Summary Objective Articular chondrocyte activation, involving aberrant proliferation and prehypertrophic differentiation, is essential for osteoarthritis (OA) initiation and progression. Disruption ...of mechanistic target of rapamycin complex 1 (mTORC1) promotes chondrocyte autophagy and survival, and decreases the severity of experimental OA. However, the role of cartilage mTORC1 activation in OA initiation is unknown. In this study, we elucidated the specific role of mTORC1 activation in OA initiation, and identify the underlying mechanisms. Method Expression of mTORC1 in articular cartilage of OA patients and OA mice was assessed by immunostaining. Cartilage-specific tuberous sclerosis complex 1 ( Tsc1 , mTORC1 upstream inhibitor) knockout (TSC1CKO) and inducible Tsc1 KO (TSC1CKOER ) mice were generated. The functional effects of mTORC1 in OA initiation and development on its downstream targets were examined by immunostaining, western blotting and qPCR. Results Articular chondrocyte mTORC1 was activated in early-stage OA and in aged mice. TSC1CKO mice exhibited spontaneous OA, and TSC1CKOER mice (from 2 months) exhibited accelerated age-related and DMM-induced OA phenotypes, with aberrant chondrocyte proliferation and hypertrophic differentiation. This was associated with hyperactivation of mTORC1 and dramatic downregulation of FGFR3 and PPR, two receptors critical for preventing chondrocyte proliferation and differentiation. Rapamycin treatment reversed these phenotypes in KO mice. Furthermore, in vitro rescue experiments demonstrated that p73 and ERK1/2 may mediate the negative regulation of FGFR3 and PPR by mTORC1. Conclusion mTORC1 activation stimulates articular chondrocyte proliferation and differentiation to initiate OA, in part by downregulating FGFR3 and PPR.
The impact of CO2 dilution on combustion of syngas (a mixture of H2, CO, and CH4) was investigated in a lab-scale gas turbine model combustor at atmospheric pressure conditions. Two mild dilution ...levels of CO2, corresponding to 15% and 34% of CO2 mole fraction in the syngas/CO2 mixtures, were experimentally investigated to evaluate the effects of CO2 dilution on the flame structures and the emissions of CO and NOx. All experiments were performed at a constant Reynolds number (Re = 10000). High-speed flame luminescence, simultaneous planar laser-induced fluorescence (PLIF) measurements of the OH radicals and particle image velocimetry (PIV) were employed for qualitative and quantitative assessment of the resulting flame and flow structures. The main findings are: (a) the operability range of the syngas flames is significantly affected by the CO2 dilution, with both the lean blowoff (LBO) limit and the flashback limit shifting towards fuel-richer conditions as the CO2 dilution increases; (b) syngas flames exhibit flame-pocket structures with chemical reactions taking place in isolated pockets surrounded by non-reacting fuel/air mixture; (c) the inner recirculation zone tends to move closer to the burner axis at high CO2 dilution, and (d) the NOx emission becomes significantly lower with increasing CO2 dilution while the CO emission exhibits the opposite trend. The flame-pocket structure is more significant with increased CO2 dilution level. The low NOx emissions and high CO emissions are the results of the flame-pocket structures.
The interactive effects of salicylic acid (SA) and nitric oxide (NO) on alleviating cadmium (Cd) toxicity in peanut (Arachis hypogaea L.) were studied. Seedlings of two cultivars (Huayu 22 — a big ...seed type, and Xiaobaisha — a small seed type) were treated with 200 μM CdCl₂without or with 0.1 mM SA or 0.25 mM sodium nitroprusside (SNP, an NO donor). Results show that the Cd exposure depressed the plant growth of both the cultivars but more of Huayu 22 than of Xiaobaisha. Exogenous SA and NO alleviated Cd toxicity in both the peanut cultivars: they improved growth, chlorophyll content, photosynthesis, and mineral nutrition. Furthermore, exogenous SA or NO decreased oxidative stress by increasing activities of antioxidant enzymes and content of non-enzymatic antioxidants. Besides, in roots and leaves of both the cultivars, exogenous SA and NO increased Cd accumulation in the cell wall and decreased Cd distribution to organelles. In particular, the effect of SA+SNP was most obvious.
A phase III trial was conducted to compare the safety and efficacy of erlotinib with that of gefitinib in advanced non-small cell lung cancer harbouring epidermal growth factor receptor mutations in ...exon 19 or 21.
Eligible patients were randomised to receive erlotinib (150 mg per day) or gefitinib (250 mg per day) orally until disease progression or unacceptable toxicity. We aimed to determine whether erlotinib is superior to gefitinib in efficacy. The primary end point was progression-free survival.
A total of 256 patients were randomised to receive erlotinib (N=128) or gefitinib (N=128). Median progression-free survival was not better with erlotinib than with gefitinib (13.0 vs 10.4 months, 95% confidence interval (CI) 0.62-1.05, P=0.108). The corresponding response rates and median overall survival were 56.3% vs 52.3% (P=0.530) and 22.9 vs 20.1 months (95% CI 0.63-1.13, P=0.250), respectively. There were no significant differences in grade 3/4 toxicities between the two arms (P=0.172).
The primary end point was not met. Erlotinib was not significantly superior to gefitinib in terms of efficacy in advanced non-small cell lung cancer with epidermal growth factor receptor mutations in exon 19 or 21, and the two treatments had similar toxicities.
With the improvement of people's living standards and oral health education, the demand for orthodontic treatment is increasing. The comprehensive goal of orthodontic treatment is not only to obtain ...esthetic dentition and appearance, but also to obtain oral health, general health and mental and psychological health. Therefore, how to effectively prevent the risks in orthodontic treatment is particularly important, and it is also an important content that orthodontists must master. In this paper, the prevention of related risks in orthodontic treatment was discussed.
Research progress on anaplastic thyroid carcinoma Liu, Z H; Bai, Y X
Zhonghua er bi yan hou tou jing wai ke za zhi = Chinese journal of otorhinolaryngology head and neck surgery,
2023-Dec-07, Letnik:
58, Številka:
12
Journal Article
Nitrile Butadiene Rubber (NBR) is a polymer material and is widely used to make rubber-moving components in industrial applications. Ageing is an important factor that affects the friction and wear ...properties of the material. This study is aimed at investigating the tribological properties of NBR and how they are affected by ageing. The shore hardness, tensile strength and tear strength of normal and aged NBR samples were measured. A CBZ-1 tribo-tester was then used to conduct sliding wear tests between NBR pins and 1Cr18Ni9Ti stainless steel discs under dry sliding conditions. The surface morphologies of the worn NBR pins were examined using laser-interference profilometry and scanning electron microscopy. Also, the friction coefficients and wear rates were analysed and compared. The results showed that ageing had a significant effect on the mechanical and tribological properties of the NBR specimens. As the ageing time and temperature increased, the friction coefficient and the shore hardness also increased. Furthermore, accelerated ageing promoted the ageing process of NBR material, which resulted in a reduction in the tensile strength and tear strength of the NBR, along with the deterioration of its wear resistance. Consequently, its wear mass losses increased with the ageing process. The main wear mechanism between the rubbing pairs was found to be fatigue wear under dry conditions. The knowledge gained herein provides a better understanding of the material degradation and wear mechanism associated with ageing, and is useful for designing and selecting proper operation conditions for prolonged applications of the material under extreme circumstances.
•Ageing and elevated temperatures affected mechanical and tribological properties of NBR.•COF and shore hardness decreased as ageing time and temperature increased.•Ageing reduced tensile and tear strengths of NBR to deteriorate its wear resistance.•Wear mechanisms between the rubbing pairs is fatigue wear.
Summary
Background
Tripartite motif‐containing protein 21 (Trim21) is an E3 ubiquitin‐protein ligase that plays pivotal roles in various diseases. However, its role in mediating keratinocyte ...inflammation, which is a hallmark of psoriasis, has not been thoroughly elucidated.
Objectives
To clarify whether Trim21 plays a pivotal role in regulating keratinocyte inflammation in psoriasis, while focusing on identifying key Trim21 substrates involved in mediating proinflammatory cytokine and chemokine production.
Materials and methods
Cytokine and chemokine secretion was examined by quantitative real‐time polymerase chain reaction (qPCR) in Trim21‐knockdown human keratinocytes. Downstream pathways and substrates of Trim21 were evaluated using immunoblotting, immunoprecipitation and immunofluorescence. The influence of Trim21 ubiquitination on its substrates was tested by in vitro ubiquitination assay, immunoprecipitation and immunofluorescence. The effectiveness of targeting Trim21 for psoriasis treatment was assessed in vivo with haematoxylin and eosin staining, immunofluorescence and qPCR.
Results
Knocking down Trim21 expression alleviated keratinocyte inflammation. Trim21 colocalized with p65/nuclear factor (NF)‐κB in the cytosol and physically bound and ubiquitinated p65 via a lysine 63 (K63) linkage. Instead of changing p65 protein stability, Trim21 enhanced the interaction of p65 with IκB kinase, which promoted p65 phosphorylation, nuclear transport and downstream gene activation. Finally, both in vitro and in vivo experiments verified that topical application of Trim21‐specific small interfering RNA markedly ameliorated imiquimod‐induced psoriasis‐like lesions.
Conclusions
Our study confirms that upregulated Trim21 in psoriatic epidermis ubiquitylates p65 and activates the NF‐κB pathway, which promotes keratinocyte inflammation. Hence, Trim21 represents a potential target for psoriasis treatment.
What is already known about this topic?
Tripartite motif‐containing protein 21 (Trim21) is implicated in the inflammatory response.
Trim21 expression is upregulated in psoriatic epidermis.
Keratinocytes from psoriatic skin secrete proinflammatory cytokines such as interleukin (IL)‐1β, IL‐8, IL‐15, IL‐23 and interferon‐γ, which evoke and promote the inflammatory process.
What does this study add?
The p65 subunit of nuclear factor (NF)‐κB is a newly recognized substrate of Trim21.
Upregulated Trim21 in psoriatic epidermis ubiquitinates p65 and facilitates the activation of the NF‐κB pathway, promoting inflammation in keratinocytes.
Trim21 is a potential target for the treatment of psoriasis.
What is the translational message?
Ubiquitination is involved in the inflammatory process in psoriasis.
Targeting the ubiquitination system for future psoriasis treatment should be explored.
Linked Comment: O’Shaughnessy. Br J Dermatol 2021; 184:8–9.
Plain language summary available online
The mammalian target of rapamycin (mTOR) signaling pathway is upregulated in the pathogenesis of many cancers. Arachidonic acid (AA) and its metabolites play critical role in the development of ...breast cancer, but the mechanisms through which AA promotes mammary tumorigenesis and progression are poorly understood. We found that the levels of AA and cytosolic phospholipase A2 (cPLA2) strongly correlated with the signaling activity of mTORC1 and mTORC2 as well as the expression levels of vascular epithelial growth factor (VEGF) in human breast tumor tissues. In cultured breast cancer cells, AA effectively activated both mTOR complex 1 (mTORC1) and mTORC2. Interestingly, AA-stimulated mTORC1 activation was independent of amino acids, phosphatidylinositol 3-kinase (PI3-K) and tuberous sclerosis complex 2 (TSC2), which suggests a novel mechanism for mTORC1 activation. Further studies revealed that AA stimulated mTORC1 activity through destabilization of mTOR-raptor association in ras homolog enriched in brain (Rheb)-dependent mechanism. Moreover, we showed that AA-stimulated cell proliferation and angiogenesis required mTOR activity and that the effect of AA was mediated by lipoxygenase (LOX) but not cyclooxygenase-2 (COX-2). In animal models, AA-enhanced incidences of rat mammary tumorigenesis, tumor weights and angiogenesis were inhibited by rapamycin. Our findings suggest that AA is an effective intracellular stimulus of mTOR and that AA-activated mTOR plays critical roles in angiogenesis and tumorigenesis of breast cancer.
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