A Systematic Molecular Pathology Study of a Laboratory Confirmed H5N1 Human Case

Autopsy studies have shown that human highly pathogenic avian influenza virus (H5N1) can infect multiple human organs other than just the lungs, and that possible causes of organ damage are either viral replication and/or dysregulation of cytokines and chemokines. Uncertainty still exists, partly because of the limited number of cases analysed. In this study, a full autopsy including 5 organ systems was conducted on a confirmed H5N1 human fatal case (male, 42 years old) within 18 hours of death. In addition to the respiratory system (lungs, bronchus and trachea), virus was isolated from cerebral cortex, cerebral medullary substance, cerebellum, brain stem, hippocampus ileum, colon, rectum, ureter, aortopulmonary vessel and lymph-node. Real time RT-PCR evidence showed that matrix and hemagglutinin genes were positive in liver and spleen in addition to positive tissues with virus isolation. Immunohistochemistry and in-situ hybridization stains showed accordant evidence of viral infection with real time RT-PCR except bronchus. Quantitative RT-PCR suggested that a high viral load was associated with increased host responses, though the viral load was significantly different in various organs. Cells of the immunologic system could also be a target for virus infection. Overall, the pathogenesis of HPAI H5N1 virus was associated both with virus replication and with immunopathologic lesions. In addition, immune cells cannot be excluded from playing a role in dissemination of the virus in vivo

A Comparison of Etiology, Pathogenesis, Vaccinal and Antiviral Drug Development between Influenza and COVID-19

Influenza virus and coronavirus, two kinds of pathogens that exist widely in nature, are common emerging pathogens that cause respiratory tract infections in humans. In December 2019, a novel coronavirus SARS-CoV-2 emerged, causing a severe respiratory infection named COVID-19 in humans, and raising a global pandemic which has persisted in the world for almost three years. Influenza virus, a seasonally circulating respiratory pathogen, has caused four global pandemics in humans since 1918 by the emergence of novel variants. Studies have shown that there are certain similarities in transmission mode and pathogenesis between influenza and COVID-19, and vaccination and antiviral drugs are considered to have positive roles as well as several limitations in the prevention and control of both diseases. Comparative understandings would be helpful to the prevention and control of these diseases. Here, we review the study progress in the etiology, pathogenesis, vaccine and antiviral drug development for the two diseases

A Novel Numerical Method for Calculating Vertical Bearing Capacity of Prestressed Pipe Piles

A novel method for calculating the vertical bearing capacity of prestressed pipe piles with the acceptable error was proposed and verified. Soils at the pile side and end were, respectively, simulated by an elastic-plastic model and a new double-line (at soft rock and soil layers) or triple-line model (at hard rock and soil layers); then, a mechanical model was established for simulating vertical bearing capacity of prestressed pipe piles, and the corresponding calculation process was carried out. The values of pile side resistance, pile end resistance, and pile end elastic displacement were first obtained from the results of high-strain dynamic testing (HSDT) and then were imported into the proposed numerical model for calculating the vertical bearing capacity of prestressed concrete pipe piles. The static load test was carried out to verify the numerical results. Besides, 20 piles were tested at two typical test sites (soft and hard rock bearing strata), of which 8 piles were arranged at the soft rock bearing stratum site and 12 piles were arranged at the hard rock bearing stratum site. The numerical results achieved from an empirical formula were also used for making a comparison. The values obtained by the proposed method were highly close to those achieved from the static load test with an error of within 10%. The outcomes indicated that the proposed numerical method can be potentially applied to predict the bearing capacity of prestressed pipe piles

Energy Evolution Analysis and Brittleness Evaluation of High-Strength Concrete Considering the Whole Failure Process

In this work, we aimed to solve the problems that exist in the brittleness evaluation method of high-strength concrete through a triaxial compression test of C60 and C70 high-strength concrete. Then, the relationship between the energy evolution of its elastic energy, dissipative energy, pre-peak total energy and additional energy and its axial strain, confining pressure, and concrete strength grade was analyzed. Taking the accumulation rate of pre-peak elastic strain energy and the dissipation rate of dissipative energy, and the release rate of post-peak elastic energy, as the evaluation indicators to characterize the brittleness of high-strength concrete. A brittleness evaluation method that reflects the whole failure process of high-strength concrete is proposed and verified by experiments. The results show that with the increase of the confining pressure, the proportion of elastic energy in the whole process of high-strength concrete failure gradually decreases. The storage rate of pre-peak elastic energy and the release rate of post-peak elastic energy are gradually reducing, the brittleness index gradually decreases, and the confining pressure inhibits the brittleness of high-strength concrete. Under the same confining pressure, the brittleness index of C70 concrete is greater than that of C60 concrete, which indicates that, with the increase of the strength grade, the brittleness level of concrete gradually increases and the ductility decreases. These findings have a certain theoretical significance for the scientific design of high-strength concrete structures and the improvement of their safety in the future

Image_1_Deficiency of C-reactive protein or human C-reactive protein transgenic treatment aggravates influenza A infection in mice.jpeg

C-reactive protein (CRP) has been shown to be a potential candidate target in the immunotherapy of severe influenza A infection. However, it is unclear on the pathogenesis associated with CRP in influenza infections. Here, we used influenza A H1N1 CA04 to infect human CRP transgenic mice (KI), CRP knockout mice (KO), and wild-type mice (WT), respectively, and compared the viral pathogenicity and associated immune response in those mice. The results showed that CA04 infection resulted in 100%, 80%, and 60% death in KO, KI, and WT mice, respectively. Compared to WT mice, CA04 infection resulted in higher TCID50 in lungs on day 3 after infection but lowered HI antibody titers in sera of survivors on day 21 after infection in KI mice. ELISA assay showed that IFN-γ concentration was significantly increased in sera of WT, KI, or KO mice on day 7 after infection, and IL-17 was remarkably increased in sera of WT mice but decreased in sera of KI mice while no significant change in sera of KO mice on day 3 or 7 after infection. Quantitative RT-PCR showed that the relative expression levels of immune checkpoint CTLA-4, LAIR-1, GITR, BTLA, TIM-3, or PD-1 mRNA in the lung presented decreased levels on day 3 or 7 after infection in KI or KO mice. The correlation analysis showed that mRNA expression levels of the 6 molecules positively correlated with viral TICD50 in WT mice but negatively correlated with viral TCID50 in KI or KO mice. However, only LAIR-1 presented a significant correlation in each lung tissue of WT, KI, or KO mice with CA07 infection statistically. IHC results showed that LAIR-1 positive cells could be found in WT, KO, or KI mice lung tissues with CA04 infection, and the positive cells were mainly distributed in an inflammatory dense area. Our results suggested that deficiency of CRP or human CRP transgenic treatment aggravates influenza A virus infection in mice. CRP is a double sword in immune regulation of influenza infection in which IL-17 and immune checkpoint may be involved.</p

Common Variable Immunodeficiency with Genetic Defects Identified by Whole Exome Sequencing

Common variable immunodeficiency (CVID) belongs to the primary immunodeficiency disorders (PIDs), presenting a profound heterogeneity in phenotype and genotype, with monogenic or complex causes. Recurrent respiratory infections are the most common clinical manifestations. CVID patients can also develop various autoimmune and lymphoproliferative complications. Genetic testing such as whole exome sequencing (WES) can be utilized to investigate likely genetic defects, helping for better clinical management. We described the clinical phenotypes of three sporadic cases of CVID, who developed recurrent respiratory infections with different autoimmune and lymphoproliferative complications. WES was applied to screen disease-causing or disease-associated mutations. Two patients were identified to have monogenic disorders, with compound heterozygous mutations in LRBA for one patient and a frameshift insertion in NFKB1 for another. The third patient was identified to be a complex form of CVID. Two novel mutations were identified, respectively, in LRBA and NFKB1. A combination of clinical and genetic diagnosis can be more extensively utilized in the clinical practice due to the complexity and heterogeneity of CVID

Combined transcriptomics and proteomics studies on the effect of electrical stimulation on spinal cord injury in rats

Electrical stimulation (ES) of the spinal cord is a promising therapy for functional rehabilitation after spinal cord injury (SCI). However, the specific mechanism of action is poorly understood. We designed and applied an implanted ES device in the SCI area in rats and determined the effect of ES on the treatment of motor dysfunction after SCI using behavioral scores. Additionally, we examined the molecular characteristics of the samples using proteomic and transcriptomic sequencing. The differential molecules between groups were identified using statistical analyses. Molecular, network, and pathway-based analyses were used to identify group-specific biological features. ES (0.5 mA, 0.1 ms, 50 Hz) had a positive effect on motor dysfunction and neuronal regeneration in rats after SCI. Six samples (three independent replicates in each group) were used for transcriptome sequencing; we obtained 1026 differential genes, comprising 274 upregulated genes and 752 downregulated genes. A total of 10 samples were obtained: four samples in the ES group and six samples in the SCI group; for the proteome sequencing, 48 differential proteins were identified, including 45 up-regulated and three down-regulated proteins. Combined transcriptomic and proteomic studies have shown that the main enrichment pathway is the hedgehog signaling pathway. Western blot results showed that the expression levels of Sonic hedgehog (SHH) (P < 0.001), Smoothened (SMO) (P = 0.0338), and GLI-1 (P < 0.01) proteins in the ES treatment group were significantly higher than those in the SCI group. The immunofluorescence results showed significantly increased expression of SHH (P = 0.0181), SMO (P = 0.021), and GLI-1 (P = 0.0126) in the ES group compared with that in the SCI group. In conclusion, ES after SCI had a positive effect on motor dysfunction and anti-inflammatory effects in rats. Moreover, transcriptomic and proteomic sequencing also provided unique perspectives on the complex relationships between ES on SCI, where the SHH signaling pathway plays a critical role. Our study provides a significant theoretical foundation for the clinical implementation of ES therapy in patients with SCI

Investigation of Lung Cancer Patients Complicated with Chronic Obstructive Pulmonary Disease in Thoracic Surgical Department

Background and objective Lung cancer is an important complication of chronic obstructive pulmonary disease (COPD), and even significantly affects the prognosis of patients with COPD. COPD also affects the postoperative complications and recurrence in patients with lung cancer. This study aims to investigate lung cancer patients complicated with COPD in thoracic surgical department. Methods All medical records of lung cancer patients discharged from the Department of Thoracic Surgery of People’s Hospital, Peking University during January 2015 and December 2015 were reviewed, including gender, age, tobacco smoke history, harmful occupational exposure, clinic symptom, chest computed tomography (CT) scanning, postoperative pathology result report, discharged diagnosis and spirometry [All patients underwent pulmonary function test are received bronchial dilation test if the based predicted value of forced expiratory volume in one second (FEV1) <70%]. Results A full set of lung function test was measured in 703 lung cancer patients. Bronchial dilation test was finished in 67 patients. 62 (92.5%) patients were diagnosed as COPD. 677 cases with lung cancer were received surgery. Bronchial dilation test was measured in 42 cases. Of them 38 (92.7%) patients were diagnosed as COPD. It was found that the patients with lung cancer and COPD was more frequent in males, elders (≥65 yr), smokers, non-adenocarcinoma patients than those of patients without COPD (P<0.05). The males and the elders (≥65 yr) were more likely to suffer from COPD (OR: 2.374-2.807, 95%CI: 1.101-7.157)(P<0.05). Only 3 patients (4.3‰) were diagnosed as COPD and received standard treatment before admission. And only 5 patients (7.1‰) were diagnosed as COPD as discharged. Conclusion The routine pulmonary function as well as bronchial dilation test are helpful for screening the patients with COPD. At present, the diagnosis and treatment of lung cancer combined with COPD is a serious problem, which needs to be paid attention to by thoracic surgeons and to join hands with physicians in order to improve the diagnosis level of COPD

Metabolic profiles in community-acquired pneumonia: developing assessment tools for disease severity

Abstract Background This study aimed to determine whether community-acquired pneumonia (CAP) had a metabolic profile and whether this profile can be used for disease severity assessment. Methods A total of 175 individuals including 119 CAP patients and 56 controls were enrolled and divided into two cohorts. Serum samples from a discovery cohort (n = 102, including 38 non-severe CAP, 30 severe CAP, and 34 age and sex-matched controls) were determined by untargeted ultra-high-performance liquid chromatography with tandem mass spectrometry (LC-MS/MS)-based metabolomics. Selected differential metabolites between CAP patients versus controls, and between the severe CAP group versus non-severe CAP group, were confirmed by targeted mass spectrometry assays in a validation cohort (n = 73, including 32 non-severe CAP, 19 severe CAP and 22 controls). Pearson’s correlation analysis was performed to assess relationships between the identified metabolites and clinical severity of CAP. The area under the curve (AUC), sensitivity and specificity of the metabolites for predicting the severity of CAP were also investigated. Results The metabolic signature was markedly different between CAP patients and controls. Fifteen metabolites were found to be significantly dysregulated in CAP patients, which were mainly mapped to the metabolic pathways of sphingolipid, arginine, pyruvate and inositol phosphate. The alternation trends of five metabolites among the three groups including sphinganine, p-Cresol sulfate, dehydroepiandrosterone sulfate (DHEA-S), lactate and l-arginine in the validation cohort were consistent with those in the discovery cohort. Significantly lower concentrations of sphinganine, p-Cresol sulfate and DHEA-S were observed in CAP patients than in controls (p  65 years (CURB-65), pneumonia severity index (PSI) and Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, while DHEA-S inversely correlated with the three scoring systems. Combining lactate, sphinganine and DHEA-S as a metabolite panel for discriminating severe CAP from non-severe CAP exhibited a better AUC of 0.911 (95% confidence interval 0.825–0.998) than CURB-65, PSI and APACHE II scores. Conclusions This study demonstrates that serum metabolomics approaches based on the LC-MS/MS platform can be applied as a tool to reveal metabolic changes during CAP and establish a metabolite signature related to disease severity. Trial registration ClinicalTrials.gov, NCT03093220. Registered retrospectively on 28 March 2017

Image_1_Single-cell RNA sequencing reveals the role of immune-related autophagy in spinal cord injury in rats.tif

Spinal cord injury refers to damage to the spinal cord due to trauma, disease, or degeneration; and the number of new cases is increasing yearly. Significant cellular changes are known to occur in the area of spinal cord injury. However, changes in cellular composition, trajectory of cell development, and intercellular communication in the injured area remain unclear. Here, we used single-cell RNA sequencing to evaluate almost all the cell types that constitute the site of spinal cord injury in rats. In addition to mapping the cells of the injured area, we screened the expression of immune autophagy-related factors in cells and identified signaling pathways by the measuring the expression of the receptor−ligand pairs to regulate specific cell interactions during autophagy after spinal cord injury. Our data set is a valuable resource that provides new insights into the pathobiology of spinal cord injury and other traumatic diseases of the central nervous system.</p