Sepsis, a hyperinflammatory response that can result in multiple organ dysfunctions, is a leading cause of mortality from infection. Here, we show that orphan nuclear receptor Nur77 (also known as ...TR3) can enhance resistance to lipopolysaccharide (LPS)-induced sepsis in mice by inhibiting NF-κB activity and suppressing aberrant cytokine production. Nur77 directly associates with p65 to block its binding to the κB element. However, this function of Nur77 is countered by the LPS-activated p38α phosphorylation of Nur77. Dampening the interaction between Nur77 and p38α would favor Nur77 suppression of the hyperinflammatory response. A compound, n-pentyl 2-3,5-dihydroxy-2-(1-nonanoyl) phenylacetate, screened from a Nur77-biased library, blocked the Nur77-p38α interaction by targeting the ligand-binding domain of Nur77 and restored the suppression of the hyperinflammatory response through Nur77 inhibition of NF-κB. This study associates the nuclear receptor with immune homeostasis and implicates a new therapeutic strategy to treat hyperinflammatory responses by targeting a p38α substrate to modulate p38α-regulated functions.
Autophagy is linked to cell death, yet the associated mechanisms are largely undercharacterized. We discovered that melanoma, which is generally resistant to drug-induced apoptosis, can undergo ...autophagic cell death with the participation of orphan nuclear receptor TR3. A sequence of molecular events leading to cellular demise is launched by a specific chemical compound, 1-(3,4,5-trihydroxyphenyl)nonan-1-one, newly acquired from screening a library of TR3-targeting compounds. The autophagic cascade comprises TR3 translocation to mitochondria through interaction with the mitochondrial outer membrane protein Nix, crossing into the mitochondrial inner membrane through Tom40 and Tom70 channel proteins, dissipation of mitochondrial membrane potential by the permeability transition pore complex ANT1-VDAC1 and induction of autophagy. This process leads to excessive mitochondria clearance and irreversible cell death. It implicates a new approach to melanoma therapy through activation of a mitochondrial signaling pathway that integrates a nuclear receptor with autophagy for cell death.
In order to control the dust pollution produced by air leg rock drill in the trolley area during the excavation of long-distance single ended tunnel, the full-scale physical model of working face was ...established by using FLUENT software, and the numerical simulation analysis of tunnel drilling ventilation and dust removal parameters was carried out. The results show that it is difficult to control the dust pollution of the face by conventional ventilation, and the drilling dust is distributed in the range of 10 m from the face; after the introduction of the long pressure and short suction ventilation scheme, when the ratio of compressed air volume to exhaust air volume is 0.72, the height of the pressure fan is 2.5 m, the distance between the pressure fan and the palm face is 20 m, and the exhaust fan is 12 m away from the palm, the dust concentration control efficiency of the working face is increased by about 60%. Therefore, in the similar long-distance single head tunnel construction, it is appropriate to adopt the dust removal method of long-distance short suction and exhaust fan to ensure the working environment.
Liver kinase B1 (LKB1) has important roles in governing energy homeostasis by regulating the activity of the energy sensor kinase AMP-activated protein kinase (AMPK). The regulation of LKB1 function, ...however, is still poorly understood. Here we demonstrate that the orphan nuclear receptor Nur77 binds and sequesters LKB1 in the nucleus, thereby attenuating AMPK activation. This Nur77 function is antagonized by the chemical compound ethyl 2-2,3,4-trimethoxy-6-(1-octanoyl)phenylacetate (TMPA), which interacts with Nur77 with high affinity and at specific sites. TMPA binding of Nur77 results in the release and shuttling of LKB1 to the cytoplasm to phosphorylate AMPKα. Moreover, TMPA effectively reduces blood glucose and alleviates insulin resistance in type II db/db and high-fat diet- and streptozotocin-induced diabetic mice but not in diabetic littermates with the Nur77 gene knocked out. This study attains a mechanistic understanding of the regulation of LKB1-AMPK axis and implicates Nur77 as a new and amenable target for the design and development of therapeutics to treat metabolic diseases.
The functionalized utilization of lignin is attracting more and more attention. In this paper, we report a 3D interconnected foamy carbon material with highly open pore structure. The carbon foam is ...synthesized by depolymerization reforming strategy. The foamy carbon has a deep internal pore channels and exhibits an enhanced electrosorption capacity. The highest desalination of the foamy carbon reaches 30.2 mg·g−1 in 500 mg·L−1 NaCl at 1.2 V with adsorption rate of 3.75 mg/g/min. Meanwhile, the optimal electrode PDLC-1 shows good regeneration capacity. Our work provides a usable way for the preparation of lignin-derived carbon foam with high-performance of capacitive deionization.
•Depolymerization-reforming lignin regulates its agglomeration behavior.•An efficient strategy to prepare carbon foam with highly open porous structures.•The ultra-high electrosorption performance and cycle stability are observed.
In reservoir flood control operation, candidate reservoir operation alternatives are evaluated, ranked and selected by a multi-criteria decision making (MCDM) method. However, deterministic methods ...cannot handle MCDM problems where uncertainties exist in both criteria performance values (PVs) and criteria weights (CWs). To solve the issue, a SMAA-VIKOR model integrating stochastic multicriteria acceptability analysis (SMAA) theory with the Viekriterijumsko Kompromisno Rangiranje (VIKOR) method is established based on Aydogan and Ozmen (2017). Moreover, we conduct a comprehensive evaluation of the model's decision making results, including risk assessment and sensitivity analysis. The case study applied to a flood control system in Dadu River in China indicates that the SMAA-VIKOR model can quickly identify the optimal alternative that meets the subjective preferences of decision makers, and has remarkable advantages compared to the traditional SMAA-2 model and the deterministic VIKOR method, which can provide theoretical support for making a robust reservoir release decision.
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•Inhibition of RIP1K produces neuroprotection against focal cerebral ischemia.•Inhibition of RIP1K directly protects ischemic neurons and astrocytes.•Inhibition of RIP1K decreases ...RIP1K–RIP3K complex formation.•Inhibition of RIP1K reduces LC3II and active cathepsin B levels and lysosomal membrane permeability.
Although the receptor-interacting protein 1 kinase (RIP1K)-regulated necroptosis can be evoked by cerebral ischemia, the effects of RIP1K in mediating neuronal and astrocytic cell death and the underlying mechanisms remain poorly understood. This study evaluates the contribution of RIP1K to ischemic stroke-induced neuronal and astrocytic cell death, and the activation of autophagic-lysosomal pathway. Using an in vitro oxygen and glucose deprivation (OGD) in primary cultured neurons or astrocytes and a permanent middle cerebral artery occlusion (pMCAO) model in rats or mice, we observed the role of RIP1K in the ischemic neuronal and astrocytic cell death and the underlying mechanisms by pharmacological or genetic inhibition of RIP1K. pMCAO or OGD condition led to an increase in RIP1K, RIP3K and RIP1K–RIP3K complex. RIP1K knockdown or necrostatin-1 (Nec-1, a specific inhibitor of RIP1K) treatment reduced infarct volume, improved neurological deficits, increased microtubule-associated protein 2 (MAP2) and glial fibrillary acidic protein (GFAP) levels, and attenuated neuronal or astrocytic necrotic cell death in the ischemic cortex. RIP1K knockdown decreased RIP1K–RIP3K complex formation, light chain 3 II (LC3II) and active cathepsin B levels and lysosomal membrane permeability (LMP). Furthermore, a combination of Nec-1 and an inhibitor of autophagy or cathepsin B produced an enhancement of protective effect on neuronal or astrocytic cell death. RIP1K-mediated necroptosis may play important roles in ischemia-induced neuronal and astrocytic cell death through the activation of autophagic-lysosomal pathway.
Sperm DNA damage is recognized as an important biomarker of male infertility. To investigate this, sperm DNA damage was assessed by the sperm chromatin dispersion （SCD） test in semen and motile ...spermatozoa harvested by combined density gradient centrifugation （DGC） and swim-up in 161 couples undergoing in vitro fertilization （IVF）. Semen analysis and sperm DNA damage results were compared between couples who did or did not achieve pregnancy. The sperm DNA damage level was significantly different between the two groups （P 〈 0.05） and was negatively correlated with IVF outcomes. Logistic regression analysis confirmed that it was an independent predictor for achieving clinical pregnancy. The effects of different levels of sperm DNA damage on IVF outcomes were also compared. There were significant differences in day 3 embryo quality, blastocyst formation rate, and implantation and pregnancy rates （P 〈 0.05）, but not in the basic fertilization rate between the two groups. Thus, sperm DNA damage as measured by the SCD appears useful for predicting the clinical pregnancy rate following IVF.
To prevent desertification, countries worldwide have made diversified efforts, and vegetation restoration has been demonstrated to be an effective approach. However, in regard to sandy land with ...limited water resources, measures such as revegetation may lead to an increased drought risk. Despite confirmed sand utilization achievements, many controversies remain regarding the advantages of desert greening, especially considering water scarcity. Therefore, the long-run and causal relationships between sandy land, water consumption, and vegetation coverage are necessarily explored. Choosing the southern margin of the Mu Us Sandy Land as the study area, this study explored the interactions between sandy land, water consumption, and normalized difference vegetation index (NDVI) of 2000–2018 with the vector autoregression (VAR) model approach. In the study area, various revegetation projects have been implemented, resulting in a notable reduction in the sandy land area. In addition, the NDVI increased from 0.196 in 2000 to 0.371 in 2018, an increase of 89.3%. The results indicated that there exist long-term stable equilibrium and causal relationships existed between water consumption and sandy land and NDVI. NDVI enhancement is relatively the direct factor that causes the increase of water consumption. It could be inferred that the implemented revegetation measures may rely on a large water consumption amount, which may further aggravate water shortages and ecological damage issues. More scientific and stronger effective water resource management measures should be locally implemented to achieve a balance between water resources and revegetation.
Purpose
A population-level description and analysis of sepsis-related mortality in China is key to the planning and assessment of interventional strategies.
Methods
Retrospective analysis of multiple ...cause of death (MCOD) recorded in the population-based national mortality surveillance system (NMSS) of China. All sepsis-related deaths occurring in 605 disease surveillance points (DSPs) covering 323.8 million population across China were included in our study. Age-standardized mortality and national estimate of sepsis-related deaths were estimated using the census population in 2010 and 2015, respectively.
Results
In 2015, a total of 1,937,299 deaths occurring in any of the 605 DSPs and standardized sepsis-related mortality rate was 66.7 (95% confidence interval CI 66.4–67.0) deaths per 100,000 population. This produced a national estimate of 1,025,997 sepsis-related deaths. Sepsis-related mortality rates exhibited significant geographic variation. In multilevel analysis, male sex (rate ratio RR 1.582, 95% CI 1.570–1.595), increasing age (RR 1.914 for 5-year group, 95% CI 1.910–1.917), and presence of comorbidity (RR 2.316, 95% CI 2.298–2.335) were independently associated with increased sepsis-related mortality. Higher disposable income (RR 0.717 for the fourth interquartile range vs. the first interquartile range, 95% CI 0.515–0.978) and mean years of education (RR 0.808 for the fourth interquartile range vs. the first interquartile range, 95% CI 0.684–0.955) were negatively associated with sepsis-related mortality. However, population-based hospital doctors were not significantly associated with sepsis-related mortality.
Conclusions
The standardized sepsis-related mortality rate in China was high and varied according to socioeconomic indices, even though some uncertainty remained.
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