Significance of the entire C-terminus in biological activities mediated by the RON receptor tyrosine kinase and its oncogenic variant RON160

The RON receptor tyrosine kinase regulates epithelial cell homeostasis and tumorigenesis by transducing multiple signals through its functional domains. The present study was to determine the significance of the entire C-terminus in RON or its variant RON160-mediated activities related to cell motility and tumorigenesis. Analysis of protein phosphorylation revealed that elimination of the entire C-terminus significantly impairs the ligand-dependent or independent RON or RON160 phosphorylation and dimerization. Phosphorylation of downstream signaling proteins such as Erk1/2, AKT, and p38 MAP kinase was also diminished in cells expressing the C-terminus-free RON or RON160. These dysfunctional activities were accompanied with the inability of truncated RON or RON160 to mediate cytoplasmic β-catenin accumulation. Functional analysis further demonstrated that truncation of the C-terminus significantly impairs RON or RON160-mediated cell proliferation, morphological changes, and cellular migration. Significantly, oncogenic RON160-mediated tumor growth in athymic nude mice was lost after the deletion of the C-terminus. Thus, the C-terminus is a critical component of the RON receptor. The entire C-terminus is required for RON or RON160-mediated intracellular signaling events leading to various cellular activities

Chinese herbal Jin-Ying-Tang attenuates the inflammatory response by inhibiting the activation of TLR4/MyD88/TRAF-6/NIK pathway at the mRNA level in LPS-stimulated mouse mammary epithelial cells

Introduction: The effects of Jin-Ying-Tang (JYT) on Toll-like Receptor 4 (TLR4) signalling transduction of lipopolysaccharide (LPS)-stimulated mouse mammary epithelial cells (MECs) in vitro were examined. Material and Methods: The cytotoxicity of JYT (0.06-62.50 mg/mL) on mouse MECs was determined by MTT assay. The MECs were co-cultured with LPS in the presence or absence of JYT (39.10 mu g/mL, 391 mu g/mL, 3910 mu g/mL). The concentrations of interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) in the culture supernatants were detected by ELISA. The mRNA expression of TLR4 and downstream TLR4 signalling molecules such as myeloid differentiation factor 88 (MyD88), tumour necrosis factor receptor associated factor 6 (TRAF-6), inhibitor kappa B (I kappa B), and nuclear factor.B inducing kinase (NIK) were determined by quantitative real-time polymerase chain reaction (qRT-PCR). Results: The results showed that the IC50 of JYT on MECs was 12.25 mg/mL and JYT could significantly decrease the concentrations of IL-6 and TNF-alpha in LPS-stimulated MECs (P < 0.05). The mRNA expression of TLR4, MyD88, TRAF-6, I kappa B, and NIK was also significantly decreased when the LPS-stimulated MECs were cocultured at appropriate concentrations of JYT (P < 0.05, P < 0.01). Conclusion: These observations indicate a potential mechanism through which JYT attenuates the systemic inflammatory response to LPS-stimulated mouse mammary epithelial cells by inhibiting the activation of TLR4/MyD88/TRAF-6/NIK pathway at the mRNA level

Chinese herbal Jin-Ying-Tang attenuates the inflammatory response by inhibiting the activation of TLR4/MyD88/TRAF-6/NIK pathway at the mRNA level in LPS-stimulated mouse mammary epithelial cells

Introduction: The effects of Jin-Ying-Tang (JYT) on Toll-like Receptor 4 (TLR4) signalling transduction of lipopolysaccharide (LPS)-stimulated mouse mammary epithelial cells (MECs) in vitro were examined. Material and Methods: The cytotoxicity of JYT (0.06-62.50 mg/mL) on mouse MECs was determined by MTT assay. The MECs were co-cultured with LPS in the presence or absence of JYT (39.10 mu g/mL, 391 mu g/mL, 3910 mu g/mL). The concentrations of interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) in the culture supernatants were detected by ELISA. The mRNA expression of TLR4 and downstream TLR4 signalling molecules such as myeloid differentiation factor 88 (MyD88), tumour necrosis factor receptor associated factor 6 (TRAF-6), inhibitor kappa B (I kappa B), and nuclear factor.B inducing kinase (NIK) were determined by quantitative real-time polymerase chain reaction (qRT-PCR). Results: The results showed that the IC50 of JYT on MECs was 12.25 mg/mL and JYT could significantly decrease the concentrations of IL-6 and TNF-alpha in LPS-stimulated MECs (P < 0.05). The mRNA expression of TLR4, MyD88, TRAF-6, I kappa B, and NIK was also significantly decreased when the LPS-stimulated MECs were cocultured at appropriate concentrations of JYT (P < 0.05, P < 0.01). Conclusion: These observations indicate a potential mechanism through which JYT attenuates the systemic inflammatory response to LPS-stimulated mouse mammary epithelial cells by inhibiting the activation of TLR4/MyD88/TRAF-6/NIK pathway at the mRNA level

Can luminous Lyman alpha emitters at zz ≃\simeq 5.7 and zz ≃\simeq 6.6 suppress star formation?

Addressing how strong UV radiation affects galaxy formation is central to understanding their evolution. The quenching of star formation via strong UV radiation (from starbursts or AGN) has been proposed in various scenes to solve certain astrophysical problems. Around luminous sources, some evidence of decreased star formation has been found but is limited to a handful of individual cases. No direct, conclusive evidence on the actual role of strong UV radiation in quenching star formation has been found. Here we present statistical evidence of decreased number density of faint (AB magnitude $\geq$ 24.75 mag) Ly\alpha emitters (LAEs) around bright (AB magnitude < 24.75 mag) LAEs even when the radius goes up to 10 pMpc for $z$ $\simeq$ 5.7 LAEs. A similar trend is found for z $\simeq$ 6.6 LAEs but only within 1 pMpc radius from the bright LAEs. We use a large sample of 1077 (962) LAEs at $z$ $\simeq$ 5.7 ($z$ $\simeq$ 6.6) selected in total areas of 14 (21) deg$^2$ with Subaru/Hyper Suprime-Cam narrow-band data, and thus, the result is of statistical significance for the first time at these high redshift ranges. A simple analytical calculation indicates that the radiation from the central LAE is not enough to suppress LAEs with AB mag $\geq$ 24.75 mag around them, suggesting additional physical mechanisms we are unaware of are at work. Our results clearly show that the environment is at work for the galaxy formation at $z$ $\sim$ 6 in the Universe.Comment: Accepted for publication at MNRA

Metal Ions Stabilize a Dimeric Molten Globule State between the Open and Closed Forms of Malic Enzyme

AbstractMalic enzyme is a tetrameric protein with double dimer quaternary structure. In 3–5M urea, the pigeon cytosolic NADP+-dependent malic enzyme unfolded and aggregated into various forms with dimers as the basic unit. Under the same denaturing conditions but in the presence of 4mM Mn2+, the enzyme existed exclusively as a molten globule dimer in solution. Similar to pigeon enzyme (Chang, G. G., T. M. Huang, and T. C. Chang. 1988. Biochem. J. 254:123–130), the human mitochondrial NAD+-dependent malic enzyme also underwent a reversible tetramer-dimer-monomer quaternary structural change in an acidic pH environment, which resulted in a molten globule state that is also prone to aggregate. The aggregation of pigeon enzyme was attributable to Trp-572 side chain. Mutation of Trp-572 to Phe, His, Ile, Ser, or Ala abolished the protective effect of the metal ions. The cytosolic malic enzyme was completely digested within 2h by trypsin. In the presence of Mn2+, a specific cutting site in the Lys-352-Gly-Arg-354 region was able to generate a unique polypeptide with Mr of 37kDa, and this polypeptide was resistant to further digestion. These results indicate that, during the catalytic process of malic enzyme, binding metal ion induces a conformational change within the enzyme from the open form to an intermediate form, which upon binding of L-malate, transforms further into a catalytically competent closed form

Analysis of preoperative and postoperative depression and anxiety in patients with osteochondral lesions of the talus

PurposeThis study aims to investigate the psychological status of patients with Hepple V osteochondral lesions of the talus (OLT) and evaluate the effect of autologous osteoperiosteal transplantation (AOPT) on their psychological well-being.MethodsFifty patients with Hepple V OLT who underwent AOPT at the Comprehensive Foot and Ankle Surgery Ward of Xi’an Honghui Hospital from November 2021 to May 2023 were included in this study. The patients were divided into two groups based on the presence or absence of preoperative symptoms of anxiety/depression. Group A comprised patients with preoperative symptoms, while Group B included patients without such symptoms. Preoperative and final follow-up assessments included the Hospital Anxiety and Depression Scale for evaluating anxiety and depression, the visual analogue scale for pain assessment, and the American Orthopaedic Foot and Ankle Society scores for assessing ankle and hindfoot function.ResultsAmong the 50 Hepple V OLT patients who obtained complete follow-up, twenty-four had preoperative symptoms of anxiety/depression, with an incidence rate of up to 48%. Patients in Groups A and B showed significant improvement in all evaluation indexes after AOPT compared to the preoperative period, but the overall prognosis of Group A was poorer than that of Group B.ConclusionAOPT can effectively improve patients’ pain, functional activities, and psychological status, and there is a significant correlation between patients’ preoperative psychological status and prognosis