TNFα-producing CD4+ T cells dominate the SARS-CoV-2-specific T cell response in COVID-19 outpatients and are associated with durable antibodies

SARS-CoV-2-specific CD4+ T cells are likely important in immunity against COVID-19, but our understanding of CD4+ longitudinal dynamics following infection and specific features that correlate with the maintenance of neutralizing antibodies remains limited. We characterized SARS-CoV-2-specific CD4+ T cells in a longitudinal cohort of 109 COVID-19 outpatients. The quality of the SARS-CoV-2-specific CD4+ response shifted from cells producing IFN{gamma} to TNF+ from five days to four months post-enrollment, with IFN{gamma}-IL21-TNF+ CD4+ T cells the predominant population detected at later timepoints. Greater percentages of IFN{gamma}-IL21-TNF+ CD4+ T cells on day 28 correlated with SARS-CoV-2 neutralizing antibodies measured seven months post-infection ({rho}=0.4, P=0.01). mRNA vaccination following SARS-CoV-2 infection boosted both IFN{gamma} and TNF producing, spike protein-specific CD4+ T cells. These data suggest that SARS-CoV-2-specific, TNF-producing CD4+ T cells may play an important role in antibody maintenance following COVID-19.

Early immune responses have long-term associations with clinical, virologic, and immunologic outcomes in patients with COVID-19

The great majority of SARS-CoV-2 infections are mild and uncomplicated, but some individuals with initially mild COVID-19 progressively develop more severe symptoms. Furthermore, mild to moderate infections are an important contributor to ongoing transmission. There remains a critical need to identify host immune biomarkers predictive of clinical and virologic outcomes in SARS-CoV-2-infected patients. Leveraging longitudinal samples and data from a clinical trial of Peginterferon Lambda for treatment of SARS-CoV-2 infected outpatients, we used host proteomics and transcriptomics to characterize the trajectory of the immune response in COVID-19 patients within the first 2 weeks of symptom onset. We define early immune signatures, including plasma levels of RIG-I and the CCR2 ligands (MCP1, MCP2 and MCP3), associated with control of oropharyngeal viral load, the degree of symptom severity, and immune memory (including SARS-CoV-2-specific T cell responses and spike (S) protein-binding IgG levels). We found that individuals receiving BNT162b2 (Pfizer-BioNTech) vaccine had similar early immune trajectories to those observed in this natural infection cohort, including the induction of both inflammatory cytokines (e.g. MCP1) and negative immune regulators (e.g. TWEAK). Finally, we demonstrate that machine learning models using 8-10 plasma protein markers measured early within the course of infection are able to accurately predict symptom severity, T cell memory, and the antibody response post-infection.

Association of Circulating ICAM3 Concentrations with Severity and Short-term Outcomes of Acute Ischemic Stroke.

Increased circulating intercellular adhesion molecule 3 (ICAM3) is associated with a risk of acute ischemic stroke. This study aims to investigate the association of serum levels of ICAM3 with the severity and short-term outcomes of ischemic stroke. This study recruited 152 stroke patients with supratentorial cerebral infarcts and 133 healthy controls. Patients were followed up for 2 weeks since admission for observation of functional outcomes. Serum ICAM3 concentrations at baseline were determined by Elisa. Serum ICAM3 concentrations were higher in stroke patients than in healthy controls. Serum concentrations of ICAM3 were not associated with stroke severity at baseline, as reflected by NIH Stroke Scale (NIHSS) and infarction volume. However, serum ICAM3 levels were positively associated with mRS scores at 2 weeks since admission. Furthermore, regression analyses found that increased serum ICAM3 levels were associated with worse short-term functional outcomes of stroke. These findings imply that circulating ICAM3 might be a potential short-term prognostic biomarker for acute ischemic stroke.

Mining transcriptomics and clinical data reveals ACE2 expression modulators and identifies cardiomyopathy as a risk factor for mortality in COVID-19 patients

Angiotensin-converting enzyme 2 (ACE2) is the cell-entry receptor for SARS-CoV-2. It plays critical roles in both the transmission and the pathogenesis of the coronavirus disease 2019 (COVID-19). Comprehensive profiling of ACE2 expression patterns will help researchers to reveal risk factors of severe COVID-19 illness. While the expression of ACE2 in healthy human tissues has been well characterized, it is not known which diseases and drugs might modulate the ACE2 expression. In this study, we developed GENEVA (GENe Expression Variance Analysis), a semi-automated framework for exploring massive amounts of RNA-seq datasets. We applied GENEVA to 28,6650 publicly available RNA-seq samples to identify any previously studied experimental conditions that could directly or indirectly modulate ACE2 expression. We identified multiple drugs, genetic perturbations, and diseases that modulate the expression of ACE2, including cardiomyopathy, HNF1A overexpression, and drug treatments with RAD140 and Itraconazole. Our unbiased meta-analysis of seven datasets confirms ACE2 up-regulation in all cardiomyopathy categories. Using electronic health records data from 3936 COVID19 patients, we demonstrate that patients with pre-existing cardiomyopathy have an increased mortality risk than age-matched patients with other cardiovascular conditions. GENEVA is applicable to any genes of interest and is freely accessible at http://genevatool.org.

Effects of carotid artery stenting on cognitive function in patients with critical internal carotid artery stenosis / 重庆医学

Objective To investigate the influence of carotid artery stenting (CS)of asymptomatic critical internal carotid artery (ICA)stenosis patients on cognitive function .Methods One hundred and fifty‐six asymptomatic patients with internal carotid arter‐y stenosis(carotid stenosis severity≥70% )were enrolled ,in whom CS was attempted .Functional assessments including alzheimer disease assessment scale‐cognitive subtest (ADAS‐Cog) ,mini‐mental state examination (MMSE) ,and trail making test A(TMTa) and B(TMTb) were done prior to 1 weeks and 3 months after the procedure .Results Successful CS was achieved in all of patients (100% ) ,only 1 patient was lost to follow‐up .There were significant improvement in ADAS‐Cog score(pre 6 .60 ± 2 .04 vs .post 5 .16 ± 1 .63 ,P<0 .01) ,MMSE score (pre 26 .32 ± 1 .06 vs .post 27 .05 ± 1 .46 ,P< 0 .01) ,TMTa (pre 108 .94 ± 17 .42 vs .post 94 .70 ± 20 .27 ,P<0 .01) ,TMTb (pre 178 .65 ± 21 .77 vs .post 148 .92 ± 23 .65 ,P<0 .01) .There was new cerebral infarction dur‐ing 3 months after surgery .Conclusion Asymptomatic critical internal carotid artery (ICA)stenosis may be one reason of cognitive impairment ,and successful CS could improve cognitive function in asymptomatic ICA stenosis .

Effect of NADPH oxidase on Toll-like receptor 4-mediated proinflammatory phenotype of cultured vascular smooth muscle cells in mice / 国际脑血管病杂志

Objective To investigate the effect of the reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase on Toll-like receptor 4 (TLR4)-mediated proinflammatory phenotype of cultured vascular smooth muscle cells (VSMCs) in mice.Methods NADPH oxidase agonist platelet-derived growth factorBB (PDGF-BB) and inhibitor apocynin were used respectively to treat cultured VSMCs from C57BL/6J and TLR4-/-mice.The fluorescent probe 2',7'-dichlorodihydrofluorescein diacetate was used to detect the reactive oxygen species (ROS) level in VSMCs.An enzyme-linked immunosorbent assay was used to detect the expressions of interleukin (IL)-6,IL-1β,and tumor necrosis factor-α (TNF-α) in VSMCs.Tetrazolium blue staining and Boyden chamber assay were used to detect the proliferation and migration of VSMC.Results The ROS levels were increased in VSMCs both from C57BL/6J and TLR4-/-mice after PDGF-BB treatment,and this could be inhibited by apocynin.PDGF-BB pretreatment significantly upregulated the expressions of IL-6 (52.69 ±3.49 ng/ml vs.35.04 ±2.74 ng/ml; P =0.001),IL-1β (79.68 ±2.33 ng/ml vs.62.38 ±0.54 ng/ml;P=0.000),and TNF-α (218.35± 5.42 ng/mlvs.124.74± 4.59 ng/ml; P=0.000) in VSMCs from C57BL/6J mice,and the abilities of proliferation (1.69 ± 0.53 vs.1.04 ± 0.40; P =0.000) and migration (42.11 ±4.05 vs.1.69 ± 0.53; P =0.000) were increased significantly; apocynin pretreatment significantly inhibit the expressions of IL-6 (42.11 ± 4.05 ng/ml vs.52.69 ± 3.49 ng/ml; P =0.010),IL-1β (67.57 ± 1.36 ng/ml vs.79.68 ±2.33 ng/ml; P =0.000) and TNF-α (156.18 ± 6.98 ng/ml vs.218.35 ± 5.42 ng/ml;P =0.000),as well as proliferation (1.23 ±0.42 vs.1.69 ±0.53; P =0.000) and migration (42.11 ±4.05 vs.52.69 ± 3.49; P =0.000).While there were no significant changes in the expressions of IL-6,IL-1β,and TNF-α in VSMCs from TLR4-/-mice after PDGF-BB and apocynin pretreatment.Conclusions NADPH oxidase-derived ROS involved in the TLR4-mediated VSMC inflammatory phenotype as well as proliferation and migration,which may be the important mechanisms of its influencing on the occurrence and development of atherosclerosis.

A study of PBL teaching methods in the practice of intra-arterial thrombolysis for ischemic stroke / 中华医学教育探索杂志

In teaching of intra-arterial thrombolysis of ischemic stroke, introducing the method of problem-based learning ( PBL ) to improve the students' learning initiative and stimulate the students' interest in search of knowledge, and guide students to form scientific clinical thinking. Through further participation in surgery, promoting the combination of theory and practice. PBL can help to improve students' ability to analyze and solve problems related to intra-arterial thrombolysis of ischemic stroke.

The detection on the p24 gene fragment of Borna disease virus in brain tissues of animals in Ili, Xin-jiang / 中华微生物学和免疫学杂志

Objective To observe the epidemiology characterization of Borna disease virus (BDV) in animal brain in Ili, Xinjiang, and to find out the potential infection of the Borna disease virus to prevent its outbreak. Methods The BDV p24 gene of animal brain tissues in Ili including 200 horses, 75 donkeys and 100 shepherd dogs was detected by fluorescence quantitative nest reverse transcriptase polymer-ase chain reaction(FQ-nRT-PCR). GFP-p24,pMD-19 plasmid contamination was excluded from positive products. Clone sequencing was used to analyze the homology of gene and amino acid sequence. Results BDV p24 gent was found in 3 Ili horses, 4 Ili donkeys and 9 shepherd dogs, and the positive ratio is 1.5%, 5.3% and 9.0%, respectively. The GFP-p24,pMD-19 were not found in BDV p40 gene and plasmid stand-ard. The sequence of BDV p24 amplification production was totally the same as He/80 virus strain. Conclu-sion Natural infection of BDV may exist in the animals(horses, donkeys and dogs)in Ili, and the epidem-ic strain of BDV in this area was homological as He/80 virus strain.

Auditory cerebral activation patterns of Chinese English learners by fMRI / 重庆医科大学学报

Objective:To identify the cerebral activation patterns associated with the processes that occur during viewing Chinese and English words in native Chinese English learners.Methods:12 right-handed Chinese English hamers were divided into two groups equally,namely English majors and non-English majors,and took semantic judgement tasks of both English and Chinese words,for whom the fMRI images were coUected.Results:To various degrees,all subjects demonstrated activation of associated cerebral regions in both hemispheres and the left hemisphere activation was more significant for most subjects.Except for elassieal regions involved in language processing,such as Wemicke areas and Broca areas,there were other activated cerebral regions,including cerebellum,limbic system and basal ganglia nucleus,etc.To sum up,there were apparent overlap for cerebral activation distribution and no specific processing areas for both tasks.The analysis of ROI(region of interest)suggested that subjects in specialized group were more dependent on right hemisphere to perform English words task.Conclus/on:Language cognition is dominated by left hemisphere,which is also shared by the right hemisphere to various degrees and thus two hemispheres work by ways of both dissociation and coordination.It is possible that working strategy of the right hemisphere in English task is related to proficiency of the second language.A variety of distinctions are shared by each subject for language cognitive patterns.