KPNA2/importin-alpha1 (karyopherin subunit alpha 2) is the primary nucleocytoplasmic transporter for some transcription factors to activate cellular proliferation and differentiation. Aberrant ...increase of KPNA2 level is identified as a prognostic marker in a variety of cancers. Yet, the turnover mechanism of KPNA2 remains unknown. Here, we demonstrate that KPNA2 is degraded via the chaperone-mediated autophagy (CMA) and that Zika virus (ZIKV) enhances the KPNA2 degradation. KPNA2 contains a CMA motif, which possesses an indispensable residue Gln109 for the CMA-mediated degradation. RNAi-mediated knockdown of LAMP2A, a vital component of the CMA pathway, led to a higher level of KPNA2. Moreover, ZIKV reduced KPNA2 via the viral NS2A protein, which contains an essential residue Thr100 for inducing the CMA-mediated KPNA2 degradation. Notably, mutant ZIKV with T100A alteration in NS2A replicates much weaker than the wild-type virus. Also, knockdown of KPNA2 led to a higher ZIKV viral yield, which indicates that KPNA2 mediates certain antiviral effects. These data provide insights into the KPNA2 turnover and the ZIKV-cell interactions.
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BFBNIB, GIS, IJS, KISLJ, NUK, PNG, UL, UM, UPUK
Acute lung injury (ALI) is an inflammatory condition and there are no effective treatments. A novel new compound---colchicine-myricetin hybrid (CMyrH) was herein designed and synthesized. To evaluate ...the activity of CMyrH in ALI, we used a bleomycin (BLM) induced BEAS-2B injury model
and established a well-recognized rat model of BLM-induced lung injury
. The results demonstrated that colchicine-myricetin hybrid protected BEAS-2B cells against BLM-induced cell injury in an increased dose manner, and reduced wet/dry weight ratio, histological scoring, and inflammation cytokines IL-1β, IL-6, IL-18, and TNF-α levels of lung tissue of the rats. Furthermore, we found colchicine-myricetin hybrid inhibited caspase-1, ASC, GSDMD, and NLRP-3 expression
. Meanwhile, we used molecular docking to analyze the binding mode of colchicine-myricetin hybrid and human neutrophil elastase (HNE), it revealed that colchicine-myricetin hybrid showed strong binding affinity toward human neutrophil elastase when compared to its parent molecules. In conclusion, It is suggested that colchicine-myricetin hybrid antagonized acute lung injury by focusing on multi-targets via multi-mechanisms, and might be served as a potential therapeutic agent for acute lung injury.
Studies have suggested that microglial IL‐6 modulates inflammatory pain; however, the exact mechanism of action remains unclear. We therefore hypothesized that PKCε and MEG2 competitively bind to ...STAT3 and contribute to IL‐6‐mediated microglial hyperalgesia during inflammatory pain. Freund's complete adjuvant (FCA) and lipopolysaccharide (LPS) were used to induce hyperalgesia model mice and microglial inflammation. Mechanical allodynia was evaluated using von Frey tests in vivo. The interaction among PKCε, MEG2, and STAT3 was determined using ELISA and immunoprecipitation assay in vitro. The PKCε, MEG2, t‐STAT3, pSTAT3Tyr705, pSTAT3Ser727, IL‐6, GLUT3, and TREM2 were assessed by Western blot. IL‐6 promoter activity and IL‐6 concentration were examined using dual luciferase assays and ELISA. Overexpression of PKCε and MEG2 promoted and attenuated inflammatory pain, accompanied by an increase and decrease in IL‐6 expression, respectively. PKCε displayed a stronger binding ability to STAT3 when competing with MEG2. STAT3Ser727 phosphorylation increased STAT3 interaction with both PKCε and MEG2. Moreover, LPS increased PKCε, MEG2, pSTAT3Tyr705, pSTAT3Ser727, IL‐6, and GLUT3 levels and decreased TREM2 during microglia inflammation. IL‐6 promoter activity was enhanced or inhibited by PKCε or MEG2 in the presence of STAT3 and LPS stimulation, respectively. In microglia, overexpression of PKCε and/or MEG2 resulted in the elevation of tSTAT3, pSTAT3Tyr705, pSTAT3Ser727, IL‐6, and TREM2, and the reduction of GLUT3. PKCε is more potent than MEG2 when competitively binding to STAT3, displaying dual modulatory effects of IL‐6 production, thus regulating the GLUT3 and TREM2 in microglia during inflammatory pain sensation.
PKCε and MEG2 competitively bind to STAT3, regulating IL‐6‐mediated GLUT3 and TREM2 during inflammatory pain. PKCε, MEG2, and STAT3 activation engaged with IL‐6‐mediated microglial GLUT3 and TREM2 during inflammatory nociceptive transmission. Under stimulation, upregulated PKCε and MEG2 competitively bind to phosphorylated STAT3 (especially, the Ser727 binding site). PKCε is dominant over MEG2 in STAT3 binding assay, subsequently increasing IL‐6 promoter activity, manifested as IL‐6 cytokine‐mediated microglial hyperalgesia during inflammatory pain. PKCε, protein kinase C epsilon; MEG2, megakaryocytes tyrosine phosphatase 2; STAT3, signal transducer and activator of transcription 3; IL‐6, interleukin 6; GLUT3, glucose transporter 3; TREM2, triggering receptor expressed on myeloid cells 2.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Polyradicals, i.e., multispin organic molecules, are playing important roles in radical-based material applications for their spin–spin interaction. A dynamic covalently bonded multispin molecule may ...endow materials with added function such as memory and switching. However, such a species has yet to be reported. We here report the synthesis, characterization, and crystal structure of a dynamic triradical species. It is generated by the self-assembly of two molecules through a Lewis acid coupled electron transfer. The crystalline species is spin-frustrated without Jahn–Teller distortion at low temperature, while it dissociates back to diamagnetic starting material in solution at high temperature. The reversible process is tracked by variable-temperature NMR, EPR, and UV–vis–NIR spectroscopy. Isolation, property study, and dynamic bonding investigation on such a species lay the foundation for the design of functional polyradicals with potential application as memory or switching devices.
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IJS, KILJ, NUK, PNG, UL, UM
In this trial, we aimed to assess the efficacy and safety of radiotherapy with nedaplatin or cisplatin in patients with locally advanced cervical cancer.
We conducted an open-label, non-inferiority, ...phase III, randomized, controlled trial. Eligible patients with stage IIB-IVA cervical carcinoma were randomly assigned to receive either nedaplatin or cisplatin for two cycles concurrently with radiotherapy. We reported the therapy-associated harms and survival. The study was registered with chictr.org.cn, number ChiCTR1800020527.
We randomly assigned 68 patients to nedaplatin-based or cisplatin-based concurrent chemoradiotherapy. Study treatment was stopped early after a data analysis found a higher number of patients suffered severe hematologic harms in the nedaplatin group than in the cisplatin group. Patients in the nedaplatin group had a significantly higher frequency of grade 3-4 neutropenia (19·4% vs. 13%;
< 0·001), severe thrombocytopenia (16·1% vs. 4·3%), and grade 1-2 anemia (51·6% vs. 43·5%) than patients in the cisplatin group. The 1-year PFS and OS in the nedaplatin and cisplatin groups were similar.
Our findings showed that nedaplatin-based concurrent chemoradiotherapy expressed remarkably higher severe hematologic harms which were mortal. Though the results were negative, the experiences and lessons we learned from it were important.
The onset and clinical presentation of systemic lupus erythematosus (SLE) are sex-related. Few studies have investigated the distinctions in clinical characteristics and treatment preferences in male ...and female SLE patients in the initial cohort. This study aimed to improve the understanding of Chinese SLE patients by characterizing the different sexes of SLE patients in the inception cohort.
Based on the initial patient cohort established by the Chinese SLE Treatment and Research Group, a total of 8713 patients (795 men and 7918 women) with newly diagnosed SLE were enrolled between April 2009 and March 2021. Of these, 2900 patients (347 men and 2553 women) were eligible for lupus nephritis (LN). A cross-sectional analysis of the baseline demographic characteristics, clinical manifestations, laboratory parameters, organ damage, initial treatment regimens, and renal pathology classification was performed according to sex.
In the SLE group, as compared to female patients, male patients had a later age of onset (male vs. female: 37.0 ± 15.8 years vs. 35.1 ± 13.7 years, P = 0.006) and a higher SLE International Collaborative Clinic/American College of Rheumatology damage index score (male vs. female: 0.47 ± 1.13 vs. 0.34 ± 0.81, P = 0.015), LN (male vs. female: 43.6% vs. 32.2%, P < 0.001), fever (male vs. female: 18.0% vs. 14.6%, P = 0.010), thrombocytopenia (male vs. female: 21.4% vs. 18.5%, P = 0.050), serositis (male vs. female: 14.7% vs. 11.7%, P = 0.013), renal damage (male vs. female: 11.1% vs. 7.4%, P < 0.001), and treatment with cyclophosphamide (CYC) (P < 0.001). The frequency of leukopenia (male vs. female: 20.5% vs. 25.4%, P = 0.002) and arthritis (male vs. female: 22.0% vs. 29.9%, P < 0.001) was less in male patients with SLE. In LN, no differences were observed in disease duration, SLE Disease Activity Index score, renal biopsy pathological typing, or 24-h urine protein quantification among the sexes. In comparisons with female patients with LN, male patients had later onset ages (P = 0.026), high serum creatinine (P < 0.001), higher end-stage renal failure rates (P = 0.002), musculoskeletal damage (P = 0.023), cardiovascular impairment (P = 0.009), and CYC use (P = 0.001); while leukopenia (P = 0.017), arthritis (P = 0.014), and mycophenolate usage (P = 0.013) rates were lower.
Male SLE patients had more severe organ damage and a higher LN incidence compared with female SLE patients; therefore, they may require more aggressive initial treatment compared to female patients.
Human-in-the-loop (HITL) system is referred to as a promising technology to extend human actions and intelligences to deep ocean. Many applications of HITL demand the remotely operated vehicle (ROV) ...to track a desired target point. However, the cyber- and physical-constrained characteristics on ROV make it challenging to achieve the tracking task. This paper is concerned with a tracking control problem for the ROV, subjected to time-varying delay in cyber channels and actuator saturation in physical channels. We design a model-free proportional-derivative (PD) controller to enforce the position tracking of ROV. For the proposed controller, Lyapunov-Krasovskii functions are constructed to analyze the stability, and then the sufficient conditions are provided to show that the tracking controller can stabilize ROV. In order to estimate and optimize the domain of attraction (DOA), the stability conditions are rearranged into a form of linear matrix inequalities (LMIs), through which the required initial stability conditions can be developed. Finally, simulation and experiment results are performed to validate the effectiveness. It is demonstrated that the designed tracking controller can guarantee asymptotic stability, while the DOA in this paper can be significantly enlarged as compared with the other ones.
•We design a model-free proportional-derivative controller to enforce the position tracking of ROV.•Sufficient conditions are given to show that the controller can stabilize ROV.•The stability conditions are rearranged into a form of LMIs, through which the initial conditions can be developed.•Simulation and experiment results are performed to validate the effectiveness.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Ammonia emissions from motor vehicles have great effect on air pollution and human health in urban areas. Recently, many countries have focus on ammonia emission measurement and control technologies ...for light-duty gasoline vehicles (LDGVs). To analyze ammonia emission characteristics, three conventional LDGVs and one hybrid electric light-duty vehicle (HEV) were evaluated over different driving cycles. The average ammonia emission factor at 23℃ was 4.5 ± 1.6 mg/km over Worldwide harmonized light vehicles test cycle (WLTC). Most ammonia emissions mainly concentrated in low and medium speed sections at cold-start stage, which were related to rich burn conditions. The increasing ambient temperatures led to the decrease of ammonia emissions, but high load caused by extremely elevated ambient temperature led to obvious ammonia emissions. The ammonia formation is also related to three-way catalytic converter (TWC) temperatures, and underfloor TWC catalyst could eliminate ammonia partly. The ammonia emission from HEV, which are significant less than LDGV, corresponded to the engine working state. The large temperature difference in the catalysts caused by power source shifts were the main reason. Exploring the effects of various factors on the ammonia emission is beneficial for revealing the instinct formation conditions, providing theoretical support for the future regulations.
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•LDGV with TWC technology is an important atmospheric source of hazardous material NH3.•The average NH3 emission factor of conventional LDGVs in the work is 4.5 ± 1.6 mg/km.•NH3 formation is related to rich burn conditions and temperatures of TWC catalysts.•HEV significantly reduces the level of NH3 emissions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Allogeneic hepatocyte transplantation is an emerging approach to treat acute liver defects. However, durable engraftment of the transplanted cells remains a daunting task, as they are actively ...cleared by the recipient's immune system. Therefore, a detailed understanding of the innate or adaptive immune cells-derived responses against allogeneic transplanted hepatic cells is the key to rationalize cell-based therapies.
Here, we induced an acute inflammatory regenerative niche (3-96 h) on the surface of the liver by the application of cryo-injury (CI) to systematically evaluate the innate immune response against transplanted allogeneic hepatic progenitors in a sustained micro-inflammatory environment.
The resulting data highlighted that the injured site was significantly repopulated by alternating numbers of innate immune cells, including neutrophils, monocytes and Kupffer cells (KCs), from 3 to 96 h. The transplanted allo-HPs, engrafted 6 h post-injury, were collectively eliminated by the innate immune response within 24 h of transplantation. Selective depletion of the KCs demonstrated a delayed recruitment of monocytes from day 2 to day 6. In addition, the intrasplenic engraftment of the hepatic progenitors 54 h post-transplantation was dismantled by KCs, while a time-dependent better survival and translocation of the transplanted cells into the injured site could be observed in samples devoid of KCs.
Overall, this study provides evidence that KCs ablation enables a better survival and integration of allo-HPs in a sustained liver inflammatory environment, having implications for rationalizing the cell-based therapeutic interventions against liver defects.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The microbial community of spontaneously fermented fish plays an important role in product sensory quality. Recently, microbiota research has seen a shift in perspective from taxonomy to function. ...The investigation of the microbial community metaproteome will reveal information on strains as well as the expressed proteins to better understand the roles of the microbiota in fermented fish.
In this study, shotgun metaproteomic methods were used to identify and annotate 2175 proteins from the traditional Chinese fermented fish Siniperca chuatsi. These proteins belonged to 553 bacterial strains of 19 phyla, including 10 strains of lactic acid bacteria. Based on the KEGG annotation system, 1217 proteins were found to be involved in metabolic pathways, among which 352 proteins were related to amino acid metabolism. Specifically, 63 amino acid degradation-related proteins were identified in Streptococcus sp., Bacillus sp., Escherichia sp., and Pseudoalteromonas sp., which indicated that these strains were potential candidates for generating aroma compounds and thus contributors to the special flavour of the fermented fish. This information on metaproteomes in fermented S. chuatsi increases the understanding of microbial metabolic modes and leads to knowledge-based improvements of the stability and palatability of fermented fish.
•A total of 2175 proteins from the microbiota in fermented fish was identified.•Biological functions of the metaproteome were characterized.•Streptococcus sp. and other strains were presumed to be flavour contributors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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