Gut microbiota-derived acetate attenuates lung injury induced by influenza infection via protecting airway tight junctions.

BACKGROUND: Gut microbiota (GM) have been implicated as important regulators of gastrointestinal symptom which is commonly occurred along with respiratory influenza A virus (IAV) infection, suggesting the involvement of the gut-to-lung axis in a host's response to IAV. IAV primarily destroys airway epithelium tight junctions (TJs) and consequently causes acute respiratory disease syndrome. It is known that GM and their metabolism produce an anti-influenza effect, but their role in IAV-induced airway epithelial integrity remains unknown. METHODS: A mouse model of IAV infection was established. GM were analyzed using 16S rRNA gene sequencing, and short-chain fatty acids (SCFAs) levels were measured. GM depletion and fecal microbiota transplantation (FMT) were conducted to validate the role of GM in IAV infection. A pair-feeding experiment was conducted to reveal whether IAV-induced GM dysbiosis is attributed to impaired food intake. Furthermore, human bronchial epithelial (HBE) cells were cocultured with IAV in the presence or absence of acetate. TJs function was analyzed by paracellular permeability and transepithelial electronic resistance (TEER). The mechanism of how acetate affects TJs integrity was evaluated in HBE cells transfected with G protein-coupled receptor 43 (GPR43) short hairpin RNA (shRNA). RESULTS: IAV-infected mice exhibited lower relative abundance of acetate-producing bacteria (Bacteroides, Bifidobacterium, and Akkermansia) and decreased acetate levels in gut and serum. These changes were partly caused by a decrease in food consumption (due to anorexia). GM depletion exacerbated and FMT restored IAV-induced lung inflammatory injury. IAV infection suppressed expressions of TJs (occludin, ZO-1) leading to disrupted airway epithelial barrier function as evidenced by decreased TEER and increased permeability. Acetate pretreatment activated GPR43, partially restored IAV-induced airway epithelial barrier function, and reduced inflammatory cytokines levels (TNF-α, IL-6, and IL-1ß). Such protective effects of acetate were absent in HBE cells transfected with GPR43 shRNA. Acetate and GPR43 improved TJs in an AMP-activated protein kinase (AMPK)-dependent manner. CONCLUSION: Collectively, our results demonstrated that GM protected airway TJs by modulating GPR43-AMPK signaling in IAV-induced lung injury. Therefore, improving GM dysbiosis may be a potential therapeutic target for patients with IAV infection.

Blood urea nitrogen to albumin ratio is a novel predictor of fatal outcome for patients with severe fever with thrombocytopenia syndrome.

Severe fever with thrombocytopenia syndrome (SFTS) is associated with a high death rate and lacks a targeted therapy plan. The ratio of blood urea nitrogen to albumin, known as BAR, is a valuable method for assessing the outlook of various infectious diseases. The objective of this research was to evaluate the effectiveness of BAR in forecasting the outcome of individuals with SFTS. Four hundred and thirty-seven patients with SFTS from two clinical centers were included in this study according to inclusion and exclusion criteria. Clinical characteristics and test parameters of SFTS patients were analyzed between survival and fatal groups. Least absolute shrinkage and selection operator (LASSO) regression and Cox regression suggested that BAR might serve as a standalone prognostic indicator for patients with SFTS in the initial phase (hazard ratio = 18.669, 95% confidence interval [CI]: 8.558-40.725, p < 0.001). And BAR had a better predictive effectiveness in clinical outcomes in patients with SFTS with an AUC of 0.832 (95% CI: 0.788-0.876, p < 0.001), a cutoff value of 0.19, a sensitivity of 0.812, and a specificity of 0.726 compared to C-reactive protein, procalcitonin, and platelet to lymphocyte ratio via receiver operating characteristic curve. KM (Kaplan Meier) curves demonstrated that high level of BAR was associated with poor survival condition in patients with SFTS. Furthermore, the high level of BAR was associated with long hospital stays and test paraments of kidney, liver, and coagulation function in survival patients. So, BAR could be used as a promising early warning biomarker of adverse outcomes in patients with SFTS.

Melatonin improves influenza virus infection-induced acute exacerbation of COPD by suppressing macrophage M1 polarization and apoptosis.

BACKGROUND: Influenza A viruses (IAV) are extremely common respiratory viruses for the acute exacerbation of chronic obstructive pulmonary disease (AECOPD), in which IAV infection may further evoke abnormal macrophage polarization, amplify cytokine storms. Melatonin exerts potential effects of anti-inflammation and anti-IAV infection, while its effects on IAV infection-induced AECOPD are poorly understood. METHODS: COPD mice models were established through cigarette smoke exposure for consecutive 24 weeks, evaluated by the detection of lung function. AECOPD mice models were established through the intratracheal atomization of influenza A/H3N2 stocks in COPD mice, and were injected intraperitoneally with melatonin (Mel). Then, The polarization of alveolar macrophages (AMs) was assayed by flow cytometry of bronchoalveolar lavage (BAL) cells. In vitro, the effects of melatonin on macrophage polarization were analyzed in IAV-infected Cigarette smoking extract (CSE)-stimulated Raw264.7 macrophages. Moreover, the roles of the melatonin receptors (MTs) in regulating macrophage polarization and apoptosis were determined using MTs antagonist luzindole. RESULTS: The present results demonstrated that IAV/H3N2 infection deteriorated lung function (reduced FEV20,50/FVC), exacerbated lung damages in COPD mice with higher dual polarization of AMs. Melatonin therapy improved airflow limitation and lung damages of AECOPD mice by decreasing IAV nucleoprotein (IAV-NP) protein levels and the M1 polarization of pulmonary macrophages. Furthermore, in CSE-stimulated Raw264.7 cells, IAV infection further promoted the dual polarization of macrophages accompanied with decreased MT1 expression. Melatonin decreased STAT1 phosphorylation, the levels of M1 markers and IAV-NP via MTs reflected by the addition of luzindole. Recombinant IL-1ß attenuated the inhibitory effects of melatonin on IAV infection and STAT1-driven M1 polarization, while its converting enzyme inhibitor VX765 potentiated the inhibitory effects of melatonin on them. Moreover, melatonin inhibited IAV infection-induced apoptosis by suppressing IL-1ß/STAT1 signaling via MTs. CONCLUSIONS: These findings suggested that melatonin inhibited IAV infection, improved lung function and lung damages of AECOPD via suppressing IL-1ß/STAT1-driven macrophage M1 polarization and apoptosis in a MTs-dependent manner. Melatonin may be considered as a potential therapeutic agent for influenza virus infection-induced AECOPD.

Melatonin Rescues Influenza A Virus-Induced Cellular Energy Exhaustion via OMA1-OPA1-S in Acute Exacerbation of COPD.

Although rapid progression and a poor prognosis in influenza A virus (IAV) infection-induced acute exacerbation of chronic obstructive pulmonary disease (AECOPD) are frequently associated with metabolic energy disorders, the underlying mechanisms and rescue strategies remain unknown. We herein demonstrated that the level of resting energy expenditure increased significantly in IAV-induced AECOPD patients and that cellular energy exhaustion emerged earlier and more significantly in IAV-infected primary COPD bronchial epithelial (pDHBE) cells. The differentially expressed genes were enriched in the oxidative phosphorylation (OXPHOS) pathway; additionally, we consistently uncovered much earlier ATP exhaustion, more severe mitochondrial structural destruction and dysfunction, and OXPHOS impairment in IAV-inoculated pDHBE cells, and these changes were rescued by melatonin. The level of OMA1-dependent cleavage of OPA1 in the mitochondrial inner membrane and the shift in energy metabolism from OXPHOS to glycolysis were significantly increased in IAV-infected pDHBE cells; however, these changes were rescued by OMA1-siRNA or melatonin further treatment. Collectively, our data revealed that melatonin rescued IAV-induced cellular energy exhaustion via OMA1-OPA1-S to improve the clinical prognosis in COPD. This treatment may serve as a potential therapeutic agent for patients in which AECOPD is induced by IAV.

Robust Cooperative Control for Heterogeneous Uncertain Nonlinear High-Order Fully Actuated Multiagent Systems.

This research is intended to address a robust cooperative control problem of heterogeneous uncertain nonlinear high-order fully actuated multiagent systems (HUN-HOFAMASs). A nonlinear HOFA system model is used to describe the multiagent systems (MASs) with heterogeneous uncertain nonlinear dynamics, which is called the HUN-HOFAMASs. A predictive terminal sliding-mode control-based robust cooperative control scheme is presented to address this problem. In this scheme, heterogeneous nonlinear dynamics of original system are offset to establish a linear constant HOFA system with the help of full actuation feature. Then, a terminal sliding-mode variable for enhancing the system robustness is introduced to handle the uncertainties. Furthermore, a linear incremental prediction model is developed in a HOFA form by means of a Diophantine equation. According to this model, the multistep terminal sliding-mode predictions are yielded to optimize the robust cooperative control performance and compensate for the network-induced communication constraints in the feedback and forward channels. Based on a linear matrix inequality (LMI) method, a necessary and sufficient criterion is derived to discuss the simultaneous consensus and stability of closed-loop HUN-HOFAMASs. The simulation and comparison results of cooperative flying around of multiple spacecraft system are shown to illustrate the capability and advantage of the presented predictive terminal sliding-mode control for robust cooperative control.

Observer-based HOFA predictive cooperative control for networked multi-agent systems under time-variant communication constraints.

This research focuses on a cooperative control problem for networked multi-agent systems (NMASs) under time-variant communication constraints (containing time-variant communication delays and time-variant data losses) in the forward and feedback channels. From the perspective of high-order fully actuated (HOFA) system theory, a HOFA system model is adopted to describe the NMAS, which is called the networked HOFA multi-agent system (NHOFAMAS). Because of complicated working scenarios over the network, the states of NMASs are immeasurable and the communication constraints are always present, such that an observer-based HOFA predictive control (OB-HOFAPC) method is designed to implement the cooperative control when existing the immeasurable states and time-variant communication constraints. In this method, a HOFA observer is established to estimate the immeasurable states for constructing a consensus control protocol. Then, an incremental prediction model (IPM) in a HOFA form is developed via a Diophantine equation to take the place of a reduced-order prediction model. Through this IPM, multi-step output ahead predictions are derived to optimize the cooperative control performance and compensate for time-variant communication constraints in real-time. The depth discussion gives a sufficient and necessary criterion to analyze the simultaneous consensus and stability for closed-loop NHOFAMASs. The capability and advantage of OB-HOFAPC method are illustrated via numerical simulation and experimental verification on a cooperative flying-around task of three air-bearing spacecraft simulators.

Characterizing Chinese undergraduate students' empathizing-systemizing profiles: a person-centered approach.

While the empathizing-systemizing (E-S) theory provides a valuable framework for explaining gender differences in STEM majors, previous studies suffer from methodological issues (i.e., the arbitrary cut-off criteria and WEIRD sampling) as well as discrepancies in the behavioral correlates of E-S types. To address the gaps, this study utilized a 3-step latent profile analysis to identify naturally occurring E-S profiles in a Chinese sample and explored the predictors and distal outcomes of the identified profiles. The study recruited 785 (aged 18-25 years, 60% female) Chinese undergraduates. Results revealed five E-S profiles: Disengaged, Empathizers, Navigating systemizers, Technological systemizers, and Self-declared allrounders. Controlling for socioeconomic status, being male predicted a higher likelihood of membership into the Technological systemizers. Besides, membership to the Navigating systemizers and Technological systemizers was associated with better intuitive physics performance. However, no significant variation was observed for social sensitivity performance across E-S profiles. Overall, our results partially conformed to previous findings, highlighting the importance of cultural adaptation and methodological considerations when classifying students' cognitive types.

The spectrum of novel ABCB11 gene variations in children with progressive familial intrahepatic cholestasis type 2 in Pakistani cohorts.

Progressive familial intrahepatic cholestasis (PFIC) is a rare childhood manifested disease associated with impaired bile secretion with severe pruritus yellow stool, and sometimes hepatosplenomegaly. PFIC is caused by mutations in ATP8B1, ABCB11, ABCB4, TJP2, NR1H4, SLC51A, USP53, KIF12, ZFYVE19, and MYO5B genes depending on its type. ABCB11 mutations lead to PFIC2 that encodes the bile salt export pump (BSEP). Different mutations of ABCB11 have been reported in different population groups but no data available in Pakistani population being a consanguineous one. We sequenced coding exons of the ABCB11 gene along with its flanking regions in 66 unrelated Pakistani children along with parents with PFIC2 phenotype. We identified 20 variations of ABCB11: 12 in homozygous form, one compound heterozygous, and seven heterozygous. These variants include 11 missenses, two frameshifts, two nonsense mutations, and five splicing variants. Seven variants are novel candidate variants and are not detected in any of the 120 chromosomes from normal ethnically matched individuals. Insilico analysis revealed that four homozygous missense variations have high pathogenic scores. Minigene analysis of splicing variants showed exon skipping and the addition of exon. This data is a useful addition to the disease variants genomic database and would be used in the future to build a diagnostic algorithm.

Liquid lens based holographic camera for real 3D scene hologram acquisition using end-to-end physical model-driven network.

With the development of artificial intelligence, neural network provides unique opportunities for holography, such as high fidelity and dynamic calculation. How to obtain real 3D scene and generate high fidelity hologram in real time is an urgent problem. Here, we propose a liquid lens based holographic camera for real 3D scene hologram acquisition using an end-to-end physical model-driven network (EEPMD-Net). As the core component of the liquid camera, the first 10 mm large aperture electrowetting-based liquid lens is proposed by using specially fabricated solution. The design of the liquid camera ensures that the multi-layers of the real 3D scene can be obtained quickly and with great imaging performance. The EEPMD-Net takes the information of real 3D scene as the input, and uses two new structures of encoder and decoder networks to realize low-noise phase generation. By comparing the intensity information between the reconstructed image after depth fusion and the target scene, the composite loss function is constructed for phase optimization, and the high-fidelity training of hologram with true depth of the 3D scene is realized for the first time. The holographic camera achieves the high-fidelity and fast generation of the hologram of the real 3D scene, and the reconstructed experiment proves that the holographic image has the advantage of low noise. The proposed holographic camera is unique and can be used in 3D display, measurement, encryption and other fields.

Molecular detection, subtyping of Blastocystis sp. in migratory birds from nature reserves in northeastern China.

Migratory birds play an important role in the cross-regional transmission of zoonotic pathogens. Assessing the presence of zoonotic pathogens carried by migratory birds is critical for disease control. However, information about Blastocystis infection in the migratory birds is very limited. Thus, we conducted this study with the aim to explore the occurrence, prevalence and subtyping of Blastocystis in four breeds of migratory birds in northeastern China. From October 2022 to April 2023, a total of 427 fresh fecal samples were obtained from four breeds of migratory birds in five nature reserves in northeastern China, and screened for Blastocystis by PCR amplification. Twenty-one (4.92 %) of the studied samples were confirmed Blastocystis-positive, and two known zoonotic subtypes ST6 and ST7 were founded, with ST7 being the major subtype. Until now, we firstly reported the infection status and subtyping of Blastocystis in the migratory Greater White-Fronted Goose, White Stork, Oriental White Stork and Bean Goose in China. More importantly, these findings present further data on the genetic diversity and transmission routes of Blastocystis and further arouse public health concerns about this organism.

Hepatic Surf4 Deficiency Impairs Serum Amyloid A1 Secretion and Attenuates Liver Fibrosis in Mice.

Liver fibrosis is a severe global health problem. However, no effective antifibrotic drugs have been approved. Surf4 is primarily located in the endoplasmic reticulum (ER) and mediates the transport of secreted proteins from the ER to the Golgi apparatus. Knockout of hepatic Surf4 (Surf4 LKO) in mice impairs very-low-density lipoprotein secretion without causing overt liver damage. Here, we found that collagen levels are significantly reduced in the liver of Surf4 LKO mice compared with control Surf4 flox mice, as demonstrated by proteomics, Western blot, and quantitative reverse transcription polymerase chain reaction. Therefore, this study aims to investigate whether and how hepatic Surf4 affects liver fibrosis. We observed that CCl4-induced liver fibrosis is significantly lower in Surf4 LKO mice than in Surf4 flox mice. Mechanistically, hepatic Surf4 deficiency reduces serum amyloid A1 (SAA1) secretion and hepatic stellate cell (HSC) activation. Surf4 coimmunoprecipitates and colocalizes with SAA1. Lack of hepatic Surf4 significantly reduces SAA1 secretion from hepatocytes, and SAA1 activates cultured human HSCs (LX-2 cells). Conditioned medium (CM) from Surf4-deficient primary hepatocytes activates LX-2 cells to a much lesser extent than CM from Surf4 flox primary hepatocytes, and this reduced effect is restored by the addition of recombinant SAA1 to CM from Surf4-deficient hepatocytes. Knockdown of SAA1 in primary hepatocytes or TLR2 in LX-2 cells significantly reduces LX-2 activation induced by CM from Surf4 flox hepatocytes but not from Surf4 LKO hepatocytes. Furthermore, knockdown of SAA1 significantly ameliorates liver fibrosis in Surf4 flox mice but does not further reduce liver fibrosis in Surf4 LKO mice. We also observe substantial expression of Surf4 and SAA1 in human fibrotic livers. Therefore, hepatic Surf4 facilitates SAA1 secretion, activates HSCs, and aggravates liver fibrosis, suggesting that hepatic Surf4 and SAA1 may serve as treatment targets for liver fibrosis.

Meta-analysis of infection and disease among household contacts of patients with drug-resistant tuberculosis / 中国热带医学

@#Abstract: Objective　To analyze the association between drug resistance and the risk of latent tuberculosis infection and disease among household contacts of patients with pulmonary tuberculosis, and to explore whether the compensatory mutation of drug-resistant Mycobacterium tuberculosis will enhance its pathogenicity or transmission ability. Methods　The English and Chinese databases, including PubMed, web of science, EMBASE, Cochrane library database, CNKI and Wanfang database, were searched by computer from the time of establishment of the database to January 2022. Cohort studies on the risk of infection and disease among household contacts of patients with drug-resistant and sensitive pulmonary tuberculosis were searched and screened according to the inclusion and exclusion criteria. The data were extracted and evaluated by NOS scale, using stata16.0 software meta-analysis to calculate the combined effect of tuberculosis infection and disease risk of family contacts, and carry out heterogeneity test, subgroup analysis and sensitivity analysis. Results　A total of 7 cohort studies involving 9653 TB index cases and 29, 734 house contacts were included. The results of meta-analysis showed that compared with drug-sensitive pulmonary tuberculosis patients, the risk of tuberculosis infection in house contacts of drug-resistant pulmonary tuberculosis patients was increased (OR=1.56, 95%CI=1.25-1.96, P<0.001), but there was no difference in the risk of incidence (RR=1.06, 95%CI=0.80-1.41, P=0.67>0.05). Subgroup analysis showed that the risk of latent tuberculosis infection in house contacts was affected by the study area, and the size of family contacts had an impact on the risk of TB . Sensitivity analysis showed that the results of meta-analysis were robust. Conclusion　Compared with drug sensitive TB patients, household contacts with drug-resistant TB patients had a higher risk of tuberculosis, but there was no difference in the risk of TB among the two groups.