Loss of ATF3 exacerbates liver damage through the activation of mTOR/p70S6K/ HIF-1α signaling pathway in liver inflammatory injury.

Activating transcription factor 3 (ATF3) is a stress-induced transcription factor that plays important roles in regulating immune and metabolic homeostasis. Activation of the mechanistic target of rapamycin (mTOR) and hypoxia-inducible factor (HIF) transcription factors are crucial for the regulation of immune cell function. Here, we investigated the mechanism by which the ATF3/mTOR/HIF-1 axis regulates immune responses in a liver ischemia/reperfusion injury (IRI) model. Deletion of ATF3 exacerbated liver damage, as evidenced by increased levels of serum ALT, intrahepatic macrophage/neutrophil trafficking, hepatocellular apoptosis, and the upregulation of pro-inflammatory mediators. ATF3 deficiency promoted mTOR and p70S6K phosphorylation, activated high mobility group box 1 (HMGB1) and TLR4, inhibited prolyl-hydroxylase 1 (PHD1), and increased HIF-1α activity, leading to Foxp3 downregulation and RORγt and IL-17A upregulation in IRI livers. Blocking mTOR or p70S6K in ATF3 knockout (KO) mice or bone marrow-derived macrophages (BMMs) downregulated HMGB1, TLR4, and HIF-1α and upregulated PHD1, increasing Foxp3 and decreasing IL-17A levels in vitro. Silencing of HIF-1α in ATF3 KO mice ameliorated IRI-induced liver damage in parallel with the downregulation of IL-17A in ATF3-deficient mice. These findings demonstrated that ATF3 deficiency activated mTOR/p70S6K/HIF-1α signaling, which was crucial for the modulation of TLR4-driven inflammatory responses and T cell development. The present study provides potential therapeutic targets for the treatment of liver IRI followed by liver transplantation

Tetramethyl pyrazine exerts anti-apoptotic and antioxidant effects in a mouse model of MPTP-induced Parkinson's disease via regulation of the expressions of Bax, Bcl-2, Nrf2 and GCLC

Purpose: To investigate the effect of tetramethyl pyrazine (TMP) on MPTP)-mediated neuronal apoptosis and oxidative imbalance in mice, and the mechanism of action involved. Methods: Forty-five mice were assigned evenly to blank control, MPTP and TMP groups. The protein concentrations of Bax, Bcl-2, cytochrome C (Cyt c), Nrf2, GCLC and cleaved caspase-3; and levels of glutathione (GSH) and thiobarbituric acid reactive products (TBARS) were evaluated and compared amongst the groups. Results: Cyt c, Bax, and cleaved caspase-3 protein levels in TMP group were significantly lower than those in MPTP group, while Bcl-2 protein expression was higher in TMP group than in MPTP mice (p < 0.05). Furthermore, TBARS was lower in TMP group than in MPTP group, while GSH level increased, relative to MPTP mice. The levels of Nrf2 and GCLC were significantly higher in TMP group than in MPTP group (p < 0.05). Conclusion: Tetramethyl pyrazine exerts anti-apoptotic and antioxidant effects on MPTP-mediated Parkinsonism via regulation of the expressions of Bax, Bcl-2, Nrf2 and glutamate-cysteine ligase catalytic subunit. Thus, TMP has potential for use in the treatment Parkinson’s disease

Modeling and dynamic analysis of spiral bevel gear coupled system of intermediate and tail gearboxes in a helicopter.

The coupled dynamic model of the intermediate and tail gearboxes’ spiral bevel gear-oblique tail shaft-laminated membrane coupling was established by employing the hybrid modeling method of finite element and lumped mass. Among them, the dynamic equation of the shaft was constructed by Timoshenko beam; spiral bevel gears were derived theoretically by the lumped-mass method, where the effects of time-varying meshing stiffness, transmission error, external imbalance excitation and the like were considered simultaneously; laminated membrane coupling was simplified to a lumped parameter model, in which the stiffness was obtained by the finite element simulation and experiment. On this basis, the laminated membrane coupling and effects of several important parameters, including the unbalance value, tail rotor excitation, oblique tail shaft’s length and transmission error amplitude, on the system’s dynamic characteristics were discussed. The results showed that the influences of laminated membrane coupling and transmission error amplitude on the coupled system’s vibration response were prominent, which should be taken into consideration in the dynamic model. Due to the bending-torsional coupled effect, the lateral vibration caused by gear eccentricity would enlarge the oblique tail shaft’s torsional vibration; similarly, the tail rotor’s torsional excitation also varies the lateral vibration of the oblique tail shaft. The coupled effect between the eccentricity of gear pairs mainly hit the torsional vibration. Also, as the oblique tail shaft’s length increased, the torsional vibration of the oblique tail shaft tended to diminish while the axis orbit became larger. The research provides theoretical support for the design of the helicopter tail transmission system

miR-202 suppresses cell proliferation in human hepatocellular carcinoma by downregulating LRP6 post-transcriptionally

AbstractMicroRNAs have emerged as important regulators of carcinogenesis. In the current study, we observed that microRNA-202 (miR-202) is downregulated in hepatocellular carcinoma (HCC) cells and tissues, indicating a significant correlation between miR-202 expression and HCC progression. Overexpression of miR-202 in HCC cells suppressed cell proliferation and tumorigenicity, while downregulation of miR-202 enhanced the cells’ proliferative capacity. Furthermore, we identified low-density lipoprotein receptor-related protein 6 (LRP6) as a direct target of miR-202. miR-202 suppresses the expression of LRP6 by binding to the 3′-untranslated region (UTR) of its mRNA. Finally, we found that silencing the expression of LRP6 is the essential biological function of miR-202 during HCC cell proliferation. Collectively, our findings reveal that miR-202 is a potential tumor suppressive miRNA that participates in carcinogenesis of human HCC by suppressing LRP6 expression

BCL6 modulates tissue neutrophil survival and exacerbates pulmonary inflammation following influenza virus infection

Neutrophils are vital for antimicrobial defense; however, their role during viral infection is less clear. Furthermore, the molecular regulation of neutrophil fate and function at the viral infected sites is largely elusive. Here we report that BCL6 deficiency in myeloid cells exhibited drastically enhanced host resistance to severe influenza A virus (IAV) infection. In contrast to the notion that BCL6 functions to suppress innate inflammation, we find that myeloid BCL6 deficiency diminished lung inflammation without affecting viral loads. Using a series of Cre-transgenic, reporter, and knockout mouse lines, we demonstrate that BCL6 deficiency in neutrophils, but not in monocytes or lung macrophages, attenuated host inflammation and morbidity following IAV infection. Mechanistically, BCL6 bound to the neutrophil gene loci involved in cellular apoptosis in cells specifically at the site of infection. As such, BCL6 disruption resulted in increased expression of apoptotic genes in neutrophils in the respiratory tract, but not in the circulation or bone marrow. Consequently, BCL6 deficiency promoted tissue neutrophil apoptosis. Partial neutrophil depletion led to diminished pulmonary inflammation and decreased host morbidity. Our results reveal a previously unappreciated role of BCL6 in modulating neutrophil apoptosis at the site of infection for the regulation of host disease development following viral infection. Furthermore, our studies indicate that tissue-specific regulation of neutrophil survival modulates host inflammation and tissue immunopathology during acute respiratory viral infection

The RRM-mediated RNA binding activity in T. brucei RAP1 is essential for VSG monoallelic expression.

Trypanosoma brucei is a protozoan parasite that causes human African trypanosomiasis. Its major surface antigen VSG is expressed from subtelomeric loci in a strictly monoallelic manner. We previously showed that the telomere protein TbRAP1 binds dsDNA through its 737RKRRR741 patch to silence VSGs globally. How TbRAP1 permits expression of the single active VSG is unknown. Through NMR structural analysis, we unexpectedly identify an RNA Recognition Motif (RRM) in TbRAP1, which is unprecedented for RAP1 homologs. Assisted by the 737RKRRR741 patch, TbRAP1 RRM recognizes consensus sequences of VSG 3'UTRs in vitro and binds the active VSG RNA in vivo. Mutating conserved RRM residues abolishes the RNA binding activity, significantly decreases the active VSG RNA level, and derepresses silent VSGs. The competition between TbRAP1's RNA and dsDNA binding activities suggests a VSG monoallelic expression mechanism in which the active VSG's abundant RNA antagonizes TbRAP1's silencing effect, thereby sustaining its full-level expression.We thank Dr. Donny Licatolasi, Dr. Anton Komar, Dr. Kurt Runge, and Catherine Z. Wang for their comments on the manuscript. This work is supported by an NIH R01 grant AI066095 (Li), an NIH S10 grant S10OD025252 (Li), Research Grants Council grants PolyU 151062/18M, 15103819, 15106421, R5050-18 and AoE/M-09/12 (Zhao), Shenzhen Basic Research Programs of China JCYJ20170818104619974 & JCYJ20210324133803009 (Zhao). Shenzhen Basic Research Program of China JCYJ20220818100215033 (Zhang). Research Grants Council grant C4041-18E (Wong, Zhang, Zhao). The publication cost is partly supported by GRHD at CSU and by PolyU.S

PPAR-γ in Macrophages Limits Pulmonary Inflammation and Promotes Host Recovery Following Respiratory Viral Infection

Alveolar macrophages (AM) play pivotal roles in modulating host defense, pulmonary inflammation, and tissue injury following respiratory viral infections. However, the transcriptional regulation of AM function during respiratory viral infections is still largely undefined. Here we have screened the expression of 84 transcription factors in AM in response to influenza A virus (IAV) infection. We found that the transcription factor PPAR-γ was downregulated following IAV infection in AM through type I interferon (IFN)-dependent signaling. PPAR-γ expression in AM was critical for the suppression of exaggerated antiviral and inflammatory responses of AM following IAV and respiratory syncytial virus (RSV) infections. Myeloid PPAR-γ deficiency resulted in enhanced host morbidity and increased pulmonary inflammation following both IAV and RSV infections, suggesting that macrophage PPAR-γ is vital for restricting severe host disease development. Using approaches to selectively deplete recruiting monocytes, we demonstrate that PPAR-γ expression in resident AM is likely important in regulating host disease development. Furthermore, we show that PPAR-γ was critical for the expression of wound healing genes in AM. As such, myeloid PPAR-γ deficiency resulted in impaired inflammation resolution and defective tissue repair following IAV infection. Our data suggest a critical role of PPAR-γ expression in lung macrophages in the modulation of pulmonary inflammation, the development of acute host diseases, and the proper restoration of tissue homeostasis following respiratory viral infections.IMPORTANCE Respiratory viral infections, like IAV and respiratory syncytial virus (RSV) infections, impose great challenges to public health. Alveolar macrophages (AM) are lung-resident immune cells that play important roles in protecting the host against IAV and RSV infections. However, the underlying molecular mechanisms by which AM modulate host inflammation, disease development, and tissue recovery are not very well understood. Here we identify that PPAR-γ expression in AM is crucial to suppress pulmonary inflammation and diseases and to promote fast host recovery from IAV and RSV infections. Our data suggest that targeting macrophage PPAR-γ may be a promising therapeutic option in the future to suppress acute inflammation and simultaneously promote recovery from severe diseases associated with respiratory viral infections

Experimental and numerical investigation of rubber damping ring and its application in multi-span shafting

A new approach for establishing the mechanical model of the rubber damping ring was studied numerically and experimentally. Firstly, parameters of Mooney–Rivlin and Prony series models of the rubber material were identified based on ISIGHT integrating with ANSYS and MATLAB, in which the rubber damping ring’s hysteresis loop was obtained by vibration experiment and ANSYS simulation, respectively; meanwhile, the dynamic stiffness and damping were calculated simultaneously by a parameter separation and identification method. Subsequently, the accuracy of the constitutive model parameters was verified experimentally. In the light of this, based on the experimental design and the approximate model method of the joint simulation platform, a mechanical model of dynamic stiffness and damping of the rubber damping ring was established. Finally, the rubber damping ring’s mathematical model was employed to perform a vibration reduction analysis in a multi-span shafting, where the numerical and experimental investigation was conducted, respectively. The results show that the theoretical and experimental error of vibration reduction rate is less than 17%, which verifies the accuracy of the mechanical model of the rubber damping ring

The safety and efficacy of carbon nanoparticle suspension injection versus indocyanine green tracer-guided lymph node dissection during radical gastrectomy (FUTURE-01): A single-center randomized controlled trial protocol

BackgroundThe use of lymph node (LN) tracers can help obtain a complete dissection of the lymph nodes and increase the detection rate of LNs and metastatic LNs. Carbon nanoparticle suspension injection (CNSI) and indocyanine green (ICG) have been widely used in radical gastrectomy in recent years. Nevertheless, the comparison of their clinical effects has not been studied.Method/designThe FUTURE-01 trial will be the first randomized, open-label, single-center trial to compare CNSI and ICG. The study started in 2021 and enrolled 96 patients according to a prior sample size calculation. The primary outcome is the number of LNs retrieved. The secondary outcomes are LN staining rate, LN metastasis rate, stained LN metastasis rate, perioperative recovery and survival.ConclusionBy comparing the safety and efficacy of CNSI and ICG tracer-guided LN dissection in patients with gastric cancer, we can determine the most appropriate LN tracer at present. With the help of LN tracers, the operation is simplified, and the prognosis of these patients is improved. Our study is a prospective exploration of the safety, efficacy, and prognosis of CNSI and ICG.Clinical trial registrationhttps://clinicaltrials.gov/ct2/show/NCT05229874?cond=NCT05229874&draw=2&rank=1, identifier NCT05229874