Search

Chronic pain is frequently comorbid with depression. However, the mechanisms underlying chronic pain-induced depression remain unclear. Here, we found that DNA methyltransferase 1 (DNMT1) was upregulated in the central amygdala (CeA) of spared nerve injury (SNI)-induced chronic pain-depression rats, and knockdown of DNMT1 could improve the depression-like behaviors in SNI rats. Additionally, a panel of differentially expressed lncRNAs, including 38 upregulated and 12 downregulated lncRNAs, were identified by microarray analysis. Bioinformatics analysis suggested that the upregulated lncRNA XR_351665 was the upstream molecule to regulate DNMT1 expression. The knockdown of XR_351665 significantly alleviated the depression-like behaviors in SNI rats, whereas overexpression of XR_351665 induced the depression-like behaviors in naïve rats. Further mechanism-related researches uncovered that XR_351665 functioned as a competing endogenous RNA (ceRNA) to upregulate DNMT1 by competitively sponging miR-152-3p, and subsequently promoted the development of chronic pain-induced depression. Our findings suggest that lncRNA XR_351665 is involved in the development of chronic pain-induced depression by upregulating DNMT1 via sponging miR-152-3p. These data provide novel insight into understanding the pathogenesis of chronic pain-induced depression and identify a potential therapeutic target. Perspective: LncRNA XR_351665 in CeA functions as a ceRNA to block the inhibitory effect of miR-152-3p on DNMT1 and contributes to the development of chronic pain-induced depression. These data suggest that manipulation of XR_351665/miR-152-3p/DNMT1 axis may be a potential method to attenuate chronic pain-induced depression.

The mechanism of how porosity affects EM wave absorption was investigated with a quantitative random network model.

The total temperature and pressure are measured as inter-stage data in axial compressor experiments. Traditional diagnosing methods of 0-dimension (0D) or 1-dimension (1D) could lead to higher errors at hub sections without the presence of the radial equilibrium equation at stator leading edges, and 3-dimensional computational fluid dynamics can hardly provide reliable results for multistage compressors. In this paper, a fast method called “Diagnosis Using Inter-stage Data” (DUID) was developed to convert experiment data into meridional flow fields, which automatically satisfies the radial equilibrium equation and provides more accurate results for axial compressors. An aeroengine fan, a 3-stage compressor and a 6-stage compressor were used to validate the DUID. Their meridional flow fields, which cannot be observed directly in test rigs, were rebuilt. Results reveal facts that hub static pressures are approximately 15% lower than the traditional 0D/1D constant assumption. Though the stator models determine the loss ratio in a single stage, the DUID can avoid the model error amplification and be robustious for multistage compressors. And the generated flow field is sensitive to changes in the total temperature. Analyses of the experiment flow fields provide more quantitative and accurate references for subsequent modifications. In conclusion, using experiment inter-stage data, the DUID can rebuild meridional flow fields, which help to improve data processing accuracy.

Numerous studies have shown that mitochondrial dysfunction manifested by increased mitochondrial permeability transition pore (mPTP) opening and reactive oxygen species (ROS) level, and decreased mitochondrial membrane potential (MMP) plays an important role in the development of neuropathic pain. Sirtuin3 (SIRT3), a nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase, has been shown to inhibit mitochondrial oxidative stress. However, the role of SIRT3 in neuropathic pain is unclear. In this study, we found that the protein and mRNA levels of SIRT3 were significantly downregulated in the spinal cords of spared nerve injury- (SNI-) induced neuropathic pain mice, while overexpression of spinal SIRT3 reversed SNI-induced pain hypersensitivity. Further study showed that SIRT3 overexpression reduced the acetylation level of lysine 166 (K166) on cyclophilin D (CypD), the regulatory component of the mPTP, inhibited the mPTP opening, decreased ROS and malondialdehyde (MDA) levels, and increased MMP and manganese superoxide dismutase (MnSOD) in SNI mice. Point mutation of K166 to arginine on CypD (CypD-K166R) abrogated SNI-induced mitochondrial dysfunction and neuropathic pain in mice. Moreover, inhibiting mPTP opening by cyclosporin A (CsA) improved mitochondrial function and neuropathic pain in SNI mice. Together, these data show that SIRT3 is necessary to prevent neuropathic pain by deacetylating CypD-K166 and further improving mitochondrial dysfunction. This study may shed light on a potential drug target for the treatment of neuropathic pain.

Emotional disorders are common comorbid conditions that further exacerbate the severity and chronicity of chronic pain. However, individuals show considerable vulnerability to the development of chronic pain under similar pain conditions. In this study on male rat and mouse models of chronic neuropathic pain, we identify the histone deacetylase Sirtuin 1 (SIRT1) in central amygdala as a key epigenetic regulator that controls the development of comorbid emotional disorders underlying the individual vulnerability to chronic pain. We found that animals that were vulnerable to developing behaviors of anxiety and depression under the pain condition displayed reduced SIRT1 protein levels in central amygdala, but not those animals resistant to the emotional disorders. Viral overexpression of local SIRT1 reversed this vulnerability, but viral knockdown of local SIRT1 mimicked the pain effect, eliciting the pain vulnerability in pain-free animals. The SIRT1 action was associated with CaMKIIα downregulation and deacetylation of histone H3 lysine 9 at theCaMKIIα promoter. These results suggest that, by transcriptional repression ofCaMKIIα in central amygdala, SIRT1 functions to guard against the emotional pain vulnerability under chronic pain conditions. This study indicates that SIRT1 may serve as a potential therapeutic molecule for individualized treatment of chronic pain with vulnerable emotional disorders.SIGNIFICANCE STATEMENTChronic pain is a prevalent neurological disease with no effective treatment at present. Pain patients display considerably variable vulnerability to developing chronic pain, indicating individual-based molecular mechanisms underlying the pain vulnerability, which is hardly addressed in current preclinical research. In this study, we have identified the histone deacetylase Sirtuin 1 (SIRT1) as a key regulator that controls this pain vulnerability. This study reveals that the SIRT1–CaMKIIaα pathway in central amygdala acts as an epigenetic mechanism that guards against the development of comorbid emotional disorders under chronic pain, and that its dysfunction causes increased vulnerability to the development of chronic pain. These findings suggest that SIRT1 activators may be used in a novel therapeutic approach for individual-based treatment of chronic pain.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) caused by the combination of environmental factors and susceptible genetic background. Experimental autoimmune encephalomyelitis (EAE) is a typical disease model of MS widely used for investigating the pathogenesis in which T lymphocytes specific for myelin antigens initiate an inflammatory reaction in CNS. It is very important to assess how lymphocytes in the CNS regulate the development of disease. However, the approach for measuring the quantity and quality of infiltrated lymphocytes in the CNS is very limited due to the difficulties in isolating and detecting infiltrated lymphocytes from the brain. This manuscript presents a protocol for that is useful for the isolation, identification, and characterization of infiltrated lymphocytes from the CNS and will be helpful for our understanding of how lymphocytes are involved in the development of the CNS autoimmune disease.

Some criteria are given in this paper for uniformly non- l n ( 1 ) , locally uniformly non- l n ( 1 ) and non- l n ( 1 ) properties of Orlicz–Bochner function spaces endowed with the Orlicz norm. As the consequence, we can immediately get the characterization of B-convexity, uniform nonsquareness, local uniform nonsquareness and nonsquareness in Orlicz–Bochner function spaces, although some of them were obtained in recent years.

Three compressors with fore-loaded, uniformly loaded and aft-loaded rotor blades are designed via streamline curvature method coupled with blade generation that uses arbitrary camber lines so as to study the effect mechanism of rotor axial blade loading distributions on compressor performance. The rotor blade loading design is achieved by modifying the flow circulation in the rotor region on the basis of ensuring the total rotor work unchanged during the through-flow solving. Based on global linear stability analysis, a stall inception prediction model is established and integrated into the compressor design process as an assessment tool of flow stability. The predicted stall inception of the fore-loaded compressor validates the model precision by comparing with experimental measurements. Steady numerical simulations show that the pressure rise and efficiency of aft-loaded compressor are the best at the mass flow rates less than design point, followed by the uniformly loaded compressor, and those of the fore-loaded compressor are the worst. Steady blade loading analysis indicates that the peak loading positions of the three types of rotors move towards the leading edge accompanying with the throttling process. The comparison of predicted stall inception points among the three compressors presents that the fore-loaded compressor is the first to enter instability state, followed by the uniformly loaded compressor, while the aft-loaded compressor is the last. The steady and unsteady flow fields show that the maximum tip loading of rotor and stator blades becomes larger at the near-stall point as the rotor becomes more fore-loaded. This finding combined with the unsteady tip clearance flow explains the flow stability distinction of the three compressors to some extent.

A new machining method for lens molds using tilt electrical discharge milling (ED milling) has been experimentally investigated. Compared with the conventional ED milling, the tilt ED milling enables efficient enlargement of discharge gap by adjusting the tilt angles of the workpiece which results in efficient chip removal and burnish surface quality. On account of this method, micro lens craters were fabricated on the tungsten carbide (WC) and silicon carbide particulate reinforced aluminum metal matrix composite (SiCp/Al) at the optimized machining parameters under various tilt angles of the workpiece. The surface morphology and material removal rate were determined with a laser scanning microscope VK-X100 (KEYENCE, Japan). Experimental results present a 60% rise in surface quality at 25° in tilt ED milling. On the basis of electromagnetic effect, the machining mechanism is analyzed in detail in tilt ED milling for lens molds.

Pain symptoms can be transmitted across generations, but the mechanisms underlying these outcomes remain poorly understood. Here, we identified an essential role for primary somatosensory cortical (S1) glutamate neuronal DNA methyl-CpG binding protein 2 (MeCP2) in the transgenerational transmission of pain. In a female mouse chronic pain model, the offspring displayed significant pain sensitization. In these mice, MeCP2 expression was increased in S1 glutamate (GluS1) neurons, correlating with increased neuronal activity. Downregulation of GluS1 neuronal MeCP2 in maternal mice with pain abolished offspring pain sensitization, whereas overexpression of MeCP2 in naïve maternal mice induced pain sensitization in offspring. Notably, single-cell sequencing and chromatin immunoprecipitation analysis showed that the expression of a wide range of genes was changed in offspring and maternal GluS1 neurons, some of which were regulated by MeCP2. These results collectively demonstrate the putative importance of MeCP2 as a key regulator in pain transgenerational transmission through actions on GluS1 neuronal maladaptation.

Recent years have seen a surging number of epigenetic studies and rapid progress in understanding of epigenetic mechanisms of gene regulation and their dysfunctions in the pathogenesis of neurological diseases such as chronic pain. As we gain increasing knowledge on the epigenetic machinery for transcriptional regulation of gene expression, all major processes of the epigenetic regulations identified so far have been implicated in the pathogenesis of pain, including histone acetylation and methylation, noncoding RNAs, and DNA methylation. This chapter reviews and summarizes research development and advances in these areas of pain epigenetics over the past decade, focusing on new findings in the last few years that address methylation and demethylation on histone proteins and DNA in pain-induced chromatin modifications.

Well leakage of fractured strata is a tricky problem while drilling. This unwieldy problem is usually caused by the poor formation of the cementing degree, the staggered-mesh of the fracture, and the low bearing capacity of the formation, which can also lead to a narrow and even unsafe window of drilling fluid density. For fractured strata, the normal plugging material has the disadvantages of unsuitable size and low strength, resulting in unsuccessful first time plugging and an increase in cost. Therefore, we developed a polymer plugging gel for the fractured strata, named XNGJ-3. XNGJ-3 is mainly made of an acrylamide monomer and is accompanied by the reactive monomers of carboxyl and hydroxyl as ingredients. XNGJ-3 has a low viscosity before gelling. At 80 °C it becomes gelled, and the gelling time was controlled within the required time of the practical application. These conditions are beneficial for making the plugging material enter the crossing fracture smoothly and occlude the fracture. XNGJ-3 also has a good deformability and can avoid being damaged during the process of fracture closure. The well leakage simulated experiment revealed that the bearing capacity of this material can reach 21 MPa and the inverse bearing capacity can reach 20 MPa. These strengths are more than twice that of common polymer plugging gels. Finally, three leaked wells in the fractured strata of the Sichuan Basin were used to verify the plugging effect of XNGJ-3. Compared with other common plugging materials, XNGJ-3 has the advantages of having a higher success rate of first time plugging, a lower economic cost, a shorter work time, and so forth, which indicate that this plugging material has a good engineering application value in dealing with well leakage of fractured strata.

Multiple sclerosis (MS) is a complex multifactorial disease that results from the interplay between environmental factors and a susceptible genetic background. Experimental autoimmune encephalomyelitis (EAE) has been widely used to investigate the mechanisms underlying MS pathogenesis. Chemokines, such as CCL2, are involved in the development of EAE. We have previously shown that thiamine deficiency (TD) induced CCL2 in neurons. We hypothesized that TD may affect the pathogenesis of EAE. In this study, EAE was induced in C57BL/6J mice by the injection of myelin oligodendroglial glycoprotein (MOG) peptides 35–55 with or without TD. TD aggravated the development of EAE, which was indicated by clinical scores and pathologic alterations in the spinal cord. TD also accelerated the development of EAE in an adoptive transfer EAE model. TD caused microglial activation and a drastic increase (up 140%) in leukocyte infiltration in the spinal cord of the EAE mice; specifically, TD increased Th1 and Th17 cells. TD upregulated the expression of CCL2 and its receptor CCR2 in the spinal cord of EAE mice. Cells in peripheral lymph node and spleen isolated from MOG-primed TD mice showed much stronger proliferative responses to MOG. CCL2 stimulated the proliferation and migration of T lymphocytes in vitro. Our results suggested that TD exacerbated the development of EAE through activating CCL2 and inducing pathologic inflammation.

Peripherally produced corticotrophin-releasing hormone (CRH) is a strong proinflammatory factor involved in many inflammatory diseases. However, to date, there is no evidence about the action of CRH on atherosclerosis, a chronic disease characterized by inflammatory reactions. In this study we observed the effect of CRH on atherosclerosis in low-density lipoprotein receptor-deficient (LDLr-/-) mice. Twelve-week-old, male LDLr-/- mice were subcutaneously injected with CRH (10microg/kg) or vehicle once a day for 8 weeks. The results indicated aortic atherosclerotic lesions were larger (P

Corticotropin-releasing factor (CRF), which activates the hypothalamic-pituitary- adrenal axis under stress, also has proinflammatory peripheral effects possibly through mast cells. The purpose of this study was to investigate the effect of urocortin (UCN), a 40-amino-acid CRF family peptide, on degranulation and intracellular calcium of rat lung mast cells. The activation and degranulation of mast cells were observed by Toluidine blue staining and transmission electron microscope. The intracellular calcium was investigated using confocal laser scanning microscopy and flow cytometry. The results indicated that all the three different concentrations of UCN (0.1, 1 and 10 microM) significantly induced the activation and degranulation of rat lung mast cells in vitro. This effect was markedly blocked by selective CRF receptor 1 (CRF-R1) antagonist antalarmin, but not by specific CRF receptor 2 (CRF-R2) antagonist antisauvagine-30 (anti-Svg-30). The results also showed that UCN caused a rapid peak increase in [Ca(2+)](i) at point of 300s after UCN treatment, followed by a decrease to a sustained plateau phase. The peak increase in [Ca(2+)](i) induced by UCN was significantly inhibited by antalarmin, but not by anti-Svg-30. This effect of UCN on [Ca(2+)](i) in rat lung mast cells was also found by flow cytometry. Regression analysis revealed a positive correlation between mast cells degranulation extent and the maximum value of [Ca(2+)](i) (P0.01). Taken together, our present study suggested that UCN induced the increase of [Ca(2+)](i) and degranulation of rat lung mast cells through CRF-R1. These findings may have implications for the pathophysiology of allergic and inflammatory lung disorders such as asthma, which is closely associated with mast cell activation and degranulation.

Based on the special rheological model of foam fluid, the mathematical models of cuttings transport for stable foam drilling in vertical/near vertical sections, the transitional section, and inclined/horizontal sections are established in this paper. The effects of various flow parameters on the cuttings bed thickness in the annulus are analyzed. The results show that inclination, annulus velocity, foam flow rate, and eccentricity are key factors affecting cuttings transport. The thickness of a cuttings bed gradually decreases with the inclination decrease of the highly deviated/horizontal sections. When the inclination is reduced to approximately 60°, the dynamic and static cuttings bed disappears and is substituted by the glide lamella, which consists of cuttings grains. Cuttings grains have various forms of movement on the lower borehole wall. When the inclination is reduced to below 30°, the cuttings are brought out of the well by the stable foam if the returning velocity of the annulus foam is larger than the depositing velocity of the cuttings. The thickness of the cuttings bed gradually decreases with the increase of annulus velocity. The increased foam quality reduces the concentration of annulus cuttings when the annulus velocity is constant and when it reaches a stable status earlier than the foam drilling fluid of lower foam quality. However, the concentration of the annulus cuttings at the final stage is constant. The thickness of the cuttings bed increases with increased eccentricity of the drill stem. When the eccentricity is large, the change of eccentricity has a high effect on the cuttings bed thickness.

PACT and its murine ortholog RAX were originally identified as a protein activator for the dsRNA-dependent, interferon-inducible protein kinase PKR. Recent studies indicated that RAX played a role in embryogenesis and neuronal development. In this study, we investigated the expression of RAX during the postnatal development of the mouse cerebellum and its role in the migration of cerebellar granule neurons (CGNs). High expression of RAX was observed in the cerebellum from postnatal day (PD) 4 to PD9, a period when the CGNs migrate from the external granule layer (EGL) to the internal granule layer (IGL). The migration of the EGL progenitor cells in vivo was inhibited by RAX knockdown on PD4. This finding was confirmed by in vitro studies showing that RAX knockdown impaired the migration of CGNs in cerebellar microexplants. PACT/RAX-regulated migration required its third motif and was independent of PKR. PACT/RAX interacted with focal adhesion kinase (FAK) and PACT/RAX knockdown disturbed the FAK phosphorylation in CGNs. These findings demonstrated a novel function of PACT/RAX in the regulation of neuronal migration.

Geometric form of Ni60 alloy fabricated by laser cladding is analyzed by a new diagnosis algorithm in which Back-propagation is combined with fuzzy classifier. In some complexity environments, the classic BP neural network appears limitation in classification. The proposed approach in this paper uses fuzzy model to the neural network structure. It considers classify variance and energy function to adjust convergence of the network. With the improved nonlinear mapping property, the proposed approach achieves perfect results with change all this term to identification ratio of 100% in our experiments, while that of the classical experiment is 57% accordingly.

The paper proposed an new diagnosis algorithm of back-propagation combine with fuzzy classify approach. For some complexity environments, the classic BP neural network appear limitation on classify issues. The paper imposed fuzzy model on neural network structure, which using classify variance and energy function to adjust convergence of the network. With the improved nonlinear mapping property, the diagnostical processing, in our experiments, shows perfect results with identify ratio of 100%, while classical experiment is 50% accordingly.

Crocetin, a unique carotenoid with potent antioxidative and anti-inflammatory activities, is a major ingredient of saffron used as an important spice and food colorant in various parts of the world. In the present study, the effects of crocetin on platelet activity and thrombosis formation were systematically investigated. Crocetin showed a dose-dependent inhibition of platelet aggregation induced by ADP, collagen, but not by arachidonic acid (AA). Crocetin significantly attenuated dense granule release, while neither platelets adhesion to collagen nor cyclic AMP level was altered by crocetin. Pretreatment with crocetin was confirmed to partially inhibit Ca (2+) mobilization via reducing both intracellular Ca (2+) release and extracellular Ca (2+) influx. Besides that, crocetin prolonged the occlusive time in electrical stimulation-induced carotid arterial thrombosis. These findings suggest that the favorable impacts of crocetin on platelet activity and thrombosis formation may be related to the inhibition of Ca (2+) elevation in stimulated platelets.

Extra-heavy oil or bitumen wells are very difficult to start up and recover because of the high oil viscosity in cold production. It is necessary to get initial mobility by reducing the viscosity of oil or bitumen when the wells are drilled. Although there are mechanical ultrasonic stimulation technologies, the penetration of ultrasonic wave in the formation is very limited and their efficiency is not very good. Hot water or steam circulation is another option. However the heat loss in the wellbore is too significant to send enough heat to the targeted interval, specifically for deep reservoirs. Solvent could be a better option from both oil viscosity reduction and operation points of view. It can be injected into the well immediately after drilling for soaking, which is a convenient method to reduce viscosity without many complicated procedure as thermal methods. The concern for using solvent to reduce viscosity is selecting the optimal solvent. This paper studied the mixture of some typical extra-heavy oil and bitumen with solvent. After fully mixed with each other, viscosity reduction and potential precipitation have been investigated. Different solvents are discussed and recommended to reduce viscosity for new well start up and work-over. A series of viscosity tests is conducted in the paper for heavy oil-solvent mixture under different temperatures to discuss the effect of three different solvents (diesel, ligarine and toluene) on viscosity reduction. Through these viscosity tests, the optimal solvent, temperature and solvent concentration for viscosity reduction are recommended. And it is found that after a solvent is placed in contact with heavy oil samples at any temperature in the range of 20 – 80C the reduction of viscosity can be significant. However, considering the economical effectiveness, diesel is not recommended. And 60–90 ligarine and toluene are better choices for starting up super heavy oil or bitumen wells. In addition, as to bitumen, due to its extremely high viscosity, using several times volume of solvent as the bitumen volume still can’t have the viscosity reduce to a desired value. So these solvents tested in the experiments are not recommended for bitumen well starting up after drilling.