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Neural precursor cell expressed developmentally downregulated 4 (NEDD4), an E3 ubiquitin ligase, is commonly upregulated in human hepatocellular carcinoma (HCC) and functions as an oncogenic factor in the progression of HCC, but the molecular mechanism needs be further explored. In this study, we found that NEDD4 could facilitate the proliferation of HCC cells, which was associated with regulating the ERK signaling. Further investigation showed that protocadherin 17 (PCDH17) was a potential substrate of NEDD4, and restoration of PCDH17 could block the facilitation of ERK signaling and HCC cells proliferation induced by NEDD4 overexpression. Whereafter, we confirmed that NEDD4 interacted with PCDH17 and promoted the Lys33-linked polyubiquitination and degradation of it via the proteasome pathway. Finally, NEDD4 protein level was found to be inversely correlated with that of PCDH17 in human HCC tissues. In conclusion, these results suggest that NEDD4 acts as an E3 ubiquitin ligase for PCDH17 ubiquitination and degradation thereby promoting the proliferation of HCC cells through regulating the ERK signaling, which may provide novel evidence for NEDD4 to be a promising therapeutic target for HCC. [ABSTRACT FROM AUTHOR]

To explore the deformation behavior and failure strength of sulfate saline silty clay at a temperature of -10℃ and confining pressures of 6~10 MPa, we have performed low-temperature triaxial shear tests on sulfate saline silty clay in Hexi region of Gansu province, China. The variation trend of deviatoric stress, volumetric strain and initial deformation modulus with confining pressure were analyzed. The results demonstrated that the stress-strain curve of frozen sulfate saline silty clay was hyperbolic and the deviatoric stress increased as the axial strain increased and was eventually constant. Owing to particle breakage and melting of ice, when the confining pressure, σ3>6 the strength decreased as the confining pressure increased and the sample exhibited volumetric shrinkage throughout the entire confining-pressure range. A constitutive model of frozen sulfate saline silty clay under high confining pressure has been proposed in combination with the Duncan Chang model and the validity of the model has been confirmed by comparison with test data. [ABSTRACT FROM AUTHOR]

Bronchiolitis obliterans syndrome (BOS) is a major impediment to lung transplant survival and is generally resistant to medical therapy. Extracorporeal photophoresis (ECP) is an immunomodulatory therapy that shows promise in stabilizing BOS patients, but its mechanisms of action are unclear. In a mouse lung transplant model, we show that ECP blunts alloimmune responses and inhibits BOS through lowering airway TGF-β bioavailability without altering its expression. Surprisingly, ECP-treated leukocytes were primarily engulfed by alveolar macrophages (AMs), which were reprogrammed to become less responsive to TGF-β and reduce TGF-β bioavailability through secretion of the TGF-β antagonist decorin. In untreated recipients, high airway TGF-β activity stimulated AMs to express CCL2, leading to CCR2+ monocyte-driven BOS development. Moreover, we found TGF-β receptor 2-dependent differentiation of CCR2+ monocytes was required for the generation of monocyte-derived AMs, which in turn promoted BOS by expanding tissue-resident memory CD8+ T cells that inflicted airway injury through Blimp-1-mediated granzyme B expression. Thus, through studying the effects of ECP, we have identified an AM functional plasticity that controls a TGF-β-dependent network that couples CCR2+ monocyte recruitment and differentiation to alloimmunity and BOS. [ABSTRACT FROM AUTHOR]

The article presents a study of the functional and structural metabolic changes within intact, living cells and three-dimensional tissues using noninvasive, multiparametric and high-resolution imaging with endogenous contrast. It monitors the biomarkers in tissues and cells that are subjected to metabolic changes using the endogenous two-photon excited fluorescence (TPEF), demonstrating that the optical biomarkers can be used for the identification of metabolic changes.

Effects of the trace element germanium (Ge) on the quench sensitivity of an Al-Zn-Mg-Zr alloy were investigated in the present work. The results showed that the Ge-bearing alloy exhibited lower quench sensitivity as compared to the Ge-free alloy. This phenomenon could be reasonably interpreted in terms of the stability of supersaturated solid solution of alloys after quenching from an elevated temperature. The apparent vacancy formation energies for the Ge-free and Ge-bearing alloys were determined to be 0.49 and 0.58 eV respectively. This suggested that the addition of a small amount of Ge was able to trap excess vacancies, leading to a decrease in the amount of coarse dispersoids and resultant low quench sensitivity in Ge-bearing alloys. Therefore, Ge could be used in alloy productions, which require a slow cooling rate to reduce the residual stresses and distortions. [ABSTRACT FROM AUTHOR]

Thermal stability plays an important role in practical application of Al-Zn-Mg-Cu alloy for oil drilling. In this work, a new four-stage aging treatment by employing a natural aging prior to re-aging is designed to improve thermal stability of Al-Zn-Mg-Cu alloy. The effect of T6, four-stage aging, three-stage aging and T74 on thermal stability was investigated by tensile testing, transmission electron microscopy (TEM) and atom probe tomography (APT). The results showed that after thermal exposure at 120 °C for 500 h, the tensile strength of the four-stage aged sample decreased only by 5.05%. APT analysis indicated that natural aging accelerates the diffusion of Mg atoms, and promotes the precipitation of GP zones during re-aging stage, and TEM observations also supports this result. Natural aging for 24 h prior to re-aging enhance the formation of GP zones, leading to an effective improvement of the strength properties and thermal stability of the studied alloy. In addition, precipitates in all aging samples gradually coarsen with the thermal exposure time increase. The influence of precipitates on mechanical properties of the investigative alloy after thermal exposure is also discussed. [ABSTRACT FROM AUTHOR]

Ischemia/reperfusion injury-mediated (IRI-mediated) primary graft dysfunction (PGD) adversely affects both short- and long-term outcomes after lung transplantation, a procedure that remains the only treatment option for patients suffering from end-stage respiratory failure. While B cells are known to regulate adaptive immune responses, their role in lung IRI is not well understood. Here, we demonstrated by intravital imaging that B cells are rapidly recruited to injured lungs, where they extravasate into the parenchyma. Using hilar clamping and transplant models, we observed that lung-infiltrating B cells produce the monocyte chemokine CCL7 in a TLR4-TRIF-dependent fashion, a critical step contributing to classical monocyte (CM) recruitment and subsequent neutrophil extravasation, resulting in worse lung function. We found that synergistic BCR-TLR4 activation on B cells is required for the recruitment of CMs to the injured lung. Finally, we corroborated our findings in reperfused human lungs, in which we observed a correlation between B cell infiltration and CM recruitment after transplantation. This study describes a role for B cells as critical orchestrators of lung IRI. As B cells can be depleted with currently available agents, our study provides a rationale for clinical trials investigating B cell-targeting therapies. [ABSTRACT FROM AUTHOR]

The occurrence and development of many diseases are highly associated with the aging of the body. Among them, osteoporosis (OP) is a common age-related disease that tends to occur in the elderly population and is highly related to the aging factors in the body. In the process of aging transmission, the senescence-related secretory phenotype (SASP) can convey the information about aging through the paracrine pathway and endocrine mechanism through the extracellular vesicles (EVs) connected to SASP. EVs can be used as a way of conduction to join the connection between micro-environmental aging and age-related illnesses. EVs are double-layer membranous vesicles separated or secreted from the cell membrane, which mainly include microvesicles (MVs) and exosomes. Vesicular bodies secreted by this exocrine form carry a variety of cell-derived related substances (including a variety of proteins, lipids, DNA, mRNA, miRNAs, etc). These substances are mainly concentrated in human body fluids, especially can be transported to all parts of the body with the blood circulation system, and participate in the interactions between cells. Osteoporosis is closely associated with aging and aging cells, suggesting EVs were active in this pathological process. In this article, the basic mechanisms of aging cells in the occurrence and progression of osteoporosis through EVs will be discussed, to explore the connection between aging and osteoporosis, thereby providing a new perspective on the occurrence and development as well as prevention and treatment of osteoporosis. [ABSTRACT FROM AUTHOR]

Microstructures and mechanical properties of Al-Cu-Mg alloys containing various Ag additions were investigated by a combination of the tensile testing and quantitative transmission electron microscopy (TEM) analysis. Our results indicated that an increase of Ag from 0.46 to 0.88wt% promoted the precipitation of Ω phase, thereby leading to the noticeable improvement on the strength properties of the underaged Al-Cu-Mg alloys at various temperatures. This enhanced precipitation of Ω phase was also accompanied by the suppressed formation of θ' phase. Despite further exposing at 300°C lead to a pronounced decrease in the number density of Ω phase, the higher plate number density was still revealed in 0.88Ag alloy rather than 0.46Ag alloy. Moreover, quantitative TEM results of the studied alloys highlighted the differences in the coarsening kinetics of Ω phase during further exposing at 300°C. Ω phase tended to experience a transition from the plate thickening to the plate lengthening by increasing Ag at 300°C. Our results also present the positive effect of pre-aging at 165°C for 2h on retarding the thickening kinetics of Ω phase at 300°C. [ABSTRACT FROM AUTHOR]

Recent studies have shown that sevoflurane can cause long-term neurotoxicity and learning and memory impairment in developing and progressively neurodegenerative brains. Sevoflurane is a widely used volatile anesthetic in clinical practice. Late gestation is a rapidly developing period in the fetal brain, but whether sevoflurane anesthesia during late gestation affects learning and memory of offspring is not fully elucidated. Histone deacetylase 2 (HDAC2) plays an important regulatory role in learning and memory. This study examined the effect of maternal sevoflurane exposure on learning and memory in offspring and the underlying role of HDAC2. The Morris water maze (MWM) test was used to evaluate learning and memory function. Q-PCR and immunofluorescence staining were used to measure the expression levels of genes related to learning and memory. The results showed that sevoflurane anesthesia during late gestation impaired learning and memory in offspring rats (e.g., showing increase of the escape latency and decrease of the platform-crossing times and target quadrant traveling time in behavior tests) and upregulated the expression of HDAC2, while downregulating the expression of the cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) and the N-methyl-D-aspartate receptor 2 subunit B (NR2B) mRNA and protein in the hippocampus of offspring in a timedependent manner. HDAC2 inhibitor suberoylanilide hydroxamic acid (SAHA) treatment alleviated all of these changes in offspring rats. Therefore, the present study indicates that sevoflurane exposure during late gestation impairs offspring rat's learning and memory via upregulation of the expression of HDAC2 and downregulation of the expression of CREB and NR2B. SAHA can alleviate these impairments. [ABSTRACT FROM AUTHOR]