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Unfolded protein response (UPR) signaling is activated under endoplasmic reticulum (ER) stress, an emerging cancer hallmark, leading to either adaptive survival or cell death, while the mechanisms underlying adaptation-death switch remain poorly understood. Here, we examined whether oncogene iASPP regulates the switch and how the mechanisms can be used in colon cancer treatment. iASPP is downregulated when cells undergo transition from adaptation to death during therapy-induced ER stress. Blocking iASPP's downregulation attenuates stress-induced cell death. Mechanistically, Hu-antigen R (HuR)-mediated stabilization of iASPP mRNA and subsequent iASPP protein production is significantly impaired with prolonged ER stress, which facilitates the degradation of GRP78, a key regulator of the UPR, in the cytosol. Because iASPP competes with GRP78 in binding the ER-resident E3 ligase RNF185, and tips the balance in favor of cell death. Positive correlation between the levels of HuR, iASPP, and GRP78 are detectable in colon cancer tissues in vivo. Genetic inhibition of iASPP/GRP78 or chemical inhibition of HuR not only inhibits tumor growth, but also sensitizes colon cancer cells' responses to BRAF inhibitor-induced ER stress and cell death. This study provides mechanistic insights into the switch between adaptation and death during ER stress, and also identifies a potential strategy to improve BRAF-inhibitor efficiency in colon cancers.

Aging results in progressive decline of renal function as well as histological alterations including glomerulosclerosis and interstitial fibrosis. The objective of current study was to test the benefits of moderate swimming exercise in aged rats on renal function and structure and investigate its molecular mechanisms. Aged rats of 21-months old were given moderate swimming exercise for 12 weeks. Swimming exercise in aged rats led to reduced plasma levels of creatinine and blood urea nitrogen. Periodic acid-Schiff staining results revealed reduced renal injury scores in aged rats after swimming exercise. Swimming exercise in aged rats mitigated renal fibrosis and downregulated the mRNA expression of Acta2, Fn, Col1a, Col4a, and Tgfb1 in kidneys. Swimming exercise in aged rats attenuated lipid accumulation and reduced levels of triglyceride in kidneys. Swimming exercise in aged rats abated oxidative stress, evidenced by reduced MDA levels and increased MnSOD activities in kidneys. Swimming exercise in aged rats inhibited NF-κB activities and reduced renal expression of pro-inflammatory cytokines including MCP-1, IL-1β and IL-6. Mechanistically, swimming exercise restored mRNA and protein expression of PPAR-α in kidney of aged rats. Furthermore, swimming exercise in aged rats increased expression of PPAR-α-targeting microRNAs including miR-21 and miR-34a. Collectively, swimming exercise activated PPAR-α, which partly explained the benefits of moderate swimming exercise in aging kidneys.

Prostacyclin (PGI2) plays key roles in shaping the immune microenvironment and modulating vasodilation, whereas its contribution to endometriosis (EMs) remains largely unclear. Our study suggested that prostacyclin synthase (PTGIS)-dependent PGI2 signaling was significantly activated in EMs, which was involved in the hypoxic microenvironment of ectopic lesions and deficient methylation status of the PTGIS promoter. Notably, in vitro assays, hypoxia promoted PTGIS expression through DNA methyltransferase 1 (DNMT1)-mediated DNA methylation deficiency in endometrial stromal cells (ESCs); PTGIS overexpression enhanced the adhesive ability of ESCs and led to elevated PGI2 production, and PGI2 triggered CD16− (encoded by FCGR3, Fc fragment of IgG receptor IIIa) natural killer (NK)-cell differentiation through PGI2 receptor (IP, PTGIR) in an ESC/NK-cell coculture system. Our rodent model experiment suggested that treatment with the PGI2 analog iloprost and adoptive transfer of fcgr3 knockout (fcgr3−/−) NK cells aggravated EMs progression and that genetic ablation of ptgis (ptgis−/−) in ectopic lesions and treatment with the PTGIR antagonist RO1138452 partially rescued this outcome. Thus, our findings identified the contribution of PGI2 to EMs progression via enhancement of the adhesive ability of ESCs and inhibition of the activity of NK cells. We hypothesized that PGI2 is a target for EMs intervention and provide a rationale for studying pharmacological PTGIR inhibition and PTGIS genetic depletion therapies as therapeutic strategies for EMs.

The modeling of concrete has always been of great interest. In this work, a yield criterion with three surfaces is proposed to capture the plastic yielding behavior under different loading conditions, including uniaxial tension/compression, biaxial tension/compression and tension-compression. Material failure, characterized by the degradation and finally the complete loss of material integrity, can be modeled by the continuum damage approach. Within finite element methods, the nonlocal enhancement of integral-type or gradient-type is often required for the well-posedness of the partial differential equation system. In this work, a localizing gradient damage model has been adopted to obtain mesh-insensitive material responses, while ruling out the unphysical broadening of the damage zone often observed in constant length scale gradient damage models. Following a consistent derivation, the plasticity-damage coupled model has been implemented into an in-house finite element framework. Several representative and demonstrative examples serve to illustrate the capability of the proposed description in concrete modeling, followed by the conclusion, where some final insights are provided.

To introduce a new fully endoscopic visualized laminar trepanning approach with a periendoscopic trephine under local anesthesia for resection of highly migrated lumbar disc herniation (LDH) and report the clinical outcomes of one year follow-up.Twenty-one patients with highly migrated LDH who underwent percutaneous endoscopic lumbar discectomy via the laminar trepanning approach from June 2019 to August 2020 were retrospectively reviewed. Patient-Reported Outcomes Measurement Information System (PROMIS) Short Forms-Pain Interference (PI) and Physical Function (PF) were selected as outcome measures. The operating duration and complication were documented.The average age of the 21 patients (15 males, 6 females) was 37.8 ± 6.0 years (29-52 years). Disc migration originated from L4/5 in 19 patients, L5/S1 in two patients. The mean operative duration was 54.1 ± 9.0 minutes (42-79 min). All patients were followed up to 12 months after the operation. PROMIS PI T-scores decreased significantly from pre-operatively mean 68.6 ± 2.4 to 54.4 ± 1.9 (P 0.001) and 47.1 ± 4.3 (P 0.001) at six weeks and 12 months, respectively. PROMIS PF T-scores improved significantly from pre-operatively mean 26.7 ± 4.7 to 44.3 ± 4.2(P 0.001) and 58.4 ± 4.0 (P 0.001) at six weeks and 12 months, respectively. No complications and disc herniation recurrences occurred.The targeted full endoscopic laminar trepanning under local anesthesia with a visualized periendoscopic trephine offers a safe, efficient and cost-effective option for the resection of highly migrated LDH.

DNA damaging agents are used as chemotherapeutics in many cancers, including hepatocellular carcinoma (HCC). However, they are associated with problems such as low sensitivity to chemotherapy and the induction of liver injury, underscoring the need to identify new therapies. Here, we investigated the differential regulatory effect of metabotropic glutamate receptor 5 (mGlu

To achieve sustainable heritage conservation, preventive conservation has gradually taken precedence over curative conservation, because it can inhibit the damage caused by various environmental factors and maximizes the preservation life of the artifacts. Due to susceptibility to environmental factors, preventive conservation has been used in the conservation of movable wooden artifacts to further protect them. Recently, digital twin technology, as a concept that transcends reality, can be mapped in virtual space to reflect the full lifecycle process of the corresponding entity, which is a superior characteristic that makes it valued and researched for health monitoring and health management of heritages. This paper proposes a health management method mainly for preventive conservation of movable wooden artifacts, integrating digital twin technology into the health management process. Using the Quanzhou Ship as a typical representative, several important components of health management are specifically analyzed, such as the five-dimensional model of the digital twin, the data interaction process of the digital twin, and the identification and assessment of risks. In particular, the process of preventive conservation of the stern based on the digital twin is presented in detail. This method provides a basis for future preventive conservation of movable wooden artifacts and has implications for the use of digital twin technology in the field of heritage conservation, especially for movable wooden artifacts.

Crystalline thermoelectrics have been developed to be potential candidates for power generation and electronic cooling, among which SnSe crystals are becoming the most representative. Herein, we realize high-performance SnSe crystals with promising efficiency through a structural modulation strategy. By alloying strontium at Sn sites, we modify the crystal structure and facilitate the multiband synglisis in p-type SnSe, favoring the optimization of interactive parameters μ and m*. Resultantly, we obtain a significantly enhanced PF ~85 μW cm−1 K−2, with an ultrahigh ZT ~1.4 at 300 K and ZTave ~2.0 among 300–673 K. Moreover, the excellent properties lead to single-leg device efficiency of ~8.9% under a temperature difference ΔT ~300 K, showing superiority among the current low- to mid-temperature thermoelectrics, with an enhanced cooling ΔTmax of ~50.4 K in the 7-pair thermoelectric device. Our study further advances p-type SnSe crystals for practical waste heat recovery and electronic cooling.

Based on the fact that the production of deep coalbed methane (CBM) in Yushe-Wuxiang Block is lower than expected, the paper is carried out uniaxial strength test and triaxial rheological test on coal measure strata reservoirs (mudstone, coal, sandstone and their composite sample) deeper than 1300 m in the block. In the uniaxial strength test, it is found that the stress–strain process of deep coal rock sample was similar to that of shallow one. The brittleness of deep coal rock sample is more obvious. It can also serve as described by the four stages of shallow coal rock sample in the compression process. The compressive strength of the coal in the combined samples will be improved in a small range, while the mudstone will be driven to produce radial tensile failure at the moment of failure. Creep characteristics of the composite sample are similar to those of the single one, and the axial deformation characteristics under lower stress (14 MPa, 18 MPa, 22 MPa) are close to those of coal. The axial deformation characteristics under extreme stress (26 MPa, 30 MPa, 34 MPa) are close to those of sandstone. The established stress-seepage coupled creep damage model can be used to describe the deformation law of each rock sample under different stresses. The permeability characteristics of the composite sample are determined by the poor permeability of the composite formation. There is a great correlation between the volume deformation and permeability evolution of the sample in the test. The permeability model based on the theory of porous media can be well fitted the relationship between volumetric strain and permeability. It is of great significance to predict the influence of creep effect on permeability under different in-situ stresses in engineering.