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CAR T cell therapy has shown dramatic clinical success in relapsed or refractory (r/r) B-ALL and other haematological malignancies. However, the loss of specific antigens, cell fratricide, T cell aplasia, and normal T cell separation are challenges in treating T cell leukemia/lymphoma with CAR T therapy. CD99 is a promising antigen to target T-ALL and AML as it is expressed on the majority of T-ALL and AML. Here, we isolated a low-affinity CD99 (12E7) antibody, which specifically recognizes leukemia cells over normal bone marrow cells. T cells transduced with an anti-CD99-specific CAR that contained the 12E7 scFv expanded with minor fratricide, maintained their cytotoxic function and mediated powerful antitumour effects. Subsequently, we conducted a pilot clinical study to evaluate the safety and feasibility of therapy with anti-CD99 CAR T cells in 4 patients with r/r T-LBL (n=1), AML (n=2) or myeloid sarcoma (MS) (n=1). The clinical overall response rate (ORR) was 50% (2/4 patients), and 1 patients (25%) achieved complete remission (CR) for 2 month. Mild cytokine release syndrome (CRS) occurred in 2 patients and the CRS no more than grade 2. Together, our results demonstrate that anti-CD99 CAR T cells specifically recognize and efficiently eliminate CD99+ leukemia cells.

The identification and treatment of mining-induced ground fissures are of great significance to mine safety and ecological and environmental protection. In this study, a novel method for ground fissure identification and exploration by infrared remote sensing onboard an unmanned aerial vehicle (UAV) was proposed. Using this method, a region of interest (ROI) that includes ground fissures directly above the middle of a long wall face, No. 12401 in the Shangwan coal mine, was monitored continuously during the day and night. Direct field measurements of ground fissure properties were also conducted to provide a calibration dataset for UAV measurements. Using the direct visible image at 5:00 pm as a reference, the average errors of the length and maximum width of Fissure I obtained from infrared images from 9:00 pm to 5:00 am on the next day, were estimated to be 1.8% and 6.5%, respectively. The diurnal variation of the fissure temperature is sinusoidal, and the range of temperature variation in the fissure decreases with the increase in depth. There is an apparent difference between the two common types of fissures depending on whether the fissure has a direct connection to an aquifer or a goaf. In this study, UAV, infrared thermal imager, and visible light camera data were successfully employed to effectively identify mining-induced ground fissures. In addition, the fissure detection error was validated, and the appropriate time for utilizing this method was obtained. Our results show that to identify the two aforementioned types of fissures, monitoring should be conducted between 3:00 am and 5:00 am. This study lays a foundation for the study and application of UAV and infrared thermal imagers for the identification of ground fissures induced by underground mining in large areas.

Lonicerae Japonicae Flos(LJF), a bulk medicinal material, has long been used in clinical settings. The main/Dao-di production areas are Shandong, Henan, and Hebei. However, no systematic study on the difference in volatile components of LJF from different areas is available at the moment. In this study, gas chromatography-mass spectrometry(GC-MS) was used to detect the volatile components in 30 batches of LJF from 3 main production areas. Based on the relative odor activity value(ROAV), the key aroma components were analyzed. Multivariate statistical analysis was performed to analyze the differential components and characteristic aroma components in the samples from the 3 areas. Finally, 113 volatiles were identified from the samples, which were mainly alcohols, esters, acids, aldehydes, ketones, and alkenes. Among the common components of the three areas, linalool, myristic acid, and α-linolenic acid methyl ester had high content. A total of 15 key and 9 modifying aroma components in LJF were determined based on ROAV. The 15 differential components can be used for origin identification. Among them,(E, E)-2,4-decadienal and hexanal contributed a lot to the aroma of LJF from Henan and α-nerol was a characteristic aroma component of LJF in Hebei. In addition, lauryl aldehyde was a biomarker of LJF from Shandong. This study can provide a reference for the origin identification and quality evaluation of LJF.

It is always big challenges for hyaluronic acid (HA) in transmembrane absorbing and efficient delivering to the skin. Pep-1, as one of the cell-penetrating peptides, has been documented to permeate various substances across cellular membranes without covalent binding. Here, a novel hyaluronic acid binding peptide (named HaBP) is designed, and then combine with Pep-1 to enhance the cell-penetrating efficiency of HA. The results of ELISA and immunofluorescence assay show that HaBP could bind with HA very well, and a combination of Pep-1 and HaBP could efficiently improve the transmembrane ability of HA. Furthermore, HA gradually enter the dermis from the surface of the skin in mice when it is administrated with both HaBP and Pep-1, while there are no obvious allergies or other adverse reactions during this process. This study find a new method to promote the efficient transmembrane and transdermal absorption of HA, and throw some light on further research on the development of hyaluronic acid and its related cosmetics or drugs. This article is protected by copyright. All rights reserved.

Underground water reservoir (UWR) technology has been used to protect mine water resources. The main underground space for UWRs is the caving zone formed by longwall mining. Broken rock mass movement in the caving zone affects the porosity distribution and seepage characteristics during the UWR’s circulation, storage, and discharge. We used a fluid-solid coupled model, implemented in PFC3D and combined with Python, to simulate water seepage in the caving zone. The influence of particle size and fluid element size on the error of the simulation results was analysed. Then, we investigated the effect of seepage on broken rock mass porosity under different stress states. Simulations with various particle sizes and compaction stresses show that the average displacement of broken rock decreases exponentially with increased stress. Because large broken particles form the primary bearing structure in the model, it is mostly small particles that move under high-stress levels, so porosity is less affected. Larger particles also migrate if the compaction stress is low; this significantly changes the porosity and leads to roof uplift. Finally, we designed an engineering scale model based on our simulation method using the actual UWR situation in a coal mine.

This study investigated the development and formation of ground fissures at panel 12,401 of the Shangwan Colliery in the Shendong mining area, characterized by the current largest mining height and an aeolian sand surface in China. An integrated monitoring method was employed to examine the ground subsidence, distribution and development pattern of ground fissures, and the relationship between fissure width and depth, including an unmanned aerial vehicle, ground penetrating radar, and real-time kinematic and manual measurements. Then, the development and formation mechanisms of ground fissures were elucidated through theoretical analysis and physical simulation. The results indicate that ultra large mining height longwall panel extraction causes a greater ground subsidence and horizontal deformation than those of the conventions, resulting in more severe damage in the permanent margin area. The ratio of burial depth to mining height (H/M) decreases to less than 30 due to the ultra large mining height, and deep-burial panel displays the characteristics of shallow coal seam mining, such as “step subsidence”. The sliding instability of the primary key stratum causes the simultaneous cutting-off of the aeolian sand layer to form step-like ground fissures. The cause of the tensile fissures is the horizontal surface deformation exceeding the deformation threshold of the aeolian sand layer, and the dynamic tensile fissures were self-restored in 2 weeks as the panel advanced. Step-like fissures connected the working face with the ground, but the depth of the tensile fissures was less than 5.0 m and increased linearly with the fissure width.

As coal mining is extended from shallow to deep areas along the western coalfield, it is of great significance to study weakly cemented sandstone at different depths for underground mining engineering. Sandstones from depths of 101.5, 203.2, 317.3, 406.9, 509.9 and 589.8 m at the Buertai Coal Mine were collected. The characteristic strength, acoustic emission (AE), and energy evolution of sandstone during uniaxial compression tests were analyzed. The results show that the intermediate frequency (125–275 kHz) of shallow rock mainly occurs in the postpeak stage, while deep rock occurs in the prepeak stage. The initiation strength and damage strength of the sandstone at different depths range from 0.23 to 0.50 and 0.63 to 0.84 of peak strength (σc), respectively, decrease exponentially and are a power function with depth. The precursor strength ranges from 0.88σc to 0.99σc, increases with depth before reaching a depth of 300 m, and tends to stabilize after 300 m. The ratio of the initiation strength to the damage strength (k) ranges from 0.25 to 0.62 and decreases exponentially with depth. The failure modes of sandstone at different depths are tension-dominated mixed tensile-shear failure. Shear failure mainly occurs at the unstable crack propagation stage. The count of the shear failure bands before the peak strength increases gradually, and increases first and then decreases after the peak strength with burial depth. The cumulative input energy, released elastic energy and dissipated energy increase with depth. The elastic release rate ranges from 0.46 × 10–3 to 198.57 × 10–3 J/(cm3 s) and increases exponentially with depth.

Economic globalization has resulted in more frequent trading frictions, some of which have escalated into trade wars such as the one between China and the US. Drawing on the same corpus built by Zhang and Forceville (Zhang, Cun & Charles Forceville. 2020. Metaphor and metonymy in Chinese and American political cartoons (2018–2019) about the Sino–US trade conflict. Pragmatics and Cognition 27(2). 476–501), and complementing insights of that paper, this paper investigates how the Sino–US trade war is metaphorically and metonymically constructed in 129 Chinese and American political cartoons respectively from a synthesized perspective. Based on comparative analyses, cross-cultural similarity and uniqueness in the semiotic, cognitive, and cultural aspects can be concluded as follows: (a) at the expression level, the shared dominant mode configuration pattern of metaphor and metonymy requires extra-textual knowledge to identify the target domain/concept while the source domain/vehicle concept is pinpointed through pictorial resources; (b) at the cognition level, “us” and “them” are distinctively evaluated by using the metonymy BODILY REACTION FOR EMOTION, cultural symbols, and the Great Chain metaphor. The Chinese cartoons converge on disapproving of “them” while the American cartoons converge on disapproving of “us” and diverge on conceptualizing “them”; (c) a variety of cross-cultural default scenarios are employed in the Chinese cartoons whereas the American cartoons utilize non-default scenarios influenced by only American cultures. Both aim for persuasiveness by employing emotionally charged source domains/vehicle concepts, but to different audiences.

Fast development of combination of nanotechnology with traditional Chinese medicine (TCM) broadens the field of application of TCM. Besides, it increases the research ideas and contributes to TCM modernization. As expected, TCM will be developed into the nanodrug delivery system by nanotechnology with careful design, which will enhance the medicinal value of TCM to cure and prevent disease based on benefits brought by nanometer scale. Here, formulations, relevant preparations methods, and characteristics of nano-TCM were introduced. In addition, the main excellent performances of nano-TCM were clearly elaborated. What is more, the review was intended to address the studies committed to application of nanotechnology in TCM over the years, including development of Chinese medicine active ingredients, complete TCM, and Chinese herbal compounds based on nanotechnology. Finally, this review discussed the safety of nano-TCM and presented future development trends in the way to realize the modernization of TCM. Overall, using the emerging nanotechnology in TCM is promising to promote progress of TCM in international platform. Recent researches on modernization of traditional Chinese medicine (TCM) urged by nanotechnology are introduced, and formulations, advantages, and applications of nano-TCM are reviewed to provide strong proofs.

BACKGROUND: Illness duration is the main index of cumulative illness severity during depression progression. Corpus callosum (CC) damage is among the most replicated neurobiological findings in major depressive disorder (MDD). We aimed to investigate the nature and extent of the association between illness duration and CC changes. METHODS: Ninety-six MDD patients and 50 controls underwent diffusion and resting-state functional magnetic resonance imaging (fMRI). White matter micro-structure and inter-hemispheric functional connectivity were quantified by fractional anisotropy (FA) and voxel-mirrored homotopic connectivity (VMHC). The CC was reconstructed by tractography and divided into five sub-regions. The associations of illness duration with FA of each CC sub-region and voxel-wise VMHC were examined using correlation analyses. Also, we investigated the potential relationship between illness duration, CC changes, and clinical variables using mediation analyses. RESULTS: In MDD patients, longer illness duration was selectively associated with lower FA of CC sub-regions 2 [partial correlation coefficient (pr) =–0.269, P=0.009] and 5 (pr=–0.296, P=0.004) as well as higher VMHC in the supplementary motor areas (pr=0.378, P

Content of multiple components (neochlorogenic acid,L-tryptophan,vicenin-2,isoquercitrin,and astragalin) in Moringa oleifera leaves was determined by high-performance liquid chromatography (HPLC),and the absolute content-time curves were plotted.Based on Fickapos;s law of diffusion and Higbieapos;s penetration theory,the parameters of the equations were calculated,and the measured results were substituted into the mathematical model to fit the equations.The n and a obtained from the equations on the decocting time factor and the solvent volume were close to each other.The dynamic models of the five components are as follows:■.The variation of the content of multiple components in M.oleifera leaves with time and solvent volume was explored.It was found that the content of the components was the highest when the leaves were decocted for 30 min with solvent volume 12 folds of the medicinal material.The dissolution and destruction of components and the diffusion movement of components are the main causes of the content change of M.oleifera leaves at different time and with different solvent volumes.The R~2of the linear equations on the content and the equations on the decocting process (5-30min and solvent volume 12-20 folds of the medicinal materials) was≥0.999 8 and≥0.9,respectively.Thus,the content determination and the decocting kinetic model had high accuracy,which can reflect the change law of the content of key components in M.oleifera leaves during the decoction.This study is expected to serve as a reference for optimizing the decocting technology.

Matching material degradation with host remodeling, including endothelialization and muscular remodeling, is important to vascular regeneration. We fabricated 3D PGS-PCL vascular grafts, which presented tunable polymer components, porosity, mechanical strength, and degrading rate. Furthermore, highly porous structures enabled 3D patterning of conjugated heparin-binding peptide, dimeric thymosin β4 (DTβ4), which played key roles in antiplatelets, fibrinogenesis inhibition, and recruiting circulating progenitor cells, thereafter contributed to high patency rate, and unprecedentedly acquired carotid arterial regeneration in rabbit model. Through single-cell RNA sequencing analysis and cell tracing studies, a subset of endothelial progenitor cells, myeloid-derived CD93

There is solid evidence for the prominent involvement of the central autonomic and default mode systems in shaping personality. However, whether functional connectivity of these systems can represent neural correlates and predictors of individual variation in personality traits is largely unknown. Resting-state functional magnetic resonance imaging data of 215 healthy young adults were used to construct the sympathetic (SN), parasympathetic (PN), and default mode (DMN) networks, with intra- and internetwork functional connectivity measured. Personality factors were assessed using the five-factor model. We examined the associations between personality factors and functional network connectivity, followed by performance of personality prediction based on functional connectivity using connectome-based predictive modeling (CPM), a recently developed machine learning approach. All personality factors (neuroticism, extraversion, conscientiousness, and agreeableness) other than openness were significantly correlated with intra- and internetwork functional connectivity of the SN, PN, and DMN. Moreover, the CPM models successfully predicted conscientiousness and agreeableness at the individual level using functional network connectivity. Our findings may expand existing knowledge regarding the neural substrates underlying personality.

The human sensorimotor cortex has multiple subregions showing functional commonalities and differences, likely attributable to their connectivity profiles. However, the molecular substrates underlying such connectivity profiles are unclear. Here, transcriptome-neuroimaging spatial correlation analyses were performed between transcriptomic data from the Allen human brain atlas and resting-state functional connectivity (rsFC) of 24 fine-grained sensorimotor subregions from 793 healthy subjects. Results showed that rsFC of six sensorimotor subregions were associated with expression measures of six gene sets that were specifically expressed in brain tissue. These sensorimotor subregions could be classified into the polygenic- and oligogenic-modulated subregions, whose rsFC were related to gene sets diverging on their numbers (hundreds vs. dozens) and functional characteristics. First, the former were specifically expressed in multiple types of neurons and immune cells, yet the latter were not specifically expressed in any cortical cell types. Second, the former were preferentially expressed during the middle and late stages of cortical development, while the latter showed no preferential expression during any stages. Third, the former were prone to be enriched for general biological functions and pathways, but the latter for specialized biological functions and pathways. Fourth, the former were enriched for neuropsychiatric disorders, whereas this enrichment was absent for the latter. Finally, although the identified genes were commonly associated with sensorimotor behavioral processes, the polygenic-modulated subregions associated genes were additionally related to vision and dementia. These findings may advance our understanding of the functional homogeneity and heterogeneity of the human sensorimotor cortex from the perspective of underlying genetic architecture.

As gene delivery tools, lentiviral vectors (LV) have broad applications in chimeric antigen receptor therapy (CAR-T). Large-scale production of functional LV is limited by the adherent, serum-dependent nature of HEK293T cells used in the manufacturing. HEK293T adherent cells were adapted to suspension cells in a serum-free medium to establish large-scale processes for functional LV production in a stirred bioreactor without micro-carriers. The results showed that 293 T suspension was successfully cultivated in F media (293 CD05 medium and SMM293-TII with 1:1 volume ratio), and the cells retained the capacity for LV production. After cultivation in a 5.5 L bioreactor for 4 days, the cells produced 1.5 ± 0.3 × 107 TU/mL raw LV, and the lentiviral transduction efficiency was 48.6 ± 2.8% in T Cells. The yield of LV equaled to the previous shake flask. The critical process steps were completed to enable a large-scale LV production process. Besides, a cryopreservation solution was developed to reduce protein involvement, avoid cell grafting and reduce process cost. The process is cost-effective and easy to scale up production, which is expected to be highly competitive.

Friction stir welding (FSW) is a relatively new welding technology. Although FSW technology has been widely used in many industries, there is a lack of effective online detection method of process parameters. Weld temperature and tool positioning are two key parameters in the study of process parameters. To realize online measurement of weld temperature and tool positioning in FSW, a measurement method of weld temperature and tool positioning is proposed by designing a new online detection device in FSW. The weld temperature measurement is realized by the material emissivity model based on the principle of infrared temperature measurement. Based on the principle of trigonometric distance measurement, the tool positioning is measured by data processing algorithm. In order to verify the feasibility of the measurement method, the welding processes of aluminum alloy with two thicknesses are detected online. The results show that the weld temperature measurement accuracy of the online detection device is within ± 2%. The measurement of tool positioning is realized. This measurement method proposed in this paper can be applied to the optimization of process design and temperature feedback control.

Friction stir welding (FSW) is a solid-phase welding method. Weld forming and welding quality are related to the heat generated by plastic flow in FSW process. Therefore, it is of great significance to realize the measurement of the viscoplastic heat generated in FSW process. In this paper, based on the working principle of rotary viscometer, the calculation model for the viscoplastic heat in friction stir welding was proposed. The validity of the calculation model was verified by simulation experiment. The correctness of the calculation model was verified by friction stir welding experiment.

Interfacial properties of van der Waals (vdW) heterostructures dominate the durability and function of their booming practical and potential applications such as opoelectronic devices, superconductors and even pandemics research. However, the strain engineering modulates of interlayer friction of vdW heterostructures consisting of two distinct materials are still unclear, which hinders the applications of vdW heterostructures, as well as the design of solid lubricant and robust superlubricity. In the present paper, a molecular model between a hexagonal graphene flake and a rectangular SLMoS2 sheet is established, and the influence of biaxial and uniaxial strain on interlayer friction is explored by molecular dynamics. It is found that the interlayer friction is insensitive to applied strains. Strong robustness of superlubricity between distinct layers is owed to the structure’s intrinsic incommensurate characteristics and the existence of Moiré pattern. In engineering practice, it is of potential importance to introduce two distinct 2D materials at the sliding contact interface to reduce the interfacial friction of the contact pair and serve as ideal solid lubricants. Our research provides a further basis to explore the nanotribology and strain engineering of 2D materials and vdW heterostructures.

Peripheral blood monocytes acquire the phenotype of myeloid-derived suppressor cells (MDSCs) by induction of cytokine or co-culture with cancer cells and are widely used to model MDSCs for

Cell division cycle‑associated 5 (CDCA5) plays a critical role in the progression of various human cancers by regulating cell cycle‑related proteins; however, the function of CDCA5 in breast cancer (BC) is poorly understood. The aim of the present study was to investigate the expression level of CDCA5 in BC and its effect on BC progression. CDCA5 was found to be highly expressed in patients with BC, as well as in BC cell lines. It was also found that a high CDCA5 expression in BC was significantly associated with a shorter survival rate. In addition, the expression level of CDCA5 was significantly increased in stem cells derived from suspension‑cultured BC cells, as compared to adherent‑cultured cells. CDCA5 knockdown in MCF7 and SKBR3 cells significantly reduced cell proliferation, migration and clone formation. At the same time, the stemness capacity of BC cells, determined by analyzing cancer stem cell marker expression and mammosphere formation, was also markedly diminished following the knockdown of CDCA5. In addition, in vivo experiments demonstrated that CDCA5 knockdown in MCF7 cells markedly reduced tumor growth. On the whole, the present study demonstrates that CDCA5 may be used as a prognostic biomarker and therapeutic target for BC.

Liver cancer is a malignant cancer phenotype for which there currently remains a lack of reliable biomarkers and therapeutic targets for disease management. Tryptophan 2,3‑dioxygenase (TDO2), a heme‑containing polyoxygenase enzyme, is primarily expressed in cells of the liver and nervous systems. In the present study, through the combination of cancer bioinformatics and analysis of clinical patient samples, it was shown that TDO2 expression in liver cancer tissue samples was significantly higher than that in normal tissues, and liver cancer patients with high TDO2 expression had a poor prognosis. Mechanistic studies on liver cancer cells showed that TDO2 promoted cancer cell migration and invasion via signal transduction through the Wnt5a pathway. Such regulation impacted the expression of cancer‑associated biomarkers, such as matrix metalloprotease 7 (MMP7) and the cell adhesion receptor CD44. Treatment with a calcium channel blocker (azelnidipine) reduced TDO2 levels and inhibited liver cancer cell migration and invasion. A mouse xenograft cancer model showed that TDO2 promoted tumorigenesis. Furthermore, azelnidipine treatment to downregulate TDO2 also decreased liver cancer development in this mouse cancer model. TDO2 is thus not only a useful liver cancer biomarker but a potential drug target for management of liver cancer.

Backgroud: To study the safety and efficacy of the multitrack and anchor point screw technique combined with the Wiltse approach for lesion debridement in the treatment of lumbar tuberculosis. Methods: We retrospectively enrolled 13 patients with lumbar spinal tuberculosis in our department from October 2014 to January 2021 who underwent unilateral multitrack multianchor screw fixation combined with contralateral Wiltse approach lesion debridement. Preoperative and final follow-up C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), preoperative, 3 months after operation, final follow-up low back pain visual analogue scale (VAS), and Oswestry disability index (ODI) were used for statistical analysis. The American Spinal Injury Association (ASIA) grades were recorded before surgery, 3 months after surgery, and at the final follow-up for all patients to evaluate the clinical effect of the surgery. Results: The average age of the 13 patients was 60.15±10.31 years old, the average operation time was 150.92±37.32 minutes, and the average blood loss was 415.39±151.91 mL; CRP (3.05±1.82 mg/L) and ESR (5.57±3.70 mm/h) returned to normal, and the difference was statistically significant compared with those before the operation (PConclusion: The multitrack multianchor point screw fixation technique combined with contralateral Wiltse approach debridement is an effective and safe method for the treatment of lumbar tuberculosis.

Chitinase-3-like protein-1 (YKL-40) is recognized as a novel neuroinflammatory biomarker related to neurodegenerative diseases. We aimed to explore whether serum YKL-40 can serve as a potential biomarker in patients with cerebral small vessel disease (CSVD), and possible neural correlates with white matter fiber damage and cognitive impairment. Blood samples were collected from 100 CSVD patients and 80 healthy controls (HCs) to measure serum YKL-40 levels. All subjects underwent diffusion tensor imaging (DTI) scanning and cognitive function assessment, and the CSVD group was classified into CSVD-no cognitive impairment (CSVD-NCI) and CSVD-mild cognitive impairment (CSVD-MCI) two subgroups. Binary logistic regression analysis was conducted to determine the independent risk factors for CSVD and CSVD-MCI. Receiver operating characteristic analysis was performed to assess the diagnostic value of YKL-40. Partial correlation analysis was carried out to explore the associations of DTI indices with YKL-40 and cognition. The serum YKL-40 levels of CSVD were significantly higher than those of the HCs, and the CSVD-MCI was higher than that in HCs and CSVD-NCI. YKL-40 was further identified as an independent risk factor for CSVD and CSVD-MCI, in addition, serum YKL-40 provided high diagnostic accuracy for CSVD and CSVD-MCI. Comparison of DTI indices showed that patients with CSVD accompanied by a significant decrease in white matter fibers integrity. Moreover, the altered DTI indices were significantly correlated with the elevated level of YKL-40 and worse cognitive performance. Our study suggests that YKL-40 may be a biomarker of CSVD and may cause cognitive impairment by disrupting white matter fiber integrity.

Liraglutide is an analogue of human glucagon-like peptide-1 (GLP-1), an endogenous intestinal hormone which play essential roles in the regulation of glycolipid metabolism. To investigate the role of lactic acid bacteria (LAB) in the lipid-lowering effect of liraglutide, forty mice were divided into normal saline-treated basal diet (NFD), normal saline-treated high-fat food (HFD), 10.0 mg/kg/d simvastatin-treated HFD (SIM + HFD), 200 and 400 μg/kg/d liraglutide-treated HFD (LL + HFD and HL + HFD) groups for 5 weeks. 16S rDNA sequencing, real-time quantitative PCR and western blot were used to detected changes of intestinal flora, cholesterol 7α-hydroxylase (CYP7A1), LDL-receptor (LDLR) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR). Results showed that liraglutide could up-regulate CYP7A1 and LDLR, whereas down-regulate HMGCR. Besides, liraglutide enhance the abundance of lactobacillaceae in gut of hyperlipidemic mice and increase the bile tolerance ability of LAB by up-regulating bile salt hydrolases, and the lysate of liraglutide-sensitive LAB could also directly down-regulate HMGCR, the key enzyme in cholesterol synthesis, and inhibit hepatocyte steatosis. These findings might provide new theoretical guidance for clinical application of liraglutide and threw a light on research and development of anti-obesity, hypolipidemic and cholesterol-lowering drugs or functional foods.

Network neuroscience has broadly conceptualized the functions of the brain as complex communication within and between large‐scale neural networks. Nevertheless, whether and how the gut microbiota influence functional network connectivity that in turn impact human behaviors has yet to be determined. We collected fecal samples from 157 healthy young adults and used 16S sequencing to assess gut microbial diversity and enterotypes. Large‐scale inter‐ and intranetwork functional connectivity was measured using a combination of resting‐state functional MRI data and independent component analysis. Sleep quality and core executive functions were also evaluated. Then, we tested for potential associations between gut microbiota, functional network connectivity and behaviors. We found significant associations of gut microbial diversity with internetwork functional connectivity between the executive control, default mode and sensorimotor systems, and intranetwork connectivity of the executive control system. Moreover, some internetwork functional connectivity mediated the relations of microbial diversity with sleep quality, working memory, and attention. In addition, there was a significant effect of enterotypes on intranetwork connectivity of the executive control system, which could mediate the link between enterotypes and executive function. Our findings not only may expand existing biological knowledge of the gut microbiota‐brain‐behavior relationships from the perspective of large‐scale functional network organization, but also may ultimately inform a translational conceptualization of how to improve sleep quality and executive functions through the regulation of gut microbiota., Gut microbiota can modulate large‐scale inter‐ and intranetwork functional connectivity (especially the executive control system) in young adulthood. Some functional network connectivity may act as mediators of the effects of gut microbiota on sleep and executive functions.

The advance speed of a longwall face is an essential factor affecting the mining pressure and overburden movement, and an effective approach for choosing a reasonable advance speed to realise coal mine safety and efficient production is needed. To clarify the influence of advance speed on the overburden movement law of a fully mechanised longwall face, a time-space subsidence model of overburden movement is established by the continuous medium analysis method. The movement law of overburden in terms of the advance speed is obtained, and mining stress characteristics at different advance speeds are reasonably explained. The theoretical results of this model are further verified by a physical simulation experiment. The results support the following conclusions. (i) With increasing advance speed of the longwall face, the first (periodic) rupture interval of the main roof and the key stratum increase, while the subsidence of the roof, the fracture angle and the rotation angle of the roof decrease. (ii) With increasing advance speed, the roof displacement range decreases gradually, and the influence range of the advance speed on the roof subsidence is 75 m behind the longwall face. (iii) An increase in the advance speed of the longwall face from 4.89 to 15.23 m/d (daily advancing of the longwall face) results in a 3.28% increase in the impact load caused by the sliding instability of the fractured rock of the main roof and a 5.79% decrease in the additional load caused by the rotation of the main roof, ultimately resulting in a 9.63% increase in the average dynamic load coefficient of the support. The roof subsidence model based on advance speed is proposed to provide theoretical support for rational mining design and mining-pressure-control early warning for a fully mechanised longwall face.

Guaipyridine alkaloids (-)-rupestine D, (-)-guaipyridine, (-)-epiguaipyridine, and (-)-cananodine together with two stereoisomers 8-epi-rupestine D and 5-epi-cananodine were synthesized enantioselectively from readily available citronellol. The key steps in this synthesis are (i) intermolecular opening of a trisubstituted epoxide for the formation of a chiral center at C-8; (ii) ring-closing metathesis for the construction of a seven-membered carbocyclic ring; and (iii) biomimetic cyclization of a 1,5-dicarbonyl compound for the construction of a pyridine-fused bicyclic skeleton.

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.