Tidal Volume-Dependent Activation of the Renin-Angiotensin System in Experimental Ventilator-Induced Lung Injury.

OBJECTIVES: Ventilator-induced lung injury (VILI) is a major contributor to morbidity and mortality in critically ill patients. Mechanical damage to the lungs is potentially aggravated by the activation of the renin-angiotensin system (RAS). This article describes RAS activation profiles in VILI and discusses the effects of angiotensin (Ang) 1-7 supplementation or angiotensin-converting enzyme (ACE) inhibition with captopril as protective strategies. DESIGN: Animal study. SETTING: University research laboratory. SUBJECTS: C57BL/6 mice. INTERVENTIONS: Anesthetized mice ( n = 12-18 per group) were mechanically ventilated with low tidal volume (LV T , 6 mL/kg), high tidal volume (HV T , 15 mL/kg), or very high tidal volume (VHV T , 30 mL/kg) for 4 hours, or killed after 3 minutes (sham). Additional VHV T groups received infusions of 60 µg/kg/hr Ang 1-7 or a single dose of 100 mg/kg captopril. MEASUREMENTS AND MAIN RESULTS: VILI was characterized by increased bronchoalveolar lavage fluid levels of interleukin (IL)-6, keratinocyte-derived cytokine, and macrophage inflammatory protein-2 (MIP2). The Ang metabolites in plasma measured with liquid chromatography tandem mass spectrometry showed a strong activation of the classical (Ang I, Ang II) and alternative RAS (Ang 1-7, Ang 1-5), with highest concentrations found in the HV T group. Although the lung-tissue ACE messenger RNA expression was unchanged, its protein expression showed a dose-dependent increase under mechanical ventilation. The ACE2 messenger RNA expression decreased in all ventilated groups, whereas ACE2 protein levels remained unchanged. Both captopril and Ang 1-7 led to markedly increased Ang 1-7 plasma levels, decreased Ang II levels, and ACE activity (Ang II/Ang I ratio), and effectively prevented VILI. CONCLUSIONS: VILI is accompanied by a strong activation of the RAS. Based on circulating Ang metabolite levels and tissue expression of RAS enzymes, classical ACE-dependent and alternative RAS cascades were activated in the HV T group, whereas classical RAS activation prevailed with VHV T ventilation. Ang 1-7 or captopril protected from VILI primarily by modifying the systemic RAS profile.

Inhibition of hepatitis C virus by an M1GS ribozyme derived from the catalytic RNA subunit of Escherichia coli RNase P.

BACKGROUND: Hepatitis C virus (HCV) is a human pathogen causing chronic liver disease in about 200 million people worldwide. However, HCV resistance to interferon treatment is one of the important clinical implications, suggesting the necessity to seek new therapies. It has already been shown that some forms of the catalytic RNA moiety from E. coli RNase P, M1 RNA, can be introduced into the cytoplasm of mammalian cells for the purpose of carrying out targeted cleavage of mRNA molecules. Our study is to use an engineering M1 RNA (i.e. M1GS) for inhibiting HCV replication and demonstrates the utility of this ribozyme for antiviral applications. RESULTS: By analyzing the sequence and structure of the 5' untranslated region of HCV RNA, a putative cleavage site (C67-G68) was selected for ribozyme designing. Based on the flanking sequence of this site, a targeting M1GS ribozyme (M1GS-HCV/C67) was constructed by linking a custom guide sequence (GS) to the 3' termini of catalytic RNA subunit (M1 RNA) of RNase P from Escherichia coli through an 88 nt-long bridge sequence. In vitro cleavage assays confirmed that the engineered M1GS ribozyme cleaved the targeted RNA specifically. Moreover, ~85% reduction in the expression levels of HCV proteins and >1000-fold reduction in viral growth were observed in supernatant of cultured cells that transfected the functional ribozyme. In contrast, the HCV core expression and viral growth were not significantly affected by a "disabled" ribozyme (i.e. M1GS-HCV/C67*). Moreover, cholesterol-conjugated M1GS ribozyme (i.e. Chol-M1GS-HCV/C67) showed almost the same bioactivities with M1GS-HCV/C67, demonstrating the potential to improve in vivo pharmacokinetic properties of M1GS-based RNA therapeutics. CONCLUSION: Our results provide direct evidence that the M1GS ribozyme can function as an antiviral agent and effectively inhibit gene expression and multiplication of HCV.

Less confidence, less forgetting: Learning with a humbler teacher in exemplar-free Class-Incremental learning.

Class-Incremental learning (CIL) is challenging due to catastrophic forgetting (CF), which escalates in exemplar-free scenarios. To mitigate CF, Knowledge Distillation (KD), which leverages old models as teacher models, has been widely employed in CIL. However, based on a case study, our investigation reveals that the teacher model exhibits over-confidence in unseen new samples. In this article, we conduct empirical experiments and provide theoretical analysis to investigate the over-confident phenomenon and the impact of KD in exemplar-free CIL, where access to old samples is unavailable. Building on our analysis, we propose a novel approach, Learning with Humbler Teacher, by systematically selecting an appropriate checkpoint model as a humbler teacher to mitigate CF. Furthermore, we explore utilizing the nuclear norm to obtain an appropriate temporal ensemble to enhance model stability. Notably, LwHT outperforms the state-of-the-art approach by a significant margin of 10.41%, 6.56%, and 4.31% in various settings while demonstrating superior model plasticity.

Microbiota profiling reveals alteration of gut microbial neurotransmitters in a mouse model of autism-associated 16p11.2 microduplication.

The gut-brain axis is evident in modulating neuropsychiatric diseases including autism spectrum disorder (ASD). Chromosomal 16p11.2 microduplication 16p11.2dp/+ is among the most prevalent genetic copy number variations (CNV) linked with ASD. However, the implications of gut microbiota status underlying the development of ASD-like impairments induced by 16p11.2dp/+ remains unclear. To address this, we initially investigated a mouse model of 16p11.2dp/+, which exhibits social novelty deficit and repetitive behavior characteristic of ASD. Subsequently, we conducted a comparative analysis of the gut microbial community and metabolomic profiles between 16p11.2dp/+ and their wild-type counterparts using 16S rRNA sequencing and liquid chromatography-mass spectrometry (LC/MS). Our microbiota analysis revealed structural dysbiosis in 16p11.2dp/+ mice, characterized by reduced biodiversity and alterations in species abundance, as indicated by α/ß-diversity analysis. Specifically, we observed reduced relative abundances of Faecalibaculum and Romboutsia, accompanied by an increase in Turicibacter and Prevotellaceae UCG_001 in 16p11.2dp/+ group. Metabolomic analysis identified 19 significantly altered metabolites and unveiled enriched amino acid metabolism pathways. Notably, a disruption in the predominantly histamine-centered neurotransmitter network was observed in 16p11.2dp/+ mice. Collectively, our findings delineate potential alterations and correlations among the gut microbiota and microbial neurotransmitters in 16p11.2dp/+ mice, providing new insights into the pathogenesis of and treatment for 16p11.2 CNV-associated ASD.

The feedback loop of EFTUD2/c-MYC impedes chemotherapeutic efficacy by enhancing EFTUD2 transcription and stabilizing c-MYC protein in colorectal cancer.

BACKGROUND: Chemoresistance presents a significant obstacle in the treatment of colorectal cancer (CRC), yet the molecular basis underlying CRC chemoresistance remains poorly understood, impeding the development of new therapeutic interventions. Elongation factor Tu GTP binding domain containing 2 (EFTUD2) has emerged as a potential oncogenic factor implicated in various cancer types, where it fosters tumor growth and survival. However, its specific role in modulating the sensitivity of CRC cells to chemotherapy is still unclear. METHODS: Public dataset analysis and in-house sample validation were conducted to assess the expression of EFTUD2 in 5-fluorouracil (5-FU) chemotherapy-resistant CRC cells and the potential of EFTUD2 as a prognostic indicator for CRC. Experiments both in vitro, including MTT assay, EdU cell proliferation assay, TUNEL assay, and clone formation assay and in vivo, using cell-derived xenograft models, were performed to elucidate the function of EFTUD2 in sensitivity of CRC cells to 5-FU treatment. The molecular mechanism on the reciprocal regulation between EFTUD2 and the oncogenic transcription factor c-MYC was investigated through molecular docking, ubiquitination assay, chromatin immunoprecipitation (ChIP), dual luciferase reporter assay, and co-immunoprecipitation (Co-IP). RESULTS: We found that EFTUD2 expression was positively correlated with 5-FU resistance, higher pathological grade, and poor prognosis in CRC patients. We also demonstrated both in vitro and in vivo that knockdown of EFTUD2 sensitized CRC cells to 5-FU treatment, whereas overexpression of EFTUD2 impaired such sensitivity. Mechanistically, we uncovered that EFTUD2 physically interacted with and stabilized c-MYC protein by preventing its ubiquitin-mediated proteasomal degradation. Intriguingly, we found that c-MYC directly bound to the promoter region of EFTUD2 gene, activating its transcription. Leveraging rescue experiments, we further confirmed that the effect of EFTUD2 on 5-FU resistance was dependent on c-MYC stabilization. CONCLUSION: Our findings revealed a positive feedback loop involving an EFTUD2/c-MYC axis that hampers the efficacy of 5-FU chemotherapy in CRC cells by increasing EFTUD2 transcription and stabilizing c-MYC oncoprotein. This study highlights the potential of EFTUD2 as a promising therapeutic target to surmount chemotherapy resistance in CRC patients.

Research on an infectious disease transmission by flocking birds.

The swarm intelligence is becoming a hot topic. The flocking of birds is a natural phenomenon, which is formed and organized without central or external controls for some benefits (e.g., reduction of energy consummation). However, the flocking also has some negative effects on the human, as the infectious disease H7N9 will easily be transmited from the denser flocking birds to the human. Zombie-city model has been proposed to help analyzing and modeling the flocking birds and the artificial society. This paper focuses on the H7N9 virus transmission in the flocking birds and from the flocking birds to the human. And some interesting results have been shown: (1) only some simple rules could result in an emergence such as the flocking; (2) the minimum distance between birds could affect H7N9 virus transmission in the flocking birds and even affect the virus transmissions from the flocking birds to the human.

Rumor diffusion in an interests-based dynamic social network.

To research rumor diffusion in social friend network, based on interests, a dynamic friend network is proposed, which has the characteristics of clustering and community, and a diffusion model is also proposed. With this friend network and rumor diffusion model, based on the zombie-city model, some simulation experiments to analyze the characteristics of rumor diffusion in social friend networks have been conducted. The results show some interesting observations: (1) positive information may evolve to become a rumor through the diffusion process that people may modify the information by word of mouth; (2) with the same average degree, a random social network has a smaller clustering coefficient and is more beneficial for rumor diffusion than the dynamic friend network; (3) a rumor is spread more widely in a social network with a smaller global clustering coefficient than in a social network with a larger global clustering coefficient; and (4) a network with a smaller clustering coefficient has a larger efficiency.

NorMASS: A normative MAS-based modeling approach for simulating incentive mechanisms of Q&A communities.

Incentive mechanisms steer users in Q&A communities to achieve community goals, which need to be cautiously reviewed and revised before actual industrial application. Simulating incentive mechanisms is significant for predicting how changes in incentive mechanisms will affect community emergence, such as user answering patterns. However, due to the complexity of Q&A communities, the challenge faced by simulating incentive mechanisms lies in the difficulty of establishing micro-macro connections in the communities to simulate their emergence. To fill this gap, this paper proposes a Normative Multi-Agent System based Simulation (NorMASS) approach to simulate community emergence. The NorMASS models a Q&A community as a normative multi-agent system and adopts agents to formally express community users. Moreover, the approach provides an open-source simulator with a data generator to simulate community emergence. An evaluation of the NorMASS comparing simulation emergence with the counterpart of an actual community demonstrates that the proposed approach provides an effective solution for simulating incentive mechanisms of Q&A communities, with a similarity of 80% or above.

Combined angiotensin-converting enzyme and aminopeptidase inhibition for treatment of experimental ventilator-induced lung injury in mice.

Introduction: Ventilator-induced lung injury (VILI) may aggravate critical illness. Although angiotensin-converting enzyme (ACE) inhibition has beneficial effects in ventilator-induced lung injury, its clinical application is impeded by concomitant hypotension. We hypothesized that the aminopeptidase inhibitor ALT-00 may oppose the hypotension induced by an angiotensin-converting enzyme inhibitor, and that this combination would activate the alternative renin-angiotensin system (RAS) axis to counteract ventilator-induced lung injury. Methods: In separate experiments, C57BL/6 mice were mechanically ventilated with low (LVT, 6 mL/kg) and high tidal volumes (HVT, 30 mL/kg) for 4 h or remained unventilated (sham). High tidal volume-ventilated mice were treated with lisinopril (0.15 µg/kg/min) ± ALT-00 at 2.7, 10 or 100 µg/kg/min. Blood pressure was recorded at baseline and after 4 h. Lung histology was evaluated for ventilator-induced lung injury and the angiotensin (Ang) metabolite profile in plasma (equilibrium levels of Ang I, Ang II, Ang III, Ang IV, Ang 1-7, and Ang 1-5) was measured with liquid chromatography tandem mass spectrometry at the end of the experiment. Angiotensin concentration-based markers for renin, angiotensin-converting enzyme and alternative renin-angiotensin system activities were calculated. Results: High tidal volume-ventilated mice treated with lisinopril showed a significant drop in the mean arterial pressure at 4 h compared to baseline, which was prevented by adding ALT-00 at 10 and 100 µg/kg/min. Ang I, Ang II and Ang 1-7 plasma equilibrium levels were elevated in the high tidal volumes group versus the sham group. Lisinopril reduced Ang II and slightly increased Ang I and Ang 1-7 levels versus the untreated high tidal volumes group. Adding ALT-00 at 10 and 100 µg/kg/min increased Ang I and Ang 1-7 levels versus the high tidal volume group, and partly prevented the downregulation of Ang II levels caused by lisinopril. The histological lung injury score was higher in the high tidal volume group versus the sham and low tidal volume groups, and was attenuated by lisinopril ± ALT-00 at all dose levels. Conclusion: Combined angiotensin-converting enzyme plus aminopeptidase inhibition prevented systemic hypotension and maintained the protective effect of lisinopril. In this study, a combination of lisinopril and ALT-00 at 10 µg/kg/min appeared to be the optimal approach, which may represent a promising strategy to counteract ventilator-induced lung injury that merits further exploration.

A Lightweight Social Computing Approach to Emergency Management Policy Selection.

In order to select effective policies for emergency management in a timely manner, this paper proposes an agile and lightweight social computing approach to facilitating policy selection, evaluation, and adjustment relative to emergency management in both quantitative and qualitative ways. The approach consists of three components represented as PZE: 1) (P) emergency management policy selecting; 2) (Z) modeling artificial societies with the zombie-city model (a general and formal artificial society model); and 3) (E) policy evaluation. The formal specification of the zombie-city model and rigorous expressions of scenarios enable rigorous description and formal reasoning of an artificial society. A feedback loop of this approach supports the iterative adjustment of emergency management policies and the creation of more effective policies. This approach is verified by applying it to a case of an infectious disease transmission with quantitative evaluations, qualitative reasoning and analysis, and iterative adjustments. Results indicate effective emergency management policies can be established with the approach in an iterative way. In contrast with existing research, our proposed approach offers the benefits of being simple, general, rapidly adaptive to changes, and low cost.