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Abstract Background Seed amplification assays (SAA) enable the amplification of pathological misfolded proteins, including α-synuclein (αSyn), in both tissue homogenates and body fluids of Parkinson’s disease (PD) patients. SAA involves repeated cycles of shaking or sonication coupled with incubation periods. However, this amplification scheme has limitations in tracking protein propagation due to repeated fragmentation. Methods We introduced a modified form of SAA, known as Quiescent SAA (QSAA), and evaluated biopsy and autopsy samples from individuals clinically diagnosed with PD and those without synucleinopathies (control group). Brain biopsy samples were obtained from 14 PD patients and 6 controls without synucleinopathies. Additionally, skin samples were collected from 214 PD patients and 208 control subjects. Data were analyzed from April 2019 to May 2023. Results QSAA successfully amplified αSyn aggregates in brain tissue sections from mice inoculated with pre-formed fibrils. In the skin samples from 214 PD cases and 208 non-PD cases, QSAA demonstrated high sensitivity (90.2%) and specificity (91.4%) in differentiating between PD and non-PD cases. Notably, more αSyn aggregates were detected by QSAA compared to immunofluorescence with the pS129-αSyn antibody in consecutive slices of both brain and skin samples. Conclusion We introduced the new QSAA method tailored for in situ amplification of αSyn aggregates in brain and skin samples while maintaining tissue integrity, providing a streamlined approach to diagnosing PD with individual variability. The integration of seeding activities with the location of deposition of αSyn seeds advances our understanding of the mechanism underlying αSyn misfolding in PD.

Abstract To study the seepage law and sectional morphological characteristics in splitting sandstones of different grain sizes, three‐dimensional morphological scanning tests and seepage characteristics tests are conducted on the splitting rock samples of siltstone, fine‐, medium‐ and coarse‐grained sandstone, and the differences in morphological characteristics and seepage law in different grain size sandstones are compared and analyzed. The test results show that the sections of siltstone and fine‐grained sandstone have the overall morphological characteristics of “one high and one low” with large undulation, while the sections of medium‐ and coarse‐grained sandstone have a more uniform distribution and less undulation. In the relationship between pressure gradient and flow velocity, siltstone and fine‐grained sandstone are precisely characterized by the Forchheimer formula, and medium‐ and coarse‐grained sandstone are well characterized by the Izbash formula, and the fitting effect is good. The results of the study are of great reference significance for improving the cross‐sectional morphological characteristics and seepage law of the splitting rock samples.

Abstract In order to reveal the disastrous mechanism of seepage instability of karst collapse column considering variable mass effect, a variable mass fluid–solid coupling mechanical model of water inrush is established, by considering the random distribution characteristics of a collapse column. Taking Qianjin coal mine as the research background, based on the Weibull distribution theory, the heterogeneous distribution characteristics of rock mass is described, and COMSOL Multiphysics numerical simulation software is employed to simulate the seepage characteristics and inrush water changes in collapse columns under different conditions of homogeneity, water pressure, and initial porosity. The research results show that the greater the homogeneity is, the more water conduction channels are formed, and the porosity increases accordingly, when considering the influence of different homogeneity on the seepage characteristics of broken rock mass, which eventually leads to water inrush accidents and a sharp increase in water inflow. Besides, when studying the seepage evolution law of different water pressures on a broken rock mass, an elevation of water pressure dramatically increases the porosity and seepage rate of the water. Over time, the broken rock particles gradually migrate and the fine particles are transported and eroded by the water flow, resulting in changes in the seepage characteristics and the formation of potential water diversion channels. Finally, when taking into account the effect of different initial porosity on the fractured rock mass seepage characteristics, the greater the original porosity is, the higher the seepage velocity is, and the particle migration increases the permeability. This leads to a more pronounced conductive water passage formation, which reveals the disastrous mechanism of seepage instability of karst collapse column considering variable mass effect.

Abstract When conducting retreat mining in segmented coal pillars, the dynamic evolution of stress and overlying strata structure is more complex than conventional working faces due to the influence of adjacent working faces. Understanding and mastering the dynamic evolution patterns of overlying strata structure after retreat mining in segmented coal pillar working faces is essential for guiding the safe recovery of coal pillar resources under similar conditions. Through statistical analysis of the types of residual coal and the mining techniques, the current research status of residual coal mining system in China has been summarized. Based on the safety recovery technology system for multi-type residual coal pillar resources at Zhaogu No.2 Mine, this paper focuses on narrow coal pillar working faces in sections with fully mined-out areas on both sides. By using research methods such as on-site measurement, theoretical analysis, numerical simulation, and engineering experiments, starting from the stress state analysis and evolution law of coal seam mining, the dynamic evolution law of the overlying rock structure of sectional coal pillars has been mastered. On this basis, a stress arch mechanical model of the mining area is constructed, and the working resistance of the support is calculated and determined, ensuring the safe recovery of the working face. The research results show that before the backfilling of the sectional coal pillar working face, the working face is affected by the overlapping mining of the goaf on both sides, presenting a “bimodal” stress distribution pattern, with a stress concentration coefficient between 1.78 and 3.2. After the extraction of segmented coal pillars, stress arches consisting of high-stress zones form along both the strike and dip of the working face. The structural support provided by stress arches undergoes a dynamic evolution process of “formation-development-elevation-stabilization” as the working face advances. Following the instability and rupture of the lower basic roof hinge structure, the stress-bearing structure shifts to the higher basic roof, continuing to provide support for the surrounding rock stress in the mining space of the working face. A stress arch mechanical model for the dip and strike of the mining area is constructed , and the shape characteristics of the overlying rock stress arch in the coal pillar working face is mastered. Based on the stress distribution law and stress arch evolution characteristics of the surrounding rock of the coal pillar working face, the maximum working resistance of the support in the working face is theoretically calculated to be 9153.48kN. Compared with the measured mine pressure data, the selected support effectively ensures the safety production of the working face.

Abstract In the mining process of the II1 coal seam at Zhaogu No. 2 coal mine, a method of stratified mining is employed, leaving relatively wide coal pillars in sections. To enhance the resource recovery rate, the mine carries out the cooperative mining of the sectional coal pillars and the lower layer coal seam. The 14,022 cooperative working face of fully-mechanized and fully-mechanized top-coal caving at Zhaogu No. 2 coal mine is taken as the research object. Through numerical simulation, theoretical calculations, and on-site industrial trials, a comprehensive analysis of the overburden structural characteristics and the support adaptability at the working face is conducted. It is clarified that a stress arch bearing structure can be formed above the sectional coal pillars during cooperative mining, and this structure is controlled by key strata. The formation of a stress arch bearing structure in the overburden above the sectional coal pillars provides protection for the underlying mining area. A formula for calculating the working resistance of hydraulic supports under the stress arch in sectional coal pillar is derived. Based on these results, the working resistance of hydraulic supports in the coal pillar area is calculated and selected. Field application shows that the working resistance of the support is 10,000 kN in the fully-mechanized top-coal caving working face, and is 9000 kN in fully-mechanized working face, meeting the support requirements and ensuring safe mining at the working face. This study provides a valuable engineering reference for achieving cooperative mining of abandoned sectional coal pillars and lower layer coal seam in stratified mining method.

Abstract With the deep extension of coal mining in China, fault water inrush has become one of the major disasters threatening the safety production of coal mine. Based on the control equations of steady state and non-Darcy seepage in fractured rock mass, the multi-parameter nonlinear dynamic seepage equations of fractured rock mass are established in this paper. Based on the nonlinear dynamics theory, the function of the state variable in the system is derived, and the influence of the gradual change of non-Darcy flow factors on the structural stability of seepage system is studied. The research achievements show that there are three branches in the equilibrium state of the seepage system. Specifically, the stability of the equilibrium state changes abruptly near the limit parameter. The seepage dynamic system of fractured rock mass has the delayed bifurcation, and the coal mine disaster such as fault water inrush occurs easily at the bifurcation point. The research results are of great significance to enrich the theory of fault water inrush in coal mine, and to reveal the disastrous mechanism of fault water inrush and guide its prevention and control technology in coal mine, which can provide the theoretical reference for predicting the water seepage stability in fractured rock mass.

Abstract A two-dimensional unsteady seepage model for coal using a finite element program is developed, and the temporal variations of key factors such as water pressure and hydraulic gradient are analyzed in this paper. Additionally, the triaxial rock mechanical experiment and utilized pneumatic fracturing equipment on raw coal samples to investigate both hydraulic and pneumatic fracturing processes are conducted. Through these experiments, the relationship between pressure and crack formation and expansion are examined. The analysis reveals that the pore pressure gradient at the coal inlet reaches its peak during rapid surges in water pressure but diminishes over time. Conversely, the pore pressure gradient at the outlet side exhibits a gradual increase. Hydraulic fracturing is most likely to occur at the water inlet during sudden increases in water pressure. Besides, as the permeability of coal decreases, the duration for seepage stabilization prolongs due to the intensified pore pressure gradient resulting from sudden increases in water pressure. Moreover, an extended period of high hydraulic gradient further increases the risk of hydraulic fracturing. The experimental findings indicate that coal samples initially experience tensile failure influenced by water and air pressure. Subsequently, mode I cracks form under pressure, propagating along the fracture surface and becoming visible. The main types of failure observed in hydraulic and pneumatic fracturing are diametrical tensile failure, and the development of fractures can be categorized into three distinct stages, which contains the initial stage characterized by slight volume changes while water pressure increases, the expansion stage when pressure reaches the failure strength, and the crack closure stage marked by little or even decreasing volume changes during pressure unloading. The acoustic emission signal accurately corresponds to these three stages.

Abstract To obtain the seepage evolution rule and water inrush mechanism of the collapse column, a multi-field coupled mechanical model for water inrush disasters caused by the collapse column is established in this paper, on the basis of the specific engineering conditions of the 1908 working face in the Qianjin coal mine. The mechanical model is composed of internal column elements within the collapse column and surrounding rock masses. The research focuses on the seepage evolution rule in the roof collapse column under different mining conditions and investigates the permeation instability mechanism of collapse column based on the transition of flow state. The research results indicate that the seepage pathway evolves continuously, ultimately forming a channel for water inrush, as the working face advances towards the collapse column. Besides, the water inflow increases rapidly when the working face advances 100 m, then gradually stabilizes, indicating that the seepage channel entry of the collapse column is in a stable stage. Meanwhile, mass loss in the collapse column gradually moves upward. the collapse column remains stable as a whole in the initial stage of water flow, with a small permeability, exhibiting linear flow. As time steps increases, particle loss in collapse column gradually extends to the upper part, forming a stable seepage channel. The flow velocity shows fluctuations with a slow declining trend over time.

Abstract In order to achieve the purpose of long-term stable mining of roadway, the strength and stability of rock mass are improved by means of grouting of fractured rock mass. In this paper, orthogonal test and numerical simulation methods were used to study the plugging performance of large amount of fly ash grouting slurry. The fluidity, water separation rate, compressive strength, setting time, stone rate and viscosity of the slurry were analyzed, and the optimal slurry ratio scheme was obtained. Under the optimal ratio scheme, the slurry transport process of the fractured rock mass was simulated, and the dynamic evolution law of the permeability of the slurry in the fractured rock mass was obtained. The study shows that the proportions of fly ash, ordinary Portland cement, loess, accelerant, expansion agent, bentonite water reducer and solidifying agent were 52.65%, 27.70%, 13.85%, 3%, 0.7%, 0.8%, 0.6% and 0.7% in the slurry ratio scheme, respectively. The slurry migration in the fractured rock mass experienced three stages, namely the filling and diffusion stage, the percolation and deposition stage and the sealing stage. The initial permeability was 971.9 mD and decreased to 45.79 mD after 1800 s, with a decrease of 95.3%. The slurry sealing performance was significantly improved, which has certain guiding significance for the application of underground grouting reinforcement engineering.

Abstract Based on the 7618 working face in Yaoqiao coal mine of Datun mining area, the activation mechanism of water-rich faults and the development characteristics of water-conducting fractures in overlying strata under the influence of faults are studied by theoretical analysis, numerical simulation and field measurement in this paper. The research results show that Anderson model and Mohr–Coulomb strength criterion are combined to establish the fault failure mechanical model, and the fault activation criterion under the influence of mining is obtained. FLAC3D numerical simulation results show that with the advance of the working face, the fault begins to be affected by the mining effect of the working face at the distance of 20 ~ 30 m from the fault. Meanwhile, with the advance of the working face, the overburden shear failure range also expands, and the fault fracture gradually expands from top to bottom. The failure zone of the working face roof is connected with the fault fracture zone. Then the fault is "activated" and causes the fault to become a water gushing channel, and finally the water gushing disaster occurs. Through numerical simulation and comparative analysis, the development height of water-conducting fracture is 73.2 m in the absence of fault, and 73.7 m in the presence of fault, indicating that the fault has little influence on the maximum development height of water-conducting fracture. The actual development height of the water-conducting fracture zone in the 7618 working face is 73.97 m and the fracture production ratio is 13.7. The research results can provide theoretical reference for the safe mining of similar working faces across faults.

Abstract In order to solve the water and gas discharge hazard caused by gob water and harmful gases (such as CO), the method of grouting overburden fractures is adopted to achieve the purpose of safe and efficient mining production in coal mines. This paper carries out the experimental research on the permeability reduction effect of grouting in fractured rock mass, expounds the relationship between gas flow rate and pressure gradient, seepage pressure and permeability, confining pressure and permeability, and analyzes the permeability change law of fractured rock mass before and after grouting. Besides, the grouting migration and permeability reduction model of fractured fine-grained sandstone is constructed by combining grouting test and numerical simulation, which reveals the dynamic evolution law of rock mass permeability in the grouting process. The results show that the permeability of the grouting rock sample decreases from 700–13,000 to 15–300 mD than that of the ungrouting rock sample, and the decrease is more than 95%, which indicates that the sealing performance of grouting slurry is better. Besides, numerical simulations show that the initial permeability of rock samples is 971.9 mD, and the permeability decreases to 45.79 mD after 1800s, and the permeability decreases to 95.3%, which is basically consistent with the experimental results after grouting. The greater the grouting pressure is, the better the grouting effect is. With the increase of the grouting pressure, the increase of the grouting effect is no longer obvious.

Abstract Shenfu Dongsheng coal field is a cross-century energy base which is developed and constructed in China. In recent years, some mines have successively entered to the coal seam of the second layer. Due to the reasons of early mining, many coal pillars are left in the coal seam of the first layer, resulting in the phenomenon of strong ore pressure in the mining range before and after the coal pillar in the lower coal seam and even causing the buckling accident. In order to solve such safety problems, this paper takes the 22,307 working face in Bulianta coal mine as the research object, adopts physical similarity simulation experiment and theoretical analysis to systematically study the overlying rock characteristics and abnormal ore pressure manifestation mechanism of shallow and close coal seam in different working stages. The results show that the roof overburden of the key layer in the lower group bends and sinks when the coal pillar is mined, resulting in the activation and instability of the “masonry beam” structure formed by the roof of the upper coal seam. When the coal pillar is discharged, the residual concentrated coal pillar and the room type coal pillar are unstable under the action of high supporting stress, resulting in shear failure of the inter-layer rock in the upper part of 22,307 working face, causing the strong dynamic pressure of the working face to appear and then leading to the buckling accident. The working resistance of the support in each stage is obtained by establishing the structure diagram of the overlying rock under each stage and the corresponding mechanical structure model. Finally, the working resistance required by the support in the mining stage under the goaf is 16,692.6 kN, the working resistance required by the support in the coal pillar stage is 19,692.6 kN, the working resistance required by the support in the mining stage under the concentrated coal pillar is 13,150.6 kN, and the working resistance required by the support in the coal pillar stage is 19,215.6 kN.

Abstract It is of great theoretical significance and engineering application value to research the diffusion law of slurry in mining fractures of rock strata to enrich grouting theory and improve grouting sealing effect. In this paper, the law of grout diffusion in fractures under different working conditions is systematically explored and analyzed, and a numerical simulation scheme of grout diffusion in a single slab crack is established. Then, the diffusion law of grouting slurry in crack under different rheological index and different consistency index is further investigated. The results show that the diffusion time of grouting slurry has no relation with the rheological index. The grout pressure at the same point increases with the increase of rheological index. When the rheological index increases by 0.1, the grout pressure increases by about 12.5%. The closer the grouting mouth is, the more the grouting pressure is affected by the rheological index. There is little relationship between the diffusion time of grouting slurry and consistency index. The grout pressure at each measurement point increases with the increase of the consistency index. When the consistency index increases by 1, the grout pressure increases by about 15% on the basis of the origin. The closer the grouting mouth is, the more the grouting pressure is affected by the consistency index. In engineering practice, when grouting slurry with large rheological index or consistency index exists, it is necessary to moderately increase the grouting pressure value.

As deep mining becomes prevalent in China's coal mining industry, coal-gas compound dynamic disasters pose increasing threat to the safety production of coal mines. This paper adopts the field data of Pingmei No. 8 coal mine for analysis, with the attempt to predict coal-gas compound dynamic disaster through convolutional neural network. Following the routine of the big data processing, we first employed Box-plot analysis and multiple interpolation method(MI)to clean the data. Combined with grey relation analysis(GRA), we established a coal-gas compound dynamic disaster index system. Then, principal component analysis(PCA)is used for dimensionality reduction of the data. Combined with the convolution neural network(CNN)in deep learning, we established the coal-gas compound dynamic disaster prediction model based on BMGP-CNN. The field data is used to compare and verify this model with BP, random forest(RF), support vector machine(SVM)and artificial neural network(ANN). It is found that BMGP-CNN model yields prediction results with satisfactory accuracy and quick convergence. The results offer implications for the prediction and prevention of coal-gas compound dynamic disasters.

We prove Li-Yau-Kröger-type bounds for Neumann-type eigenvalues of the biharmonic operator on bounded domains in a Euclidean space. We also prove sharp estimates for lower order eigenvalues of a biharmonic Steklov problem and of the Laplacian, which directly implies two sharp Reilly-type inequalities for the corresponding first nonzero eigenvalue.

Objective To analyze the forkhead box L2 neighbor (FOXL2NB) expression in colorectal cancer (CRC) and its potential clinical significance, and to explore the role of FOXL2NB in CRC cells. Methods Real time qPCR and Western blot were used to analyze the expression of FOXL2NB in CRC tissues and cells. Transwell and CCK-8 assay were used to investigate the effect of FOXL2NB on the proliferation and migration in SW620 cell line. Kaplan-Meier and multivariate Cox regression analysis were used to evaluate the prognostic significance of FOXL2NB in CRC patients. CIBERSORT R package was used to calculate the correlation between FOXL2NB expression and immune cell infiltration in CRC tissues. limma R package was used to calculate the genes that significantly correlated with FOXL2NB expression. Results The mRNA and protein levels of FOXL2NB were significantly increased in CRC cell lines and tissues (P＜ 0.05). High level of FOXL2NB was associated with shorter overall survival and progression free survival in CRC patients (P＜ 0.05), which could be used as an independent risk factor for CRC prognosis (HR=2.27, 95% CI=1.78-2.9, P＜ 0.001). FOXL2NB knockdown inhibited the migration and proliferation of CRC cells. Cell adhesion molecules and tumor immune-related pathways were significantly enriched in CRC with high FOXL2NB expression, CD8+ T cells and activated dendritic cells were significantly increased, while M0 macrophages were significantly decreased. FOXL2NB expression was positively correlated with SCRT2, MGAT5B, SELENOV, FOXB1, KCNA4, LRRC14B and SLC32A1 genes. Conclusions FOXL2NB is highly expressed in CRC and potentially predicts poor prognosis. FOXL2NB might promote CRC cell proliferation and migration.

In deep mining, coal-rock is in a state of three unequal forces, and the intermediate principal stress has the influence on the deformation and strength characteristics of coal-rock. This study studied the deformation and seepage characteristics of gas-bearing composite coal-rock under different intermediate principal stresses by using true triaxial gas-solid coupling seepage test device for coal and rock. The results show : ① With the increase of intermediate principal stress, the strain in the direction of maximum principal stress first increases and then decreases when the peak strength is reached, and there is widening gap between the strain in the direction of intermediate principal stress and the strain in the direction of minimum principal stress.② Under low intermediate principal stress, the strain in the intermediate principal stress direction shows expansion and deformation, and when there is relatively high intermediate principal stress, the ε2-Δσ curve reaches the peak and then bounces back, and the strain in the intermediate principal stress direction finally shows compression and deformation.③ With the increase of intermediate principal stress, the trough value of relative permeability coefficient decreases, and the peak inflection point of relative permeability coefficient curve is consistent with the inflection point of ε1-Δσ curve.④ When the stress peak is reached, the total input energy of the specimen first increases and then decreases, which is similar to the changes of the specimen strength: The elastic strain energy first increases and then decreases, the dissipative energy continues to increase, Ue/U first increases and then decreases, and Ud/U first decreases and then increases.

Maintaining mitochondrial homeostasis is a potential therapeutic strategy for various diseases, including neurodegenerative diseases, cardiovascular diseases, metabolic disorders, and cancer. Selective degradation of mitochondria by autophagy (mitophagy) is a fundamental mitochondrial quality control mechanism conserved from yeast to humans. Indeed, small-molecule modulators of mitophagy are valuable pharmaceutical tools that can be used to dissect complex biological processes and turn them into potential drugs. In the past few years, pharmacological regulation of mitophagy has shown promising therapeutic efficacy in various disease models. However, with the increasing number of chemical mitophagy modulator studies, frequent methodological flaws can be observed, leading some studies to draw unreliable or misleading conclusions. This review attempts (a) to summarize the molecular mechanisms of mitophagy; (b) to propose a Mitophagy Modulator Characterization System (MMCS); (c) to perform a comprehensive analysis of methods used to characterize mitophagy modulators, covering publications over the past 20 years; (d) to provide novel targets for pharmacological intervention of mitophagy. We believe this review will provide a panorama of current research on chemical mitophagy modulators and promote the development of safe and robust mitophagy modulators with therapeutic potential by introducing high methodological standards.

In this paper, we investigate the buckling problem of the drifting Laplacian of arbitrary order on a bounded connected domain in complete smooth metric measure spaces (SMMSs) supporting a special function, and successfully obtain a general inequality for its eigenvalues. By applying this general inequality, if the complete SMMSs considered satisfy some curvature constraints, we can obtain a universal inequalities for eigenvalues of this buckling problem.

As the first cyclin-dependent kinases 4 and 6 inhibitors, palbociclib significantly improved the survival of the patients with the hormone receptor-positive and human epidermal growth factor receptor-2 negative breast cancer. Palbociclib is a crucial landmark in the development history of antineoplastic drugs. This article reviews the mechanism of palbociclib, and summarizes the clinical trials, side effects, and the application of palbociclib.

The research on coal breaking mechanism by high-pressure water jet can provide theoretical basis for water jet equipment manufacturing and construction technology research. In this paper, based on the investigation of a large number of related literatures at home and abroad, we summarized the relevant theories of coal breaking mechanism by high pressure water jet. From the perspective of the structure of water jet and mechanical properties of coal, this paper introduces the stress wave theory of crushing, quasi-static elastic fracture theory, the theory of cavitation and broken and crack propagation mechanism of broken coal at all stages about crushing theory researches. In view of the applicability and limitations of various current coal breaking theories, it is suggested that further research can be carried out from three directions: improving the coal breaking mechanism of water jet, two-phase jet and new jet mode.

Water inrush in the working face caused by seepage instability of fault fracture zone is a major disaster which threatens the safety production in a coal mine. Based on the principle of fluid mechanics, a nonlinear mechanical model with three flow fields is established in this paper. Combining with the actual situation of a fault fracture zone in a coal mine, a multicoupled numerical model is built in COMSOL Multiphysics, in order to study the water pressure and flow velocity in the three flow fields and the flow state of fluids in the aquifer and fault under different ratios of fault permeability and aquifer permeability. The research results show that the permeability in the fault fracture zone is an essential factor affecting the danger of water inrush, and the pressure and flow velocity in the boundary zone of the adjacent flow field varies significantly. Besides, the water inrush in the fault fracture zone is a gradual dynamic process, and the fluid flow from the aquifer through the fault gradually changes from a linear flow state into a nonlinear flow state. Meanwhile, the non-Darcy effect increases and decreases with the growth and decrease of the permeability in the fault fracture zone.

As a cellular bulk degradation and survival mechanism, autophagy is implicated in diverse biological processes. Genome-wide association studies have revealed the link between autophagy gene polymorphisms and susceptibility of autoimmune diseases including systemic lupus erythematosus (SLE) and inflammatory bowel disease (IBD), indicating that autophagy dysregulation may be involved in the development of autoimmune diseases. A series of autophagy modulators have displayed protective effects on autoimmune disease models, highlighting the emerging role of autophagy modulators in treating autoimmune diseases. This review explores the roles of autophagy in the autoimmune diseases, with emphasis on four major autoimmune diseases [SLE, rheumatoid arthritis (RA), IBD, and experimental autoimmune encephalomyelitis (EAE)]. More importantly, the therapeutic potentials of small molecular autophagy modulators (including autophagy inducers and inhibitors) on autoimmune diseases are comprehensively analyzed.

In this paper, we study the eigenvalue problem of poly-drifting Laplacian on complete smooth metric measure space (M,⟨,⟩,e−ϕdv)\left(M,\langle ,\rangle ,{e}^{-\phi }{\rm{d}}v), with nonnegative weighted Ricci curvature Ricϕ≥0{{\rm{Ric}}}^{\phi }\ge 0 for some ϕ∈C2(M)\phi \in {C}^{2}\left(M), which is uniformly bounded from above, and successfully obtain several universal inequalities of this eigenvalue problem.

A recent research paper published in Journal of Cell Biology by Chen and colleagues describes a novel mechanism by which the MAM (Mitochondrial-associated endoplasmic reticulum membrane) protein FUNDC1 (FUN14 domain-containing protein 1) regulates mitochondrial division through altered protein post-translational modifications under hypoxic stress. The authors found that in a hypoxic environment, the endoplasmic reticulum-localized deubiquitinating enzyme USP19 accumulates at the MAM and interacts with the enriched mitochondrial outer membrane protein FUNDC1, which subsequently induces its deubiquitination and promotes the oligomerization and activity of DRP1, and mitochondria eventually divide in the presence of DRP1. This article provides new insights into the regulation of mitochondrial dynamics by FUNDC1 under hypoxic condition.

The 52307 working face with large mining height in Daliuta coal mine is chosen as the research background, where there is the special mining condition in the overburden structure with a buried depth of more than 150 m and only one layer of key structure in Shendong mining area. Using the methods of similarity simulation experiment and theoretical analysis, the overburden movement law based on the arch mechanical model of plane contact block is systematically researched. The research results indicate that before the initial weight, the main key layer appears layered fracture in the mining process, and its lower rock layer becomes a part of the collapse zone. Before the initial weight, the upper key layer forms a “fixed supported beam” structure. When the beam reaches the limit length, shear failure occurs in the middle position; during the periodic weight, the upper key layer breaks into the plane contact block arch structure close to the same size. Relying on the friction between the contact planes, it has a certain displacement but does not collapse completely. The load transmitted from overburden is transmitted to the rear of the gob through the semiarch characteristics of the structure; the sliding instability and rotary deformation instability of the plane contact block arch structure are analyzed. The fracture of the key layer lags behind the mining position of the working face by a certain distance, due to the influence of the fracture angle of collapse zone in the advancing process of working face. The research results provide an important guiding significance for prediction and prevention for dynamic disaster of rock strata in working face with large mining height.

BackgroundHormones and immune imbalance are critical factors in polycystic ovary syndrome (PCOS). The alternation of immune microenvironment of oocytes may play a significant role in infertility of PCOS patients.ObjectiveThis study explores the role of follicular fluid microenvironment change in inflammatory pathways activation of granulosa cells (GCs) in PCOS women infertility.MethodsWe enrolled 27 PCOS patients and 30 controls aged 22 to 38 years who underwent IVF and collected their luteinized granulosa cells (LGCs). Meanwhile, a granulosa-like tumor cell line (KGN) as a cell-model assisted this study. Key inflammatory markers in human ovarian GCs and follicular fluid were detected by RT-qPCR, Western blotting, or ELISA. The KGN cells were treated with follicle supernatant mixed with normal medium to simulate the microenvironment of GCs in PCOS patients, and the inflammation indicators were observed. The assembly of NLRP3 inflammasomes was detected by immunofluorescence techniques. Dihydroethidium assay and EdU proliferation assay were used to detect ROS and cell proliferation by flow cytometry.ResultsCompared with normal controls (n = 19), IL-1β (P = 0.0005) and IL-18 (P = 0.021) in the follicular fluid of PCOS patients (n = 20) were significantly increased. The NF-κB pathway was activated, and NLRP3 inflammasome was formatted in ovarian GCs of PCOS patients. We also found that inflammation of KGN cells was activated with LPS irritation or stimulated by follicular fluid from PCOS patients. Finally, we found that intracellular inflammation process damaged mitochondrial structure and function, which induced oxidative stress, affected cellular metabolism, and impaired cell proliferation.ConclusionInflammatory microenvironment alteration in the follicular fluid of PCOS patients leads to activated inflammatory pathway in GCs, serving as a crucial factor that causes adverse symptoms in patients. This study provides a novel mechanism in the inflammatory process of PCOS.

AIM: To investigate the curative effect of coaxial microincisional phacoemulsification combined with AcrySof ReSTOR intraocular lens implantation on senile cataract. METHODS: Totally 66 patients(66 eyes)with age-related cataract who were admitted to the hospital from April 2015 to August 2017 were enrolled in the study. All of them were treated with coaxial microincisional phacoemulsification combined with intraocular lens implantation. All 32 cases underwent AcrySof ReSTOR intraocular lens implantation were included in observation group, while 34 cases underwent monofocal intraocular lens implantation were included in control group. The visual acuity, contrast sensitivity, stereoacuity, pseudo-accommodation power and satisfaction with visual function were compared between the two groups. RESULTS: The near and middle vision, near stereoacuity, near and distant pseudo-accommodation power of naked eyes in observation group were significantly better than those in control group at 3mo after surgery(PPPCONCLUSION: The curative effect of coaxial microincisional phacoemulsification combined with AcrySof ReSTOR intraocular lens implantation is significant on cataract. Compared with monofocal lens, it can improve the visual acuity, pseudo-accommodation power and visual related quality of life. However, the contrast sensitivity is reduced.

Abstract Background Ovarian cancer (OC) is the second most frequent gynecological cancer and is associated with a poor prognosis because OC progression is often asymptoma-tic and is detected at a late stage. There remains an urgent need for novel targeted therapies to improve clinical outcomes in ovarian cancer. As a nitric oxide prodrug, JS-K is reported highly cytotoxic to human cancer cells such as acute myeloid leukemia, multiple myeloma and breast cancer. This study is aim to investigate the influence of JS-K on proliferation and apoptosis in ovarian cancer cells and explored possible autophagy-related mechanisms, which will contribute to future ovarian cancer therapy and supply theory support that JS-K holds great promise as a novel therapeutic agent against ovarian cancer. Methods The cytotoxicity, extracellular ROS/RNS activity and apoptotic effect of JS-K and indicated inhibitors on ovarian cancer cells in vitro were evaluated by MTT assay, extracellular ROS/RNS assay, caspases activities assay and western blot. Further autophagy effect of JS-K and indicated inhibitors were examined by MTT assay, cell transfection, immunofluorescence analysis, transmission electron microscopy (TEM) analysis and western blot on ovarian cancer cells in vitro. In vivo, the BALB/c-nude female mice with SKOV3 ovarian cancer cells xenograft were used to examine the efficacy of JS-K treatment on tumor growth. PCNA and p62 proteins were analyzed by immunohistochemistry. Results In vitro, JS-K inhibited the proliferation of ovarian cancer cells, induced apoptosis and cell nucleus shrinkage, enhanced the enzymatic activity of caspase-3/7/8/9, and significantly increased the production of ROS/RNS in ovarian cancer A2780 and SKOV3 cells, these effects were attenuated by inhibition of NAC. In addition, JS-K induced autophagy-related proteins and autophagosomes changes in ovarian cancer A2780 and SKOV3 cells. In vivo, JS-K inhibited tumor growth, decreased p62 protein expression and increased the expression levels of PCNA in xenograft models which were established using SKOV3 ovarian cancer cells. Conclusion Taken together, we demonstrated that ROS/RNS stress-mediated apoptosis and autophagy are mechanisms by which SKOV3 cells undergo cell death after treatment with JS-K in vitro. Moreover, JS-K inhibited SKOV3 tumor growth in vivo. An alternative therapeutic approach for triggering cell death in cancer cells could constitute a useful multimodal therapies for treating ovarian cancer, which is known for its resistance to apoptosis-inducing drugs.

Autophagy (here refers to macroautophagy) is a catabolic pathway by which large protein aggregates and damaged organelles are first sequestered into a double-membraned structure called autophagosome and then delivered to lysosome for destruction. Recently, tremendous progress has been made to elucidate the molecular mechanism and functions of this essential cellular metabolic process. In addition to being either a rubbish clearing system or a cellular surviving program in response to different stresses, autophagy plays important roles in a large number of pathophysiological conditions, such as cancer, diabetes, and especially neurodegenerative disorders. Here we review recent progress in the role of autophagy in neurological diseases and discuss how dysregulation of autophagy initiation, autophagosome formation, maturation, and/or autophagosome-lysosomal fusion step contributes to the pathogenesis of these disorders in the nervous system.

Mitochondria-associated ER membranes (MAMs) represent a crucial intracellular signaling hub, that regulates various cellular events including Ca2+ homeostasis, lipid metabolism, mitochondrial function, and cellular survival and death. All of these MAM-mediated cellular events contribute to carcinogenesis. Indeed, altered functions of MAMs in several types of cancers have been documented, in particular for breast cancer. Over the past years, altered expression of many MAM-resident proteins have been reported in breast cancer. These MAM-resident proteins play an important role in regulation of breast cancer initiation and progression. In the current review, we discuss our current knowledge about the functions of MAMs, and address the underlying mechanisms through which MAM-resident proteins regulate breast cancer. A fuller understanding of the pathways through which MAMs regulate breast cancer, and identification of breast cancer-specific MAM-resident proteins may help to develop novel therapeutic strategies for breast cancer.

The mitochondrion, the ATP-producing center, is both physically and functionally associated with almost all other organelles in the cell. Mitochondrial-associated membranes (MAMs) are involved in a variety of biological processes, such as lipid exchange, protein transport, mitochondrial fission, mitophagy, and inflammation. Several inflammation-related diseases in the cardiovascular system involve several intracellular events including mitochondrial dysfunction as well as disruption of MAMs. Therefore, an in-depth exploration of the function of MAMs will be of great significance for us to understand the initiation, progression, and clinical complications of cardiovascular disease (CVD). In this review, we summarize the recent advances in our knowledge of MAM regulation and function in CVD-related cells. We discuss the potential roles of MAMs in activating inflammation to influence the development of CVD.

Mitochondria serve as an energy plant and participate in a variety of signaling pathways to regulate cellular metabolism, survival and immunity. Mitochondrial dysfunction, in particular in cardiomyocytes, is associated with the development and progression of cardiovascular disease, resulting in heart failure, cardiomyopathy, and cardiac ischemia/reperfusion injury. Therefore, mitochondrial quality control processes, including post-translational modifications of mitochondrial proteins, mitochondrial dynamics, mitophagy, and formation of mitochondrial-driven vesicles, play a critical role in maintenance of mitochondrial and even cellular homeostasis in physiological or pathological conditions. Accumulating evidence suggests that mitochondrial quality control in cardiomyocytes is able to improve cardiac function, rescue dying cardiomyocytes, and prevent the deterioration of cardiovascular disease upon external environmental stress. In this review, we discuss recent progress in understanding mitochondrial quality control in cardiomyocytes. We also evaluate potential targets to prevent or treat cardiovascular diseases, and highlight future research directions which will help uncover additional mechanisms underlying mitochondrial homeostasis in cardiomyocytes.

Ubiquitin–proteasome system (UPS) and autophagy–lysosome pathway (ALP) are two major systems for protein quality control (PQC) in eukaryotic cells. Interconnectivity between these two pathways has been suggested, but the molecular detail of how they impact each other remains elusive. Proteasomal deubiquitinase (DUB) is an important constituent in the UPS and has proved to be a novel anticancer target. We have previously found that a novel DUB inhibitor, nickel complex NiPT, induces apoptosis in both cultured tumor cell lines and cancer cells from acute myeloid leukemia human patients. In this study, we found that NiPT triggered autophagy both in vitro and in vivo. Mechanistically, NiPT targets two DUBs, USP14, and UCHL5, and increased the total cellular level of polyubiquitination. Deletion of the Ubiquitin Associated (UBA) domain of P62 that is required for polyubiquitin binding prevented NiPT-induced autophagy. NiPT-induced autophagy is through either concomitant activation of AMP-activated protein kinase (AMPK) and inhibition of mechanistic target of rapamycin (mTOR) signaling, or eliciting endoplasmic reticulum (ER)-stress by activating activating transcription factor 4 (ATF4) and C/EBP-homologous protein (CHOP). Moreover, NiPT could induce more lung cancer cells undergoing apoptosis if it synergistically uses autophagy inhibitors, suggesting that NiPT-induced autophagy protects cancer cell from death. Collectively, our findings demonstrate that autophagy inhibition enhances the anticancer effects of proteasomal DUB inhibitor and might be an effective treatment strategy for lung cancer.

AIM: To study and analyze the clinical effect of phacoemulsification with intraocular lens(IOL)implantation in patients with acute angle-closure glaucoma complicated with cataract. METHODS: From June 2016 to January 2018, 80 patients with acute angle-closure glaucoma and cataract admitted to our hospital were enrolled in this study. They were divided into two groups according to random number table. They were divided into observation group and control group, respectively. The patients in the control group were treated by phacoemulsification and IOL implantation. The observation group were treated with combined surgery for glaucoma and cataract. The difference between the two groups was compared. RESULTS: After operation, the visual acuity, intraocular pressure and complications of the observation group were better than those of the control group(PCONCLUSION: The clinical effect of phacoemulsification with IOL implantation in the treatment of acute angle-closure glaucoma with cataract is of great clinical value.

Abstract High-risk patients with rheumatic heart disease (RHD) who were undergoing valve replacement surgery (VRS) were not identified entirely. This study included 1782 consecutive patients with RHD who were undergoing VRS to explore the relationship between hypoalbuminemia and adverse outcomes and to confirm whether hypoalbuminemia plays a role in risk evaluation. A total of 27.3% of the RHD patients had hypoalbuminemia. In-hospital deaths were significantly higher in the hypoalbuminemic group than in the non-hypoalbuminemic group (6.6% vs 3.1%, P = 0.001). Hypoalbuminemia was an independent predictor of in-hospital death (OR = 1.89, P = 0.014), even after adjusting for the Euro score. The addition of hypoalbuminemia to Euro score enhanced net reclassification improvement (0.346 for in-hospital death, P = 0.004; 0.306 for 1-year death, p = 0.005). A Kaplan-Meier curve analysis revealed that the cumulative rate of 1-year mortality after the operation was higher in patients with a new Euro score ≥6. These findings indicated that hypoalbuminemia was an independent risk factor for in-hospital and 1-year mortality after VRS in patients with RHD, which might have additive prognostic value to Euro score.

Background: Although emerging research is demonstrating the potential health impact of exergaming, investigations have primarily been conducted in laboratory settings among small samples with short-term interventions. Information on the effectiveness of exergaming in underserved children's objective physical activity (PA) in population-based settings is also scarce. Moreover, most empirical studies have only included 1 type of exergame in the intervention. Therefore, this study's purpose was to investigate the long-term impact of a multigame exergaming intervention among underserved children integrated within school curricula. Specifically, this study examined the effect of exergaming on children's accelerometer-determined sedentary behavior (SB), light PA, moderate-to-vigorous PA (MVPA), and energy expenditure (EE) over 2 years as compared with regular physical education (PE) classes. Methods: A total of 261 second- and third-grade children (134 girls, 127 boys; mean age 8.27 years) were recruited from 2 Texas elementary schools. Children's pre-test 3-day SB, light PA, MVPA, and EE at school were assessed in the fall of 2012. Participants were assigned to 1 of 2 groups: (1) exergaming/PE group (125 min weekly of exergaming-based PA program) and (2) comparison group (125 min weekly of PE). PA (SB, light PA, and MVPA) and EE outcome variables were assessed again in 2013 (post-test) and 2014 (follow-up). Results: Significant time effects were observed for SB (F(1, 162) = 25.0, p 0.05, η2 = 0.004). Subsequent pairwise comparisons revealed significant increases from pre- to post-test for light PA (p 0.05). Conversely, significant decreases occurred in light PA (p

To obtain a superhydrophobic aluminum alloy surface, a kind of special coupling structure was fabricated on the aluminum alloy surface by a couple ways which was electro-brush plating combined with laser processing. The surface has excellent anti-adhesion and corrosion resistance property. The contact angle can reach as high as 155.1°, while the sliding angle less than 5.6°. The morphological feature, chemical structures, and wettability of resultant surfaces were characterized by scanning electronic microscope (SEM), X-ray diffraction (XRD) and water contact angle measurements. The surface corrosion resistance was researched by a corrosion resistance experiment. The results show that surface consists of micro-scale grooves and like-cauliflower mastoids, the grooves in a regular arrangement with mastoid structures for a coupling structure on the surface. The special coupling structure makes the surface already have superhydrophobicity. The wettability of the surface changes from hydrophilicity to superhydrophobicity. There have no peaks from other phases can be detected between electro-brush plating surface and aluminum alloy substrates. The peak intensity is changed by laser processing, and the organization structure of the material is further refined. The corrosion resistance of the surface that is fabricated by couple ways improves.

Summary: Very little is known about the spatiotemporal generation of lipid droplets (LDs) from the endoplasmic reticulum (ER) and the factors that mediate ER-LD contacts for LD growth. Using super-resolution grazing incidence structured illumination microscopy (GI-SIM) live-cell imaging, we reveal that upon LD induction, the ER-localized protein DFCP1 redistributes to nascent puncta on the ER, whose formation depends on triglyceride synthesis. These structures move along the ER and fuse to form expanding LDs. Fusion and expansion of DFCP1-labeled nascent structures is controlled by BSCL2. BSCL2 depletion causes accumulation of nascent DFCP1 structures. DFCP1 overexpression increases LD size and enhances ER-LD contacts, while DFCP1 knockdown has the opposite effect. DFCP1 acts as a Rab18 effector for LD localization and interacts with the Rab18-ZW10 complex to mediate ER-LD contact formation. Our study reveals that fusion of DFCP1-labeled nascent structures contributes to initial LD growth and that the DFCP1-Rab18 complex is involved in tethering the ER-LD contact for LD expansion. : Li et al. used super-resolution GI-SIM imaging to reveal that during LD biogenesis, the ER-localized protein DFCP1 redistributes to nascent LD structures, which further fuse to form expanding LDs. DFCP1 acts as a Rab18 effector for LD localization and interacts with the Rab18-ZW10 complex to mediate ER-LD contact formation. Keywords: DFCP1, BSCL2, Rab18, membrane contact, lipid droplets

Angiotensin II (AngII), a vasoactive peptide that elevates arterial blood pressure and results in hypertension, has been reported to directly induce vascular endothelial cell apoptosis. Recent work has demonstrated that propofol pre-treatment attenuates angiotensin II-induced apoptosis in human coronary artery endothelial cells. However, the underlying mechanism remains largely unknown. Here, we investigated human umbilical vein endothelial cells (HUVECs) subjected to angiotensin II-induced apoptosis in the presence or absence of propofol treatment and found that angiotensin II-induced apoptosis was attenuated by propofol in a dose-dependent manner. Furthermore, ELISA assays demonstrated that the ratio of angiotensin (1-7) (Ang (1-7)) to Ang II was increased after propofol treatment. We examined the expression of ACE2, Ang (1-7) and Mas and found that the ACE2-Ang (1-7)-Mas axis was up-regulated by propofol, while ACE2 overexpression increased phosphorylated endothelial nitric oxide synthase (phosphorylated eNOS) expression and siACE2 resulted in the repression of endothelial nitric oxide synthase (eNOS) phosphorylation. In conclusion, our study revealed that propofol can inhibit endothelial cell apoptosis induced by Ang II by activating the ACE2-Ang (1-7)-Mas axis and further up-regulating the expression and phosphorylation of eNOS.

BackgroundPostoperative thrombocytopenia has been reported to be correlated with adverse events, but the prognostic value of baseline thrombocytopenia is unclear. This study was undertaken to evaluate the relationship between preoperative thrombocytopenia and adverse outcomes in patients with rheumatic heart disease who underwent valve replacement surgery. Methods and ResultsA total of 1789 patients with rheumatic heart disease undergoing valve replacement surgery were consecutively enrolled and postoperatively followed up for 1 year. Patients were stratified on the basis of presence (n=495) or absence (n=1294) of thrombocytopenia (platelet count,