hydrolase domain and two bacterial Src homology 3-binding (SH3b) domains. Further characterization showed that CrfP could be exported to extracellular bacterial cells and lytic S. suis strains of different serotypes, and this finding was verified by TEM and a turbidity assay. To investigate the potential effect of CrfP in vivo, a gene-deletion mutant (ΔcrfP) was constructed. Instead of stopping the natural transformation process, the inactivation of CrfP clearly reduced the effective transformation rate. Overall, these findings provide evidence showing that CrfP is important for S. suis serovar 2 competence.

Context Peucedanol is a major extract of Peucedanum japonicum Thunb. (Apiaceae) roots, which is a commonly used herb in paediatrics. Its interaction with cytochrome P450 enzymes (CYP450s) would lead to adverse effects or even failure of therapy. Objective The interaction between peucedanol and CYP450s was investigated. Materials and methods Peucedanol (0, 2.5, 5, 10, 25, 50, and 100 μM) was incubated with eight human liver CYP isoforms (CYP1A2, 2A6, 3A4, 2C8, 2C9, 2C19, 2D6, and 2E1), in pooled human liver microsomes (HLMs) for 30 min with specific inhibitors as positive controls and untreated HLMs as negative controls. The enzyme kinetics and time-dependent study (0, 5, 10, 15, and 30 min) were performed to obtain corresponding parameters in vitro. Results Peucedanol significantly inhibited the activity of CYP1A2, 2D6, and 3A4 in a dose-dependent manner with IC50 values of 6.03, 13.57, and 7.58 μM, respectively. Peucedanol served as a non-competitive inhibitor of CYP3A4 with a Ki value of 4.07 μM and a competitive inhibitor of CYP1A2 and 2D6 with a Ki values of 3.39 and 6.77 μM, respectively. Moreover, the inhibition of CYP3A4 was time-dependent with the Ki/Kinact value of 5.44/0.046 min/μM. Discussion and conclusions In vitro inhibitory effect of peucedanol on the activity of CYP1A2, 2A6, and 3A4 was reported in this study. As these CYPs are involved in the metabolism of various drugs, these results implied potential drug-drug interactions between peucedanol and drugs metabolized by CYP1A2, 2D6, and 3A4, which needs further in vivo validation.

This study was based on similar physicochemical characteristics of pseudorabies virus (PRV) and African swine fever virus (ASFV). A cellular model for evaluation of disinfectants was established with PRV as an alternative marker strain. In the present study, we evaluated the disinfection performance of commonly used commercialized disinfectants on PRV to provide a reference for the selection of good ASFV disinfectants. In addition, the disinfection (anti-virus) performances for four disinfectants were investigated based on the minimum effective concentration, onset time, action time, and operating temperature. Our results demonstrated that glutaraldehyde decamethylammonium bromide solution, peracetic acid solution, sodium dichloroisocyanurate, and povidone-iodine solution effectively inactivated PRV at concentrations 0.1, 0.5, 0.5, and 2.5 g/L on different time points 30, 5, 10, and 10 min, respectively. Specifically, peracetic acid exhibits optimized overall performance. Glutaraldehyde decamethylammonium bromide is cost effective but requires a long action time and the disinfectant activity is severely affected by low temperatures. Furthermore, povidone-iodine rapidly inactivates the virus and is not affected by environmental temperature, but its application is limited by a poor dilution ratio such as for local disinfection of the skin. This study provides a reference for the selection of disinfectants for ASFV.

Abstract Antimicrobial peptides have been attracting increasing attention for their multiple beneficial effects. In present study, a novel AMP with a molecular weight of 1875.5 Da, was identified from the genome of Lactobacillus casei HZ1. The peptide, which was named as LHH1 was comprised of 16 amino acid residues, and its α-helix content was 95.34% when dissolved in 30 mM SDS. LHH1 exhibited a broad range of antimicrobial activities against Gram-positive bacteria and fungus. It could effectively inhibit Staphylococcus aureus with a minimum inhibitory concentration of 3.5 μM and showed a low hemolytic activity. The scanning electron microscope, confocal laser scanning microscope and flow cytometry results showed that LHH1 exerted its antibacterial activity by damaging the cell membrane of Staphylococcus aureus. Meanwhile, LHH1 also exhibited anti-cancer cell activities against several cancer cells via breaking the cell membrane of MGC803, HCT116 and C666-1 cancer cells.

BackgroundPoor sleep quality is related to depression. However, the investigation of the neural basis for poor sleep quality in individuals with major depression (MD) is limited.MethodsResting state functional and structural MRI data were derived from 114 MD individuals and 74 normal controls (NCs). Fractional amplitude of low-frequency fluctuation (fALFF) and gray matter volume (GMV) were used to measure function and structure of the brain. Pittsburgh Sleep Quality Index (PSQI) was performed to evaluate subjective sleep quality. Correlations were carried out to investigate links of PSQI score with brain imaging indices in MD and NCs, separately. We also examined the differences in fALFF and GMV of brain regions related to PSQI score between MD and NCs.ResultsIn contrast to NCs, MD individuals had higher PSQI score. The higher PSQI score was associated with lower fALFF and lower GMV in bilateral precuneus in MD individuals. Moreover, the MD individuals exhibited increased fALFF in bilateral precuneus compared with NCs. However, the correlation between subjective sleep quality and neuroimaging parameters was not significant in NCs.ConclusionThe implication of these findings is that the function and structure of precuneus provides a neural basis for subjective poor sleep quality in MD. Understanding this may lead to better intervention of depression and associated sleep complaints.

Evidence suggests the pivotal role of vitamin D in the pathophysiology of major depressive disorder (MDD) via its effects on the brain. Gender differences exist in both depression and vitamin D level. Our objective was to investigate the association between gender, vitamin D, clinical manifestations, and functional network connectivity in a large sample of MDD patients and healthy controls. Resting-state functional MRI data were collected from 122 patients and 119 controls, with independent component analysis adopted to examine large-scale inter- and intranetwork functional connectivity. Serum concentration of vitamin D (SCVD) and clinical manifestations were also assessed. MDD patients exhibited lower SCVD than controls in females but not males. Moreover, we identified a female-specific association between lower SCVD and poorer cognitive performance. Concurrently, MDD-related functional network connectivity changes were correlated with SCVD in females as well as depression and anxiety symptoms in female patients. Remarkably, MDD- and SCVD-related functional network connectivity alterations mediated the associations between SCVD and cognition in females. Aside from providing evidence for a female-specific neurobiological mechanism whereby low vitamin D might contribute to MDD and its associated clinical characteristics, our findings inform a novel conceptualization that adjuvant vitamin D supplementation therapy may yield clinical benefits in improving treatment outcomes in female patients with MDD.

Background: It has been reported that type 2 diabetes (T2DM) is associated with olfactory identification (OI) impairments and cognitive decline. However, the relationship between OI impairments and cognitive decline is largely unknown in T2DM patients.Methods: Sixty-eight T2DM patients and 68 healthy controls underwent 3D-T1 MRI scans, olfactory and cognitive assessments. The cortical thickness of olfaction-related brain regions, olfactory and cognitive scores were compared between groups. Correlation analyses were carried out among cognition, olfaction, and cortical thickness of olfaction-related brain regions.Results: First, the cognitive and olfactory test scores of T2DM patients were lower than healthy subjects. Second, higher olfactory scores were associated with increased cortical thickness in the left parahippocampal gyrus and bilateral insula in T2DM. Third, higher olfactory scores were associated with higher cognitive performance in T2DM. Fourth, some cognitive performances were related to cortical thickness in the left parahippocampal gyrus and left insula in T2DM.Conclusion: These findings indicated that olfactory dysfunction may be useful for future applications that attempt to predict cognitive decline or develop tailored therapies in T2DM patients.

Objectives. The purpose of this study was to explore the effects of sodium-glucose cotransporter-2 (SGLT-2) inhibitors on urine albumin to creatinine ratio (UACR) in type 2 diabetes mellitus (T2DM) patients and to recommend appropriate medication care scheme. Methods. 8371 T2DM patients from four dapagliflozin studies and two canagliflozin studies were collected for analyzing with nonlinear mixed effect model (NONMEM). The change rates of UACR from baseline were intended to be evaluation indicators. Results. In the present study, there was no significant difference in the effects on UACR using dapagliflozin or canagliflozin treatment in T2DM patients. The maximal effect (Emax) and the treatment duration of reaching half of Emax (ET50) from SGLT-2 inhibitors on UACR in T2DM patients were -19.2% and 0.448 weeks, respectively. Further, the treatment duration to reach 25%, 50%, 75%, and 80% Emax was 0.150 weeks, 0.448 weeks, 1.344 weeks, and 1.792 weeks, respectively. Namely, for achieving the plateau period (80% of Emax) of SGLT-2 inhibitors on UACR in T2DM patients, 10 mg/day dapagliflozin (or 100 mg/day canagliflozin) should be taken for at least 1.792 weeks. Conclusions. To our knowledge, the present study explored the effects of SGLT-2 inhibitors on UACR in T2DM patients, meanwhile, recommended appropriate medication care scheme for the first time.

Floor failure in deep coal mining above confined aquifers with high-water pressure may induce floor water inrush disasters. Considering the effects of mining stress and nonuniformly distributed water pressure, a mechanical calculation model of the island longwall panel in up-dip mining was established, and the stress distribution and floor failure characteristics were analyzed. The failure characteristics of the floor at NO. 2129 panel in Xingdong coal mine were detected by the borehole televiewer and microseismic monitoring system to validate the theoretical model. The results indicated that the floor failure characteristics along the strike and inclination of the island longwall panel in up-dip mining were “asymmetric inverted saddle-shaped” and “spoon-shaped,” respectively. The maximum floor failure depths before and after roof hydraulic fracturing (RHF) were 45.7 m and 29.1 m, respectively. The theoretical calculation results of the maximum depths of floor failure were 45.1 m and 29.9 m, respectively. The theoretical failure characteristics were consistent with those measured on site. The stress concentration magnitude and floor failure depth on the side of the isolated coal pillar were greater than those of other areas, and the water-inrush-prone zones were concentrated on the side of the isolated coal pillar near the intersection of the working face and the roadway. The research results could provide a certain reference for floor failure and water inrush mechanisms under complex geological conditions in deep mining.

Abstract Background Foxp3+CD4+ regulatory T cells (Treg) constitutes a key event in autoimmune diseases. STAT5b is the critical link between the IL-2/15 and FOXP3, the master regulator of Treg cells. Methods The CD3+T cell and Foxp3+CD4+ regulatory T cells were overexpressioned or knockdown MKL-1 and STAT5a and tested for Treg cell development and function. Direct interaction of MKL-1 and STAT5a were analyzed by coimmunoprecipitation assays, Luciferase assay, Immunofluoresence Staining and Yeast two-hybrid screening. The effect of MKL-1 and STAT5a on the Treg genes expression was analyzed by qPCR and western blotting and Flow cytometry. Results However, the molecular mechanisms mediating STAT5b-dependent Treg genes expression and Treg cell phenotype and function in autoimmune diseases are not well defined. Here, we report that the MKL-1 is a coactivator for the major Treg genes transcription factor STAT5b, which is required for human Treg cell phenotype and function. The N terminus of STAT5b, which contains a basic coiled-coil protein–protein interaction domain, binds the C-terminal activation domain of MKL-1 and enhances MKL-1 mediated transcriptional activation of Treg-specific, CArG containing promoters, including the Treg-specific genes Foxp3. Suppression of endogenous STAT5b expression by specific small interfering RNA attenuates MKL-1 transcriptional activation in cultured human cells. The STAT5b–MKL-1 interaction identifies a role of Treg-specific gene regulation and regulated mouse Treg cell development and function and suggests a possible mechanism for the protective effects of autoimmune disease Idiopathic Thrombocytopenic Purpura (ITP). Conclusions Our studies demonstrate for the first time that MKL-1 is a coactivator for STAT5b, the regulator of Treg cell development and function. Video abstract

Purpose: miR-5100 participates in the proliferation of lung cancer and pancreatic cancer cells, and participates in the differentiation of osteoblasts. However, the regulation of gastric cancer cells in gastric cancer cells remains unclear. Experimental design: The blood of patients was collected to detect the expression level of miR-5100, and the apoptosis and autophagy levels of cells were detected using western blot, flow cytometry, and confocal. At the same time, in vitro tumor formation experiments in nude mice were used to verify the results of in vitro experiments. Results: The expression of miR-5100 is related to the prognosis of gastric cancer, miR-5100 can enhance the apoptosis level of gastric cancer cells and inhibit the occurrence of autophagy by targeting CAAP1. MKL1 can inhibit the apoptosis of gastric cancer cells and promote the occurrence of autophagy by targeting CAAP1. At the same time, MKL1 can also increase the expression of miR-5100. Conclusions: Our research reveals the mechanism by which the MKL1/miR-5100/CAAP1 loop regulates apoptosis and autophagy levels in gastric cancer cells, and miR-5100 is expected to become a new potential target for gastric cancer treatment. Keywords: MKL1, miR-5100, CAAP1, Autophagy, Apoptosis, Gastric cancer

Many dynamic disasters such as coal wall caving and roof falling have happened during longwall face crossing fault. Combined with the coal seam geological conditions in the 1302 longwall face AB coal mine, the paper comprehensively studies the overlying strata movement and the stress evolution laws of stope during superhigh-water material (SHWM) backfilling longwall face across fault by UDEC numerical simulation, theoretical analysis and on-site measurement. The results show that the stress during stable state is affected by the fault will increases abnormally. While the longwall face pass through the fault, the stress will abated and the vertical displacement of the overlying strata of two sides of the fault is significantly different. The fault significant blocks the propagation of stress and development of plastic zone. The superhigh-water material filling mining management roof has good protection effect on the roof when the longwall face encounters fault, which can effectively weaken the blocks effect of fault on stress propagation and plastic zone development. The numerical simulation results are consistent with the field experiments, and the research result provides theoretical basis and technical guidance for safe and efficient production during superhigh-water material backfilling longwall face through the fault.

Abstract The fluid‐solid coupling simulation of fractured coal and rock is helpful to study the influence of the fracture structure on the stress sensitivity of the permeability. Therefore, a key factor in improving the reliability of such a numerical simulation is selecting parameters that match measured laboratory results. This paper firstly illustrates the use of a common inversion method to select the fluid‐solid coupling parameters through the constant joint stiffness method (CJSM). The main principle, application range, and the shortcomings of this method (CJSM) are analyzed: It can be used to simulate the measured results in a lower stress range. However, the stress sensitivity of permeability is zero when the stress reaches the critical stress (the stress where the hydraulic aperture reaches the residual hydraulic aperture). In order to solve this problem, a numerical simulation method for fluid‐solid coupling using the varying joint stiffness method (VJSM) is proposed based on the characteristic that the compressibility of a fracture decreases with increasing stress. In this method, the compressibility of the hydraulic aperture can be changed by increasing the joint stiffness during the loading process. Thus, the hydraulic aperture can continuously change and there is no need to set the residual hydraulic aperture. Finally, fluid‐solid coupling simulations under different stress states were performed using the VJSM in this study. The numerical simulation results were basically consistent with the experimental results, which indicated that a fluid‐solid coupling simulation using the VJSM can match experimental results very well and can be further used to study the influence of the persistent fracture angle on the permeability.