Asthma control associated with anxiety and depression in asthmatic children following post-acute COVID-19.

BACKGROUND: Poor asthma control may adversely affect mental health. Our study investigates the correlation between inadequate asthma control, exhaled nitric oxide (FENO) levels, and anxiety and depression among pediatric asthma patients with COVID-19. METHODS: This prospective case-control study enrolled 520 asthmatic children (8-15 years), including 336 patients diagnosed with COVID-19 after rapid antigen testing at home and 184 age-matched asthmatic patients without COVID-19 infection. FENO and spirometry were performed 1 month after COVID-19 infection. Scores for Child Anxiety-Related Disorders (SCARED) and depression screen derived from Patient Health Questionnaire-9 (PHQ-9) to assess their mental health status. Childhood asthma control test (C-ACT), FENO levels, and spirometry were correlated with the SCARED and PHQ-9 questionnaires. RESULTS: SCARED subscales, including generalized anxiety disorder, social anxiety disorder, school avoidance, and depression scores from PHQ-9, exhibited a significant increase in asthmatic patients diagnosed with COVID-19 (p < .05). Among asthmatic children with SARS-CoV-2 infection, the poor asthma control group exhibited the highest SCARED and PHQ-9 measurements (p < .01). Multiple linear regression analysis indicated that reduced C-ACT scores and elevated FENO levels in asthmatic children with COVID-19 were significant risk factors for both anxiety and depression scores (p < .05). Lower C-ACT scales were associated with high scores of SCARED (r = -0.471) and PHQ-9 (r = -0.329) in asthmatic children (p < .001). CONCLUSIONS: The current study emphasizes the need for healthcare professionals to closely monitor asthma control in asthmatic children to prevent heightened risks of depression and anxiety during the ongoing COVID-19 pandemic.

Stem cell exosome-loaded Gelfoam improves locomotor dysfunction and neuropathic pain in a rat model of spinal cord injury.

BACKGROUND: Spinal cord injury (SCI) is a debilitating illness in humans that causes permanent loss of movement or sensation. To treat SCI, exosomes, with their unique benefits, can circumvent limitations through direct stem cell transplantation. Therefore, we utilized Gelfoam encapsulated with exosomes derived from human umbilical cord mesenchymal stem cells (HucMSC-EX) in a rat SCI model. METHODS: SCI model was established through hemisection surgery in T9 spinal cord of female Sprague-Dawley rats. Exosome-loaded Gelfoam was implanted into the lesion site. An in vivo uptake assay using labeled exosomes was conducted on day 3 post-implantation. Locomotor functions and gait analyses were assessed using Basso-Beattie-Bresnahan (BBB) locomotor rating scale and DigiGait Imaging System from weeks 1 to 8. Nociceptive responses were evaluated through von Frey filament and noxious radiant heat tests. The therapeutic effects and potential mechanisms were analyzed using Western blotting and immunofluorescence staining at week 8 post-SCI. RESULTS: For the in vivo exosome uptake assay, we observed the uptake of labeled exosomes by NeuN+, Iba1+, GFAP+, and OLIG2+ cells around the injured area. Exosome treatment consistently increased the BBB score from 1 to 8 weeks compared with the Gelfoam-saline and SCI control groups. Additionally, exosome treatment significantly improved gait abnormalities including right-to-left hind paw contact area ratio, stance/stride, stride length, stride frequency, and swing duration, validating motor function recovery. Immunostaining and Western blotting revealed high expression of NF200, MBP, GAP43, synaptophysin, and PSD95 in exosome treatment group, indicating the promotion of nerve regeneration, remyelination, and synapse formation. Interestingly, exosome treatment reduced SCI-induced upregulation of GFAP and CSPG. Furthermore, levels of Bax, p75NTR, Iba1, and iNOS were reduced around the injured area, suggesting anti-inflammatory and anti-apoptotic effects. Moreover, exosome treatment alleviated SCI-induced pain behaviors and reduced pain-associated proteins (BDNF, TRPV1, and Cav3.2). Exosomal miRNA analysis revealed several promising therapeutic miRNAs. The cell culture study also confirmed the neurotrophic effect of HucMSCs-EX. CONCLUSION: Implantation of HucMSCs-EX-encapsulated Gelfoam improves SCI-induced motor dysfunction and neuropathic pain, possibly through its capabilities in nerve regeneration, remyelination, anti-inflammation, and anti-apoptosis. Overall, exosomes could serve as a promising therapeutic alternative for SCI treatment.

Relationship between the Number of Repeats in the Neck Regions of L-SIGN and Augmented Virus Replication and Immune Responses in Dengue Hemorrhagic Fever.

C-type lectins play a crucial role as pathogen-recognition receptors for the dengue virus, which is responsible for causing both dengue fever (DF) and dengue hemorrhagic fever (DHF). DHF is a serious illness caused by the dengue virus, which exists in four different serotypes: DEN-1, DEN-2, DEN-3, and DEN-4. We conducted a genetic association study, during a significant DEN-2 outbreak in southern Taiwan, to explore how variations in the neck-region length of L-SIGN (also known as CD209L, CD299, or CLEC4M) impact the severity of dengue infection. PCR genotyping was utilized to identify polymorphisms in variable-number tandem repeats. We constructed L-SIGN variants containing either 7- or 9-tandem repeats and transfected these constructs into K562 and U937 cells, and cytokine and chemokine levels were evaluated using enzyme-linked immunosorbent assays (ELISAs) following DEN-2 virus infection. The L-SIGN allele 9 was observed to correlate with a heightened risk of developing DHF. Subsequent results revealed that the 9-tandem repeat was linked to elevated viral load alongside predominant T-helper 2 (Th2) cell responses (IL-4 and IL-10) in K562 and U937 cells. Transfecting K562 cells in vitro with L-SIGN variants containing 7- and 9-tandem repeats confirmed that the 9-tandem repeat transfectants facilitated a higher dengue viral load accompanied by increased cytokine production (MCP-1, IL-6, and IL-8). Considering the higher prevalence of DHF and an increased frequency of the L-SIGN neck's 9-tandem repeat in the Taiwanese population, individuals with the 9-tandem repeat may necessitate more stringent protection against mosquito bites during dengue outbreaks in Taiwan.

Long-term PM2.5 exposure is associated with asthma prevalence and exhaled nitric oxide levels in children.

BACKGROUND: Exhaled nitric oxide concentration (FENO) is a marker of airway inflammation. This study aimed to evaluate the association of air pollution exposure with FENO levels and asthma prevalence with respiratory symptoms in school children. METHODS: We analyzed 4736 school children who reside in six townships near industrial areas in central Taiwan. We evaluated asthmatic symptoms, FENO, and conducted the environmental questionnaire. The personal exposure of PM2.5, NO, and SO2 was estimated using land-use regression models data on children's school and home addresses. RESULTS: Annual exposure to PM2.5 was associated with increased odds of physician-diagnosed asthma (OR = 1.595), exercise-induced wheezing (OR = 1.726), itchy eyes (OR = 1.417), and current nasal problems (OR = 1.334) (P < 0.05). FENO levels in the absence of infection were positively correlated with age, previous wheezing, allergic rhinitis, atopic eczema, near the road, and for children with high exposure to PM2.5 (P < 0.05). An increase of 1 µg/m3 PM2.5 exposure was significantly associated with a 1.0% increase in FENO levels for children after adjusting for potential confounding variables, including exposures to NO and SO2. CONCLUSIONS: Long-term exposures to PM2.5 posed a significant risk of asthma prevalence and airway inflammation in a community-based population of children. IMPACT: Annual exposure to PM2.5 was associated with increased odds of physician-diagnosed asthma and nasal problems and itchy eyes. Long-term exposures to PM2.5 were significantly associated with FENO levels after adjusting for potential confounding variables. This is first study to assess the association between FENO levels and long-term air pollution exposures in children near coal-based power plants. An increase of 1 µg/m3 annual PM2.5 exposure was significantly associated with a 1.0% increase in FENO levels. Long-term exposures to PM2.5 posed a significant risk of asthma prevalence and airway inflammation in a community-based population of children.

Case report: Presentations and cytokine profiles of inflammatory non-pulmonary COVID-19 and related diseases in children.

The coronavirus disease 2019 (COVID-19) pandemic has evolved to dynamic waves of different SARS-CoV-2 variants. Initially, children diagnosed with COVID-19 presented pulmonary involvement characterized by mild diseases. In the later waves of the COVID-19 pandemic, life-threatening non-pulmonary inflammatory diseases such as (1) aseptic meningoencephalitis (ME), (2) acute necrotizing encephalopathies (ANE), and (3) multisystem inflammatory syndrome in children (MIS-C) have been reported, affecting the pediatric population. To alert timely identification and prevention of the life-threatening non-pulmonary COVID-19, we present the cases of ME, ANE, and MIS-C in terms of clinical manifestation, cytokine profile, and follow-up consequences. Based on the immunopathogenesis and risk factors associated with non-pulmonary COVID-19, we delineate strategies for an early diagnosis and treatment to reduce morbidity and mortality in children.

Pathogenesis and novel therapeutics of regulatory T cell subsets and interleukin-2 therapy in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a heterogeneous multisystem inflammatory disease with wide variability in clinical manifestations. Natural arising CD4+ regulatory T cells (Tregs) play a critical role in maintaining peripheral tolerance by suppressing inflammation and preventing autoimmune responses in SLE. Additionally, CD8+ regulatory T cells, type 1 regulatory T cells (Tr1), and B regulatory cells also have a less well-defined role in the pathogenesis of SLE. Elucidation of the roles of various Treg subsets dedicated to immune homeostasis will provide a novel therapeutic approach that governs immune tolerance for the remission of active lupus. Diminished interleukin (IL)-2 production is associated with a depleted Treg cell population, and its reversibility by IL-2 therapy provides important reasons for the treatment of lupus. This review focuses on the pathogenesis and new therapeutics of human Treg subsets and low-dose IL-2 therapy in clinical benefits with SLE.

Profiling humoral responses to COVID-19 immunization in Kawasaki disease using SARS-CoV-2 variant protein microarrays.

Kawasaki disease (KD) is a form of acute systemic vasculitis syndrome that predominantly occurs in children under the age of 5 years. Its etiology has been postulated due to not only genetic factors but also the presence of foreign antigens or infectious agents. To evaluate possible associations between Kawasaki disease (KD) and COVID-19, we investigated humoral responses of KD patients against S-protein variants with SARS-CoV-2 variant protein microarrays. In this study, plasma from a cohort of KD (N = 90) and non-KD control (non-KD) (N = 69) subjects in categories of unvaccinated-uninfected (pre-pandemic), SARS-CoV-2 infected (10-100 days after infection), and 1-dose, 2-dose, and 3-dose BNT162b2 vaccinated (10-100 days after vaccination) was collected. The principal outcomes were non-KD-KD differences for each category in terms of anti-human/anti-His for binding antibodies and neutralizing percentage for surrogate neutralizing antibodies. Binding antibodies against spikes were lower in the KD subjects with 1-dose of BNT162b2, and mean differences were significant for the P.1 S-protein (non-KD-KD, 3401; 95% CI, 289.0 to 6512; P = 0.0252), B.1.617.2 S-protein (non-KD-KD, 4652; 95% CI, 215.8 to 9087; P = 0.0351) and B.1.617.3 S-protein (non-KD-KD, 4874; 95% CI, 31.41 to 9716; P = 0.0477). Neutralizing antibodies against spikes were higher in the KD subjects with 1-dose of BNT162b2, and mean percentage differences were significant for the 1-dose BNT162b2 B.1.617.3 S-protein (non-KD-KD, -22.89%; 95% CI, -45.08 to -0.6965; P = 0.0399), B.1.1.529 S-protein (non-KD-KD, -25.96%; 95% CI, -50.53 to -1.376; P = 0.0333), BA.2.12.1 S-protein (non-KD-KD, -27.83%; 95% CI, -52.55 to -3.115; P = 0.0195), BA.4 S-protein (non-KD-KD, -28.47%; 95% CI, -53.59 to -3.342; P = 0.0184), and BA.5 S-protein (non-KD-KD, -30.42%; 95% CI, -54.98 to -5.869; P = 0.0077). In conclusion, we have found that KD patients have a comparable immunization response to healthy individuals to SARS-CoV-2 infection and COVID-19 immunization.

Comparisons of Cytokines, Growth Factors and Clinical Efficacy between Platelet-Rich Plasma and Autologous Conditioned Serum for Knee Osteoarthritis Management.

This study aimed to directly compare the contents and the clinical efficacy of the two autologous blood-derived products, platelet-rich plasma (PRP) and autologous conditioned serum (ACS) for osteoarthritis (OA) treatment. The contents of standard-prepared PRP and ACS prepared at 37 °C for 1 h, 3 h, 6 h, and 24 h from healthy volunteers were compared. The clinical efficacy of pain relief in patients with Stage III knee OA was evaluated by a patient-reported visual analog scale (VAS) pain rating. PDGF-BB levels in ACS 1 h were significantly higher than those in PRP, and the levels in ACS preparations remained stable. IGF-1 level of ACS 24 h showed a significant increase compared to those of other ACS preparations and PRP. ACS 3 h showed a turning of IL-1Ra level and revealed a time-dependent increase up to 24 h. ACS 6 h showed a turning increase in TNF-α levels. ACS 3 h was chosen for clinical comparison with PRP. The reduction in pain VAS in the ACS group was significantly more compared to those of the PRP group (p = 0.028). However, PRP showed significant earlier improvement (p < 0.001). Conclusion: ACS contained higher levels of PDGF-BB and IL-1Ra and provided better improvement in pain relief compared to PRP.

First-trimester urinary extracellular vesicles as predictors of preterm birth: an insight into immune programming.

Background: The programming of innate and adaptive immunity plays a pivotal role in determining the course of pregnancy, leading to either normal term birth (TB) or preterm birth (PB) through the modulation of macrophage (M1/M2) differentiation. Extracellular vesicles (EVs) in maternal blood, harboring a repertoire of physiological and pathological messengers, are integral players in pregnancy outcomes. It is unknown whether urinary EVs (UEVs) could serve as a non-invasive mechanistic biomarker for predicting PB. Methods: This study investigated first-trimester UEVs carrying M1 messengers with altered immune programming, aiming to discern their correlation to subsequent PB. A birth cohort comprising 501 pregnant women, with 40 women experiencing PB matched to 40 women experiencing TB on the same day, was examined. First-trimester UEVs were isolated for the quantification of immune mediators. Additionally, we evaluated the UEV modulation of "trained immunity" on macrophage and lymphocyte differentiations, including mRNA expression profiles, and chromatin activation modification at histone 3 lysine 4 trimethylation (H3K4me3). Results: We found a significant elevation (p < 0.05) in the particles of UEVs bearing characteristic exosome markers (CD9/CD63/CD81/syntenin) during the first trimester of pregnancy compared to non-pregnant samples. Furthermore, UEVs from PB demonstrated significantly heightened levels of MCP-1 (p = 0.003), IL-6 (p = 0.041), IL-17A (p = 0.007), IP-10 (p = 0.036), TNFα (p = 0.004), IL-12 (p = 0.045), and IFNγ (p = 0.030) relative to those from TB, indicative of altered M1 and Th17 differentiation. Notably, MCP-1 (>174 pg/mL) exhibited a sensitivity of 71.9% and specificity of 64.6%, and MCP-1 (>174 pg/mL) and IFNγ (>8.7 pg/mL) provided a higher sensitivity (84.6%) of predicting PB and moderate specificity of 66.7%. Subsequent investigations showed that UEVs from TB exerted a significant suppression of M1 differentiation (iNOS expression) and Th17 differentiation (RORrT expression) compared to those of PB. Conversely, UEVs derived from PB induced a significantly higher expression of chromatin modification at H3K4me3 with higher production of IL-8 and TNFα cytokines (p < 0.001). Implications: This pioneering study provides critical evidence for the early detection of altered M1 and Th17 responses within UEVs as a predictor of PB and early modulation of altered M1 and Th17 polarization associated with better T-cell regulatory differentiation as a potential prevention of subsequent PB.

Pathogenesis and Preventive Tactics of Immune-Mediated Non-Pulmonary COVID-19 in Children and Beyond.

The COVID-19 pandemic has evolved to immune escape and threatened small children and the elderly with a higher severity and fatality of non-pulmonary diseases. These life-threatening non-pulmonary COVID-19 diseases such as acute necrotizing encephalopathies (ANE) and multisystem inflammatory syndrome in children (MIS-C) are more prevalent in children. However, the mortality of multisystem inflammatory syndrome in adults (MIS-A) is much higher than that of MIS-C although the incidence of MIS-A is lower. Clarification of immunopathogenesis and genetic susceptibility of inflammatory non-pulmonary COVID-19 diseases would provide an appropriate guide for the crisis management and prevention of morbidity and fatality in the ongoing pandemic. This review article described three inflammatory non-pulmonary COVID-19 diseases including (1) meningoencephalitis (ME), (2) acute necrotizing encephalopathies (ANE), and (3) post-infectious multisystem inflammatory syndrome in children (MIS-C) and in adults (MIS-A). To prevent these life-threatening non-pulmonary COVID-19 diseases, hosts carrying susceptible genetic variants should receive prophylactic vaccines, avoid febrile respiratory tract infection, and institute immunomodulators and mitochondrial cocktails as early as possible.

Small Airway Dysfunction Measured by Impulse Oscillometry and Fractional Exhaled Nitric Oxide Is Associated With Asthma Control in Children.

Background: Impulse oscillometry (IOS) and fractional exhaled nitric oxide (FeNO) are sensitive and non-invasive methods to measure airway resistance and inflammation, although there are limited population-based studies using IOS and FeNO to predict asthma control. Objective: This study aimed to investigate the utility of IOS and FeNO for assessing childhood asthma control in terms of small airway dysfunction and airway inflammation. Methods: This prospective observational cohort study enrolled 5,018 school children (aged 6-12 years), including 560 asthmatic children and 140 normal participants. FeNO, spirometry, IOS, bronchial dilation test, total IgE, and childhood asthma control test (C-ACT) were measured. FeNO, IOS, spirometry, and C-ACT results were correlated with childhood asthma with and without control. Results: Uncontrolled asthmatic children had abnormal FeNO, IOS, and spirometric values compared with control subjects (P < 0.05). IOS parameters with R5, R5-R20, X5, Ax, △R5, and FeNO can predict lower C-ACT scales by the areas under receiver operating characteristic curves (AUCs) (0.616, 0.625, 0.609, 0.622, 0.625, and 0.714). A combination of FeNO (>20 ppb) with IOS measure significantly increased the specificity for predicting uncontrolled asthma patients compared with FeNO alone (P < 0.01). A multiple regression model showed that small airway parameter (R5-R20) was the strongest risk factor [OR (95% CI): 87.26 (7.67-993.31)] for uncontrolled asthma patients. Poor control with lower C-ACT scales correlated with high FeNO (r = -0.394), R5 (r = -0.106), and R5-R20 (r = -0.129) in asthmatic children (P < 0.05). Conclusion: A combined use of FeNO and IOS measurements strongly predicts childhood asthma with or without control.

Cancer-Associated Fibroblasts Promote Tumor Aggressiveness in Head and Neck Cancer through Chemokine Ligand 11 and C-C Motif Chemokine Receptor 3 Signaling Circuit.

The tumor microenvironment (TME) plays a crucial role in tumor progression. One of its key stromal components, cancer-associated fibroblasts (CAFs), may crosstalk with cancer cells by secreting certain cytokines or chemokines. However, which important mediator(s) are released by CAFs, and the underlying molecular mechanism, remain largely unknown. In the present study, we isolated patient-derived CAFs and normal fibroblasts (NFs). Using microarray analysis, we detected chemokine ligand 11 (CCL11) overexpression in CAFs compared to NFs. CCL11 administration promoted the migration and invasion of head and neck cancer (HNC) cells with enhanced cancer stem cell-like properties and induction of epithelial-to-mesenchymal transition. Furthermore, neutralization of CCL11 activity reversed the aggressive phenotype of CAF-induced cancer cells. Confocal microscopy showed colocalization of CCL11 and CC chemokine receptor 3 (CCR3) on HNC cells. Moreover, immunohistochemical analysis of clinical samples from 104 patients with HNC showed that expression of CCL11 and CCR3 were significantly correlated with poor overall survival (p = 0.003 and 0.044, respectively). Collectively, CCL11 expressed on CAFs promotes HNC invasiveness, and neutralization of CCL11 reverses this effect. We propose that the CCL11/CCR3 signaling circuit is a potential target for optimizing therapeutic strategies against HNC.

Near Infrared Spectroscopy Detects Change of Tissue Hemoglobin and Water Levelsin Kawasaki Disease and Coronary Artery Lesions.

Background: Kawasaki disease (KD) is a form of systemic vasculitis that mainly affects children under the age of five years old. Limb swelling and redness are among the primary symptoms of KD. Previous studies have reported that wireless optical monitoring systems can identify limb indurations characteristics in patients with KD. Therefore, we conducted this study to monitor the dynamic changes in different stages of KD and the disease outcome of coronary artery lesions (CAL).Methods: KD patients who were admitted for intravenous immunoglobulin (IVIG) treatment and controls with or without fever were enrolled in this study. Near infrared spectroscopy data were collected for KD patients at different stages, including before (within one day before IVIG treatment, KD1) and shortly after IVIG treatment (within three days, KD2), at least 21 days after IVIG (KD3), 6 months later (KD4), 1 year later (KD5), 2 years later (KD6), and 3 years later (KD7).Results: This study included a total of 350 pieces of data, including data from 20 healthy controls, 64 fever controls, 53 KD1, 67 KD2, 58 KD3, 28 KD4, 25 KD5, 15 KD6, and 20 KD7. The relative HbO2 of the KD1 group were significantly lower than those of the healthy group (0.298 ± 0.01 vs. 0.304 ± 0.05, p = 0.028) but no significant differences were found with the fever group. The HbT concentrations of KD1 group showed significantly lower than health group (0.632 ± 0.019 vs. 0.646 ± 0.021, p = 0.001) but no significant difference with fever control. Relative levels of HbO2, HbT and Hb showed significant difference between KD1 and health control while StO2 and H2O showed difference between KD1 and fever control. The relative H2O concentration was significantly higher in KD patients with CAL formation than without (p < 0.005). Conclusion: This report is the first to use near infrared spectroscopy to detect changes in tissue hemoglobin and water levels at different stages of KD in patients and showed that water content was significantly associated with CAL formation. This non-invasive device may benefit physicians by serving for early identification of KD from fever illness.

Number of Kawasaki Disease Admissions Is Associated with Number of Domestic COVID-19 and Severe Enterovirus Case Numbers in Taiwan.

Background: Non-pharmaceutical interventions (NPIs) introduced in response to the COVID-19 pandemic, including mask-wearing and social distancing, have changed the prevalence of circulating viruses in the community. Since viral infections represent a potential triggering factor for the development of Kawasaki disease (KD), we examined the relationship between KD admission rates and the number of COVID-19, severe influenza, and severe enterovirus infections both before and after the COVID-19 pandemic. Methods: We conducted a retrospective study using data obtained from the Chang Gung Research Database (including seven Taiwanese hospitals and more than 10,000 beds) and the Centers for Disease Control in Taiwan from January 2018 to December 2020. We recorded the number of KD admissions, as well as COVID-19, severe influenza, and severe enterovirus infections. Results: The numbers of KD admissions, severe enterovirus infections, and severe influenza infections were significantly lower from April to September 2020. The number of KD hospitalizations was positively correlated with the number of domestic COVID-19 cases (p = 0.001). A decrease in KD admission numbers was positively correlated with a decrease in severe enterovirus case numbers (p = 0.007). Conclusion: Our findings provide further evidence that viral infections may be an important trigger factor in the development of KD. Therefore, NPIs may not only prevent transmissible viral infections in children, but also decrease the risk of KD.

Bio-Scaffolds as Cell or Exosome Carriers for Nerve Injury Repair.

Central and peripheral nerve injuries can lead to permanent paralysis and organ dysfunction. In recent years, many cell and exosome implantation techniques have been developed in an attempt to restore function after nerve injury with promising but generally unsatisfactory clinical results. Clinical outcome may be enhanced by bio-scaffolds specifically fabricated to provide the appropriate three-dimensional (3D) conduit, growth-permissive substrate, and trophic factor support required for cell survival and regeneration. In rodents, these scaffolds have been shown to promote axonal regrowth and restore limb motor function following experimental spinal cord or sciatic nerve injury. Combining the appropriate cell/exosome and scaffold type may thus achieve tissue repair and regeneration with safety and efficacy sufficient for routine clinical application. In this review, we describe the efficacies of bio-scaffolds composed of various natural polysaccharides (alginate, chitin, chitosan, and hyaluronic acid), protein polymers (gelatin, collagen, silk fibroin, fibrin, and keratin), and self-assembling peptides for repair of nerve injury. In addition, we review the capacities of these constructs for supporting in vitro cell-adhesion, mechano-transduction, proliferation, and differentiation as well as the in vivo properties critical for a successful clinical outcome, including controlled degradation and re-absorption. Finally, we describe recent advances in 3D bio-printing for nerve regeneration.

The Functional DNA Methylation Signatures Relevant to Altered Immune Response of Neonatal T Cells with l-Arginine Supplementation.

l-Arginine is an important nutrient in the infant diet that significantly regulates the maturation of the immune system in neonates, including the maturation of CD4+ T cells. The biological activities of CD4+ T cells differ substantially between neonates and adults, and these differences may be governed by epigenetic processes. Investigating these differences and the causative processes may help understand neonatal and developmental immunity. In this study, we compared the functional DNA methylation profiles in CD4+ T cells of neonates and adults, focusing on the role of l-arginine supplementation. Umbilical cord blood and adult CD4+ T cells were cultured with/without l-arginine treatment. By comparing DNA methylation in samples without l-arginine treatment, we found that CD4+ T cells of neonatal cord blood generally showed higher DNA methylation than those of adults (average CpG methylation percentage 0.6305 for neonate and 0.6254 for adult, t-test p-value < 0.0001), suggesting gene silencing in neonates. By examining DNA methylation patterns of CpG dinucleotides induced by l-arginine treatment, we found that more CpG dinucleotides were hypomethylated and more genes appeared to be activated in neonatal T-cells as compared with adult. Genes activated by l-arginine stimulation of cord blood samples were more enriched regarding immune-related pathways. CpG dinucleotides at IL-13 promoter regions were hypomethylated after l-arginine stimulation. Hypomethylated CpG dinucleotides corresponded to higher IL-13 gene expression and cytokine production. Thus, DNA methylation partially accounts for the mechanism underlying differential immune function in neonates. Modulatory effects of l-arginine on DNA methylation are gene-specific. Nutritional intervention is a potential strategy to modulate immune function of neonates.

Immunopathogenesis of Different Emerging Viral Infections: Evasion, Fatal Mechanism, and Prevention.

Different emerging viral infections may emerge in different regions of the world and pose a global pandemic threat with high fatality. Clarification of the immunopathogenesis of different emerging viral infections can provide a plan for the crisis management and prevention of emerging infections. This perspective article describes how an emerging viral infection evolves from microbial mutation, zoonotic and/or vector-borne transmission that progresses to a fatal infection due to overt viremia, tissue-specific cytotropic damage or/and immunopathology. We classified immunopathogenesis of common emerging viral infections into 4 categories: 1) deficient immunity with disseminated viremia (e.g., Ebola); 2) pneumocytotropism with/without later hyperinflammation (e.g., COVID-19); 3) augmented immunopathology (e.g., Hanta); and 4) antibody-dependent enhancement of infection with altered immunity (e.g., Dengue). A practical guide to early blocking of viral evasion, limiting viral load and identifying the fatal mechanism of an emerging viral infection is provided to prevent and reduce the transmission, and to do rapid diagnoses followed by the early treatment of virus neutralization for reduction of morbidity and mortality of an emerging viral infection such as COVID-19.

Higher senescence associated secretory phenotype and lower defense mediator in urinary extracellular vesicles of elders with and without Parkinson disease.

Youth fountain and aging culprits are usually sought and identified in blood but not urine. Extracellular vesicles (EVs) possess parental cell properties, circulate in blood, CSF and urine, and provide paracrine and remote cell-cell communication messengers. This study investigated whether senescence-associated secretory phenotype (SASP) and immune defense factors in EVs of urine could serve as biomarkers in elderly individuals with and without a comorbidity. Urine samples from young adults and elderly individuals with and without Parkinson disease (PD) were collected and stored at - 80 °C until studies. Urine EVs were separated from a drop-through solution and confirmed by verifying CD9, CD63, CD81 and syntenin expression. The EVs and drop-through solution were subjected to measurement of SASP cytokines and defense factors by Milliplex array assays. Many SASP cytokines and defense factors could be detected in urinary EVs but not urinary solutions. Elderly individuals (age > 60) had significantly higher levels of the SASP-associated factors IL-8, IP-10, GRO, and MCP-1 in EVs (p < 0.05). In contrast, some defense factors, IL-4, MDC and IFNα2 in EVs had significantly lower levels in elderly adults than in young adults (age < 30). Patients with and without PD exhibited a similar SASP profile in EVs but significantly lower levels of IL-10 in the EVs from patients with PD. This study used a simple device to separate urinary EVs from solution for comparisons of SASP and defense mediators between young adults and elders with and without PD. Results from this study indicate that aging signature is present in EVs circulating to urine and the signatures include higher inflammatory mediators and lower defense factors in urinary EVs but not solutions, suggesting a simple method to separate urinary EVs from solutions for searching aging mechanistic biomarkers may make prediction of aging and monitoring of anti-senolytic interventions possible.

Perspective of Immunopathogenesis and Immunotherapies for Kawasaki Disease.

Kawasaki Disease (KD) is an acute inflammatory illness that mostly occurs in children below 5 years of age, with intractable fever, mucocutaneous lesions, lymphadenopathy, and lesions of the coronary artery (CAL). KD is sharing clinical symptoms with systemic inflammatory syndrome in children (MIS-C) which is related to COVID-19. Certain genes are identified to be associated with KD, but the findings usually differ between countries and races. Human Leukocyte Antigen (HLA) allele types and toll-like receptor (TLR) expression are also correlated to KD. The acute hyperinflammation in KD is mediated by an imbalance between augmented T helper 17 (Th17)/Th1 responses with high levels of interleukin (IL)-6, IL-10, IL-17A, IFN-γ, and IP-10, in contrast to reduced Th2/Treg responses with lower IL-4, IL-5, FoxP3, and TGF-ß expression. KD has varying phenotypic variations regarding age, gender, intravenous immunoglobulin (IVIG) resistance, macrophage activation and shock syndrome. The signs of macrophage activation syndrome (MAS) can be interpreted as hyperferritinemia and thrombocytopenia contradictory to thrombocytosis in typical KD; the signs of KD with shock syndrome (KDSS) can be interpreted as overproduction of nitric oxide (NO) and coagulopathy. For over five decades, IVIG and aspirin are the standard treatment for KD. However, some KD patients are refractory to IVIG required additional medications against inflammation. Further studies are proposed to delineate the immunopathogenesis of IVIG-resistance and KDSS, to identify high risk patients with genetic susceptibility, and to develop an ideal treatment regimen, such as by providing idiotypic immunoglobulins to curb cytokine storms, NO overproduction, and the epigenetic induction of Treg function.

Corrigendum: Phenotype, Susceptibility, Autoimmunity, and Immunotherapy Between Kawasaki Disease and Coronavirus Disease-19 Associated Multisystem Inflammatory Syndrome in Children.

[This corrects the article DOI: 10.3389/fimmu.2021.632890.].