In the implementation of management error proofing, enterprises need to carry out risk evaluation and ranking of management activities error, to determine error proofing improvement order. We note ...that management function failure is different from industrial failure, and the management activity error as its cause is also different from operational or device error, so the method generally used in industry is not suitable for the risk assessment of management activity error. To address this issue, this study integrates the FMEA (failure modes and effect analysis) with the ISO9001 standardized management system framework describing multilevel and multi-attribute management activities, and the human errors that may lead to functional failure of quality management activities are identified at each level and each category. The three factors (severity (S), occurrence (O), and detection (D)) of errors in each management activity are evaluated and integrated into the risk priority number for each quality management activity error. The two major defects of the traditional FMEA in the practical application process are as follows: (1) the evaluation of error attributes of various management activities is basically qualitative language description, which cannot be quantified; (2) the other one disadvantage is that it ignores the fact that three factors have the different weights in the system rather than equality, and not considering the relative importance of between them. In this article, the fuzzy set theory and the grey relational decision theory are, respectively, applied to improve the two defects and to improve the accuracy of the decision. Finally, a numerical example of a coal mine is given to verify the effectiveness of the proposed method. This study provides a basis for managers and practitioners to quantitatively evaluate and prevent errors in management activities.
Thermal cycling induced micro-cracks can change the physical and mechanical properties of geothermal energy reservoir, which may influence the heat and mass transfer performance as well as the ...stability of the reservoir. In this study, thermal cycling treatment was carried out on granite over the temperature range of 20–300 °C with 1–20 thermal cycles. The results show that thermal cycling promotes the initiation and propagation of intergranular and intragranular cracks, which are evenly distributed in all directions. With increase in the number of thermal cycles, the crack density (Pl) increases, resulting in increased permeability (K). The path of seepage passage is mainly between the mineral particles. Moreover, the critical crack propagation radius (rc) of rock decreases with increasing cracking degree, which leads to the decrease in rock fracture resistance. In particular, the fracture toughness (Keff) of granite decreases most when it is subjected to 1–5 thermal cycles. Water-cooling thermal cycling and cooling rate can significantly affect the micro-crack evolution, permeability and ability of granite to resist fracture. The changes in mechanical and physical properties observed in this work can provide basic theoretical reference for the rational selection of geothermal energy mining methods and process parameters, as well as the study of reservoir stability evaluation.
Alzheimer’s disease (AD) is the most common neurodegenerative disease featuring progressive impairments in memory, cognition, and behavior and ultimately leads to death. The histopathological changes ...of Alzheimer’s disease include neuronal and synaptic loss, formation of extracellular senile plaques and intracellular neurofibrillary tangles in brain. Multiple lines of evidence indicate that oxidative stress not only strongly participates in an early stage of Alzheimer’s disease prior to cytopathology, but plays an important role in inducing and activating multiple cell signaling pathways that contribute to the lesion formations of toxic substances and then promotes the development of Alzheimer’s disease. Many years of studies show that antioxidant therapies have enjoyed general success in preclinical studies. Therefore, this paper mainly focuses on the recent developments of common used antioxidant therapies for Alzheimer’s disease and thus provides indications for future potential antioxidant therapeutic strategies of neurodegenerative diseases.
The failure characteristics and the various induced fractures of shale are investigated in this paper. Brazilian tests were conducted for different inclination angles of the weak planes of shale (
θ
...= 0, 15, 30, 45, 60, 75, 90°). Different loading rates were applied (
V
= 0.005 kN/s, 0.02 kN/s, 0.1 kN/s, and 0.5 kN/s). The results show that there is an increase in the Brazilian split strength (BSS) with the increase in the inclination angle from 0° to 90°, with possibly a local dip for 45°. When
θ
= 45°, both the split modulus (
E
s
) and the absorbed energy (
U
) had the minimum values, whereas the fracture maximum deviation distance (
L′
max
) had the maximum value. The geometrical trajectory of the fracture in shale samples can be classified into three types, namely the through fracture, the non-through fracture, and the multiple fracture. The BSS,
E
s
, and
U
of shale gradually increased with the increase in loading rate. Additionally, the fracture is more close to the center. This is because, as the loading rate increases, the time for the propagation and evolution of internal damage of shale decreases.
Alzheimer's disease (AD) is the most prevalent neurodegenerative disease worldwide. With the increasing trend of population aging, the estimated number of AD continues to climb, causing enormous ...medical, social and economic burden to the society. Currently, no drug is available to cure the disease or slow down its progression. There is an urgent need to improve our understanding on the pathogenesis of AD and develop novel therapy to combat it. Despite the two well-known pathological hallmarks (extracellular amyloid plaques and intracellular Neurofibrillary Tangles), the exact mechanisms for selective degeneration and loss of neurons and synapses in AD remain to be elucidated. Cumulative studies have shown neuroinflammation plays a central role in pathogenesis of AD. Neuroinflammation is actively involved both in the onset and the subsequent progression of AD. Microglia are the central player in AD neuroinflammation. In this review, we first introduced the different theories proposed for the pathogenesis of AD, focusing on neuroinflammation, especially on microglia, systemic inflammation, and peripheral and central immune system crosstalk. We explored the possible mechanisms of action of stem cell therapy, which is the only treatment modality so far that has pleiotropic effects and can target multiple mechanisms in AD. Mesenchymal stem cells are currently the most widely used stem cell type in AD clinical trials. We summarized the ongoing major mesenchymal stem cell clinical trials in AD and showed how translational stem cell therapy is bridging the gap between basic science and clinical intervention in this devastating disorder.
Activation of RIPK1 controls TNF-mediated apoptosis, necroptosis and inflammatory pathways
. Cleavage of human and mouse RIPK1 after residues D324 and D325, respectively, by caspase-8 separates the ...RIPK1 kinase domain from the intermediate and death domains. The D325A mutation in mouse RIPK1 leads to embryonic lethality during mouse development
. However, the functional importance of blocking caspase-8-mediated cleavage of RIPK1 on RIPK1 activation in humans is unknown. Here we identify two families with variants in RIPK1 (D324V and D324H) that lead to distinct symptoms of recurrent fevers and lymphadenopathy in an autosomal-dominant manner. Impaired cleavage of RIPK1 D324 variants by caspase-8 sensitized patients' peripheral blood mononuclear cells to RIPK1 activation, apoptosis and necroptosis induced by TNF. The patients showed strong RIPK1-dependent activation of inflammatory signalling pathways and overproduction of inflammatory cytokines and chemokines compared with unaffected controls. Furthermore, we show that expression of the RIPK1 mutants D325V or D325H in mouse embryonic fibroblasts confers not only increased sensitivity to RIPK1 activation-mediated apoptosis and necroptosis, but also induction of pro-inflammatory cytokines such as IL-6 and TNF. By contrast, patient-derived fibroblasts showed reduced expression of RIPK1 and downregulated production of reactive oxygen species, resulting in resistance to necroptosis and ferroptosis. Together, these data suggest that human non-cleavable RIPK1 variants promote activation of RIPK1, and lead to an autoinflammatory disease characterized by hypersensitivity to apoptosis and necroptosis and increased inflammatory response in peripheral blood mononuclear cells, as well as a compensatory mechanism to protect against several pro-death stimuli in fibroblasts.
Reactive astrogliosis is an early event in Alzheimer's disease (AD) brain and plays a key role in synaptic degeneration in AD development. Zinc accumulates in extracellular fraction and synaptosomes ...in AD human brains with its effect on reactive astrocytes remaining unknown. Through Western blotting, Quantitative polymerase chain reaction (qPCR), and immunofluorescence detection on primary astrocytes treated by zinc and/or zinc chelator, we revealed that zinc induced harmful A1‐type reactive astrogliosis in cultured primary astrocytes; the latter, promoted synaptic degeneration in primary neurons. The mechanism investigation showed that zinc induced activation of extracellular regulated protein kinase (ERK) and Janus kinase 2 (JAK2), which phosphorylated signal transduction and transcription activator 3 (Stat3) at serine 727 (S727‐Stat3) and tyrosine 705 (Y705‐Stat3), respectively, resulting in activation of Stat3. Stat3 phosphorylation at S727 by ERK plays a key role in zinc‐induced astrogliosis. These data imply a new molecular mechanism of reactive astrogliosis in AD, in which excessive zinc activates Stat3 through up‐regulating ERK signaling pathway.
Zinc activates extracellular regulated protein kinases (ERK) to phosphorylate signal transduction and transcription activator 3 (Stat3) at serine 727 (S727), resulting in Stat3 activation and A1‐type astrogliosis. Zinc also activates Janus kinase 2 (JAK2) to induce phosphorylation of Stat3 at tyrosine 705 (Y705), but Stat3 phosphorylation at this site is not indispensable for astrocytes activation by zinc. The pro‐inflammatory factors released by active astrocytes promote synaptic degeneration in neurons.
ABSTRACT
The mechanism of exosomes derived from activated hepatic stellate cells (HSCs) involved in liver fibrosis is poorly understood. We previously reported that hypoxia‐inducible factor 1 (Hif‐1) ...regulated HSC activation, and, therefore, we investigated in current work whether Hif‐1 regulates exosome secretion and the metabolic switch of HSCs, thus affecting the metabolism of liver nonparenchymal cells. In this study, the characteristics of exosomes from HSCs were assessed via electron microscopy, Western blot analysis, and acetylcholinesterase activity. Confocal microscopy was used to measure the uptake of exosomes by quiescent HSCs, Kupffer cells (KCs), and liver sinusoidal endothelial cells (LSECs). Hif‐1α was inhibited via 2‐ME or specific small interfering RNAs to investigate its role in exosomes derived from HSCs. It was determined that glucose transporter 1 and pyruvate kinase M2 were increasingly expressed in fibrotic liver samples, cell lysates, and exosomes derived from activated HSCs. Exosomes released from HSCs were associated with activation and glucose uptake of HSCs. Delivery of exosomes from activated HSCs induced glycolysis of quiescent HSCs, KCs, and LSECs. Disruption of Hif‐1 expression suppressed the glycolysis effect delivered by exosomes. Conclusively, our results demonstrated that exosomes secreted by activated HSCs affect the metabolic switch of liver nonparenchymal cells via delivery of glycolysis‐related proteins. These findings represent a novel mechanism that contributes to liver fibrosis and has significant implications for new diagnosis and treatment of liver diseases.—Wan, L., Xia, T., Du, Y., Liu, J., Xie, Y., Zhang, Y., Guan, F., Wu, J., Wang, X., Shi, C. Exosomes from activated hepatic stellate cells contain GLUT1 and PKM2: a role for exosomes in metabolic switch of liver nonparenchymal cells. FASEB J. 33, 8530–8542 (2019). www.fasebj.org
The blasting vibration in deep mining affects the safety of the adjacent roadways. To estimate the stability of a deep rock mass opening during blasting excavation, the dynamic responses of the deep ...rock mass subjected to blast loading are investigated in this study. The relationships between the blasting vibration velocity and the frequency over time, horizontal distance, and depth are analyzed, and the stress distribution of the surrounding rock mass is depicted through field tests and numerical simulation. The failure mechanism of deep rock mass is thus revealed, and a new safety criterion regarding the blasting vibration of the deep rock mass is put forward. The results indicate that the vertical vibration velocity is higher than the horizontal vibration velocity and that the vertical tension of the seismic wave of the blast is larger than that of the shearing action in the near-blasting field, which contrasts that of the far field. Both the vibration velocity and frequency decrease with an increase in time, distance, and depth, and the range of influence of the blasting vibration in terms of depth is larger than that for the horizontal direction. Therefore, the deep rock mass is more vulnerable to damage than the shallow rock mass under blast loading. In addition, the surrounding rock stress tends to transfer from the arc foot on the blasting side to the straight wall on the rear side, and the shear stress is ahead of the tensile stress. It was verified through a case calculation that the new criterion has practical value and can be used as a guide for evaluating the blasting vibration effects of the deep rock mass.
The present study aims to investigate the genotype distribution of Human papillomavirus (HPV) and variations of HPV18 and HPV58 infection among 6538 females in Luoyang city during 2019-2021. The ...overall positive rate of females with HPV infection was 12.34%, with 9.74% were infected with single HPV and 2.60% with multiple HPVs. The prevalent rate of high-risk HPV (HR-HPV) was 9.85% and the top five HR-HPV genotypes were HPV52 (1.94%), HPV16 (1.93%), HPV58 (1.48%), HPV51 (1.02%) and HPVV39 (0.99%). Two peaks of HPV infections rates were observed in females aged ≤ 20 and 61-65 years old. To characterize mutations, 39 HPV18 and 56 HPV58 L1, E6 and E7 genes were sequenced and submitted to GenBank. In the HPV18 E6-E7-L1 sequences, 38 nucleotides changes were observed with 10/38 were non-synonymous mutations (5 in E6 gene, 1 in E7 gene and 4 in L1 gene). In the HPV58 E6-E7-L1 sequences, 53 nucleotides changes were observed with 23/53 were non-synonymous mutations (3 in E6 gene, 5 in E7 gene and 15 in L1 gene). Phylogenetic analysis based on L1 gene showed that 92.3% (36/39) of HPV18 isolates fell into sublineage A1 and 7.7% (3/39) belonged to A5. For HPV58, 75.0% (42/56) isolates belonged to sublineage A1 and 25.0% (14/56) were sublineage A2. There was no association between amino mutation and cervical lesions. The present study provides basic information about the distribution, genotypes and variations of HPV among females population in Luoyang city, which would assist in the formulation of HPV screening and vaccination programs and preventive strategies for HPV-attributable cancer in this region.
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